Vol 19.1 - Sleep Disorders.2013

Continuum: Lifelong Learning in NeurologySleep Disorders, Volume 19, Issue 1,
February 2013
Issue Overview
Sleep Disorders, February 2013;19(1)
Continuum: Lifelong Learning in Neurology is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of the Continuum: Lifelong Learning in Neurology Sleep Disorders issue,
participants will be able to:
Discuss the core science concepts of sleep-wake regulation and the underlying
neurochemistry and pathophysiology of major sleep disorders such as sleep apnea, narcolepsy,
circadian rhythm abnormalities, restless legs syndrome, and parasomnias
Apply strategies for diagnosis and assessment of patients with common sleep disturbances
likely to be encountered by neurologists
Evaluate, assess, and list the differential diagnosis for children, adults, and older adult patients
who present with hypersomnia, insomnia, and abnormal nighttime behaviors
Recognize the importance of polysomnography and other common laboratory testing in sleep
medicine
Summarize the new treatment options and tools used in the assessment for common sleep
disorders
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Discuss the impact and etiology of sleepiness in physicians and learn to apply potential
countermeasures to help alleviate fatigue
Apply ethical principles to the care of patients who present with the diagnosis of REM sleep
behavior disorder
Core Competencies
The Continuum Sleep Disorders issue covers the following core competencies:
Patient Care
Medical Knowledge
Practice-Based Learning and Improvement
Interpersonal and Communication Skills
Professionalism
Systems-Based Practice
Disclosures
CONTRIBUTORS
Alon Y. Avidan, MD, MPH, FAASM, Guest Editor

Professor of Neurology, Director, UCLA Sleep Disorders Center, Department of Neurology,
David Geffen School of Medicine at UCLA, Los Angeles, California
*Dr Avidan is a member of the speakers bureaus of GlaxoSmithKline, Purdue Pharma, Teva Pharmaceuticals, and
UCB, and serves as a consultant for Merck & Co, Inc.
Dr Avidan reports no disclosure.
Zahreddin Alsheikhtaha, MBBS, RPSGT

Polysomnography Technician Reader, Cleveland Clinic Sleep Disorders Center, Cleveland, Ohio
* Dr Alsheikhtaha reports no disclosure.
Hyrar Attarian, MD, FAASM, FCCP

Associate Professor of Neurology, Sleep Medicine Fellowship Program Director, Feinberg
School of Medicine, Northwestern University, Chicago, Illinois
*Dr Attarian receives personal compensation for activities with American Physicians Institute.
Dr Attarian discusses the unlabeled use of melatonin and light boxes to advance or delay circadian rhythms.

Ronald D. Chervin, MD, MS, FAASM, FAAN
Professor of Neurology, Michael S. Aldrich Collegiate Professor of Sleep Medicine; Director,
University of Michigan Sleep Disorders Center, University of Michigan Health System, Ann
Arbor, Michigan
*Dr Chervin has consulted for Proctor & Gamble and Zansors, LLC; receives compensation for serving on boards
from the American Academy of Sleep Medicine, International Pediatric Sleep Association, and the NIH; serves as
section editor for and receives royalty payments from UpToDate; receives licensing fees through the University of
Michigan from Zansors, LLC; and receives grants from Fisher & Paykel, the NIH, and Philips Respironics.
Dr Chervin reports no disclosure.
Joseph Daley, MD, PhD

Assistant Professor of Neurology, University of Alabama at Birmingham and Birmingham
Veterans Affairs Medical Center, Birmingham, Alabama
* Dr Daley reports no disclosure.
Nancy Foldvary-Schaefer, DO, MS, FAASM

Professor, Cleveland Clinic Lerner College of Medicine; Director, Cleveland Clinic Sleep
Disorders Center; Staff, Epilepsy Center, Cleveland Clinic, Cleveland, Ohio
*Dr Foldvary-Schaefer has served on the speakers bureaus of Jazz Pharmaceuticals and UCB; has received an
honorarium for co-editing an issue of Sleep Clinics; and has received royalty payments for authorship of a textbook
on sleep medicine from Oxford University Press. Dr Foldvary-Schaefer also receives research support from
Cleveland Medical Devices, Inc, and ResMed.
Dr Foldvary-Schaefer reports no disclosure.
Glen P. Greenough, MD, FAASM

Assistant Professor of Neurology and Psychiatry, Geisel School of Medicine at Dartmouth,
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
*Dr Greenough has received a grant from Dartmouth Center for Clinical and Translational Science Pilot and
Collaborative Studies Program.
Dr Greenough reports no disclosure.
Timothy F. Hoban, MD
Professor of Pediatrics and Neurology, University of Michigan, Ann Arbor, Michigan
*Dr Hoban has performed medicolegal review of pediatric neurology-related cases.
Dr Hoban discusses the use of treatments for sleep apnea in children, including nasal steroids and maxillary
expansion devices, which are unlabeled.
Douglas Kirsch, MD, FAASM

Clinical Instructor, Harvard Medical School, Brookline, Massachusetts; Regional Medical
Director, Sleep HealthCenters, Brighton, Massachusetts
*Dr Kirsch reports no disclosure.
Clete A. Kushida, MD, PhD

Professor, Medical Director, Stanford Sleep Medicine Center, Stanford University, Redwood
City, California
*Dr Kushida has consulted for Apnex Medical, Inc and Seven Dreamers Laboratories and has received royalties
from Philips Respironics. Dr Kushida has received research support from Apnex Medical, Inc; GlaxoSmithKline;
Impax Laboratories, Inc; Merck & Co, Inc; Pacific Medico Co, Ltd; ResMed; and XenoPort, Inc.
Dr Kushida discusses the unlabeled use of selective serotonin reuptake inhibitors, serotonin-norepinephrine
reuptake inhibitors, and tricyclic antidepressants for the treatment of narcolepsy with cataplexy; melatonin for the

treatment of idiopathic hypersomnia; and amantadine, lithium, lamotrigine, valproic acid, and modafinil for the
treatment of Kleine-Levin syndrome.
Samit Malhotra, MD
Fellow, Stanford Sleep Medicine Center, Stanford University, Redwood City, California
*Dr Malhotra reports no disclosure.
Jennifer Rose V. Molano, MD

Assistant Professor, University of Cincinnati College of Medicine, Cincinnati, Ohio
*Dr Molano reports no disclosure.
David N. Neubauer, MD
Associate Professor, Department of Psychiatry, Johns Hopkins University School of Medicine,
Baltimore, Maryland
*Dr Neubauer serves on the advisory board of Purdue Pharma.
Dr Neubauer reports no disclosure.
Lori Panossian, MD, MS

Clinical Associate, Center for Sleep and Circadian Neurobiology, University of Pennsylvania,
Philadelphia, Pennsylvania
*Dr Panossian reports no disclosure.
Clifford B. Saper, MD, PhD, FAAN, FRCP

James Jackson Putnam Professor of Neurology, Chairman, Department of Neurology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
*Dr Saper serves as Editor Emeritus for The Journal of Comparative Neurology.
Dr Saper reports no disclosure.
Anita Valanju Shelgikar, MD

Assistant Professor of Neurology, Sleep Medicine Fellowship Program Director, University of
Michigan, Ann Arbor, Michigan
*Dr Shelgikar has received an honorarium from Elsevier for her authorship of a book chapter.
Dr Shelgikar reports no disclosure.
Michael H. Silber, MBChB, FAAN

Professor of Clinical Neurology, Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota
*Dr Silber reports no disclosure.
Dr Silber discusses the unlabeled use of gabapentin, pregabalin, opioids, and benzodiazepines for the treatment of
restless legs syndrome.
Michael Thorpy, MD
Professor of Clinical Neurology, Albert Einstein College of Medicine, New York, New York
*Dr Thorpy serves on the speakers bureaus and consults for Jazz Pharmaceuticals and Teva Pharmaceuticals and
has provided expert witness testimony for a legal case on a sleepiness motor vehicle accident.
Dr Thorpy reports no disclosure.
Stephanie Vertrees, MD
Fellow, Medical Ethics, Weill Cornell Medical College, New York Presbyterian Hospital;
Fellow, Neuromuscular Medicine, Hospital for Special Surgery, New York, New York
*Dr Vertrees reports no disclosure.

Aleksandar Videnovic, MD, MSc
Assistant Professor of Neurology, Northwestern University, Chicago, Illinois
*Dr Videnovic reports no disclosure.
Dr Videnovic discusses the unlabeled use of melatonin, ramelteon and supplemental light exposure to advance
circadian rhythms and treat jet-lag disorder.
Mari Viola-Saltzman, DO
Clinical Educator, Pritzker School of Medicine, NorthShore University HealthSystem, Evanston,
Illinois
*Dr Viola-Saltzman reports no disclosure.
Nathaniel F. Watson, MD, MSc

Associate Professor, Department of Neurology, University of Washington (UW) School of
Medicine; Codirector, UW Medicine Sleep Center, University of Washington, Seattle,
Washington
*Dr Watson serves on the Board of Directors for the American Academy of Sleep Medicine and the American Sleep
Medicine Foundation.
Dr Watson reports no disclosure.
Phyllis C. Zee, MD, PhD

Benjamin and Virginia T. Boshes Professor in Neurology, and Director, Sleep Disorders Center,
Feinberg School of Medicine, Northwestern University, Chicago, Illinois
*Dr Zee has received personal compensation for activities with Jazz Pharmaceuticals; Merck & Co, Inc; Perdue
Pharma; Philips Respironics; Sanofi-Aventis; Takeda Pharmaceutical Company Limited; UCB; and Zeo, Inc. Dr
Zee receives research support from Philips Respironics.
Dr Zee discusses the unlabeled use of melatonin for the treatment of circadian disorders.
VIDEO EDITOR
Marcel Hungs, MD, PhD

Director, Sleep Disorders Clinic, Neurologic Associates of St Paul, Maplewood, Minnesota
*Dr Hungs serves as a speaker for GlaxoSmithKline and Pfizer Inc.
Dr Hungs reports no disclosure.
MULTIPLE-CHOICE QUESTION WRITERS
Douglas J. Gelb, MD, PhD, FAAN

Professor of Neurology, University of Michigan, Ann Arbor, Michigan
*Dr Gelb reports no disclosure.
Adam Kelly, MD
Assistant Professor of Neurology, University of Rochester Medical Center; Chief of Neurology,
Highland Hospital, Rochester, New York
*Dr Kelly reports no disclosure.
*Relationship Disclosure
Unlabeled Use of Products/Investigational Use Disclosure
Methods of Participation and Instructions for Use

Continuum: Lifelong Learning in Neurology is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished faculty who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, , and comprehensive CME and self-assessment offerings, including a self-
assessment pretest, multiple-choice questions with preferred responses, and a patient
management problem. For detailed instructions regarding Continuum CME and self-assessment
activities, visit aan.com/continuum/cme.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuums goal of establishing lifelong learning patterns
can be met.

LIFELONG LEARNING IN NEUROLOGY
Sleep Disorders
Volume 19 Number 1 February 2013
CONTRIBUTORS
Alon Y. Avidan, MD, MPH, FAASM, Guest Editor
Professor of Neurology, Director, UCLA Sleep Disorders Center, Department of
Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California
*Dr Avidan is a member of the speakers bureaus of GlaxoSmithKline, Purdue Pharma,
Teva Pharmaceuticals, and UCB, and serves as a consultant for Merck & Co, Inc.
Dr Avidan reports no disclosure.
Zahreddin Alsheikhtaha, MBBS, RPSGT

Polysomnography Technician Reader, Cleveland Clinic Sleep Disorders Center,
Cleveland, Ohio
* Dr Alsheikhtaha reports no disclosure.
Hyrar Attarian, MD, FAASM, FCCP

Associate Professor of Neurology, Sleep Medicine Fellowship Program Director,
Feinberg School of Medicine, Northwestern University, Chicago, Illinois
*Dr Attarian receives personal compensation for activities with American Physicians Institute.
Dr Attarian discusses the unlabeled use of melatonin and light boxes to advance or delay
circadian rhythms.
Ronald D. Chervin, MD, MS, FAASM, FAAN

Professor of Neurology, Michael S. Aldrich Collegiate Professor of Sleep
Medicine; Director, University of Michigan Sleep Disorders Center, University of
Michigan Health System, Ann Arbor, Michigan
*Dr Chervin has consulted for Proctor & Gamble and Zansors, LLC; receives compensation for
serving on boards from the American Academy of Sleep Medicine, International Pediatric
Sleep Association, and the NIH; serves as section editor for and receives royalty payments
from UpToDate; receives licensing fees through the University of Michigan from Zansors, LLC;
and receives grants from Fisher & Paykel, the NIH, and Philips Respironics.
Dr Chervin reports no disclosure.
Joseph Daley, MD, PhD

Assistant Professor of Neurology, University of Alabama at Birmingham and
Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
* Dr Daley reports no disclosure.
Continuum (Minneap Minn) 2013;19(1) www.aan.com/continuum

CONTRIBUTORS continued
Nancy Foldvary-Schaefer, DO, MS, FAASM
Professor, Cleveland Clinic Lerner College of Medicine; Director, Cleveland Clinic
Sleep Disorders Center; Staff, Epilepsy Center, Cleveland Clinic, Cleveland, Ohio
*Dr Foldvary-Schaefer has served on the speakers bureaus of Jazz Pharmaceuticals and UCB;
has received an honorarium for co-editing an issue of Sleep Clinics; and has received royalty
payments for authorship of a textbook on sleep medicine from Oxford University Press.
Dr Foldvary-Schaefer also receives research support from Cleveland Medical Devices, Inc,
and ResMed.
Dr Foldvary-Schaefer reports no disclosure.
Glen P. Greenough, MD, FAASM

Assistant Professor of Neurology and Psychiatry, Geisel School of Medicine at
Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
*Dr Greenough has received a grant from Dartmouth Center for Clinical and Translational
Science Pilot and Collaborative Studies Program.
Dr Greenough reports no disclosure.
Professor of Pediatrics and Neurology, University of Michigan, Ann Arbor, Michigan
*Dr Hoban has performed medicolegal review of pediatric neurology-related cases.
Dr Hoban discusses the use of treatments for sleep apnea in children, including nasal steroids
and maxillary expansion devices, which are unlabeled.

Clinical Instructor, Harvard Medical School, Brookline, Massachusetts; Regional
Medical Director, Sleep HealthCenters, Brighton, Massachusetts
*Dr Kirsch reports no disclosure.
Clete A. Kushida, MD, PhD

Professor, Medical Director, Stanford Sleep Medicine Center, Stanford
University, Redwood City, California
*Dr Kushida has consulted for Apnex Medical, Inc and Seven Dreamers Laboratories and has
received royalties from Philips Respironics. Dr Kushida has received research support from Apnex
Medical, Inc; GlaxoSmithKline; Impax Laboratories, Inc; Merck & Co, Inc; Pacific Medico Co, Ltd;
ResMed; and XenoPort, Inc.
Dr Kushida discusses the unlabeled use of selective serotonin reuptake inhibitors,
serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants for the treatment
of narcolepsy with cataplexy; melatonin for the treatment of idiopathic hypersomnia; and
amantadine, lithium, lamotrigine, valproic acid, and modafinil for the treatment of
Kleine-Levin syndrome.
www.aan.com/continuum February 2013

Samit Malhotra, MD
Fellow, Stanford Sleep Medicine Center, Stanford University, Redwood City,
California
*Dr Malhotra reports no disclosure.

Assistant Professor, University of Cincinnati College of Medicine, Cincinnati, Ohio
*Dr Molano reports no disclosure.
Associate Professor, Department of Psychiatry, Johns Hopkins University School
of Medicine, Baltimore, Maryland
*Dr Neubauer serves on the advisory board of Purdue Pharma.
Dr Neubauer reports no disclosure.
Lori Panossian, MD, MS

Clinical Associate, Center for Sleep and Circadian Neurobiology, University of
Pennsylvania, Philadelphia, Pennsylvania
*Dr Panossian reports no disclosure.

James Jackson Putnam Professor of Neurology, Chairman, Department
of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, Massachusetts
*Dr Saper serves as Editor Emeritus for The Journal of Comparative Neurology.
Dr Saper reports no disclosure.
Anita Valanju Shelgikar, MD

Assistant Professor of Neurology, Sleep Medicine Fellowship Program Director,
University of Michigan, Ann Arbor, Michigan
*Dr Shelgikar has received an honorarium from Elsevier for her authorship of a book chapter.
Dr Shelgikar reports no disclosure.

Professor of Clinical Neurology, Center for Sleep Medicine, Mayo Clinic,
Rochester, Minnesota
*Dr Silber reports no disclosure.
Dr Silber discusses the unlabeled use of gabapentin, pregabalin, opioids, and benzodiazepines
for the treatment of restless legs syndrome.
Michael Thorpy, MD
Professor of Clinical Neurology, Albert Einstein College of Medicine, New York,
New York
*Dr Thorpy serves on the speakers bureaus and consults for Jazz Pharmaceuticals and Teva
Pharmaceuticals and has provided expert witness testimony for a legal case on a sleepiness
motor vehicle accident.
Dr Thorpy reports no disclosure.
Stephanie Vertrees, MD
Fellow, Medical Ethics, Weill Cornell Medical College, New York Presbyterian
Hospital; Fellow, Neuromuscular Medicine, Hospital for Special Surgery, New
York, New York
*Dr Vertrees reports no disclosure.
Aleksandar Videnovic, MD, MSc

Assistant Professor of Neurology, Northwestern University, Chicago, Illinois
*Dr Videnovic reports no disclosure.
Dr Videnovic discusses the unlabeled use of melatonin, ramelteon and supplemental light
exposure to advance circadian rhythms and treat jet-lag disorder.
Mari Viola-Saltzman, DO
Clinical Educator, Pritzker School of Medicine, NorthShore University
HealthSystem, Evanston, Illinois
*Dr Viola-Saltzman reports no disclosure.
www.aan.com/continuum February 2013

Nathaniel F. Watson, MD, MSc
Associate Professor, Department of Neurology, University of Washington (UW)
School of Medicine; Codirector, UW Medicine Sleep Center, University of
Washington, Seattle, Washington
*Dr Watson serves on the Board of Directors for the American Academy of Sleep Medicine
and the American Sleep Medicine Foundation.
Dr Watson reports no disclosure.
Phyllis C. Zee, MD, PhD

Benjamin and Virginia T. Boshes Professor in Neurology, and Director, Sleep
Disorders Center, Feinberg School of Medicine, Northwestern University,
Chicago, Illinois
*Dr Zee has received personal compensation for activities with Jazz Pharmaceuticals; Merck
& Co, Inc; Perdue Pharma; Philips Respironics; Sanofi-Aventis; Takeda Pharmaceutical
Company Limited; UCB; and Zeo, Inc. Dr Zee receives research support from Philips
Respironics.
Dr Zee discusses the unlabeled use of melatonin for the treatment of circadian disorders.
VIDEO EDITOR
Marcel Hungs, MD, PhD
Director, Sleep Disorders Clinic, Neurologic Associates of St Paul,
Maplewood, Minnesota
* Dr Hungs serves as a speaker for GlaxoSmithKline and Pfizer Inc.
Dr Hungs reports no disclosure.
MULTIPLE-CHOICE QUESTION WRITERS

Douglas J. Gelb, MD, PhD, FAAN
Professor of Neurology, University of Michigan, Ann Arbor, Michigan
* Dr Gelb reports no disclosure.
Adam Kelly, MD
Assistant Professor of Neurology, University of Rochester Medical Center; Chief
of Neurology, Highland Hospital, Rochester, New York
* Dr Kelly reports no disclosure.

Volume 19 Number 1 february 2013

www.aan.com/continuum
Sleep Disorders Denotes Video Content
Guest Editor: Alon Y. Avidan, MD, MPH, FAASM
Editors Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
REVIEW ARTICLES
The Neurobiology of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19
Approach to and Evaluation of Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32

Anita Valanju Shelgikar, MD; Ronald D. Chervin, MD, MS, FAASM, FAAN
Chronic Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50

Primary Hypersomnias of Central Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67

Samit Malhotra, MD; Clete A. Kushida, MD, PhD, RPSGT
Sleep-Disordered Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86

Lori Panossian, MD, MS; Joseph Daley, MD, PhD
Complex Nocturnal Behaviors: Nocturnal Seizures

and Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .104
Nancy Foldvary-Schaefer, DO, MS, FAASM; Zahreddin Alsheikhtaha, MBBS, RPSGT
Circadian Rhythm Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .132

Phyllis C. Zee, MD, PhD; Hrayr Attarian, MD, FAASM, FCCP; Aleksandar Videnovic, MD, MSc
Sleep and Comorbid Neurologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148

Nathaniel F. Watson, MD, MSc; Mari Viola-Saltzman, DO
Sleep-Related Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .170

Sleep Disorders in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .185

Volume 19 Number 1 www.aan.com/continuum 0000

7
ETHICAL PERSPECTIVES
Ethical Considerations in REM Sleep Behavior Disorder . . . . . . . . . . . . . . . . .199
Stephanie Vertrees, MD; Glen P. Greenough, MD, FAASM
PRACTICE ISSUES
Sleep and Fatigue Countermeasures for the Neurology
Resident and Physician . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .204
Alon Y. Avidan, MD, MPH, FAASM
In-Home Testing for Obstructive Sleep Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . .223

Coding for Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .229

APPENDIXES
Appendix A: Epworth Sleepiness Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .236
Appendix B: An Algorithm for In-Home Testing for Obstructive
Sleep Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237
SELF-ASSESSMENT AND CME

Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
Instructions for Completing the Self-Assessment Pretest and Tally Sheet . . . . . . .11
Self-Assessment Pretest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Instructions for Completing CME and Tally Sheet . . . . . . . . . . . . . . . . . . . . . . . .241
Multiple-Choice Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .243
Multiple-Choice QuestionsPreferred Responses . . . . . . . . . . . . . . . . . . . . . . .252
Patient Management Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .269
Patient Management ProblemPreferred Responses . . . . . . . . . . . . . . . . . . . .274
Michael Thorpy, MD
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .284
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Back Cover
8 www.aan.com/continuum February 2013

Learning Objectives
Upon completion of the Continuum: Lifelong Learning in Neurology
Sleep Disorders issue, participants will be able to:
Discuss the core science concepts of sleep-wake regulation and the underlying

neurochemistry and pathophysiology of major sleep disorders such as sleep

apnea, narcolepsy, circadian rhythm abnormalities, restless legs syndrome,
and parasomnias
Apply strategies for diagnosis and assessment of patients with common sleep

disturbances likely to be encountered by neurologists

Evaluate, assess, and list the differential diagnosis for children, adults, and older

adult patients who present with hypersomnia, insomnia, and abnormal nighttime
behaviors
Recognize the importance of polysomnography and other common laboratory

testing in sleep medicine

Summarize the new treatment options and tools used in the assessment for

common sleep disorders

Discuss the impact and etiology of sleepiness in physicians and learn to apply

potential countermeasures to help alleviate fatigue

Apply ethical principles to the care of patients who present with the diagnosis of

REM sleep behavior disorder
Core Competencies
The Sleep Disorders issue covers the following core competencies:
Patient Care

Medical Knowledge

Practice-Based Learning and Improvement

Interpersonal and Communication Skills

Professionalism

Systems-Based Practice

1
SELF-ASSESSMENT

INSTRUCTIONS FOR THE CONTINUUM Sleep Disorders
SELF-ASSESSMENT PRETEST
To earn American Board of Psychiatry and Volume 19 Number 1 FEBRUARY 2013
Neurology (ABPN) Maintenance of Certification
(MOC) self-assessment participation credit for this Tally Sheet
issue of , complete the Self-Assessment
Pretest in one of three ways: SELF-ASSESSMENT PRETEST RESPONSES
1. Go to www.aan.com/continuum/cme and complete After completing this tally sheet, please enter your
the test online (available to subscribers only), or
answers online at
2. Read through the questions in the issue and www.aan.com/continuum/cme.
mark your answers on the adjacent tally sheet
before entering them online at 1. a b c d e 14. a b c d e
www.aan.com/continuum/cme, or
3. Request a faxable paper scorecard if you do not
2. a b c d e 15. a b c d e
have computer access or you are a nonsubscriber
who has purchased a single issue (send an email to
ContinuumCME@aan.com); however, we encourage 3. a b c d e 16. a b c d e
all subscribers to use the online system.
Once you have completed the Self-Assessment 4. a b c d e 17. a b c d e
Pretest, use your results as a guide as you read the
issue. To obtain self-assessment CME credits, you
must complete the post-reading Multiple-Choice 5. a b c d e 18. a b c d e
Questions at the end of the issue, along with an
issue evaluation. No self-assessment credit will 6. a b c d e 19. a b c d e
be awarded for completing the Self-Assessment
Pretest alone.
7. a b c d e 20. a b c d e
Upon completion of the Self-Assessment Pretest and
post-reading Multiple-Choice Questions, participants
may earn up to 12 AMA PRA Category 1 CreditsTM toward 8. a b c d e 21. a b c d e
ABPN MOC self-assessment (part 2). Self-assessment
credits earned will appear on AAN member CME
transcripts within 2 business days and may be 9. a b c d e 22. a b c d e
viewed at www.aan.com/education/certificate. AAN
nonmember subscribers may request a transcript of 10. a b c d e 23. a b c d e
credits earned by contacting AAN Member Services
at memberservices@aan.com or (800) 879-1960.
11. a b c d e 24. a b c d e
AMA PRA Category 1 Credits not designated for
self-assessment may be obtained by completing
only the 40 post-reading Multiple-Choice Questions 12. a b c d e 25. a b c d e
(up to 10) and/or the Patient Management Problem
(up to 2) found at the end of the issue. 13. a b c d e
Participants have up to 3 years from the date of
publication to earn CME credits. No CME will be
awarded for the Sleep Disorders issue after
February 29, 2016.
The ABPN has reviewed Continuum: Lifelong

Learning in Neurology and has approved this
product as part of a comprehensive lifelong
learning and self-assessment program, which is
mandated by the American Board of Medical
Specialties as a necessary component of
maintenance of certification.

Continuum (Minneap Minn) 2013;19(1) www.aan.com/continuum 11

Self-Assessment
Self-Assessment Pretest 4. Which of the following results is most likely to be abnormal in

patients with idiopathic hypersomnia?
A. apnea-hypopnea index on overnight polysomnogram
B. mean sleep latency on multiple sleep latency test
The Self-Assessment Pretest is designed C. sleep architecture on overnight polysomnogram
to help neurologists meet the American Board of Psychiatry D. spinal fluid hypocretin
and Neurology (ABPN) self-assessment and lifelong learning E. total sleep time on overnight polysomnogram
component (part 2) for Maintenance of Certification (MOC).
To obtain self-assessment CME credits, complete the Self- 5. Which of the following brain structures is most involved in
normal circadian rhythm function?
Assessment Pretest (25 questions) before reading this issue.
Pretest results are intended to help you focus your learning by A. centromedian nucleus of thalamus
identifying your current knowledge gaps with regard to B. nucleus basalis of Meynert
the topic. After submitting your pretest responses, study the C. red nucleus
entire issue using your pretest results as a guide to direct D. superior colliculus
your learning. Then complete the 40 Multiple-Choice Ques- E. suprachiasmatic nucleus of hypothalamus
tions at the end of the issue. Upon completion of both
6. A 64-year-old man has a 15-year history of episodes in which he
the Self-Assessment Pretest and the dives out of bed in the early morning hours, sometimes bruising
Multiple-Choice Questions, you may earn up to 12 AMA PRA himself. He is alert immediately after the episodes and often
Category 1 CreditsTM toward self-assessment. remembers that he had been dreaming about being chased and
AMA PRA Category 1 Credits for may diving to escape. The episodes usually occur 1 or 2 hours before
be obtained by completing only the 40 Multiple-Choice he planned to get up for the day. Which of the following physical
Questions, but these credits will not qualify for self- examination findings is most likely?
assessment without completion of the Self-Assessment A. bilateral cataracts
Pretest. B. bradykinesia
C. percussion myotonia
D. prominent temporal arteries
E. tongue fasciculations
7. Bilevel positive airway pressure may be most effective in treating

sleep apnea in which of the following settings?
1. Which of the following medications has no known abuse potential A. claustrophobia
and is therefore not listed on the Drug Enforcement Adminis- B. coexistent oxygen requirement
tration class schedule? C. high pressure requirement
A. eszopiclone D. neck circumference greater than 45.72 cm (18 in)
B. ramelteon E. symptoms present in supine and lateral decubitus positions
C. temazepam
D. zaleplon 8. Which of the following categories of medications is considered to
E. zolpidem be a possible cause of secondary restless legs syndrome?
A. antidepressants
2. For patients with which of the following is it appropriate to B. beta-adrenergic antagonists
use portable sleep monitoring instead of standard, attended, C. estrogen-containing oral contraceptives
in-laboratory polysomnography? D. nonsteroidal anti-inflammatory drugs
A. congestive heart failure E. opioids
B. Duchenne muscular dystrophy
C. high pretest probability of severe obstructive sleep apnea 9. In patients with sleep-disordered breathing, continuous positive
D. insomnia airway pressure has most convincingly been shown to reduce
E. severe asthma which of the following?
A. blood glucose
3. The ascending arousal system is thought to begin in which of the B. blood pressure
following anatomic areas? C. body mass index
A. basal forebrain D. risk of heart attack
B. hypothalamus E. risk of stroke
C. rostral pons
D. superior colliculi
E. thalamic relay nuclei
Continuum (Minneap Minn) 2013;19(1):1315 www.aan.com/continuum 13

Self-Assessment
10. A 63-year-old man is seen for a possible sleep disorder. Over the 16. Which of the following best characterizes the results for most children
past several years, he has injured himself on multiple occasions who undergo adenotonsillectomy for obstructive sleep apnea?
while climbing out of bed during the night. During an overnight A. improved academic performance, improved sleep quality,
polysomnogram, he shouts and occasionally flails his arms as if he is normalized sleep respiratory parameters
in an altercation. This patient is at increased risk of developing B. improved academic performance, improved sleep quality,
which of the following neurologic conditions? residual sleep respiratory parameter abnormalities
A. ALS C. improved academic performance, unchanged sleep quality,
B. Alzheimer disease residual sleep respiratory parameter abnormalities
C. cerebral amyloid angiopathy D. unchanged academic performance, improved sleep quality,
D. dementia with Lewy bodies normalized sleep respiratory parameters
E. subacute combined degeneration E. unchanged academic performance, unchanged sleep quality,
residual sleep respiratory parameters
11. The Epworth Sleepiness Scale is most reliable when used to do
which of the following? 17. A 34-year-old executive is taking a transatlantic flight in several
weeks. He is concerned about symptoms of jet lag upon arrival
A. establish the diagnosis of obstructive sleep apnea and asks about strategies to minimize these effects. Which of the
B. follow a patients self-assessment of sleepiness over time following regimens of melatonin has been shown to minimize
C. identify the presence of major depression the effects of jet lag due to eastbound travel?
D. measure the severity of narcolepsy
E. rule out the diagnosis of obstructive sleep apnea A. 0.5 mg nightly for several weeks before flying
B. 1.0 mg upon awakening for several weeks before flying
12. Which of the following would be considered a maladaptive C. 2.0 mg in the early evening for several days before flying
behavior in patients with chronic insomnia? D. 5.0 mg nightly starting on day of flight
E. use as needed once arriving at destination
A. consuming one alcoholic beverage before sleep each night
B. eliminating caffeine intake after noon 18. Which of the following conditions is most closely associated with
C. intermittently using over-the-counter sleep aids (eg, analgesics daytime sleepiness?
with PM formulation)
D. limiting time spent in bed while awake A. blepharospasm
E. turning off televisions and other screens while attempting to B. cervical dystonia
fall asleep C. essential tremor
D. oromandibular dystonia
13. Which of the following medications is most likely to be effective E. writers cramp
for both the excessive daytime somnolence and the cataplexy
experienced by patients who have narcolepsy? 19. Compared with modafinil, armodafinil has which of the following
properties?
A. armodafinil
B. methamphetamine A. greater efficacy for treatment of cataplexy
C. methylphenidate B. greater efficacy for treatment of excessive daytime sleepiness
D. modafinil C. greater efficacy for treatment of hypnagogic and hypnopompic
E. sodium oxybate hallucinations
D. longer half-life
14. A 41-year-old man is seen in clinic for the evaluation of ex- E. lower cost
cessive daytime sleepiness and morning headaches. Obstructive
sleep apnea (OSA) is suspected. Which of the following physical 20. A 41-year-old woman has had progressively worsening symptoms
examination findings is commonly seen in patients with OSA? of restless legs syndrome during the day over the past year despite
intermittent increases in her pramipexole dose. She currently
A. congenital absence of the uvula takes 0.50 mg in the early afternoon and 0.75 mg before bedtime.
B. microglossia Which of the following is the best next step in management?
C. neck circumference less than 43.2 cm (17 in)
D. prior tonsillectomy/adenoidectomy A. additional pramipexole in the morning
E. retrognathia B. carbidopa/levodopa
C. gabapentin
15. Which of the following best characterizes the effects of sleep D. iron dextran infusion
stages on the expression of interictal epileptic discharges? E. methadone
A. inhibited in both non-REM (NREM) and REM sleep 21. Which of the following conditions is associated with an
B. inhibited in NREM sleep and promoted in REM sleep increased risk of childhood obstructive sleep apnea?
C. inhibited in REM sleep and promoted in NREM sleep
D. promoted in both NREM and REM sleep A. absence epilepsy
E. unaffected by sleep stage B. cyclic vomiting
C. Down syndrome
D. postYvaricella ataxia
E. spina bifida

Self-Assessment
22. When resident physicians obtain inadequate amounts of sleep 24. The development of K complexes on an EEG is characteristic of
(eg, less than 5 hours per night), which of the following takes place? which stage of sleep?
A. decreased fragmentation of sleep A. stage REM
B. decreased urge to nap B. stage N1
C. improved efficiency of sleep C. stage N2
D. increased homeostatic drive to sleep D. stage N3
E. no change in normal circadian rhythms E. wake
23. Which of the following is true of the maintenance of wakeful- 25. Which of the following medications is most effective for REM
ness test but not of the multiple sleep latency test? sleep behavior disorder?
A. patients are instructed to try to stay awake A. clonazepam
B. standard testing protocol extends over more than 6 hours B. modafinil
C. test is conducted during the patients typical waking hours C. nortriptyline
D. test is only reliable in patients with sufficient amount of D. sodium oxybate
sleep the night before E. venlafaxine
E. test results are typically abnormal in patients with narcolepsy

Editors Preface
* 2013, American Academy

of Neurology.
Editors Preface
In the true spirit of the Drs Lori Panossian and
name , it is Joseph Daly discuss sleep-
my privilege to begin my disordered breathing, of
editorship at the start of which sleep apnea is the
the 20th anniversary year most prevalent, empha-
of this journal and with size the consequences of
the publication of this this disorder in regard to
educationally rich issue both daytime alertness
on sleep disorders, the and overall health, and up-
production of which was date us on management
well under way when the approaches.
editor-in-chief baton was In their review of noc-
passed to me by Dr Aaron turnal seizures and the
Miller. Dr Alon Avidan, parasomnias, Drs Nancy
the guest editor for this
In the true spirit Foldvary-Schaefer and
issue, has assembled an of the name Zahreddin Alsheikhtaha
expert faculty to teach us , it is draw attention to the clin-
the state of the art of my privilege to ical and pathophysiologic
sleep medicine.
begin my editorship overlap of nocturnal fron-
This issue begins with tal lobe epilepsy with
an overview by Dr at the start of the some of the other disor-
Clifford Saper on the ba- 20th anniversary ders that present as com-
sic neuroanatomy and year of this journal. plex behaviors during
neurophysiology of sleep sleep and emphasize the
and its disorders, an expert explanation importance of video polysomnography
of a topic that underlies many of the with EEG in evaluation of these pa-
subsequent clinical discussions. Next, tients. Drs Phyllis Zee, Hrayr Attarian,
Drs Anita Shelgikar and Ronald Chervin and Aleksandar Videnovic discuss the
discuss the clinical assessment of pa- human circadian rhythms and the
tients with sleep disorders, emphasizing pathophysiology, clinical manifestations,
important historical clues and examina- and management of the increasingly
tion findings, and elucidate the major recognized circadian rhythm disorders.
diagnostic tests used to evaluate sleep- Drs Nathaniel Watson and Mari Viola-
related symptoms. Saltzman review the co-occurrence of
Dr David Neubauer discusses chronic sleep dysfunction and other neurologic
insomnia, including a discussion of the disorders and remind us that sleep-
nonpharmacologic and pharmacologic related symptoms may be important
management of this most common harbingers (eg, REM behavior disorder
sleep-related disorder. Drs Samit and "-synucleinopathies), integral man-
Malhotra and Clete Kushida discuss the ifestations (eg, hypnic headache), or risk
primary hypersomnias of central origin, factors (eg, sleep-disordered breathing
of which the prototypical disorder is and cerebrovascular disease) for neuro-
narcolepsy, and provide an approach logic disease. Dr Michael Silber provides
to their evaluation and management. a review of sleep-related movement

disorders, with an emphasis on restless national sleep experts to enhance the
legs syndrome. His extensive discus- text. This video material, available to our
sion of management of this common, readers via the online, PDF, or iPad ver-
distressing, but treatable condition sions of , provides es-
will be of benefit to our patients. pecial clarity for those disorders that
Dr Timothy Hoban reviews sleep dis- involve movement or sound.
orders in children from infancy to Like all issues, ample
adolescence, a topic of particular clin- opportunities for CME abound. Drs
ical interest to readers who care for Douglas Gelb and Adam Kelly have
children; however, given the ubiqui- carefully constructed multiple-choice
tousness of sleep issues in children, questions based on the material in the
this article is a must read for those core articles. Reading the material, an-
readers with children at home. swering the questions, and reviewing
In this issues Ethical Perspectives the explanatory discussions will assess
article, Drs Stephanie Vertrees and Glen and enhance your knowledge of the ma-
Greenough present a practical analysis terial, and you will be able to earn up to
of the dilemma of whether to disclose 10 AMA PRA Category 1 CME CreditsTM.
the risk of the possible future devel- Beginning with this issue we also pro-
opment of an "-synucleinopathy to a vide the alternative opportunity to ob-
patient presenting with REM sleep be- tain up to 12 AMA PRA Category 1 CME
havior disorder. Credits specifically approved by the
This issue features two Practice arti- American Board of Psychiatry and Neu-
cles along with a discussion of relevant rology (ABPN) for self-assessment. Sim-
coding. First, Dr Avidan reviews the ply submit the Self-Assessment Pretest
history and current status of resident before reading the material and com-
work-hour regulations and the potential pleting the postreading Multiple-Choice
effects of sleep deprivation on trainee Questions. The Patient Management
alertness and patient safety, and pre- Problem, written by Dr Michael Thorpy,
sents a sleep medicine perspective on involves a young woman with exces-
recommendations for countermeasures sive daytime sleepiness. By following
for sleepiness in trainees. This discus- her case and answering multiple-choice
sion is applicable to all of our readers, questions corresponding to important
especially since the potential for sleep diagnostic and therapeutic decision
deprivation in neurologists is not re- points along her course you will have
stricted to residency. Next, Dr Douglas the opportunity to earn up to 2 AMA
Kirsch reviews the growing role of in- PRA Category 1 CME Credits.
home testing for obstructive sleep ap- Please join me in thanking Dr Avidan
nea, including descriptions of patients and his expert authors who have created
who mayVor may notVbe appropriate a issue that will be of
for in-home testing. Finally, Dr Jennifer real benefit to our clinical assessment
Molano reviews diagnostic coding for and management of our patients with
sleep symptoms and sleep disorders, as sleep-related symptoms.
well as the appropriate procedural I also want to personally thank
codes for commonly used tests for sleep Dr Miller for his mentorship and lead-
disorders. ership, and for his 10 devoted years as
This issue is rich in video material, the editor-in-chief of ,a
thanks to the tireless (no pun intended) publication that continued to grow in
dedication of Dr Avidan and Dr Marcel stature and national and international
Hungs, who gathered videos from inter- circulation under his tenure and has

Editors Preface
impacted the education of neurologists Finally, on a sad note, I would like to

and the care of patients worldwide. dedicate this issue to the fond memory
I am extremely pleased to be joining of Dr Elliott Mancall and his pioneering
the wonderful AAN editorial team of and visionary work as the founding
Andrea Weiss, executive editor, Amanda editor-in-chief of from
Tourville, program manager, and Katie 1993 to 2002, who passed away on
Izzo, production editor, who seemingly January 2, 2013. Although I never
work round the clock (thanks to the worked with Dr Mancall professionally,
absence of editorial work-hour rules) to I had the fortunate pleasure of meeting
create . I also look for- him on several occasions and will always
ward to working with our expert associ- remember a very pleasant walk I took
ate editors, the members of the editorial with him to a bookstore on an extended
board, and our publishing experts at break between examining oral board
Lippincott Williams & Wilkins. candidates for the ABPN in 1999. In
My vision for is that 1994, Dr Mancalls and Dr Theodore
it will continue to meet the clinical Munsats originally stated editorial vision
neurology educational needs of all prac- was for to provide our
ticing neurologists throughout their ca- membership with an educational op-
reers. To ensure this goal is met, portunity that will assist them in provid-
will continue to publish ing the very best of neurologic care
core clinical neurology topics within for their patients.1 We and our pa-
3-year curricular cycles, but the number tients have greatly benefited from
of topics over each cycle will increase Dr Mancalls keen vision and his legacy.
from the current 12 to 15 (one issue per
year will be noncore, for topics less VSteven L. Lewis, MD
likely to need revisiting within 3 years). I Editor-in-Chief
also envision that will
remain an indispensable print refer-
ence on each neurologists shelf, even REFERENCE
as we continue to enhance the unique 1. Munsat TL, Mancall EL, DesLauriers MP. The
AAN launches a new education program:
capabilities of the online and mobile CONTINUUM Lifelong Learning in Neurology.
versions. Neurology 1994;44(4):771Y772.

Review Article
The Neurobiology
Address correspondence to
Dr C. B. Saper, Department
of Neurology, Beth Israel
Deaconess Medical Center,
of Sleep 300 Brookline Avenue,

Boston, MA 02215,
csaper@bidmc.harvard.edu.
Clifford B. Saper, MD, PhD, FAAN, FRCP Relationship Disclosure:
Dr Saper serves as Editor
Emeritus for The Journal of
Comparative Neurology.
ABSTRACT Unlabeled Use of
Products/Investigational
Purpose of Review: The basic circuitries that regulate wake-sleep cycles are Use Disclosure:
described, along with how these are affected by different disease states and how Dr Saper reports no
those alterations lead to the clinical manifestations of those disorders. disclosure.
Recent Findings: The discovery of both sleep-promoting neurons in the ventro- * 2013, American Academy
of Neurology.
lateral preoptic nucleus and wake-promoting neurons, such as the lateral hypo-
thalamic orexin (also called hypocretin) neurons, has allowed us to recognize that
these two populations of neurons are mutually antagonistic (ie, inhibit each other)
and form a flip-flop switch, a type of circuit that results in rapid and complete
transition in behavioral state. The same principle applies to the circuitry controlling
transitions between REM sleep and non-REM (NREM) sleep.
Summary: The flip-flop switch circuitry of the wake-sleep regulatory system pro-
duces the typical sleep pattern seen in healthy adults, with consolidated waking
during the day and alternation between NREM and REM sleep at night. Breakdown
in this circuitry both results in and explains the manifestations of a variety of sleep
disorders including insomnia, narcolepsy with cataplexy, and REM sleep behavior
disorder.
Continuum (Minneap Minn) 2013;19(1):1931.
CLINICAL OBSERVATIONS FIRST stem lesions who had intact cerebral

DEFINED WAKE-SLEEP hemispheres nevertheless fell into co-
The subject of sleep has fascinated matose states. This issue was addressed
both philosophers and clinicians since by Baron Constantin von Economo, a
the earliest times. It was not until neu- neurologist practicing in Vienna who
rologists began thinking about the witnessed the onset of a new type of
brain systems that support wakefulness encephalitis in an epidemic of ence-
and how damage to them causes coma, phalitis lethargica that began around
however, that a mechanistic basis for 1915. During this epidemic, he found
sleep and wakefulness was estab- that his patients fell into two groups.
lished.1,2 The first neurologist to pro- One group became excessively
duce a cogent theory about the origins sleepy, sometimes sleeping as many as
of wakefulness was John Hughlings 20 hours a day. The patients would wake
Jackson, who argued in the late 19th up to eat and remain cognitively intact
century that consciousness was the during that time but would then fall
sum total of the activity of the cerebral back to sleep. Many of these patients
cortex and that loss of consciousness also had eye movement abnormalities.
occurred when this activity was pre- Von Economo recognized this com-
vented. By the early days of the 20th bination of signs from the work of
century, however, it became apparent Ludwig Mauthner, who had reported
that some patients with upper brain- in 1890 that patients with Wernicke

Neurobiology of Sleep
KEY POINT
h von Economo was the encephalopathy also developed sleepi- had survived the encephalitis but had
first neurologist to ness and impaired eye movements. persistent difficulty maintaining wake-
recognize that specific Mauthners patients had had lesions fulness. Many of these patients, when
brain lesions could along the caudal third ventricle and told a joke, would lose muscle tone
identify brain circuitry the cerebral aqueduct; von Economo and fall helplessly to the ground. In
controlling wake-sleep found that his patients had lesions in a the early 1920s, neurologists in Lon-
cycles. similar distribution. Based on these don and Philadelphia also reported
observations, von Economo proposed seeing more of these patients, whom
that an ascending arousal system orig- they diagnosed with narcolepsy. In the
inating in the upper brainstem kept the few cases that ended in autopsy, le-
forebrain awake in an intact brain. sions were found in the posterior part
The second group of patients who of the hypothalamus. These cases
emerged in this same epidemic had convinced S.A. Kinnier Wilson, who
the opposite syndrome. They had a examined them at Queen Square Hos-
great deal of difficulty falling asleep, pital in London, that the pathologic
slept fitfully, awoke early, and could basis of narcolepsy resided in the pos-
not fall back to sleep. These patients terior hypothalamus.
might be awake 20 or more hours per As this review will show, these neu-
day, and many of them had movement rologists were correct in their deduc-
disorders. The lesions in these tions. Case 1-1 describes a modern-day
patients were found to include the patient who presented with hypersom-
area around the rostral third ventricle nolence that resolved into narcolepsy
and extend into the basal ganglia. due to a brain lesion similar to those de-
These cases caused von Economo to scribed above.
posit that a sleep-promoting influence
existed that arose from the region of THE ASCENDING AROUSAL SYSTEM
the rostral third ventricle. Finally, as In the 1930s, Fr2d2ric Bremer showed
the epidemic of encephalitis lethargica that if he transected the brainstem of a
waned after World War I, a third group cat between the inferior and superior
of patients emerged. These patients colliculi, the animal would fall into an
Case 1-1
An 18-year-old male college freshman who had been an outstanding student suddenly began to
have trouble with his grades. On examination, he had short stature and delayed puberty. A
craniopharyngioma was found on an MRI scan of the brain and was surgically removed.
Postoperatively, he fell into a coma and was found to have bilateral infarction of most of the
hypothalamus that extended laterally into the basal forebrain and amygdala and caudally into the
midbrain (Figure 1-1). He was treated for panhypopituitarism and eventually awoke, but over the
next year he slept for more than 12 hours each day. He eventually returned to about 10 hours of
sleep per night with a 1- to 2-hour nap each afternoon, but he still experienced several episodes of
excessive sleepiness each day that resolved with a short nap. When told a joke, he had occasional
episodes of weakness that sometimes resulted in his falling to the ground without injury. He had vivid
visual hallucinations when drowsy and brief episodes of paralysis as he fell asleep or emerged from
sleep. EEG did not show evidence of a seizure disorder, but a polysomnogram showed a sleep latency
of 1.0 minute, with REM sleep latency of 1.5 minutes and 15 spontaneous awakenings during the
night without evidence of sleep apnea. A multiple sleep latency test showed that he fell asleep in less
Continued on page 21

Continued from page 20
FIGURE 1-1 A, A drawing from von Economos original article illustrating a lesion at the junction of the midbrain
and the diencephalon that he found to be the cause of excess sleepiness in patients with encephalitis
lethargica. This compares closely with the lesion found in this patient, who had an infarct involving the
mesodiencephalic junction following removal of a craniopharyngioma. In both the sagittal (B) and axial (C) MRI scans, the
lesion in this patient extends more rostrally than the lesion illustrated by von Economo, into the region occupied by the orexin
neurons in the posterior lateral hypothalamus. The patient experienced initial excess sleepiness for about 1 year, followed by
continuing narcolepsy.
Reprinted with permission from Scammell TE et al, Neurology.3 B 2001, American Academy of Neurology. www.neurology.org/content/56/12/
1751.abstract?sid=18583a9c-2ed2-4715-867f-177d4bdd29d3.
than 30 seconds on average at all times of the day, and he entered REM sleep with a latency of 3.5
minutes on all four nap attempts. He was HLA-DQB1*0602 negative, but measurement of CSF orexin
levels showed them to be about half that of normal controls.
Comment. This young man had the upper brainstem lesion that von Economo proposed as a cause
of prolonged somnolence, as well as subsequent narcolepsy from involvement of the orexin neurons
in the posterior hypothalamus.3
irreversible coma. Later studies showed vates the thalamus, particularly the
no loss of wakefulness if the transection relay nuclei (such as the ventroposte-
was placed in the midpons or lower. rior complex or mediodorsal nucleus)
This work established the origin in the and the reticular nucleus. The latter is
rostral pons and caudal midbrain of the important because the reticular nu-
ascending pathway that keeps the fore- cleus consists of gamma-aminobutyric
brain awake. Although investigators at acidYmediated (GABA-ergic) neurons
the time attributed this arousal influ- that project back into the thalamus and
ence to the reticular formation, later inhibit it. The arousal system inhibits the
studies showed that the pathway origi- reticular nucleus, thus opening the way
nates from neurons in discrete cell for thalamocortical transmission. The
groups and is associated with specific second pathway mainly contains mono-
neurotransmitters. This arousal system aminergic neurons and includes the
takes two main ascending pathways2,4 noradrenergic locus coeruleus, seroto-
(Figure 1-2). One pathway, which comes ninergic dorsal and median raphe nu-
mainly from cholinergic neurons in clei, glutamatergic parabrachial nucleus,
the pedunculopontine and laterodor- dopaminergic periaqueductal gray mat-
sal tegmental nuclei, primarily inner- ter, and histaminergic tuberomammillary

FIGURE 1-2 A series of schematic drawings of the arousal system (A), the sleep-promoting
system (B), and their mutually inhibitory interactions (C). A, The monoaminergic
arousal system (green) includes neurons in the noradrenergic locus coeruleus
(LC), glutamatergic parabrachial nucleus (PB) and precoeruleus area (PC), serotoninergic
dorsal raphe (DR), dopaminergic ventral periaqueductal gray matter (vPAG), and histaminergic
tuberomammillary nucleus (TMN). Their ascending axons run through the hypothalamus, where
they contact lateral hypothalamic orexin neurons (blue) and basal forebrain (BF) cholinergic, and
GABA-ergic neurons (light blue). All of these systems directly innervate the cerebral cortex and
contribute to its arousal. The cholinergic pedunculopontine (PPT) and laterodorsal tegmental
nuclei (LDT) (light blue) innervate the thalamus and promote the arrival of sensory information
(green) to the cerebral cortex. B, The GABA-ergic ventrolateral preoptic nuclei (VLPO) and
median preoptic nuclei (MnPO) (magenta) innervate the components of the arousal system
and actively inhibit them during sleep. C, The arousal systems also innervate the preoptic
sleep-promoting cell groups and inhibit them. This sets up the conditions for a flip-flop switch
that ensures rapid and complete transitions.
Reprinted from Saper CB et al, Neuron.4 B 2010, with permission from Elsevier. www.cell.com/neuron/retrieve/pii/
S0896627310009748.

KEY POINTS
nucleus. Neurons in each of these sites sleep.9 In addition, an ascending sleep- h The ascending arousal
send axons through the lateral hypothal- promoting influence has been traced system begins in the
amus to the basal forebrain and cerebral to the lower pons or medulla, and re- upper pons and
cortex. In addition, peptidergic (ie, cent work suggests that it may originate contains two branches,
orexin, or hypocretin) and glutamatergic in GABA-ergic neurons in the caudo- one to the thalamus and
neurons in the lateral hypothalamus and lateral pontine reticular formation.10 the other through the
cholinergic and GABA-ergic neurons in hypothalamus and basal
the basal forebrain that project to the THE FLIP-FLOP SWITCH MODEL forebrain, both of
cerebral cortex contribute to the path- OF SLEEP-WAKE REGULATION which activate the
way. All of these pathways serve to The GABA-ergic neurons in the ven- cerebral cortex.
activate the cerebral cortex so that it trolateral preoptic nucleus are also h Sleep-promoting
can efficiently process sensory input. innervated by neurons in many of the neurons in the preoptic
arousal systems, and the effects of that area, posterior lateral
THE SLEEP-INDUCING SYSTEM innervation are also inhibitory. When hypothalamus, and
possibly the lower
The neurons in the ascending arousal two pathways inhibit each other, they
brainstem inhibit the
system are inhibited during sleep by produce the conditions for what elec-
neurons in the arousal
GABA-ergic input. A major source of trical engineers call a flip-flop switch. areas during sleep.
this input is from neurons in the ventro- In this type of switching system, when
lateral preoptic nucleus (Figure 1-2). one side gains control, it turns off the h The mutual inhibition
between the
Ventrolateral preoptic neurons con- other side, thus stabilizing its own
wake-promoting
tain both GABA and galanin, an inhib- firing.2,4 Such switches are designed and sleep-promoting
itory neuropeptide, and innervate most into electronic circuitry to produce two circuits produces a
of the components of the arousal sys- stable states with rapid transitions flip-flop switch, which
tem.2,4 The ventrolateral preoptic neu- between them. Sleep is normally ensures rapid and
rons are mainly active during sleep, driven by physiologic systems that complete transitions
and damage to these neurons dramat- accumulate sleep need (a homeostatic between sleep and
ically reduces the amount of sleep that input) and vary by time of day (a wakefulness.
an animal achieves, similar to von circadian input). These inputs change
Economos patients who had lesions very slowly over a period of hours. If
in this area.5,6 Other neurons in the there were no flip-flop switch in the
median preoptic nucleus also fire dur- sleep-wake system, the person might
ing sleep and innervate many of the drift slowly between wake and sleep
same targets.7,8 The median preoptic states over the course of the day.
neurons are also GABA-ergic but do Instead, the transitions into and out
not contain galanin. During sleep dep- of sleep take place over just seconds to
rivation in animals, the median pre- minutes (Figure 1-3).4,11 Most people
optic neurons show activation, but the spend 98% or more of their day in one
ventrolateral preoptic neurons are not state or the other and less than 2% in
activated until the animal actually falls transition. This seems to occur be-
asleep.7 Thus, the median preoptic cause of the mutual antagonism
neurons are thought to respond to sig- between sleep-promoting and wake-
nals, such as buildup of extracellular promoting systems in the brain.
adenosine, that indicate the accumu-
lated need to sleep, and may in part SLEEP ITSELF CONTAINS
work by activating ventrolateral pre- DIFFERENT STATES
optic neurons. Other hypothalamic As a normal person falls asleep,
neurons, which contain the peptide the EEG slows from the typical awake
melanin-concentrating hormone as well state (desynchronized, with some alpha
as GABA, also are most active during rhythm, particularly posteriorly) to the

EEG begins to increase in frequency

again as the person passes from deep
slow-wave to lighter stages of sleep. As
the EEG reaches the theta range, an
abrupt transition to a desynchronized
EEG that is more similar to the waking
state may occur. The person does not
awaken during such a transition or
become more arousable, despite the de-
synchronized EEG. At the same time, a
change in EMG from a state of low but
constant muscle tone to virtual absence
of muscle tone (atonia) occurs. The
persons eyes may move, thus giving
this stage the descriptive name rapid
eye movement, or REM, sleep. People
more frequently report dreaming dur-
ing awakenings from REM versus non-
REM (NREM) sleep, and the dreams
tend to be longer and involve more so-
cial interaction.
INSOMNIA IS CAUSED BY
HYPERAROUSAL
Insomnia, the inability to get enough
A pair of graphs comparing the firing of sleep to function normally despite ade-
FIGURE 1-3
neurons in the noradrenergic locus quate opportunity, is the most common
coeruleus (LC) (green) and histaminergic
tuberomammillary neurons (TMN) (gray) with basal forebrain sleep complaint.12,13 Insomnia may be
wake-promoting (blue) and preoptic sleep-promoting (red) primary (ie, not associated with another
neurons across the time of transition between wakefulness
and light non-REM sleep. Firing of the LC leads and the TMN disorder), but it is also seen in many
follows the transition from sleep to wake, but a sharp change other disorders, ranging from pain to
in the firing of the preoptic sleep-promoting neurons and the depression. Insomnia may also be inter-
basal forebrain wake-promoting neurons occurs in the half
second before the transition, suggesting that they may cause the mittent, which is usually associated with
transition. Conversely, a sharp increase in the firing of preoptic various stressors, or it may be chronic.
sleep-promoting neurons begins just before the onset of sleep.
PET studies of the brains of patients
Reprinted from Saper CB et al, Neuron.4 B 2010, with permission from
Elsevier. www.cell.com/neuron/retrieve/pii/S0896627310009748.
who have chronic insomnia show that
there is abnormal activation not only of
the components of the arousal system,
KEY POINT theta range (4 Hz to 7 Hz). As sleep including the hypothalamus and upper
h Sleep is divided into REM deepens, the EEG rhythm slows fur- brainstem, but also their targets, espe-
sleep, characterized by ther, and occasional very slow (delta) cially the medial prefrontal cortex and
a fast EEG and muscle waves appear (K complexes). Sleep the amygdala. EEG studies show that
atonia, and non-REM
spindles, which are waxing and waning subjects with insomnia often have
sleep, during which the
periods of alpha-frequency EEG, be- nearly normal amounts of sleep, as
EEG is slow and high
voltage, and muscle tone
gin to occur. As the person enters the measured by traditional scoring meth-
is present but low. deeper stages of sleep (stages N2 and ods (which identify NREM sleep by slow
N3), the slower frequencies predomi- activity and REM sleep by EMG atonia
nate, with greater amounts of delta and a fast EEG). However, analysis of
activity. After about 45 minutes, the higher frequencies in the EEG, such as

KEY POINTS
the gamma (greater than 30 Hz) range, get out of bed and may hurt them- h Primary insomnia is
shows that the brains of subjects with selves by falling over furniture, walk- associated with a state
insomnia have excess gamma activ- ing into walls, or even falling out of of coactivation of
ity.12,14 As gamma activity is associated windows. Studies over the past dec- both arousal- and
with waking cortical activity, the EEG in ade have found that most people with sleep-promoting
insomnia actually shows components of idiopathic REM sleep behavior disorder systems, resulting in a
wake and sleep at the same time, that is, go on to develop a synucleinopathy, different state in which
constituting a different state from either most commonly Parkinson disease or the EEG simultaneously
traditional sleep or wakefulness. This Lewy body dementia, although some shows both the slowing
disparity may account for why, after a develop multiple system atrophy.19,20 of non-REM sleep and
the fast frequencies
night in the sleep laboratory, the clini- Surprisingly, the mean time from diag-
associated with active
cian thinks that the patient was asleep nosis of REM sleep behavior disorder
wakefulness.
for most of the night whereas the to diagnosis of the synucleinopathy is
patient reports that she was awake for about 12 years, with over 80% devel- h REM sleep behavior
disorder is due to a
most of the night. This sleep state oping a synucleinopathy within 20 years.
failure of atonia circuitry
misperception is not on the part of the Conversely, about 30% of patients with
during REM sleep,
patient, but rather the clinician, who is Parkinson disease or Lewy body demen- allowing the patient to
using traditional sleep scoring methods tia have clear evidence of REM sleep act out dreams, which
that do not measure the high-frequency behavior disorder in the sleep labora- often are violent.
cortical arousal. tory. However, the loss of REM atonia is
intermittent and there may be relatively
REM SLEEP IS DRIVEN BY little REM sleep during the first night in
NEURONS IN THE PONS the laboratory. In addition, reports of
Recent studies have shown that neu- calling out, thrashing about in bed, or
rons in the upper pons generate the getting out of bed are common when
state of REM sleep.15,16 These neurons the patient with Parkinson disease has a
are located in the region just ventral bed partner, but many such patients
to the locus coeruleus in cats, mice, sleep alone. Thus, the prevalence of
and probably humans, and just ventral REM sleep behavior disorder in patients
to the laterodorsal tegmental nucleus with Parkinson disease may be under-
in rats, and are variously called the estimated. Pathologic examination of
subcoeruleus area or the sublatero- the brains of patients with synucleino-
dorsal nucleus by different authors pathies frequently shows damage to the
(Figure 1-4). Lesions in this area may subcoeruleus region.21 However, it
cause intermittent loss of some of the remains to be established whether this
features of REM sleep. For example, is the cause of the sleep disorder.
neurons in the lower part of the Other characteristics of REM sleep,
sublaterodorsal area are glutamatergic, such as the rapid eye movements and
and they cause the loss of muscle tone EEG desynchronization, also appear to
(atonia) during REM sleep, which be driven by neurons in the sublater-
prevents the acting out of dreams. odorsal region, but each of these
Lesions of this region cause intermit- phenomena may be controlled by
tent loss of atonia during REM sleep, different populations of neurons.4,15
leading to a condition called REM Thus, it is possible for the phenomena
sleep behavior disorder, in which normally associated with REM sleep to
dreams are acted out (Case 1-2).15,17 become fragmented and for patients
People with REM sleep behavior dis- to show only some of the typical charac-
order call out, thrash around, and teristics. This issue will be addressed
fight off attackers. Some individuals below when considering narcolepsy.

FIGURE 1-4 A series of schematic drawings to illustrate the circuitry thought to be involved
in switching into and out of REM sleep. A, Neurons in the sublaterodorsal
nucleus (SLD) and adjacent precoeruleus region (PC) (red) fire during REM sleep
and are thought to be the generator for REM sleep. The SLD/PC neurons are inhibited by
neurons in the ventrolateral periaqueductal gray matter (vlPAG) and adjacent lateral pontine
tegmentum (LPT) (gold), and inhibit them, as well. This mutually inhibitory relationship is thought
to set up another flip-flop switch, for regulating the transitions into and out of REM sleep.
B, The REM-off area is regulated by excitatory inputs from the orexin neurons and the
monoaminergic locus coeruleus (LC) and dorsal raphe (DR), which prevent REM sleep, and by
inhibitory inputs from the ventrolateral preoptic nucleus (VLPO) and cholinergic laterodorsal and
pedunculopontine tegmental nuclei (LDT/PPT), which promote REM sleep. C, During REM sleep,
the REM generator neurons in the SLD/PC send ascending projections to the hypothalamus and
basal forebrain that promote a dreaming state and descending projections to the brainstem that
cause rapid eye movements and muscle atonia. The atonia is produced by inputs from the SLD to
medullary and spinal inhibitory interneurons, which hyperpolarize the alpha motor neurons.
Reprinted from Saper CB et al, Neuron.4 B 2010, with permission from Elsevier. www.cell.com/neuron/retrieve/pii/
S0896627310009748.

KEY POINT
Case 1-2 h REM generator neurons

in the upper pons are
A 61-year-old man was seen for evaluation of a right-hand tremor,
tonically inhibited by
slowness of movement, and abnormal gait. On examination, he had a
REM-off neurons in the
soft voice, decreased blinking, and decreased facial expression. He had
lower midbrain, which
increased tone and a pill-rolling tremor of the right hand, and he wrote
gate the entry into REM
with small letters. The patient walked with a stooped posture, reduced
sleep.
arm swing, and had short steps. A diagnosis of idiopathic Parkinson disease
was made, and the patient was started on levodopa, which improved his
symptoms.
The patient was a widower who lived alone. He noted that on several
occasions he had awakened on the floor with a bruise on his shin, which
he had apparently injured when falling across the bedside table. During
a sleep laboratory evaluation, he had two brief episodes during REM sleep
in which he called out while fighting violently against an imagined
intruder. He awakened during one particularly active episode and, when
questioned, indicated that he dreamed he took off his shoe and hit the
intruder over the head with it. Review of the videotape showed him
pantomiming the attack.
He was treated initially with 1 mg clonazepam at bedtime, which
reduced the frequency of attacks but did not eliminate them. Melatonin,
up to 9 mg at bedtime, did not further alter the frequency. He eventually
had to place his mattress on the floor and remove all the furniture from
the room. He placed a strap across his body during sleep that prevented
him from getting out of bed without waking up.
Comment. Many patients with Parkinson disease or Lewy body
dementia have REM sleep behavior disorder. In some cases, the sleep
disorder precedes onset of the movement disorder by 10 years or
more.17,18 However, unless the patient gets out of bed during the attacks,
the diagnosis often depends upon the report of a partner who sleeps in
the same room. Up to 90% of patients diagnosed with idiopathic REM
sleep behavior disorder are male, with a peak onset in the seventh and
eighth decades of life. Whether this represents a sex difference or an
ascertainment bias is not known.
The sublaterodorsal neurons that monoaminergic systems (such as the

control REM sleep are normally under locus coeruleus and raphe, which
GABA-ergic inhibition from nearby cease firing during REM sleep). All of
interneurons located just rostrally, in these influences normally regulate
the ventrolateral periaqueductal gray REM sleep. In addition, GABA-ergic
matter and in the adjacent part of the neurons in the sublaterodorsal nucleus
lateral pontine tegmentum.15,22 When project back to the ventrolateral peri-
these interneurons are firing, they aqueductal gray matter and may inhibit
prevent REM sleep (ie, they are REM- the REM-off neurons during REM sleep.
off neurons). The REM-off neurons This relationship produces the condi-
receive input from the ventrolateral tions for another flip-flop switch, con-
preoptic nucleus and the lateral hypo- trolling REM sleep, which may account
thalamus (both orexin and melanin- for the relatively rapid and complete
concentrating hormone neurons), as transitions between NREM and REM
well as the local cholinergic neurons sleep, which occur over seconds to a
(which fire during REM sleep) and few minutes.4

KEY POINT
h Orexin neurons in OREXIN NEURONS STABILIZE of which are excitatory, so the effect
the posterior lateral THE SLEEP AND REM SWITCHES of this peptide is to activate its targets.
hypothalamus stabilize The orexin neurons, which reside in These targets include the ascending
the sleep-wake and the the posterior lateral hypothalamus, monoaminergic systems, the basal
REM switches. contact neurons at multiple levels of forebrain cholinergic system, and the
the sleep-wake regulatory system.23,24 REM-off neurons. Orexin neurons typ-
There are two orexin receptors, both ically fire most vigorously during an
aroused wake state in which a person
is actively exploring the environment
(eg, while walking).25,26 This relation-
ship makes it very difficult to fall
asleep while standing or moving
about, which of course protects against
falls, and is used by sleep-deprived shift
workers to remain awake, especially
during night work. Because the orexin
neurons target the monoaminergic
arousal and REM-off neurons, the brain
is stabilized in the normal waking state
and transition to REM sleep from a
waking state is almost impossible for
an intact person (Figure 1-5).4
The effects of loss of the orexin neu-
rons are consistent with these observa-
tions.27 A person who has lost orexin
The two flip-flop switches controlling neurons is sleepy during the day and
FIGURE 1-5 wake-sleep transitions (upper left) and falls asleep easily during lulls in stim-
REM-non-REM transitions (lower right) form
a cascade. During wakefulness, the activity ulation. Because less tone is present in
of the monoaminergic cell groups (locus coeruleus [LC], the REM-off system, people may fall
tuberomammillary neurons [TMN], dorsal raphe [DR],
parabrachial nucleus/precoeruleus area [PB/PC], and ventral
into REM sleep very shortly after sleep
periaqueductal gray matter [vPAG]) inhibit both the preoptic onset, and experience fragments of
sleep-promoting neurons (ventrolateral preoptic nuclei [VLPO] REM sleep while awake. For example,
and median preoptic nuclei [MnPO]) and pontine REM-promoting
neurons (pedunculopontine tegmental nuclei [PPT], laterodorsal REM atonia may occur during wakeful-
tegmental nuclei [LDT], PB/PC, sublaterodorsal nucleus [SLD]). ness. When this occurs in the border
This prevents a waking person from directly entering REM
sleep. The strength of the monoaminergic system in stabilizing zone between sleep and wake, it is
both switches is reinforced by the orexin (ORX) neurons, called sleep paralysis. Sleep paralysis
which are excitatory and fire during wakefulness, and the
melanin-concentrating (MCH) neurons that inhibit the can occur in normal people, especially
monoamine systems and the REM-off cell groups (ventrolateral if they have been sleep deprived.
periaqueductal gray matter [vlPAG], lateral pontine tegmentum
[LPT]), and fire primarily during sleep and fastest during
Some may also have REM-type dreams
REM sleep. In the absence of the ORX neurons in patients with during the border zone between wake
narcolepsy, both switches are destabilized. The instability of and sleep. When this phenomenon
the wake-sleep switch produces excess sleepiness during
the wake period and excess waking during the sleep period. occurs while falling asleep, such dreams
The instability of the REM switch causes rapid, and in some are called hypnagogic hallucinations;
cases, direct entry into REM from the waking state, as well as
fragments of REM sleep, such as muscle atonia (cataplexy) and if they occur while awakening, they
dreaming (hypnagogic hallucinations), to occur while awake. are called hypnopompic hallucina-
Red lines represent inhibitory pathways and green lines show
excitatory pathways. tions. Such hallucinations are rare in
normal people unless they have been
Reprinted from Saper CB et al, Neuron.4 B 2010, with permission from
Elsevier. www.cell.com/neuron/retrieve/pii/S0896627310009748. sleep deprived, but are very similar to
peduncular hallucinosis, which occurs

in patients who have lesions of the laughter or joy. These attacks are called
midbrain that presumably affect the cataplexy. Cataplexy does not occur in
REM control circuitry. REM atonia may normal subjects but is a cardinal feature
also occur abruptly while awake, often of narcolepsy (Case 1-3). Patients with
when a person is active and experiencing narcolepsy often report sleep paralysis
Case 1-3
A 20-year-old male college student was referred to the neurologist from the student health center for
excessive daytime sleepiness. He had been well, sleeping from midnight or 1:00 AM until 7:00 AM or
8:00 AM during most nights of the week and longer on weekends, until about 2 months earlier. At that
time, he had a nonspecific flulike illness. One to 2 weeks later, he began to have difficulty staying
awake during the day and maintaining sleep during the night. In classes he often felt overcome with
sleepiness during a lecture, and napped for 15 to 20 minutes, after which he felt refreshed. One
evening while sitting in a chair reading, he realized that he could not move. He tried to get up to ask
for help but was unable to move for about 5 minutes before the ability to move returned. On another
occasion, while with friends at a pizza parlor, he slumped uncontrollably to the floor while laughing
at a joke and was unable to move for 1 to 2 minutes.
He noted that he had gained a few pounds, although his appetite had not increased; however, he
admitted to engaging in less exercise and athletics. The general medical and neurologic examinations
were normal. An overnight sleep study showed that he had frequent awakenings. A multiple sleep
latency test performed the next day showed that he fell asleep in less than 5 minutes on each of five
attempts and had short-onset REM periods in three of these.
Genetic testing for HLA-DQB1*0602 was positive. Spinal fluid orexin levels were only 10% of normal.
A diagnosis of narcolepsy was made, and the patient was treated with venlafaxine, a combined
norepinephrine and serotonin reuptake inhibitor, in the morning because venlafaxine increases the
monoaminergic tone in the brainstem and blocks entry into REM sleep. He also required treatment
with modafinil during the day to prevent excessive sleepiness.
Two months later he continued to experience episodes of cataplexy and was started on sodium
oxybate (gamma-hydroxybutyrate) at bedtime and again when awakening at 3:00 AM. This drug
causes profound and consolidated delta sleep, and the patient found that he was less sleepy the next
day and had no further attacks of cataplexy.
Comment. The peak age of onset of narcolepsy is in the teens and twenties, and most patients have
had symptoms for several weeks or months before they seek attention.27 This patient had sleep
attacks, sleep paralysis, and attacks of cataplexy. The increased fragmentation of sleep is also a
common finding in narcolepsy. It may seem paradoxical, but most patients with narcolepsy with
cataplexy both fall asleep too much during wakefulness and wake up too much during sleep.2,4 This
relationship can be explained by the flip-flop switch model of sleep-wake regulation. Similarly, the
entry directly from wakefulness into fragments of REM sleep (eg, atonia) is thought to be due to loss
of orexins stabilization of the non-REM flip-flop switch.4
Patients with narcolepsy often have a small reduction in appetite but a larger reduction in activity
levels, which can result in modest weight gain.
The onset of narcolepsy with cataplexy usually occurs during the second or third decade of life and
is associated with loss of the orexin neurons and low orexin levels in the CSF. While in some cases
(such as the ones described by von Economo or in the patient described previously in Case 1-1) this is
due to a lesion involving the posterior lateral hypothalamus, in most patients there is no apparent
structural damage. It is believed that the loss of orexin neurons during adolescence or early adulthood
is most likely due to an autoantibody that occurs in many populations, mainly in individuals with
the HLA-DQB1*0602 genotype, and evidence exists for an increase in frequency following influenza
epidemics.28 Narcolepsy without cataplexy also occurs, but it is not associated with low CSF orexin
levels in most patients, in whom the cause remains unknown.

KEY POINT
and hypnagogic or hypnopompic hallu- preoptic nucleus on NREM and REM sleep.
h The loss of orexin J Neurosci 2000;20(10):3830Y3842.
neurons produces cinations as well, even when not sleep
deprived. Surprisingly, narcoleptic pa- 7. Gvilia I, Xu F, McGinty D, Szymusiak R.
narcolepsy, which is Homeostatic regulation of sleep: a role
characterized by state tients not only fall asleep too often for preoptic area neurons. J Neurosci
instability: falling asleep during the day, but they also wake up 2006;26(37):9426Y9433.
too often when awake, too often at night. It is difficult to 8. Uschakov A, Gong H, McGinty D, et al.
waking up too often understand this predisposition if one Efferent projections from the median
when asleep, and considers the orexin neurons to be preoptic nucleus to sleep- and
falling into partial REM arousal-regulatory nuclei in the rat brain.
solely wake-promoting. On the other Neuroscience 2007;150(1):104Y120.
states such as atonia hand, if one recognizes that the role of
(cataplexy) or dreaming 9. Verret L, Goutagny R, Fort P, et al. A role
orexin is to stabilize the wake-sleep flip- of melanin-concentrating hormone
(hypnagogic or
flop switch in the waking state, then producing neurons in the central regulation
hypnopompic of paradoxical sleep. BMC Neurosci
hallucinations).
loss of consolidated wakefulness will
2003;4:19.
inevitably diminish accumulation of
10. Batini C, Moruzzi G, Palestin M, et al.
homeostatic sleep drive during the day Persistent patterns of wakefulness in the
and thus cause excess transitions of the pretrigeminal midpontine preparation.
flip-flop switch from sleep into wakeful- Science 1958;128(3314):30Y32.
ness during the night as well. This 11. Takahashi K, Kayama Y, Lin JS, Sakai K.
property of flip-flop switchesVthat any- Locus coeruleus neuronal activity during the
sleep-waking cycle in mice. Neuroscience
thing that weakens them will cause 2010;169(3):1115Y1126.
increased transitions in both statesV
12. Cano G, Mochizuki T, Saper CB. Neural
can be derived mathematically from circuitry of stress-induced insomnia in rats.
their properties. This model also pre- J Neurosci 2008;28(40):10167Y10184.
dicts that if sleep can be consolidated 13. Nofzinger EA, Buysse DJ, Germain A, et al.
(eg, by giving a drug such as sodium Functional neuroimaging evidence for
oxybate), then daytime waking of nar- hyperarousal in insomnia. Am J Psychiatry
2004;161(11):2126Y2128.
coleptic patients will be more consoli-
dated as well, with fewer transitions to 14. Perlis ML, Smith MT, Andrews PJ, et al.
Beta/Gamma EEG activity in patients
sleep or cataplexy. with primary and secondary insomnia and
good sleeper controls. Sleep 2001;24(1):
110Y117.
REFERENCES
15. Lu J, Sherman D, Devor M, Saper CB. A
1. Saper CB, Plum F. Disorders of consciousness.
putative flip-flop switch for control of REM
In: Frederiks JAM, ed. Handbook of clinical
sleep. Nature 2006;441(7093):589Y594.
neurology. Vol 45. Amsterdam: Clinical
Neuropsychology, Elsevier, 1985:107Y128. 16. Luppi PH, Gervasoni D, Verret L, et al.
Paradoxical (REM) sleep genesis: the
2. Saper CB, Scammell TE, Lu J. Hypothalamic
switch from an aminergic-cholinergic to a
regulation of sleep and circadian rhythms.
GABAergic-glutamatergic hypothesis.
Nature 2005;437(7063):1257Y1263.
J Physiol Paris 2006;100(5Y6):271Y283.
3. Scammell TE, Nishino S, Mignot E, Saper CB.
17. Boeve BF, Silber MH, Saper CB, et al.
Narcolepsy and low CSF orexin (hypocretin)
Pathophysiology of REM sleep behaviour
concentration after a diencephalic stroke.
disorder and relevance to neurodegenerative
Neurology 2001;56(12):1751Y1753.
disease. Brain 2007;130(pt 11):2770Y2788.
4. Saper CB, Fuller PM, Pedersen NP, et al. Sleep
18. Claassen DO, Josephs KA, Ahlskog JE, et al.
state switching. Neuron 2010;68(6):1023Y1042.
REM sleep behavior disorder preceding
5. Szymusiak R, Alam N, Steininger TL, other aspects of synucleinopathies by
McGinty D. Sleep-waking discharge up to half a century. Neurology 2010;75(6):
patterns of ventrolateral preoptic/anterior 494Y499.
hypothalamic neurons in rats. Brain Res
19. Schenck CH, Bundlie SR, Mahowald MW.
1998;803(1Y2):178Y188.
Delayed emergence of a parkinsonian
6. Lu J, Greco MA, Shiromani P, Saper CB. disorder in 38% of 29 older men initially
Effect of lesions of the ventrolateral diagnosed with idiopathic rapid eye

movement sleep behaviour disorder. 24. Peyron C, Tighe DK, van den Pol AN, et al.
Neurology 1996;46(2):388Y393. Neurons containing hypocretin (orexin)
project to multiple neuronal systems.
20. Postuma RB, Gagnon JF, Vendette M, et al.
J Neurosci 1998;18(23):9996Y10015.
Quantifying the risk of neurodegenerative
disease in idiopathic REM sleep 25. Lee MG, Hassani OK, Jones BE. Discharge of
behavior disorder. Neurology 2009;72(15): identified orexin/hypocretin neurons across
1296Y1300. the sleep-waking cycle. J Neurosci
2005;25(28):6716Y6720.
21. Braak H, Del TK, Rub U, et al. Staging of
brain pathology related to sporadic 26. Mileykovskiy BY, Kiyashchenko LI, Siegel JM.
Parkinsons disease. Neurobiol Aging Behavioral correlates of activity in
2003;24(2):197Y211. identified hypocretin/orexin neurons.
Neuron 2005;46(5):787Y798.
22. Sapin E, Lapray D, Berod A, et al.
Localization of the brainstem GABAergic 27. Scammell TE. The neurobiology, diagnosis,
neurons controlling paradoxical (REM) sleep. and treatment of narcolepsy. Ann Neurol
PLoS One 2009;4(1):e4272. 2003;53(2):154Y166.
23. Chemelli RM, Willie JT, Sinton CM, et al. 28. Han F, Lin L, Warby SC, et al. Narcolepsy
Narcolepsy in orexin knockout mice: onset is seasonal and increased following
molecular genetics of sleep regulation. Cell the 2009 H1N1 pandemic in China. Ann
1999;98(4):437Y451. Neurol 2011;70(3):410Y417.

Review Article
Approach to and
Dr Anita Valanju Shelgikar,
Medical School Sleep
Disorders Center, C728 Med
Inn Building, 1500 East
Medical Center Dr,
Ann Arbor, MI 48109-0845,
Evaluation of Sleep
avalanju@med.umich.edu.
Relationship Disclosure:
Dr Shelgikar has received an
Disorders
honorarium from Elsevier for
her authorship of a book Anita Valanju Shelgikar, MD; Ronald Chervin, MD, MS, FAASM, FAAN
chapter. Dr Chervin has
consulted for Proctor &
Gamble and Zansors, LLC;
receives compensation for
ABSTRACT
serving on boards from the Purpose of Review: This article provides a framework for the clinical assessment of
American Academy of Sleep patients with sleep-related complaints and outlines a systematic approach to a
Medicine, International
Pediatric Sleep Association, sleep-specific history and physical examination, subjective assessment tools, and
and the NIH; serves as section diagnostic testing modalities.
editor for and receives royalty Recent Findings: Physical examination findings may suggest the presence of a sleep
payments from UpToDate;
receives licensing fees disorder, and obstructive sleep apnea in particular, but the clinical history remains the
through the University of most important element of the assessment for most sleep problems. While nocturnal
Michigan from Zansors, LLC; polysomnography in a sleep laboratory remains the gold standard for diagnosis of
and receives grants from
Fisher & Paykel, the NIH, and sleep-disordered breathing, out-of-center testing may be considered when the clinician
Philips Respironics. has a high pretest suspicion for obstructive sleep apnea and the patient has no
Unlabeled Use of significant cardiopulmonary, neuromuscular, or other sleep disorders.
Use Disclosure:
Summary: Sleep-related symptoms are common in adult and pediatric patients. A
Drs Shelgikar and Chervin comprehensive sleep history, physical examination with detailed evaluation of the head
report no disclosures. and neck, and judicious use of sleep-specific questionnaires guide the decision to
* 2013, American Academy pursue diagnostic testing. Understanding of the benefits and limitations of various
of Neurology.
diagnostic modalities is important as the spectrum of testing options increases.
INTRODUCTION information given by the patient should,

The NIH Sleep Disorders Research Plan,1 when possible, be supplemented by a
updated in November 2011, indicates bed partner, family member, or room-
a 25% to 30% prevalence of sleep and mate who may have different insight
circadian disorders in the general adult into the patients behavior during sleep
population. The exact prevalence of or daytime mood and cognitive func-
sleep disorders in neurologic disease is tioning. Whether the presenting sleep
Supplemental digital content: unknown but in some instances may be complaint is excessive daytime sleepi-
Videos accompanying this ar-
ticle are cited in the text as higher than in the general population. ness, poor sleep quality, insomnia (diffi-
Supplemental Digital Content. Focused assessment and management culty falling or staying asleep), or
Videos may be accessed by
clicking on links provided in of impaired sleep or alertness may im- abnormal behavior during sleep, a uni-
the HTML, PDF, and iPad prove quality of life, improve produc- form approach to the sleep history
versions of this article; the
URLs are provided in the print tivity, reduce accidents, or attenuate facilitates a thorough medical decision-
version. Video legends begin progression of a coexisting neurologic making process. Table 2-1 details the es-
on page 48.
disease or facilitate recovery from it. sential components of the sleep history.
A chief complaint of daytime sleepi-
SLEEP HISTORY ness should invite questions about its
A detailed sleep history is the central nature and severity, timing, circum-
component of the evaluation. Historical stances, and possible underlying causes.

TABLE 2-1 Components of the Sleep History
b Presenting Sleep-Related Symptom b Time of Symptoms (Time During

Onset the Sleep Period That Symptoms
Occur)
Precipitating/predisposing factors
Duration b Daytime Functioning
Frequency Daytime sleepiness
Severity Mood disturbance
Impaired school or work
b Associated Nocturnal Symptoms
performance
Sleep-disordered breathing
Decreased alertness while driving
Snoring
Impaired interpersonal
Witnessed apneas relationships
Morning headache Decreased concentration or
Mouth breathing memory
Acid reflux Cataplexy or hypnagogic or
Nasal congestion hypnopompic hallucinations
Nocturia Leg discomfort, urge to move,
or spontaneous movements
Erectile dysfunction
Nocturnal dyspnea b Sleep Schedule and Sleep Hygiene
Nocturnal behavior Bed time
Sleepwalking Sleep latency
Sleeptalking Wake time
Sleep eating Rise time (when patient gets up
from bed)
Leg movement
Details of bedtime routine
Dream enactment
Description of activities during
Bruxism nocturnal awakenings
Nocturnal awakenings
b Use of Sleep Aids and Stimulants
Timing in night
Over-the-counter (including
Precipitants herbal) agents
Duration Prescription medications
Frequency Caffeine
Activities while awake Energy drinks
Other symptoms
Leg discomfort
Urge to move
Sleep paralysis
Sleepiness is thought to result from neu- desire to rest,3 and is postulated to

robiologic processes that regulate circa- represent a process that is distinct from
dian rhythms and the drive to sleep,2 and sleepiness. However, patients often
some individuals will clearly articulate interchangeably use the terms tired-
sleepiness as a tendency to doze un- ness, sleepiness, and fatigue.3,4 Pa-
intentionally. Fatigue is defined as tients with obstructive sleep apnea (OSA),
reversible, motor, and cognitive impair- and possibly other sleep disorders as-
ment with reduced motivation and sociated with daytime sleepiness, may

Approach and Evaluation
KEY POINTS
h Information from the report fatigue, tiredness, or lack of countries indicate that approximately
patient, medical record, energy at times even when they deny 30% of the general adult population
and any available bed sleepiness.4 Interestingly, these symp- reports one or more insomnia symp-
partner, friend, or toms (like sleepiness) appear to tom.8 Because insomnia is so common,
family member can improve with treatment of the under- neurologists routinely encounter pa-
clarify the extent and lying OSA.5 A clear understanding of tients with the symptom. As the etiol-
consequences of the whether the patient experiences an ogy of insomnia is often multifactorial,
patients sleep-related overwhelming urge to sleep during the evaluation can be complex and
symptoms. the day may help the clinician decide requires a detailed history that explores
h The 3P framework of which diagnostic studies to pursue, and many potential contributors.
insomnia comprises also guides discussion about potential A helpful framework in which to con-
predisposing, diagnoses that may contribute to the sider a patients insomnia is known as
precipitating, and patients symptoms. Special attention the 3P model,9 which aids identifica-
perpetuating factors. should be paid to situations in which tion of possible causes of insomnia and
Discussion of all factors
the patients sleepiness becomes evi- highlights potential targets for treat-
facilitates identification
dent. Does the patient doze during con- ment. This model calls for temporal
of potential treatment
targets.
versation, while at work, or while driving? classification of factors that affect a pa-
Is the patients concentration or memory tients insomnia: characteristics that
impaired because of sleepiness? Dozing predispose a person to develop in-
while operating heavy machinery or a somnia, events that precipitate the in-
motor vehicle can lead to devastating somnia acutely, and behaviors and
outcomes, and this has both individual attitudes that perpetuate insomnia and
and public health implications. Daytime may cause it to become chronic. Com-
sleepiness that impairs a patients func- mon predisposing factors include per-
tional capabilities can threaten job se- sonality traits, such as excessive worrying
curity and have a negative impact on or cognitive hyperarousal, or the degree
interpersonal relationships. The con- to which a persons preferred sleeping
text of a patients daytime sleepiness times differ from social norms.9 Precip-
highlights its severity and impact. itating factors are often readily identi-
The symptom of insomnia is de- fied as major life transitions, such as
fined as difficulty with sleep initiation change in marital status, death in the
or maintenance, waking too early, or family, or change in employment. How-
sleep that is nonrestorative, despite ever, subtler challenges to a persons
ample opportunity to sleep.6 Disorders routine or environment may also pre-
that cause insomnia have diagnostic cipitate the onset of insomnia. In some
criteria to specify that the insomnia situations, the patients sleep normal-
symptoms should be accompanied by izes upon resolution of the precipitant;
at least one manifestation of daytime in other cases, behaviors and mindsets
impairment (such as fatigue, mood dis- accrued during the acute phase of the
turbance, headaches, or gastrointestinal insomnia can perpetuate the patients
symptoms in response to sleep loss), or sleep disturbance. Such perpetuating
impaired memory, concentration, or factors can include perceived associa-
performance. The point prevalence of tions between the sleeping environ-
insomnia is estimated at 6% to 15% in ment and inability to sleep or escalated
the general population but is clearly use of caffeine throughout the day.
higher among certain subgroups, such Other important details include specif-
as patients with psychiatric disease.7 ics about the patients insomnia at the
Population-based studies done with present time, including the latency to
varied adult samples from multiple sleep; timing, duration, and causes of

Case 2-1
A 44-year-old man with a long-standing history of loud, frequent snoring
presented because of his wifes concerns related to his snoring. His wife
had witnessed him to have occasional pauses in his breathing during sleep,
and at times he awakened to his snoring. He reported frequent acid
reflux and morning headaches. Approximately once per month he would
awaken feeling like my heart is racing and I need to catch my breath.
He had occasional nasal congestion but always awakened with a dry
mouth and sore throat. He denied any leg discomfort, but his wife had
told him that he tossed and turned frequently during sleep.
His sleep schedule was the same every night: he was in bed by 10:00 PM,
fell asleep immediately without the use of any sleep aids, and awakened
at 6:00 AM feeling tired. He had up to four nocturnal awakenings per
night; two were attributed to nocturia and the rest were of unknown
etiology. Each awakening lasted a few minutes, and he fell asleep again
easily. He had had a few episodes of sleepwalking as a child, but none since
the age of 8 years.
He felt sleepy during the day, with a propensity to doze unintentionally
while reading or watching television. He denied drowsiness while driving but
limited his driving to his 20-minute commute to and from work; his wife
drove for longer distances and he would often sleep in the passenger seat. His
sleepiness was worse in the midafternoon, and if given the opportunity he
would nap for 1 hour on the weekends. He found naps to be somewhat
refreshing. He drank two to three cups of coffee every morning and had a
12-oz caffeinated soda with lunch. His sleepiness had not caused him to make
any mistakes in his job as a physical therapist, although he felt that he had
potential for further improvement in his job performance. He also reported
feeling more irritable in recent months, but this had not caused any
difficulties at home or work.
Comment. This case illustrates the multiple components of a concise
but still detailed sleep history. The patients daytime symptoms provide
insight about the effects of the patients untreated sleep disorder.
nocturnal awakenings; behaviors dur- discomfort associated with an urge to

ing nocturnal awakenings; and latency move that worsens at night and
to fall back asleep after each awakening. improves with leg movement indicates
A useful approach is to ask the patient restless legs syndrome and may con-
for a detailed, start-to-finish description tribute to the patients poor sleep
of the entire typical sleep period and quality and impair daytime functioning.
daytime period. Any medications pre- Sleep paralysis and hypnagogic or
viously or currently used to facilitate hypnopompic hallucinations are not
sleep should also be identified. specific to a particular sleep disorder,
The sleep history should screen while a history of cataplexy is patho-
for potentially relevant sleep disorders gnomonic for narcolepsy and must be
that may cause excessive daytime sleep- explored when a patient presents with
iness or insomnia (Case 2-1). The reports of central hypersomnia rather
presence of symptoms such as snor- than SDB. When relevant, the clinician
ing, witnessed apneas, and morning should also ask about nocturnal behav-
headaches raises the suspicion for iors, specifically ones that may pose risk
sleep-disordered breathing (SDB). Leg of injury to the patient or bed partner,

KEY POINT
h Details of facial such as sleepwalking, driving or cook-
morphology, nasal ing while asleep, or dream-enactment
airway patency, and oral behavior. If the patient reports such
airway crowding are behavior, further inquiry must be made
key features of the about the frequency of these events and
sleep-specific any history of injury sustained due to the
examination. sleep-related behavior. Details of the
sleep history permit a thorough differ-
ential diagnosis and can also guide a
discussion of safety concerns.
PHYSICAL EXAMINATION
A comprehensive, multisystem exami-
nation is an important aspect of the FIGURE 2-2 Retrognathia. Retrognathia
sleep evaluation. Measurement of the is derived from the terms
retro (backward) and
weight, height, body mass index (BMI), gnathos (jaw). With retrognathia, one or
neck circumference, and blood pres- both jaws recede with respect to the frontal
plane of the forehead. The condition may
sure and heart rate should be per- predispose a patient to obstruction of the
formed for nearly all patients with airway and sleep apnea by displacing the
tongue against the retropharyngeal region,
symptoms related to sleep or alertness. compromising airflow. Retrognathia is
Other salient features of the general sometimes corrected through surgical
repositioning or advancement of the mandible.
examination include auscultation for
any cardiac or respiratory abnormalities Reprinted from Kryger MH, Elsevier.12 B 2010, with
permission from Elsevier.
and identification of peripheral edema.
A focused neurologic examination
should be guided by the patients his- tus endorses symptoms of restless legs
tory. For instance, a mental status as- syndrome, it is worthwhile to assess for
sessment should be considered if a stocking-glove distribution sensory loss
patient with excessive daytime sleepi- and weakness.
ness also complains of memory loss. If a Detailed examination of the head
patient with a history of diabetes melli- and neck should be performed as part
of a comprehensive sleep evaluation.
The patients facial morphology should
be assessed for features of long face
syndrome, which includes infraorbital
darkening, mouth breathing, elongated
midface, and nasal atrophy.10 A 2009
review11 reports that previous observa-
tional and cross-sectional studies have
shown a relationship between chronic
nasal obstruction and OSA. Thus, a thor-
ough nasal examination should be per-
formed on patients with sleep-related
Nasal septal deviation. This complaints. Examination of the nasal
FIGURE 2-1
structural abnormality can airway should include evaluation for
predispose a patient to have
sleep-disordered breathing. symmetry of the nares, nasal septum de-
viation (Figure 2-1),12 and nasal turbi-
Reprinted from Kryger MH, Elsevier.12 B 2010, with
permission from Elsevier. nate hypertrophy. A bedside assessment
of nasal airflow can be accomplished by

asking the patient to press the index divided patients into three classes. Two
finger against the left nostril and take a years later,15 this was modified to de-
deep breath in on the right side; this scribe four groups: class I, class II, class
should be repeated on the opposite III, and class IV. Figure 2-3 16 illustrates
side as well. The patients facial mor- the modified Mallampati classification
phology should be assessed for man- assessed with the tongue protruded.
dibular retrognathia (Figure 2-2).12 With The Friedman palate position classifi-
the patients head in a neutral posi- cation,17 also commonly referenced,
tion, a virtual line is drawn from the utilizes the same four categories but is
vermillion border of the lower lip to done with the tongue at rest and not
the chin. Mandibular retrognathia is extended. Either the Mallampati or
suggested if the anterior prominence of Friedman classification may be used to
the chin is 2 mm or more behind the describe the patency of the oral airway.
virtual line.13 Tonsils should be classified based on
The modified Mallampati classifica- the degree of hypertrophy (Figure 2-4)12:
tion is commonly used for assessment grade I, tonsils are inside the tonsillar
of the oral airway in patients with fossa lateral to the posterior pillars;
suspected SDB. The Mallampati classi- grade II, tonsils occupy 25% of the
fication14 was developed to identify oropharynx; grade III, tonsils occupy
patients in whom tracheal intubation 50% of the oropharynx; and grade IV,
would be difficult; the initial description tonsils occupy at least 75% of the
FIGURE 2-3 Modified Mallampati classification. The class is determined by looking at the
anatomy of the oral cavity and describes tongue size relative to oropharyngeal
size. The test is conducted with the patient seated, the head held in a neutral
position, and the mouth wide open and relaxed. The subsequent classification is assigned based
upon the pharyngeal structures that are visible.
Reprinted from Huang HH et al, BMC Gastroenterol.16 B 2011, BioMed Central Ltd. www.biomedcentral.com/1471-230X/11/12.

may contribute to mass loading on the

upper airway in patients with OSA. The
patients neck circumference should be
measured at the superior border of the
cricothyroid membrane.19 A neck cir-
cumference greater than 40 cm (15.7
in) has been shown to be predictive of
OSA with 61% sensitivity and 93%
specificity, regardless of sex.20
Assessment of the patients anterior
and posterior dentition can also re-
veal anatomic findings that may pre-
dispose a person to certain sleep
disorders. Two features to note in eval-
uation of the anterior dentition are
overjet and overbite (Figure 2-6).21
Overjet, as shown in Figure 2-7,12 is
FIGURE 2-4 Tonsil size grading. This the horizontal distance between the
structural abnormality can
predispose a patient to have upper right central incisor and the
sleep-disordered breathing. buccal surface of the corresponding
Reprinted from Kryger MH, Elsevier.12 B 2010, with lower tooth, while overbite is the ver-
permission from Elsevier. tical distance between these two
points.22 These measurements are typ-
oropharynx and nearly meet in the mid- ically reported in millimeters. The An-
line.13 A high-arched, narrow hard pal- gle classification system is used to
ate (Figure 2-5)18 may predispose the describe the first molar position on
patient to have SDB. Katz and col-
leagues19 have shown that patients with
OSA have significantly increased neck
circumference compared to nonapneic
snorers; greater distribution of neck fat
FIGURE 2-6 Overjet and

overbite. Overjet
is defined as
FIGURE 2-5 Deficient maxillary increased projection of the upper
development in teeth in front of the lower teeth
an individual with as measured parallel to the
Down syndrome leading to high occlusal plane. Overbite is the
and narrow hard palate. vertical overlapping of maxillary
teeth over mandibular teeth,
Reprinted with permission from Cheng usually measured perpendicular
RHW, et al, InTech.18 B 2011, W. Keung to the occlusal plane.
Leung. www.intechopen.com/books/
prenatal-diagnosis-and-screening-for- Reprinted from Saccucci M et al, Scoliosis.21
down-syndrome/oral-health-in-individuals- B 2011, BioMed Central Ltd. www.
with-down-syndrome. scoliosisjournal.com/content/6/1/15.

KEY POINT
sion. Of note, the mesiobuccal surface h Classification of the
is the aspect of the tooth that is adja- patients dentition helps
cent to the cheek mucosa. to evaluate the position
The Adult Obstructive Sleep Apnea of the maxillary arch
Task Force of the American Academy relative to the
of Sleep Medicine (AASM) recommen- mandibular arch.
Overjet.
ded in recent clinical guidelines24 that
FIGURE 2-7 Displacement the following physical findings may
of the suggest the presence of OSA: increased
mandibular teeth posteriorly in
relationship to the maxillary teeth neck circumference (greater than 43.2
results in more posteriorly crowded cm [17 in] in men, greater than 40.6 cm
upper airways, predisposing
patients for the development [16 in] in women), BMI 30 kg/m2 or
of obstructive sleep apnea. greater, modified Mallampati classifica-
Reprinted from Kryger MH, Elsevier.12 tion of III or IV, presence of retrognathia,
B 2010, with permission from Elsevier. lateral peritonsillar narrowing, macro-
glossia, tonsillar hypertrophy, elongated/
the mandibular and maxillary dental enlarged uvula, high-arched/narrow
arches.23 Figure 2-8 shows class I oc- hard palate, nasal abnormalities (eg,
clusion and class II and III malocclu- polyps, deviation, valve abnormalities,
FIGURE 2-8 Angle class occlusion/malocclusion. A, Angle class I occlusion, also known as
neutrocclusion. The mandibular and maxillary dental arches have a normal
anterior-posterior relationship. The mesiobuccal groove of the mandibular first
molar interdigitates with the mesiobuccal cusp of the maxillary first molar. B, Angle class II
malocclusion, also known as distoclusion. The mandibular dental arch is in distal anterior-posterior
relationship to the maxillary dental arch. The mesiobuccal groove of the mandibular first molar is
distal to the mesiobuccal cusp of the maxillary first molar. C, Angle class III malocclusion, also
known as mesioclusion. The mandibular dental arch is in mesial anterior-posterior relationship to
the maxillary dental arch. The mesiobuccal groove of the mandibular first molar is mesial to the
mesiobuccal cusp of the maxillary first molar.
Reprinted from Morcos SS, Patel PK, Clin Plast Surg.23 B 2007, with permission from Elsevier. www.sciencedirect.com/science/
article/pii/S0094129807000843.

KEY POINTS
h The Epworth Sleepiness and turbinate hypertrophy), and/or reasonably well validated, and com-
Scale, a patient-completed overjet. To prevent overlooking these monly used. They can help to increase
questionnaire, assesses findings, a thorough head and neck standardization in evaluations of patients
the patients subjective assessment as described in Table 2-2 by different clinicians or across centers.
tendency to doze during should be incorporated into the phys- Perhaps the most well-known and
sedentary situations in ical examination of all patients who widely used is the Epworth Sleepiness
recent times, not only present with sleep-related complaints. Scale,25 a subjective assessment of the
at the moment the patients daytime sleep propensity in
questionnaire is SUBJECTIVE ASSESSMENT recent times. As shown in Appendix A,
completed. Several patient-completed question- the Epworth Sleepiness Scale asks the
h The Epworth Sleepiness naires are inexpensive and time-efficient, responder to use a four-point Likert
Scale should not be scale (0, 1, 2, or 3) to indicate the
used in lieu of diagnostic likelihood of dozing in eight distinct
testing but may be a
TABLE 2-2 Head and Neck sedentary conditions. A total score of 10
valuable component Examination or greater, out of a possible 24, suggests
of ongoing clinical
excessive daytime sleepiness.25 While
evaluation. b Face the Epworth Sleepiness Scale score can
Features of long face syndrome be easily incorporated into the clinical
Infraorbital darkening evaluation, it should not be used as a
Mouth breathing substitute for objective measurement of
Elongated midface sleepiness. The Epworth Sleepiness Scale
Nasal atrophy score may correlate to a limited extent
b Oral Airway
with the presence and severity of OSA,26
but some studies have failed to find any
Mandibular retrognathia
statistically significant association with
Low soft palate (modified
Mallampati classification)
mean sleep latency on multiple sleep la-
tency tests, or with severity of OSA.27
Large or boggy uvula
The most advantageous use of the
Erythematous pillars
Epworth Sleepiness Scale may be to follow
Tonsillar hypertrophy
an individuals self-assessment of sleep-
High, narrow hard palate iness longitudinally, and it may also serve
Neck circumference as an indicator of treatment response.
Overjet Many other questionnaires may be
Overbite utilized in a clinical sleep evaluation;
Angle classification some pertain to overall sleep quality,
(malocclusion) while others are disorder-specific. The
Macroglossia Patient Reported Outcomes Measure-
Worn occlusive surfaces ment Information System (PROMIS) is
(suggestive of bruxism) an NIH-supported system of measures
b Nasal Airway for patient-reported health status and
Symmetry of the nares includes questions on sleep disturb-
Nasal septum deviation ance. The Pittsburgh Sleep Quality
Nasal airflow
Index (PSQI) is a validated question-
naire that inquires about sleep quality
Collapse of nasal alae on
inspiration and disturbances over the previous
month.28 The parent-completed Pe-
b Neck
diatric Sleep Questionnaire29 contains
Neck circumference a validated, reliable 22-item scale to
help assess risk for SDB in children.

The STOP-BANG questionnaire, devel- level of insomnia may be assessed with
oped and validated in preoperative the Insomnia Severity Index (ISI), a
patients, is a sensitive screening tool validated 7-item questionnaire.32
for OSA. Four questions address snor- A sleep diary (Figure 2-9)33 allows a
ing, tiredness during daytime, observed patient to chart daily sleep and wake
apnea, and high blood pressure, whereas times and should be maintained for at
four other measures focus on increased least 2 consecutive weeks. Review of
OSA risk factors of BMI (greater than 35 this information allows the clinician
kg/m2), age (older than 50 years), neck to estimate the total amount of sleep
circumference (greater than 40 cm the patient obtains in a 24-hour pe-
[15.75 in]), and gender (male preva- riod. The sleep diary also can provide
lence).30 The International Restless insight into the patients sleep pattern.
Legs Syndrome Study Group Rating Scale Is sleep obtained at the same times
(IRLS) is a validated assessment of dis- every day? Is the patients sleep con-
ease severity for patients with restless solidated or fragmented across 24
legs syndrome.31 The patients perceived hours? Does the patient sleep and
FIGURE 2-9 Sleep diary completed by a 46-year-old woman who presented with difficulty falling asleep. Vertical lines
represent when the patient went to bed, M refers to when medication was taken, black shading represents
time asleep, and unshaded white areas are time spent awake.
Diary template reprinted from YOURSLEEP.aasmnet.org from the American Academy of Sleep Medicine, yoursleep.aasmnet.org/pdf/sleepdiary.pdf.33

KEY POINT
h A daily sleep diary helps wake at conventional times, or does saturation.34 The recommended record-
to summarize a patients he or she appear to be a night owl ing montage used in NPSG, as shown
sleep-wake schedule or morning lark? Answers to these in Figure 2-10, includes central (C3-A2,
more accurately than questions, as provided by the sleep C4-A1), frontal (F3-A2, F4-A1), and
memory often allows diary, may reveal factors that contrib- occipital (O1-A2, O2-A1) EEGs, left and
and can facilitate ute to sleep-related concerns. Use of right eye electrooculograms, mental/
construction of sleep diaries can be particularly help- submental surface EMG, and ECG leads.
personalized plans ful in patients with suspected circadian Other recorded parameters include
for management of rhythm sleep disorders (including shift thoracic and abdominal effort, oxygen
circadian rhythm sleep work), behaviorally induced insufficient saturation, nasal/oral airflow, and body
disorders and insomnia.
sleep, or inadequate sleep hygiene. position. Use of a microphone to
record snoring is recommended but
OBJECTIVE MEASURES not required.34 A full, 16-lead EEG
Nocturnal polysomnography (NPSG) (Figure 2-11)35 and video recording
or related assessments are indicated may be performed when nocturnal
for the diagnosis and assessment of seizures are suspected. Leg surface
SDB, and for positive airway titration EMG leads are recommended, and
in patients with confirmed SDB. The additional arm EMG leads may be
procedure can also provide information applied when the clinical history sug-
about EEG activity, nocturnal move- gests complex sleep-related motor be-
ments, cardiac rhythm, and oxygen haviors, such as dream enactment. In
FIGURE 2-10 A 1-minute epoch from a nocturnal polysomnogram showing obstructive sleep
apnea in a 46-year-old man who presented with snoring, daytime sleepiness,
and headaches. It depicts the standard recording montage that includes the
following leads: central (C3-M2, C4-M1), frontal (F3-M2, F4-M1), and occipital (O1-M2, O2-M1)
EEGs; left and right eye electrooculograms (E1-M2, E2-M1); mental/submental electromyogram
(Chin1-Chin2); electrocardiogram (ECG1-ECG2, ECG2-ECG3); snore volume (SNORE); nasal
pressure transducer (NPRE); nasal/oral airflow (N/O); thoracic (THOR) and abdominal (ABD)
effort; arterial oxyhemoglobin saturation (SpO2); plethysmography (Pleth); and left and right eye
electromyograms (LAT1-LAT2, RAT1-RAT2).

KEY POINT
h The complex
classification of portable
testing devices reflects
the multitude of designs
available to clinicians
and will undoubtedly
change as technology
advances.
FIGURE 2-11 A, The international 10Y20 system for EEG electrode placement refers to the
10% and 20% interelectrode distances. Even electrode numbers (2, 4, 6, 8)
represent the right hemisphere, and odd electrode numbers (1, 3, 5, 7)
represent the left hemisphere. B, Recommended F4-M1, C4-M1, O2-M1 placements of EEG
electrodes as set forth by the American Academy of Sleep Medicine (AASM).
Adapted from Iber C et al, American Academy of Sleep Medicine.35 Used with permission of the American Academy of
Sleep Medicine, Darien, IL, 2012.
most cases the diagnostic NPSG is done lar, oximetry, position, effort, and res-
on 1 night, although NPSG on 2 con- piratory parameters.36 Within each of
secutive nights may be considered in the six SCOPER categories, a level of 0
the evaluation of parasomnias. through 5 is assigned as indicated by
Four categories of sleep monitoring the type of sensor or measurement
devices for use in the diagnosis of sleep that the device uses for that category.
disorders have often been described.34 The most recent clinical guidelines,
These are type 1, standard, attended, in- published by the Portable Monitoring
laboratory polysomnography; type 2, Task Force of the AASM37 for use of
comprehensive portable, unattended unattended portable monitoring in
polysomnography; type 3, modified the diagnosis of OSA in adult patients,
portable sleep apnea testing (often car- recommend that portable monitoring
diorespiratory studies that do not record only be performed in conjunction with
sleep); and type 4, continuous single or a comprehensive sleep evaluation by
dual bioparameter recording (eg, pulse (or supervised by) a practitioner board-
oximetry). However, this categorization certified in sleep medicine or eligible
may not effectively classify the plethora for the certification examination. These
of out-of-center testing devices currently guidelines state that portable monitor-
available for clinical use. Therefore, a ing may be used in place of NPSG in
new device classification system has patients with a high pretest probability
recently been proposed. This schema, of moderate to severe OSA. Portable
known as the SCOPER system, catego- monitoring should not be used in
rizes out-of-center testing devices based patients with significant medical comor-
on measurement of sleep, cardiovascu- bidities (including, but not limited to,

KEY POINT
h Careful consideration moderate to severe pulmonary disease, The aforementioned testing proce-
should be given to neuromuscular disease, or congestive dures are primarily used in the evalua-
the indications for heart failure), in patients with other tion of SDB. Other testing modalities
out-of-center testing. sleep disorders (including central sleep are useful in the diagnosis of other
Attended nocturnal apnea, periodic limb movement disor- categories of sleep disorders. The mul-
polysomnography is der, insomnia, parasomnias, circadian tiple sleep latency test (MSLT) and its
indicated if a portable rhythm disorders, or narcolepsy), or as variant, the maintenance of wakefulness
study yields a negative a screening tool. The use of portable test (MWT), are used in the evaluation of
or technically monitoring may be indicated for the hypersomnia. The conventional record-
inadequate result. diagnosis of OSA in patients for whom ing montage is similar to that used for
attended NPSG is not possible because nocturnal polysomnography: central, fron-
of immobility, safety, or critical illness. tal, and occipital EEGs, left and right eye
Portable monitoring may be indi- electrooculograms, mental/submental
cated to monitor the response to non- EMG, and ECG leads. Measurement of
continuous positive airway pressure thoracic and abdominal effort, oxygen
treatments for OSA, including oral saturation, and nasal/oral airflow are not
appliances, upper airway surgery, and required but may help explain delayed
weight loss. The algorithm shown in sleep latencies for patients in whom
Appendix B may help in the determi- respiratory disturbances interfere with
nation of an adult patients candidacy sleep onset.
for out-of-center testing for the diag- The MSLT is a validated tool that is
nosis of OSA. An example of portable considered the de facto standard for
(or home) monitoring technology is objective assessment of excessive day-
shown in Supplemental Digital Con- time sleepiness.38 The recommended
tent 2-1, links.lww.com/CONT/A15. protocol38 involves five 20-minute nap
Recommended technology for port- opportunities held at 2-hour intervals
able monitoring should record, at mini- throughout the day. If sleep is ob-
mum, airflow, respiratory effort, and served, the patient is allowed to sleep
blood oxygenation; the airflow, effort, for at least 15 minutes. The sleep la-
and oximetric biosensors typically used tency for each nap is measured as the
for attended NPSG should be used.37 time from the start of the nap trial to
These guidelines, published in 2007, the first epoch of sleep. A sleep la-
will likely continue to evolve as new tency of 20 minutes is assigned to nap
technologies emerge and are found to trials during which no sleep is
be effective. The current guidelines observed.39 The mean sleep latency,
recommend that out-of-center testing calculated as the average sleep latency
be performed under the auspices of an across all nap trials, is the final result.
AASM-accredited comprehensive sleep The presence and number of sleep-
medicine program and that a board- onset REM periods (SOREMPs) is also
certified/eligible sleep specialist review determined, as this information can
the raw data from a portable monitor- help to establish a diagnosis of narco-
ing device. All patients who undergo lepsy without cataplexy or to confirm
portable monitoring for the diagnosis of narcolepsy with cataplexy.
OSA should have a follow-up visit to The MSLT should be started 1.5 to
review test results. Negative or techni- 3.0 hours following completion of a
cally inadequate portable monitoring nocturnal polysomnogram, which
studies should be followed by attended, should record at least 6 hours of sleep
in-laboratory NPSG if the clinical suspi- in order for determination of the mean
cion for SDB remains high.37 sleep latency to be valid. Drugs that may

KEY POINTS
interfere with sleep latency or REM la- assessment of OSA syndrome or to h The multiple sleep
tency should be discontinued 2 weeks assess response to treatment of SDB, latency test is the gold
before testing, whenever possible. A and is not routinely indicated for eval- standard for objective
screen may be performed on the day of uation of sleepiness in medical or assessment of daytime
testing if there is suspicion that pre- neurologic disorders (except for narco- sleepiness, but
scribed or illicit substances may con- lepsy), insomnia, or circadian rhythm interpretation of the
tribute to the patients sleepiness.38 disorders. results must be made
No large, multicenter, systematically The MWT provides an objective meas- within the clinical
collected normative data are available ure of a patients ability to remain awake, context of the patients
for mean sleep latency values on the rather than the tendency to fall asleep, history.
MSLT.38 Nonetheless, a mean sleep la- during the day. The key difference h In the multiple sleep
tency of greater than 10 minutes is of- between the MWT and the MSLT is that latency test, the patient
ten considered normal, whereas a mean in the former, the patient is asked to try is instructed to try to
sleep latency of 8 to 10 minutes is con- to stay awake under circumstances con- sleep during each nap
trial. In the maintenance
sidered a physiologic gray zone.40 The ducive to sleep, rather than to fall asleep.
of wakefulness test, the
normative data for children are classi- The MWT provides an objective, vali-
patient is instructed to
fied by Tanner stage of development, dated assessment of the ability to remain try to remain awake
though the MSLT is typically not per- awake for a defined length of time.38 The during the nap trial.
formed in children aged younger than 6 recommended protocol includes four
h A baseline nocturnal
or 7 years because some daytime nap- 40-minute trials that begin at 2-hour
polysomnogram is
ping may still be normal in young intervals, with the first trial to start 1.5 to required before a
children.41 The second edition of the 3.0 hours after the patients wake-up multiple sleep latency
International Classification of Sleep time. A nocturnal polysomnogram on test and considered, but
Disorders: Diagnostic and Coding the preceding night is not required. not required, before a
Manual (ICSD-2)42 requires the pres- However, the patient should obtain a maintenance of
ence of a mean sleep latency of less sufficient amount of sleep during the wakefulness test.
than 8 minutes and two or more night before the MWT. Each trial is
SOREMPs as part of the diagnostic terminated after 40 minutes if no sleep
criteria for narcolepsy without cata- occurs, or after unequivocal sleep onset
plexy. However, the ICSD-2 also notes (defined as three continuous epochs
that a mean sleep latency of less than 8 of stage N1 sleep or one epoch of any
minutes may occur in up to 30% of the other stage of sleep) has occurred.38
general population. Therefore, while One indication for the MWT is to as-
the MSLT is a helpful and widely used sess an individuals ability to remain
tool, it remains an imperfect gold stand- awake when his or her inability to re-
ard in the assessment of daytime sleepi- main awake constitutes a public or
ness. This necessitates that the personal safety issue. This can become
evaluation of daytime sleepiness not a pressing issue for individuals em-
rest on the MSLT results alone but ployed in the transportation,43 con-
assimilate the clinical history, subjective struction, or health care industries.
complaints, diagnostic study results, and The MWT may be indicated to assess
other pertinent medical information.38 treatment response in patients with
Practice parameters from the known excessive daytime sleepiness.
AASM state that the MSLT is indicated Limited amounts of normative data
for diagnostic confirmation of sus- are available for the MWT. Historically,
pected narcolepsy and may be indi- multiple testing protocols make syn-
cated to differentiate idiopathic thesis of results more challenging. The
hypersomnia from narcolepsy.38 The MWT is used much less often in clinical
MSLT is not indicated for routine practice compared to the MSLT. Patient

KEY POINTS
h Actigraphy can be age may also affect the mean sleep la- mation about the patients sleep pat-
useful in evaluation and tency values on both the MWT and the tern or response to treatment. When
treatment of circadian MSLT43 and may represent evolution of polysomnography is not available,
rhythm sleep disorders circadian rhythm and sleep architec- actigraphy is indicated to estimate total
and in management of ture across the lifetime. A study of 383 sleep time in patients with OSA.45
insomnia. patients with narcolepsy with cataplexy
h Neuroimaging is not examined the clinical and polysomno- OTHER ASSESSMENT
routinely indicated in graphic data at the time of diagnosis MODALITIES
the clinical evaluation of (age range 5 to 84 years) and found a Laboratory evaluation and neuroimag-
sleep disorders and progressive decrease in the number of ing with either CT or MRI may be
should be pursued on a SOREMPs and a progressive increase in considered on an individual basis as
case-by-case basis. the mean sleep latency on the MSLT as indicated by the clinical history. Com-
a function of age.44 Given its limita- plete blood count (CBC), serum chem-
tions, the MWT may thus be used to istries, or measures of thyroid function
supplement the clinical history in the may be obtained if an underlying med-
assessment of ability to stay awake but ical disorder is thought to contribute to
should not be the sole determinant of the patients sleep symptoms. For
this parameter. instance, these laboratory studies may
Actigraphy is also used in the clinical be considered when daytime fatigue is a
evaluation of patients with sleep disor- predominant symptom. Serum iron
ders, particularly circadian rhythm sleep studies, including ferritin level, should
disorders. An actigraph is a watchlike be checked in patients with restless legs
device that is worn on the wrist for an syndrome.46 Neuroimaging should be
extended period, usually in the range of considered in patients with antecedent
weeks. The actigraph records move- trauma, or for any sleep disorder pa-
ment and uses an algorithm to estimate tient with an abnormal neurologic ex-
the amounts of sleep and wake time amination, to evaluate for a structural
during the recording period. Analysis etiology of the patients symptoms.
software uses movement to estimate
when sleep and wakefulness have APPROACH TO THE PATIENT
occurred. Review of the data can pro- Evaluation of suspected sleep disorders
vide objective insight into the patients is best accomplished by a stepwise,
sleep pattern, including timing and multidimensional approach (Case 2-2).
duration of major sleep disruptions. A thorough sleep history includes de-
Actigraphy is indicated as part of the tailed description of sleep-related symp-
evaluation of patients with advanced toms, nocturnal behaviors, the patients
sleep-phase syndrome, delayed sleep- sleep schedule, level of daytime sleepi-
phase syndrome, and shift work disor- ness, and subsequent effects on daytime
der and may be indicated in the evalua- functioning. Collateral history from the
tion of jet lag disorder and nonY24-hour patients bed partner or family is often
sleep-wake syndrome, including that necessary to understand the severity and
associated with blindness.45 It can also context of the patients symptoms. Sub-
serve as a measure of treatment re- jective assessments of sleepiness, such
sponse in patients with insomnia and as the Epworth Sleepiness Scale, are
circadian rhythm sleep disorders. For easily administered and useful to track
populations in which traditional sleep symptomatic progression or treatment
monitoring may be challenging, such response from one visit to the next.
as pediatric or older adult patients, Certain physical examination findings
actigraphy may provide valuable infor- may also raise clinical suspicion of

KEY POINT
Case 2-2 h Careful assimilation of

the clinical history, the
A 23-year-old woman reported a 4-year history of insomnia. Throughout
sleep-specific physical
college she was a night owl, never scheduled classes that started before
examination, patient
1:00 PM, and always did well in school. During the past 6 months, she
questionnaires, and
developed progressive difficulty staying awake in her job as a financial
diagnostic test results
analyst and was concerned about how this might affect her job performance.
leads to the most
During the week she was in bed by midnight but was unable to fall
accurate assessment of
asleep until 2:00 AM and awoke with difficulty to an alarm at 6:00 AM,
patients with symptoms
feeling tired. She denied any thought rumination or physical discomfort
related to sleep or
at bedtime. She had tried over-the-counter sleep aids that provided no
alertness.
symptomatic improvement and worsened morning grogginess. On
weekends she slept from 2:00 AM to 11:00 AM and awakened feeling
pretty good. She had nocturia up to once per night and occasional
morning headaches. She had no bed partner but reported gasping
respirations, nocturnal palpitations, and snort arousals. On about 4 nights
per week, she experienced a sensation of needing to move her legs
while trying to fall asleep. This sensation was relieved by movement and
was worse at night than during the day. Her legs sometimes moved
spontaneously at night or while seated quietly for long periods during
the day. She felt sleepy during the afternoon, especially while working
at her computer. She denied drowsiness while driving. She occasionally
took a 30-minute nap on the weekend and found it to be refreshing.
She drank one to two cups of coffee every morning and had a 12-oz diet
caffeinated soda at 3:00 PM. Her sleepiness had not caused her to make
any mistakes at work, and she denied any mood disturbance.
Physical examination was notable for a body mass index of 32 kg/m2, neck
circumference of 38.1 cm (15 in), and modified Mallampati class III oral airway.
Nasal passages were narrow with turbinate hypertrophy bilaterally, and
hard palate was high-arched and narrow. No micrognathia or retrognathia was
present. She had molar occlusion class I bilaterally with no overjet or overbite.
The general, cardiac, respiratory, and neurologic examinations were normal.
Comment. This case illustrates how discussion of the chief complaint raises
suspicion for multiple sleep disorders. The history suggests a circadian rhythm
sleep disorder, particularly delayed sleep-phase syndrome, sleep-disordered
breathing, and restless legs syndrome. Diagnostic evaluation should include
nocturnal polysomnogram with consideration to perform testing at the patients
preferred sleep time, and serum iron studies. Sleep diaries and/or actigraphy
may be considered for further assessment of the patients sleep pattern.
particular sleep disorders. For patients phy may be considered to better char-
in whom multiple sleep disorders are acterize the patients sleep pattern.
suspected, systematic use of diagnostic Actigraphy may then again be pursued
testing allows for accurate identification to gauge treatment response upon man-
of specific diagnoses. In a patient with agement of the patients insomnia.
insomnia and symptoms suggestive of The diagnostic modalities available
SDB, nocturnal polysomnography should for evaluation of sleep disorders are
be the first procedure performed. If rapidly evolving. In-laboratory nocturnal
the insomnia persists despite adequate polysomnography currently remains the
treatment of SDB, further evaluation gold standard for assessment of SDB.
with sleep diaries and possibly actigra- However, the multitude of out-of-center

testing devices continues to grow, and 7. Ebben MR, Spielman AJ.

Non-pharmacological treatments for
many may provide useful alternatives insomnia. J Behav Med 2009;32(3):244Y254.
that under appropriate circumstances
8. Roth T. Insomnia: definition, prevalence,
could allow more expedient, conven- etiology, and consequences. J Clin Sleep
ient, and less costly evaluations of Med 2007;3(5 suppl):S7YS10.
increased numbers of patients who 9. Yang CM, Spielman AJ, Glovinsky P.
previously had only limited or delayed Nonpharmacologic strategies in the
access to sleep services. management of insomnia. Psychiatr Clin
North Am 2006;29(4):895Y919; abstract viii.
VIDEO LEGEND 10. Katz ES, DAmbrosio CM. Pediatric

Supplemental Digital Content 2-1 obstructive sleep apnea syndrome. Clin
Chest Med 2010;31(2):221Y234.
Home sleep study. Video demonstrates a home
sleep study using an unattended type 3 portable 11. Kohler M, Bloch KE, Stradling JR. The role of
monitoring device. The patient is a 56-year-old the nose in the pathogenesis of obstructive
sleep apnea. Curr Opin Otolaryngol Head
man who is experiencing morning headaches
Neck Surg 2009;17(1):33Y37.
and concentration and alertness problems at
work. He has a history of mild snoring and ar- 12. Kryger MH. Atlas of clinical sleep medicine.
terial hypertension. His Epworth Sleepiness Philadelphia, PA: Elsevier, 2010.
Scale score is 18, his neck circumference is 13. Zonato AI, Martinho FL, Bittencourt LR,
19 in, he has a Mallampati classification score of et al. Head and neck physical examination:
III, and his body mass index is 41 kg/m. The comparison between nonapneic and
apnea-hypopnea index is 84 events/h. Channels obstructive sleep apnea patients.
recorded in this sleep study include arterial Laryngoscope 2005;115(6):1030Y1034.
oxyhemoglobin saturation, heart rate, oral-nasal 14. Mallampati SR, Gatt SP, Gugino LD, et al.
pressure flow, snoring, inductive plethysmog- A clinical sign to predict difficult tracheal
raphy for chest efforts, and body position. intubation: a prospective study. Can Anaesth
links.lww.com/CONT/A15 Soc J 1985;32(4):429Y434.
B 2013 Marcel Hungs, MD, PhD. Used with 15. Samsoon GL, Young JR. Difficult tracheal
permission. intubation: a retrospective study.
Anaesthesia 1987;42(5):487Y490.
REFERENCES 16. Huang HH, Lee MS, Shih YL, et al.

Modified Mallampati classification
1. National Institutes of Health: National
as a clinical predictor of peroral
Center on Sleep Disorders Research.
esophagogastroduodenoscopy tolerance.
Sleep disorders research plan.
BMC Gastroenterol 2011;11:12.
www.nhlbi.nih.gov/health/prof/sleep/
201101011NationalSleepDisordersResearch- 17. Friedman M, Ibrahim H, Bass L. Clinical
PlanDHHSPublication11-7820.pdf. Published staging for sleep-disordered breathing.
November 2011. Otolaryngol Head Neck Surg 2002;127(1):
13Y21.
2. Dinges DF. An overview of sleepiness and
accidents. J Sleep Res 1995;4(S2):4Y14. 18. Cheng RHW, Yiu CKY, Leung WK.
Oral health in individuals with Down
3. Mills RJ, Young CA. A medical definition
syndrome. In: Dey S, ed. Prenatal diagnosis
of fatigue in multiple sclerosis. QJM 2008;
and screening for down syndrome.
101(1):49Y60.
InTech. www.intechopen.com/books/
4. Chervin RD. Sleepiness, fatigue, tiredness, howtoreference/prenatal-diagnosis-and-
and lack of energy in obstructive sleep screening-for-down-syndrome/oral-health-
apnea. Chest 2000;118(2):372Y379. in-individuals-with-down-syndrome.
Published 2011. Accessed August 24, 2012.
5. Chotinaiwattarakul W, OBrien LM, Fan L,
Chervin RD. Fatigue, tiredness, and lack of 19. Katz I, Stradling J, Slutsky AS, et al. Do
energy improve with treatment for OSA. patients with obstructive sleep apnea
J Clin Sleep Med 2009;5(3):222Y227. have thick necks? Am Rev Respir Dis
1990;141(5 pt 1):1228Y1231.
6. American Academy of Sleep Medicine.
The international classification of sleep 20. Kushida CA, Efron B, Guilleminault C. A
disorders: diagnostic and coding manual. predictive morphometric model for the
2nd ed. Westchester, IL: American Academy obstructive sleep apnea syndrome. Ann
of Sleep Medicine, 2005. Intern Med 1997;127(8 pt 1):581Y587.

21. Saccucci M, Tettamanti L, Mummolo S, et al. 35. Iber C, Ancoli-Israel S, Chesson A, et al.
Scoliosis and dental occlusion: a review of The AASM manual for scoring of sleep and
the literature. Scoliosis 2011;6:15. associated events: rules, terminology and
technical specifications. 1st ed. Westchester,
22. Battagel JM, Kotecha B. Dental side-effects
IL: American Academy of Sleep Medicine,
of mandibular advancement splint wear in
2007.
patients who snore. Clin Otolaryngol
2005;30(2):149Y156. 36. Collop NA, Tracy SL, Kapur V, et al.
Obstructive sleep apnea devices for
23. Morcos SS, Patel PK. The vocabulary of
out-of-center (OOC) testing: technology
dentofacial deformities. Clin Plast Surg
evaluation. J Clin Sleep Med 2011;7(5):
2007;34(3):589Y599.
531Y548.
24. Epstein LJ, Kristo D, Strollo PJ Jr, et al.
37. Collop NA, Anderson WM, Boehlecke B,
Clinical guideline for the evaluation,
et al. Clinical guidelines for the use of
management and long-term care of
unattended portable monitors in the
obstructive sleep apnea in adults. J Clin
diagnosis of obstructive sleep apnea in adult
Sleep Med 2009;5(3):263Y276.
patients. Portable Monitoring Task Force
25. Johns MW. A new method for measuring of the American Academy of Sleep
daytime sleepiness: the Epworth sleepiness Medicine. J Clin Sleep Med 2007;3(7):
scale. Sleep 1991;14(6):540Y545. 737Y747.
26. Johns MW. Daytime sleepiness, snoring, and 38. Littner MR, Kushida C, Wise M, et al.
obstructive sleep apnea. The Epworth Standards of Practice Committee of the
Sleepiness Scale. Chest 1993;103(1):30Y36. American Academy of Sleep Medicine.
Practice parameters for clinical use of the
27. Chervin RD, Aldrich MS. The Epworth
multiple sleep latency test and the
Sleepiness Scale may not reflect objective
maintenance of wakefulness test. Sleep
measures of sleepiness or sleep apnea.
2005;28(1):113Y121.
Neurology 1999;52(1):125Y131.
39. Carskadon MA, Dement WC, Mitler MM,
28. Buysse DJ, Reynolds CF 3rd, Monk TH,
et al. Guidelines for the multiple sleep
et al. The Pittsburgh Sleep Quality Index: a
latency test (MSLT): a standard measure of
new instrument for psychiatric practice and
sleepiness. Sleep 1986;9(4):519Y524.
research. Psychiatry Res 1989;28(2):193Y213.
40. van den Hoed J, Kraemer H, Guilleminault C,
29. Chervin RD, Hedger K, Dillon JE, Pituch KJ.
et al. Disorders of excessive daytime
Pediatric sleep questionnaire (PSQ): validity
somnolence: polygraphic and clinical data
and reliability of scales for sleep-disordered
for 100 patients. Sleep 1981:4(1):23Y37.
breathing, snoring, sleepiness, and behavioral
problems. Sleep Med 2000;1(1):21Y32. 41. Hoban TF, Chervin RD. Assessment of
sleepiness in children. Semin Pediatr
30. Chung F, Yegneswaran B, Liao P, et al. STOP
Neurol 2001;8(4):216Y228.
questionnaire: a tool to screen patients for
obstructive sleep apnea. Anesthesiology 42. ICSD-2. The international classification of
2008;108(5):812Y821. sleep disorders pocket version: diagnostic
and coding manual. 2nd ed. Westchester,
31. Walters AS, LeBrocq C, Dhar A, et al.
IL: American Academy of Sleep Medicine,
Validation of the International Restless Legs
2005.
Syndrome Study Group rating scale for
restless legs syndrome. Sleep Med 2003; 43. Arand D, Bonnet M, Hurwitz T, et al.
4(2):121Y132. The clinical use of the MSLT and MWT.
Sleep 2005;28(1):123Y144.
32. Bastien CH, Vallieres A, Morin CM.
Validation of the Insomnia Severity Index 44. Dauvilliers Y, Gosselin A, Paquet J, et al.
as an outcome measure for insomnia Effect of age on MSLT results in patients
research. Sleep Med 2001;2(4):297Y307. with narcolepsy-cataplexy. Neurology
2004;62(1):46Y50.
33. YOURSLEEP.aasmnet.org from the American
Academy of Sleep Medicine. Two week 45. Morgenthaler T, Alessi C, Friedman L,
sleep diary. yoursleep.aasmnet.org/pdf/ et al. Practice parameters for the use of
sleepdiary.pdf. Accessed August 24, 2012. actigraphy in the assessment of sleep and
sleep disorders: an update for 2007. Sleep
34. Kushida CA, Littner MR, Morgenthaler T,
2007;30(4):519Y529.
et al. Practice parameters for the indications
for polysomnography and related 46. Gamaldo CE, Earley CJ. Restless legs
procedures: an update for 2005. Sleep syndrome: a clinical update. Chest
2005;28(4):499Y521. 2006;130(5):1596Y1604.

Review Article
Chronic Insomnia
Dr David N. Neubauer, Johns
Hopkins Bayview Medical
Center, 4940 Eastern Ave,
Box 151, Baltimore, MD David N. Neubauer, MD
21224, neubauer@jhmi.edu.
Dr Neubauer serves on the
advisory board of Purdue
Pharma.
ABSTRACT
Unlabeled Use of Purpose of Review: This article provides an overview of current strategies for
Products/Investigational evaluating and treating patients who experience chronic insomnia.
Use Disclosure:
Dr Neubauer reports no
Recent Findings: The US Food and Drug Administration (FDA) has approved several
disclosure. medications for the treatment of insomnia that incorporate a variety of pharmacody-
* 2013, American Academy namic and pharmacokinetic properties, thus allowing the development of a cus-
of Neurology. tomized therapeutic approach. FDA-approved medications include +-aminobutyric
acidYmodulating benzodiazepine receptor agonists, a melatonin receptor agonist,
and a histamine receptor agonist. Psychological and behavioral techniques combined
as cognitive-behavioral therapy also have been shown to be effective in the treat-
ment of chronic insomnia.
Summary: Insomnia is the most common sleep disturbance and represents a chronic
condition for many people. Difficulty falling asleep and maintaining sleep are highly
prevalent problems in patients with neurologic disorders. Multiple factors typically
contribute to insomnia. Accordingly, a rather broad approach to evaluating patients
is warranted. Evidence-based guidelines support the use of cognitive and behavioral
strategies and selected medications in the treatment of patients with chronic
insomnia.
INTRODUCTION broader roles in promoting wellness

Insomnia is among the most commonly and bringing about improvements in
reported clinical complaints in general some comorbid conditions. In fact, neu-
medicine and is highly prevalent in rologists should educate all patients
patients treated in neurology prac- about the importance of getting ade-
tices.1,2 Sleep disturbances often result quate sleep and address their sleep
from multiple causes and may neces- problems, just as patients are encour-
sitate multimodal management for aged to improve other aspects of a
eventual success, and by employing healthy lifestyle, such as diet and exercise.
established evaluation guidelines and
evidence-based therapies, it should be WHAT IS INSOMNIA?
possible to help most patients with Most basically, an insomnia disorder is
insomnia achieve significant improve- persistent difficulty falling asleep or
ments in their sleep.3 Addressing the remaining asleep, with some element
sleep concerns of these patients can of daytime impairment that is presum-
have a considerable effect on improving ably related to the sleep problem.
their sense of well-being and the quality Contemporary views conceptualize
of their lives. Emerging evidence docu- chronic insomnia as a 24-hour condition
ments that poor sleep is associated with that may involve hyperarousal, leading
a wide range of negative health out- to both the nighttime and daytime
comes; therefore, enhancement of symptomatology.4 Several nosologies
sleep quantity and quality may have offer criteria for insomnia and specific

KEY POINTS
insomnia diagnoses. While the fourth asleep, problems remaining asleep, h Poor sleep, whether due
edition of the Diagnostic and Statisti- awakening excessively early, or a sense to inadequate quality or
cal Manual of Mental Disorders (DSM- of sleep that is not refreshing. This quantity, increases the
IV) (and evolving DSM-V) and the inadequate sleep must be in the con- risk for multiple chronic
International Classification of Diseases, text of the patient having had the comorbid health
Ninth Revision (ICD-9) and ICD-10 in- opportunity to be sleeping. Patients conditions.
corporate useful categorizations of may describe various patterns of de- h Wellness promotion
sleep disorders, including various types layed sleep onset, multiple brief or should include good
of insomnia, the most comprehensive extended awakenings, and a feeling quality sleep along with
organization of insomnia is outlined in that their sleep is very light and easily a healthy diet and
the International Classification of interrupted. Often, concern about the exercise plan.
Sleep Disorders: Diagnostic and Cod- daytime consequences motivates peo- h The diagnosis of
ing Manual, Second Edition: Diagnos- ple to seek help for their inadequate insomnia requires some
tic and Coding Manual (ICSD-2), sleep. These daytime complaints very degree of daytime
although a third edition currently is in often are fatigue and poor concentra- impairment in addition
development. The ICSD-2 defines gen- tion but also may include low mood to persistent difficulty
eral criteria for insomnia (Table 3-1) and irritability, poor motivation, low falling asleep or
energy, various physical symptoms, remaining asleep.
and specific criteria for 11 individual in-
somnia disorders (Table 3-2). and an increased tendency to make h Insomnia currently is
The general ICSD-2 insomnia criteria mistakes. Patients with chronic insom- conceptualized as a
include required nighttime and day- nia typically worry greatly about their disorder of the wake
time elements.5 The nighttime sleep inability to sleep well and the negative system resulting in
round-the-clock
complaint may involve difficulty falling impact it has on their lives. The criteria
hyperarousal.
TABLE 3-1 International Classification of Sleep Disorders, Second

Edition: Diagnostic and Coding Manual Diagnostic
Criteria for General Insomniaa
A. A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking

up too early, or sleep that is chronically nonrestorative or poor in quality. In
children, the sleep difficulty is often reported by the caretaker and may consist of
observed bedtime resistance or inability to sleep independently.
B. The above sleep difficulty occurs despite adequate opportunity and
circumstances for sleep.
C. At least one of the following forms of daytime impairment related to the
nighttime sleep difficulty is reported by the patient:
1. Fatigue or malaise
2. Attention, concentration, or memory impairment
3. Social or vocational dysfunction or poor school performance
4. Mood disturbance or irritability
5. Daytime sleepiness
6. Motivation, energy, or initiative reduction
7. Proneness for errors or accidents at work or while driving
8. Tension, headaches, or gastrointestinal symptoms in response to sleep loss
9. Concerns or worries about sleep
a
Reprinted from American Academy of Sleep Medicine.5 Used with permission of the American
Academy of Sleep Medicine, Darien, IL, 2012.

Chronic Insomnia
KEY POINTS
h During the daytime TABLE 3-2 International Classification of Sleep Disorders, Second
most patients with Edition: Diagnostic and Coding Manual Diagnostic Criteria
chronic insomnia feel for Specific Insomnia Disordersa
fatigued but not sleepy.
h Chronic insomnia 1. Adjustment insomnia
associated with daytime 2. Psychophysiological insomnia
consequences affects 3. Paradoxical insomnia
about one in 10 adults. 4. Idiopathic insomnia
5. Insomnia due to mental disorder
6. Inadequate sleep hygiene
7. Behavioral insomnia of childhood
8. Insomnia due to drug or substance
9. Insomnia due to medical condition
10. Insomnia not due to substance or known physiologic condition, unspecified
11. Physiologic insomnia, unspecified
a
Reprinted from American Academy of Sleep Medicine.5 Used with permission of the American
options for daytime consequences are poor sleep and accompanying distress
listed in Table 3-1. It is interesting that continue, people may develop malad-
patients with chronic insomnia rarely aptive behaviors (eg, increased daytime
describe excessive daytime sleepiness. caffeine intake, bedtime alcohol, and
Often it is just the opposite: they excessive time in bed) that contribute
describe a pleasant past when they to continued sleep difficulty, and they
were able to nap but now find that it is may develop a psychologically con-
frustratingly impossible to catch up on ditioned arousal associated with the
sleep during the daytime. Perhaps this bedroom and bedtime routines that
is a manifestation of a hypothesized perpetuates the insomnia.
round-the-clock hyperarousal process. For many patients, insomnia is a
The prevalence of insomnia varies nightly problem that persists from
with the population.1 Women and older months to years, although any temporal
adults are at somewhat greater risk for patterns are possible: people may have
insomnia. In the general population recurrent insomnia episodes lasting
about one of three adults reports at weeks to months interspersed with
least occasional symptoms of insomnia, relatively good sleep, or they may have
while roughly one of 10 has chronic intermittent sleep difficulty several
symptoms with reports of daytime nights each week or month. In some
consequences. It is common for brief cases the sleep disturbance is seemingly
insomnia episodes to have identifiable random in occurrence and duration,
precipitants, such as situational crises, and for others it is highly predictable
schedule changes, acute health prob- in association with work or social
lems, and medication changes. Chronic schedules or in relation to physiologic
insomnia, persisting for at least 1 changes, as with the menstrual cycle.
month, often has a more complex eti- Insomnia may be described as primary
ology with multiple predisposing and insomnia and conceptualized as an
precipitating factors and processes that independent disorder when no con-
perpetuate the insomnia over time. As comitant disorders seem to contribute

KEY POINTS
to the sleep disturbance. In contrast, a ducive to sleep. Behavioral insomnia h Patients with chronic
patient with sleep difficulty presumably of childhood is reserved for sleep insomnia frequently
influenced by the presence of another difficulties in children and incorporates have comorbid
disorder, such as major depression, sleep-onset association and limit- conditions associated
fibromyalgia, substance abuse, or ob- setting subtypes. Examples include per- with their sleep
structive sleep apnea, may be viewed as sistent problems when children are disturbance.
having a comorbid type of insomnia. unable to fall asleep independently or h Use a comprehensive
The ICSD-2 psychophysiological, para- routinely stall attempts to fall asleep. approach in evaluating
doxical, and idiopathic insomnias are The insomnia due to a mental dis- chronic insomnia; the
examples of primary insomnia. order and insomnia due to a medi- etiology is multifactorial
According to the ICSD-2 nosology, cal condition diagnoses assume the for most patients.
patients meeting the general insomnia presence of the associated condition
criteria (Table 3-1) can be diagnosed and a clear temporal association with
with one of the specific insomnia the sleep disturbance, and generally are
disorders (Table 3-2). Each of the used when the insomnia is severe
insomnia disorders has associated cri- enough to warrant independent treat-
teria. Adjustment insomnia occurs in ment. Insomnia due to a drug or sub-
temporal relationship with an identifi- stance represents sleep problems clearly
able stressor and lasts less than 3 temporally associated with the intoxica-
months. Sleep should improve with tion or withdrawal from a wide range of
the resolution of the stressor. In some medications or abuse substances.
cases, adjustment insomnia may evolve
into a chronic form and warrant a new EVALUATION
insomnia diagnosis. People with psy- The best general advice for considering
chophysiological insomnia experience the causes of a patients insomnia is to
conditioned heightened arousal associ- think very broadly about the etiology
ated with the bed, bedroom, and bed- and expect multiple factors that may
time routines. Learned sleep-preventing predispose the person to sleep difficulty,
associations perpetuate the sleep diffi- precipitate an insomnia episode, and
culty in this chronic form of insomnia. perpetuate the sleep disturbance over
The diagnosis of paradoxical insom- time.3,6 Whatever triggered the sleep
nia may be applied in situations where difficulty is not necessarily what cur-
a clear mismatch occurs between the rently contributes to persistent symp-
patients description of severe sleep toms. The clinical guidelines for
difficulty compared with objective evi- evaluating insomnia published by the
dence of apparently adequate sleep. American Academy of Sleep Medicine
Idiopathic insomnia refers to per- emphasize the essential role of the
sistent insomnia without identifiable patient history, focusing not just on
precipitants that begins insidiously in the specific sleep-related symptoms but
childhood and continues chronically also on possible psychiatric, medical,
into adulthood. The inadequate sleep and substance use disorders. Whenever
hygiene diagnosis may be applied when possible, a bed partner or other family
patients engage in behaviors that would member should be interviewed to
be expected to interfere with normal provide information regarding the pa-
sleep. These detrimental behaviors tients snoring, breathing irregularities,
may include sleep-wake schedule or any sleep-related movement or
problems, use of sleep-disrupting sub- behavioral abnormalities. Patient-
stances, and evening routines or a completed questionnaires and sleep
bedroom environment that is not con- logs or diaries can supplement the

Chronic Insomnia
KEY POINTS
h Sleep logs and insomnia patient evaluation. A log or management may require several con-
questionnaires completed diary covering several weeks can be current strategies and in some cases a
by patients are very quite helpful in highlighting patterns of staged approach that may involve fur-
helpful in the insomnia sleep disturbance and are especially ther testing.3 The diversity of influences
evaluation process. useful to show where school or work on sleep and wakefulness makes a
h Sleep laboratory studies schedules affect the timing of sleep or universal treatment algorithm impossi-
are not routinely where circadian rhythm sleep-phase dis- ble. The management of insomnia must
performed in the orders influence the timing of insomnia be customized for individual patients. It
insomnia evaluation, symptoms. The comprehensive insom- is possible, however, to offer several
but they are invaluable nia evaluation also should include phys- general principles in the attempt to
for selected patients ical and mental status examinations. help patients achieve refreshing sleep
with risk factors for Sleep laboratory testing, while not a rou- and alertness at appropriate times
comorbid sleep tine element in the insomnia workup, throughout their sleep-wake cycles.
disorders. can be quite useful when there is sus- Overall, it is important to collaborate
h It is useful to establish picion that a concomitant sleep disorder with patients in developing clear treat-
clear goals with patients (eg, sleep-disordered breathing) may be ment goals regarding their nighttime
when treating their contributing to the insomnia symptoms. and daytime symptoms, monitor pa-
insomnia symptoms. Essential elements of the sleep history tients for therapeutic progress and
h Always consider the include the specific insomnia com- possible adverse effects, and revise the
potential influences of plaints, daytime activities and func- therapeutic plan as necessary.
sleep-disordered tioning, sleep-wake schedule routines, The chronic insomnia treatment plan
breathing and circadian and other sleep-related symptoms (eg, should address any comorbid condi-
rhythm sleep disorders
snoring, movements, and behaviors). tions revealed in the comprehensive
when evaluating
Questions should focus on the timing evaluation that are recognized as poten-
insomnia symptoms.
of the insomnia symptoms, estimates of tial factors undermining satisfactory
sleep onset and total sleep times, and sleep. Of course, it may not be possible
the frequency and character of awak- to eliminate comorbid medical and psy-
enings. Is the difficulty primarily sleep chiatric disorders, but attempts should
onset or sleep maintenance, or is it a be made to optimize their manage-
combination of the two? Further inqui- ment. For example, improved treatment
ries should target the evening routines of a pain syndrome, seizure disorder,
and bedroom setting. Are situational or Parkinson disease, asthma, and major
environmental variables apparent? Is depression may allow more consoli-
the patient taking medications or using dated sleep. It is especially important
substances that may affect sleep? Patients to identify and address other sleep
also should be asked about previous disorders that may cause insomnia
sleep difficulty and the results of any symptoms (Case 3-1). Common sleep
treatment approaches. disorders resulting in difficulty falling
asleep or remaining asleep include
TREATMENT obstructive sleep apnea and circadian
General Considerations phase disturbances (advanced or de-
The treatment of chronic insomnia is layed), although some other sleep dis-
often challenging. While a solution to a orders (eg, parasomnias) may present
patients inability to sleep soundly is primarily with insomnia complaints. It
sometimes a simple matter, more com- is not unusual for patients to seek help
monly multimodal approaches and clin- for severe insomnia symptoms and ex-
ical creativity are necessary. Since perience a complete resolution of their
insomnia may result from various pro- sleep difficulty as a result of being di-
cesses, often simultaneously, effective agnosed with obstructive sleep apnea

KEY POINT
Case 3-1 h Be sure to review the

complete list of a
A 63-year-old widow presented at the sleep clinic seeking a solution to the
insomnia she experienced for at least 5 years. She described occasional patients medications to
difficulty falling asleep but light and frequently interrupted sleep later identify possible
during the night. She never felt refreshed when she got out of bed in the sleep-disturbing effects.
morning. She estimated getting between 4 and 6 hours of sleep most
nights. During the daytime she usually felt fatigued, although she did
not experience inadvertent sleep episodes. She napped about once each
week. Her history was notable for depression 6 years before, at the time
of her husbands death. She took a selective serotonin reuptake inhibitor
antidepressant at that time but stopped a few years later. She denied
feeling depressed currently but admitted that she felt miserable because of
her sleep difficulty. Her medical history was notable for hypertension that
was well controlled with medication. She denied snoring. Her physical
examination was unremarkable, except for mildly elevated blood pressure
and a body mass index of 27 kg/m2. Because of her risk factors for
obstructive sleep apnea, a polysomnographic study was recommended.
The patient was seen for follow-up soon after the sleep study to review
the results, which demonstrated an apnea-hypopnea index of 45 events/h
associated with modest oxygen desaturations. (Apnea-hypopnea index
severity: four or fewer events per hour is considered normal; five to 15,
mild; 15 to 30, moderate; and more than 30, severe.) The sleep stage
distribution showed excess non-REM stage N1 sleep, representing 30%
of the 320 minutes that she slept. Frequent arousals and several brief
awakenings occurred during the study night. When shown the sleep study
results, she initially argued that the files had been mixed up because she
could not possibly have sleep apnea. She said that she was familiar with
sleep apnea because her obese brother slept with one of those masks
and youre not putting one on me. With further education and
encouragement she agreed to try nasal continuous positive airway pressure
treatment. The sleep center staff spent considerable time reassuring her
and helping her become familiar with the equipment. With continuous
positive airway pressure treatment, her sleep was much improved.
Comment. Sleep apnea should be on the treating physicians mental radar
in all patients presenting with insomnia, especially sleep maintenance
difficulty, but even with patients experiencing sleep-onset difficulty. No
treatment for insomnia will help until the apnea is treated.
and subsequently receiving continuous and marketing of caffeinated products.

positive airway pressure (CPAP) or re- Good general advice for patients with
lated treatments. insomnia is to avoid all caffeine past
An initial approach to treating insom- lunchtime, although some may need to
nia also must consider the potential discontinue using it completely. Reduc-
influence of any medications patients tion or elimination of evening alcohol
are taking and other substances they additionally may be necessary to im-
may be using regularly. It may be prove sleep quality and duration.
possible to recommend an alternate
medication or dosage timing that is less Education and Healthy
likely to interfere with sleep. Greater at- Sleep Habits
tention now must be given to caffeine The treatment of chronic insomnia be-
intake because of the growing diversity gins with patient education regarding

Chronic Insomnia
KEY POINT
h Strongly encourage basic processes that influence sleep and may be important for patients with
healthy sleep habits for ways to maximize the functioning of the insomnia. A relaxing evening routine
all patients. Primary natural mechanisms regulating the should enhance sleep onset, in con-
treatment modalities sleep-wake cycle.3 Ensuring that pa- trast to a flurry of evening activities
may fail if patients have tients follow sleep hygiene recommen- leading up to turning off the bedroom
irregular bedtime hours dations may not represent a cure for light with the expectation of a rapid
or drink excessive chronic insomnia, but attention to sleep onset. Although many people fall
caffeinated beverages. relevant behavioral and sleep environ- asleep while watching television, pa-
ment guidelines can help enhance tients with insomnia may find that the
sleep and provide an important foun- stimulation of viewing television has
dation for other therapeutic strategies. an immediate and sustained effect
A typical list of healthy sleep behaviors that undermines sleep onset. Exciting
is provided in Table 3-3.7 The patient drama and disturbing evening news
history will determine the initial focus may not be soporific. Moreover, view-
for suggested sleep hygiene changes. ing televisions and other screens (eg,
Generally, patients should attempt to laptops, video game devices, and smart
maintain regularity in their bedtime phones) may have the biological effect
and wake-up times, and they certainly of promoting a phase delay that could
should allocate sufficient time in bed further undermine the ability to fall
for adequate sleep. On the other hand, asleep at a desired time. The bedroom
excessive wakeful time in bed may environment should be relatively dark
reinforce frustrating arousal and per- and free of disturbing noises. White
petuate a conditioned association of noise from a bedside fan or a device
the sleep environment with sleepless- marketed to generate background
ness. Although routine napping may noise may be comforting and help
not be problematic for some individu- block out potentially arousing extrane-
als, avoiding afternoon or evening naps ous sounds. For most individuals, the
a
TABLE 3-3 Healthy Sleep Habits
b At Night
Use the bed and bedroom for sleep and sex only.
Establish a regular bedtime routine and a regular sleep/wake schedule.
Do not eat or drink too much close to bedtime.
Create a sleep-promoting environment that is dark, cool, and comfortable.
Avoid disturbing noises; consider a bedside fan or white-noise machine to
block out disturbing sounds.
b During the Day
Consume less or no caffeine, particularly late in the day.
Avoid alcohol and nicotine, especially close to bedtime.
Exercise, but not within 3 hours before bedtime.
Avoid naps, particularly in the late afternoon or evening.
Keep a sleep diary to identify your sleep habits and patterns that you can
share with your doctor.
a
Reprinted with permission from National Sleep Foundation.7 www.sleepfoundation.org/article/
sleep-related-problems/insomnia-and-sleep.

KEY POINT
ideal bedroom temperature for sus- distortions that can contribute to the h Psychological and
tained sleep is neutral to slightly cool. predisposition and perpetuation of in- behavioral strategies
Warm rooms tend to promote more somnia. CBT-I generally blends advice combined as
awakenings. Certainly a comfortable regarding healthy sleep habits, close cognitive-behavioral
sleep surface may facilitate sound attention to the scheduled time in therapy for insomnia
sleep, but an expensive new mattress bed, guidelines on when to attempt to have been shown to be
rarely represents a cure for chronic sleep, and cognitive psychotherapy to effective in numerous
insomnia. reframe maladaptive beliefs and well-controlled studies.
assumptions regarding sleep and in-
Psychological and Behavioral somnia (Case 3-2). Abundant evidence
Strategies has demonstrated both the short-term
A variety of well-defined psychological and sustained benefits of CBT-I.10 At
and behavioral approaches have been a minimum, CBT-I involves a cognitive
effective in treating patients with in- component and at least one behavioral
somnia.8 In a therapeutic setting, these element, such as sleep restriction ther-
strategies typically are combined as apy or stimulus control therapy. Ad-
cognitive-behavioral therapy for insom- ditional options include relaxation
nia (CBT-I).9 The elements of CBT-I therapy, biofeedback, and paradoxical
address factors that regulate the sleep- intention. CBT-I may be performed in a
wake cycle, psychological processes structured format with weekly to
that can affect sleep, and cognitive biweekly group or individual sessions,
Case 3-2
A 32-year-old single woman came to the sleep center for help with the insomnia
that had been worsening in recent months. She said that sleep had been a
problem for her since she started college. She now worked as an accountant in a
large corporation and found this very stressful. She had difficulty falling asleep
and then experienced repeated awakenings. Her sleep was never refreshing. She
described feeling exhausted throughout the daytime but being unable to fall
asleep if she tried to nap. She worried all day about whether she would be
able to sleep that night, and that concern intensified as bedtime approached.
Occasionally she would fall asleep on the sofa while watching television, but
then would get into bed only to have a sense of her mind racing. Her primary care
physician recommended a commonly prescribed hypnotic, which helped a little,
but she took it only once or twice a week because she feared becoming dependent
on it. She had recently started seeing a therapist to discuss the stress in her life
regarding her work, family issues, and relationship with her boyfriend. Her
examination was unremarkable except for 2+ tonsillar enlargement and a body
mass index of 27 kg/m2. She said no one had told her that she snored. She
drank one cup of coffee in the morning and avoided caffeine sources later in
the day. She rarely drank alcoholic beverages.
Comment. This patient is an excellent candidate for cognitive-behavioral
therapy for insomia, which will target her thoughts about sleep and insomnia
and provide specific behavioral guidelines. Her psychotherapy probably would
help with her assorted life stressors, but it does not directly address her
immediate sleep problems. The hypnotic may continue to be helpful on an
as-needed basis. She does have mild risk factors for obstructive sleep apnea,
so a future sleep study should be considered as her evaluation and treatment
continue.

Chronic Insomnia
and it may be provided by a certified cycle. Therefore, the bedtime is de-

behavioral sleep medicine specialist or layed and adjusted earlier or later ac-
less formally in any treatment setting. cording to the updated average sleep
While CBT-I has been best studied with duration. Specific sleep restriction ther-
a formalized approach over a series of apy guidelines are listed in Table 3-4.
sessions, studies have reported the The goal of stimulus control therapy
benefits of streamlined and more flex- is to help patients associate going to
ible schedules.11 bed with falling asleep.12 It is assumed
Sleep restriction therapy addresses that with chronic insomnia the bed-
the common problem of patients with room and bedtime routines have
insomnia spending excessive wakeful become stimuli associated with wake-
time in bed, while also generating in- fulness through a process of psycho-
creased homeostatic pressure for sleep logical conditioning reinforced over
in order to promote improved sleep time as people remain in bed while
onset and maintenance.6 Generally, awake, frustrated, and mentally aroused.
sleep restriction therapy involves limit- With stimulus control therapy, patients
ing patients time in bed to the amount are advised to go to bed and attempt
of sleep they report achieving on an sleep only when they feel sleepy and
average night, although the time in bed able to fall asleep. They are instructed to
typically would not be restricted to less get out of bed and go to another room if
than 5 hours. They maintain nightly they are unable to fall asleep within
sleep logs throughout the therapy. The about 10 minutes. The processes of at-
morning rise time usually is planned as tempting sleep when sleepy should be
an individuals desired wake-up time repeated as necessary. The routine is
and is kept the same throughout the followed with extended middle-of-the-
therapy to allow morning light expo- night awakenings. The stimulus con-
sure to reinforce the circadian system trol therapy guidelines also require that
and its influence on the sleep-wake patients maintain a regular morning
a
TABLE 3-4 Sleep Restriction Therapy Guidelines
b Initial Instructions
Allow yourself to be in bed only the amount of time determined by your
average nightly sleep from a 2-week sleep log. (Do not limit your time
in bed to less than 5 hours.)
Delay your bedtime to restrict your time in bed.
Awaken by alarm the same time every day of the week at your typical
workday wake-up time.
Do not nap.
Expect some daytime fatigue and sleepiness with shorter time in bed schedules.
b Time in Bed Adjustments
Reassess the sleep log weekly and change bedtime to adhere to guidelines
according to your average sleep efficiency (sleep time divided by time in bed).
If sleep efficiency is Q90%, bedtime is adjusted 15 to 30 minutes earlier.
If sleep efficiency is e85%, bedtime is adjusted 15 minutes later.
a
Reprinted with permission from Ebben MR, Spielman AJ, J Behav Med.6 B 2009, Springer
Science and Business Media. link.springer.com/article/10.1007%2Fs10865-008-9198-8.

a
TABLE 3-5 Stimulus Control Therapy Guidelines
1. Lie down intending to sleep only when you are sleepy.

2. Do not use your bed for anything except sleep. Do not read, watch television,
eat, or worry in bed. Sexual activity is the only exception to this rule. On such
occasions, the instructions are to be followed afterward when you intend to
go to sleep.
3. If you find yourself unable to fall asleep, get up and go to another room. Stay
up as long as you wish and then return to the bedroom to sleep. Do not
watch the clock, but get out of bed if you do not fall asleep immediately. The
goal is to associate your bed with falling asleep quickly. If you are in bed for
more than 10 minutes without falling asleep and have not gotten up, you are
not following this instruction.
4. If you still cannot fall asleep, repeat rule 3. Do this as often as is necessary
throughout the night.
5. Set your alarm and get up at the same time every morning irrespective of
how much sleep you got during the night. This will help your body acquire a
consistent sleep rhythm.
6. Do not nap during the day.
a
Data from Bootzin RR, Perlis ML, J Clin Psychiatry.12
wake-up time and avoid daytime nap- Pharmacologic Approaches

ping. Finally, the bed should be used for People with insomnia often try many
no activities other than sleep and sexual different remedies, some prescribed
relations. Stimulus control therapy guide- and evidence-based and some that are
lines are shown in Table 3-5. neither. Similarly, prescribers treating
With paradoxical intention, pa- patients with insomnia utilize a wide
tients are advised to go to bed at their range of medications, some indicated
normal bedtimes but attempt to remain for treating sleep disorders and others
awake instead of expecting to fall as- because they just might work and not
leep. The underlying idea is that pa- be too risky. It is useful to categorize
tients may be able to reduce the worry these assorted substances into four
and anxiety they experience when try- broad groups based in part on regula-
ing to fall asleep. Relaxation therapy tory issues, but also to a limited extent
also may help reduce the tension and on pharmacodynamics: (1) medications
anxiety patients with insomnia feel while approved by the US Food and Drug
awake in bed. Relaxation techniques Administration (FDA) for the treatment
may include progressive relaxation, of insomnia; (2) prescription medica-
abdominal breathing, guided imagery, tions, generally sedating agents, not
and types of yoga and meditation. formally indicated for the treatment of
Practicing these approaches to relaxa- insomnia; (3) over-the-counter prod-
tion at times when patients are not ucts marketed as sleep aids, which by
attempting to sleep should make them definition are regulated by the FDA but
more valuable when patients eventu- do not require a prescription; (4) the
ally employ them to aid with sleep huge collection of unregulated com-
onset. Similarly, biofeedback strategies pounds that are commercially available
may help people develop relaxation or perhaps grown or collected from nat-
skills that can facilitate sleep. ural sources. One other pharmacologic

Chronic Insomnia
TABLE 3-6 US Food and Drug AdministrationYApproved Insomnia Medications
US Food and Drug

Doses Half-Life AdministrationYApproved Most Common
Medicationa,b (mg)c (hours) Indications Side Effects
Benzodiazepine Immediate Releaseb
Flurazepam 15, 30 48Y120 Treatment of insomnia Dizziness, drowsiness,
characterized by difficulty lightheadedness, staggering,
in falling asleep, frequent loss of coordination, falling
nocturnal awakenings, and/or
early morning awakening
Temazepam 7.5, 15, 8Y20 Short-term treatment Drowsiness, dizziness,
22.5, 30 of insomnia lightheadedness, difficulty
with coordination
Triazolam 0.125, 2Y4 Short-term treatment Drowsiness, headache,
0.25 of insomnia dizziness, lightheadedness,
pins and needles feelings on
skin, difficulty with coordination
Quazepam 7.5, 15 48Y120 Treatment of insomnia Drowsiness, headache
characterized by difficulty
in falling asleep, frequent
nocturnal awakenings, and/or
early morning awakenings
Estazolam 1, 2 8Y24 Short-term management of Somnolence, hypokinesia,
insomnia characterized by dizziness, abnormal
difficulty in falling asleep, coordination
frequent nocturnal awakenings,
and/or early morning awakenings;
administered at bedtime
improved sleep induction
and sleep maintenance
Nonbenzodiazepine Immediate Release
Zolpidem 5, 10 1.5Y2.4 Short-term treatment of Drowsiness, dizziness,
insomnia characterized by diarrhea, drugged feelings
difficulties with sleep initiation
Zaleplonc 5, 10 1 Short-term treatment of Drowsiness, lightheadedness,
insomniaI.shown to dizziness, pins and needles
decrease the time to feeling on skin, difficulty
sleep onset with coordination
Eszopiclone 1, 2, 3 5Y7 Treatment of insomniaI. Unpleasant gustatory and metallic
administered at bedtime taste in mouth, dry mouth,
decreased sleep latency and drowsiness, dizziness, headache,
improved sleep maintenance symptoms of the common cold
Nonbenzodiazepine Extended Release (ER)
Zolpidem ER 6.25, 12.5 2.8Y2.9 Treatment of insomnia Headache, sleepiness, dizziness
characterized by difficulties
with sleep onset and/or
sleep maintenance (as measured
by wake time after sleep onset)
Continued on next page

TABLE 3-6 Continued
US Food and Drug

Doses Half-Life AdministrationYApproved Most Common
Medicationa,b (mg)c (hours) Indications Side Effects
Nonbenzodiazepine Alternate Delivery
Zolpidem oral 5, 10 ~2.5 Short-term treatment of Drowsiness, dizziness,
spray insomnia characterized by diarrhea, drugged feelings
Zolpidem 5, 10 ~2.5 Short-term treatment of Drowsiness, dizziness,
sublingual insomnia characterized by diarrhea, drugged feelings
Zolpidem 1.75, 3.5 ~2.5 As needed for the treatment Headache, nausea, fatigue
sublingual of insomnia when a
middle-of-the-night
awakening is followed by
difficulty returning to sleepd
Selective Melatonin Receptor Agonist
Ramelteon 8 1.0Y2.6 Treatment of insomnia Drowsiness, tiredness,
characterized by difficulty dizziness
with sleep onset
Selective Histamine H1 Receptor Antagonist
Doxepin 3, 6 15.3 Treatment of insomnia Somnolence/sedation,
characterized by difficulties nausea, upper respiratory
with sleep maintenance tract infection
a
All medications listed have a Drug Enforcement Administration (DEA) class of IV with the exceptions of ramelteon and doxepin, which
have no DEA class.
b
All medications have a pregnancy category of C with the exception of those listed under the heading of Benzodiazepine Immediate
Release, which are categorized as X.
c
Initial dose depends on the patients age and comorbid conditions. Maximum doses are the highest pill strength with the exception of
zaleplon, which may be prescribed for 20 mg at bedtime.
d
Patient must have 4 hours of sleep remaining before using this medication.
approach to the sleep problem that is all specify use for insomnia, and in some KEY POINT
highly regulated, rarely recommended, cases further suggest use for sleep onset, h Insomnia medications
but commonly consumed is alcohol. sleep maintenance, or returning to sleep approved by the US
Food and Drug
The sedating effect of alcohol may following an awakening. Table 3-6
Administration include
facilitate sleep onset, but the subse- shows the generic names, available
+-aminobutyric acid
quent sleep is more likely to be disrup- doses, approximate elimination half-life, response modulators, a
ted, with a negative net effect. indication, Drug Enforcement Adminis- melatonin receptor
FDA-approved insomnia medica- tration (DEA) schedule, and pregnancy agonist, and a histamine
tions. The medications specifically ap- category for each of these medications. H1 receptor antagonist.
proved by the FDA for the treatment of The benzodiazepine receptor ago-
insomnia comprise three major pharma- nists (BZRAs) include the two broad
codynamic actions: (1) +-aminobutyric categories of benzodiazepine and non-
acid (GABA) response modulator, (2) benzodiazepine BZRA hypnotics, all of
melatonin receptor agonist, and (3) his- which are allosteric modulators of
tamine receptor antagonist. All have been GABA responses at the GABAA receptor
evaluated for efficacy and safety at spe- complex. The GABAA receptor com-
cific recommended doses in populations plex is a pentameric transmembrane
of insomnia subjects.13 The indications structure with a central chloride ion

Chronic Insomnia
KEY POINTS
h Benzodiazepine receptor channel surrounded by five subunits, may aid sleep onset. The degree to
agonist hypnotics all most typically two alpha, two beta, which the medications continue to
are allosteric modulators and one gamma. A GABA attachment exert a sedating effect that is desired
of +-aminobutyric acid site between alpha and beta subunits (continued sleep) or undesired (morn-
responses at the GABAA allows the net inhibitory GABA agonist ing grogginess) depends on the elimi-
receptor complex. action of an inward flow of chloride nation half-life, as well as the initial dose.
h In addition to ions that increases the polarity across BZRA hypnotics typically are well
immediate-release and the membrane and decreases the like- tolerated. The list of potential rare ad-
extended-release pill lihood of an action potential. The verse effects is long; however, those
and tablet formulations, allosteric benzodiazepine receptor site reported most commonly in clinical
benzodiazepine on the alpha-gamma subunit interface trials include drowsiness, dizziness,
receptor agonist permits BZRA compounds to attach in a headache, and lightheadedness. 13
hypnotics are available manner that positively modulates the Ataxia and anterograde amnesia may
in oral spray and GABA action by allowing an enhanced occur within a few hours after taking
sublingual dissolvable
inward chloride ion flow and thereby a the medication. Patients may experi-
formulations.
greater inhibitory effect.14 The very ence rebound insomnia on abrupt dis-
broad distribution of GABAA receptors continuation following nightly use for
suggests that the BZRA hypnotic action several weeks or longer. These medi-
may be a widespread brain effect; how- cations are associated with a low abuse
ever, there likely also is a targeted ef- potential and therefore are designated
fect at key sleep-wake cycle regulatory by the DEA as schedule IV medications.
nuclei within the hypothalamus (eg, Benzodiazepine hypnotics are Preg-
ventrolateral preoptic nuclei).15 nancy Category X, and nonbenzodiaze-
The BZRA hypnotics, benzodiazepines are Pregnancy Category C.
pines and nonbenzodiazepines, share Benzodiazepine and nonbenzodia-
the same fundamental pharmacody- zepine BZRA hypnotics are available in
namic action, although it has been immediate-release formulations. Zolpi-
argued that the latter category may be dem is the one compound now pro-
differentiated based on varying selectiv- duced in an extended-release tablet as
ity for different GABAA alpha subunit well as in an oral spray and sublingual
subtypes. In general, benzodiazepines dissolvable alternate delivery formula-
appear to be less discriminative among tions. All BZRA hypnotic formulations
alpha subtypes compared with the non- are intended for bedtime use with the
benzodiazepine BZRA hypnotics, while exception of the lower-dose dissolvable
certain nonbenzodiazepines have in- formulation indicated for returning to
creased selectivity for alpha-1 or alpha-3 sleep following nighttime awakenings.
subtypes. The clinical implications of The formal indications for the BZRA
these pharmacologic properties remain hypnotics note that they are intended
an area of research interest. In contrast, for short-term treatment, although no
the BZRA hypnotic compounds vary limitation on the duration of use is
considerably in their pharmacokinetic implied for eszopiclone and zolpidem
profiles, especially in the elimination extended-release.
half-lives ranging from about 1 hour to a A single melatonin receptor agonist
few days. With the exception of triazo- is approved by the FDA for treating in-
lam, the benzodiazepines are moderate somnia. Ramelteon is a selective agonist
to long acting, while the nonbenzodia- of the melatonin type (MT)1 and MT2
zepines range from very short to inter- receptors, which are present in high con-
mediate durations of action. All are centrations in the hypothalamic supra-
relatively rapidly absorbed and thus chiasmatic nuclei (SCN).16 Melatonin is

KEY POINT
produced by the pineal gland in a ing insomnia. The specific indication h Low-dose doxepin is
process regulated by the SCN circadian is for the treatment of insomnia char- approved for the
system. Normally melatonin levels are acterized by difficulty with sleep treatment of insomnia
low throughout daytime, gradually rise maintenance. Among the tricyclic anti- characterized by
in the evening as nighttime approaches, depressants, doxepin is unusual for its difficulty with sleep
peak during the typical nighttime sleep very high selectivity for H1 histamine maintenance.
hours, and decline by the end of the receptor antagonist activity. Accord-
night. The evening melatonin rise and ingly, the key pharmacodynamic action
MT1 agonist action decrease the SCN- is antihistamine-promoted sedation.
driven wake-promoting stimulation that The available doses are as high as
is present during the latter hours of the 150 mg, and the depression prescribing
wake period and thereby facilitate bedtime guidelines are as high as 300 mg daily;
sleep onset. The MT2 effect relates to re- however, the low-dose formulations ap-
inforcement of the circadian timing and proved for insomnia are just 3 mg and
helps maintain the regular daily rhythm. 6 mg. In clinical trials, commonly re-
The ramelteon indication is for the ported adverse events were somnolence/
treatment of insomnia characterized by sedation, nausea, and upper respiratory
difficulty with sleep onset. While it may tract infection. Doxepin should not be
benefit sleep maintenance early during prescribed for patients with untreated
the night, it is not likely to be helpful for narrow-angle glaucoma or severe urinary
early morning awakenings. Ramelteon retention, or for people also taking
is produced in a single 8-mg dose that monoamine oxidase inhibitors. With no
the prescribing instructions recom- abuse potential, doxepin is considered a
mend for all patient groups, although nonscheduled medication. It is classi-
it should not be prescribed for patients fied as Pregnancy Category C.
with severe liver disease or people While each of the FDA-approved
concomitantly taking fluvoxamine, a insomnia medications may have unique
potent cytochrome P450 enzyme 1A2 side-effect profiles and warnings, the
isozyme inhibitor. The prescribing FDA has required certain warnings for
guidelines suggest that ramelteon be all of the insomnia medications. One
taken about 30 minutes before bedtime. warning relates to rare severe anaphy-
Drowsiness, tiredness, and dizziness are lactic and anaphylactoid reactions.
the most common side effects. Studies The other broad warning targets possi-
with ramelteon have demonstrated ble abnormal thinking and behavior
safety in patients with mild hepatic following hypnotic doses, and it notes
disease, moderate to severe chronic the potential for complex behaviors
obstructive pulmonary disease, and mild associated with amnesia. Examples
to moderate obstructive sleep apnea. include driving, preparing and eating
Ramelteon has no abuse potential and is foods, talking on the telephone, and
considered a nonscheduled medication. engaging in sexual behaviors when not
It is classed as Pregnancy Category C. fully awake. Patients are advised to dis-
The single selective histamine recep- continue the medication if these symp-
tor antagonist approved by the FDA toms occur. Other general warnings
for insomnia treatment is low-dose relate to ensuring that patients have
doxepin. This tricyclic was approved sufficient time in bed following a med-
for depression over 40 years ago, but ication dose, and the potential for next-
clinical experience and eventually clin- day drowsiness or impairment.
ical trials demonstrated that very low Off-label prescription insomnia phar-
doses were safe and effective in treat- macotherapy. Many antidepressant,

Chronic Insomnia
KEY POINT
h Beware of the antipsychotic, antiepileptic, and other fore, these medications should be used
anticholinergic effects sedating psychotropic medications at with greater caution in older adults and
associated with times are prescribed specifically to treat in people taking other medications
over-the-counter insomnia symptoms. While this ap- incorporating anticholinergic effects.
antihistamines people proach occasionally may be effective, The elimination half-lives are relatively
often use as sleep aids. very little evidence is available to guide long and may lead to morning groggi-
health care providers regarding the ness following bedtime use. Patients
safety and efficacy of these medications may become tolerant to the sedating
for populations of patients with insom- effect with continued use.17 This leads
nia. The practice is less problematic some people to escalate their nightly
when patients have comorbid condi- dose to several hundred milligrams.
tions for which the medications are in- Unregulated compounds. This final
dicated and where the choice of a more category is defined not so much by what
sedating option is beneficial for the it is, but rather by what it is not. These
individual. However, these medications are nonprescription and nonYover-the-
are also often prescribed (sometimes as counter products that typically are mar-
a first-line treatment) for people with keted as dietary supplement sleep aids,
chronic insomnia and no relevant although people sometimes use fresh
comorbidities. The risk-benefit ratio of herbs and other plant products. Gener-
these medications for insomnia may be ally this pharmacologic approach falls
very different than that associated with within the realm of complementary and
the indicated condition. Among the anti- alternative medicine. Hundreds of un-
depressants, trazodone, amitriptyline, regulated sleep aid products are avail-
mirtazapine, and doxepin often have able. They may be promoted as single
been prescribed in this manner; histor- compounds or as combinations of ingre-
ically, doxepin has been prescribed for dients, while some of the plant-derived
insomnia at a higher dose than the new products contain innumerable different
low-dose, FDA-approved formulation. molecules. Common ingredients in-
Quetiapine is the antipsychotic most clude valerian, hops, chamomile, pas-
commonly utilized for insomnia. Some sionflower, and kava kava. Convincing
antiepileptic examples include gaba- evidence is minimal regarding efficacy,
pentin, pregabalin, and tiagabine. but fortunately these compounds typi-
Over-the-counter sleep aids. All over- cally are regarded as safe. The one
the-counter sleep aids are antihist- major safety exception is kava kava, for
amines. While most of these products which the FDA has issued a warning re-
contain diphenhydramine as the active garding possible hepatic toxicity.18
ingredient, some contain doxylamine. Oddly, melatonin also falls into this un-
The over-the-counter sleep aids are regulated group and is one of the most
marketed as single compounds or common ingredients. Abundant evi-
combined with analgesics as PM for- dence supports the use of melatonin,
mulations. The antihistamine sedating particularly with circadian rhythm sleep
effect is the desired pharmacodynamic disorders (Case 3-3).19
action, although these drugs can inter- The insomnia pipeline. The develop-
act with other receptors and lead to ment of new pharmacologic approaches
common and sometimes serious side to treating insomnia has been actively
effects. Most problematic is the anti- investigated for decades. The most re-
cholinergic action that may contribute cent FDA approvals for insomnia have
to dry mouth, constipation, urinary re- been for new formulations and re-
tention, confusion, and delirium. There- finements of previously approved

KEY POINTS
compounds. Several novel pharmaco- pattern, habits and routines, and co- h Melatonin, which is
dynamic directions have been explored morbid conditions.3 As noted above, it unregulated in the
in recent years, although most have been is especially useful to elaborate specific United States, may be
abandoned because of safety problems treatment goals with the patient and to beneficial in the
or insufficient efficacy. One unique strat- monitor symptoms and the results of treatment of certain
egy that continues to be investigated is therapeutic strategies over time. Educa- circadian rhythm sleep
the use of orexin receptor antagonists.20 tion regarding sleep and individualized disorders, especially
Alternate GABA modulators and melato- recommendations about sleep-enhancing in people with a
nin receptor agonists also are being behaviors should be the foundation of phase-delay pattern.
studied as possible insomnia treatments. treatment for all patients. Cognitive h Currently the most
and behavioral strategies always should promising novel pipeline
Developing an Insomnia be incorporated into the treatment compounds are orexin
Treatment Plan plan, and in some cases that will in- receptor antagonists.
A comprehensive insomnia evaluation volve referral to a CBT-I specialist. Phar-
should provide the basis for developing macotherapy is an additional option.
a customized plan for therapy consid- Fortunately, numerous FDA-approved
ering the patients chief complaint, medications with various pharmacody-
sleep-wake cycle symptoms, lifestyle namic and pharmacokinetic properties are
Case 3-3
A 20-year-old man presented for evaluation at the insistence of the dean of
students at his college because he had missed many classes, performed poorly on
examinations, and been placed on academic probation. He was a sophomore
majoring in business administration and was threatened with not being able to
return for his junior year. During the evaluation, he stated that he was very
motivated to do well in college and complete his degree but had tremendous
difficulty getting up for any morning classes. He slept through multiple loud
alarms or turned them off and immediately returned to deep sleep. Usually
he did not fall asleep until some point between 2:00 AM and 4:00 AM. When in
high school, he would stay up late and then sleep late the next day on weekends
and vacations, but the problem became much more severe during his freshman
year of college. That next summer he had worked at a restaurant most nights
until midnight and did not go to bed until about 5:00 AM. He would then sleep
until the next afternoon. His sleep problems during his sophomore year had been
significantly worse. He became very frustrated about his inability to get to sleep
earlier and wake up for required classes. He had briefly tried taking a prescribed
hypnotic at about midnight, but it seemed to have no effect.
Comment. Difficulty falling asleep or staying asleep is often a symptom of a
circadian rhythm phase disorder that is not necessarily apparent to patients
or their health care providers. Phase-delayed patients have great difficulty
falling asleep at a desired earlier bedtime, and phase-advanced patients report
habitually waking up too early. These disorders should be apparent when the
evaluation considers the sleep propensity throughout the 24-hour cycle and
the persons longstanding sleep patterns. That this man did not benefit from
the hypnotic taken hours before his typical sleep-onset time is not surprising
since he was within the temporal zone of maximum circadian arousal usually
experienced by people earlier in the evening. Strategically timed evening
melatonin and morning bright-light exposure may be helpful for phase-delayed
patients such as this one.

Chronic Insomnia
available, allowing choices to best 6. Ebben MR, Spielman AJ. Non-pharmacological

treatments for insomnia. J Behav Med
manage patients symptoms consider- 2009;32(3):244Y254.
ing their patterns of sleep disturbance,
7. National Sleep Foundation. Cant sleep?
life circumstances, and related health What to know about insomnia. www.
issues. Attention to circadian factors will sleepfoundation.org/article/sleep-related-
be important for some patients, and problems/insomnia-and-sleep. Accessed
May 4, 2010.
strategic exposure to light or darkness
8. Morgenthaler T, Kramer M, Alessi C, et al.
may be valuable therapeutically. Many
Practice parameters for the psychological
possible insomnia treatment approaches and behavioral treatment of insomnia: an
can be explored over time with patients update. An American Academy of Sleep
who do not initially respond to therapy. Medicine report. Sleep 2006;29(11):1415Y1419.
9. Edinger JD, Means MK. Cognitive-behavioral
CONCLUSIONS therapy for primary insomnia. Clin Psychol
Rev 2005;25(5):539Y558.
Insomnia is a widespread health con-
10. Morin CM, Bootzin RR, Buysse DJ, et al.
cern that may result from multiple Psychological and behavioral treatment of
diverse processes. A comprehensive insomnia: update of the recent evidence
insomnia evaluation may reveal factors (1998-2004). Sleep 2006;29(11):1398Y1414.
that undermine the experience of sat- 11. Germain A, Moul DE, Franzen PL, et al.
isfying sleep and daytime alertness, al- Effects of a brief behavioral treatment for
late-life insomnia: preliminary findings.
though in some cases specific causes J Clin Sleep Med 2006;2(4):403Y406.
may not be readily discernible. Most 12. Bootzin RR, Perlis ML. Nonpharmacologic
often the evaluation will lead to a ra- treatments of insomnia. J Clin Psychiatry
tional treatment plan that incorporates 1992;53(suppl):37Y41.
evidence-based therapies, such as CBT-I 13. Krystal AD. A compendium of placebo-controlled
and pharmacotherapeutic approaches. trials of the risks/benefits of pharmacological
treatments for insomnia: the empirical basis
Sleep difficulties can contribute to other for U.S. clinical practice. Sleep Med Rev
health problems and to a worsening 2009;13(4):265Y274.
quality of life for patients. All patients 14. Gottesmann C. GABA mechanisms and
should be screened for sleep disorders, sleep. Neuroscience 2002;111(2):231Y239.
and appropriate treatments should be 15. Saper CB, Fuller PM, Pedersen NP, et al. Sleep
pursued. Satisfying sleep should be viewed state switching. Neuron 2010;68(6):1023Y1042.
as an essential component of wellness. 16. Kato K, Hirai K, Nishiyama K, et al.
Neurochemical properties of ramelteon
(TAK-375), a selective MT1/MT2 receptor
REFERENCES agonist. Neuropharmacology
1. Buysse DJ. Chronic insomnia. Am J Psychiatry 2005;48(2):301Y310.
2008;165(6):678Y686.
17. Richardson GS, Roehrs TA, Rosenthal L, et al.
2. Dyken ME, Afifi AK, Lin-Dyken DC. Tolerance to daytime sedative effects of H1
Sleep-related problems in neurologic antihistamines. J Clin Psychopharmacol
diseases. Chest 2012;141(2):528Y544. 2002;22(5):511Y515.
3. Schutte-Rodin S, Broch L, Buysse D, et al. 18. U.S. Food and Drug Administration Center
Clinical guideline for the evaluation and for Food Safety and Applied Nutrition.
management of chronic insomnia in adults. Kava-containing dietary supplements may
J Clin Sleep Med 2008;4(5):487Y504. be associated with severe liver injury.
www.fda.gov/food/resourcesforyou/consumers/
4. Bonnet MH, Arand DL. Hyperarousal and
ucm085482.htm. Accessed January 18, 2013.
insomnia: state of the science. Sleep Med
Rev 2010;14(1):9Y15. 19. Barion A, Zee PC. A clinical approach to
circadian rhythm sleep disorders. Sleep Med
5. American Academy of Sleep Medicine. The
2007;8(6):566Y577.
international classification of sleep
disorders: diagnostic & coding manual, 20. Ioachimescu OC, El-Solh AA. Pharmacotherapy
ICSD-2. 2nd ed. Westchester, IL: American of insomnia. Expert Opin Pharmacother
Academy of Sleep Medicine, 2005. 2012;13(9):1243Y1260.

Review Article
Primary Hypersomnias
Dr Clete A. Kushida, Stanford
University Center for Human
Sleep Research, 780 Welch
of Central Origin Rd, Suite 203, Palo Alto, CA

94304, clete@stanford.edu.
Samit Malhotra, MD; Clete A. Kushida, MD, PhD, RPSGT Dr Kushida has consulted for
Apnex Medical, Inc, and
Seven Dreamers Laboratories
and has received royalties
ABSTRACT from Philips Respironics.
Dr Kushida has received
Purpose of Review: This review discusses the various causes of primary hyper- research support from
somnias with emphasis on clinical recognition, diagnosis, and treatment options. Apnex Medical, Inc;
Recent Findings: Narcolepsy is probably the most fascinating syndrome causing GlaxoSmithKline; Impax
Laboratories, Inc; Merck & Co,
excessive daytime sleepiness. With increasing understanding of the hypocretin/orexin Inc; Pacific Medico Co, Ltd;
pathways and the neurotransmitters that subserve the role of wakefulness and sleep, ResMed; and XenoPort, Inc.
newer therapeutic modalities with promising results are being investigated and Dr Malhotra reports no
disclosure.
opening new frontiers in the treatment of this rare but devastating disease. Unlabeled Use of
Summary: This article reviews the primary hypersomnias of central origin. Where Products/Investigational
possible, clinical cases that highlight and explain the clinical syndromes are included. Use Disclosure:
Dr Kushida discusses the
Treatment modalities and future directions are also discussed to help the clinician unlabeled use of selective
identify and treat the underlying disorder. serotonin reuptake inhibitors,
serotonin-norepinephrine
reuptake inhibitors, and
Continuum (Minneap Minn) 2013;19(1):6785. tricyclic antidepressants for
the treatment of narcolepsy
with cataplexy; melatonin for
the treatment of idiopathic
INTRODUCTION Classification of Sleep Disorders, Sec- hypersomnia; and
amantadine, lithium,
The symptom of hypersomnia is com- ond Edition: Diagnostic and Coding lamotrigine, valproic acid,
Manual (ICSD-2) lists a number of and modafinil for the
monly encountered in clinical practice treatment of Kleine-Levin
and can occur as a result of a sleep- conditions that are grouped under this syndrome. Dr Malhotra
related breathing disorder, or it may also category of sleep disorders (Table 4-1).2 reports no disclosure.
It may be normal for a preschooler * 2013, American Academy
occur secondary to a circadian rhythm of Neurology.
disorder or other causes of disturbed to sleep 12 hours a night, but the same
nocturnal sleep. When hypersomnia does amount of nocturnal sleep with symp-
not result from the aforementioned con- toms of EDS in an adult may raise sus-
ditions, it is termed hypersomnia of picion for a sleep disorder. Sleep needs
central origin. It is defined as an inability are individual, and the National Sleep
to maintain an alert state during the Foundation provides an outline of nor-
major waking episodes of the day. mal sleep time based on the age of the
Excessive daytime sleepiness (EDS) person (Table 4-2).1
is the cardinal manifestation common Supplemental digital content:
to all types of hypersomnia. In com- NARCOLEPSY ticle are cited in the text as
parison to hypersomnia due to various Introduction Supplemental Digital Content.
pathologies, such as sleep-disordered A disorder of REM sleep, narcolepsy is clicking on links provided in
breathing, hypersomnia of central ori- the classic hypersomnia of central origin. the HTML, PDF, and iPad
gin is a rare cause of EDS. It is im- EDS and episodic loss of muscle tone URLs are provided in the print
portant for the treating clinician to be were identified in 1877 by Westphal,3 version. Video legends begin
on page 83.
cognizant of disease entities that con- and 3 years later, Gelineau coined the
stitute the umbrella term hypersomnia term narcolepsy. Subsequently, Adie
of central origin, to be able to diagnose recognized the loss of muscle tone as
them, and, most importantly, to manage part of the constellation of the disease
them appropriately. The International and named it cataplexy. Investigation

Hypersomnias
KEY POINT
h Most whites and African TABLE 4-1 International Classification of Sleep Disorders, Second
Americans who have Edition: Diagnostic and Coding Manual Diagnostic
narcolepsy with Criteria for Hypersomniaa
cataplexy are positive
for HLA-DQB1*0602, b Narcolepsy With Cataplexy
showing a strong
b Narcolepsy Without Cataplexy
association with this
Narcolepsy due to medical condition
human leukocyte Narcolepsy, unspecified
antigen type.
b Recurrent Hypersomnia
Kleine-Levin syndrome
Menstrual-related hypersomnia
b Idiopathic Hypersomnia With Long Sleep Time
b Idiopathic Hypersomnia Without Long Sleep Time
Behaviorally induced insufficient sleep syndrome
Hypersomnia due to medical condition
Hypersomnia due to drug or substance
Hypersomnia not due to substance or known physiologic condition
(nonorganic hypersomnia)
Physiologic (organic) hypersomnia, unspecified
a
Modified from American Academy of Sleep Medicine.2 Used with permission of the American
into the etiology of this disorder es- Additional research identified the
tablished an association with HLA-DR2 hypocretin/orexin pathway and its abil-
in the Japanese population with narco- ity to regulate sleep and wakefulness.6
lepsy.4 Most whites and African Americans The finding of undetectable CSF levels
who have narcolepsy with cataplexy of hypocretin-17 and hypothalamic
were also positive for HLA-DQB1*0602, hypocretinergic cell dropout in patients
showing a strong association with this with narcolepsy and cataplexy further
human leukocyte antigen (HLA) type.5 confirmed this association.
TABLE 4-2 Age-Specific Sleep Needs as Recommended by the

National Sleep Foundationa
Age Sleep
Newborns (0Y2 months) 12Y18 hours
Infants (3Y12 months) 14Y15 hours
Toddlers (1Y3 years) 12Y14 hours
Preschoolers (3Y5 years) 11Y13 hours
School-aged children (5Y10 years) 10Y11 hours
Preteenaged and teenaged children (10Y17 years) 8.5Y9.25 hours
Adults 7Y9 hours
a
Reprinted with permission from National Sleep Foundation.1 www.sleepfoundation.org/article/
how-sleep-works/how-much-sleep-do-we-really-need.

Criteria for Narcolepsy With Cataplexya
A. Excessive daytime sleepiness present for at least 3 months.

B. Definite history of cataplexy, ie, loss of muscle tone triggered by laughter or
strong emotions.
C. Should be confirmed by multiple sleep latency test preceded by an overnight
polysomnogram consisting of at least 6 hours of sleep. A sleep latency of 8
minutes or less plus two or more sleep-onset REM periods are considered
abnormal. Alternatively, a decreased CSF hypocretin level (G110 pg/mL) can
be used.
D. The hypersomnia is not better explained by another sleep disorder, medical
or neurologic disorder, mental disorder, medication use, or substance use
disorder.
a
Epidemiology or CNS trauma or disease before mak-

The prevalence of this disease is between ing a diagnosis of narcolepsy without
0.03% and 0.05% of the population.8 cataplexy. First-degree relatives of
Both sexes are equally affected, with patients with narcolepsy have a 1% to
mean age at onset in the mid-twenties. 2% risk of developing this disorder. The
A peak occurs around 15 years and ICSD-2 diagnostic criteria for narco-
another near 35 years, suggesting a lepsy with and without cataplexy are
bimodal distribution. Narcolepsy with- outlined in Table 4-3 and Table 4-4.
out cataplexy is comparatively less
common than narcolepsy with cata- Clinical Symptoms
plexy. It is prudent to exclude secon- The classic symptoms of narcolepsy in-
dary hypersomnia resulting from clude EDS, cataplexy, hypnagogic hallu-
systemic disease, drugs or medications, cinations, and sleep paralysis.

Criteria for Narcolepsy Without Cataplexya
A. Excessive daytime sleepiness present for at least 3 months.

B. Cataplexy is absent or very doubtful.
C. Must be confirmed by multiple sleep latency test preceded by an overnight
polysomnogram consisting of at least 6 hours of sleep. A sleep latency of 8
minutes or less plus two or more sleep-onset REM periods are considered
abnormal.
D. The hypersomnia is not better explained by another sleep disorder, medical
or neurologic disorder, mental disorder, medication use, or substance use
disorder.
a

Hypersomnias
KEY POINTS
h Naps are usually Excessive daytime sleepiness. EDS than a few minutes. Subsequent recur-
refreshing and often is usually the heralding feature of ring attacks are deemed less stressful
recommended as part of narcolepsy, manifesting as episodes as patients readily recognize the phe-
the treatment plan for of an inadvertent and irresistible urge nomenon and its transient nature.
narcolepsy. Short to sleep that appears without warning. Sleep paralysis, which occurs in two-
daytime naps lasting These may last seconds to minutes and thirds of patients with narcolepsy, is
about 30 minutes can are known as sleep attacks. Sedentary not pathognomonic of narcolepsy as
result in the attenuation and boring settings may predispose to it can be present even in the healthy
of the sleep drive for a and enhance the symptom of EDS. population,9 commonly in the setting
few hours. Naps are usually refreshing and often of sleep deprivation.
h Symptoms of subtle recommended as part of the treatment Hallucinations. Simple or complex
muscle weakness in plan. Short daytime naps lasting about visual hallucinations are experienced
cataplexy include 30 minutes can result in the attenuation by approximately two-thirds of patients
slurring of speech, of the sleep drive for a few hours.9 with narcolepsy. These may either
buckling of knees, jaw
Cataplexy. Cataplexy is defined as occur during the period of transition
dropping, or even
the sudden, involuntary loss or decrease from wakefulness to sleep (hypnagogic)
nodding of the head
and should be
of muscle tone. Episodes are most com- or from sleep to wakefulness (hypno-
specifically elicited monly precipitated by laughter; how- pompic) with the former being typical of
during history taking. ever, other intense positive emotions narcolepsy. Other forms, such as audi-
such as joy, elation, and even surprise tory and tactile hallucinations, may also
h A rare sustained
cataplectic episode,
can be potential triggers. These attacks be experienced. It is imperative to ex-
status cataplecticus, may either be profound, with general- clude an underlying psychiatric condi-
may occur following ized atonia resulting in falls and injuries, tion as a cause of the hallucinations that
abrupt discontinuation or consist of localized loss of muscle do not occur exclusively during sleep.
of medications used to tone that may be missed if this diag- Hallucinations during sleep stage tran-
treat cataplexy. This is nosis is not considered (Supplemental sition are also reported in healthy
also referred to as Digital Content 4-1, links.lww.com/ people9 and, therefore, are also not
rebound cataplexy. CONT/A16). Symptoms of subtle mus- pathognomonic of narcolepsy.
cle weakness include slurring of speech, Disturbed nighttime sleep. Al-
buckling of knees, jaw dropping, or though not a part of the classic tetrad,
even nodding of the head and should nighttime sleep disturbance is an es-
be specifically elicited during history sential symptom of narcolepsy, and for
taking. The diagnosis may be delayed this reason several efforts at character-
by several years if these key symptoms izing the nocturnal sleep of these pa-
are not elicited on initial evaluation. Most tients have been made. A large number
cataplectic attacks last a short duration, of patients with narcolepsy experience
a few seconds to a few minutes.10 How- vivid dreams, sleep fragmentation due
ever, a rare sustained cataplectic episode, to multiple arousals, early morning
status cataplecticus, may occur follow- awakenings, nocturnal eating, and unre-
ing abrupt discontinuation of medica- freshing nocturnal sleep.11
tions used to treat cataplexy. This state is Automatic behavior. Nearly half of
also referred to as rebound cataplexy. all patients with narcolepsy experience
Sleep paralysis. A terrifying experi- automatic behavior,11 which is described
ence when it occurs for the first time, as the act of pursuing a purposeful be-
sleep paralysis is characterized by an havior with no reminiscence of it. Pa-
inability to move while being totally tients either seem awake and alert or
aware of ones surroundings. Typically may appear inattentive during an epi-
occurring either at arousal or at sleep sode. Intrusion of microsleep into wake-
onset, these events rarely last more fulness is believed to account for this

KEY POINTS
symptom. Sleep deprivation may precip- onset of symptoms of EDS.11 Case 4-1 h The presence of a
itate automatic behavior in normal indi- demonstrates a typical presentation of sleep-onset REM period
viduals and therefore this symptom is narcolepsy. on an overnight sleep
also not pathognomonic of narcolepsy. study of a patient with
Pathophysiology a history of excessive
Associated Conditions The connection between major histo- daytime sleepiness and
Periodic limb movements of sleep. compatibility complex and narcolepsy muscle atonia that
Very common in the narcoleptic pa- was initially reported in the Japanese occurs in the setting of
tient, periodic limb movements of sleep population and led to the consider- an emotional outburst
(PLMS) may occur in 60% of these pa- ation of an autoimmune basis in the may be suggestive of a
diagnosis of narcolepsy
tients. These are characterized as a development of narcolepsy. An asso-
with cataplexy.
cluster of limb movements occurring ciation of HLA-DR with narcolepsy was
during sleep that resemble a triple flexion reported in the Japanese population, h Hypocretin-1 and
response. This is a polysomnographic and subsequently other HLA types hypocretin-2 are the
two peptides that result
finding and it should be remembered were also associated with narcolepsy,
from the splitting of
that patients with PLMS may or may not with the most closely linked being
their precursor,
have symptoms of restless legs during HLA-DQB1*0602. Twelve percent to preprohypocretin.
wakefulness. PLMS are more prevalent 34% of the general population has this Hypocretin-1 is
as the patient gets older, tend to be allele, and more than 90% of patients implicated in human
more prevalent in REM sleep, and are with narcolepsy and cataplexy test pos- narcolepsy.
associated with more sleep disruption itive for this HLA type.12 The HLA link is
than in controls, most likely because of less certain in patients with narcolepsy
the PLMS-associated arousals. without cataplexy, although more than
REM sleep behavior disorder. REM 40% of these patients are positive for
sleep behavior disorder is an associated this HLA.12 Additionally, up to 30% of
condition present in 7% to 36% of pa- patients positive for HLA-DQB1*0602
tients with narcolepsy (Supplemental do not have narcolepsy.5,12
Digital Content 4-2, links.lww.com/ The discovery of the hypocretin/
CONT/A17). The term REM sleep orexin neurons in the lateral hypothal-
behavior disorder may be misleading, amus furthered understanding of the
since patients with narcolepsy may dem- pathophysiology of this disorder.6
onstrate an increase in phasic and/or Hypocretin-1 and hypocretin-2 are
tonic muscle activity in nocturnal REM the two peptides that result from the
sleep without the associated behavioral splitting of their precursor, preprohy-
component needed to make a diagno- pocretin. Hypocretin-1 is implicated in
sis of REM sleep behavior disorder. human narcolepsy. These hypocretin
peptides bind to their own specific
Presentation receptors, which are found in the his-
Both EDS and cataplexy will be present taminergic tuberomamillary nucleus,
in about half of the patients when the the ventrolateral preoptic nucleus, the
diagnosis of narcolepsy is made, and cholinergic pedunculopontine nucleus,
about 40% will progress and show symp- the brainstem monoaminergic system,
toms of cataplexy later in the course of and also diffusely in the basal forebrain.13
their disease. Occasionally, the onset of As previously mentioned, patients who
REM-related muscle atonia (cataplexy) have narcolepsy with cataplexy show
precipitated by intense emotions occurs low or undetectable CSF hypocretin
more than 40 years later, although most levels, with most patients testing pos-
patients will experience their first epi- itive for HLA-DQB1*0602.7 Addition-
sode of cataplexy within 10 years of the ally, histologic examination on brain

Hypersomnias
Case 4-1
An 8-year-old boy was brought to the office by his parents because of
a 2-week history of abrupt onset of overwhelming sleepiness. He was
inappropriately falling asleep in the day despite getting over 10 hours
of uninterrupted nocturnal sleep. No history of sleep paralysis or visual
hallucinations could be elucidated from the patient or his family. He
described an episode of falling off his bicycle without any clear reason, and
another episode when his knees buckled and he fell to the ground after
hearing his brother tell a joke. (The accompanying video [Supplemental
Digital Content 4-3, links.lww.com/CONT/A18] demonstrates a different
patient with similar clinical history and presentation.) He had an unexplained
weight gain of about 3 kg (6 lbs) over 2 months. He had nothing remarkable
in his medical or psychiatric history and no history of recent trauma or
medication use. His routine blood work and EEG were normal, as was the MRI
of the brain with and without gadolinium. An overnight polysomnogram
(PSG) was normal, with a subsequent multiple sleep latency test (MSLT)
showing a mean sleep-onset latency of 2.3 minutes and a sleep-onset REM
period (SOREMP) on each of the five naps. Human leukocyte antigen typing
was positive for HLA-DQB1*0602, and CSF hypocretin level was undetectable.
Comment. The patients history of a rather abrupt onset of excessive
daytime sleepiness (EDS) and episodes of muscle atonia that occurred
during an emotionally charged situation was highly suggestive of narcolepsy
with cataplexy. This diagnosis was confirmed with a normal PSG and a MSLT
positive for multiple SOREMPs and a sleep-onset latency shorter than 8
minutes. HLA typing for HLA-DQB1*0602 and abnormal CSF hypocretin levels
may help confirm the diagnosis if the MSLT results are equivocal, unlike
in this case. Additionally, the presence of a SOREMP on an overnight sleep
study with a history of EDS and muscle atonia that occurs in the setting of
an emotional outburst may also be suggestive of a diagnosis of narcolepsy
with cataplexy. An MSLT is still necessary to confirm this diagnosis since the
presence of a SOREMP on an overnight PSG is not included in the diagnostic
criteria outlined in the International Classification of Sleep Disorders,
Second Edition: Diagnostic and Coding Manual. Treatment was initiated
with sodium oxybate 3 g in two divided doses, resulting in improvement of
the patients symptoms of EDS and cataplexy. The sodium oxybate dose
was increased to 4.5 g in three divided doses a few months later.
tissue in patients with narcolepsy affected during a cataplectic episode.

showed evidence of hypocretin neuro- Since magnetic stimulation via the
nal cell loss in the lateral hypothalamus transcranial route is not impaired in
(Figure 4-1). cataplexy, presynaptic inhibition of the
The inhibition of the motor effector afferent sensory neuron has been pro-
of the H reflex is the proposed mech- posed as an alternative mechanism for
anism for the development of the atonic the development of cataplexy.15
process encountered in cataplexy. This
mirrors the mechanism that explains the Diagnostic Tools
atonia normally seen in REM sleep.14 Epworth Sleepiness Scale. The Epworth
However, this theory cannot explain the Sleepiness Scale (Appendix A) assesses
general loss of muscle tone and areflexia subjective daytime sleepiness through
seen in muscles that are not clinically a short and simple questionnaire. The

FIGURE 4-1 Prehypocretin messenger RNA in the lateral hypothalamus stains darkly in the
control subject (B), but is undetectable in the patient with narcolepsy (A).
f = fornix.
Modified from Nishino S, et al, Sleep Med Clin.19 B 2012, with permission from Elsevier.
www.sciencedirect.com/science/article/pii/S1556407X12000434.
chance of falling asleep in eight com- bed and try to fall asleep during each
mon situations is graded from 0 to 3. A of the five naps. Sleep onset as well as
total score greater than 10 is indicative the presence of REM sleep during the
of EDS.16 nap is noted. REM sleep occurring within
Multiple sleep latency test. The 15 minutes of sleep onset is deemed a
multiple sleep latency test (MSLT) SOREMP. A short sleep-onset latency of
was designed to record the physio- less than 8 minutes is considered ab-
logic tendency to fall asleep in the abnormal. If this short sleep-onset latency
sence of external alerting factors.17 To is accompanied by at least two SOR-
be considered valid, the MSLT has to be EMPs, a diagnosis of narcolepsy may be
preceded by an overnight sleep study made in the right clinical setting.18 If
polysomnogram (PSG), essentially to the patient does not sleep during a nap,
ensure that the patient is not sleep the nap is interrupted after 20 minutes
deprived and has slept sufficiently. and the patient waits for the next nap
Sleep-disordered breathing that may time.17
account for the symptom of EDS and Polysomnogram. Patients with nar-
may give a false-positive MSLT is also colepsy often show abnormalities on
ruled out with the PSG. Although a the PSG that include a decrease in total
diagnosis of sleep-disordered breathing sleep time, a short sleep-onset latency,
does not rule out narcolepsy, it makes it sleep fragmentation, REM without ato-
less likely to be the sole cause of the nia, and PLMS. Often, the presence of a
EDS. Avoidance of all medications influ- SOREMP on the PSG may alert a phy-
encing sleep from 2 weeks before the sician to consider narcolepsy in the dif-
test is necessary, although sometimes ferential diagnosis in a patient with EDS.
impractical. HLA. Testing for serum HLA-DQB1*
For the MSLT, five 20-minute naps 0602 typing is available and more com-
at 2-hour intervals are scheduled dur- monly seen in patients with narcolepsy
ing the day, and the patient, dressed and cataplexy. However, there is a
in street clothes, is instructed to lie in higher chance for narcolepsy patients

Hypersomnias
KEY POINT
h A finding of low (less without cataplexy to be HLA negative pending on the presence or absence
than 110 pg/mL) or than positive, and upward of 30% of of cataplexy. These criteria take into
undetectable CSF the general population may be positive consideration the duration of symp-
hypocretin levels will for this HLA type without having symptoms, the presence or absence of
nearly always be seen in toms of narcolepsy.5,12 cataplectic events, and specific diag-
patients with true Hypocretin. CSF measurement of nostic modalities used to make the
narcolepsy with hypocretin is commercially available, distinction between narcolepsy with
cataplexy. and the finding of low (less than 110 cataplexy and narcolepsy without cata-
pg/mL) or undetectable CSF hypocre- plexy (Tables 4-3 and 4-4).
tin levels will nearly always be seen Another issue that a clinician may
in patients with true narcolepsy with face is whether to draw blood for HLA
cataplexy.7 typing and/or CSF analysis for hypo-
cretin levels. In the presence of cata-
Diagnostic Criteria plexy with a positive MSLT, these tests
The ICSD-2 has developed slightly may not be necessary. However, they
different criteria for narcolepsy, de- may help to confirm the diagnosis
TABLE 4-5 Pharmacologic Treatment of Excessive Daytime Sleepiness
Drug Dosage Common Side Effects

Stimulants
d-Amphetamine 5Y10 mg once or twice daily Palpitations, tachycardia, elevated
(morning and noon) blood pressure, anorexia, weight loss,
insomnia, psychosis (rare), potential
Maximum daily dose 60 mg
for abuse
Methamphetaminea 5Y10 mg once or twice daily Same as d-amphetamine, more

(morning and noon) anorexigenic, very high abuse
potential
Methylphenidate HCl 10Y20 mg once or twice daily Same as d-amphetamine, less
(morning and noon) anorexigenic, less abuse potential
Wake-Promoting Agents
Modafinil 100Y200 mg once or twice daily Headache, nausea, insomnia
(morning and noon)
Maximum daily dose 400 mg,
although 600 mg has been used
Armodafinil 150Y250 mg once or twice daily Similar to modafinil
Other
Sodium oxybateb Starting dose 1.5 g taken at Headache, nausea, dizziness,
bedtime and again 2Y4 hours enuresis, worsened sleep-disordered
after sleep onset breathing
Usual effective dose 4.5Y6 g
per night
Maximum daily dose 9 g
a
Methamphetamine is not approved by the US Food and Drug Administration (FDA) for narcolepsy.
b
Sodium oxybate is also FDA-approved for treatment of cataplexy.

in the presence of equivocal MSLT the serotonin transporter.20 The first
results. accounts of methylphenidate usage at
doses up to 300 mg in treating EDS in
Treatment patients with narcolepsy date back to
Excessive daytime sleepiness. Stimu- 1959.
lants have been the mainstay of treatment, Wake-promoting agents. Modafinil
but with the advent of wake-promoting is a nonamphetamine wake-promoting
agents and the availability of sodium agent whose mechanism of action is
oxybate, additional treatment options not yet fully elucidated. However, it
are now available for the treatment of is thought to not only increase the
EDS (Table 4-5). release of monoamines, such as nor-
Stimulants. Various amphetamines epinephrine and dopamine, but also
(eg, d-amphetamine, methamphetamine) elevate hypothalamic histamine levels.
and methylphenidate are included in this Wake-promoting agents have become
class of medications that have been used the favored medication and are the
for the treatment of EDS. Pemoline was first-line agents for treating EDS in
taken off the market by the US Food and narcolepsy,21 and modafinil may be
Drug Administration (FDA) because of used at up to 400 mg in divided doses.
its association with idiosyncratic liver Armodafinil is an active enantiomer of
failure leading either to transplantation the racemic drug modafinil and has the
or death and therefore will not be same indications for use as modafinil.
discussed here. However, it has a considerably longer
The initial reports of amphetamine half-life and a longer wake-promoting
use for the treatment of EDS dates back effect than modafinil.22 It was approved
to 1935, when nine patients with narco- by the FDA for treating EDS in narco-
lepsy were treated with Benzedrine.5 lepsy in June 2007. The dose is either
Amphetamines, therefore, were the prin- 150 mg or 250 mg given daily in the
cipal agents used for the treatment of morning.
the symptom of EDS associated with The use of +-hydroxybutyrate, also
narcolepsy. Amphetamines alleviate known as sodium oxybate, for treat-
sleepiness by blocking dopamine reup- ment of narcolepsy dates back to
take at the nerve terminal and revers- 1979. +-Hydroxybutyrate became infa-
ing its transporter action at the synaptic mous as the date rape drug and
cleft. Amphetamines also facilitate the subsequently went into medical obliv-
free cytosolic movement of dopamine ion. A renewed interest in sodium
contained in storage vesicles and its oxybate led to well-designed random-
release in the synaptic region by inter- ized double-blind studies comparing
acting with the vesicular monoamine different doses of sodium oxybate to
transporter 2. Additionally, at higher placebo in the treatment of EDS, cata-
doses, these compounds prevent deg- plexy, and overall sleep efficiency.23
radation of the catecholamines by act- Although its exact mechanism of ac-
ing as an inhibitor of monoamine tion remains unclear, it is known that
oxidase.10 Divided doses of up to 60 sodium oxybate is naturally occurring
mg of d-amphetamine are given on and has its own receptors as well as an
waking up and at noon. Methamphet- affinity for activating +-aminobutyric
amine shares a mechanism of action acid B receptors.10 Its efficacy for day-
similar to all amphetamines, as does time alertness in combination with mod-
methylphenidate, except that methyl- afinil is superior to either drug taken
phenidate has a weak binding effect on alone.21 Sodium oxybate consolidates

Hypersomnias
and counters sleep fragmentation seen norepinephrine uptake inhibitors, were

in patients with narcolepsy by signifi- investigated. Table 4-6 lists the medi-
cantly increasing slow-wave sleep. It is cations that are prescribed for the treat-
available as a liquid formulation and ment of cataplexy along with their doses
prescribed to be taken at bedtime and and notable side effects. Currently, none
about 2 to 4 hours later. The patients of these medications is FDA-approved
set an alarm and take the medication 2 for the treatment of cataplexy.10
to 4 hours after bedtime. Based on the Tricyclic antidepressants. This was
dosing studies, the recommended the first class of medications available
starting dose is 3 g in divided doses to for the treatment of cataplexy, and imipr-
a maximum of 9 g a night. amine was the first drug used for this
Cataplexy. Treatment is directed purpose. Protriptyline and clomipramine
toward prevention of the occurrence are probably the most widely used drugs
of muscle atonia and thereby prevent- from this class and share the common
ing falls and injuries. Various medica- mechanism of action of blocking norepi-
tions were tried with this goal in mind, nephrine reuptake to improve cata-
and the first observed improvement in plexy.10 Although these medications
treatment of cataplectic events dates belong to the class of antidepressants,
back to 1960 with imipramine. This the doses needed to treat cataplexy effe-
paved the way for other tricyclic anti- ctively are well below those used for the
depressants to become the drugs of treatment of depression, with anticholi-
choice for treating cataplexy. Subse- nergic side effects remaining the same.
quently, other agents that alter the Selective serotonin reuptake inhib-
metabolism of norepinephrine, namely itors. The most commonly prescribed
the selective serotonin reuptake inhib- medication from this class is fluoxe-
itors (SSRIs) and the selective serotonin tine. It is inferior in efficacy to the
TABLE 4-6 Medications Used in the Treatment of Cataplexy
Drug Dosage Common Side Effects

Tricyclic
Imipramine Start with 10Y25 mg given at bedtime Dry mouth, constipation, drowsiness
Maximum effective dose 125Y150 mg
Protriptyline Start with 5Y10 mg given at bedtime Same as imipramine
Maximum effective dose 60 mg
Clomipramine Start with 10Y25 mg given at bedtime Same as imipramine
Maximum effective dose 10Y150 mg
Selective serotonin reuptake inhibitor
Fluoxetine Start with 10Y20 mg in the morning Nausea, insomnia, diarrhea
Maximum dose 60 mg
Fluvoxamine Start with 25Y50 mg in the morning Nausea, diarrhea, headache
Can be given in divided doses
(morning/lunch) to a maximum of 300 mg
Serotonin-norepinephrine reuptake inhibitor
Venlafaxine Start with 75 mg in the morning Nausea, constipation, somnolence,
Can be given in divided doses dry mouth, dizziness
(morning/lunch) to a maximum of 375 mg

KEY POINTS
tricyclics in its anticataplectic effect mal studies have demonstrated en- h Various medications
largely because of the affinity of the hanced histaminergic neurotransmission treat the individual
SSRIs toward the serotonin pathway.10 as well as stimulation of the H1 receptors symptoms of narcolepsy
Therefore, higher doses of the SSRIs postsynaptically with H3 autoreceptor in- with cataplexy, but
are usually required to see similar ther- verse agonists and antagonists.25 With the sodium oxybate is
apeutic effects. current understanding of the hypocretin/ favored over the
Selective serotonin norepinephrine orexin pathway in regulating wakeful- others because of its
uptake inhibitors. The most frequently ness, and knowledge regarding the effectiveness in treating
used medication in this class is venla- association of narcolepsy in patients the primary symptoms,
faxine, which is effective in doses lower with low or undetectable hypocretin including excessive
daytime sleepiness and
than those used to treat depression. levels and hypocretin cell destruction,
REM-related atonia
Venlafaxine along with modafinil and it is intuitive that hypocretin replace-
(cataplexy),
sodium oxybate are the most used and ment therapy would be the most ratio- simultaneously.
continued medications for treatment of nal approach for treatment of narcolepsy.
narcolepsy and cataplexy when compared This has been tried, with encouraging h Idiopathic hypersomnia
has an unknown
to stimulants and TCAs, as well as SSRIs, results, in animal studies with central ad-
etiology and is typified
which are tried but rarely continued. ministration of hypocretin-1.26 An intra- by symptoms of
nasal hypocretin delivery method has nonrefreshing sleep
Management Considerations also been tried. Gene therapy and cell with difficulty waking
Management is symptomatic rather transplantation have been investigated up, which could either
than curative. Although various medi- as therapeutic options in animal mod- be in the morning or
cations treat the individual symptoms, els. Additionally, in their review of the after a nap.
sodium oxybate is favored over the orexin receptors, Scammell and Winrow27
others because of its effectiveness in have suggested the possibility of de-
treating the primary symptoms, includ- veloping orexin receptor agonists that
ing EDS and REM-related atonia (cata- may promote wakefulness in narcolepsy
plexy), simultaneously. If EDS persists, patients with EDS. Since more and more
the addition of a wake-promoting agent evidence indicates an immune-mediated
or stimulant is advisable. In narcolepsy death of the hypocretin-secreting neu-
without cataplexy, either a wake-promoting rons in the development of narcolepsy,
agent or a stimulant, or even sodium focus has shifted to immunotherapy,
oxybate, may be tried as first-line ther- although without much success. Plasma
apy. To help the treating physician make exchange, immunoglobulins, and ste-
therapeutic choices, practice parameters roids have been tried with no clear
have been published by the American benefits.
Academy of Sleep Medicine.24 Treatment
directed specifically for associated disor- IDIOPATHIC HYPERSOMNIA
ders (such as REM sleep behavior dis- Introduction
order, sleep-disordered breathing, and Idiopathic hypersomnia (IH) was first
PLMS) should be used. described in the 1950s by Roth to dis-
tinguish patients with EDS who were
Future Directions not narcoleptics.28 It has an unknown
Since antihistamine agents cause drow- etiology and is typified by symptoms
siness, various manipulations of the his- of nonrefreshing sleep with difficulty
tamine receptor have been attempted waking up, which could either be in the
in order to develop therapeutic targets morning or after a nap. IH continues to
for the treatment of EDS. Stimulation of be a poorly understood entity, and a
postsynaptic H1 receptors has been diagnosis of IH is made only after other
shown to increase wakefulness, and ani- causes of EDS have been excluded. It is

Hypersomnias
therefore a diagnosis of exclusion and an inability to perform mental or phys-

must be made with caution. ical tasks immediately upon waking up
is commonly encountered but is not
Epidemiology pathognomonic of IH and therefore not
Since IH is a poorly understood entity, considered as part of the diagnostic
the precise prevalence of this disorder criteria. Inappropriate sleep intrusion is
remains unknown. Patients with nar- commonly seen. This can be disturbing
colepsy outnumber patients with IH and also dangerous. Patients also fre-
by a ratio of 10:1 based on a general quently show a depressed mood, but
survey of sleep clinics, with both sexes the diagnostic criteria for mood disor-
being equally affected.29 A familial pre- der as laid out in the Diagnostic and
disposition has been noted with symp- Statistical Manual of Mental Disor-
toms typically starting in the teenage ders, Fourth Edition for mood disorder
years or as a young adult. CSF hypo- must not be met.29 Case 4-2 describes a
cretin levels are normal, and an HLA typical presentation.
association is inconclusive.30
Pathophysiology
Clinical Manifestations The cause of IH is speculative, as little is
The cardinal manifestation of IH is known of its pathophysiology. Abnormal
EDS despite a normal total sleep time melatonin secretion and a circadian dys-
and an absence of sleep-disordered function have been postulated. Aberrant
breathing and normal sleep architec- homeostatic sleep drive has also been
ture in an overnight sleep study. suggested based on the finding of a
Clinically, patients report difficulty lesser quantity of slow-wave sleep in these
waking up in the morning, feel sleepy patients. Additionally, an association
during the day, and typically want to with the hypocretin/orexin system and
return to sleep. Naps are not refresh- hypothalamic dysfunction has been
ing, even if they last a few hours. Sleep proposed, but evidence in this regard
inertia or a feeling of grogginess and is lacking.
Case 4-2
A 22-year-old woman presented to the sleep clinic with abrupt-onset sleepiness
following a week of flulike symptoms. She had an unremarkable medical
and psychiatric history and was employed as a cashier in a local bank. Three
months before her presentation, her total sleep time was about 9 to 11 hours
per night and she took no daytime naps. Meticulous history elucidated no
cataplectic events. Routine laboratory and imaging studies were normal. An
overnight polysomnogram showed a prolonged sleep time of more than
10 hours. The multiple sleep latency test showed a mean sleep-onset latency of
0.6 minutes and no sleep-onset REM period on any of the five naps. Human
leukocyte antigen typing was negative for HLA-DQB1*0602; CSF hypocretin
level was not checked. After ruling out medication or substance abuse, a
diagnosis of idiopathic hypersomnia (IH) was made. Wake-promoting agents
were started, and the patient responded well to therapy.
Comment. IH is one of the most baffling conditions encountered by the
sleep physician. As the name suggests, the cause is unknown, and at this
time IH tends to be a catch-all diagnosis after other causes of hypersomnia
have been effectively ruled out. Treatment is symptomatic with stimulants
and wake-promoting agents.

Criteria for Idiopathic Hypersomnia With Long Sleep Timea
A. Almost daily excessive daytime sleepiness occurring for at least 3 months.

B. Documented prolonged nocturnal sleep of at least 10 hours with laborious
morning or end-of-nap arousals.
C. Nocturnal polysomnogram (PSG) excludes other causes of daytime sleepiness.
D. PSG documents a short sleep latency and a prolonged sleep period of greater
than 10 hours.
E. A multiple sleep latency test performed after the overnight PSG will show a
mean sleep latency of less than 8 minutes and fewer than two sleep-onset
REM episodes.
F. The condition is not explained by another sleep disorder, medical or
neurologic disorder, mental disorder, medication use, or substance use
disorder.
a
Diagnosis diaries are powerful tools to document

The diagnostic criteria as laid out by the sleep-wake schedule.31
the ICSD-2 are presented in Table 4-7
and Table 4-8. Subjective sleepiness is Differential Diagnosis
estimated using the Epworth Sleepi- Other causes of hypersomnia (Table 4-1)
ness Scale and objectified with the need to be meticulously considered and
MSLT. To help differentiate circadian excluded before a diagnosis of IH can
rhythm disorder, actigraphy and sleep be made.

Criteria for Idiopathic Hypersomnia Without Long
Sleep Timea
A. Almost daily excessive daytime sleepiness occurring for at least 3 months.

B. Normal nocturnal sleep of at least 6 hours and less than 10 hours with
laborious morning or end-of-nap arousals.
C. Nocturnal polysomnogram (PSG) excludes other causes of daytime sleepiness.
D. PSG documents a normal sleep period of greater than 6 hours but less than
10 hours.
E. A multiple sleep latency test performed after the overnight PSG will show a
mean sleep latency of less than 8 minutes and fewer than two sleep-onset
REM episodes.
F. The condition is not explained by another sleep disorder, medical or
neurologic disorder, mental disorder, medication use, or substance use
disorder.
a

Hypersomnias
KEY POINTS
h Naps are usually not Treatment first patients in Germany and New
refreshing in patients It is advisable to try behavioral interven- York, respectively.33 The syndrome
with idiopathic tions even if they are of unclear value in consists of symptoms of hyperphagia,
hypersomnia, in treatment of IH. Issues pertaining to hypersomnia, and hypersexuality.
contrast to patients sleep hygiene need to be emphasized, Case 4-3 outlines the typical presenta-
with narcolepsy, who including planning or taking naps if tion of this condition.
find scheduled naps possible. Naps, however, are usually Epidemiology. KLS is a rare cause
very rewarding. not refreshing in patients with IH, in of hypersomnia, with an estimated
h Kleine-Levin syndrome contrast to patients with narcolepsy, prevalence of 1 in 1 million. Although
consists of symptoms who find scheduled naps very reward- the peak age at initial presentation is
of hyperphagia, ing. Increasing the total time spent in usually in the second decade of life,
hypersomnia, bed is also not useful and should not be patients 4 years old and 80 years old
and hypersexuality. have been reported in the literature.
recommended. Approach to pharma-
h Kleine-Levin syndrome is cologic treatment is similar to that of nar- KLS is more common in men, who
a clinical diagnosis, and colepsy. Stimulants and wake-promoting outnumber women by a ratio of 2:1. A
the investigations are agents are the mainstay of treatment. disproportionately large number of
done merely to rule out cases are found in the Ashkenazi Jewish
Treatment with melatonin as well as
other causes of hyper-
levothyroxine has also been tried with population compared to patients of
somnia.
some success.32 Antidepressants have other ethnicities. No clear association
no role in the treatment of IH. has been demonstrated to suggest an
inheritable trait or genetic susceptibility
RECURRENT HYPERSOMNIA for the development of KLS, although
Kleine-Levin Syndrome one-third of patients with KLS report
Introduction. Kleine-Levin syndrome associated birth or developmental
(KLS) is a classic, but rare, cause of issues.34,35 Familial cases have also
recurrent hypersomnia. The eponym been reported, but these are rare.
was coined by Critchley and Hoffman Clinical presentation. The initial
in 1942, recognizing the work of episode in KLS is frequently preceded
Kleine and Levin, who reported the by a precipitating factor in 9 of 10
Case 4-3
A 23-year-old man experienced multiple episodes, each lasting a few days,
of hypersomnolence, binge eating, and excessive and inappropriate
sexual arousal occurring intermittently during the past 2 years. During
these episodes he was sleeping 18 to 20 hours a day. When awake, he
would go on an eating binge or report inappropriate sexual arousals.
These episodes would last days to weeks and be followed by spontaneous
and complete resolution of symptoms. He did not report any prodromal
symptoms and often had partial amnesia for his behavior during
these episodes. During one of these episodes he had an overnight
polysomnogram which showed increased sleep time but was otherwise
normal. Other laboratory and imaging studies were also normal.
Comment. Kleine-Levin syndrome is a clinical diagnosis, and the
investigations are done merely to rule out other causes of hypersomnia. As
in this case, a history of recurrent episodes of excessive daytime sleepiness
with binge eating and hypersexuality are key features of Kleine-Levin
syndrome. Various medications have been tried to treat this condition,
but none has been consistently effective.

KEY POINTS
patients. Infection or high fever is the Diagnosis. The diagnostic criteria are h Most episodes of
most common complaint. Stress, alco- outlined in the ICSD-2 with an empha- Kleine-Levin syndrome
hol use, travel, and sleep deprivation sis on the recurrence of the disorder resolve spontaneously
have also been reported to precipitate (Table 4-9). within a 30-day period,
symptoms of this syndrome. Less than Polysomnogram. Studies evaluat- and the interepisode
15% of patients can identify a prodromal ing PSGs done during and between hiatus almost never
event to account for recurrent episodes. episodes of hypersomnia show a tre- surpasses 15 months.
Clinically, patients report periods of mendous amount of discrepancy when h SPECT has demonstrated
excessive sleepiness that may last 2 days the results are compared. Therefore, no a reduced perfusion of
to 4 weeks with recurrence of symptoms clear and beneficial conclusions can be the thalamus during an
at least once per year. Patients typically drawn. Sleep study evaluation done by active Kleine-Levin
have normal cognitive functioning with Huang and colleagues showed no dif- syndrome episode that
normal alertness between episodes. ferences between PSG done during and eventually reversed to
EDS is explained by no other medical, between episodes. However, when the normal as the symptoms
resolved.
neurologic, sleep, or psychiatric disor- results were divided into the start and
der, nor by substance abuse or medica- end of episodes and analyzed sepa-
tion use. Few symptoms differ between rately, slow-wave sleep increased and
the sexes, although men present with REM sleep decreased significantly dur-
significantly more symptoms of hyper- ing the later half.36 MSLT performed in
sexuality than women. During an active patients with KLS has also shown
episode, the sleep needs increase dras- inconsistent results and is therefore
tically, with patients sleeping in excess of not used as a diagnostic criterion, em-
12 hours over a 24-hour period. Most phasizing the point that KLS is a clinical
episodes resolve spontaneously within diagnosis.
a 30-day period, and the interepisode Imaging studies. CT and MRI scans
hiatus almost never surpasses 15 months. have always been normal in patients
The recurrence of episodes becomes less with idiopathic KLS.33 SPECT, however,
frequent, less severe, and shorter in has demonstrated a reduced perfusion
duration as time passes. Persistent re- of the thalamus during an active KLS
missions have been reported in patients episode that eventually reversed to
when the disease started before adult- normal as the symptoms resolved. This
hood and when hypersexuality was not was the most reliable finding, present
present.34,35 in all subjects investigated.37

Edition: Diagnostic and Coding Manual Diagnostic Criteria
for Recurrent Hypersomnia (Kleine-Levin Syndrome and
Menstrual-Related)a
A. Recurrent episodes of excessive sleepiness last 2 days to 4 weeks.

B. The episodes recur at least once a year.
C. The patient has normal alertness, cognitive functioning, and mental status
between attacks.
D. The hypersomnia is not better explained by another sleep disorder, medical or
neurologic disorder, mental disorder, medication use, or substance use disorder.
a

Hypersomnias
KEY POINT
h Women with CSF analysis. One study demonstra- association of depression in up to one-
menstrual-related ted a decrease in the CSF hypocretin third of women with menstrual-related
hypersomnia experience level during a KLS episode when com- hypersomnia. No familial cases of this
episodes of recurrent pared with the baseline during an disorder have been identified. Some
sleepiness coinciding asymptomatic period and suggested a case reports indicate that treatment with
with their menstrual hypothalamic dysfunction that is inter- oral contraceptives may be effective. It is
cycles. mittent.38 It is not clear whether this suggested that the episodes of hyper-
decline in CSF hypocretin occurs as a somnia are triggered by progesterone,
cause or an effect of a KLS episode, or and the instigation of anovulatory cycles
even whether it occurs consistently. with oral contraceptive treatment causes
Pathology. Because KLS is a rare dis- an inhibitory effect on progesterone
order, brain tissue analysis is uncom- secretion, resulting in resolution of symp-
mon. No specific abnormalities of the toms. However, this concept is purely
hypothalamus have been demonstrated, hypothetic with no conclusive evidence
however.39 supporting or refuting it.
Treatment. Various treatments In addition to the primary hyper-
have been tried in patients with KLS. somnias described above, other causes
Only a limited number of patients have of hypersomnia as classified by the
demonstrated a major response to treat- ICSD-2 are briefly discussed below.
ment with valproic acid, lithium, aman-
tadine, or lamotrigine.35,40Y42 Modafinil BEHAVIORALLY INDUCED
has been tried and showed a decrease INSUFFICIENT SLEEP SYNDROME
in the duration of the episodes but had Classified under the category of hyper-
no effect on recurrence. Since the con- somnia of central origin, this cause of
dition is intermittent, the clinician has hypersomnia occurs as a result of sleep
to be careful before reporting a certain deprivation and is most commonly seen
treatment option successful, as it may among adolescents. It usually does not
in reality only coincide with the end of need intense investigation because the
an episode. history of sleep deprivation and of pa-
tients catching up on their sleep on
MENSTRUAL-RELATED weekends makes the diagnosis obvious.
HYPERSOMNIA If a sleep study is done, it will show a
Menstrual-related hypersomnia is a short sleep-onset latency and high sleep
very rare condition. Women with this efficiency and may occasionally also
disorder experience episodes of recur- reveal a SOREMP. Sleep deprivation
rent sleepiness coinciding with their may be a result of social or work-related
menstrual cycles. A diagnostic crite- factors, and patients may report neu-
rion, similar to one recommended for rocognitive impairment as a result of
KLS, has been put forth in the ICSD-2 insufficient sleep time. Stimulant med-
(Table 4-9). A review by Billiard and ications are not recommended, since
colleagues43 compared occurrence of behavioral modifications are sufficient
this disorder with other forms of to treat this condition.
recurrent hypersomnias, such as KLS,
in women and found that the onset of HYPERSOMNIA DUE TO
hypersomnia may occur at menarche, OTHER CAUSES
during menstruation alone, or during Metabolic syndromes, toxic or infec-
menstruation in conjunction with other tious disease processes, and drugs may
factors such as alcohol use or a bout of cause hypersomnia by depressing CNS
influenza. This review also noted the alerting centers. Traumatic brain injury

KEY POINT
(TBI) and neurodegenerative processes conducting an orchestra. The patient becomes
excited, has loss of muscle tone with unbuck- h Posttraumatic
that directly affect the CNS are also hypersomnia is
ling of the knees, and falls to the ground.
known to cause hypersomnia. When Consciousness is preserved completely, and he prevalent and often
evaluating a patient with hypersomnia, never loses awareness. He recovers quickly, missed as a cause
the history of medical conditions, such regaining his muscle strength and standing up of unexplained
as Niemann-Pick type C disease, Prader- as if he never experienced the episode. hypersomnia.
Willi syndrome, myotonic dystrophy, links.lww.com/CONT/A16
Parkinson disease, cervical spine or B 2013 Geert Mayer, MD, PhD. Used with
permission.
whiplash injury, and TBI, should either
be specifically asked for or investigated, Supplemental Digital Content 4-2
as deemed necessary. Posttraumatic REM sleep behavior disorder in a child. Video
hypersomnia is prevalent and often demonstrates REM sleep behavior disorder
missed as a cause of unexplained hyper- (RBD) in a child. RBD in children is narcolepsy
somnia. Other causes include multiple unless proven otherwise. Although the electro-
sclerosis, vascular disorders, and ence- graphic recordings are blurry, the video shows
the patient exhibiting dream enactment behavior
phalitis. Patients with EDS and symp- with loss of muscle tone during REM sleep. Pa-
toms of neuromyelitis optica who are tients with RBD require in-depth review and
positive for antiYaquaporin 4 antibody assessment for CNS hypersomnia, which is also a
(AQP4) have also been reported, sug- manifestation of anomalous REM sleep control.
gesting an immunologic attack to AQP4 links.lww.com/CONT/A17
resulting in damage to hypocretin- B 2013 Sona Nevsmalova, MD, DSc. Used with
secreting neurons and the develop- permission.
ment of secondary narcolepsy. Reports Supplemental Digital Content 4-3

of moderately decreased hypocretin Child cataplexy. Video demonstrates laughter-
levels in patients with secondary narco- induced cataplexy in a child. This child has the
lepsy exist in the literature. There are hypocretin gene defect leading to narcolepsy
also reports of improvement in symp- with cataplexy. He is dancing and playing, and
toms of hypersomnia in secondary children are laughing in the background,
which leads him to become excited and lose
narcolepsy with improvement in the muscle tone in the legs. While the condition is
causative neurologic disorder and con- exclusively genetically based in animals, it is not
comitant improvement in hypocretin the case in humans, and was not the case in this
levels. In addition to medical causes, a patient.
complete list of all current medications links.lww.com/CONT/A18
should be reviewed, since a simple mea- B 2013 Sona Nevsmalova, MD, DSc. Used with
sure of discontinuing a medication known permission.
to cause hypersomnia may be sufficient

to treat the patient effectively. The use of REFERENCES
over-the-counter medication and illicit 1. National Sleep Foundation. How much sleep
drug use must be elicited. When the cause do we really need? www.sleepfoundation.
of hypersomnia cannot be explained on org/article/how-sleep-works/how-much-
sleep-do-we-really-need. Accessed
the basis of an underlying medical con- December 5, 2012.
dition, medication, or drug use, the pos-
sibility of a psychiatric disorder should International classification of sleep
be considered and investigated. disorders, second edition: diagnostic and
coding manual. Westchester, IL: American
Academy of Sleep Medicine, 2005.
VIDEO LEGENDS 3. Schenck CH, Bassetti CL, Arnulf I, Mignot E.
Supplemental Digital Content 4-1 English translations of the first clinical
Adult cataplexy. Video demonstrates cataplexy reports on narcolepsy and cataplexy by
elicited by the strong emotional stimulus of Westphal and Gelineau in the late 19th

Hypersomnias
century, with commentary. J Clin Sleep Med 18. Littner MR, Kushida C, Wise M, et al.
2007;3(3):301Y311. Practice parameters for clinical use of
the multiple sleep latency test and the
4. Juji T, Satake M, Honda Y, Doi Y. HLA
maintenance of wakefulness test. Sleep
antigens in Japanese patients with narcolepsy.
2005;28(1):113Y121.
All the patients were DR2 positive. Tissue
Antigens 1984;24(5):316Y319. 19. Nishino S, Deguzman C, Yamadera W, et al.
Neurochemistry and biomarkers of
5. Mignot E, Lin X, Arrigoni J, et al. DQB1*0602
narcolepsy and other primary and
and DQA1*0102 (DQ1) are better markers
secondary hypersomnias. Sleep Med Clin
than DR2 for narcolepsy in Caucasian and
2012;7(2):233Y248.
black Americans. Sleep 1994;17(8 suppl):
S60YS67. 20. Kuczenski R, Segal DS. Effects of
methylphenidate on extracellular dopamine,
6. de Lecea L, Kilduff TS, Peyron C, et al. The
serotonin, and norepinephrine: comparison
hypocretins: hypothalamus-specific peptides
with amphetamine. J Neurochem
with neuroexcitatory activity. Proc Natl
1997;68(5):2032Y2037.
Acad Sci USA 1998;95(1):322Y327.
21. Moldofsky H, Broughton RJ, Hill JD. A
7. Nishino S, Ripley B, Overeem S, et al.
Hypocretin (orexin) deficiency in human randomized trial of the long-term,
narcolepsy. Lancet 2000;355(9197):39Y40. continued efficacy and safety of modafinil
in narcolepsy. Sleep Med 2000;1(2):
8. Ohayon MM, Priest RG, Zulley J, et al. 109Y116.
Prevalence of narcolepsy symptomatology
and diagnosis in the European general 22. Nishino S, Okuro M. Armodafinil for
population. Neurology 2002;58(12):1826Y1833. excessive daytime sleepiness. Drugs Today
(Barc) 2008;44(6):395Y414.
9. Dauvilliers Y, Billiard M, Montplaisir J.
Clinical aspects and pathophysiology of 23. Xyrem International Study Group. Further
narcolepsy. Clin Neurophysiol 2003;114(11): evidence supporting the use of sodium
2000Y2017. oxybate for the treatment of cataplexy:
a double-blind, placebo-controlled study
10. Bassetti CL, Billiard M, Mignot E, eds. Lung in 228 patients. Sleep Med 2005;6(5):
biology in health and disease: narcolepsy 415Y421.
and hypersomnia. Volume 220. New York,
NY: Informa Healthcare, 2007. 24. Morgenthaler TI, Kapur VK, Brown T,
et al. Practice parameters for the treatment
11. Sturzenegger C, Bassetti CL. The clinical of narcolepsy and other hypersomnias
spectrum of narcolepsy with cataplexy: a of central origin. Sleep 2007;30(12):
reappraisal. J Sleep Res 2004;13(4):395Y406. 1705Y1711.
12. Mignot E, Hayduk R, Black J, et al. HLA 25. Lin JS. Brain structures and mechanisms
DQB1*0602 is associated with cataplexy in involved in the control of cortical
509 narcoleptic patients. Sleep 1997;20(11): activation and wakefulness, with emphasis
1012Y1020. on the posterior hypothalamus and
13. Nishino S. The hypothalamic peptidergic histaminergic neurons. Sleep Med Rev
system, hypocretin/orexin and vigilance 2000;4(5):471Y503.
control. Neuropeptides 2007;41(3):117Y133. 26. Fujiki N, Yoshida Y, Ripley B, et al. Effects
14. Guilleminault C, Gelb M. Clinical aspects and of IV and ICV hypocretin-1 (orexin A) in
features of cataplexy. AdvNeurol 1995;67: hypocretin receptor-2 gene mutated
65Y77. narcoleptic dogs and IV hypocretin-1
replacement therapy in a
15. Overeem S, Reijntjes R, Huyser W, et al. hypocretin-ligand-deficient narcoleptic
Corticospinal excitability during laughter: dog. Sleep 2003;26(8):953Y959.
implications for cataplexy and the
comparison with REM sleep atonia. J Sleep 27. Scammell TE, Winrow CJ. Orexin receptors:
Res 2004;13(3):257Y264. pharmacology and therapeutic
opportunities. Annu Rev Pharmacol
16. Johns MW. A new method for measuring Toxicol 2011;51:243Y266.
daytime sleepiness: the Epworth Sleepiness
Scale. Sleep 1991;14(6):540Y545. 28. Roth B, Nevsimalova S, Rechtschaffen A.
Hypersomnia with sleep drunkenness.
17. Richardson GS, Carskadon MA, Flagg W, et al.
Arch Gen Psychiatry 1972;26(5):456Y462.
Excessive daytime sleepiness in man: multiple
sleep latency measurement in narcoleptic 29. Aldrich MS. The clinical spectrum of
and control subjects. Electroencephalogr narcolepsy and idiopathic hypersomnia.
Clin Neurophysiol 1978;45(5):621Y627. Neurology 1996;46(2):393Y401.

30. Heier MS, Evsiukova T, Vilming S, et al. 36. Huang YS, Lin YH, Guilleminault C.
CSF hypocretin-1 levels and clinical Polysomnography in Kleine-Levin syndrome.
profiles in narcolepsy and idiopathic CNS Neurology 2008;70(10):795Y801.
hypersomnia in Norway. Sleep 2007;30(8):
37. Huang YS, Guilleminault C, Kao PF, Liu FY.
969Y973.
SPECT findings in the Kleine-Levin
31. Bruck D, Parkes JD. A comparison of syndrome. Sleep 2005;28(8):955Y960.
idiopathic hypersomnia and narcolepsy-
38. Podesta C, Ferreras M, Mozzi M, et al.
cataplexy using self report measures and
Kleine-Levin syndrome in a 14-year-old girl:
sleep diary data. J Neurol Neurosurg
CSF hypocretin-1 measurements. Sleep Med
Psychiatry 1996;60(5):576Y578.
2006;7(8):649Y651.
32. Montplaisir J, Fantini L. Idiopathic
39. Carpenter S, Yassa R, Ochs R. A pathologic
hypersomnia: a diagnostic dilemma. A
basis for Kleine-Levin syndrome. Arch
commentary of Idiopathic hypersomnia
Neurol 1982;39(1):25Y28.
(M. Billiard and Y. Dauvilliers). Sleep Med
Rev 2001;5(5):361Y362. 40. Muratori F, Bertini N, Masi G. Efficacy of
lithium treatment in Kleine-Levin syndrome.
33. Critchley M, Hoffman H. The syndrome of
Eur Psychiatry 2002;17(4):232Y233.
periodic somnolence and morbid hunger
(Kleine-Levin syndrome). Br Med J 41. Surges R, Walker MC. A case of late-onset
1942;1(4230):137Y139. Kleine-Levin syndrome responding to
lamotrigine. Sleep Med 2009;10(3):394.
34. Arnulf I, Zeitzer JM, File J, et al. Kleine-Levin
syndrome: a systematic review of 186 cases 42. Crumley FE. Valproic acid for Kleine-Levin
in the literature. Brain 2005;128(pt 12): syndrome. J Am Acad Child Adolesc
2763Y2776. Psychiatry 1997;36(7):868Y869.
35. Arnulf I, Lin L, Gadoth N, et al. Kleine-Levin 43. Billiard M, Jaussent I, Dauvilliers Y, Besset A.
syndrome: a systematic study of 108 Recurrent hypersomnia: A review of 339
patients. Ann Neurol 2008;63(4):482Y493. cases. Sleep Med Rev 2011;15(4):247Y257.

Review Article
Sleep-Disordered
Dr Lori Panossian,
University of Pennsylvania,
Translational Research
Laboratories, 125 South
31st St Room 2125,
Philadelphia, PA 19104,
Breathing
lori.panossian@uphs.upenn.
edu. Lori Panossian, MD, MS; Joseph Daley, MD, PhD
Drs Panossian and Daley
report no disclosures. ABSTRACT
Unlabeled Use of
Purpose of Review: This article introduces readers to the clinical presentation,
Use Disclosure: Drs Panossian diagnosis, and treatment of sleep-disordered breathing and reviews the associated
and Daley report no risk factors and health consequences.
disclosures.
Recent Findings: Sleep-disordered breathing is associated with significant impair-
of Neurology. ments in daytime alertness and cognitive function as well as adverse health out-
comes. The initial treatment of choice is positive airway pressure. Improvements in
technology and mask delivery systems have helped to make this treatment more
comfortable and convenient for many patients.
Summary: Sleep-disordered breathing, particularly in the form of obstructive sleep
apnea, is highly prevalent in the general population and has important implications
for neurology patients. Sleep-disordered breathing is characterized by repetitive pe-
riods of cessation in breathing, termed apneas, or reductions in the amplitude of a
breath, known as hypopneas, that occur during sleep. These events are frequently
associated with fragmentation of sleep, declines in oxygen saturation, and sym-
pathetic nervous system activation with heart rate and blood pressure elevation.
Obstructive sleep apnea, which represents cessation of airflow, develops because of
factors such as anatomic obstruction of the upper airway related to obesity, excess
tissue bulk in the pharynx, and changes in muscle tone and nerve activity during
sleep. Central sleep apnea represents cessation of airflow along with absence or
significant reduction in respiratory effort during sleep and is more commonly found
in the setting of congestive heart failure, neurologic disorders, or cardiopulmonary
disease.
INTRODUCTION acterized by diminished amplitude of

Sleep-disordered breathing is an over- the inspiratory breath (30% to 90% air-
arching term used to describe various flow reduction for at least 10 seconds
distinct or occasionally overlapping syn- with at least 4% reduction in baseline
dromes, including obstructive sleep oxygen saturation), as depicted in
apnea (OSA), central sleep apnea, Figure 5-1.1 Although the AASM rec-
and hypoventilation. Sleep-disordered ommends the former definition of a
breathing is characterized by intermit- hypopnea, the alternative AASM defi-
tent periods of apnea, hypopnea, or nition may be appropriate to use for
respiratory effortYrelated arousals selected patients: a hypopnea is scored
(RERAs). Obstructive apnea events con- when airflow drops by at least 50% for
sist of transient cessations in airflow at least 10 seconds with either an
(90% or greater airflow reduction for associated 3% or greater reduction in
at least 10 seconds, as defined by the oxygen saturation, or an associated
American Academy of Sleep Medicine arousal from sleep.1 RERAs are periods
[AASM]), whereas hypopneas are char- of increased respiratory effort with

FIGURE 5-1 Polysomnographic example of obstructive apnea. A 60-second epoch of polysomnography during non-REM stage
N2 sleep demonstrating an obstructive apnea, defined as a 90% or greater loss of airflow for at least 10 seconds
with preserved respiratory effort. Note the absence of airflow through the nose and mouth despite ongoing
respiratory effort (as seen by the tracings of thoracic and abdominal movement), signifying obstruction of the upper airway with
consequences including oxygen desaturation and an EEG arousal from sleep. Channels from top to bottom represent EEG (left and
right central, left and right occipital), electrooculogram (left and right eyes), chin EMG, EKG, snoring, nasal pressure transducer, oral
thermistor, respiratory effort (thoracic and abdominal movement), and arterial oxygen saturation.
EEG = electroencephalograph; EMG = electromyogram; EKG = electrocardiogram; SaO2 = arterial oxygen saturation.
decreased airflow, crescendo snoring, tion. A subtype of sleep-disordered KEY POINTS

and transient EEG arousals from sleep breathing termed upper airway resist- h An obstructive apnea is
defined as cessation of
that do not meet AASM criteria for ance syndrome occurs among some
airflow with continued
apneas or hypopneas.2 patients with primarily RERAs, without
respiratory effort due to
The respiratory events that occur in associated significant oxygen desatura- complete upper airway
sleep-disordered breathing are typically tion or frank apneas and hypopneas. occlusion.
transitory and self-limited. They often Upper airway resistance syndrome is
h A hypopnea is a partial
induce brief arousals or microarousals thought to have similar pathophysiol-
decrement in airflow with
from sleep, which in turn restore a ogy and presents with similar symp- an associated physiologic
normal breathing pattern.3 Apneas and toms as OSA.2 consequence, either an
hypopneas frequently cause transient OSA occurs as a result of apneas and arousal or oxygen
oxygen desaturation, but this may not hypopneas that are primarily caused by desaturation, due to
always occur, especially among patients physical obstruction of the extrathoracic partial upper airway
with normal baseline pulmonary func- upper airway. Typically during these collapse.

Sleep-Disordered Breathing
events, complete or partial collapse of cessation or significant reduction in

soft tissue and pharyngeal musculature respiratory effort or drive (Figure 5-2).
occurs during sleep. This pattern can Respiratory effort, mediated by CNS
vary by stage of sleep and by body or brainstem respiratory control centers
head position and tends to be partic- in the pons and medulla, can be
ularly severe when in the supine posi- assessed during polysomnography
tion or during REM sleep. The normal (PSG) by the use of thoracic and
skeletal muscle atonia associated with abdominal respiratory inductance ple-
REM sleep can exacerbate airway col- thysmography belts. The belts detect
lapse in susceptible people.4,5 movements of the chest and abdomen
On the other hand, central sleep during inspiration and expiration,
apnea (CSA) is unrelated to physical which are surrogates for respiratory
obstruction but instead is caused by effort. In central apnea, transient
FIGURE 5-2 Polysomnographic example of central apnea. A 60-second epoch of polysomnography during non-REM stage N1
sleep demonstrating a central apnea, defined as a minimum of 10 seconds of airflow loss with associated absence
of respiratory effort. Note the absence of airflow through the nose and mouth and the loss of respiratory effort in
the chest and abdomen. The event is terminated by an EEG arousal from sleep. Channels from top to bottom represent EEG (left
and right central, left and right occipital), electrooculogram (left and right eyes), chin EMG, EKG, snoring, nasal pressure transducer,
oral thermistor, respiratory effort (thoracic and abdominal movement), and arterial oxygen saturation.

KEY POINTS
pauses in respiratory effort result in men.6,7 When not including sleepiness h A mixed apnea is
cessation of airflow, often followed by symptoms in the criteria, the preva- defined as a period of
oxygen desaturation or an arousal from lence of OSA characterized solely by airflow cessation without
sleep. Combinations of central and ob- apnea or hypopnea events is 9% among respiratory effort followed
structive apneas can occur in the same middle-aged women and 24% in men. by a period of resumed
individual, a condition termed complex This number may actually be an under- effort with continued
sleep apnea syndrome when the estimate of the true prevalence. Most decrements in airflow.
events occur with sufficient frequency. epidemiologic studies for OSA were h Obstructive sleep apnea
When a combination of central and performed during the previous 2 de- is a highly prevalent
obstructive components occurs within cades; in the interim, advances have condition that occurs
the same breath, it is termed a mixed occurred in the sensitivity of polysom- predominantly in
apnea. During mixed apneas, no res- nographic equipment (thereby increas- middle-aged or
piratory effort occurs during the initial ing the likelihood of detection of OSA), older men and
portion of the breath, followed by and rates of obesity, which is a major postmenopausal women.
resumption of effort but persistently risk factor for OSA, have significantly
diminished or absent airflow. increased.8 OSA is 1.5 to 4.0 times
more common in men, and prevalence
OBSTRUCTIVE SLEEP APNEA also increases with age.7,9 After meno-
Epidemiology and Risk Factors pause, womens risk approximates that
OSA is highly prevalent in the general of men (Case 5-1).7 Craniofacial bony
population. Population-based studies dimensions are a significant contributor
estimate the prevalence of OSA among even in the absence of obesity, espe-
working people aged 30 to 60 to be cially among Asian populations and
approximately 2% of women and 4% of some whites.10
Case 5-1
A 63-year-old woman reported unrefreshing sleep and frequent awakenings during which she felt
sweaty and hot with nocturia twice nightly. She snored softly and often awoke with a dull bitemporal
headache that resolved spontaneously within hours. She was postmenopausal, and her daytime hot
flashes had stopped at age 56. She requested a prescription for sleeping pills to prevent awakenings.
During the day, she felt tired and had difficulty concentrating and remembering tasks. She slept for
8 hours nightly and had a regular bedtime. She had no cataplexy, sleep paralysis, hypnagogic
hallucinations, or dream enactment behavior.
Examination findings were blood pressure, 123/78 mm Hg; body mass index, 27 kg/m2; and neck
circumference, 38.6 cm (15.2 in). Nasal turbinates and septum were normal, uvula and tonsils were not
enlarged, and no macroglossia or retrognathia was present. The hard palate was high-arched and
narrow. The peritonsillar lateral walls had redundant tissue.
Polysomnography (PSG) demonstrated moderate obstructive sleep apnea (OSA) with an overall
apnea-hypopnea index (AHI) of 16 events/h, supine AHI of 19 events/h, and REM-sleep AHI of
43 events/h (Figure 5-3). The oxygen saturation nadir was 83%. The periodic limb movement index
was 8 per hour. The PSG was repeated for continuous positive airway pressure (CPAP) titration.
The patient was fitted with a variety of masks and liked a nasal mask best. At a CPAP pressure
of 9-cm water, the AHI improved to 2 events/h, supine AHI to 3 events/h, and REM-sleep AHI
to 0 events/h. The oxygen saturation nadir was 94%. The periodic limb movement index was
0 events/h.
After 6 weeks of using CPAP, she reported significantly improved symptoms. She initially had
difficulty falling asleep with CPAP but was now using it for 8 hours nightly with refreshing sleep

and improved
subjective memory
and concentration.
Awakenings were
now rare, and her
nocturia and
morning headaches
had resolved.
Comment. Women
may have atypical
OSA presenting FIGURE 5-3 Hypnogram of REM-related apnea. This hypnogram summarizes stages of sleep
symptoms, with older over the course of the night and temporally correlates them with respiratory events.
As shown by the red arrows, this patient exhibits apneas and hypopneas (vertical
age; lower body mass dashes) that occur primarily during periods of REM sleep (horizontal green bars).
index; and lower
incidence of snoring,
witnessed apneas, or choking arousals. Symptoms often develop when the woman is perimenopausal.
Sleep-maintenance insomnia may present similarly, but patients with OSA-suggestive features (eg, snoring,
morning headaches, oropharyngeal crowding) should first undergo evaluation for sleep-disordered
breathing. Sedative-hypnotic drugs can worsen OSA severity and are contraindicated in untreated OSA.
The PSG also demonstrated mild periodic limb movements, which can be secondary to untreated OSA
and frequently resolve with CPAP. OSA was moderate overall but severe during REM sleep (Figure 5-3).
Isolated REM-related OSA can also occur but has an unknown impact on long-term health.
A family history of snoring or sleep- ease, multiple system atrophy, and neu-
disordered breathing can increase ones romuscular disorders that weaken the
risk of OSA, possibly because of similar diaphragm (causing hypoventilation) or
craniofacial anatomic features as well as pharynx (contributing to OSA), such as
similar incidences of obesity among myasthenia gravis or ALS (Table 5-1).16Y25
relatives. Behavioral risk factors for
OSA include use of sedatives or alcohol Pathophysiology
and sleeping in the supine position. Most people with OSA have normal re-
OSA incidence is especially high in spiratory patterns during wakefulness
people with certain medical comorbid- with appropriate feedback control sys-
ities, including type 1 and type 2 tems. However, changes occur during
diabetes mellitus, polycystic ovarian sleep that predispose them to a sleep-
syndrome, congestive heart failure, disordered breathing pattern. A normal
stroke, or Down syndrome.7,11Y13 Hypo- sleep-related decrease, which occurs in
thyroidism can also exacerbate OSA.14 neuronal excitatory input to pharyngeal
While frequently associated with snor- dilator muscles, is excessively reduced
ing, chronic nasal obstruction plays a among many individuals with OSA,
relatively minor role in the pathogene- resulting in hypotonic pharyngeal mus-
sis of OSA, although use of intranasal cles and increased risk of airway col-
steroid medications can help to improve lapse.26 This abnormality may be due
the efficacy of OSA treatment.15 Neuro- to impaired sensory, cortical, or motor
logic disorders associated with an in- components of the upper airway reflex
creased risk of sleep-disordered breathing that serves to resist upper airway col-
include stroke, epilepsy, Parkinson dis- lapse in response to negative pressure

KEY POINT
TABLE 5-1 Mechanisms of Sleep-Disordered Breathing Induction in h Obstructive sleep apnea

Key Neurologic Diseases is viewed as a primarily
mechanical problem of
Type and Presumed Mechanism of the upper airway, with
Neurologic Disease Sleep-Disordered Breathing both neuronal and
Acute stroke Obstructive sleep apnea (OSA): dysphagia and upper anatomic factors
airway muscle weakness, supine positioning.19 contributing to
increased collapsibility.
Central sleep apnea: injury to brainstem respiratory
control centers, cerebral edema, impaired consciousness.20
Neuromuscular disease OSA: upper airway muscle weakness.
Central sleep apnea: weakness of chest wall
muscles and diaphragm, exacerbated by
sleep-related physiologic muscle relaxation.21
Parkinson disease No clear association. OSA (when present)
possibly caused by motor symptoms affecting
upper airway patency at the level of the glottis.22
Multiple system atrophy OSA: respiratory stridor during sleep.
Cheyne-Stokes respirations: caused by vocal
cord abductor paralysis, bulbar weakness, injury
to brainstem respiratory control neurons.23,24
Epilepsy OSA: Antiepileptic drugs can exacerbate OSA risk
factors such as obesity, increased neck circumference,
and upper airway collapsibility. Vagus nerve
stimulators can affect respiration during sleep.25
during inspiration.27 Sensory deficits airway pressure even while awake. When
may include impaired functioning of coupled with even a normal degree of
mechanoreceptors that sense airflow, reduced pharyngeal muscle tone dur-
pressure, and muscle tone.28 Cortical ing sleep, airway obstruction occurs.31
arousability may be blunted during ap- Craniofacial factors can include a high-
neas, hypoxia, or hypercapnia. Motor arched palate and insufficient pro-
nerve dysfunction may reduce activa- trusion or width of the maxilla and
tion of important pharyngeal dilator mandible.10 Common soft tissue fea-
muscles such as the genioglossus, re- tures include adenotonsillar hypertro-
sulting in pharyngeal muscle hypotonia phy, an elongated and edematous uvula,
and increased susceptibility to airway and an enlarged tongue relative to
collapse.27,29 Snoring-induced vibratory the size of the oropharyngeal cavity
trauma and mechanical strain from re- (macroglossia). Obesity can significantly
peated upper airway collapse may con- contribute to soft tissue hypertrophy
tribute to the development of irreversible and narrowing of the pharyngeal space.
peripheral nerve injury in OSA.28,30 Each of these predisposing factors may
Anatomic factors also play a prom- be present to differing degrees in dif-
inent role. People with OSA can have ferent people.
differences in upper airway soft tissue
volume and craniofacial anatomy that Symptoms
result in a narrowed pharyngeal lumen, The diagnosis of OSA is based on a
causing abnormal increases in upper combination of clinical and PSG criteria.

KEY POINT
h Symptoms suggestive of The clinical presentation of OSA may 43.2 cm [17 in] in men or greater than
obstructive sleep apnea include symptoms such as snoring, or equal to 40.6 cm [16 in] in women)
include snoring; apneas in sleep that are witnessed by and obese body habitus as determined
witnessed apneas; observers, a history of awakenings by a BMI of greater than 30 kg/m2. The
arousals associated with associated with a sensation of choking anatomy of the face and oral cavity is
choking, gasping, and or gasping for air, nocturia, morning also helpful in gauging the likelihood of
diaphoretic awakenings headaches, heavy diaphoresis during developing a mechanical obstruction
from sleep; and excessive sleep (especially in the upper chest during sleep. One prospective study
daytime sleepiness. and neck area), and excessive daytime of 420 subjects found an up to 2.6-fold
sleepiness. The degree of subjective increase in the adjusted odds ratio for
daytime sleepiness can be gauged using OSA if subjects had abnormal morpho-
the Epworth Sleepiness Scale (see the metric measures of the upper airway.
article Approach to and Evaluation These included narrowing of the pos-
of Sleep Disorders), an eight-question terior pharyngeal space due to im-
measure of the subjective likelihood of pingement by peritonsillar tissues,
the patient dozing unintentionally in tonsillar hypertrophy, macroglossia
various common daytime situations.32 (tongue enlarged above the level of
An Epworth Sleepiness Scale score the mandibular occlusion plane), retro-
greater than 10 of 24 is consistent with gnathia (recessed chin), and enlarged
subjective excessive daytime sleepiness. uvula (greater than 1.5 cm [0.6 in] in
Screening tools such as the STOP-BANG length or greater than 1.0 cm [0.4 in] in
questionnaire or Berlin Questionnaire width).42 Such physical measures of
can also aid practitioners in assessing oral cavity parameters, BMI, neck cir-
their patients OSA risks.33,34 Patients cumference, and pharyngeal adiposity
may report memory problems, irrita- are strongly associated with OSA.43,44
ble mood, and reduced alertness and Thus, facial morphology and orophar-
concentration.35 People with OSA have yngeal examination are important parts
a significantly higher risk of motor of the OSA evaluation. The Mallampati
vehicle accidents because of impaired classification, originally developed to
alertness or falling asleep while driving, assess for ease of endotracheal intuba-
and this risk does not necessarily cor- tion, has also been adapted to help
relate with the severity of the OSA.36 predict likelihood of OSA (see the
This issue can be of particular concern article Approach to and Evaluation of
for commercial drivers.37 OSA is also Sleep Disorders).45
associated with nocturnal gastroeso-
phageal reflux because obstructive Polysomnography
events can increase intra-abdominal Patients who have history and ex-
pressure, which may eventually weaken amination findings suggestive of OSA
lower esophageal sphincter tone.38,39 should undergo confirmatory testing
Less common symptoms include peri- with PSG. Full PSG combines EEG for
odic limb movements in sleep, dream determination of sleep stages, surface
enactment behavior, and sleepwalking EMG to measure neck muscle tone and
caused by incomplete arousals trig- limb movements, electrooculogram for
gered by obstructive events.40,41 assessing eye movements, respiratory
inductance plethysmography belts for
Physical Examination measurement of thoracic and abdomi-
Suggestive physical examination find- nal respiratory effort, pulse oximetry,
ings for OSA include an enlarged neck ECG, and monitors to detect snoring
circumference (greater than or equal to and airflow movement through the

FIGURE 5-4 Polysomnographic depiction of Cheyne-Stokes respirations. A 5-minute epoch from a polysomnogram depicting
Cheyne-Stokes respirations, defined as three or more cycles of crescendo-decrescendo respiratory amplitude
alternating with central apneas. Red curved arrows denote resumption of crescendo-decrescendo breathing
pattern. Channels from top to bottom represent EEG (left and right central, left and right occipital), electrooculogram (left
and right eyes), chin EMG, EKG, snoring, nasal pressure transducer, oral thermistor, respiratory effort (thoracic and abdominal
movement), and arterial oxygen saturation.
nose and mouth (Figure 5-1, Figure 5-2, they tend to underestimate the severity KEY POINT
Figure 5-4). While PSG is typically per- of OSA, particularly when apneas or h Polysomnography is the
formed in the sleep laboratory, this test hypopneas are associated with arousals diagnostic modality of
choice for obstructive
has also been adapted and simplified without significant oxygen desatura-
sleep apnea and other
for home diagnostic use, with meas- tion. AASM guidelines recommend
sleep disorders,
ures of airflow and oxygenation but using portable monitors for diagnosis although monitors with
without use of EEG in some circum- only in patients with a high pretest fewer channels have
stances. In the appropriate clinical probability of OSA and no significant been validated in certain
context, home portable monitor test- medical comorbidities.47 Further dis- populations for
ing can result in satisfactory treatment cussion of home sleep testing is pro- obstructive sleep apnea
outcomes that are comparable to using vided in the article In-Home Testing detection.
in-laboratory PSG.46 However, because for Obstructive Sleep Apnea.
most home monitors cannot distin- The severity of OSA is determined by
guish between sleep and wake states, the AHI, which is a measure of the

KEY POINTS
h The apnea-hypopnea number of apneas and hypopneas per associated with OSA also include plate-
index is the measure hour. In adults, an AHI of 5 events/h or let aggregation, vascular endothelial cell
used to define the greater is consistent with a diagnosis of dysfunction, and metabolic dysregula-
severity of sleep OSA. The AHI is further gradated to tion, which can increase the overall
apnea; 5 or greater is quantify the degrees of severity of OSA, incidence of coronary artery disease
considered to be with an AHI between 5 events/h and and stroke and worsen glycemic con-
abnormal. 14 events/h considered mild OSA, 15 to trol in patients with diabetes melli-
h Continuous positive 29 events/h considered moderate OSA, tus. 50,52,53 Among patients with
airway pressure uses and 30 events/h or greater considered epilepsy, OSA can worsen seizure fre-
forced air to stent the severe OSA. quency if left untreated.54 It can also
airway open and reduce increase the risk of developing demen-
obstructive events. Long-Term Consequences tia and exacerbate the degree of cogni-
Many patients are motivated to initiate tive dysfunction in people with mild
treatment for OSA due to symptoms cognitive impairment.55,56
such as excessive daytime sleepiness,
fragmented sleep, and bed partner re- Treatment Options
ports of snoring and periods of breath- The mainstay of treatment for OSA
ing cessation. However, some patients consists of the delivery of positive airway
experience no overt daytime symptoms pressure (PAP) through a tightly fitted
and may be reluctant to treat an asymp- facial mask. The pressurized air acts as a
tomatic disorder. In all instances, it is pneumatic stent to maintain patency
the clinicians responsibility to counsel of the upper airway during sleep. PAP
patients about the serious potential treatment typically uses room air,
consequences of OSA and the impor- although supplemental oxygen may also
tance of adequate treatment. Educating be used if a concurrent pulmonary
patients about the pathophysiology and problem is present. Different PAP modal-
consequences of OSA, including the ities include CPAP, wherein a set air
risks of drowsy driving, can significantly pressure is delivered throughout sleep;
affect treatment adherence.48 auto-CPAP, which detects variations in
Untreated, OSA can cause or exacer- the degree of obstruction and automati-
bate a substantial number of medical cally adjusts the amount of air pressure
comorbidities. Most of the sequelae to compensate; and bilevel PAP, which
stem from physiologic changes that delivers two different air pressures with
occur in response to chronic apneas or each breath (a higher pressure during
hypopneas. Fragmentation of sleep due inspiration and a lower pressure during
to repeated respiratory arousals can expiration), noninvasively ventilating the
adversely affect wake behavior, includ- patient (Table 5-2). The appropriate
ing mood, concentration, vigilance, and pressure settings are typically deter-
attention (Case 5-1).49 Intermittent mined during a PAP titration PSG. PAP
hypoxia and hypercapnia over time is a highly effective treatment for OSA,
can increase cardiovascular risk and successfully normalizing AHI and im-
cause neuronal injury.50,51 OSA is also proving waking symptoms in most pa-
associated with altered sympathetic and tients. It is therefore considered the
catecholaminergic neuronal activity, current treatment of choice for OSA.
with overcompensatory elevations in Limitations of PAP treatment are
autonomic tone that increase risk of primarily related to patient discomfort
hypertension, cor pulmonale, conges- or difficulty acclimating to the device.
tive heart failure, arrhythmias, and Technologic advances in delivery sys-
sudden death. Physiologic changes tems have helped with some of these

TABLE 5-2 Summary of Treatment Options for Sleep-Disordered Breathing
Treatment Modality Specific Treatment Indication

Positive airway pressure (PAP)
Continuous positive airway Obstructive sleep apnea (OSA)
pressure (CPAP) Central/complex sleep apnea in
some cases
Bilevel PAP OSA with intolerance of CPAP pressure
or aerophagia (unintentional passage
of air through the lower esophageal
sphincter into the stomach during
PAP treatment)
Central/complex sleep apnea,
Cheyne-Stokes respirations
Obesity hypoventilation syndrome
Neuromuscular disease or diaphragmatic
weakness
Adaptive servo-ventilation Central/complex sleep apnea,
Cheyne-Stokes respirations
Oral appliances
Tongue retaining device Mild to moderate OSA
Mandibular repositioning device Severe OSA with PAP intolerance
Soft palate lifting device Mild to moderate OSA
Positional therapy Avoidance of supine sleep Primarily positional OSA
Surgical treatments
Septoplasty Nasopharyngeal obstruction
Turbinate reduction
Adenoidectomy
Tonsillectomy Oropharyngeal obstruction
Uvulopalatopharyngoplasty
Midline glossectomy Hypopharyngeal obstruction
Base-of-tongue reduction
Genioglossus advancement
Hyoid suspension
Mandibular advancement
Tracheostomy Tracheal obstruction
Maxillomandibular advancement Obstruction at multiple sites
Bariatric surgery Morbid obesity
Expiratory positive airway Single-use nasal EPAP Mild OSA

pressure (EPAP)

issues. Some newer mask styles such as OSA with significant medical comorbid-
the nasal pillows interface are smaller ities when all other treatment options
with less obtrusive headgear. The use of have been exhausted. A recent update
heated humidification has helped re- of AASM practice parameters reviewing
duce nasal congestion and mouth dry- studies of surgical treatment options for
ness that can occur with PAP treatment. OSA found varying degrees of success
Treatment of chronic nasal congestion for these procedures, and no one
with intranasal saline or steroid sprays procedure was consistently effective.58
can also improve PAP tolerance. For One of the most commonly performed
patients with claustrophobia, gradual procedures, uvulopalatopharyngoplasty,
desensitization programs have been appears to be more effective in mild
used with some success.57 Bilevel PAP OSA and has an approximately 40% to
may be better tolerated by patients 50% success rate.59 However, surgical
requiring higher PAP pressures and is success is defined by most studies as a
also an effective treatment for CSA. 50% reduction in baseline AHI; there-
For some patients, OSA is primarily fore, the postoperative AHI may remain
present when sleeping in the supine in the abnormal range and patients may
position because of mechanical changes still have significant residual OSA.60,61
associated with neck positioning and The surgical cure rate (AHI less than 5
gravity. The severity of their OSA events/h) of uvulopalatopharyngoplasty
improves dramatically when sleeping in is estimated at 16%.59
the lateral or prone positions. For such Other alternatives to PAP ther-
patients, an effective treatment may apy include oral appliances, typically
exclusively consist of using special pil- fashioned by dentists or oral surgeons
lows or other positioning devices to specializing in OSA, which can be used
help them avoid supine sleep. This in some patients with mild to moderate
strategy is termed positional therapy. disease (Table 5-2).62 A variety of styles
It is associated with modest reductions of oral appliances are available, and
in the AHI but is less effective for most work by repositioning the man-
severe OSA. A concern is that treat- dible to increase forward and down-
ment may not be completely effective ward protrusion, thereby widening the
throughout the night or that patient upper airway space in the posterior
adherence to therapy may wane with pharynx.63 A recently developed treat-
time. However, a recent study demon- ment for OSA is nasal expiratory pos-
strated a reasonable compliance of 74% itive airway pressure (EPAP), which is a
and persistent efficacy in lowering AHI single-use device sealed into each
after 3 months of use at home.32 nostril with adhesive. Its mechanical
Surgical treatment options for OSA valves provide high expiratory resist-
consist of a variety of procedures in- ance, creating positive airway pressure
tended to reduce pharyngeal soft tissue during expiratory breaths and acting as
bulk and correct nasal obstruction a pneumatic splint to maintain upper
(Table 5-2). These range from more airway patency.64 A multicenter, double-
aggressive surgeries, such as maxillo- blind, randomized, controlled trial
mandibular advancement and uvulopa- found that 3 months of nasal EPAP
latopharyngoplasty, to somewhat less reduced AHI by at least 50% from a
complex procedures, such as radiofre- baseline in the mild to low-moderate
quency ablation and soft palatal OSA range (median baseline AHI
implants.47 Tracheostomy is also used 13.8 events/h to 16.7 events/h) in 51%
but is typically reserved for very severe of patients.64 Therefore, nasal EPAP may

KEY POINT
be a useful new treatment option for related to changes in hemodynamics in h A central apnea is
mild OSA, but insufficient data exist for the left heart, and consequent augmen- defined by cessation of
its role in moderate to severe OSA with tation of peripheral and central chemo- airflow without evidence
significant oxygen desaturation events. sensitivity. This hypersensitivity can lead of respiratory effort.
No effective pharmacologic treatment for to an exaggerated response to the fall in
OSA is available, and oxygen treatment partial pressure of arterial oxygen (PaO2)
in the absence of PAP is also ineffec- and rise in PaCO2 seen during a single
tive.65 Weight loss (by either surgical apnea, overstimulating ventilation and
means or dietary and lifestyle modifi- again reducing PaCO2 below the apneic
cations) should be recommended for threshold.69 This can lead to a cyclic
all obese patients with OSA and can pattern of hyperventilation and hypoven-
significantly improve sleep-disordered tilation, known as Cheyne-Stokes respira-
breathing.66,67 The various treatment tions (Figure 5-4).4 Central apneas can
options for sleep-disordered breathing also be seen in other hypocapnic states,
are summarized in Table 5-2. such as the periodic breathing of high
altitudes. Central apneas may also occur
CENTRAL SLEEP APNEA in the setting of hypercapnia. Medica-
Central apnea is defined as at least a 10- tions such as opiates can lead to CSA by
second period of loss of airflow with suppressing neuronal activity in respi-
the absence of respiratory effort indica- ratory brain centers.70 Diseases of brain-
tive of a brief loss of ventilatory drive.1 stem or autonomic dysfunction, such
During sleep, respiration is primarily as multiple system atrophy or lesions
dictated by partial pressure of arterial of the cervical spinal cord, may be as-
carbon dioxide (PaCO2). There is a sociated with central apneas.
level of PaCO2 below which a pause in
breathing will occur, termed the apneic SLEEP-RELATED
threshold.68 The apneic threshold is HYPOVENTILATION
higher during wake than sleep; thus, a Sleep-disordered breathing also en-
brief central apnea may normally be compasses hypoventilation, which can
observed during the transition from be exacerbated during sleep or may
wake to sleep at sleep initiation and precede the onset of hypoventilation
following brief arousals, as the PaCO2 during wakefulness. These conditions
levels rise again to the level that will include obesity hypoventilation syn-
stimulate respiration. drome (OHS), hypoventilation due to
The respiratory control system is neuromuscular disorders, medication-
regulated by pulmonary vagal receptors related hypoventilation, hypoventila-
and central and peripheral chemore- tion with brainstem dysfunction, and
ceptors. Central sensors in the medulla central alveolar hypoventilation.
are stimulated by hypercapnia, while OHS is defined as a triad of obesity
peripheral sensors in the carotid body (BMI of 30 kg/m2 or greater): (1) waking
are driven by both hypercapnia and hypercapnia (PaCO2 of 45 mm Hg or
hypoxia. Voluntary mechanisms com- greater), (2) hypoxemia (PaO2 of 70 mm
pensate for any disruptions in this Hg or less), and (3) sleep-disordered
automated control during wakefulness breathing in the absence of any other
and are absent during sleep, which may cause of hypoventilation such as pul-
facilitate the emergence of abnormal monary disease, metabolic conditions,
breathing patterns (Case 5-2). or neuromuscular disorders.71 The
For instance, in heart failure, CSA can type of sleep-disordered breathing seen
develop because of chronic hypocapnia in OHS is most commonly OSA, but

Case 5-2
A 57-year-old man presented with a long history of snoring and disrupted sleep. He went to bed
regularly between 10:00 PM and 11:00 PM, and would fall asleep quickly. He aroused briefly twice a
night for nocturia and awakened at 7:30 AM. He often fell asleep unintentionally when inactive. His
Epworth Sleepiness Scale score was 15 of 24, consistent with hypersomnolence.
His medical history was notable for nonischemic cardiomyopathy, congestive heart failure with
an ejection fraction of 15% to 20%, hypertension, and type 2 diabetes mellitus. His medications
included carvedilol, hydralazine, lisinopril, and furosemide.
Examination findings were blood pressure, 146/70 mm Hg; heart rate, 68; height, 1.8 m (5 ft 11 in);
weight, 82 kg (181 lbs); body mass index, 25.31 kg/m2. Notable findings included a crowded
oropharynx and a modified Mallampati class IV airway. No peripheral edema was present.
A diagnostic polysomnogram (PSG) demonstrated severe obstructive sleep apnea (OSA) with an
apnea-hypopnea index of 40 events/h and oxyhemoglobin saturation nadir of 73%. During the
continuous positive airway pressure (CPAP) titration PSG at CPAP levels that alleviated his obstructive
events, significant central sleep apnea (CSA) emerged, with several prolonged episodes of
crescendo-decrescendo breathing consistent with Cheyne-Stokes respirations (Figure 5-4).
Adaptive servo-ventilation titration PSG found that at settings of an end-expiratory pressure of 7 cm
of water with variable-pressure inspiratory support, both the obstructive and central apneas improved
(residual apnea-hypopnea index of 4.6 events/h) and oxyhemoglobin saturation nadir improved to 86%.
At follow-up after 1 month of therapy, the patient reported a great alleviation of his hypersomnolence.
Comment. The most common condition associated with CSA is congestive heart failure. Often, the
Cheyne-Stokes respiratory pattern is observed. First-line therapy for this condition in the setting of heart
failure is medical optimization, as this may dramatically improve sleep-disordered breathing. However,
CSA and Cheyne-Stokes respirations may persist even when the patients heart failure is well controlled.
Severe OSA may prevent the manifestation of central apnea on PSG, and this breathing pattern may only
emerge once CPAP therapy is initiated. The clinical significance of CPAP-emergent central apnea, also
termed complex sleep apnea, remains controversial as it self-resolves over time in most cases. Given this
patients underlying heart failure, an alternate mode of pressure support was justified. Adaptive
servo-ventilation and other modes of variable pressure support use a constant end-expiratory pressure to
reduce or eliminate obstructive events. On a breath-by-breath basis, they deliver varying levels of
inspiratory pressure support to maintain the tidal volume and overall minute ventilation.
10% of patients also have sleep hypo- cated OSA they also have concurrent
ventilation (PaCO2 that is at least 10 dyspnea, peripheral edema, and other
mm Hg greater in sleep than in wak- physical examination findings of cor
ing, or significant oxygen desaturations pulmonale.72 OHS is a diagnosis of
unrelated to apneas or hypopneas).71 exclusion; once other causes of hypo-
This syndrome is distinct from simple ventilation have been ruled out, the
obesity with OSA, in that OHS patients diagnosis is based on physical exami-
have increased risk of pulmonary hyper- nation, PSG findings, and hypercapnia
tension, more severe upper airway ob- on an arterial blood gas. The preferred
struction, abnormally high mechanical treatment is nocturnal CPAP, or bilevel
load on respiratory muscles due to adi- PAP for patients with predominantly
posity, and blunted compensatory respi- central hypoventilation.73
ratory drive in response to hypercapnia Hypoventilation is frequently seen in
and hypoxia.71 Patients often present the setting of neuromuscular disease as-
with typical OSA symptoms of snoring, sociated with decreased vital capacity and
nocturnal apneas, and excessive daytime respiratory muscle weakness. Hypoven-
sleepiness, but in contrast to uncompli- tilation is further exacerbated during

KEY POINT
sleep, especially during REM sleep tion, particularly bilevel PAP with or h Central sleep apnea can
when ventilation is driven primarily by without a backup rate.78,79 be seen in a variety of
the diaphragm because of normal Another condition characterized by conditions, including
REM-related skeletal muscle atonia. central events is central alveolar hypo- congestive heart failure,
Patients who are dependent on skeletal ventilation, which comes in two forms, medullary lesions, and
accessory muscles of respiration may acquired and congenital. Acquired cen- autonomic dysregulation.
experience profound hypoventilation tral alveolar hypoventilation may be
during REM sleep, especially if there is seen following injury to the respiratory
concurrent diaphragmatic weakness centers in the medulla, for instance
such as in ALS.74 Symptoms can in- from trauma, encephalitis, neoplasms,
clude excessive daytime sleepiness, or stroke. A much rarer, congenital,
headaches, and poor sleep quality with central hypoventilation syndrome typi-
nightmares and enuresis.75 Treatment cally presents in the first year of life with
with noninvasive mechanical ventila- hypoxia, hypercapnia, and prolonged
tion modalities such as bilevel PAP central apneas during sleep, although a
can alleviate symptoms in the short late-onset form has been described in
term and may prolong survival in pa- adults.80,81 This condition is caused by
tients with motor neuron diseases.75 trinucleotide expansion mutations in
Chronic opioid medication use can the PHOX2B gene, a transcription
also result in sleep hypoventilation. factor regulating development of the
Opioids binding to CNS receptors impair autonomic nervous system.82
central respiratory control centers, with Several options are available for treat-
ensuing central apnea, hypoventilation, ment of central sleep apnea.83 CPAP,
or ataxic breathing pattern.70,76 Patients bilevel PAP, and other ventilator sup-
on long-term opioid treatment have a port modalities, such as ASV, have been
greater risk of hypoxemia in sleep that extensively studied (Table 5-2). CPAP
is independent of apneas or hypopneas. may improve left ventricular ejection
Treatment consists of PAP, particularly fraction and, if titrated to adequately
bilevel PAP with a backup rate in pa- treat the sleep-disordered breathing,
tients with significant central apneas or improves survival. One caveat to this
hypoventilation.77 CPAP can be effective is that most studies were done before
but may exacerbate central apneas; use the widespread use of spironolactone
of adaptive servo-ventilation (ASV) is or beta-blockers for treatment of heart
controversial in this setting and requires failure; patients on these more effective
further study. medications may therefore show a
Hypoventilation may ensue after smaller magnitude of cardiac improve-
brainstem or spinal cord injury because ment with CPAP. ASV or bilevel PAP (in
of lesions to neural pathways control- spontaneous mode with patient-triggered
ling diaphragm, chest, and abdominal breaths, or with an automated backup
muscles.78 Hypotonia of respiratory respiratory rate) have similarly benefi-
muscles can result in a restrictive ven- cial effects on cardiac function and may
tilatory defect with hypercapnia and be used to improve comfort if higher
hypoxia and increased work of breath- levels of CPAP pressure are needed,
ing. This can lead to alveolar hypoven- or to improve ventilation in hyper-
tilation that is exacerbated during carbia. The use of supplemental oxygen
sleep, especially REM sleep. Diagnostic is typically limited to patients with CSA
tests include arterial blood gas analysis who are unable to comply with PAP
and PSG. Optimal treatment consists of therapy. Also, the use of acetazolamide,
noninvasive positive pressure ventila- a carbonic anhydrase inhibitor, induces

KEY POINT
a metabolic acidosis that may lead to a 6. Young T, Palta M, Dempsey J, et al. The
h Successful treatment of occurrence of sleep-disordered breathing
central sleep apnea decrease in central apnea frequency, among middle-aged adults. N Engl J Med
associated with heart although the evidence is much weaker 1993;328(17):1230Y1235.
failure is associated with for its effectiveness when compared to 7. Lee W, Nagubadi S, Kryger MH, et al.
improved cardiac either oxygen or PAP.55 Epidemiology of obstructive sleep apnea: a
function and survival. population-based perspective. Expert Rev
Respir Med 2008;2(3):349Y364.
CONCLUSION
Sleep-disordered breathing is a highly 8. Li Y, Veasey SC. Neurobiology and
neuropathophysiology of obstructive sleep
prevalent disorder and can occur co- apnea. Neuromolecular Med 2012;14(3):
morbid to many medical and neurologic 168Y179.
conditions. Untreated, it may signifi- 9. Mehra R, Stone KL, Blackwell T, et al.
cantly affect daytime alertness and Prevalence and correlates of sleep-disordered
concentration; increase risk of cardio- breathing in older men: osteoporotic
fractures in men sleep study. J Am Geriatr
vascular events, such as stroke, ar- Soc 2007;55(9):1356Y1364.
rhythmia, or myocardial infarction; 10. Sutherland K, Lee RW, Cistulli PA. Obesity
worsen hypertension; exacerbate mood and craniofacial structure as risk factors
disorders; and interfere with optimal for obstructive sleep apnoea: impact
of ethnicity. Respirology 2012;17(2):
seizure control. PAP, the first-line treat-
213Y222.
ment option, is safe and effective in
11. Schober AK, Neurath MF, Harsch IA.
normalizing breathing during sleep. Prevalence of sleep apnoea in diabetic
Other treatment options include craniofa- patients. Clin Respir J 2011;5(3):165Y172.
cial or upper airway surgery, oral ap- 12. van Dijk M, Donga E, van Dijk JG, et al.
pliances, and weight loss. Effective Disturbed subjective sleep characteristics in
treatment of sleep-disordered breathing adult patients with long-standing type 1
diabetes mellitus. Diabetologia 2011;54(8):
can reduce symptoms of excessive day- 1967Y1976.
time sleepiness, snoring, and fragmented
13. Dyken ME, Lin-Dyken DC, Poulton S, et al.
sleep and may improve health outcomes. Prospective polysomnographic analysis of
obstructive sleep apnea in down syndrome.
Arch Pediatr Adolesc Med 2003;157(7):
REFERENCES 655Y660.
1. Iber C, Ancoli-Israel S, Chesson A, Quan SF.
14. Resta O, Pannacciulli N, Di Gioia G, et al.
The AASM manual for the scoring of sleep
High prevalence of previously unknown
and associated events: rules, terminology,
subclinical hypothyroidism in obese patients
and technical specifications. Westchester, IL:
referred to a sleep clinic for sleep disordered
American Academy of Sleep Medicine, 2007.
breathing. Nutr Metab Cardiovasc Dis
2. American Academy of Sleep Medicine. 2004;14(5):248Y253.
International classification of sleep
15. Kohler M, Bloch KE, Stradling JR. The role of
disorders, second edition: diagnostic and
the nose in the pathogenesis of obstructive
sleep apnoea and snoring. Eur Respir J
2007;30(6):1208Y1215.
3. Martin SE, Engleman HM, Kingshott RN,
16. Perrin C, DAmbrosio C, White A, Hill NS.
Douglas NJ. Microarousals in patients with
Sleep in restrictive and neuromuscular
sleep apnoea/hypopnoea syndrome. J Sleep
respiratory disorders. Semin Respir Crit Care
Res 1997;6(4):276Y280.
Med 2005;26(1):117Y130.
4. Jordan AS, White DP, Lo YL, et al. Airway
17. Manni R, Terzaghi M. Comorbidity between
dilator muscle activity and lung volume
epilepsy and sleep disorders. Epilepsy Res
during stable breathing in obstructive sleep
2010;90(3):171Y177.
apnea. Sleep 2009;32(3):361Y368.
18. Gaig C, Iranzo A. Sleep-disordered breathing
5. Huang J, Zhang J, Lam SP, et al. Amelioration
in neurodegenerative diseases. Curr Neurol
of obstructive sleep apnea in REM sleep
Neurosci Rep 2012;12(2):205Y217.
behavior disorder: implications for the
neuromuscular control of OSA. Sleep 2011; 19. Johnson KG, Johnson DC. Frequency of
34(7):909Y915. sleep apnea in stroke and TIA patients: a

meta-analysis. J Clin Sleep Med 2010;6(2): 33. Chung F, Subramanyam R, Liao P, et al. High
131Y137. STOP-Bang score indicates a high probability
of obstructive sleep apnoea. Br J Anaesth
20. Bassetti CL. Sleep and stroke. Semin Neurol
2012;108(5):768Y775.
2005;25(1):19Y32.
34. Kang K, Park KS, Kim JE, et al. Usefulness of
21. Arnulf I, Similowski T, Salachas F, et al. Sleep
the Berlin Questionnaire to identify patients
disorders and diaphragmatic function in
at high risk for obstructive sleep apnea: a
patients with amyotrophic lateral sclerosis.
population-based door-to-door study
Am J Respir Crit Care Med 2000;161(3 pt 1):
[published online ahead of print September
849Y856.
29, 2012]. Sleep Breath 2012. doi:10.1007/
22. Schulte EC, Winkelmann J. When Parkinsons s11325-012-0767-2.
disease patients go to sleep: specific sleep 35. Jackson ML, Howard ME, Barnes M.
disturbances related to Parkinsons disease. Cognition and daytime functioning in
J Neurol 2011;258(suppl 2):S328YS335.
sleep-related breathing disorders. Prog
23. Shimohata T, Shinoda H, Nakayama H, et al. Brain Res 2011;190:53Y68.
Daytime hypoxemia, sleep-disordered 36. Ellen RL, Marshall SC, Palayew M, et al.
breathing, and laryngopharyngeal findings Systematic review of motor vehicle crash risk
in multiple system atrophy. Arch Neurol in persons with sleep apnea. J Clin Sleep
2007;64(6):856Y861.
Med 2006;2(2):193Y200.
24. Benarroch EE, Schmeichel AM, Low PA, et al. 37. George CF. Sleep apnea, alertness, and
Depletion of putative chemosensitive motor vehicle crashes. Am J Respir Crit Care
respiratory neurons in the ventral medullary Med 2007;176(10):954Y956.
surface in multiple system atrophy. Brain
2007;130(pt 2):469Y475. 38. Emilsson OI, Janson C, Benediktsdottir B,
et al. Nocturnal gastroesophageal reflux,
25. van Golde EG, Gutter T, de Weerd AW. Sleep lung function and symptoms of obstructive
disturbances in people with epilepsy; sleep apnea: results from an epidemiological
prevalence, impact and treatment. Sleep survey. Respir Med 2012;106(3):459Y466.
Med Rev 2011;15(6):357Y368.
39. Shepherd K, Hillman D, Holloway R,
26. Tangel DJ, Mezzanotte WS, White DP. Eastwood P. Mechanisms of nocturnal
Influence of sleep on tensor palatini EMG gastroesophageal reflux events in
and upper airway resistance in normal men. obstructive sleep apnea. Sleep Breath
J Appl Physiol 1991;70(6):2574Y2581. 2011;15(3):561Y570.
27. Broderick M, Guilleminault C. Neurological 40. Iranzo A, Santamaria J. Severe obstructive
aspects of obstructive sleep apnea. Ann N Y sleep apnea/hypopnea mimicking REM sleep
Acad Sci 2008;1142:44Y57. behavior disorder. Sleep 2005;28(2):203Y206.
28. Guilleminault C, Huang YS, Kirisoglu C, 41. Remulla A, Guilleminault C. Somnambulism
Chan A. Is obstructive sleep apnea syndrome (sleepwalking). Expert Opin Pharmacother
a neurological disorder? A continuous 2004;5(10):2069Y2074.
positive airway pressure follow-up study.
Ann Neurol 2005;58(6):880Y887. 42. Schellenberg JB, Maislin G, Schwab RJ.
Physical findings and the risk for obstructive
29. Horner RL, Innes JA, Guz A. Reflex sleep apnea. The importance of
pharyngeal dilator muscle activation by oropharyngeal structures. Am J Respir Crit
stimuli of negative airway pressure in awake Care Med 2000;162(2 pt 1):740Y748.
man. Sleep 1993;16(8 suppl):S85YS86.
43. Kushida CA, Efron B, Guilleminault C. A
30. Saboisky JP, Butler JE, Gandevia SC, Eckert predictive morphometric model for the
DJ. Functional role of neural injury in obstructive sleep apnea syndrome. Ann
obstructive sleep apnea. Front Neurol Intern Med 1997;127(8 pt 1):581Y587.
2012;3:95.
44. Li Y, Na L, Ye J, et al. Upper airway fat tissue
31. Isono S, Remmers JE, Tanaka A, et al. distribution differences in patients with
Anatomy of pharynx in patients with obstructive sleep apnea and controls as well
obstructive sleep apnea and in normal as its effect on retropalatal mechanical
subjects. J Appl Physiol 1997;82(4): loads. Respir Care 2012;57(7):1098Y1105.
1319Y1326.
45. Mallampati SR, Gatt SP, Gugino LD, et al. A
32. Johns MW. A new method for measuring clinical sign to predict difficult tracheal
daytime sleepiness: the Epworth Sleepiness intubation: a prospective study. Can Anaesth
Scale. Sleep 1991;14(6):540Y545. Soc J 1985;32(4):429Y434.

46. Kuna ST, Gurubhagavatula I, Maislin G, et al. 59. Holty JE, Guilleminault C. Surgical options
Noninferiority of functional outcome in for the treatment of obstructive sleep
ambulatory management of obstructive apnea. Med Clin North Am 2010;94(3):
sleep apnea. Am J Respir Crit Care Med 479Y515.
2011;183(9):1238Y1244.
60. Hobson JC, Robinson S, Antic NA, et al. What
47. Epstein LJ, Kristo D, Strollo PJ Jr, et al. is success following surgery for obstructive
Clinical guideline for the evaluation, sleep apnea? The effect of different
management and long-term care of polysomnographic scoring systems.
obstructive sleep apnea in adults. J Clin Laryngoscope 2012;122(8):1878Y1881.
Sleep Med 2009;5(3):263Y276.
61. Caples SM, Rowley JA, Prinsell JR, et al.
48. Bollig SM. Encouraging CPAP adherence: Surgical modifications of the upper airway
it is everyones job. Respir Care 2010;55(9): for obstructive sleep apnea in adults: a
1230Y1239. systematic review and meta-analysis. Sleep
2010;33(10):1396Y1407.
49. Sforza E, Haba-Rubio J, De Bilbao F, et al.
Performance vigilance task and sleepiness in 62. Krishnan V, Collop NA, Scherr SC. An
patients with sleep-disordered breathing. evaluation of a titration strategy for
Eur Respir J 2004;24(2):279Y285. prescription of oral appliances for
obstructive sleep apnea. Chest 2008;133(5):
50. Shamsuzzaman AS, Gersh BJ, Somers VK.
1135Y1141.
Obstructive sleep apnea: implications for
cardiac and vascular disease. JAMA 63. Chan AS, Lee RW, Cistulli PA. Dental
2003;290(14):1906Y1914. appliance treatment for obstructive sleep
apnea. Chest 2007;132(2):693Y699.
51. Zhu Y, Fenik P, Zhan G, et al. Selective loss of
catecholaminergic wake active neurons in 64. Berry RB, Kryger MH, Massie CA. A novel
a murine sleep apnea model. J Neurosci nasal expiratory positive airway pressure
2007;27(37):10060Y10071. (EPAP) device for the treatment of
obstructive sleep apnea: a randomized
52. Trombetta IC, Somers VK, Maki-Nunes C,
controlled trial. Sleep 2011;34(4):479Y485.
et al. Consequences of comorbid sleep apnea
in the metabolic syndromeVimplications for 65. Morgenthaler TI, Kapen S, Lee-Chiong T,
cardiovascular risk. Sleep 2010;33(9): et al. Practice parameters for the medical
1193Y1199. therapy of obstructive sleep apnea. Sleep
2006;29(8):1031Y1035.
53. Redline S, Yenokyan G, Gottlieb DJ, et al.
Obstructive sleep apnea-hypopnea and 66. Anandam A, Akinnusi M, Kufel T, et al.
incident stroke: the Sleep Heart Health Study. Effects of dietary weight loss on obstructive
Am J Respir Crit Care Med 2010;182(2): sleep apnea: a meta-analysis [published
269Y277. online ahead of print February 29, 2012].
Sleep Breath 2012. doi:10.1007/
54. Vaughn BV, DCruz OF. Sleep and epilepsy.
s11325-012-0677-3.
Semin Neurol 2004;24(3):301Y313.
67. Greenburg DL, Lettieri CJ, Eliasson AH.
55. Yaffe K, Laffan AM, Harrison SL, et al.
Effects of surgical weight loss on measures
Sleep-disordered breathing, hypoxia, and
of obstructive sleep apnea: a meta-analysis.
risk of mild cognitive impairment and
Am J Med 2009;122(6):535Y542.
dementia in older women. JAMA 2011;
306(6):613Y619. 68. Malhotra A, Owens RL. What is central sleep
apnea? Respir Care 2010;55(9):1168Y1178.
56. Kim SJ, Lee JH, Lee DY, et al. Neurocognitive
dysfunction associated with sleep quality 69. Yumino D, Bradley TD. Central sleep apnea
and sleep apnea in patients with mild and Cheyne-Stokes respiration. Proc Am
cognitive impairment. Am J Geriatr Thorac Soc 2008;5(2):226Y236.
Psychiatry 2010;19(4):374Y381.
70. Walker JM, Farney RJ, Rhondeau SM, et al.
57. Means MK, Edinger JD. Graded exposure Chronic opioid use is a risk factor for the
therapy for addressing claustrophobic development of central sleep apnea and
reactions to continuous positive airway ataxic breathing [erratum published in J Clin
pressure: a case series report. Behav Sleep Sleep Med 2007;3(6):table of contents].
Med 2007;5(2):105Y116. J Clin Sleep Med 2007;3(5):455Y461.
58. Aurora RN, Casey KR, Kristo D, et al. Practice 71. Mokhlesi B. Obesity hypoventilation
parameters for the surgical modifications of syndrome: a state-of-the-art review. Respir
the upper airway for obstructive sleep apnea Care 2010;55(10):1347Y1362; discussion
in adults. Sleep 2010;33(10):1408Y1413. 1363Y1365.

72. Chau EH, Lam D, Wong J, et al. Obesity 78. Castriotta RJ, Murthy JN. Hypoventilation
hypoventilation syndrome: a review of after spinal cord injury. Semin Respir Crit
epidemiology, pathophysiology, and Care Med 2009;30(3):330Y338.
perioperative considerations.
79. Selim BJ, Junna MR, Morgenthaler TI.
Anesthesiology 2012;117(1):188Y205.
Therapy for sleep hypoventilation and
73. Borel JC, Tamisier R, Gonzalez-Bermejo J, central apnea syndromes. Curr Treat Options
et al. Noninvasive ventilation in mild Neurol 2012;14(5):427Y437.
obesity hypoventilation syndrome: a
randomized controlled trial. Chest 2012; 80. Patwari PP, Carroll MS, Rand CM, Kumar R,
Harper R, Weese-Mayer DE. Congenital
141(3):692Y702.
central hypoventilation syndrome and the
74. Vazquez-Sandoval A, Huang EJ, Jones SF. PHOX2B gene: a model of respiratory and
Hypoventilation in neuromuscular disease. autonomic dysregulation. Respir Physiol
Semin Respir Crit Care Med 2009;30(3): Neurobiol 2012;173(3):322Y335.
348Y358.
81. Healy F, Marcus CL. Congenital central
75. Annane D, Orlikowski D, Chevret S, et al. hypoventilation syndrome in children.
Nocturnal mechanical ventilation for chronic Paediatr Respir Rev 2011;12(4):253Y263.
hypoventilation in patients with neuromuscular
and chest wall disorders. Cochrane Database 82. Eckert DJ, Jordan AS, Merchia P, Malhotra A.
Syst Rev 2007(4):CD001941. Central sleep apnea: pathophysiology and
treatment. Chest 2007;131(2):595Y607.
76. Yue HJ, Guilleminault C. Opioid medication
and sleep-disordered breathing. Med Clin 83. Aurora RN, Chowdhuri S, Ramar K, et al.
North Am 2010;94(3):435Y446. The treatment of central sleep apnea
syndromes in adults: practice parameters
77. Guilleminault C, Cao M, Yue HJ, Chawla P. with an evidence-based literature review
Obstructive sleep apnea and chronic opioid and meta-analyses. Sleep 2012;35(1):
use. Lung 2010;188(6):459Y468. 17Y40.

Review Article
Dr Nancy Foldvary-Schaefer,
Cleveland Clinic, 9500 Euclid
Ave, Cleveland, OH 44195,
Complex Nocturnal
foldvan@ccf.org.
Dr Foldvary-Schaefer has
Behaviors: Nocturnal
served on the speakers
bureaus of Jazz
Pharmaceuticals and UCB; has
Seizures and Parasomnias
received an honorarium for
co-editing an issue of Sleep Nancy Foldvary-Schaefer, DO, MS, FAASM;
Clinics; and has received Zahreddin Alsheikhtaha, MBBS, RPSGT
royalty payments for
authorship of a textbook on
sleep medicine from
Oxford University Press. ABSTRACT
Dr Foldvary-Shaefer also
receives research support
Purpose of Review: This article summarizes the clinical and electrophysiologic mani-
from Cleveland Medical festations of nocturnal seizures, particularly nocturnal frontal lobe epilepsy (NFLE),
Devices, Inc, and ResMed. parasomnias, and other disorders presenting with complex behaviors in sleep. The
Dr Alsheikhtaha reports no
disclosure.
evaluation and treatment of patients with complex nocturnal behaviors can be chal-
Unlabeled Use of lenging. While the differential diagnosis of sleep-related movements, including
Products/Investigational physiologic and pathologic phenomena, is extensive, the focus of evaluation in pa-
Use Disclosure: tients with complex nocturnal behaviors distinguishes between nocturnal seizures and
Drs Foldvary-Schaefer and
Alsheikhtaha report parasomnias.
no disclosures. Recent Findings: Seizures in NFLE have a wide range of complexity and severity,
* 2013, American Academy overlapping considerably with the disorders of arousal from non-REM (NREM) sleep.
of Neurology. Video polysomnography with EEG (VPSG-EEG) has identified key clinical features
useful in differentiating these disorders. A dysfunctional arousal mechanism involving
the cholinergic system is involved in the pathophysiology of the autosomal dominant
form of NFLE and NREM parasomnias. The high prevalence of parasomnias in NFLE
families further confounds their distinction. VPSG-EEG combines PSG with compre-
hensive EEG to evaluate unexplained nocturnal behaviors when epileptic seizures are
suspected. This procedure provides improved detection of interictal and ictal EEG
abnormalities and time-synchronized correlation of clinical and neurophysiologic
phenomena.
Summary: The diagnosis of complex nocturnal behaviors is among the most difficult
to establish in sleep medicine clinics and laboratories. VPSG-EEG is indicated in the
evaluation of patients with complex nocturnal behaviors when routine EEG is non-
diagnostic. Ongoing research is necessary to fully elucidate the pathophysiology of
these disorders, which share a host of clinical manifestations.
Supplemental digital content:

ticle are cited in the text as
Supplemental Digital Content. INTRODUCTION ment disorders discussed elsewhere in
clicking on links provided in Characterizing the nature of complex this issue may warrant
the HTML, PDF, and iPad nocturnal behaviors is one of the most consideration. The differential diagnosis
URLs are provided in the print difficult diagnostic challenges in sleep of complex nocturnal behaviors includes
version. Video legends begin medicine. An accurate diagnosis of sleep- seizures with tonic and/or hypermotor
on page 127.
related events generally relies on the features, disorders of arousal from NREM
correct distinction between nocturnal sleep, REM sleep behavior disorder
seizures and disorders of arousal from (RBD), and sleep-related dissociative
non-REM (NREM) sleep, although other disorders. Like parasomnias, nocturnal
parasomnias and the sleep-related move- seizures occur during entry into sleep,

KEY POINT
within sleep, or during arousals from h Sleep is an important
sleep, and have a broad range of semi- TABLE 6-1 Differential
Diagnosis of modulator of EEG
ology, including autonomic nervous sys- Complex Nocturnal abnormalities and
tem changes, skeletal muscle activation, Behaviors seizures in patients with
and seemingly purposeful, goal-directed epilepsy; non-REM sleep
complex behaviors outside of con- b Sleep-Related Epilepsy activates and REM
sciousness. Ill-defined EEG manifesta- sleep inhibits epileptic
b Disorders of Arousal From
tions and activation by sleep deprivation Non-REM Sleep discharges and seizures.
and stress are features of both nocturnal Confusional arousals
seizures and parasomnias. Disorders as- Sleepwalking
sociated with complex nocturnal behav- Sleep terrors
iors are generally chronic conditions b REM Sleep Behavior Disorder
that lead to injury, sleep disruption, b Other Parasomnias
and daytime difficulties when diagnosis Sleep-related dissociative
and treatment are delayed. In this disorder
article, the clinical and electrophysio- Sleep-related groaning
logic manifestations of disorders pre- (catathrenia)
senting with complex behaviors in sleep b Sleep-Related Movement
are reviewed (Table 6-1). Disorders
Periodic limb movement
NOCTURNAL SEIZURES disorder
Rhythmic movement disorder
Basic Concepts Relating to
Sleep and Epilepsy b Psychogenic Seizures
The modulatory effects of the sleep-wake b Nocturnal Panic Attacks
cycle on seizures and the EEG in epilepsy b Sleep-Related Breathing
have been recognized for over a century. Disorders
Neuronal networks generating wakeful-
b Nocturnal Wandering
ness, NREM sleep, and REM sleep give Associated With Dementia and
rise to different physiologic character- Other Forms of Cognitive
istics influencing the likelihood of seizure Impairment
occurrence.1,2 NREM sleep is a state of
EEG synchronization and relative pres-
ervation of antigravity muscle tone. expression of seizures. The activating
Synchronous oscillations of cortical neu- effects of NREM sleep and sleep depri-
rons that generate sleep spindles, K vation on seizure occurrence and the
complexes, and tonic background slow expression of IEDs have been exten-
waves during NREM sleep promote sively reviewed.3 Several epileptic disor-
seizure propagation and the expression ders characterized by seizures occurring
of interictal epileptic discharges (IEDs). predominately or exclusively from sleep,
In contrast, REM sleep is characterized the so-called sleep-related epilepsies,
by EEG desynchronization and loss of have been recognized (Table 6-2; Sup-
skeletal muscle tone. Desynchronization plemental Digital Content 6-1, links.
of the EEG impedes seizure propagation lww.com/CONT/A30).
and the expression of IEDs during REM The prevalence and natural history of
sleep and wakefulness. Preservation of sleep-related epilepsies is poorly eluci-
antigravity muscle tone during NREM dated. In the largest prospective study,
sleep permits expression of seizure- 7.5% of 1200 patients had seizures
related movements, while its absence restricted to sleep, only 11.0% of whom
during REM sleep blocks the clinical developed wake seizures, typically within

Complex Nocturnal Behaviors
tomatogenic area may represent the

TABLE 6-2 Sleep-Related electrical seizure onset or the earliest
Epilepsy Syndromes
spread of the electrical seizure activity
b Benign focal epilepsy of from a silent area to symptomatogenic
childhood with centrotemporal areas, in which case early clinical mani-
spikes festations can erroneously suggest origin
b Panayiotopoulos syndrome from distant areas within the activated
network.
b Nocturnal frontal lobe epilepsy
According to a semiologic seizure
Autosomal dominant classification proposed in the late 1990s,
nocturnal frontal lobe epilepsy seizures are classified as auras, auto-
b Lennox-Gastaut syndrome (tonic nomic seizures, dialeptic seizures (ie,
seizures) having the main manifestation of alter-
b Landau-Kleffner syndrome ation in consciousness independent of
ictal EEG features), motor seizures, and
b Epilepsy with continuous spike
waves in sleep
special seizures.5 While virtually all sei-
zure types arise from both sleep and
waking states, the type of seizures
producing complex nocturnal behaviors
2 years of the first nocturnal seizure.4 For and most likely to be confused with
a variety of reasons, the prevalence of parasomnias are motor seizures. Motor
sleep-related epilepsies is likely to be seizures are differentiated as simple and
underestimated. This is due in part to complex. Simple motor seizures are
the broad spectrum of seizure semi- characterized by movements that are
ology; in some patients, clinical features simple and unnatural, similar to those
are mild and unrecognized; in others, elicited by electrical stimulation of pri-
clinical features of NREM arousal disor- mary motor areas. These include myo-
ders are interpreted by the patient and clonic, tonic, clonic, tonic-clonic, and
observers as benign and not warranting versive seizures. Complex motor sei-
medical attention. zures are characterized by relatively
complex movements simulating natural
Seizure Semiologic but inappropriate movements for the
Classification Related to situation. Complex motor seizures are
Complex Nocturnal Behaviors subclassified as hypermotor, automotor
The differentiation of nocturnal seizures (ie, having distal limb or oral automatisms
and parasomnias requires some knowl- as the main manifestation), and gelastic
edge of the localizing value of seizure (seizures in which the main motor
semiology in the focal epilepsies. Clinical manifestation is laughter). Hypermotor
manifestations of focal seizures vary by seizures feature complex movements that
the location and involved network of the are repetitive, high-amplitude, and high-
seizure-onset zone and the speed of velocity involving the trunk and prox-
propagation, producing activation or imal extremities. Consciousness is
inhibition of brain regions. In the pre- usually preserved. The differential diag-
surgical evaluation of patients with nosis of complex nocturnal behaviors
pharmacoresistant epilepsy, the sympto- includes seizures with tonic and/or
matogenic zone is the region of the hypermotor features, disorders of arousal
brain responsible for the initial symp- from NREM sleep, RBD, and other para-
toms of a seizure, defined by history and somnias, including sleep-related disso-
video EEG (VEEG) recordings. A symp- ciative disorders, movement disorders

KEY POINT
of sleep (rhythmic movement disor- longer, attacks and coined the term h The differential diagnosis
ders) (Supplemental Digital Content nocturnal paroxysmal dystonia (NPD) of complex nocturnal
6-2, links.lww.com/CONT/A31), and to describe the entity, uncertain as to behaviors includes
conditions classified as normal var- whether the cases had an epileptic nocturnal seizures,
iants such as benign sleep myoclonus basis. Over time, VEEG permitted the non-REM arousal
of infancy (Supplemental Digital Con- recording of similar nocturnal behaviors disorders, REM sleep
tent 6-3, links.lww.com/CONT/A32) having complex, often violent, motor behavior disorder, and
and psychogenic movements (Supple- manifestations with electrographic other parasomnias such
mental Digital Content 6-4, links. abnormalities supporting an epileptic as sleep-related
lww.com/CONT/A33). origin within the frontal lobe. Thus, dissociative disorders.
NPD was replaced by nocturnal frontal
Nocturnal Seizures With lobe epilepsy (NFLE).
Complex Behaviors Nocturnal frontal lobe epilepsy.
In 1981, Lugaresi and Cirignotta de- Frontal lobe epilepsy (FLE) is the sec-
scribed five patients with frequent at- ond most common focal epilepsy in
tacks in light NREM sleep, characterized adolescents and adults. About 18% of
by violent movements of the limbs, patients referred to tertiary care centers
neck, and trunk, having dystonic and for pharmacoresistant focal seizures
tonic features.6 The attacks, called hyp- have FLE,7 and patients with isolated
nogenic paroxysmal dystonia, were FLE represent about 11% of all patients
short in duration and lacked epilepti- whose long-term seizure-free outcome
form EEG features but responded to has been reported.8 Figure 6-1 illustrates
carbamazepine therapy. In a subse- frontal lobe epilepsy syndromes and
quent report, the authors described the seizure semiologies produced by
additional patients with similar, but activation of these areas. The distinction
FIGURE 6-1 Dorsolateral (left) and medial (right) schematics of the brain highlighting the
symptomatogenic areas in nocturnal frontal lobe epilepsies. Activation of the
precentral (primary motor) region produces contralateral clonic movements;
premotor region activation produces tonic posturing, usually proximal, bilateral, asymmetric, and
version; dorsolateral prefrontal region activation produces hypermotor behavior, complex
automatisms, and version; frontal operculum region activation produces facial grimacing and
salivation; activation of the ventromedial prefrontal region produces hypermotor behavior,
autonomic activation, and affective changes (eg, agitation, fear). Activation of the premotor and
prefrontal regions is characteristic of nocturnal frontal lobe epilepsy.

KEY POINTS
h Seizures in nocturnal of these syndromes can be challenging automatisms, such as fumbling and
frontal lobe epilepsy because of the complexity of function- grasping of objects or clothing, charac-
consist of hypermotor ally interconnected frontal areas and the teristic of temporal lobe seizures, may
activity involving complex variability of epileptic propagation pat- be observed. Episodes typically last 10 to
movements of the trunk terns. Consequently, seizures of frontal 30 seconds; longer seizures may sec-
and proximal extremities lobe origin have diverse, often bizarre ondarily generalize. Characteristics of sei-
that are repetitive, high manifestations. Scalp EEG is often of zures arising from the anterior cingulate
amplitude, and high limited value because epileptic foci, in or orbitofrontal cortext include fear (with
velocity and asymmetric particular on the mesial and basal brain or without a matching facial expression),
tonic seizures having surfaceVthe origin of seizures in laughter without mirth, and autonomic
dystonic, dyskinetic, and
NFLEVare relatively inaccessible for manifestations, including mydriasis, fa-
repetitive proximal
movements that are
surface electrodes; EMG and movement cial flushing, and tachycardia.14 The ictal
highly stereotyped and
artifacts during seizures contaminate the sequence of behaviors is rapid and in-
frequent, often with EEG signal; and paradoxic lateralization cludes extrapyramidal signs, such as tonic
preserved consciousness. and secondary bilateral synchrony add or dystonic posturing of the limbs and
to the complexity when interpreting the choreoathetoid or ballistic movements.
h Sudden, brief, and
asymmetric tonic
EEG.9Y11 Sudden, brief, and asymmetric tonic
posturing of one or NFLE is a heterogeneous disorder in posturing of one or more extremities,
more extremities, which 90% or more of seizures occur commonly with both sides affected
commonly with both during sleep.12 Familial, sporadic, idio- simultaneously, suggests early activation
sides affected pathic, cryptogenic, and symptomatic of the supplementary sensorimotor area
simultaneously, suggests forms have been reported. NFLE is (SSMA).15 Classic manifestations of
early activation of the characterized by complex motor behav- SSMA seizures include the fencing pos-
supplementary iors, typically of the hypermotor type, ture, a position in which the contrala-
sensorimotor area. involving repetitive, high-amplitude, and teral upper extremity is extended, the
high-velocity movements of the trunk ipsilateral arm flexed and abducted at
and proximal extremities and asym- the shoulder, and the head rotated
metric tonic seizures having dystonic, contralateral to the seizure focus; the
dyskinetic, and repetitive proximal move- M2e posture, consisting of contrala-
ments. Seizures are highly stereotyped teral shoulder abduction, elbow flexion,
and frequent with abrupt onset and and head deviation toward the affected
offset, often with preserved conscious- arm; and the figure-of-four extension of
ness, occurring in clusters from NREM the contralateral upper extremity across
sleep stages N1 and N2. Daytime sei- the chest and ipsilateral arm flexion
zures occur in approximately 30% of at the elbow. These postures are often
patients. The lifetime prevalence of accompanied by vocalizations and pre-
arousal disorders is nearly fivefold served awareness. Negative motor sei-
greater in relatives of probands with NFLE zures characterized by indescribable or
than controls, suggesting an intrinsic poorly localized subjective symptoms,
link between parasomnias and NFLE.13 followed by repetitive involuntary vocal-
Complex motor seizures in NFLE have izations, inability to speak, and arrest of
hypermotor manifestations, including voluntary movements of extremities
marked agitation with body rocking, with preserved awareness, can arise
kicking, boxing, thrashing, pedaling, from activation of the rostral SSMA.16
bending, hitting, running, spitting, and Seizures typical for SSMA epilepsy may
various types of vocalization that include arise from epileptogenic lesions in the
shouting and swearing.11,12 Case 6-1 is precuneus, lateral dorsal frontal cortex,
an example of NFLE with hypermotor orbitofrontal cortex, prefrontal region,
seizures (Figure 6-2). Distal manual and cingulate gyrus with subsequent

Case 6-1
A 26-year-old woman presented with a history of arousals from sleep
with uncontrollable movements since 13 years of age. Episodes abruptly
awakened her every night, sometimes multiple times, usually beginning
as soon as she started to fall asleep. She described a feeling of panic and
moved around in bed in an uncontrollable manner, grasping at the bed
sheets and turning from side to side for 10 to 20 seconds. She had full
recall of episodes. Rarely, similar episodes occurred when she was napping
during the daytime. On several occasions, she presented to the emergency
department during the night when frequent episodes prevented her
from sleeping. These nights typically occurred after she was sleep deprived
or surrounding menses. Treatment with lorazepam aborted the attacks.
She had a normal birth and development and denied a family history of
epilepsy, febrile convulsions, head trauma, and CNS infections. Over the
years, she was treated with several antiepileptic drugs, including
carbamazepine, lamotrigine, gabapentin, and lacosamide, without
improvement. Her most recent physician recommended that she
discontinue medications because the episodes continued and EEGs had
always been normal, suggesting that she did not have epilepsy.
Comment. This case illustrates the key features of NFLE (nocturnal frontal
lobe epilepsy): seizures occurring exclusively or nearly so from sleep at any
time of the night typically beginning at sleep onset, multiple episodes in a
given night, hypermotor activity associated with preserved awareness, and
relatively short-duration attacks. Seizures that are unresponsive to medical
therapy and multiple normal EEGs over time raised concern for a nonepileptic
parasomnia. However, approximately one-fourth of patients with NFLE have
pharmacoresistant seizures, and many have normal EEG even during typical
attacks. The patient had a normal 3-T MRI. Because of the high index of
suspicion for NFLE, an ictal SPECT study was performed and revealed a
dominant focus of hyperperfusion in the right anterior insular and adjacent
deep frontal region suggestive of right hemisphere focal epilepsy. An invasive
EEG investigation was planned.
ictal propagation into the SSMA, under- tion clustering in a single night. Epilep-
scoring the concept that the sympto- tic discharges were observed on EEG in
matogenic zone may be at some four cases, and antiepileptic drug (AED)
distance from the epileptogenic zone. therapy led to complete remission in
More prolonged seizures lasting 30 all, suggesting an epileptic origin dis-
to 180 seconds, characterized by arousal tinct from the NREM arousal disorders.
and agitated walking, running, jumping, A VPSG-EEG analysis of 100 patients
and pacing with variable degrees of with NFLE found seizures to have
responsiveness, are observed in a minor- variable degrees of complexity and
ity of patients with NFLE.12,17 First durationVranging from minor stereo-
described in 1977 by Pedley and Guille- typed movements lasting a few seconds
minault,17 the term episodic nocturnal to stereotyped large proximal move-
wandering (ENW) was coined to de- ments with dystonic features lasting
scribe sleepwalking episodes in six as long as 30 secondsVand ENW co-
young adults associated with screaming existing in the same patient.12 Seizures
or unintelligible vocalization; complex, during daytime wakefulness similar to
often violent automatisms; and ambula- those during sleep were observed in

FIGURE 6-2 Components of a presurgical evaluation in a 26-year-old woman with

pharmacoresistant nocturnal frontal lobe epilepsy. Hypermotor seizures are
characterized by abrupt arousals associated with uncontrollable movements,
including grasping, thrashing, and crawling (A) with preserved awareness lasting 10 to 20 seconds
and occurring multiple times per night with a scalp EEG devoid of epileptiform activity and obscured
by muscle and movement artifact (B). Ictal SPECT with flush time of 12 seconds reveals a dominant
focus of hyperperfusion (red) in the right anterior insular and adjacent deep frontal region (C).

KEY POINTS
34% of patients. Mean age at onset 15q24 with mutations in the transmem- h Autosomal dominant
was 14 years. A personal or family his- brane region of the neuronal nicotinic nocturnal frontal lobe
tory of parasomnia was present in 34% acetylcholine receptor alpha-4 subunit epilepsy is associated
and 39% of cases, respectively. Fami- (CHRNA4), beta-2 subunit (CHRNB2), with mutations in the
lial seizure clustering was present in and alpha-2 subunit (CHRNA2)21 and transmembrane region of
25% of patients. Epileptic abnormal- corticotrophin-releasing hormone.22 All the neuronal nicotinic
ities were recorded on interictal EEG but one of these mutations are located acetylcholine receptor
in 33%, and ictal patterns were dis- in the second transmembrane region, alpha-4 subunit
cernible in 56% of cases. Only 12% of which serves as the major ion pore- (CHRNA4), beta-2
patients had frontal lobe abnormalities forming domain of the receptor. These subunit (CHRNB2), and
alpha-2 subunit
on neuroimaging. While 17% of pa- mutations confer a gain of function with
(CHRNA2) and
tients chose to forgo therapy because increased sensitivity to acetylcholine that
corticotrophin-releasing
they did not feel their seizures were is the proposed basis for epileptogene- hormone.
incapacitating, seizures were pharma- sis through regulation of ascending
coresistant in approximately 30% of arousal pathways. h While sleep-related
complex motor seizures
cases and consistently recurred after In the largest clinical and polysomno-
have been considered
AED withdrawal. Most cases of NFLE graphic study of ADNFLE involving 30 pathognomonic for
treated surgically have histopathologic unrelated Italian families, 40 individuals nocturnal frontal lobe
confirmation of Taylor-type focal cort- had frequent nocturnal motor seizures epilepsy, extrafrontal
ical dysplasia (malformation of cortical with a wide range of complexity and origin is observed in up
development associated with balloon severity, overlapping considerably with to 30% of patients,
cells),18 and a significant association the parasomnias and indistinguishable most often from the
between sleep-related epilepsy and from the sporadic form.23 Daytime temporal and insular
Taylor-type focal cortical dysplasia in seizures were reported in 37% of cases, regions but also from
pharmacoresistant cases has been and 58% of those affected reported the posterior cortex.
reported.19 Therefore, patients with sleep disorder symptoms, including
persistent nocturnal seizures despite daytime sleepiness or tiredness and dif-
two or more appropriately chosen ficulty waking. Mean age at onset
AEDs should be referred for surgical was 11.8 years (1.0 to 30.0 years). Day-
evaluation. time EEGs were normal in 88%, but the
Autosomal dominant nocturnal sleep EEG showed IEDs in 50% of
frontal lobe epilepsy. In 1994, Scheffer cases. The interictal and ictal EEGs
and colleagues20 introduced the term were normal in 26% of subjects. Prior
autosomal dominant frontal epilepsy, misdiagnosis was common as only 18%
now known as autosomal dominant of patients had been previously diag-
nocturnal frontal lobe epilepsy (ADN- nosed with epilepsy.
FLE), to describe clusters of brief, sleep- Other focal epilepsies. While sleep-
related motor seizures with frontal lobe related complex motor seizures have
semiology in members of six families, been considered pathognomonic for
many of whom were misdiagnosed as NFLE, extrafrontal origin is observed in
having parasomnias or psychogenic up to 30% of patients, most often from
attacks. ADNFLE was the first human the temporal and insular regions but
focal epilepsy to follow single-gene in- also from the posterior cortex.24 Most
heritance, believed to constitute as patients with temporal lobe epilepsy
many as 25% of NFLE cases. Subse- (TLE) exhibit characteristic semiology,
quently, a variety of molecular defects including auras of a rising epigastric
have been identified in ADNFLE fami- sensation, fear, deja vu, or depersonal-
lies. Linkage studies localized genes for ization evolving to behavioral arrest
ADNFLE to chromosomes 20q13 and with staring and oroalimentary and limb

automatisms (Table 6-3).25 Seizures Pure insular epilepsy typically presents

restricted to sleep are uncommon in with laryngeal discomfort, retrosternal
TLE, constituting 9% of cases in one or abdominal heaviness, perioral and
series.26 Infrequent and nonclustered contralateral hemibody somatosensory
seizures, rare family history of epilepsy, symptoms, and dysphonic or dysarthric
low prevalence of childhood febrile speech followed by tonic activity of the
convulsions, and a better surgical out- contralateral face and arm.28 However,
come characterized 26 patients with seizures arising from the insula can
nocturnal TLE compared with age- spread rapidly to adjacent areas mim-
matched, nonlesional TLE with predom- icking TLE or other focal epilepsies,
inantly diurnal seizures.27 or begin simultaneously in temporal,
TABLE 6-3 Seizure Symptomatology in Temporal Versus Frontal

Lobe Epilepsya
Frontal Lobe Temporal Lobe

Feature Epilepsy Epilepsy
Onset and offset Sudden Gradual
Duration Brief (G1 minute) Longer (91 minute)
Occurrence Often sleep related Usually awake
Seizure clusters Common Uncommon
Aura type Olfactory, gustatory, Epigastric, psychic,
cephalic auditory
Time to motor component Early, prominent Later in ictal sequence
Automatisms Uncommon Common
Autonomic signs Uncommon unless Common
onset in orbitofrontal
or cingulum
Vocalization Common Uncommon
Unilateral clonic activity Common Uncommon
Unilateral dystonic arm Uncommon Common
posturing
Asymmetric tonic posturing Common Uncommon
Versive head or eyes Common Uncommon
Violent motor behaviors Common Uncommon
Preserved awareness Common Common if nondominant
Ictal laughing Forceful, mirthless Natural, mirthful
Secondarily generalized Common Uncommon
seizure
Tendency for status Common Uncommon
epilepticus
Postictal paresis Common Uncommon
Postictal confusion Uncommon Common
a
Adapted from Unnwongse K, et al, Curr Neurol Neurosci Rep.25

KEY POINT
frontal, or parietal regions, leading to produced by a faulty arousal network h Parasomnias are
difficulty in localization. (Case 6-2, Figure 6-3). These parasom- undesirable physical
nias typically arise from slow-wave sleep events or experiences
PARASOMNIAS in the first half of the nocturnal sleep that occur during entry
Parasomnias are undesirable physical period, but may arise from other NREM into sleep, within sleep,
events or experiences that occur during stages at any time during sleep, includ- or during arousals from
entry into sleep, within sleep, or during ing daytime naps. Sleep deprivation and sleep and involve
arousals from sleep.29 The word para- recovery from sleep deprivation due to complex, seemingly
somnia is derived from the Greek slow-wave sleep rebound; mental and purposeful, goal-directed
para meaning alongside of and the physical stress; fever; menses; envi- behaviors without
consciousness.
Latin somnus for sleep. In contrast to ronmental stimuli; sleep disorderY
the sleep-related movement disorders producing arousals, including sleep
characterized by simple movements not apnea and periodic limb movements;
associated with dream mentation, the neurologic and psychiatric comorbid
parasomnias typically involve complex, conditions; alcohol; and medications,
seemingly purposeful, goal-directed particularly psychotropic drugs, can
behaviors without consciousness. Be- precipitate arousal disorders. Most
cause sleep and wakefulness are not affected individuals exhibit a spectrum
mutually exclusive states, dysfunction in of behaviors, and a few patients have
the orchestration of neural pathways features of RBD, known as parasomnia
regulating wake, NREM sleep, and REM overlap syndrome. In contrast to noc-
sleep produces state dissociation result- turnal seizures, episodes are not typi-
ing in the ability to perform complex cally stereotyped. Disorders of arousal
motor behaviors outside of conscious- have a genetic basis, although environ-
ness. A recently reported example of mental factors and psychiatric illnesses
state dissociation was recorded during have been implicated in their patho-
an invasive EEG evaluation, in which physiology. NREM arousal disorders can
sleep was recorded from hippocampal cause daytime sleepiness and psycho-
and frontal association cortex contacts social impairment, including perform-
simultaneous to wake EEG activity in the ance deficiency at the workplace and
motor, cingulate, insular, amygdalar, and academic underachievement. Injuries
temporopolar regions during a confu- are common in patients with sleep-
sional arousal.30 While event stereotypy, walking and sleep terrors. Among 100
distinct onset and offset, and occurrence consecutive adults with repeated sleep-
from sleep favor the diagnosis of noctur- related injury, sleepwalking and sleep
nal seizures, waxing and waning clinical terrors were the most common diag-
manifestations, long duration (more noses, constituting 54% of cases; the
than 2 minutes), and absence of extrapy- remainder resulted from RBD (34%),
ramidal features suggest parasomnias. dissociative states, and nocturnal sei-
zures.31 The treatment of arousal dis-
Disorders of Arousal From orders is usually limited to patient and
Non-REM Sleep family education and safeguarding the
In contrast to sleep-related epilepsy, few bedroom to prevent injury. Benzodia-
polysomnographic studies of the arousal zepines, tricyclic antidepressants, and
disorders have been published. The hypnosis have been used in particularly
NREM parasomnias include confusional resistant cases with variable success.
arousals, night terrors, and sleepwalking, Confusional arousals. Confusional
classified as distinct entities but in reality arousals (eg, sleep drunkenness, ex-
representing a spectrum of behaviors cessive sleep inertia) are episodes of

KEY POINT
h Arousal disorders can be mental confusion or confusional behav- of minors and adults can occur during
precipitated by sleep ior during an arousal or awakening from confusional arousals. Sudden, forced
deprivation and nocturnal sleep or a daytime nap. Re- awakening can precipitate episodes.
recovery from sleep sponsiveness to environmental stimuli The prevalence of confusional arousals
deprivation due to is reduced, although patients appear to is over 15.0% in children29 and 2.9% to
slow-wave sleep be awake and may exhibit goal-directed 4.2% in adults.32 Episodes in children
rebound; mental and behaviors. Speech is generally slow and typically remit spontaneously, but sleep-
physical stress; fever; devoid of content. Affected individuals walking often presents in adolescence
menses; environmental typically appear bewildered, have little or adulthood. Confusional arousals may
stimuli; sleep to no memory of the event, and may act present de novo in adulthood and can
disorderYproducing
out aggressively toward bystanders. be difficult to differentiate from focal
arousals, including sleep
Motor and autonomic system involve- seizures.
apnea and periodic limb
movements; neurologic
ment characteristic of sleepwalking and Sleepwalking. Sleepwalking (som-
and psychiatric sleep terrors is lacking. Duration is nambulism) is characterized by a se-
comorbid conditions; usually a few minutes, although epi- quence of complex behaviors in sleep,
alcohol; and medications, sodes as long as several hours have including ambulation that is more elab-
particularly psychotropic been described. Episodes typically arise orate and seemingly goal-directed than
drugs. from the first part of the sleep period; usually seen in confusional arousals.
however, confusional arousals can arise Episodes begin with an arousal from
during the transition from sleep to slow-wave sleep with the individual
wakefulness in the morning from light looking around, appearing confused,
NREM sleep. Examples of confusional before leaving the bed (Supplemental
arousal are illustrated by the accompa- Digital Content 6-7, links.lww.com/
nying videos (Supplemental Digital CONT/A36). Ambulation is typically slow
Content 6-5, links.lww.com/CONT/ and quiet with the eyes open, but more
A34; Supplemental Digital Content agitated behaviors, including running
6-6, links.lww.com/CONT/A35). Abnor- and jumping with vocalization in an
mal sexual behaviors (sexsomnia) rang- attempt to escape a perceived threat,
ing from masturbation to sexual assault preparing foods, eating, cleaning, and
Case 6-2
A 35-year-old man presented with his wife reporting abnormal behaviors
in sleep. At 11:30 PM one night 2 months before presentation, he jumped
from his third-story bedroom window, fracturing both of his legs. He
vaguely recalled thinking he was escaping a house fire. While recovering
in a rehabilitation facility, he was involved in an altercation with an
attendant after he wandered outside his room. He was wrestled to the
ground when he became agitated after being shaken awake, prompting
transfer to a psychiatric ward, where he was evaluated and discharged a
few days later without further treatment. His wife reported less dramatic
episodes 2 to 3 times per week during which he would wander outside of
his room asleep or wake up confused, typically within a few hours of sleep
onset. Similar episodes had occurred in childhood. He generally would
not respond during episodes and had little or no recollection of what had
transpired. He reported mild daytime sleepiness and snoring, but denied
gasping or choking in sleep. His body mass index was 33 kg/m2, but his
examination was otherwise normal. He wore a cast on his right leg.

Comment. This case illustrates the spectrum of complex behaviors

seen in the disorders of arousal from non-REM sleep. While classified as
sleepwalking, sleep terrors, or confusional arousals for nosologic purposes,
these behaviors often coexist in the same patient. Most episodes occur in
the first third of the sleep period, where slow-wave sleep predominates.
The frequency of sleepwalking episodes varies considerably from case to
case, ranging from isolated, rare occurrences to multiple episodes per
night. Events may cluster for several nights, followed by remission for
weeks to months. Sleepwalking and confusional arousals are commonly
precipitated by sleep deprivation, emotional or physical stress, fever,
comorbid psychiatric and neurologic disorders, and medications. Because
of the presence of sleep-related injury and clinical suspicion of sleep
apnea, a polysomnogram with EEG was performed in this patient and
revealed moderate obstructive sleep apnea (apnea-hypopnea index of
28 events/h) and several unprovoked arousals from slow-wave sleep.
Safeguards to secure a safe sleep environment were recommended, and
the patient was instructed to avoid alcohol and sleep deprivation.
Treatment with continuous positive airway pressure followed an
in-laboratory titration study, resulting in a near cessation of arousal
episodes. Treatment of sleep disorders producing sleep fragmentation
such as obstructive sleep apnea often reduces the frequency of parasomnia
episodes in both children and adults.
FIGURE 6-3 Non-REM arousal disorder. A 30-second videopolysomnograph-EEG epoch

showing an adult with nonstereotyped nocturnal behaviors since childhood.
The patient awoke from slow-wave sleep at approximately 1 AM (arrow),
appeared confused, and tried to get out of bed. The EEG shows a delta sleep pattern without
epileptiform features that becomes obscured by movement artifact. She had no recollection
of the event the following morning.

KEY POINTS
h The non-REM parasomnias driving, have been reported. In other ized by sudden arousal and sitting up in
include confusional cases, inappropriate behaviors are ob- bed associated with a cry or vocalization
arousals, sleep terrors, served, such as urinating in a closet or and intense autonomic system activa-
and sleepwalking, rearranging furniture. Episodes usually tion (Supplemental Digital Content
classified as distinct terminate spontaneously with the pa- 6-8, links.lww.com/CONT/A37; Supple-
entities but in reality tient waking up in a different location or mental Digital Content 6-9, links.
representing a spectrum returning to bed without incident. Pa- lww.com/CONT/A38; Supplemental
of behaviors produced tients appear confused and can be Digital Content 6-10, links.lww.com/
by a faulty arousal agitated or aggressive when aroused. CONT/A39; Supplemental Digital Con-
system. Violent acts, including homicide and tent 6-11, links.lww.com/CONT/A40).
h The presenting sexual molestation, have been reported. Tachycardia, tachypnea, diaphoresis,
complaint in REM sleep Complete amnesia for the event usually facial flushing, and mydriasis are com-
behavior disorder is occurs, although some patients have monly observed. Affected individuals
recurrent dream-enacting partial recollection the following day. appear frightened and confused and
behaviors, including
The frequency of episodes varies con- are inconsolable and difficult to arouse,
vocalizations and motor
siderably from case to case, ranging typically with no recollection of events
activity in relation to
altered dream mentation.
from isolated, rare occurrences to multi- the following morning. In contrast to
Sleep-related injuries to ple episodes per night with clustering children, adults with sleep terrors may
the affected person or for several nights, followed by pro- bolt out of bed in a violent or agitated
bed partner occur in longed periods of remission. Nightly manner with some dream recollection
approximately one-third episodes that cluster are rare. Sleep- after the event. Sleep terrors affect 1.0%
of cases. walking affects as many as 17% of to 6.5% of children and 2.6% of adults,32
children and 4% of adults, with peak typically peaking in the early school-age
prevalence between ages 8 and 12.33,34 years and remitting by adolescence.
Most affected children had confusional Episodes typically last several minutes
arousals at an earlier age. Sleepwalking and are followed by the patient calmly
typically begins in the first decade of life and quietly returning to sleep.
and remits spontaneously in late child-
hood or adolescence, although onset in REM Sleep Behavior Disorder
adulthood is observed. Childhood-onset RBD is the REM sleep parasomnia that
sleepwalking continues into adulthood presents with complex nocturnal behav-
in 20% of cases. Sleepwalking has a iors that are occasionally challenging
strong genetic predisposition, with first- to differentiate from nocturnal seizures
degree relatives of sleepwalkers having and at times overlap with disorders of
at least a 10-fold increased likelihood of arousal. The presenting complaint in
the condition compared to the gen- RBD is recurrent dream-enacting behav-
eral population.33 Sleepwalking was iors, including vocalizations and motor
inherited as an autosomal dominant dis- activity in relation to altered dream
order with reduced penetrance in a mentation (Case 6-3) (Supplemental
four-generation family with localization Digital Content 6-12, links.lww.com/
to chromosome 20q12-q13.12, the first CONT/A41).35,36 Sleep-related injuries
genetic locus identified that contains to the affected person or bed partner
the adenosine deaminase gene.35 In- occur in approximately one-third of
hibition of adenosine metabolism in- cases (Supplemental Digital Content
creases slow-wave sleep, rendering this 6-13, links.lww.com/CONT/A42). In
the most likely candidate gene in link- contrast to the NREM disorders of
age analysis. arousal, patients typically wake up
Sleep terrors. Sleep terrors (ie, night abruptly at the end of an episode and
terrors, pavor nocturnus) are character- are alert and able to recount a coherent

Case 6-3
A 64-year-old man presented with snoring and daytime sleepiness. During
the interview, he reluctantly described having vivid dreams associated
with violent movements, yelling, and swearing in sleep. He appeared
embarrassed by these behaviors and expressed remorse when telling the
story of how he once repeatedly punched and kicked his wife while
dreaming that he was fending off an attacker. In turn, his wife stated
adamantly that this behavior was highly uncharacteristic of her loving
husband. Similar, though milder, episodes occurred sporadically, usually in
the early morning hours from 2:00 AM to 4:00 AM. His wife once found him
with blood dripping from his eyelid, bruises on his face, and the bedside
table on the floor; she assumed that he had struck himself in his sleep.
After an episode, he would usually wake up and provide a detailed
account of his dream. His medical history was notable only for diet-controlled
hyperlipidemia. He exercised regularly and avoided alcohol and drugs. His
family history was notable for Alzheimer disease in his mother.
Comment. Violent dream-enacting behaviors arising from sleep in an older
man raise concern for REM sleep behavior disorder (RBD). A polysomnography
with EMG recordings from both upper and lower extremities was performed.
The study ruled out sleep apnea (apnea-hypopnea index was 4.5 events/h),
although frequent periodic limb movements were seen in NREM sleep. During
REM sleep, EMG was increased and limb twitching was observed, confirming
the diagnosis of RBD. A thorough neurologic examination ruled out features
of Parkinson disease, dementia with Lewy bodies, and multiple system
atrophyVdegenerative disorders associated with RBD. Treatment with
low-dose clonazepam at bedtime was recommended. Home safety precautions
were implemented, including the removal of potentially dangerous objects
from the bedroom and placement of a cushion around the bed. Almost
immediately after the patient started treatment, the frequency of his violent
behaviors declined markedly.
dream of being confronted, chased, or with the eyes closed. Primitive behav-
attacked by unfamiliar people, animals, iors (including chewing, eating, drink-
insects, or other beings. Vocalizations ing, urination, defecation, and sexual
and motor behaviors are strikingly con- behaviors) that may manifest in NFLE
sistent with the reported dream con- and NREM arousals disorders were only
tent. Vocalizations including talking, recently reported as part of the behav-
arguing, laughing, yelling, screaming, ioral spectrum of RBD.37 RBD episodes
and swearing are often described as usually occur in the early morning
being out of character for the individ- hours preceding the morning awaken-
ual. The spectrum of motor behaviors ing, when REM sleep predominates,
in RBD overlaps both with NFLE and and less commonly during the first
disorders of arousal and includes repet- REM period at least 90 minutes after
itive proximal movements such as ges- sleep onset. Dream-enacting episodes
turing, punching, slapping, grabbing, may occur even earlier in the sleep
kicking, running, and jumping, often period in patients with narcolepsy and
performed in a self-protective manner. comorbid RBD. Episodes occur sporadi-
Unlike sleepwalking, people rarely walk cally an average of once per week and
out of the room, and episodes occur rarely nightly or in clusters. Typical

duration is less than 2 minutes. Three ance should not be better explained by
subtypes of abnormalities related to any other sleep disorder; medical, men-
RBD have been described: (1) subclin- tal, or neurologic condition; medica-
ical RBD, characterized by polysomno- tion; or substance use.
graphic findings consistent with RBD in RBD usually emerges later in life,
the absence of a clinical history of typically after age 50, although it can
dream enactment; (2) parasomnia over- present at any age and has a striking
lap disorder, comprising RBD com- male predominance. For reasons not
bined with a disorder of arousal; and understood, RBD is about 9 times more
(3) status dissociatus, characterized by a common in men than in women. The
state of dissociation without clear sleep estimated prevalence of RBD based on
stages but with REM-related behaviors a UK telephone survey of people aged 15
resembling RBD in patients with neuro- to 100 years old is 0.5%.32 The patho-
logic disorders. RBD is the only para- physiology of RBD (Figure 6-5)38 re-
somnia requiring polysomnographic quires bilateral pontine tegmental
confirmation.29 The diagnosis of RBD lesions resulting in loss of REM atonia
is made in patients with REM sleep and disinhibition of locomotor path-
without atonia (RSWA) in the chin or ways, thereby facilitating dream en-
limb EMG and either sleep-related actment. The condition is frequently
injurious, potentially injurious, or dis- associated with the "-synucleinopathies
ruptive behaviors documented by his- that include Parkinson disease, demen-
tory or abnormal REM sleep behaviors tia with Lewy bodies, and multiple
documented on PSG (Figure 6-4). EEG system atrophy. These disorders share
abnormalities suggestive of epilepsy a common pathologic lesion composed
must be absent, and the sleep disturb- of abnormal aggregates of "-synuclein
FIGURE 6-4 REM sleep behavior disorder (RBD). A 30-second polysomnograph epoch
showing an elderly man with RBD. The arrow indicates the point during REM
sleep when augmentation of EMG activity is seen, followed within seconds
by the emergence of abnormal dream-enacting behavior. Note the elevated EMG activity in
the upper and lower extremity and chin EMG channels (REM sleep without atonia) with
simultaneous REMs in the electrooculogram (left: E1-M2, right: E2-M1) and EEG appearance of
REM sleep.
SAO2 = arterial oxygen saturation.

FIGURE 6-5 Pathophysiology of REM sleep behavior disorder. Muscle atonia during REM sleep results from pontine-mediated
perilocus coeruleus inhibition of motor activity. This pontine activity exerts an excitatory influence on medullary centers
(magnocellularis neurons) via the lateral tegmentum reticular tract that, in turn, hyperpolarizes the spinal motor neuron
postsynaptic membranes via the ventrolateral reticulospinal tract.
38
Modified from Avidan AY, Prim Care. B 2005, with permission from Elsevier. www.sciencedirect.com/science/article/pii/S009545430500028X.
protein in specific brain nuclei. RBD exacerbating or even causing RBD.

may precede the diagnosis of a degen- These include psychotropic and antide-
erative disorder by up to 50 years39 with pressant medications, including selec-
a mean latency of 12.7 years from the tive serotonin reuptake inhibitors,
onset of RBD to the first manifestation serotonin-norepinephrine reuptake
of neurodegeneration,36 serving as an inhibitorsVparticularly venlafaxineV
indicator of an evolving synucleinopathy and tricyclic antidepressants. Alcohol
in as many as two-thirds of cases. Pa- and drug abuse or withdrawal and
tients with neurologic lesions involving caffeine can also trigger RBD. The
the REM generator centers in the brain treatment of RBD centers on reducing
due to stroke, multiple sclerosis, or clinical manifestations that lead to sleep-
neoplasm have also been reported to related injuries.40 Modifying the sleep
develop RBD. While the condition is environment to protect patients and
more common in older men, its pres- bed partners from injury is advised.
ence in younger patients should raise Despite the lack of randomized clinical
the possibility of narcolepsy. Several trials, clonazepam is remarkably effec-
drug classes have been implicated in tive in treating RBD and is considered

KEY POINT
h REM sleep behavior first-line therapy. Melatonin and prami- study, a history of sleep-related events
disorder usually pexole are also effective in small series was more often reported by patients
emerges later in life, and are preferred in patients with with PNES than by patients with phar-
typically after age 50, dementia, gait disorders, and obstructive macoresistant epilepsy (59% versus
and has a striking sleep apnea (OSA). Treatment of comor- 47%).42 Sleep-related PNES were signifi-
male predominance. bid sleep disorders, including OSA, is cantly associated with convulsive seiz-
The condition is recommended as RBD-like behaviors ure semiology, AED polytherapy, social
frequently associated with may be due solely to OSA, a condition security benefits, mood disorders, sui-
the "-synucleinopathies, known as pseudo-RBD. cide attempts, physical abuse, and
which include Parkinson fatigue. Like parasomnias, PNES are
disease, dementia with Sleep-Related Dissociative characterized by waxing and waning
Lewy bodies, and Disorders patterns and long duration (more than
multiple system atrophy.
Sleep-related dissociated disorders 2 minutes). Motor manifestations
emerge at the transition from wake to include jactitation (restless tossing in
sleep or shortly following awakening bed), asynchronous movements, side-
with EEG evidence of wakefulness.29 to-side head movements, pelvic thrust-
Most patients have psychiatric comor- ing, opisthotonic posturing, prolonged
bidities, including mood disorders, post- body flaccidity, and preserved aware-
traumatic stress disorder, and a history ness during bilateral motor activity.
of sexual abuse. Episodes are non- Affective manifestations, vocalizations,
stereotyped and feature screaming, ictal moaning and crying, emotive
running, and self-mutilating, violent be- speech, ictal stuttering, and heart rate
haviors that may represent a reenact- elevations may be seen in PNES, pa-
ment of prior traumatic events. Driving, rasomnias, and nocturnal seizures,
cooking, and eating can occur. The although postictal crying is most com-
patient usually has complete amnesia mon in patients with PNES. Ictal eye
for episodes that can last from minutes closure and jaw clenching suggest
to an hour or longer. Injuries are com- PNES, whereas lateral tongue bites,
mon. Among 100 consecutive adults with urinary incontinence, event-related
repeated sleep-related injury, 7% were injury, and myalgia support the diagno-
diagnosed with dissociative states.31 Dis- sis of epilepsy. Occurrence only in the
sociative disorders preferentially affect presence of observers and events trig-
females. gered by emotional stress raise suspi-
Psychogenic nonepileptic seizures cion for PNES. Approximately 70% of
(PNES) occurring in relation to sleep PNES cases develop between the sec-
may be considered a form of sleep-re- ond and fourth decades of life, usually
lated dissociative disorder. PNES are in females, but children and older
highly prevalent and difficult to differ- adults are also affected.43 The EEG in
entiate from frontal lobe seizures, espe- PNES shows a normal waking alpha
cially those arising from the mesiobasal rhythm during behavioral unresponsive-
frontal regions. PNES are classically con- ness. Historical features, including
sidered to arise from wakefulness, as chronic pain disorders, somatization
psychological stress exceeding ones disorder, and histrionic personality,
capacity is the typical precipitant. How- have a high predictive value for the
ever, 55% of patients with PNES in diagnosis of PNES. Epileptic seizures
one series had seizures arising from coexist in 10% to 60% of cases. Con-
pseudosleep, defined as behavioral sequently, long-term VEEG is recom-
sleep associated with EEG evidence of mended in patients with abnormal
wakefulness.41 In a prospective UK EEGs in whom PNES is suspected.

KEY POINT
Pathophysiologic Associations datory (eg, biting, teeth chattering), h Activation of common
Between Nocturnal Frontal emotional (eg, fear, vocalizations), loco- pattern generators is
Lobe Epilepsy and Parasomnias motor (eg, pedaling, crawling, wander- responsible for the
Among the various types of parasom- ing, running), and copulatory (eg, pelvic overlapping semiology
nias, the NREM arousal disorders appear thrusting) behaviors. of nocturnal seizures
to have the strongest association with and arousal disorders.
NFLE. Consequently, a common patho- EVALUATION OF PATIENTS WITH
physiologic mechanism involving chol- COMPLEX NOCTURNAL
inergic pathways in the ascending BEHAVIORS
arousal system has been hypothesized. The diagnosis of nocturnal seizures and
Various mutations in the neuronal nic- parasomnias is often achieved through a
otinic acetylcholine receptor in ADNFLE comprehensive clinical history provided
families suggest a molecular basis for the by the patient and bed partner or other
disorder. These ion channel receptors observers that includes timing, fre-
are widely distributed on neuronal and quency, semiology, and evolution of
glial membranes in cortical and subcort- typical events (Table 6-4). Following
ical regions of the brain, regulating the the clinical history, EEG is the primary
release of acetylcholine, +-hydroxybutyric modality for the confirmation of sus-
acid, and glutamate, and having a pected epilepsy and, therefore, in the
modulatory effect on arousals at the evaluation of patients with complex
cortical and thalamic levels. Receptor nocturnal behaviors. The yield of EEG
mutations confer a gain of function with varies with the duration of the study,
increased sensitivity to acetylcholine patient state, recording technique,
that may lead to changes in the excit- and presence or absence of recorded
ability of networks of cortical and sub- events. When the diagnosis is not con-
cortical neurons preferentially affecting firmed by outpatient EEG procedures,
the mesial frontal area, thereby facilitat- further evaluation in the sleep labora-
ing intrinsic epileptogenesis and, at the tory or epilepsy monitoring unit may be
same time, altering arousal mechanisms warranted. Additional investigations
and destabilizing sleep.21 may be indicated, depending on the
Activation of common pattern gener- clinical presentation and EEG findings
atorsVgenetically determined or such as MRI, functional neuroimaging
learned neural circuits located in the (eg, PET, ictal SPECT), and laboratory
mesencephalon, pons, and spinal cord analyses, including genetic testing. Vali-
that code for self-sustained patterns of dated questionnaires useful in discrim-
behavior subserving innate motor inating between NFLE and parasomnias
behaviors essential for survivalVis pro- may enhance the diagnostic accuracy of
posed to underlie the similar semiologic the clinical history.
manifestations of nocturnal seizures and
parasomnias.44 During sleep states and Video Polysomnography With
seizures, a temporary disruption of Electroencephalography
higher brain centers can produce ster- VPSG-EEG is indicated in the evaluation
eotyped motor behaviors, including of patients with complex nocturnal be-
through activation of brainstem and haviors. However, capturing a typical
spinal cord common pattern genera- event can be challenging in the out-
tors. A broad spectrum of clinical man- patient setting during a single night of
ifestations may be observed, including recording. While a limited number of
alimentary (eg, bruxism, chewing, swal- EEG channels is adequate for sleep
lowing, lip smacking), defensive or pre- staging in routine PSG, the identification

TABLE 6-4 Differentiating Nocturnal Frontal Lobe Epilepsy and

Parasomnias
REM Sleep
Nocturnal FrontalArousal Behavior
Feature Lobe Epilepsy Disorders Disorder
Age at onset Variable, typically Usually first Over 50 years
first or second decade of life
decade of life
Sleep stage of origin Non-REM N1 or Non-REM N3 REM
N2, sleep-wake
transitions
Timing of episodes Anytime First third of Last third of
sleep period sleep period
Duration of episodes 5 to 60 seconds 2 to 30 Seconds to
minutes 2 minutes
Frequency of episodes Nightly clusters Sporadic, rare Sporadic, rare
clusters clusters
Onset and offset Sudden Gradual Sudden
Semiology of episodes Highly stereotyped, Not Not highly
hypermotor, stereotyped, stereotyped,
asymmetric variable vocalizations with
tonic/dystonic complexity self-protective
behaviors and
dream recall
Level of consciousness Usually preserved Variable Poorly responsive
during episodes
Postictal confusion Typically absent Present Absent
Risk of injury Low High Moderate
Video-polysomnography Epileptic activity Slow-wave REM sleep without
with EEG findings in G50% sleep arousals, atonia
rhythmic delta
pattern
of epileptic abnormalities requires more evaluation of complex nocturnal behav-

extensive monitoring.45 In studies com- iors. Due to the limitations of capturing
paring abbreviated (4- and 7-channel) a typical event in 1 night of recording,
EEG montages with 18-channel record- long-term VEEG over several days in an
ings, temporal and parieto-occipital sei- epilepsy monitoring unit is preferred
zures were more accurately distinguished when episodes do not occur nightly or
from arousals and artifacts using 7- and every other night, primary sleep disor-
18-channel recordings, while expanded ders such as OSA are not suspected, a
montages did not increase the detection history of postictal agitation or wander-
of frontal lobe seizures.46,47 Therefore, ing exists, and patient cooperation is
more comprehensive EEG recordings uncertain. During long-term VEEG, pa-
with synchronized high-quality video tients taking AEDs can undergo super-
and additional EMG in patients with vised drug withdrawal, increasing the
suspected RBD are required in the yield of the study.

KEY POINTS
VPSG-EEG has several advantages from slow-wave sleep), ictal EEG fea- h Video polysomnogram-EEG
over routine PSG, including the im- tures were much less useful, with only has several advantages
proved ability to identify interictal and 38% of seizures associated with defini- over routine
ictal EEG abnormalities and correlate tive ictal patterns. polysomnogram,
clinical behaviors with neurophysiologic The stage from which nocturnal including the improved
parameters. The procedure is recom- events emerge and event timing relative ability to identify
mended for the evaluation of (1) com- to sleep onset provide important diag- interictal and ictal EEG
plex nocturnal behaviors when the nostic information. Sleep-related sei- abnormalities and
clinical history and routine EEG are in- zures usually arise from NREM sleep correlate clinical
conclusive; (2) sleep-related events that and often during sleep-wake transitions behaviors with
neurophysiologic
are violent or potentially injurious; (3) anytime during the sleep period. In
parameters.
parasomnias with unusual or atypical contrast, NREM arousal disorders arise
features; (4) situations with forensic predominantly from slow-wave sleep, h Complex nocturnal
considerations; and (5) presumed para- usually in the first third of the sleep behaviors can be
differentiated by the
somnias or nocturnal seizures not period. RBD episodes occur from REM
state from which
responsive to conventional therapy.45 sleep preferentially in the last one-third
episodes emerge.
In an early study involving 122 patients of the sleep period where REM sleep Nocturnal seizures
with complex nocturnal behaviors, predominates. typically arise from light
VPSG-EEG provided a definite diag- non-REM sleep often
nosis in 35% of cases, with epilepsy EEG Findings in Patients With during sleep-wake
being most common.48 Supportive evi- Nocturnal Seizures and transitions, while
dence of sleep terrors or epilepsy was Parasomnias arousal disorders arise
obtained in 35%, and the study was Nocturnal seizures. The electrographic from slow-wave sleep
inconclusive in 34% of cases. Among manifestations of nocturnal seizures preferentially during the
100 consecutive adults with history of with complex behavioral manifestations first third of the sleep
sleep-related injury, the procedure pro- depend on a variety of factors, includ- period, and REM sleep
behavior disorder
vided conclusive diagnostic information ing the size, location, and propagation
episodes present from
in 65% of cases and was helpful in characteristics of the ictal generator;
REM sleep preferentially
another 26%.31 location and number of recording elec- during the last third of
In a recent VPSG-EEG analysis of 120 trodes; and the attenuating character- the sleep period.
events of 44 patients with NFLE or NREM istics of the skull and other intervening
arousal disorders, 94% of events were tissues. In many cases, the EEG shows
correctly classified using a diagnostic IEDs in the region harboring the
decision tree based on a cluster analy- epileptogenic lesion. This is particularly
sis.49 Semiologic features strongly favor- true in TLE, in which a unilateral focal
ing the diagnosis of arousal disorders preponderance of IEDs predicts the
included interactive behavior, failure to area of seizure origin with a probability
wake after the event, and indistinct of more than 95%.50 Similarly, localized
offset. Crying or sobbing, coherent ictal EEG patterns are more common in
speech in sentences, and normal arousal TLE compared to extratemporal epilep-
behaviors, such as scratching and rub- sies (90% versus 50%) and least likely in
bing the face, were also strongly sug- seizures arising from the mesial frontal
gestive of an arousal disorder. In region (24%).51
contrast, hypermotor features, grunting, The EEG is often normal in patients
grimacing, and dystonic posturing fa- with epileptogenic lesions arising from
vored NFLE. While sleep stage at event deep or midline regions or who show
onset was discriminatory (82% of sei- seemingly generalized epileptic activity
zures occurred during sleep stage N1 or due to rapid propagation to the contrala-
N2, and 100% of arousal disorders arose teral hemisphere. Epileptic abnormalities

may be restricted to the vertex and tivity. The EEG features of NREM arousal
therefore missed if data are reviewed disorders are more variable and less
on montages not incorporating midline definitive than those associated with
electrode placements. Seizures are com- seizures and overlap with seizures aris-
monly obscured by artifact due to the ing from the mesial and basal cortical
prominent motor activity of nocturnal regions.53 NREM parasomnias typically
frontal seizures (Figure 6-2B). In produce generalized, hypersynchro-
patients with NFLE, VEEG recordings nous delta waves with superimposed
typically reveal an event frequency faster frequencies without considerable
dramatically exceeding estimates based evolution (Figure 6-3). The arousal
on the clinical history, owing to under- itself can consist of any frequency, in-
detection of frequent minor stereo- cluding rhythmic delta activity sugges-
typed motor events associated with tive of a persistent sleep pattern or a
arousal in the presence or absence of predominance of alpha activity more
epileptiform discharges.52 The involve- widespread and less reactive than the
ment of basal and mesial cortices not waking background, suggestive of par-
directly accessible to scalp EEG, rapid tial wakefulness. EEG state dissociation
spread of EEG activity within and out- with a posteriorly dominant alpha
side these areas, and tangential orienta- rhythm and delta activity anteriorly
tion of the spike source are responsible combined with vertex waves or sleep
for the lower yield of scalp EEG in FLE. spindles that is consistent with light
The EEG may be normal even during a sleep has been reported.49 Slow-wave
seizure if the episode is brief and the sleep arousals in the absence of clinical
epileptic generator is distant from the events are supportive of an arousal
recording electrodes. Therefore, a nor- disorder. An increase in delta power
mal EEG does not exclude the diagnosis immediately preceding arousal and in
of epilepsy. slow-wave sleep percentage across the
Disorders of arousal from NREM sleep period may be observed.53 Sleep
sleep. Because the diagnosis of NREM deprivation for 24 hours before PSG
arousal disorders can often be made and forced arousal from auditory stimuli
with an adequate level of certainty induce somnambulistic episodes in
based on clinical history alone, labora- sleepwalkers, thereby increasing the
tory evaluation is not routinely indi- yield of testing.54 A normal PSG does
cated. VPSG-EEG is recommended in not exclude the diagnosis of an arousal
patients with (1) potentially injurious disorder.
night behaviors or behaviors otherwise REM sleep behavior disorder. PSG
disruptive to the bed partner or house- is valuable in confirming the diagnosis
hold members; (2) atypical features or of RBD. PSG should be tailored in pa-
features suggestive of nocturnal seiz- tients with RBD to include expanded
ures, daytime consequences such as EEG and EMG monitoring of the upper
sleepiness, and failure to respond to and lower limbs as motor manifesta-
appropriate therapy; and (3) suspected tions may be restricted to the upper
comorbid primary sleep disorders such extremities. The pathognomonic poly-
as OSA, as their treatment can lead to somnographic finding in patients with
a reduction in event frequency and clinical suspicion of RBD is RSWA
severity. (Figure 6-4). In isolation, RSWA is some-
VPSG-EEG can help to confirm the times referred to as preclinical or sub-
diagnosis of arousal disorders largely by clinical RBD. REM sleep is characterized by
excluding the presence of epileptic ac- primarily low-amplitude mixed-frequency

a
TABLE 6-5 The Frontal Lobe Epilepsy and Parasomnia Scale
Clinical Feature Score

Age at onset
At what age did the patient have Aged G55 years 0
the first clinical event? Aged Q55 years j1
Duration
What is the duration of a typical event? G2 minutes +1
2Y10 minutes 0
910 minutes j2
Clustering
What is the typical number of events to occur 1Y2 0
in a single night? 3Y5 +1
95 +2
Timing
At what time of night do events most Within 30 minutes of sleep onset +1
commonly occur? Other times 0
Symptoms
Are the events associated with a definite aura? Yes +1
No 0
Does the patient ever wander outside the Yes j2

bedroom during the events? No (or uncertain) 0
Does the patient perform complex, directed Yes j2

behaviors during events? No (or uncertain) 0
Is there a clear history of prominent dystonic Yes +1

posturing, tonic limb extension, or cramping No (or uncertain) 0
during events?
Stereotypy of events
Are the events highly stereotyped or variable Highly stereotyped +1
in nature? Some variability/uncertain 0
Highly variable j1
Recall
Does the patient recall the events? Yes, lucid recall +1
No or vague recollection only 0
Vocalization
Does the patient speak during the events and, No 0
if so, is there subsequent recollection of this speech? Yes, sounds only or single words 0
Yes, coherent with incomplete or no recall j2
Yes, coherent speech with recall +2
Total Score
a
Reprinted with permission from Derry CP, et al, Arch Neurol.56 B 2006, American Medical Association. All rights reserved.
archneur.jamanetwork.com/article.aspx?articleid=791451.
EEG activity, REMs, and low chin EMG of the epoch having increased chin
tone.55 RSWA is identified by sustained EMG amplitude and/or excessive transient
muscle activity in REM sleep with 50% muscle activity defined by the presence

KEY POINT
h REM sleep behavior of five or more 3-second epochs within contrast to seizures involving autonomic
disorder is the only a 30-second epoch containing transient network activation and arousal disor-
parasomnia that muscle activity at least 0.5 seconds in ders, tachycardia is uncommon in RBD.
requires diagnostic duration. No minimum number of
confirmation by epochs of abnormal motor activity is Other diagnostic modalities
polysomnography. required to confirm the presence of The Frontal Lobe Epilepsy and Para-
The pathognomonic RSWA. Recording full-blown RBD epi- somnias (FLEP) Scale has been pro-
polysomnographic sodes is rare in the sleep laboratory, and posed as an adjunct to the clinical
finding in patients with most cases are confirmed by the pres- history in the evaluation of complex
clinical suspicion of REM ence of RSWA and minor clinical fea- nocturnal behaviors.56 The scale con-
sleep behavior disorder
tures, such as low-intensity vocalizations sists of 11 items addressing semiologic
is REM sleep without
and/or nonspecific movements lacking features developed to differentiate fron-
atonia.
goal-directed content. Periodic limb tal lobe seizures from NREM disorders
movements in sleep, typically without of arousal (Table 6-5). A score of zero
arousal, are commonly observed. In or less favors the diagnosis of an NREM
FIGURE 6-6 MRI of a 49-year-old woman with stereotyped

complex nocturnal behaviors consisting of
arousal with a panicked sensation, grasping
and pronation, and tachycardia with preserved awareness
unresponsive to antiepileptic drug therapy and long
misinterpreted as a parasomnia. Numerous video EEG recordings
were normal without ictal or interictal epileptiform findings. Her
Frontal Lobe Epilepsy and Parasomnias Scale score of 5 (+1 for
duration G2 min; +1 for 3 to 5 events in a single night; +1 for
timing within 30 minutes of sleep onset; +1 for highly
stereotyped events; and +1 for lucid recall) suggested a diagnosis
of nocturnal frontal lobe epilepsy. A 3-T MRI revealed a
hyperintensity extending from the ependymal surface of the
superior margin of the right frontal horn to the overlying cortex of
the ventral aspect of the superior frontal sulcus (arrow) suggestive
of a malformation of cortical development. Invasive EEG
recorded spikes and seizures in the depth of the superior frontal
sulcus corresponding to the MRI lesion. Lesionectomy was
performed, resulting in a seizure-free state for 5 years.

parasomnia, whereas patients scoring and hypermotor behaviors that are ster-
3 or greater are likely to have NFLE eotyped for the individual subject; are
(Figure 6-6). Indeterminate scores brief, typically lasting 20 to 30 seconds;
require further evaluation. The scale and are associated with preserved aware-
has been shown to have high positive ness without postictal confusion or
(91%) and negative (100%) predictive amnesia. The absence of epileptiform
values, but misdiagnosis can occur es- features on EEG in many NFLE cases
pecially in cases of RBD. NFLE was re- further complicates the differentiation of
liably diagnosed using the FLEP Scale these disorders. VPSG-EEG is indicated in
with a sensitivity of 100% and a specif- the evaluation of patients with complex
icity of 90% in the initial validation nocturnal behaviors when routine EEG
study. This scale does not help in the is nondiagnostic. Ongoing research is
differentiation of other types of epilep- necessary to fully elucidate the patho-
tic seizures and parasomnias. physiology of these disorders, which
Multiple screening questionnaires share a host of clinical manifestations.
for RBD have been developed for use
in situations where a diagnosis is not VIDEO LEGENDS
confirmed by PSG due to absence of Supplemental Digital Content 6-1
REM sleep or where PSG is not feasible. Nocturnal frontal lobe epilepsy seizure. Video
Such cases include patients with severe demonstrates a bilateral, asymmetric, tonic seizure
with semiology characteristic of frontal lobe
cognitive impairment, inaccessibility to
(mesial) activation in a 32-year-old man with a
a sleep laboratory with ample expertise, normal MRI, no interictal discharges on scalp EEG,
and situations in which the cost of and a nonlocalizable scalp ictal EEG pattern. An
testing is difficult to justify because of ictal SPECT shows hyperperfusion in the left medial
infrequent or mild clinical manifesta- frontal lobe, so a stereo EEG evaluation is planned.
tions. Two such instruments, the Mayo The patient is medically intractable, with repet-
itive seizures at sleep-wake transition at bedtime
Sleep Questionnaire and the REM Sleep most nights that have not responded to medi-
Behavior Disorder Screening Question- cation. The seizures routinely wake him up, but
naire, are reported to have a sensitivity he typically can recall what happens during the
of 96% to 98% and specificity of 55% to seizure and responds immediately thereafter.
69% for confirmed PSG.35 links.lww.com/CONT/A30
B 2013 Nancy Foldvary-Schaefer, DO, MS, FAASM.
CONCLUSIONS Used with permission.
The diagnosis of complex nocturnal Supplemental Digital Content 6-2

behaviors is among the most difficult Rhythmic movement disorder. Video demon-
to establish in sleep medicine clinics and strates head rolling in an adult man. The stereo-
laboratories. An accurate diagnosis of typed and repetitive movement artifact is
sleep-related events generally relies on depicted at the frequency of 1 Hz to 2 Hz.
links.lww.com/CONT/A31
the correct distinction between noctur-
B 2013 Geert Mayer, MD, PhD. Used with permission.
nal seizures and parasomnias. While
several epilepsy syndromes arise prefer- Supplemental Digital Content 6-3
entially from sleep, NFLE is the disorder Benign sleep myoclonus in infancy. Video
most difficult to differentiate from para- demonstrates benign sleep myoclonus in in-
somnias. In contrast to the parasomnias, fancy, a disorder of quiet sleep. Its main character-
nocturnal frontal lobe seizures typically istics include rhythmic myoclonic jerks when
drowsy or asleep (that stop in wakefulness), and a
have an abrupt, explosive onset that normal encephalogram during the episodes.
awakens the patient from light NREM links.lww.com/CONT/A32
sleep; are accompanied by sustained B 2013 Sona Nevs<malova, MD, DSc. Used with
asymmetric dystonic, tonic posturing, permission.

Supplemental Digital Content 6-4 Supplemental Digital Content 6-9

Psychogenic movements. Video shows a 56-year- Sleep terror. Video demonstrates sleep terror
old woman with psychogenic movement of both in an adult woman. She screams suddenly,
hands at bedtime. She is alert and has no urge to beginning from slow-wave non-REM sleep. The
move her hands. The movements interfere with video segment after the event illustrates con-
her sleep onset, disappear in sleep, and reoccur versation with the technologist in which the
upon awakening. The movements are at times patient recalls being awakened, but has little
also seen during the day in wakefulness. recollection for the event, and returns to base-
links.lww.com/CONT/A33 line fairly quickly.
B 2013 Marcel Hungs, MD, PhD. Used with links.lww.com/CONT/A38
permission. B 2013 Rama Maganti, MD. Used with permission.
Supplemental Digital Content 6-5 Supplemental Digital Content 6-10

Confusional arousal. Video demonstrates confu- Sleep terror. Video demonstrates sleep terror in
sional arousal in an adult man. The patient has an a 46-year-old woman with a childhood history of
arousal, appears confused, and gets out of bed, sleep terror who started having episodes of
demonstrating automatic behavior. This is an screaming in the middle of the night, to which
example of a hybrid attack in which the patient she was oblivious. If her husband was home and
begins the episode with a confusional arousal and able to wake her, she sometimes reported seeing
proceeds for exhibit somnambulistic behavior. spiders on the bed but often did not know what
links.lww.com/CONT/A34 had happened. The terrors started the previous
B 2013 Sona Nevs<malova, MD, DSc. Used with year during a period of significant stress in the
permission. patients personal life. After a normal polysom-
nogram, the patient was admitted for video-EEG
Supplemental Digital Content 6-6 monitoring. This event occurs 45 minutes after
Confusional arousal. Video demonstrates confu- sleep onset, and the EEG of the event shows a
sional arousal in an adult man, demarcated by mixture of large-amplitude very slow delta
sudden arousal, confusion, searching behavior, and activity in the frontal and temporal leads and
rapid return to baseline with amnesia for the event faster alphalike activity in the posterior leads.
when conversing with the technologist. The patient did not have time to go to hypno-
links.lww.com/CONT/A35 therapy sessions. She responded to clomipramine
B 2013 Rama Maganti, MD. Used with permission. but had adverse events and was subsequently
put on 1 mg of clonazepam at bedtime. With
Supplemental Digital Content 6-7 this dose, she experienced good control of the
Sleepwalking. Video demonstrates sleepwalking events.
in a 34-year-old woman on zolpidem for chronic links.lww.com/CONT/A39
severe insomnia. The patient was seen by a B 2013 Hrayr Attarian, MD, FAASM, FCCP. Used
community sleep doctor for episodes of sleep- with permission.
walking and sleep smoking. She had let herself
out of her house a few times, so safety was a Supplemental Digital Content 6-11
concern. After a normal polysomnogram, the pa- Sleep terror in a child. Video demonstrates an
tient was started on clonazepam, which made her episode of sleep terror in a child that consists of
symptoms worse, and she was referred to a sleep sudden arousal, increase in sympathetic tone,
center for a consultation. Video EEG showed nor- confusion, aggressive behavior, inconsolability,
mal N2 sleep during the entire 30-minute episode and increased aggression.
of sleepwalking (edited here for brevity). links.lww.com/CONT/A40
links.lww.com/CONT/A36 B 2013 Sona Nevs<malova, MD, DSc. Used with
B 2013 Hrayr Attarian, MD, FAASM, FCCP. Used permission.
with permission.
Supplemental Digital Content 6-12
Supplemental Digital Content 6-8 REM sleep behavior disorder. Video demon-
Sleep terror. Video demonstrates sleep terror in strates REM sleep behavior disorder in an adult
an adult man who experiences sudden arousal man. Note the purposeful body movements
from non-REM sleep with screaming and amnesia correlating with dream enactment against elec-
for the event. trographic augmentation of EMG tone.
links.lww.com/CONT/A37 links.lww.com/CONT/A41
B 2013 Geert Mayer, MD, PhD. Used with permission. B 2013 Geert Mayer, MD, PhD. Used with permission.

Supplemental Digital Content 6-13 polygraphic overview of 100 consecutive
REM sleep behavior disorder. Video dem- cases. Brain 1999;122(pt 6):1017Y1031.
onstrates aggressive behavior in patients with 13. Bisulli F, Vignatelli L, Naldi I, et al. Increased
REM sleep behavior disorder necessitating frequency of arousal parasomnias in families
prompt safety modifications and pharmacologic with nocturnal frontal lobe epilepsy: a
interventions. common mechanism? Epilepsia 2010;
links.lww.com/CONT/A42 51(9):1852Y1860.
B 2013 Geert Mayer, MD, PhD. Used with permission. 14. Rheims S, Ryvlin P, Scherer C, et al. Analysis
of clinical patterns and underlying
epileptogenic zones of hypermotor seizures.
Epilepsia 2008;49(12):2030Y2040.
REFERENCES
1. Shouse MN, Farber PR, Staba RJ. 15. Morris HH 3rd, Dinner DS, Luders H, et al.
Physiological basis: how NREM sleep Supplementary motor seizures: clinical and
components can promote and REM sleep electroencephalographic findings.
components can suppress seizure discharge Neurology 1988;38(7):1075Y1082.
propagation. Clin Neurophysiol 2000; 16. Ikeda A, Hirasawa K, Kinoshita M, et al.
111(suppl 2):S9YS18. Negative motor seizure arising from the
2. Steriade M, Contreras D, Amzica F. negative motor area: is it ictal apraxia?
Synchronized sleep oscillations and their Epilepsia 2009;50(9):2072Y2084.
paroxysmal developments. Trends Neurosci 17. Pedley TA, Guilleminault C. Episodic
1994;17(5):199Y208. nocturnal wanderings responsive to
3. Foldvary-Schaefer N, Grigg-Damberger M. anticonvulsant drug therapy. Ann Neurol
Sleep and epilepsy: what we know, dont 1977;2(1):30Y35.
know, and need to know. J Clin Neurophysiol 18. Nobili L, Francione S, Mai R, et al. Surgical
2006;23(1):4Y20. treatment of drug-resistant nocturnal
4. DAlessandro R, Guarino M, Greco G, et al. frontal lobe epilepsy. Brain 2007;130(pt 2):
Risk of seizures while awake in pure sleep 561Y573.
epilepsies: a prospective study. Neurology 19. Nobili L, Cardinale F, Magliola U, et al.
2004;62(2):254Y257. Taylors focal cortical dysplasia increases the
5. Luders H, Acharya J, Baumgartner C, et al. A risk of sleep-related epilepsy. Epilepsia
new epileptic seizure classification based 2009;50(12):2599Y2604.
exclusively on ictal semiology. Acta Neurol 20. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al.
Scand 1999;99(3):137Y141. Autosomal dominant frontal epilepsy
6. Lugaresi E, Cirignotta F. Hypnogenic misdiagnosed as sleep disorder. Lancet
paroxysmal dystonia: epileptic seizure or a 1994;343(8896):515Y517.
new syndrome? Sleep 1981;4(2):129Y138. 21. Hoda JC, Gu W, Friedli M, et al. Human
7. Rasmussen T. Surgery for central, parietal nocturnal frontal lobe epilepsy:
and occipital epilepsy. Can J Neurol Sci pharmacogenomic profiles of pathogenic
1991;18(4 suppl):611Y616. nicotinic acetylcholine receptor beta-subunit
mutations outside the ion channel pore. Mol
8. Tellez-Zenteno JF, Dhar R, Wiebe S. Pharmacol 2008;74(2):379Y391.
Long-term seizure outcomes following
epilepsy surgery: a systematic review and 22. Combi R, Dalpra L, Ferini-Strambi L, Tenchini
meta-analysis. Brain 2005;128(pt 5):1188Y1198. ML. Frontal lobe epilepsy and mutations of
the corticotropin-releasing hormone gene.
9. Jobst BC, Siegel AM, Thadani VM, et al. Ann Neurol 2005;58(6):899Y904.
Intractable seizures of frontal lobe origin:
clinical characteristics, localizing signs, and 23. Oldani A, Zucconi M, Asselta R, et al.
results of surgery. Epilepsia 2000;41(9): Autosomal dominant nocturnal frontal lobe
1139Y1152. epilepsy. A video-polysomnographic and
genetic appraisal of 40 patients and
10. McGonigal A, Chauvel P. Frontal lobe delineation of the epileptic syndrome. Brain
epilepsy: seizure semiology and presurgical 1998;121(pt 2):205Y223.
evaluation. Pract Neurol 2004;4(5):260Y273.
24. Proserpio P, Cossu M, Francione S, et al.
11. Unnwongse K, Wehner T, Foldvary-Schaefer Epileptic motor behaviors during sleep:
N. Mesial frontal lobe epilepsy. J Clin anatomo-electro-clinical features. Sleep Med
Neurophysiol 2012;29(5):371Y378. 2011;12(suppl 2):S33YS38.
12. Provini F, Plazzi G, Tinuper P, et al. Nocturnal 25. Unnwongse K, Wehner T, Foldvary-Schaefer
frontal lobe epilepsy. A clinical and N. Selecting patients for epilepsy surgery.

Curr Neurol Neurosci Rep 2010;10(4): occur in REM sleep behavior disorder.
299Y307. Neurology 2009;72(6):551Y557.
26. Billiard M. Epilepsies and the sleep-wake 38. Avidan AY. Sleep disorders in the older
cycle. In: Sterman MB, Shouse MN, patient. Prim Care 2005;32(2):563Y586.
Passouant P, eds. Sleep and epilepsy. New
39. Claassen DO, Josephs KA, Ahlskog JE, et al.
York, NY: Academic Press; 1982:269Y286.
REM sleep behavior disorder preceding
27. Bernasconi A, Andermann F, Cendes F, et al. other aspects of synucleinopathies by up to
Nocturnal temporal lobe epilepsy. half a century. Neurology 2010;75(6):
Neurology 1998;50(6):1772Y1777. 494Y499.
28. Isnard J, Guenot M, Sindou M, et al. Clinical 40. Aurora RN, Zak RS, Maganti RK, et al. Best
manifestations of insular lobe seizures: a practice guide for the treatment of REM
stereo-electroencephalographic study. sleep behavior disorder (RBD). J Clin Sleep
Epilepsia 2004;45(9):1079Y1090. Med 2010;6(1):85Y95.
29. American Academy of Sleep Medicine. The 41. Benbadis SR, Lancman ME, King LM,
international classification of sleep disorders Swanson SJ. Preictal pseudosleep: a new
second edition: diagnostic and coding finding in psychogenic seizures. Neurology
manual. Westchester, IL: American Academy 1996;47(1):63Y67.
of Sleep Medicine; 2005.
42. Duncan R, Oto M, Russell AJ, et al.
30. Terzaghi M, Sartori I, Tassi L, et al. Dissociated Pseudosleep events in patients with
local arousal states underlying essential psychogenic non-epileptic seizures:
clinical features of non-rapid eye movement prevalence and associations. J Neurol
arousal parasomnia: an intracerebral Neurosurg Psychiatry 2004;75(7):1009Y1012.
stereo-electroencephalographic study
43. Devinsky O, Gazzola D, LaFrance WC Jr.
[published online ahead of print February 14,
Differentiating between nonepileptic and
2012]. J Sleep Res 2012. doi:10.1111/
epileptic seizures. Nat Rev Neurol 2011;7(4):
j.1365-2869.2012.01003.
210Y220.
31. Schenck CH, Milner DM, Hurwitz TD,
44. Tassinari CA, Gardella E, Cantalupo G, et al.
et al. A polysomnographic and clinical
Central pattern generators relationships to
report on sleep-related injury in 100 adult
parasomnias and sleep-related epileptic
patients. Am J Psychiatry 1989;146(9):
seizures. Sleep Med Clin 2012;7:125Y134.
1166Y1173.
32. Ohayan MM, Guilleminault C, Priest RG. 45. Kushida CA, Littner MR, Morgenthaler T,
Night terrors, sleepwalking, and confusional et al. Practice parameters for the indications
arousals in the general population: their for polysomnography and related
procedures: an update for 2005. Sleep 2005;
frequency and relationship to other sleep
and mental disorders. J Clin Psychiatry 28(4):499Y521.
1999;60(4):268Y276. 46. Foldvary N, Caruso AC, Mascha E, et al.
33. Hublin C, Kaprio J, Partinen M, et al. Identifying montages that best detect
Prevalence and genetics of sleepwalking: a electrographic seizure activity during
population-based twin study. Neurology polysomnography. Sleep 2000;23(2):
1997;48(1):177Y181. 221Y229.
34. Licis AK, Desruisseau DM, Yamada KA, et al. 47. Foldvary-Schaefer N, De Ocampo J, Mascha
Novel genetic findings in an extended family E, et al. Accuracy of seizure detection using
pedigree with sleepwalking. Neurology abbreviated EEG during polysomnography.
2011;76(1):49Y52. J Clin Neurophysiol 2006;23(1):68Y71.
35. Boeve BF. REM sleep behavior disorder: 48. Aldrich MS, Jahnke B. Diagnostic value of
updated review of the core features, the REM video-EEG polysomnography. Neurology
sleep behavior disorder-neurodegenerative 1991;41(7):1060Y1066.
disease association, evolving concepts, 49. Derry CP, Harvey AS, Walker MC, et al.
controversies, and future directions. Ann N Y NREM arousal parasomnias and their
Acad Sci 2010;1184:15Y54. distinction from nocturnal frontal lobe
36. Schenck CH, Mahowald MW. REM sleep epilepsy: a video EEG analysis. Sleep
behavior disorder: clinical, developmental, 2009;32(12):1637Y1644.
and neuroscience perspectives 16 years after
50. Holmes MD, Dodrill CB, Wilensky AJ, et al.
its formal identification in SLEEP. Sleep
Unilateral focal preponderance of interictal
2002;25(2):120Y138.
epileptiform discharges as a predictor of
37. Oudiette D, De Cock VC, Lavault S, et al. seizure origin. Arch Neurol 1996;53(3):
Nonviolent elaborate behaviors may also 228Y232.

51. Foldvary N, Klem G, Hammel J, et al. The 54. Pilon M, Montplaisir J, Zadra A. Precipitating
localizing value of ictal EEG in focal epilepsy. factors of somnambulism: impact of sleep
Neurology 2001;57(11):2022Y2028. deprivation and forced arousals. Neurology
2008;70(24):2284Y2290.
52. Terzaghi M, Sartori I, Mai R, et al. Coupling
of minor motor events and epileptiform 55. Iber C, Ancoli-Israel S, Chesson A, et al. The
discharges with arousal fluctuations in NFLE. AASM manual for the scoring of sleep and
Epilepsia 2008;49(4):670Y676. associated events: rules, terminology and
technical specifications. Westchester, IL:
53. Schenck CH, Pareja JA, Patterson AL, American Academy of Sleep Medicine, 2007.
Mahowald MW. Analysis of
polysomnographic events surrounding 252 56. Derry CP, Davey M, Johns M, et al.
slow-wave sleep arousals in thirty-eight Distinguishing sleep disorders from seizures:
adults with injurious sleepwalking and sleep diagnosing bumps in the night [published
terrors. J Clin Neurophysiol 1998;15(2): erratum appears in Arch Neurol 2006;
159Y166. 63(7):1037]. Arch Neurol 2006;63(5):705Y709.

Review Article
Circadian Rhythm
Dr Phyllis C. Zee, Northwestern
University, 710 North Lake
Shore Dr, Chicago, IL 60611,
p-zee@northwestern.edu.
Dr Zee has received personal
Abnormalities
compensation for activities Phyllis C. Zee, MD, PhD; Hrayr Attarian, MD, FAASM, FCCP;
with Jazz Pharmaceuticals;
Merck & Co, Inc; Perdue Aleksandar Videnovic, MD, MSc
Pharma; Philips Respironics;
Sanofi-Aventis; Takeda
Pharmaceutical Company
Limited; UCB; and Zeo, Inc. ABSTRACT
Dr Zee receives research Purpose: This article reviews the recent advances in understanding of the funda-
support from Philips
Respironics. Dr Attarian
mental properties of circadian rhythms and discusses the clinical features, diagnosis,
receives personal and treatment of circadian rhythm sleep disorders (CRSDs).
compensation for activities Recent Findings: Recent evidence strongly points to the ubiquitous influence of
with American Physicians
Institute. Dr Videnovic reports
circadian timing in nearly all physiologic functions. Thus, in addition to the prominent
no disclosure. sleep and wake disturbances, circadian rhythm disorders are associated with cognitive
Unlabeled Use of impairment, mood disturbances, and increased risk of cardiometabolic disorders. The
Products/Investigational recent availability of biomarkers of circadian timing in clinical practice has improved
Use Disclosure: Dr Zee
discusses the unlabeled use of our ability to identify and treat these CRSDs.
melatonin for the treatment of Summary: Circadian rhythms are endogenous rhythms with a periodicity of
circadian disorders. Dr Attarian approximately 24 hours. These rhythms are synchronized to the physical environment
discusses the unlabeled use of
melatonin and light boxes to by social and work schedules by various photic and nonphotic stimuli. CRSDs result
advance or delay circadian from a misalignment between the timing of the circadian rhythm and the external
rhythms. Dr Videnovic environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its
melatonin, ramelteon, and afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase,
supplemental light exposure to nonY24-hour, and irregular sleep-wake rhythm disorders). The most common symp-
advance circadian rhythms and toms of these disorders are difficulties with sleep onset and/or sleep maintenance and
treat jet-lag disorder.
excessive sleepiness that are associated with impaired social and occupational
of Neurology. functioning. Effective treatment for most of the CRSDs requires a multimodal approach
to accelerate circadian realignment with timed exposure to light, avoidance of bright
light at inappropriate times, and adherence to scheduled sleep and wake times. In
addition, pharmacologic agents are recommended for some of the CRSDs. For delayed
sleep-phase, nonY24-hour, and shift work disorders, timed low-dose melatonin
can help advance or entrain circadian rhythms; and for shift work disorder, wake-
enhancing agents such as caffeine, modafinil, and armodafinil are options for the
management of excessive sleepiness.
OVERVIEW OF THE HUMAN hormone secretion, glucose homeosta-

CIRCADIAN SYSTEM sis, and cell-cycle regulation. The timing
Circadian rhythms are physiologic and of these physiologic rhythms may
behavioral cycles with a recurring perio- become altered, leading to changes in
dicity of approximately 24 hours, gen- the phase relationship of rhythms to
erated by the endogenous biological each other, which can cause internal
pacemaker, the suprachiasmatic nucleus desynchronization. This loss of coordi-
(SCN), located in the anterior hypothal- nation of rhythms may have negative
amus.1 These rhythms control a variety consequences on rest-activity cycles
of biological processes, such as sleep- and other physiologic and behavioral
wake cycle, body temperature, feeding, functions.

KEY POINTS
Circadian Entrainment tinct neurochemical properties.1 While h Circadian rhythms are
Circadian rhythms are synchronized with +-aminobutyric acid is the dominant physiologic and
the earths rotation by daily adjustments neurotransmitter in the SCN, present in behavioral cycles with a
in the timing of the SCN, following the nearly all SCN neurons, SCN neuropep- recurring periodicity of
exposure to stimuli that signal the time tides are highly localized within either approximately 24 hours,
of day. These stimuli are known as the core or shell nuclei. The SCN core generated by the
zeitgebers (German for time-givers), contains high density of vasoactive in- endogenous biological
of which light is the most important and testinal polypeptide, gastrin-releasing pacemaker, the
peptide, and bombesin-containing neu- suprachiasmatic
potent stimulus. The magnitude and
rons. Somatostatin and neurophysin are nucleus, located in the
direction of the change in phase de-
anterior hypothalamus.
pends on when within the circadian dominant neurochemicals within the
system the light pulse is presented. A SCN shell. h Circadian rhythms are
The SCN receives photic information synchronized with the
plot of phase changes according to the
from the retina via direct (retinohypo- earths rotation by
time of light stimulus presentation
daily adjustments in
provides a phase response curve. Expo- thalamic) and indirect (retinogeniculate)
the timing of the
sure to light results in a phase response pathways.3 The melanopsin-containing
suprachiasmatic
curve with delays in the early subjective ganglion cells of the retina are the pri- nucleus, following the
night (ie, evening) and advances in the mary photoreceptors for the circadian exposure to stimuli that
late subjective night (ie, early morning). system. The SCN also receives nonphotic signal the time of day.
In addition to light, feeding schedules, information from the raphe nuclei. Sev- These stimuli are
activity, and the hormone melatonin eral less-characterized afferents con- known as zeitgebers
can also affect the circadian timing.1 verge in the SCN from basal forebrain, (German for
The timing of melatonin secretion by pons, medulla, and posterior hypothal- time-giver), of
the pineal gland is regulated by the SCN, amus. The major efferents from the SCN which light is the most
project to the subparaventricular zone important and potent
with the onset of secretion approxi-
and the paraventricular nucleus of the stimulus. The magnitude
mately 2 hours before natural sleep time
and direction of the
and being highest during the middle of hypothalamus, dorsomedial hypothal-
change in phase depends
the night.1 Melatonin onset measured amus, thalamus, preoptic and retrochias-
on when within the
in a dim light environment (DLMO) is a matic areas, stria terminalis, lateral circadian system the
stable marker of circadian phase and is septum, and intergeniculate nucleus. light pulse is presented.
used in research as well as clinical prac- The SCN also communicates via diffu-
tice to determine the timing of the en- sion of humoral signals to the rest of
dogenous circadian rhythm. the brain. These diffusible SCN outputs
likely include transforming growth fac-
Neuroanatomy and tor !, cardiotrophinlike cytokine, and
Neurochemistry prokineticin 2. A major development
The central circadian timing system has in chronobiology research has been
three distinct components: (1) a circa- the discovery of circadian clocks in
dian pacemaker, the SCN, (2) input non-SCN brain regions and almost all
pathways for light and other stimuli that peripheral tissues.4 While the signals
synchronize the pacemaker to the envi- mediating communication between the
ronment, and (3) output rhythms that SCN and peripheral oscillators remain
are regulated by the pacemaker. The under extensive investigation, it is clear
SCN is the central pacemaker that links that the central clock (ie, SCN) and pe-
the 24-hour changes in the external ripheral clocks may have distinct circa-
environment with the 24-hour changes dian synchronizers. The SCN, however,
in the internal environment (Figure 7-1).2 is most likely dominant in maintain-
The SCN is composed from the core ing circadian rhythmicity of peripheral
and shell subnuclei, which have dis- clocks.

Circadian Rhythm Abnormalities
FIGURE 7-1 Schematic illustration of the pathway responsible for entrainment of melatonin
secretion by light. The circadian regulation of melatonin secretion is dependent on
an indirect pathway that originates in photosensitive ganglion cells in the retina and
reaches the suprachiasmatic nucleus, the circadian pacemaker, via the retinohypothalamic tract.
The suprachiasmatic nucleus controls the sympathetic output to the pineal gland, which is responsible
for melatonin secretion via an inhibitory projection to the paraventricular nucleus of the
hypothalamus. This pathway is responsible for the peak of melatonin secretion during darkness.
2
Reprinted with permission from Benarroch EE, Neurology. B 2008, American Academy of Neurology. www.neurology.
org/content/71/8/594.extract.
Genetic Regulation During the night, the PER-CRY repressor

Circadian rhythms are determined complex is degraded, and the cycle
genetically by a core set of clock genes, starts again (Figure 7-2). Circadian clock
including three Per genes (the period genes control a significant proportion
homolog 1 gene, Per1; the period homo- of the genome. It is estimated that ap-
log 2 gene, Per2; the period homolog 3 proximately 10% of all expressed genes
gene, Per3); the circadian locomotor out- are under regulation of the clock genes.
put cycles kaput gene, Clock; the cycle Furthermore, peripheral tissues contain
gene, Bmal1; and two plant cryptochrome independent clocks. It is likely that
gene homologs (the cryptochrome 1 peripheral clocks are synchronized by
gene, Cry1, and the cryptochrome 2 gene, an input directly from the SCN or SCN-
Cry2).5 These genes and their products mediated messages. Several excellent
interact to form transcription-translation reviews are available for more detailed
feedback loops that provide the molec- overview of the molecular regulation of
ular basis of circadian rhythmicity. Dur- the circadian system,3,6,7
ing the day, Clock interacts with BMal1
to activate transcription of the Per and CIRCADIAN RHYTHM SLEEP
Cry genes, resulting in high levels of DISORDERS
these transcripts. PER and CRY proteins Circadian rhythm sleep disorders
translocate to the nucleus and inhibit (CRSDs) are chronic patterns (for at
CLOCKYB-MAL1-mediated transcription. least 1 month) of sleep-wake rhythm

disturbances due to alterations of the
circadian timing system or to a misalign-
ment between the timing of the endog-
enous circadian rhythm and the sleep-
wake times required by school or work
schedules. As a result, patients present
with impairments in sleep and wake
functioning. The diagnosis of all CRSDs
is based on a careful history and sleep
diary with actigraphy. Polysomnography
(PSG) is not routinely indicated to
establish the diagnosis. However, PSG
is indicated to assess for other comorbid
sleep disorders. In addition to comorbid
FIGURE 7-2 Simplified representation of the transcription
sleep disorders, psychiatric disordersV cycle.
particularly depression and anxietyVare
common in patients with nearly all types
of CRSDs and should be considered in
the differential diagnosis.
to be common (33%) in patients with KEY POINT
Delayed Sleep-Phase Disorder hepatic cirrhosis.8 h Delayed sleep-phase
Delayed sleep-phase disorder (DSPD) Pathophysiology. Multiple biological disorder is characterized
by chronic or recurrent
is characterized by a chronic or recur- and behavioral factors contribute to the
inability to fall asleep
rent inability to fall asleep and wake up development of DSPD. The postulated
and wake up at socially
at socially acceptable times, resulting in mechanisms for DSPD include (1) de- acceptable times,
symptoms of difficulty falling asleep and creased response to the phase-advancing resulting in symptoms
excessive daytime sleepiness, particu- effect of light in the morning,9 (2) in- of difficulty falling
larly in the morning. By definition, in creased sensitivity to the phase-delay asleep and excessive
relation to socially acceptable times, there response of evening light, and (3) a longer daytime sleepiness,
is a more than 2-hour delay in the major than normal time to complete one cir- particularly in
sleep period. Patients have difficulty wak- cadian cycle (ie, long circadian period). the morning.
ing up in the morning and are often Familial cases and the demonstration of
late for work or school. When patients polymorphisms of circadian clock genes
are allowed to sleep at their biologically in DSPD indicate a genetic basis for this
preferred time and wake up sponta- condition.10 Environmental, behavio-
neously after their major sleep period, ral, and psychological factors also play
sleep and daytime function normalize. a role in the development of DSPD.
Epidemiology. The prevalence of For example, individuals with a delayed
DSPD is 0.2% to 10.0% depending on circadian phase are more likely to work
severity and the population groups sur- in the evening and be exposed to
veyed. Milder cases are more prevalent, evening light, which can further delay
as are cases among adolescents and the timing of circadian rhythms, or they
young adults. There appears to be no wake up late, thus perpetuating the
sex predilection, but among adolescents vicious cycle of late sleep and late wake
the phase delay occurs at an older age in times.11
males than in females, with males reach- Clinical presentation and diagnosis.
ing their peak at age 21 and females Patients with DSPD usually fall asleep
at age 17. A familial predisposition for between 1:00 AM and 6:00 AM and wake
DSPD also occurs, and DSPD appears up in the late morning to early afternoon,

KEY POINT
h Diagnosis of delayed as outlined in the International Classi- cially during morning hours, in addition
sleep-phase disorder is fication of Sleep Disorders, Second to habitual tardiness and morning absen-
made by careful history Edition: Diagnostic and Coding Man- ces. Diagnosis is made by careful history
and well-kept sleep ual. Conditioned insomnia and chronic and well-kept sleep diaries with or with-
diaries with or without sleep deprivation may develop as a com- out actigraphy for a minimum of 7 days
actigraphy for a plication of DSPD. In addition, patients (preferably 14 days) (Case 7-1). Stand-
minimum of 7 days with DSPD tend to have decreased ardized chronotype questionnaires are
(preferably 14 days). academic and work performance, espe- useful tools to assess the chronotype
Case 7-1
A 21-year-old man presented with nightly complaints of difficulty falling asleep
that started 4 to 5 years earlier. He had no problem staying asleep, but it
took several hours to fall asleep, and he had difficulty staying alert during the
workday. He was concerned because his work performance was suffering and he
had been seen dozing at his desk. Actigraphy recording of his sleep and wake
cycle is shown in Figure 7-3.
FIGURE 7-3 Representative actogram of patient with delayed sleep-phase disorder. The blue
arrows indicate sleep onset and the red arrows indicate the end of the major
sleep period. The black horizontal arrows indicate naps. In high-amplitude
actigraphy, dense bars are representative of wakefulness, and low, sparse bars are representative
of sleep. Note that sleep onset is 2:00 AM to 4:00 AM and the end of the major sleep period varies
from 8:00 AM all the way to 1:00 PM (on day 7). On day 5, when total sleep duration was from
2:00 AM to 7:00 AM, the patient takes two naps, resulting in less sleep homeostatic drive, and
therefore sleep onset the next night is not until 5:00 AM.
Comment. Typical of patients with delayed sleep-phase disorder, this man had
significant sleep-onset insomnia and was then sleepy while at work because of chronic sleep
deprivation and because he was forced to be awake during a part of his circadian sleep time.

KEY POINT
of eveningness and morningness. Advanced Sleep-Phase Disorder h Bright light (full spectrum
In addition, a delay in the timing of Advanced sleep-phase disorder (ASPD) or blue enriched) in the
objective circadian rhythms, such as the is characterized by an advance in the morning for 2 hours
DLMO or urinary 6-sulfatoxymelatonin, phase of the major sleep episode in shortly after the
is desirable to confirm the delayed cir- relation to the desired or required sleep minimum of the core
cadian phase. Depression, anxiety, and and wake-up times. Patients have body temperature
personality disorders are more com- chronic or recurrent difficulty staying rhythm (typically
mon among patients with DSPD. awake until the desired or socially occurring 2 to 3 hours
before natural wake-up
Treatment. The American Academy acceptable bedtime, together with an
time) has been shown to
of Sleep Medicine (AASM) practice pa- earlier than desired wake-up time. When
successfully advance
rameters recommend appropriately patients are allowed to choose their circadian rhythms in
timed morning light exposure and preferred schedule, sleep quality and patients with delayed
evening exogenous melatonin either duration are normal for age. sleep-phase disorder.
alone or in combination as effective Epidemiology. ASPD is less com-
treatments for DSPD (Figure 7-4). The mon than DSPD. The estimated preva-
combination of light therapy and mel- lence is 1% in the general population,
atonin has been shown to have com- which is likely an underestimate since
plementary benefits.12 Bright light (full many individuals successfully adapt
spectrum or blue enriched) in the their social and work schedules to the
morning for 2 hours shortly after the advanced sleep phase.19 Both sexes are
minimum of the core body temper- equally affected by the disorder. The
ature rhythm (typically occurring 2 to 3 onset of ASPD is typically during mid-
hours before natural wake-up time) has dle age. Several studies suggest that age
been shown to successfully advance may be a risk factor for ASPD, likely on
circadian rhythms in patients with the basis of a phase advance of the
DSPD.13 Melatonin 0.5 mg to 5 mg circadian pacemaker with aging.17
given 5.0 to 6.5 hours before DLMO (13 Pathophysiology. A shortened circa-
to 14 hours after natural wake-up dian period has been postulated to be
time)14 advances sleep and rise times, involved in the pathogenesis of ASPD.
while administration closer to DLMO Genetic factors likely play an important
is less effective. Effectiveness lasts up role in the development of ASPD.
to 1 year with daily melatonin intake, Several families with ASPD inherited in
but relapses can occur in up to 90% of an autosomal dominant mode have
people after they discontinue their been described. Two gene mutations
melatonin. Time to relapse ranges have been identified in some of these
from 1 day to 6 months with the more families, affecting the circadian clock
severe DSPD cases relapsing faster.15 gene hPer2 and the casein kinase 1
Furthermore, melatonin has been delta gene.20 These mutations result
shown to improve depression in in a shortened circadian period. Addi-
patients with DSPD.16 Although it has tional mechanisms include an attenu-
been reported that vitamin B12 may be ated ability to phase delay because of a
effective as an adjunctive treatment to dominant phase advance region of the
bright light, it was not recommended phase response curve to light and
by the 2007 AASM practice parameters increased retinal sensitivity to light in
as a treatment for DSPD.17 There is the morning,21 resulting in a stronger
also limited evidence suggesting a advancing signal for the circadian clock.
therapeutic benefit of combining light Clinical presentation and diagnosis.
therapy with cognitive-behavioral ther- Patients with ASPD typically present
apy in adolescents with DSPD.18 with symptoms of daytime sleepiness,

KEY POINTS
h Patients with advanced most prominent in the late afternoon or tive circadian rhythms, such as the
sleep-phase disorder early evening hours; sleep maintenance DLMO or urinary 6-sulfatoxymelatonin,
typically present with difficulty; and early morning awakening. is desirable to confirm the advanced cir-
symptoms of daytime Individuals with ASPD are usually sleepy cadian phase.
sleepiness (most and struggle to stay awake between Treatment. The AASM practice
prominent in the late 6:00 PM and 9:00 PM and wake up earlier parameter recommends sleep-wake
afternoon or early than desired, between 2:00 AM and 5:00 AM. scheduling and timed light exposure
evening hours) sleep The diagnosis of ASPD is based on a as the primary treatments for ASPD.
maintenance difficulty, detailed sleep history accompanied by a Practical therapeutic approaches for
and early morning sleep diary and, if feasible, actigraphy ASPD include timed light exposure in
awakening.
over a period of least 7 days (preferably the evening and avoiding light in early
h Practical therapeutic 14 days) to demonstrate advanced morning hours (Figure 7-4). Melatonin
approaches for advanced sleep and wake times. Major depressive or hypnotics may be beneficial for sleep
sleep-phase disorder disorders should be carefully differenti- maintenance insomnia. Bright light
include timed light
ated from ASPD. Standardized chrono- administered before the nadir of body
exposure in the evening
type questionnaires are useful tools to core temperature is a potent stimulus
and avoiding light in
early morning hours.
assess the chronotype of eveningness for delaying circadian phase. The most
Melatonin or hypnotics and morningness. Patients with ASPD commonly used treatment for ASPD
may be beneficial for will score as morning types. In addi- is early-evening light therapy, usually
sleep-maintenance tion, an advance in the timing of objec- between 7:00 PM and 9:00 PM. This
insomnia.
FIGURE 7-4 Summary of treatment approaches for delayed sleep-phase disorder and advanced
sleep-phase disorder. Bright light administered before the nadir of body
core temperature is a potent stimulus for delaying circadian phase. The most
commonly used treatment for advanced sleep-phase disorder is early-evening light therapy, usually
between 7:00 PM and 9:00 PM. This approach has been shown to improve sleep duration and sleep
maintenance, as well as daytime performance. The combination of light therapy and melatonin
has been shown to have complementary benefits. Bright light in the morning for 1 to 2 hours
shortly after the minimum of the core body temperature rhythm advances circadian rhythms and
0.5 mg to 5 mg of melatonin taken 5 to 6.5 hours before dim light melatonin onset (13 to 14 hours
after natural wake-up time) results in advanced sleep and wake times in patients with delayed
sleep-phase disorder.
MLT = melatonin.

approach has been shown to improve Pathophysiology. Multiple physio-
sleep duration and sleep maintenance, logic, behavioral, and environmental
as well as daytime performance. How- factors contribute to the development
ever, results of evening light therapy of ISWRD. The most likely mechanisms
have not been uniformly positive.22 include central degeneration of SCN
Compliance with timed light exposure neurons and decreased exposure or
can be challenging, and bright light may input of external synchronizing agents,
irritate the eyes, particularly in older such as light and activity that result in a
adults. A chronotherapeutic approach of weakened central circadian oscillation
advancing bedtime by 3 hours every 2 and temporal disorganization of circa-
days has been reported effective in ASPD; dian rhythms.26 The problem is perpe-
however, the scheduling constraint of tuated by a variety of factors inherent
this approach limits its use in clinical in the lifestyles of older adults in nurs-
practice. Based on the phase response ing homes and other similar living
curve to melatonin, administration of facilities. Institutionalized elderly pa-
melatonin in early morning will advance tients get significantly less exposure to
the circadian phase, although clinical light in both amount and intensity. This
evidence of the efficacy or safety of is a result of lower levels of light indoors
melatonin for the treatment of ASPD is and the fact that most eye diseases,
lacking. While hypnotic agents are pre- such as cataracts, reduce light input to
scribed for the management of sleep the SCN even further. Compounding
maintenance symptoms associated with the diminished light exposure is the
ASPD, their efficacy and safety have not reduction in other external synchron-
been systematically studied. izers such as structured social and
physical activities. Decreased mobility,
Irregular Sleep-Wake Rhythm adverse effect on sleep and alertness by
Disorder medications, and increased napping
Irregular sleep-wake rhythm disorder also play a role in the development
(ISWRD) is characterized by a tempo- of ISWRD.26 Genetic factors have been
rally disorganized sleep and wake pat- implicated in the development of
tern, such that multiple sleep and wake ISWRD in Alzheimer disease.27
periods occur throughout the 24-hour Clinical presentation and diagnosis.
cycle. This disorder is more prevalent In patients with ISWRD, sleep bouts
in older adults with dementia and in occur in three or more short intervals of
patients with developmental disorders. approximately 1 to 4 hours each, spread
Epidemiology. ISWRD is common over 24 hours. The longest bout gen-
among institutionalized older adults, erally occurs between 2:00 AM and
particularly those with Alzheimer dis- 6:00 AM. The overall amount of sleep
ease and those with late afternoon- per 24-hour period, however, is relatively
evening agitation or sundowning. Age normal for the patients age.23 Because of
alone is not a risk factor for ISWRD, fragmented sleep and multiple daytime
but age-related neurologic and psychi- naps, patients usually present with
atric disorders are.23 ISWRD has also symptoms of sleep maintenance insom-
been described in patients with head nia and excessive daytime sleepiness. In
trauma, children with developmental addition to the typical symptomatology,
delay, and patients with schizophre- diagnosis requires a history of a mini-
nia, particularly those with positive mum of three irregular sleep-wake
symptoms,24 independent of daytime cycles in a 24-hour cycle recorded for
functioning.25 14 days by sleep diary and/or actigraphy.

KEY POINTS
h Creating a cognitively Treatment. Creating a cognitively Epidemiology. Sleep disturbances in
enriched environment enriched environment with structured people who are blind are common, and
with structured social and social and physical activity during the approximately 50% may have N24HSWD.
physical activity during day is an important therapeutic modal- Much less commonly, N24HSWD can
the day is an important ity, especially if combined with a healthy occur in sighted people. Onset of symp-
therapeutic modality for bedtime routine and a nocturnal envi- toms typically occurs during the second
patients with irregular ronment conducive to sleep. Measures or third decade of life.29 In blind and
sleep-wake rhythm include minimizing noise and light dur- sighted individuals, there is a male
disorder, especially if ing the scheduled sleep period and predilection with a ratio of 2.6/1.30
combined with a healthy addressing issues such as nocturia and Pathophysiology. The etiology of
bedtime routine and a
enuresis to reduce sleep disturbances N24HSWD in blind people is clearly a
nocturnal environment
at night. Light, however, remains the marked decrease or absence of light
conducive to sleep.
most effective therapeutic intervention. perception. However, not all patients
h NonY24-hour sleep-wake Exposure to 3000 lux to 5000 lux bright who are blind exhibit this lack of
disorder is characterized
light for 2 hours every morning for 4 entrainment, because in some, light
by a chronic or recurrent
weeks has been shown to improve information from the retinal ganglion
pattern of sleep and
wake cycles that are not
daytime alertness, decrease napping, cells can still reach the SCN, or other
synchronized to the consolidate nighttime sleep, and re- synchronizing agents (such as struc-
24-hour environment. duce nocturnal agitation.23 Melatonin tured social and physical activity) can
Typically a consistent daily alone has not been shown to be sufficiently entrain circadian rhythms.30
drift (usually to later and consistently effective in treating ISWRD Although the exact mechanism in
later times) of sleep-onset in older adults or in patients with sighted individuals remains to be eluci-
and wake-up times Alzheimer disease. However, effective- dated, evidence suggests that a long
occurs. ness may be improved when melatonin circadian period that is beyond the
at bedtime is combined with light normal range of entrainment is likely a
during the day.21 Small open-label trials risk factor.30 Other postulated mecha-
using doses of 2 mg to 20 mg of mel- nisms that can lead to an abnormal
atonin have shown some benefit in interaction between sleep homeostasis
children with developmental disor- and endogenous circadian rhythms
ders.28 Controlled-release formulation include (1) decreased photosensitivity,30
appeared more effective than immedi- (2) alteration and reduction of social
ate release in this subpopulation. The cues because of psychiatric illnessY
AASM practice parameters recommend induced social withdrawal,21 (3) muta-
using a combination of environmental tion in the creatinine kinase 1 ( (CK1()
and behavioral modifications and bright gene,21 and (4) desynchrony between
light therapy for ISWRD. the melatonin and sleep rhythms.30
Clinical presentation and diagnosis.
Non24-Hour Sleep-Wake The presenting symptoms depend on
Disorder when the person is required to sleep in
NonY24-hour sleep-wake disorder relation to his or her nonentrained
(N24SWD) (nonentrained rhythm disor- endogenous circadian rhythm of sleep-
der formerly known as free-running wake propensity. Patients typically
rhythm disorder) is characterized by a present with symptoms of insomnia,
chronic or recurrent pattern of sleep and excessive daytime sleepiness, or both
wake cycles that are not synchronized to for several weeks. These symptomatic
the 24-hour environment. Typically a episodes alternate with days to weeks
consistent daily drift (usually to later in which the patient is asymptomatic.
and later times) of sleep-onset and The prevailing complaint is the interfer-
wake-up times occurs. ence of the sleep-wake schedule with

KEY POINT
work, school, and other social obliga- DSPD. Most sighted patients with h In blind patients with
tions.29 Patients with this disorder can N24HSWD also have an evening chro- nonY24-hour
have, at various times, excessive day- notype. A misdiagnosis can be problem- sleep-wake disorder,
time sleepiness and sleep-onset insom- atic, as chronotherapy for DSPD may melatonin is the
nia or early morning awakenings. induce a nonY24-hour rhythm. In the therapeutic mainstay
Napping is quite common, and careful largest cohort of sighted N24HSWD pa- together with strong
analysis of sleep-wake rhythms may tients, one-fourth had received a pre- structured behavioral
reveal two distinct sleep-wake cycle vious misdiagnosis of DSPD.21 and social cues such as
periods separated by phase jumps (ie, Treatment. In blind patients with timing of meals, planned
when sleep onset is delayed for more N24SWD, melatonin is the therapeutic activities, and regular
physical exercise. This
than 4 hours).21 mainstay together with strong struc-
same approach is
Diagnosis is made by a careful history tured behavioral and social cues, such
recommended for
and documenting that the sleep com- as timing of meals, planned activities, sighted persons, with the
plaints are present for at least 2 months. and regular physical exercise.29 This additional option of
A minimum of 14 days of sleep diary same approach is recommended for bright light exposure in
and/or actigraphy can be very helpful. sighted persons, with the additional the morning shortly after
Actigraphy of a patient with N24HSWD is option of bright light exposure in the awakening.
shown in Figure 7-5. Continuous core morning shortly after awakening. Al-
body temperature measurements, if though the dose of melatonin for the
feasible, or serial measurements of the treatment of N24HSWD varies among
timing of the melatonin rhythm from studies, a practical recommendation is
serum, saliva, or urine can be confirma- to start with a higher dose (3 mg to
tory as they exhibit the same nonY24- 10 mg) 1 hour before bedtime or a few
hour rhythm as the disorder itself.21 hours before predicted DLMO for the
Frequent comorbid psychiatric condi- first month. Entrainment usually occurs
tions, primarily mood disorders, need within 3 to 9 weeks but must be main-
to be addressed as well. Care has to be tained by regular low-dose (0.5 mg)
taken to differentiate N24HSWD from melatonin to prevent a relapse. If the
FIGURE 7-5 Actigraphy record of a sighted patient with nonY24-hour sleep-wake disorder.
Note the daily delay drift of the onset and offset of the sleep-wake rhythm with a
circadian period that is longer than 24 hours.

KEY POINT
h Internal desynchronization initiation dose fails, an alternate method nization is somewhat faster with west-
of physiologic rhythms is a 0.5-mg dose over a period of several bound travel (1.0 hour per day)
resulting from time-zone months. Most blind patients whose cir- compared with eastbound travel (1.5
changes is responsible for cadian period is close to 24 hours can hours per day). Not all travelers crossing
most of the symptoms maintain entrainment with very low multiple time zones develop jet-lag dis-
of jet-lag disorder. The nightly doses of 20 2g to 300 2g. order, but most will experience some
severity of jet lag depends Vitamin B12 trials have been unsuccess- level of sleep and wake disturbance.
on several variables, ful in sighted patients, but evidence Clinical presentation and diagnosis.
including the number of from case reports suggests that a com- Patients with jet-lag disorder typically
time zones crossed and bination of timed melatonin doses of present with symptoms of recurrent
the direction of travel.
0.5 mg to 5.0 mg taken nightly at 9:00 PM, insomnia and daytime somnolence as
exposure to bright light, and a regular a result of rapid travel across two or
sleep-wake schedule is successful in en- more time zones. The sleep disturb-
training these patients.17 ance leads to clinically significant im-
pairment in daytime functioning. The
Jet-Lag Disorder most common sleep disturbances asso-
Jet-lag disorder results from travel across ciated with jet lag are sleep fragmenta-
several time zones and subsequent mis- tion, early morning awakenings, and
alignment of the internal circadian clock sleep-initiation insomnia. People travel-
and the destinations local time. Symp- ing eastward develop difficulty falling
toms of jet lag usually emerge within 1 to asleep and awakening the next day.
2 days after travel. Main manifestations Westbound travelers experience exces-
of jet lag are generalized malaise, sleep sive somnolence in the early evening,
disturbances, impaired daytime alert- and early morning awakening. In addi-
ness, poor appetite, diminished cognition to impairments of sleep and wake
tive performance, depressed mood, function, travelers affected by jet lag
irritability, and anxiety. report gastrointestinal disturbances,
Pathophysiology. Internal desynch- menstrual irregularities, and the exacer-
ronization of physiologic rhythms bation of affective disorders. Cognitive
resulting from time-zone changes is impairment emerging from jet lag may
responsible for most of the symptoms have serious consequences, such as
of jet-lag disorder. The severity and type impaired decision-making for business
of jet-lag symptoms depend on several travelers or impaired performance in
variables, including the number of time athletes.33 Effects of jet lag not only
zones crossed and the direction of affect travelers but can also have rather
travel.31 Eastward travel may be more significant consequences for airline
difficult to adapt to than westward pilots and need to be considered when
travel, because the former requires planning work schedules, stopover
advancing circadian rhythms and the durations, and rest periods between
latter a phase delay. Humans generally flights.
have an endogenous circadian period Treatment. The main objective in
that is slightly longer than 24 hours, so treating jet lag is to improve sleep
that a delay shift is more easily quality and daytime alertness by realign-
achieved. Older adults may have more ing the endogenous circadian rhythm
difficulty with circadian realignment with the required or desired sleep and
than younger people.32 Typically, symp- wake times of the destinations time
toms of jet lag subside within a few days zone. However, when the time in the
but may persist for a few weeks in some destination is expected to be brief
travelers. The speed of this resynchro- (2 days or less), circadian adaptation

KEY POINT
may be counterproductive and treat- Immediate-release melatonin appears h Nonpharmacologic
ment should be aimed at improving or to be more effective than extended- treatment approaches are
alleviating jet-lag symptoms.34 release formulations.34 A Cochrane important in the
Nonpharmacologic treatment ap- Review of 10 randomized placebo- management of jet-lag
proaches are important in the man- controlled trials of melatonin and air disorder. Strategic
agement of jet-lag disorder. Strategic travel concluded that melatonin at doses exposure and avoidance
exposure and avoidance of exposure to of 2 mg to 5 mg taken before bedtime of exposure to light have
light have been utilized as an effective over 2 to 4 days is effective in reducing been utilized as an
treatment approach. Inappropriate jet-lag symptoms.35 A combination ap- effective treatment
timing of light exposure may result in proach incorporating melatonin with approach.
further desynchronization of the circa- timed physical activity and light exposure
dian system at the destination. The usually results in additional improve-
optimal timing or avoidance of light ments of symptoms.
exposure depends on the direction of Ramelteon, an MT1/MT2 melatonin
travel and the number of time zones receptor agonist with greater affinity for
crossed.9 For example, after an east- melatonin receptors and longer half-life
bound flight from Chicago to Paris, compared to melatonin, may be effec-
passengers should avoid bright light tive in treating symptoms of jet lag. In a
in early morning and expose them- recent placebo-controlled study, a sig-
selves to bright light in late morning nificant decrease in sleep latency was
and afternoon (to advance circadian achieved with administration of ramel-
rhythms). If flying westbound, efforts teon (1 mg), administered at bedtime
should be made to stay awake during for 4 nights at the new destination.36 In
the daylight hours, maximize light this study, beneficial effects of ramel-
exposure in the afternoon and early teon were strongly influenced by light
evening, and not sleep until nighttime exposure since only participants main-
at the destination. Shifting the circa- tained in constant dim light had signifi-
dian clock by using timed exposure to cant differences in latency to persistent
light several days before travel may be sleep. Further studies are needed to
useful in minimizing jet-lag symptoms prove the efficacy of ramelteon for jet lag.
but has practical limitations for a fre- Several other pharmacologic agents,
quent business traveler. including caffeine and hypnotic medica-
Currently, no US Food and Drug tions, have been explored as options to
Administration (FDA)Yapproved phar- alleviate jet-lag symptoms. Short-acting
macologic agents are available for the hypnotic medications can be used to
treatment of jet-lag disorder. Based on treat insomnia associated with jet lag.9
its ability to phase shift circadian rhythms Several studies demonstrated beneficial
and its potential soporific effect, melato- effects of caffeine on fatigue and the
nin has been studied. Administration of reduced alertness associated with jet lag.
melatonin at doses of 0.5 mg to 10 mg in In a randomized placebo-controlled
the early evening hours several days study of modafinil, improved alertness
before eastbound travel followed by ad- and other jet-lag symptoms were
ministration at bedtime at the destina- achieved after administration of 150 mg
tion effectively reduces symptoms of of modafinil.37 Based on the AASM
jet lag.22 Significant improvements with practice parameters, timed melatonin
melatonin were demonstrated by self- administration is recommended as treat-
reported sleep and mood measures as ment for jet-lag disorder. Additional
well as objective circadian measures treatment options include maintain-
(ie, melatonin and cortisol rhythms). ing home-based sleep hours for brief

KEY POINTS
h Based on the American travel, short-term hypnotic use for help not only by showing total sleep
Academy of Sleep insomnia, and caffeine to alleviate day- duration but also by demonstrating
Medicine practice time sleepiness. circadian-sleep misalignment.21 On
parameters, timed nonworking days, individuals with
melatonin Shift Work Disorder SWD tend to revert back to more
administration is Shift work disorder (SWD) is character- traditional daytime activities and night
recommended as ized by a history of chronic (at least 1 sleep schedules, contributing further
treatment for jet-lag month) excessive sleepiness during the to the circadian misalignment. Night
disorder. required wake (work) time and/or shift workers and rotating shift work-
h Night shift workers and insomnia symptoms during the associ- ers get less sleep than day workers or
rotating shift workers ated required or desired sleep period evening shift workers. Night shift
get less sleep than day that occurs in relation to unconventional workers generally have no difficulty
workers or evening shift work schedules. falling asleep but complain primarily
workers. Epidemiology. Almost 20% of the of difficulty maintaining sleep during
h Shift work disorder is workforce in the developed world is the late morning or afternoon. Exces-
accompanied by engaged in shift work. The prevalence sive sleepiness is most marked during
significant social and of SWD is approximately 1% in the gen- the last half of the work hours and
economic burdens in the eral population and up to 10% among while commuting to home at the end
form of accidents, lost
night and rotating shift workers. In the of the shift. Other symptoms of SWD
days of work, poorer
general population, men are slightly at include chronic fatigue, malaise, mood
performance, and
increased health care use.
higher risk than women for SWD.38 In disorder, and nonspecific complaints,
certain populations, such as nurses, the such as dyspepsia and decreased
prevalence of SWD can reach about libido.29 Risk of alcohol and substance
40%.38 abuse is increased, as is the risk of
Pathophysiology. The primary etiol- weight gain, hypertension, and cardio-
ogy of SWD is the opposition of vascular disease, and some studies sug-
required sleep and wake times to their gest an association with breast and
endogenous circadian rhythm of sleep endometrial cancer.39 In addition to
and wake propensity. This often results the medical comorbidities, SWD is ac-
in shortened sleep duration by 1 to 4 companied by significant social and eco-
hours. In addition, trying to stay awake nomic burdens in the form of accidents,
during the night, when the circadian lost days of work, poorer performance,
alertness signal is low, leads to excessive and increased health care use.39
sleepiness during the work hours.21 Treatment. The primary aim of treat-
The overnight shift is usually associated ment is to improve alertness during the
with the most severe symptoms, but required wake time and sleep quality
patients may report symptoms of SWD during the scheduled sleep time. All
with any shift that requires one to be patients with SWD should be counseled
awake at an adverse circadian time. regarding conservative nonpharmaco-
Tolerance to the effects of shift work logic measures. These include opti-
may vary with age, chronotype, comor- mizing the sleep environment (eg,
bid sleep disorders, social situation, and darkened room, comfortable temper-
distance of commute between home ature, noise reduction), adherence to
and work.21 good sleep habits (eg, maintain a regular
Clinical presentation and diagno- sleep and wake schedule, avoid exces-
sis. The diagnosis is made by careful sive caffeine), patient and family educa-
history of symptoms and work sched- tion, and scheduled naps when possible.
ule. A minimum of 2 weeks of sleep Appropriately timed light therapy has
logs with or without actigraphy can been shown to accelerate circadian

Case 7-2
A 26-year-old female security
guard reported chronic
fatigue and difficulty
keeping up with her duties.
She had started her job
4 months ago and worked
8- to 9-hour night shifts for
4 to 5 consecutive days (from
11:00 PM or midnight to
7:00 AM). On days off she
usually went to bed when
her husband did at midnight
and slept until late morning.
She reported difficulty
staying asleep during the
day when off duty, and
sleepiness and decreased
concentration during her
shift at night. She described
malaise, anxiety, and
decreased libido. When
working, she consumed
large amounts of caffeine
and sugar to help her stay
awake. Her sleep-wake diary
before and after treatment is
shown in Figure 7-6.
Comment. As shown in
Figure 7-6, after appropriate
treatment the patient
is sleeping in the compromised
circadian position with
sleep and wake times
that allow time for some
social activities during her
days off, yet the change in
sleep-wake times between
days off and days on duty is Sleep-wake diary of a patient with shift work disorder. A, Patients sleep
FIGURE 7-6
not dramatically different. diary for 1 week before treatment. B, Patients sleep diary for 1 week
This sleep-wake schedule after 1 month of treatment with a combination of intermittent naps
when possible before the shift, bright light exposure (yellow) during the shift, and
allows for more sleep avoidance of light on the morning commute (sunglasses) together with maintaining a
consolidation and longer dark and quiet bedroom. In addition, 3 mg of melatonin (purple pill) was started to
sleep duration throughout improve sleep as needed. Bright light exposure for 30 minutes to 1 hour (light bulb)
was also initiated shortly after awakening during work days. During days off, she was
the week. instructed to maintain a compromised sleep and wake schedule so that she would have
time with her husband and friends, but not completely revert to a daytime schedule.
adaptation to night shift work. For night 3- or 6-hour blocks or in 20-minute or

shift workers, bright light exposure rang- 1-hour blocks (ending 2 hours before
ing from 1000 lux to 10,000 lux either in the end of the shift) has been shown to

KEY POINT
accelerate circadian adaptation to night clinical correlations. Neurology 2008;71(8):
h For night shift workers, 594Y598.
bright light exposure work and improve both alertness and
3. Dardente H, Cermakian N. Molecular
ranging from 1000 lux performance (Case 7-2).40 Complemen-
circadian rhythms in central and peripheral
to 10,000 lux either in tary to light exposure during work, it is clocks in mammals. Chronobiol Int 2007;
3- to 6-hour blocks or in important to avoid bright light expo- 24(2):195Y213.
20-minute to 1-hour sure during the morning commute by 4. Cermakian N, Boivin DB. The regulation of
blocks (ending 2 hours using appropriate eyewear.17 central and peripheral circadian clocks in
before the end of the humans. Obes Rev 2009;10(10 suppl 2):25Y36.
Data on the use of melatonin, at
shift) has been shown to various doses, have produced conflict- 5. Takahashi JS, Hong HK, Ko CH, McDearmon
accelerate circadian EL. The genetics of mammalian circadian
ing results. However, melatonin when order and disorder: implications for
adaptation to night
taken at bedtime does appear to physiology and disease. Nat Rev Genet 2008;
work and improve
modestly improve daytime sleep, but 9(10):764Y775.
both alertness and
performance.
without any significant impact on 6. Ko CH, Takahashi JS. Molecular components
nighttime alertness or performance. of the mammalian circadian clock. Hum
Mol Genet 2006;15:R271YR277.
All other pharmacologic modalities fail
7. Lowrey PL, Takahashi JS. Mammalian
to address the circadian misalignment
circadian biology: elucidating genome-wide
but can be used for improving alert- levels of temporal organization. Annu Rev
ness during work hours or sleep Genomics Hum Genet 2004;5:407Y441.
during the scheduled sleep time. 8. Montagnese S, Middleton B, Mani AR, et al.
Therefore, pharmacologic agents Sleep and circadian abnormalities in patients
with cirrhosis: features of delayed sleep
should be used in combination with
phase syndrome? Metab Brain Dis 2009;
light and behavioral modalities. Hyp- 24(3):427Y439.
notics are not specifically indicated for 9. Kolla BP, Auger RR. Jet lag and shift work
SWD but may be prescribed for the sleep disorders: how to help reset the
treatment of insomnia that is often internal clock. Cleve Clin J Med 2011;78(10):
675Y684.
seen in these patients. Caffeine com-
bined with timed naps improves per- 10. Archer SN, Carpen JD, Gibson M, et al.
Polymorphism in the PER3 promoter
formance and alertness during the associates with diurnal preference and
night shift.41 The wake-promoting delayed sleep phase disorder. Sleep 2010;
agents modafinil (200 mg) and armo- 33(5):695Y701.
dafinil (150 mg) have been shown to 11. Crowley SJ, Carskadon MA. Modifications to
improve performance and alertness weekend recovery sleep delay circadian
phase in older adolescents. Chronobiol Int
when taken at the beginning of the 2010;27(7):1469Y1492.
night shift.17 Both modafinil and armo-
12. Paul MA, Gray GW, Lieberman HR, et al.
dafinil are approved by the FDA for the Phase advance with separate and
treatment of excessive sleepiness as- combined melatonin and light treatment.
sociated with SWD. The AASM practice Psychopharmacology (Berl) 2011;214(2):
515Y523.
parameters recommend planned nap-
13. Smith MR, Revell VL, Eastman CI. Phase
ping before and/or during the work shift,
advancing the human circadian clock with
timed light exposure, and stimulants blue-enriched polychromatic light. Sleep
such as caffeine or modafinil during the Med 2009;10(3):287Y294.
night shift to improve alertness.17 14. Crowley SJ, Acebo C, Fallone G, Carskadon
MA. Estimating dim light melatonin onset
(DLMO) phase in adolescents using summer
REFERENCES or school-year sleep/wake schedules.
1. Golombek DA, Rosenstein RE. Physiology Sleep 2006;29(12):1632Y1641.
of circadian entrainment. Physiol Rev 2010;
15. van Geijlswijk IM, Korzilius HP, Smits MG.
90(3):1063Y1102.
The use of exogenous melatonin in delayed
2. Benarroch EE. Suprachiasmatic nucleus and sleep phase disorder: a meta-analysis.
melatonin: reciprocal interactions and Sleep 2010;33(12):1605Y1614.

16. Rahman SA, Kayumov L, Shapiro CM. meta-analysis. Dev Med Child Neurol 2009;
Antidepressant action of melatonin in the 51(5):340Y349.
treatment of Delayed Sleep Phase
29. Kanathur N, Harrington J, Lee-Chiong T Jr.
Syndrome. Sleep Med 2010;11(2):131Y136.
Circadian rhythm sleep disorders. Clin Chest
17. Dodson ER, Zee PC. Therapeutics for Med 2010;31(2):319Y325.
circadian rhythm sleep disorders. Sleep Med
30. Uchiyama M, Lockley S. Non-24-hour
Clin 2010;5(4):701Y715.
sleep-wake syndrome in sighted and blind
18. Gradisar M, Dohnt H, Gardner G, et al. patients. Sleep Med Clin 2009;4:195Y211.
A randomized controlled trial of
31. Bjorvatn B, Pallesen S. A practical approach
cognitive-behavior therapy plus bright light
to circadian rhythm sleep disorders. Sleep
therapy for adolescent delayed sleep phase
Med Rev 2009;13(1):47Y60.
disorder. Sleep 2011;34(12):1671Y1680.
32. Moline ML, Pollak CP, Monk TH, et al.
19. Ando K, Kripke DF, Ancoli-Israel S. Delayed
Age-related differences in recovery from
and advanced sleep phase symptoms. Isr J
simulated jet lag. Sleep 1992;15(1):28Y40.
Psychiatry Relat Sci 2002;39(1):11Y18.
33. Srinivasan V, Singh J, Pandi-Perumal SR,
20. Xu Y, Padiath QS, Shapiro RE, et al. Functional
et al. Jet lag, circadian rhythm sleep
consequences of a CKIdelta mutation causing disturbances, and depression: the role of
familial advanced sleep phase syndrome. melatonin and its analogs. Adv Ther 2010;
Nature 2005;434(7033):640Y644.
27(11):796Y813.
21. Reid KJ, Zee PC. Circadian rhythm sleep 34. Suhner A, Schlagenhauf P, Johnson R, et al.
disorders. Handb Clin Neurol 2011;99: Comparative study to determine the optimal
963Y977. melatonin dosage form for the alleviation
22. Morgenthaler TI, Lee-Chiong T, Alessi C, of jet lag. Chronobiol Int 1998;15(6):655Y666.
et al. Practice parameters for the clinical 35. Herxheimer A, Petrie KJ. Melatonin for
evaluation and treatment of circadian the prevention and treatment of jet lag.
rhythm sleep disorders. An American Cochrane Database Syst Rev 2002;(2):
Academy of Sleep Medicine report. Sleep CD001520.
2007;30(11):1445Y1459.
36. Zee PC, Wang-Weigand S, Wright KP Jr,
23. Zee PC, Vitiello MV. Circadian rhythm sleep et al. Effects of ramelteon on insomnia
disorder: irregular sleep wake rhythm type. symptoms induced by rapid, eastward travel.
Sleep Med Clin 2009;4(2):213Y218. Sleep Med 2010;11(6):525Y533.
24. Afonso P, Brissos S, Figueira ML, Paiva T. 37. Rosenberg RP, Bogan RK, Tiller JM, et al.
Schizophrenia patients with predominantly A phase 3, double-blind, randomized,
positive symptoms have more disturbed placebo-controlled study of armodafinil for
sleep-wake cycles measured by actigraphy. excessive sleepiness associated with jet lag
Psychiatry Res 2011;189(1):62Y66. disorder. Mayo Clin Proc 2010;85(7):630Y638.
25. Wulff K, Dijk DJ, Middleton B, et al. Sleep 38. Flo E, Pallesen S, Mageroy N, et al. Shift
and circadian rhythm disruption in work disorder in nursesVassessment,
schizophrenia. Br J Psychiatry 2012;200(4): prevalence and related health problems.
308Y316. PLoS One 2012;7(4):e33981.
26. Zhou QP, Jung L, Richards KC. The 39. Culpepper L. The social and economic
management of sleep and circadian burden of shift-work disorder. J Fam Pract
disturbance in patients with dementia. Curr 2010;59(1 suppl):S3YS11.
Neurol Neurosci Rep 2012;12(2):193Y204.
40. Burgess HJ, Sharkey KM, Eastman CI.
27. Hida A, Kusanagi H, Satoh K, et al. Bright light, dark and melatonin can
Expression profiles of PERIOD1, 2, and 3 in promote circadian adaptation in night shift
peripheral blood mononuclear cells from workers. Sleep Med Rev 2002;6(5):407Y420.
older subjects. Life Sci 2009;84(1Y2):33Y37.
41. Ker K, Edwards PJ, Felix LM, et al. Caffeine
28. Braam W, Smits MG, Didden R, et al. for the prevention of injuries and errors
Exogenous melatonin for sleep problems in in shift workers. Cochrane Database Syst Rev
individuals with intellectual disability: a 2010;(5):CD008508.

Review Article
Sleep and Comorbid

Dr Nathaniel F. Watson,
Harborview Medical Center,
UW Medicine Sleep Center,
325 Ninth Ave, Box 359803,
Seattle, WA, 98104,
nwatson@uw.edu.
Neurologic Disorders
Relationship Disclosure: Nathaniel F. Watson, MD, MSc; Mari Viola-Saltzman, DO
Dr Watson serves on the
Board of Directors for the
American Academy of Sleep
Medicine and the American ABSTRACT
Sleep Medicine Foundation.
Dr Viola-Saltzman reports no Purpose of Review: An understanding of the impact of sleep on neurologic
disclosure. disorders, and the impact of neurologic disorders on sleep, provides fresh opportunities
Unlabeled Use of for neurologists to improve the quality of life and functioning of their patients.
Use Disclosure: Drs Watson
Recent Findings: Sleep-disordered breathing (SDB) is a risk factor for cerebrovascular
and Viola-Saltzman report no disease and should be considered in all TIA and stroke patients. Sleep disorders can
disclosures. amplify nociception and worsen headache disorders; and some headaches, including
* 2013, American Academy those related to SDB and hypnic headache, are sleep specific. REM sleep behavior
of Neurology.
disorder may be an early sign of neurodegenerative disease. Focal lesions of almost any
etiology (eg, multiple sclerosis and CNS malignancies) in the hypothalamus, basal
forebrain, or brainstem may result in sleep disturbance, sleepiness, and insomnia.
Sleep-related hypoventilation and fatigue are common in neuromuscular disease. SDB
and epilepsy are mutually facilitatory, and poor sleep can exacerbate epilepsy.
Summary: Continued surveillance for sleep disorders by neurologists is rewarded by new
treatment avenues in their patients with the possibility of improved clinical outcomes.
INTRODUCTION increases incident stroke risk.2Y6 Even

Sleep medicine is neurology; all sleep mild SDB is associated with increased
disorders emanate from or involve the incident stroke5 and increased risk of
central or peripheral nervous system. composite stroke, TIA, or death.6 The
Even sleep-disordered breathing (SDB), reverse is also true: incident cardiovas-
considered by many a pulmonary or cular disease is associated with worsen-
otolaryngologic disorder, is caused in ing of SDB over a 5-year period.7
large part by ineffective maintenance of Incident stroke in particular increases
oropharyngeal muscle tone in sleep. The central SDB, which is common following
intersection between sleep and neuro- stroke, and may represent silent brain
logic disorders is broad and deep. Al- ischemia disturbing central respiratory
Supplemental digital content:
most every neurologic disorder affects mechanisms.8 Table 8-1 presents a syn-
ticle are cited in the text as or is affected by sleep. opsis of epidemiologic studies assessing
Supplemental Digital Content. incident stroke in patients with SDB.
clicking on links provided in
CEREBROVASCULAR DISEASE Stroke timing favors a role for SDB.
the HTML, PDF, and iPad AND SLEEP-DISORDERED Awakening increases sympathetic
versions of this article; the BREATHING
URLs are provided in the print nervous system activity and the renin-
version. Video legends begin Multiple well-adjusted, cross-sectional angiotensin-aldosterone axis, causing a
on page 165.
studies show a dose-response relation- sharp morning rise in arterial blood
ship between sleep-disordered breath- pressure and heart rate. Both ischemic
ing (SDB) severity and odds of prevalent and hemorrhagic stroke have a peak
stroke.1,2 Longitudinal studies also dem- incidence in the morning hours, with
onstrate that increased SDB severity ischemic stroke occurring about the time

TABLE 8-1 Synopsis of Studies Assessing Incident Stroke in Patients With
Number
Time of Events Fully Adjusted
Followed (Strokes) Odds Ratio or
Study N= (Years) Observed Hazard Ratio P Value Comments
2
Arzt 1189 4 21 OR: 3.08 .120 Unadjusted OR: 4.31
(95% CI; 0.74Y12.81) (1.31Y14.15), P=.02
Munoz3 394 6 20 HR: 2.52 .040 HR presented for subjects
(95% CI; 1.04Y6.01) with severe obstructive
sleep apnea (apnea-hypopnea
index [AHI] Q30 events/h)
Redline4 5422 ~8 193 HR: 2.86 .016 Incident stroke was not
(95% CI; 1.10Y7.40) associated with AHI
quartiles in women
HR presented for highest
AHI quartile (919 events/h);
P value is for trend
Valham5 392 10 47 HR: 3.56 .011 HR presented for subjects
(95% CI; 1.56Y8.16) with moderate to severe
obstructive sleep apnea
(AHI Q15 events/h); P value is
for trend
Yaggi6 1022 ~3 88 HR: 1.97 .010 Outcome was incident
(95% CI; 1.12Y3.48) stroke and death
OR = odds ratio; CI = confidence interval; HR = hazard ratio.
most people are waking up to start their indices and lower mean oxygen sat-
day.9 Interestingly, none of the more uration levels. The presence of severe
common vascular risk factors or other sleep apnea (apnea-hypopnea index
etiologic factors for stroke (including [AHI] greater than 30 events/h) was
patient demographics, vascular distribu- independently associated with wake-up
tion, ischemic heart disease, previous stroke.11
myocardial infarction, diabetes mellitus, During healthy nocturnal sleep, both
hypertension, smoking, hyperlipidemia, systolic and diastolic blood pressures
stroke severity and recurrence, stroke drop by 10% to 20% from respective
subtype, and other clinical features) vary daytime mean levels. Some patients,
in a statistically significant manner referred to as nondippers, have less than
according to the clock time of stroke a 10% decline in blood pressure relative
onset.10 The temporal pattern of stroke to respective daytime means. Nondip-
points to the impact of circadian factors ping, over time, likely contributes to left
on vascular tone, coagulative balance, ventricular hypertrophy, renal pathol-
and blood pressure. Perhaps most com- ogy, and deleterious effects on brain
pellingly, a case-control study compar- vasculature such as atheromatous nar-
ing subjects with wake-up stroke to rowing or occlusion of larger cerebral
those without wake-up stroke found vessels, thickening of cerebral arteries by
the wake-up stroke group had higher lipohyalinosis, and increased blood co-
apnea-hypopnea and obstructive apnea agulability. Nondipping blood pressure

Comorbid Neurologic Disorders
KEY POINTS
h Sleep-disordered pattern is associated with stroke inde- by approximately 1.5 mm Hg to 2.5
breathing is a term that pendent of sex and race.12 Stroke risk is mm Hg and diastolic blood pressure by
encompasses all increased by 80% for every 5 mm Hg 1.5 mm Hg to 2.0 mm Hg.16,17 In
breathing disturbances increase in sleep-time blood pressure.13 another two meta-analyses reporting
in sleep, including Obstructive sleep apnea (OSA) is one of changes in blood pressure obtained by
obstructive sleep apnea, the most common causes of nondip- ambulatory monitoring, CPAP use was
central sleep apnea, ping nocturnal blood pressure. associated with an approximately 1.0
Cheyne-Stokes The effect of SDB on blood pressure mm Hg to 1.5 mm Hg reduction in
respirations, and upper is not confined only to the sleep period. both 24-hour systolic and diastolic blood
airway resistance Approximately 50% to 60% of patients pressure.18,19 In subgroup analyses,
syndrome.
with OSA are hypertensive, while about severe OSA (more than 30 events per
h Sleep-disordered 30% to 40% of hypertensive patients hour), higher blood pressure levels, and
breathing is an have OSA.14 Peppard and colleagues15 greater CPAP adherence were associ-
independent risk factor performed a 4-year, population-based, ated with larger reductions in blood
for stroke.
prospective cohort study of OSA and pressure.16Y19
hypertension. After adjusting for multi-
ple confounders, they found that even Additional Obstructive Sleep
people with few episodes of apnea or ApneaRelated Factors That
hypopnea (0.1 events/h to 4.9 events/h) Increase Stroke Risk
at baseline had 42% greater odds of OSA increases systemic sympathetic
having hypertension at follow-up than nervous system activity and atrial size
people with no episodes. They also (through left ventricular hypertrophy
found those with mild SDB (AHI of 5.0 and increased transmural pressure),
events/h to 14.9 events/h) and those which increases the risk of atrial fibrilla-
with more severe SDB (AHI of 15.0 or tion, a major stroke risk factor.20 In ad-
more events/h) had approximately 2 and dition, cardioverted atrial fibrillation is
3 times, respectively, the odds of having more likely to recur in untreated versus
hypertension at follow-up than those treated OSA patients.21 Sleep disrup-
with no episodes of apnea or hypo- tion and chronic intermittent hypoxia
pnea.15 Resistant hypertension is defined in OSA increase oxidative stress and
as blood pressure that requires four or vascular inflammation, which results in
more antihypertensive medications. endothelial dysfunction characterized by
Stunningly, 80% to 90% of these patients reduced vasodilatation and enhanced
have OSA. Pathophysiologic mecha- vasoconstriction, including chronic pro-
nisms include activation of the renin- thrombotic and procoagulant activity.22
angiotensin-aldosterone system by Apneas are associated with reduced
intermittent hypoxia and aldosterone- cerebral perfusion and delayed cere-
related fluid retention causing para- brovascular compensatory response to
pharyngeal edema.14 Thus, OSA is a risk changes in blood pressure.23,24 CPAP
factor for hypertension and a major risk therapy has beneficial effects on vas-
factor for stroke. cular function and inflammatory and
oxidative stress in these patients.25 OSA
Treatment of Obstructive Sleep is associated with patent foramen ovale
Apnea to Improve Blood Pressure (PFO), an important cause of crypto-
In two meta-analyses reporting changes genic stroke. During an obstructive ap-
in blood pressure levels, patients ran- nea, large intrathoracic pressure swings
domized to continuous positive airway and hypoxic pulmonary vasoconstric-
pressure (CPAP) therapy compared with tion act in concert to alter the interatrial
controls reduced systolic blood pressure pressure balance in favor of right to left

PFO shunting,26 which may be pre- pliant group.31 Long-term CPAP treat-
ventable with CPAP therapy.27 The ment in moderate to severe OSA and
presence of sleep apnea, including the ischemic stroke is associated with a re-
duration and severity of disease, is duction in excess risk of mortality.32
associated with carotid intima-media Treatment of OSA by CPAP in stroke
thickness,28 some of which is reversi- patients undergoing rehabilitation im-
ble with the application of CPAP ther- proved functional and motor, but not
apy.29 SDB is also associated with neurocognitive, outcomes.33 Random-
diabetes mellitus and insulin resist- ized controlled trials are ongoing with
ance, with the strength of association in- the goal of determining whether CPAP
creasing as a function of OSA severity.30 therapy for OSA can prevent incident
The effect of CPAP therapy on glucose cardiovascular disease and death.
metabolism in patients with OSA has
yet to be established. Figure 8-1 dis- Sleep-Disordered Breathing
plays the complicated risk-factor rela- Following Stroke
tionship between SDB and stroke. Acutely poststroke, over two-thirds of 161
stroke patients had an AHI of more than
Treatment of Sleep-Disordered 10 events/h. After 3 months, both the
Breathing to Prevent Stroke AHI and central apnea index were signifi-
In patients with previous cardiovascular cantly lower than in the acute phase,
events and moderate to severe OSA, predominantly because of reductions
those noncompliant with CPAP therapy in central apneas, since the obstructive
had an increased incidence of new apnea index remained unchanged. Inter-
ischemic stroke compared to the com- estingly, stroke location, type, or vascular
FIGURE 8-1 Interplay of risk factors for sleep-disordered breathing (SDB) and stroke. SDB influences stroke through shared risk
factors, facilitation of traditional stroke risk factors, and physiology unique to SDB. The latter likely explains why
SDB is associated with incident stroke after adjustment for many of these other risk factors.

KEY POINTS
h Sleep-disordered territory was not associated with SDB in Unfortunately, despite the strength of
breathing should be this study.34 This, along with the fact that the evidence, SDB is regularly unrecog-
considered in all stroke SDB frequency and severity are the nized and undiagnosed in both primary
and TIA patients. same for stroke and TIA patients,35 care and neurology/stroke clinics across
h Cervical dystonia is suggests that although stroke itself can the country. Considering what is at
associated with reduced worsen SDB through effects on orophar- stake, evaluation for SDB is essential
sleep quality and yngeal musculature and brainstem respi- to the workup of any TIA or stroke
sleepiness, even when ratory centers, the SDB likely precedes patient. The identification and treat-
compared to patients the vascular event in most cases. ment of SDB in these patients provides
with other focal a tremendous opportunity for neurolo-
movement disorders. Sleep Duration and Stroke gists and stroke specialists to mitigate
Pathophysiology the adverse effects of cerebrovascular
A recent study found both short and disease (Case 8-1).37
long sleep durations to be associated
with stroke, independent of age, sex, MOVEMENT DISORDERS AND
body mass index, physical activity, smok- SLEEP IMPAIRMENT
ing, alcohol use, screen time (eg, time Sleep and movement disorders overlap in
spent in front of TVs, computers, tablets, a number of important ways. This section
smart phones), country of birth, marital focuses on the sleep-related ramifications
status, education, and employment sta- of the dystonias, choreiform disorders,
tus. Compared with a sleep duration of tremors, and tics. Other sections of this
7 hours (referent), the multivariate odds article address other movement disorder-
ratio (OR) of stroke for various sleep related issues, including the relation-
durations was as follows: less than 6 ship of sleep with Parkinson disease
hours, OR = 1.54 (1.36Y1.75); 6 hours, (PD) and dementia with Lewy bodies.
OR = 1.25 (1.14Y1.38); 8 hours, OR = Sleep impairment and its secondary
1.08 (1.00Y1.17); and 9 hours or more, symptoms have substantial quality of life
OR = 1.50 (1.38Y1.62).36 The exact ramifications for patients with dystonia.
mechanism is unknown but likely re- Cervical dystonia is associated with re-
lated to effects on metabolic, endo- duced sleep quality and sleepiness, even
crine, and autonomic nervous systems. when compared to other focal move-
Conclusions. SDB is an indepen- ment disorders.38 A number of poly-
dent risk factor for stroke. It meets the somnographic abnormalities have been
criteria of biological plausibility, predic- reported, including problems with sleep
tiveness, dose-responsiveness, and pre- initiation and maintenance, reduced
stroke measurability. SDB is associated sleep efficiency, abnormal or reduced
with many known stroke risk factors, REM sleep, and changes in spindle
including incident hypertension, endo- activity.39 Similar to other nonmotor
thelial dysfunction, oxidative stress, dystonia symptoms, the etiology of
vascular inflammation, prothrombotic sleep abnormalities includes primary ef-
and procoagulant factors, arrhythmias, fects of dystonia and secondary effects
diabetes, PFO, and carotid intima- of pain and medications (eg, benzodia-
media thickness. Treatment of SDB zepines, anticholinergics). Some forms
with CPAP improves many stroke risk of dystonia, including blepharospasm
factors, including reducing hyperten- and Meige syndrome, may persist dur-
sion and carotid intima-media thick- ing sleep, although frequency and se-
ness, reversing right to left shunting in verity are often decreased.
PFO, and reducing recurrence of atrial Sleep problems are present in nearly
fibrillation following cardioversion. 90% of patients with Huntington disease

KEY POINT
Case 8-1 h Sleep disturbance is

present in nearly 90%
An obese 59-year-old hypertensive man presented to his primary care
of patients with
physician because of a transient episode of difficulty speaking 2 days earlier.
Huntington disease,
In the course of the examination, the physician found evidence for atrial
with most rating it a
fibrillation. Diagnostic testing included echocardiography significant for
significantly important
patent foramen ovale (PFO) with a positive bubble test indicating right to
factor in overall health
left shunting, and hypercholesterolemia. Carotid ultrasound was normal.
impairment.
The physician referred the patient to a cardiologist for cardioversion of his
atrial fibrillation, and prescribed warfarin, metoprolol, and simvastatin.
The patients atrial fibrillation was successfully cardioverted 4 weeks after
warfarin therapy, and warfarin was switched to aspirin 4 weeks after
cardioversion. Three weeks later, the patient presented to the emergency
department aphasic and hemiparetic from a large left middle cerebral artery
distribution stroke and was found to have recurrent atrial fibrillation.
Comment. This obese older man with hypertension, atrial fibrillation,
and PFO is at high risk for having sleep-disordered breathing (SDB).
Because no evaluation and management of the SDB was done, the patient
was at higher risk for recurrent atrial fibrillation following cardioversion
and subsequent stroke. Although whether treatment of SDB with
continuous positive airway pressure reduces incident stroke is unknown, it is
clear that untreated sleep apnea increases the risk of recurrence of atrial
fibrillation following cardioversion. PFO is also associated with SDB, but
atrial fibrillation is a more likely explanation for the stroke mechanism in
this patient. Evaluation for SDB should be performed in TIA and stroke
patients as part of their stroke workup.
(HD), with nearly two-thirds rating sleep which are increased in HD and may
dysfunction as either very or moderately represent chorea rather than periodic
important factors contributing to overall limb movement disorder.41 HD is asso-
health impairment.40 As HD progresses, ciated with brainstem atrophy, even
non-REM (NREM) sleep stages N1 and before caudate atrophy and in one small
N2 are increased, and NREM sleep stage study, REM sleep behavior disorder
N3 and REM are decreased. In contrast (RBD) was observed in 12% of patients
to other neurodegenerative diseases, with HD.42 In general, chorea and
patients with HD show a higher density dyskinesias decrease and may even dis-
of sleep spindles compared to healthy appear during sleep, making these un-
control subjects. Actigraphy studies likely major sleep disrupters in HD, as
show patients with HD have significantly opposed to dystonia, dementia, body
more movements and increased activity pain, and nocturia, which more likely
during sleep compared with controls. impair sleep in this disorder. Atrophy in
With increasing HD severity, sleep the dorsolateral hypothalamus (site of
latency increases, sleep maintenance hypocretin/orexin production) and ante-
becomes more difficult, sleep efficiency rior ventral hypothalamus (site of the
reduces, wakefulness after sleep onset suprachiasmatic nucleus) may explain
increases, circadian rhythmicity be- sleepiness and circadian and other sleep
comes compromised, and sleepiness disruption in this disorder.
ensues.41 SDB, narcolepsy, and restless When compared to age- and sex-
legs syndrome are not more common in matched controls, patients with essential
patients with HD, as opposed to peri- tremor have poorer nocturnal sleep qual-
odic limb movements of sleep (PLMS), ity but not increased daytime sleepiness.43

KEY POINTS
h Sleep is impaired in However, pain and fatigue scores were and diagnostic groups (eg, migraine, clus-
20% to 50% of elevated among patients with essential ter, tension-type). Variations in circadian
children and young tremor, suggesting many misconstrue timing of sleep and sleep duration out-
adults with Tourette sleepiness as fatigue. RBD does not appear side typical norms (ie, 7 to 9 hours per
syndrome. to be associated with essential tremor. night) are common headache triggers. Al-
h Obstructive sleep apnea Caregiver observations indicate sleep though sleep and headache associations
is a common cause for problems in 20% to 50% of children and are diverse, sleep dysfunction influences
headache upon young adults with Tourette syndrome. headache threshold through effects on
awakening, particularly Difficulties in falling and staying asleep, sleep regulatory processes.47 Relative to an
if it dissipates during the separation anxiety in the evening, and age- and sex-matched chronic headacheY
course of the day. parasomnias were the most common free comparison group, headache pa-
h Bruxism should be problems.44 Children with tic disorder tients slept significantly shorter durations
considered as a potential and Tourette syndrome have objective (6.7 versus 7.0 hours), reported longer
cause for headache sleep impairment indicated by reduced sleep latencies (31.4 versus 21.1 min-
upon wakening. sleep efficiencies, prolonged sleep utes), and took longer to resume sleep
h Patients with cluster latencies, and increased arousal indi- following nighttime awakening (28.5
headache have an ces.44,45 The disturbed sleep of children versus 14.6 minutes).48
eightfold increased with Tourette syndrome is accompa- Chronic morning headache occurs in
risk of obstructive nied by increased short-lasting motor nearly 8% of the population, with sleep
sleep apnea when activity in NREM sleep, which likely complaints more typical among those
compared to age- and represents tic activity during sleep.44 with tension-type than migraine head-
sex-matched controls. ache.49 Of migraine patients, 24% de-
HEADACHE DISORDERS scribe headache onset during sleep or
AND SLEEP upon awakening as opposed to 12% of
Sleep and headache have a complicated tension-type headache patients.46 Head-
interrelationship. Although a history of ache is more common among people
headache upon awakening raises a con- with SDB than the general population,
cern for a space-occupying CNS lesion, and habitual snoring is more typical of
this symptom is more likely to represent chronic daily headache than episodic
SDB, especially in obese men with headache. Morning headache is over 3
tension-type headache pain that dissi- times more common in snorers and
pates during the course of the day. In apneics compared to healthy controls.
some instances, sleep improves head- Bruxism is another potential cause for
ache, as exemplified by the typical pa- morning headache. In a study of over
tient with migraine lying in a dark, quiet 1000 patients with migraine, sleep dis-
room. In other instances, such as hypnic turbance and oversleeping were recog-
headache, sleep and specific sleep stages nized as headache precipitants by 50%
trigger the headache. Headache pain, or and 37% of patients, respectively, while
pain of any kind, adversely affects sleep 85% reported sleeping as a means to
architecture, duration, and quality; and relieve headache. Many reported occa-
patients with sleep disorders report over sional sleep-onset (53%) and mainte-
4 times more headaches than healthy nance (61%) difficulties. Almost two-
controls.46 thirds reported morning headaches.50
Sleep disorders such as insomnia, Cluster headache patients have an eight-
SDB, sleep-related movement disor- fold increase in OSA compared to age-
ders, and circadian rhythm disorders and sex-matched controls, and a 24-fold
are disproportionately observed in spe- increase when overweight or obese.51
cific headache patterns (eg, chronic Treatment of OSA has been shown to
daily headache, awakening headache) improve cluster headache control.46

KEY POINTS
Hypnic headache is a rare primary h Hypnic headache is
headache disorder in older adults char- TABLE 8-2 Common Screening
Instruments sleep specific, occurring
acterized by moderate, throbbing, bilat- relative to REM sleep at
eral, or unilateral sleep-related headache b Sleepiness a consistent time of
attacks with typical onset in REM sleep. Epworth Sleepiness Scale the night.
Headache duration can be anywhere Stanford Sleepiness Scale h Epilepsy and
from 15 minutes to 3 hours. In REM, Karolinska Sleepiness Scale
sleep-disordered
dorsal raphe and locus coeruleus activity b Sleep-Disordered Breathing breathing are mutually
is absent and these areas, along with Berlin Questionnaire facilitatory, with higher
the periaqueductal gray, are essential Multivariate Apnea Prediction rates of each disorder
components of the human antinoci- Index observed in patients
STOP-BANG questionnaire with the other disorder
ceptive system. Hypnic headache may
therefore represent REM-related mal- b Insomnia when compared to the
function of these neuroanatomic re- Insomnia Severity Index general population.
gions, although this may not be specific b Sleep Quality h One in five patients with
since migraine and cluster headache Pittsburgh Sleep Quality Index epilepsy has seizures
onset also commonly occur in REM. exclusively during sleep.
Because many patients with hypnic h Most sleep-related
headache experience headache onset at disorders can contribute to difficulty in seizures occur out of
a consistent time of night, areas involved managing seizures, and epilepsy can non-REM sleep, most
in circadian rhythm generation, such as disrupt normal sleep, initiating or wor- often non-REM sleep
the suprachiasmatic nucleus (SCN), also sening sleep disorders. Patients with stage N2.
may be involved. The SCN has afferent epilepsy commonly report poor sleep
and efferent connections with the peri- quality, increased nocturnal awakenings,
aqueductal gray, further strengthening early morning awakenings, difficulty ini-
this notion. Caffeine, either at bedtime or tiating sleep, and excessive daytime
following headache onset, is an effective sleepiness. Nineteen percent of general-
treatment but concerns for sleeplessness ized seizures occur during sleep, as com-
limit its use. Lithium, indomethacin, and pared to 51% of localization-related
melatonin are also helpful in some pa- seizures. One in five patients with epi-
tients, along with other headache med- lepsy has seizures exclusively during
ications on a case-by-case basis.52 sleep. Examples of focal-onset epilepsy
Because sleep and headache are so occurring predominantly during sleep
tightly linked, diagnosing and treating include benign focal epilepsy with cen-
comorbid sleep disorders afford an trotemporal spikes, and nocturnal fron-
opportunity to improve the headache tal lobe epilepsy. Many patients have
problem. The most likely sleep disorders awakening epilepsy, occurring within
for headache causality are SDB, sleep 2 hours of waking; juvenile myoclonic
deprivation, and circadian rhythm dis- epilepsy is a classic example. Table 8-3
turbances. A number of good screening provides a list of epilepsies with a pre-
instruments are available for clinical use dilection for occurrence out of sleep.
to help identify headache patients that Most sleep-related seizures occur out
might benefit from consultation with a of NREM sleep, with NREM sleep stage
sleep medicine specialist (Table 8-2). N2 being the most common. This sleep
stage likely facilitates focal spikes and
EPILEPSY AND SLEEP epileptic activity through thalamocorti-
Sleep disorders and epilepsy are fre- cal hypersynchrony, as represented by
quently comorbid. The relationship be- characteristic sleep spindles and K com-
tween the two can be reciprocal; sleep plexes. Hypersynchronous delta activity

KEY POINT
h Nocturnal frontal lobe syndrome (Table 8-4). These patients
TABLE 8-3 Common have brief stereotyped hyperkinetic or
epilepsy can be difficult Sleep-Related
to distinguish from Epilepsies tonic motor seizures that occur in
parasomnias, with clusters during sleep following sudden
stereotypia, minimal b Nocturnal frontal lobe epilepsy arousals. Kicking and movement of legs,
postevent confusion, arms, and trunk are seen. Patients
b Nocturnal temporal lobe epilepsy
and shorter duration typically maintain consciousness during
providing clues that the b Benign focal epilepsy with the seizures, which usually last less than
event was epileptic in centrotemporal spikes
60 seconds and are stereotyped in
nature. b Juvenile myoclonic epilepsy nature. Seizures usually begin in child-
b Continuous spike-wave hood and persist throughout life. The
discharges during sleep disorder demonstrates an autosomal
b Childhood epilepsy with
dominant inheritance pattern with an
occipital paroxysms approximate penetrance of 70%. Seiz-
ures involve deep mesial frontal gener-
b Generalized tonic-clonic
seizures upon awakening
ators and may lack ictal and interictal
EEG correlates. For all these reasons,
nocturnal frontal lobe epilepsy can be
difficult to differentiate from NREM
in NREM sleep stage N3 also facilitates parasomnias (Table 8-5) (Case 8-2).55
epileptiform activity. Nighttime interic- Historically, sleep deprivation has
tal activity is more suggestive of the been used to provoke epileptic-related
location of the seizure focus than day- EEG activity. Sleep itself may activate
time interictal activity.53 Seizures are interictal activity in approximately one-
least likely to occur out of REM sleep, third of patients with epilepsy and up to
but when they do, they can provide the 90% of people with sleep-wakeYrelated
most accurate seizure localization of
any sleep stage. Seizures and epilepti-
form abnormalities are typically ob- TABLE 8-4 Characteristics of
served during sleep stage transitions Autosomal
Dominant Nocturnal Frontal
and unstable sleep characterized by Lobe Epilepsy
cortical arousals. Temporal lobe epi-
lepsy is the most common sleep- b Brief nocturnal seizures
related epilepsy, not because of a
particular sleep-related predilection, b Prominent motor movements
but because of the common nature of b Little or no postictal confusion
this seizure type. Frontal lobe seizures b Frequent clusters
have the greatest penchant to occur
b Often misdiagnosed as sleep
out of sleep. Approximately 61% of
disorder
frontal lobe seizures begin during
sleep, as opposed to 11% of temporal b Involves the neuronal nicotinic
acetylcholine receptor " 4
lobe seizures. Temporal lobe seizures
(CHRNA4) subunit
are more likely to generalize when they
originate from sleep, and nocturnal b Two genetic loci identified
(20q13.2-3 and 15q24)
temporal lobe epilepsy is thought to
portend a more favorable outcome fol- b Mutations in neuronal nicotinic
lowing epilepsy surgery.54 acetylcholine receptor genes
CHRNA4 and CHRNB2
Autosomal dominant nocturnal fron-
tal lobe epilepsy is a distinct clinical

TABLE 8-5 Pearls for Differentiating NonREM Parasomnias From
Nocturnal Frontal Lobe Epilepsy
NonREM Nocturnal Frontal Lobe

Event Characteristic Parasomnia Epilepsy
Timing in the sleep period Early Anytime
Sleep stage Non-REM N3 Any, but Non-REM
N2 is most common
Epileptiform discharges seen on No Yes or no
polysomnography
Stereotypia present No Yes
Awakening No Yes
Duration of event 30 seconds to 30 seconds to
30 minutes 2 minutes
Postevent confusion Yes Typically minor
or state-dependent epilepsies. Sleep is unknown, sleep deprivation likely

deprivation activates epileptiform dis- activates epileptiform discharges
charges on sleep-wake EEGs and is there- through direct effects of sleep loss.
fore useful in evaluation of suspected Neurologists should be aware that sleep
epilepsy. Although the exact mechanism deprivationYprovoked seizures may
Case 8-2
A 28-year-old man was brought to clinic by his wife with the complaint
that he was waking up screaming and thrashing at night. This had begun
about 6 months earlier and occurred approximately every 2 weeks. The
events would occur at any time of the night, but were slightly less likely
during the final portion of the sleep period. The patient would awaken
abruptly, thrashing and screaming incoherently. The events lasted about
30 seconds and ended abruptly; the patient may or may not have any
memory of the event. The duration and characteristics of the event were
consistent over time. Neither the patient nor his family had a history of
sleepwalking, head injury, encephalitis, or epilepsy. His neurologic
examination and routine EEG results were normal. He was admitted for
7 days of inpatient EEG monitoring during which two typical events were
captured, but no ictal EEG correlate was found. The events resolved with a
treatment trial of carbamazepine.
Comment. This case of nocturnal frontal lobe epilepsy highlights the
difficulty in differentiating nocturnal seizures from parasomnias. In this case,
the events are stereotypic, have no predilection for the first third of the
night (when non-REM sleep stage N3 is more prominent), are brief, and lack
substantial postevent confusion, thereby arguing in favor of a diagnosis of
nocturnal frontal lobe epilepsy. The lack of a family history suggests this is not
the heritable type. Although events were captured on EEG monitoring, the
lack of an ictal correlate does not obviate the diagnosis, as deep mesial frontal
generators may insidiously trigger the events. The correct management in
this case is a treatment trial, which if successful, helps confirm the diagnosis.

KEY POINT
h Medication side effects alter seizure semiology and therefore effects on sleep quality or duration and
should always be not confuse these as nonepileptic events. acute and chronic effects of intermittent
considered as a cause of Compared to the general popula- hypoxia and sympathetic activation
sleepiness in a patient tion, patients with epilepsy experience on epileptogenic regions of the brain.
with epilepsy. substantially more sleep disturbance, The reverse is also true: SDB is more
characterized by increased sleep latency prevalent in patients with epilepsy than
and number of awakenings during night in the general population.58 Depending
as well as alterations in normal sleep on epilepsy severity and SDB definition,
architecture due to seizures, interictal between 20% and 80% of epilepsy pa-
epileptiform discharges, or medication tients have been reported to have
side effects (Table 8-6).56 Nearly two- comorbid SDB.59 In a study of refractory
thirds of patients with epilepsy have ex- epilepsy patients, 33% were found to
cessive daytime sleepiness as defined by have OSA, with seizures more likely to
the Epworth Sleepiness Scale, and night occur at night than during the day.
awakening is more common in patients Postulated reasons for this association
with epilepsy than in normal controls, include antiepileptic drugYassociated
with increased seizure frequency por- weight gain (eg, valproate, gabapentin),
tending increased sleep disturbance. hypothyroidism, polycystic ovarian dis-
Epilepsy is more prevalent in patients ease, and the effect of chronic epilepsy
with SDB than in the general popula- on brainstem respiratory control centers
tion.57 Possible reasons include OSA and nuclei involved in airway patency.
a
TABLE 8-6 Effect of Antiepileptic Drugs on Sleep
Effects on Sleep
Effects on Sleep Disorders
Stage Stage Stage
Drug Efficiency Latency N1 N2 N3 REM Improves/Treats Worsens
Phenobarbitol Y , Y j 0 , Sleep-onset Obstructive
insomnia sleep apnea
(OSA)
Phenytoin 0 , j j , 0 or , None known None known
Carbamazepine 0 0 0 0 0 0 Restless legs RLS
syndrome (RLS)
Valproate Y 0 j , 0 0 None known OSA
Ethosuximide Y Y j Y , Y None known None known
Gabapentin 0 0 0 0 j j RLS OSA
b
Lamotrigine 0 0 0 j , j None known None known
c
Topiramate 0 , 0 0 0 0 OSA None known
Tiagabine Y Y Y Y j Y Insomnia None known
Levetiracetam Y Y Y Y j Y None known None known
Pregabalin j Y Y Y j Y None known OSA
REM = rapid eye movement; j = increase; , = reduction; Y = not reported; 0 = no change.
a
Reprinted with permission from Eriksson SH, Curr Opin Neurol.54 journals.lww.com/co-neurology/pages/articleviewer.aspx?year=2011&
issue=04000&article=00014&type=abstract.
b
Lamotrigine may be associated with insomnia.
c
Due to change in weight.

KEY POINTS
Benzodiazepines and barbiturates may AD.63 Degeneration of cholinergic neu- h When approaching a
cause suppression in responsiveness of rons in the SCN and ventrolateral pre- sleep problem in a patient
carbon dioxide and oxygen desaturation optic nucleus, critical for homeostatic with neurodegenerative
and increase upper airway musculature maintenance of the circadian rhythm disease, medication side
relaxation. Vagus nerve stimulation treat- and sleep initiation, leads to sleep-wake effects should always be
ment for epilepsy has been reported to disturbances in AD. Sundowning, char- considered as a causative
increase airway disturbance during sleep acterized by confusion, wandering, factor, particularly with
in some patients.60 This therapy is hyperactivity, restlessness, and agitation, cholinergic, antipsychotic,
thought to increase airway resistance is common and typically occurs during and sedative hypnotic
from increasing lateral laryngeal muscular low-light hours in the late afternoon and medications.
tone or by interfering with the respira- early evening in these patients. People h Sundowning is common
tory sensory feedback. with mild to moderate dementia spend in patients with
Seizure control may improve with 15% of the day napping, while those neurodegenerative
treatment of OSA. In one study, treat- with severe dementia spend 29% of the diseases; treatment is best
focused on
ment of OSA produced a 50% or greater day napping, which leads to further
nonpharmacologic
reduction of seizures, with some patients sleep difficulty at night. Cholinergic
measures, such as
becoming seizure free. Excessive day- medications, the primary treatment for improved sleep hygiene
time sleepiness also improved, despite AD, can cause insomnia and dream and a consistent daytime
no changes or higher doses of antiepi- disturbances. Sedative-hypnotic medica- schedule, that include
leptic drugs.61 Another study showed tions, used for sleep induction or light exposure and
that children with epilepsy treated sur- behavioral modification in AD, can have regular physical activity.
gically for their SDB had a 53% median significant side effects such as sleep
seizure reduction, with about one-third disruption and increased injury risk.
becoming seizure free.62 For all these Antipsychotic medications, if used for
reasons, symptoms of daytime sleepi- agitation or sleep induction, can cause
ness and poor sleep should not neces- daytime hypersomnia. Melatonin is
sarily be considered the result of sometimes used to regulate circadian
epilepsy until other causes have been rhythms but may not be effective as
evaluated. Epilepsy patients should be monotherapy for sleep disturbances
routinely asked about these symptoms in these patients. Nonpharmacologic
and referred to a sleep specialist when treatments, including light therapy, ex-
appropriate with the goal of improving ercise, and sleep-hygiene modification,
quality of life and seizure control. are safe and effective alternatives.
In PD, muscle rigidity, tremors, and
NEURODEGENERATIVE dystonia can lead to difficulty with sleep
DISEASES AND SLEEP initiation and maintenance. Carbidopa-
Neurodegenerative diseases, such as Alz- levodopa, used to treat PD, may cause
heimer disease (AD) and PD, are com- nightmares and insomnia. Depression
monly associated with sleep disorders and anxiety (and antidepressants such as
such as SDB, RBD, restless legs syndrome, selective serotonin reuptake inhibitors)
insomnia, and circadian rhythm sleep may also perpetuate insomnia in these
disorders (Table 8-7). Sleep disruption patients.
in people with neurodegenerative disease Cell loss in brainstem nuclei that
may lead to worsened cognitive status modulate respiration, along with bulbar
and functional ability, increased caregiver and diaphragmatic muscle dysfunction,
burden, and perhaps, most importantly, increase the risk of SDB in neurodege-
hastened institutionalization. nerative disease. Patients with PD are at
Persistent sleep disturbances are risk of developing SDB due to hypoki-
present in up to 44% of patients with nesia and rigidity causing upper airway

TABLE 8-7 Prevalence Estimates of Sleep Disorders in Neurodegenerative Disorders
Sleep-Disordered REM Sleep Restless Legs

Disorder Breathing Hypersomnia Behavior Disorder Syndrome
Parkinson disease Obstructive sleep apnea 20Y50% 25Y50% Up to 52%
(OSA): 27Y52% (sleep attacks
(apnea-hypopnea index 1Y20%)
[AHI] 95 events/h)
21Y34% (AHI 915 events/h)
Multiple system OSA: 15Y37% 28Y50% 69Y90% 28%
atrophy
Stridor: 30Y42%
Central sleep apnea
(CSA): present
Cheyne-Stokes
respiration: present
Dementia with Not characterized Present 950% No known
Lewy bodies association
Alzheimer disease OSA: 70Y80% (AHI 95 Up to 69% Case reports support No known
events/h) this association association
Up to 53% (AHI 910 events/h)
Spinocerebellar Stridor (SCA types 1 SCA type 3: SCA type 2: 80% SCA type 3:
ataxia (SCA) and 3): present 45% 30Y55%
OSA (SCA type 3): SCA type 3: 46% SCA types 1
20Y25% and 6: 23%
SCA type 2:
18%
ALS Sleep-disordered 23% No known 19Y25%
breathing: 17Y76% association
Hypoventilation
(most common)
CSA
OSA
REM = rapid eye movement.
obstruction, restrictive lung disease (ie, moderate AD, treatment of OSA with
chest wall rigidity and postural abnor- CPAP improves nocturnal sleep qual-
malities), and autonomic dysfunction. ity and excessive daytime sleepiness.
However, patients with PD tend to have However, compliance with CPAP is a
lower body weight, which reduces OSA challenge in this population. Donepezil
occurrence. SDB may also be worsened has been shown to improve OSA in AD,
by antianxiolytic and pain medications likely by stimulating the neurochemical
prescribed for these patients. In mild to regulation of breathing during sleep.64

KEY POINTS
Central sleep apnea and Cheyne- ting factors specific to SDB in myopa- h REM sleep behavior
Stokes breathing pattern can be observed thies include weakness of oropharyngeal disorder can
in neurodegenerative diseases and are muscles, tonsillar hypertrophy, obesity, herald preclinical
related to degeneration of the ventral and craniofacial dysmorphias. Breathing synucleinopathies, and
arcuate nucleus and the pre-Botzinger alterations become particularly evident as such patients with
complex of the medulla (neural areas during REM sleep when respiration REM sleep behavior
responsible for respiratory chemosensi- becomes diaphragm dependent. Central disorder should be
tivity and rhythmogenesis).65 Stridor in apneas due to alterations in central re- followed for signs and
patients with multiple system atrophy or spiratory drive may be present. Frequent symptoms of these
certain spinal cerebellar ataxias and nocturnal awakenings, daytime sleepi- diseases over time.
nocturnal hypoventilation in ALS are ness and fatigue, morning headaches, h Indicators of
associated with increased mortality.66 and difficulty concentrating should cue sleep-disordered
Excessive daytime sleepiness is fre- the practitioner to perform an over- breathing in patients
quent in patients with neurodegenerative night polysomnogram and check for with neuromuscular
disorders include
disorders. The degree of excessive day- laboratory evidence of hypoxia and
disrupted nocturnal
time sleepiness correlates with the hypercapnia. Diurnal hypercapnia is
sleep, daytime sleepiness
severity of AD.67 Sleep attacks can occur indicated by a PaCO2 greater than 45 and fatigue, morning
in patients with PD and dementia with mm Hg. Nocturnal hypoventilation is headache, and trouble
Lewy bodies.68 Dopamine agonists, used defined as a PaCO2 greater than 55 mm concentrating.
to treat symptoms such as tremor in PD, Hg for 10 minutes or more or a 10 mm
may also induce sudden sleep attacks.69 Hg or greater increase in PaCO2 during
RBD (Supplemental Digital Content sleep (in comparison to an awake su-
8-1, links.lww.com/CONT/A19) is asso- pine value) to a value exceeding 50 mm
ciated with disruption of the normal Hg for 10 minutes or more. Nocturnal
paralysis-inducing mechanisms of REM hypoxia can be indicated by a low mean
sleep and may herald the onset of PD saturation, high desaturation index, and
or other synucleinopathies by 20 years
or more (Figure 8-2).70 Dream-enacting
behaviors can lead to injury to the pa-
tient or bed partner and are typically
treated with clonazepam or melatonin
(Case 8-3). In PD, an increased fre-
quency of restless legs syndrome and
periodic limb movement disorder may
be present, especially in patients not
treated with levodopa.71
NEUROMUSCULAR DISEASE
AND SLEEP
In general, sleep disorders from neuro-
muscular diseases occur because of
sleep-related ventilatory difficulties (and
respiratory failure), particularly in later FIGURE 8-2 Survival curve of patients with idiopathic REM
sleep behavior disorder. At 5 years survival
stages of the disease. Respiratory com- time, 17% of patients went on to develop a
promise may be related to diaphragmatic neurodegenerative disorder, and at 10 years survival time,
40% of patients developed a neurodegenerative disorder.
weakness, restrictive lung disease from
intercostal muscle weakness, kyphosco- Modified from Postuma RB, et al, Neurology.68 B 2009, with permission
from American Academy of Neurology. www.neurology.org/content/72/
liosis, or pulmonary microatelectasis 15/1296.abstract.
from chronic hypoventilation. Contribu-

Case 8-3
A 68-year-old, right-handed man presented with symptoms of loud snoring and nocturnal awakenings
related to nocturia and dreams in which he is fighting off an animal such as a lion or an ape. He would
awaken from these dreams swinging his arms and yelling and in the past had struck his wife in bed.
He found these behaviors embarrassing since they had occurred on long plane flights and tour bus
rides. His medical history included lumbar stenosis, prostate carcinoma status-post resection, and
diverticulosis. He took a baby aspirin, multivitamin, and calcium daily. He had no family history of
neurodegenerative disease, but two brothers also had undiagnosed dream-enacting behaviors.
His vital signs were within normal range, he was not orthostatic, body mass index was 24 kg/m2, and
general examination was nonrevealing. His MiniYMental State Examination score was 29/30. No signs
of dysarthria, hypophonia, or ataxic speech were present, and the remainder of the neurologic
FIGURE 8-3 Thirty-second polysomnogram fragment showing increased chin tone in REM sleep and limb movements.
Channels are as follows: electrooculogram (left: LOC-A2, right: ROC-A1); chin EMG (Chin1-Chin2); EEG (left
central [C3-A2], right central [C4-A1], left occipital [O1-A2], right occipital [O2-A1]), two ECG channels; limb
EMG (LAT1-LAT2); snore channel; nasal-oral airflow (N/O); respiratory effort (thoracic [THOR], abdominal [ABD]); and
oxygen saturation (SpO2). Tonic EMG activity is consistent with REM sleep behavior disorder when present in more than
50% of the total 30-second epoch duration with an amplitude of at least twice the background EMG muscle tone or more
than 10 6V. Phasic EMG activity includes any burst of activity lasting between 0.1 and 5.0 seconds with an amplitude
exceeding twice the background EMG activity irrespective of its morphology. The green arrow points to increased muscle
tone in the chin EMG lead while the blue arrow points to increased muscle tone in the limb EMG lead.
Figure courtesy of Alon Y. Avidan, MD, MPH, FAASM.

examination results were normal. Overnight polysomnography showed minimal sleep-disordered

breathing, oxygen desaturation nadir of 91%, and increased muscle tone during REM sleep (Figure 8-3).
No epileptiform discharges were seen.
Clonazepam 0.5 mg nightly was prescribed, and the patient was ensured a safe sleeping
environment. He tolerated the medication, and the dream-enacting behaviors ceased. During the
next 2 years, no signs of tremor, gait impairment, or dementia were apparent.
Comment. This case of REM sleep behavior disorder (RBD) highlights protean aspects of the disease.
This disorder typically involves older men, can precede the onset of synucleinopathies such as
dementia with Lewy bodies in some but not all patients, and may result in substantial injury to
patients or their bed partners. Increased chin EMG tone in REM sleep is the polysomnographic
hallmark of the disease. Exposure to selective serotonin reuptake inhibitors or tricyclic antidepressants
can provoke the disorder. Treatment focuses on creating a safe sleeping environment (eg, remove
sharp furniture edges and mirrors, lock bedroom doors, close windows) and benzodiazepines, most
commonly clonazepam. Melatonin and dopamine agonists have also been used with some success. All
patients with RBD should undergo a thorough neurologic examination and be followed over time for
evidence of parkinsonism. In the event of focal findings, neuroimaging is recommended since RBD
can also be precipitated by brainstem lesions of almost any cause.
high hypoxemic burden such as an is average volume-assured pressure sup- KEY POINT
oxygen saturation of 88% or less for 5 port, which automatically adjusts pres- h Objective tests indicating
consecutive minutes. Other indicators sure support to maintain a target tidal nocturnal hypoventilation
in neuromuscular disease
of SDB in neuromuscular disease in- volume. Regardless of NPPV type or set-
include daytime PaCO2
clude a maximal inspiratory pressure of tings, supplemental oxygen may also be
greater than 45 mm Hg,
less than 60-cm water and a forced vital required and tracheostomy becomes a nocturnal oximetry
capacity of less than 50% predicted.72 consideration in advanced disease. showing oxygen
Daytime predictors of sleep hypoventi- Myotonic dystrophy type 1 (DM1) is saturation of 88% or less
lation in Duchenne muscular dystro- the most common adult-onset form of for 5 consecutive
phy are a forced expiratory volume of muscular dystrophy, and hypersomnia minutes, nocturnal
less than 40% and a base excess greater is a key clinical feature of the disease. PaCO2 of greater than
than 4 mmol per liter.73 Subjective and objective sleepiness (as- 55 mm Hg for 10
Noninvasive positive-pressure ventila- sessed by the Epworth Sleepiness Scale minutes or more or a 10
tion (NPPV) is the most common initial and multiple sleep latency test, respec- mm Hg or greater
treatment for SDB in neuromuscular tively) is present in 70% of patients with increase in PaCO2 during
sleep (compared to
disorders and improves survival and DM1.75 Excessive daytime sleepiness in
wake) to a value
quality of life in patients with ALS.74 This DM1 is frequently persistent and unaf-
exceeding 50 mm Hg for
may involve bilevel positive airway pres- fected by napping, unlike that of patients 10 minutes or more,
sure with expiratory pressure set to pre- with narcolepsy, who tend to feel maximal inspiratory
vent airway obstruction and inspiratory refreshed after naps. Patients with DM1 pressure of less than
pressure set for ventilation purposes. frequently meet diagnostic criteria for 60-cm water, and forced
Ventilation is often a greater concern narcolepsy, and methylphenidate and vital capacity of less than
than airway obstruction and may nec- modafinil are effective treatments for 50% predicted.
essitate pressure-support windows as sleepiness in these patients. Regarding
large as 10-cm water or more. In many myasthenia gravis, 40% to 60% of
cases, the presence of central apneas clinically stable patients have SDB.76
necessitates a back-up rate to deliver a Insomnia is associated with neuro-
breath if the patient fails to trigger an muscular diseases and often induced by
inspiratory effort. Another NPPV option steroids for treatment of disorders such

KEY POINTS
h When treating patients as inflammatory myopathies. PLMS are increased risk of fatigue in MS. Sleepi-
with neuromuscular increased in DM1 compared to controls ness and fatigue in MS are commonly
disorders with bilevel and associated with sleep disturbance.77 treated with modafinil, although its ef-
positive airway pressure, Lastly, restless legs syndrome is increased fectiveness is uncertain.
improving ventilation is in ALS and associated with increased Narcolepsy and RBD occur more
often more important sleep complaints.78 frequently in patients with MS. Case
than relieving airway reports suggest an association between
obstruction, and wide DEMYELINATING DISEASE acute disseminated encephalomyelitis
pressure-support windows AND SLEEP and neuromyelitis optica with hyper-
may be necessary. As with stroke or tumor, lesion location somnia and secondary narcolepsy.
h Multiple sclerosis lesions in multiple sclerosis (MS) is critical to Insomnia is common in MS, present in
in brain areas the presence or absence of sleepiness, up to 40% of patients. Common MS
subserving sleep onset, insomnia, or specific sleep disorders. symptoms, such as pain, spasticity, blad-
alertness, and REM Hypothalamic lesions involving the tuber- der dysfunction, depression, anxiety,
sleep paralysis can
omammillary nucleus or hypocretin/ and medications (ie, immunomodula-
precipitate insomnia,
orexin production can cause sleepiness. tors, such as interferon and corticoste-
sleepiness, and REM
sleep behavior disorder.
Pontine lesions involving areas such as roids) all likely contribute to difficulty
the sublaterodorsal tegmental nucleus falling and staying asleep. Restless legs
h Insomnia is common in can precipitate RBD. Lesions involving syndrome may be seen in MS patients
multiple sclerosis and
the ventrolateral preoptic nucleus can and is associated with greater disabil-
likely due to many
disease-related factors,
predispose to insomnia. For these rea- ity,86 although these symptoms may be
such as pain, spasticity, sons, attention to lesion location on confused with other frequent MS com-
bladder dysfunction, neuroimaging can prove insightful when plaints such as paresthesias, dysesthe-
depression, anxiety, and addressing sleep concerns in MS. sias, pain, and spasticity. PLMS are also
medication side effects. Fatigue and sleepiness are common highly prevalent in MS.84 Intrathecal
h Sellar or suprasellar complaints in MS and are frequently baclofen, for treatment of spasticity,
malignancies can intertwined. In a cross-sectional survey reduces PLMS but increases obstructive
indirectly cause of 1063 people with MS, those with MS and central respiratory events, especially
sleep-disordered had more sleep disturbances (and day- in patients receiving bolus compared to
breathing by time somnolence) compared to a group continuous intrathecal administration.87
endocrinologic of chronically ill patients and a group of Generally speaking, poor sleep in MS is
dysfunction causing healthy individuals.79 Conversely, multi- an independent predictor of quality of
obesity. ple studies dispute sleepiness as an MS life.88
symptom.80,81 Fatigue may be related
to sleepiness, as sleep disruption can CNS MALIGNANCIES AND SLEEP
cause or worsen fatigue through CNS Malignancies disrupt sleep through both
activation and increased inflammation. direct and indirect effects. Cerebral tu-
When focusing on fatigued subsets of mors, especially those located in the
MS patients, those with fatigue are sig- sellar or suprasellar regions (ie, cranio-
nificantly sleepier than nonfatigued pharyngioma, pilocytic astrocytoma, and
patients with MS,82,83 although this is pituitary adenoma) can induce sleepi-
disputed by other studies showing ness through direct neoplastic involve-
normal Epworth Sleepiness Scale scores ment or pressure exertion on the
and sleep latencies on the multiple hypothalamus, with a corresponding
sleep latency test between the two reduction in hypocretin (orexin) as the
groups.84,85 SDB is more frequent in likely causative factor. Sellar or supra-
fatigued (27.0%) versus nonfatigued MS sellar tumors may also cause endo-
patients (2.5%), and the presence of a crine dysfunction, indirectly producing
sleep disorder is associated with an sleepiness and sleep disturbances by

KEY POINT
promoting obesity and subsequent OSA. a risk factor for stroke and, as with all h Secondary narcolepsy
Insomnia in these patients may result stroke risk factors, its investigation can occur from
from alterations in melatonin production should be considered in every TIA and treatment of CNS
by the pineal gland. Brainstem gliomas stroke patient for secondary prevention. malignancies with
and hemispheric tumors (ie, those Whether diagnosing and treating SDB is surgical resection or
with bilateral hemisphere invasion or a good stroke primary prevention strat- radiation therapy in the
edema causing increased intracranial egy is yet to be definitively determined, perihypothalamic region.
pressure and/or cerebral herniation) but in the meantime it is probably
have also demonstrated somnogenic reasonable and safe to assume that
capabilities, with disruption of the re- treating SDB will positively affect future
ticular activating system as the likely risk of cerebrovascular disease. Sleep
cause. In addition, paraneoplastic dis- affects all headache disorders, and two
orders such as anti-Ma2 encephalitis disorders (hypnic and sleep apnea head-
are associated with sleepiness.89 Nu- ache) are sleep specific and may occur
merous case reports document secon- upon awakening. Neurodegenerative
dary narcolepsy and sleepiness related diseases, MS, and CNS malignancies
to treatment of cerebral tumors with can influence sleep quality, continuity,
radiation and surgical instrumentation and sleepiness and precipitate SDB or
and/or resection. Radiation therapy has RBD by involving nuclei and pathways
been implicated in somnolence syn- involved in automatic control of respira-
drome, a poorly described hypersomnia tion, dream-related paralysis, alertness,
in children receiving cranial irradiation and circadian rhythmicity.
for acute lymphocytic leukemia. Chemo-
therapeutics and immunomodulators VIDEO LEGEND
Supplemental Digital Content 8-1
used to treat cerebral tumors may
REM sleep behavior disorder. Video montage
induce insomnia or somnolence. Meth-
of REM sleep behavior disorder demonstrating
ylphenidate, amphetamines, and modafi- vigorous, aggressive, and violent behaviors during
nil are effective in the treatment of REM sleep in an older adult male patient. Note
sleepiness in children with brain tumors. violent and aggressive dream enactment correlat-
SDB may be caused by tumors in- ing with dream sequence, placing both the pa-
volving the brainstem leading to dys- tient and the bed partner at risk for injury.
function of the respiratory centers and
B 2013 Carlos Schenk, MD. Used with permission.
nuclei involved in diaphragmatic and
bulbar muscle control. RBD may pre-
sent when a brainstem lesion disrupts REFERENCES
1. Shahar E, Whitney CW, Redline S, et al.
the normal paralysis-inducing mecha- Sleep-disordered breathing and
nisms of REM sleep. Restless legs syn- cardiovascular disease: cross-sectional results
drome has been described as the initial of the sleep heart health study. Am J Respir
Crit Care Med 2001;163(1):19Y25.
complaint in a patient with a foramen
magnum tumor,90 and PLMS have been 2. Arzt M, Young T, Finn L, et al. Association of
sleep-disordered breathing and the
observed in patients with thoracic spi- occurrence of stroke. Am J Respir Crit Care
nal cord tumors.91 Med 2005;172(11):1447Y1451.
3. Munoz R, Duran-Cantolla J, Martinez-Vila E,
CONCLUSIONS et al. Severe sleep apnea and risk of ischemic
Sleep dysfunction and neurologic disor- stroke in the elderly. Stroke 2006;37(9):
2317Y2321.
ders are deeply intertwined, and the
4. Redline S, Yenokyan G, Gottlieb DJ, et al.
neurologist is well served to consider
Obstructive sleep apnea-hypopnea and incident
the interaction of sleep with almost stroke: the sleep heart health study. Am J
every patient entering the clinic. SDB is Respir Crit Care Med 2010;182(2):269Y277.

5. Valham F, Mooe T, Rabben T, et al. Increased obstructive sleep apnea. Hypertension 2007;
risk of stroke in patients with coronary 50(2):417Y423.
artery disease and sleep apnea: a 10-year
18. Haentjens P, Van Meerhaeghe A,
follow-up. Circulation 2008;118(9):955Y960.
Moscariello A, et al. The impact of
6. Yaggi HK, Concato J, Kernan WN, et al. continuous positive airway pressure on
Obstructive sleep apnea as a risk factor for blood pressure in patients with obstructive
stroke and death. N Engl J Med 2005; sleep apnea syndrome: evidence from a
353(19):2034Y2041. meta-analysis of placebo-controlled
randomized trials. Arch Intern Med 2007;
7. Chami HA, Resnick HE, Quan SF, Gottlieb DJ.
167(8):757Y764.
Association of incident cardiovascular
disease with progression of sleep-disordered 19. Mo L, Gai J, He QY. The effect of chronic
breathing. Circulation 2011;123(12):1280Y1286. intermittent hypoxia caused by obstructive
sleep apnea hypopnea syndrome on blood
8. Munoz R, Duran-Cantolla J, Martinez-Vila E,
pressure [in Chinese]. Zhonghua Jie He He
et al. Central sleep apnea is associated with
Hu Xi Za Zhi 2007;30(12):898Y903.
increased risk of ischemic stroke in the
elderly. Acta Neurol Scand 2012;126(3): 20. Kohli P, Balachandran JS, Malhotra A.
183Y188. Obstructive sleep apnea and the risk for
cardiovascular disease. Curr Atheroscler Rep
9. Manfredini R, Boari B, Smolensky MH, et al.
2011;13(2):138Y146.
Circadian variation in stroke onset: identical
temporal pattern in ischemic and 21. Kanagala R, Murali NS, Friedman PA, et al.
hemorrhagic events. Chronobiol Int 2005; Obstructive sleep apnea and the recurrence
22(3):417Y453. of atrial fibrillation. Circulation 2003;
107(20):2589Y2594.
10. Casetta I, Granieri E, Fallica E, et al. Patient
demographic and clinical features and 22. Lurie A. Endothelial dysfunction in adults
circadian variation in onset of ischemic with obstructive sleep apnea. Adv Cardiol
stroke. Arch Neurol 2002;59(1):48Y53. 2011;46:139Y170.
11. Hsieh SW, Lai CL, Liu CK, et al. Obstructive 23. Balfors EM, Franklin KA. Impairment of
sleep apnea linked to wake-up strokes. cerebral perfusion during obstructive sleep
J Neurol 2012;259(7):1433Y1439. apneas. Am J Respir Crit Care Med 1994;
150(6 pt 1):1587Y1591.
12. Phillips RA, Sheinart KF, Godbold JH, et al.
The association of blunted nocturnal blood 24. Urbano F, Roux F, Schindler J, Mohsenin V.
pressure dip and stroke in a multiethnic Impaired cerebral autoregulation in
population. Am J Hypertens 2000;13(12): obstructive sleep apnea. J Appl Physiol
1250Y1255. 2008;105(6):1852Y1857.
13. Pringle E, Phillips C, Thijs L, et al. Systolic 25. Oyama J, Yamamoto H, Maeda T, et al.
blood pressure variability as a risk factor for Continuous positive airway pressure therapy
stroke and cardiovascular mortality in the improves vascular dysfunction and decreases
elderly hypertensive population. J Hypertens oxidative stress in patients with the metabolic
2003;21(12):2251Y2257. syndrome and obstructive sleep apnea
syndrome. Clin Cardiol 2012;35(4):231Y236.
14. Dudenbostel T, Calhoun DA. Resistant
hypertension, obstructive sleep apnoea and 26. Lau EM, Yee BJ, Grunstein RR, Celermajer
aldosterone. J Hum Hypertens 2012;26(5): DS. Patent foramen ovale and obstructive
281Y287. sleep apnea: a new association? Sleep Med
Rev 2010;14(6):391Y395.
15. Peppard PE, Young T, Palta M, Skatrud J.
Prospective study of the association 27. Pinet C, Orehek J. CPAP suppression of
between sleep-disordered breathing and awake right-to-left shunting through patent
hypertension. N Engl J Med 2000;342(19): foramen ovale in a patient with obstructive
1378Y1384. sleep apnoea. Thorax 2005;60(10):880Y881.
16. Alajmi M, Mulgrew AT, Fox J, et al. Impact 28. Ciccone MM, Scicchitano P, Mitacchione G,
of continuous positive airway pressure et al. Is there a correlation between osas
therapy on blood pressure in patients with duration/severity and carotid intima-media
obstructive sleep apnea hypopnea: a thickness? Respir Med 2012;106(5):740Y746.
meta-analysis of randomized controlled
29. Hui DS, Shang Q, Ko FW, et al. A prospective
trials. Lung 2007;185(2):67Y72.
cohort study of the long-term effects of
17. Bazzano LA, Khan Z, Reynolds K, He J. Effect CPAP on carotid artery intima-media
of nocturnal nasal continuous positive thickness in obstructive sleep apnea
airway pressure on blood pressure in syndrome. Respir Res 2012;13:22.

30. Bulcun E, Ekici M, Ekici A. Disorders of 44. Kostanecka-Endress T, Banaschewski T,
glucose metabolism and insulin resistance in Kinkelbur J, et al. Disturbed sleep in
patients with obstructive sleep apnoea children with Tourette syndrome: a
syndrome. Int J Clin Pract 2012;66(1):91Y97. polysomnographic study. J Psychosom Res
2003;55(1):23Y29.
31. Martinez-Garcia MA, Campos-Rodriguez F,
Soler-Cataluna JJ, et al. Increased incidence 45. Kirov R, Kinkelbur J, Banaschewski T,
of nonfatal cardiovascular events in stroke Rothenberger A. Sleep patterns in children
patients with sleep apnoea: effect of CPAP with attention deficit hyperactivity disorder,
treatment. Eur Respir J 2012;39(4):906Y912. tic disorder, and comorbidity. J Child
Psychol Psychiatry 2007;48(6):561Y570.
32. Martinez-Garcia MA, Soler-Cataluna JJ,
Ejarque-Martinez L, et al. Continuous 46. Rains JC, Poceta JS. Headache and sleep
positive airway pressure treatment reduces disorders: review and clinical implications
mortality in patients with ischemic stroke for headache management. Headache 2006;
and obstructive sleep apnea: a 5-year 46(9):1344Y1363.
follow-up study. Am J Respir Crit Care Med
47. Rains JC, Poceta JS. Sleep and headache
2009;180(1):36Y41.
disorders: clinical recommendations for
33. Ryan CM, Bayley M, Green R, et al. Influence headache management. Headache 2006;
of continuous positive airway pressure on 46(suppl 3):S147YS148.
outcomes of rehabilitation in stroke patients
48. Spierings EL, van Hoof MJ. Fatigue and sleep
with obstructive sleep apnea. Stroke 2011;
in chronic headache sufferers: an age- and
42(4):1062Y1067.
sex-controlled questionnaire study.
34. Parra O, Arboix A, Bechich S, et al. Time Headache 1997;37(9):549Y552.
course of sleep-related breathing disorders
49. Ohayon MM. Prevalence and risk factors of
in first-ever stroke or transient ischemic
morning headaches in the general population.
attack. Am J Respir Crit Care Med 2000;
Arch Intern Med 2004;164(1):97Y102.
161(2 pt 1):375Y380.
50. Kelman L, Rains JC. Headache and sleep:
35. Bassetti C, Aldrich MS. Sleep apnea in acute
examination of sleep patterns and
cerebrovascular diseases: final report on
complaints in a large clinical sample of
128 patients. Sleep 1999;22(2):217Y223.
migraineurs. Headache 2005;45(7):904Y910.
36. Magee CA, Kritharides L, Attia J, et al.
51. Nobre ME, Leal AJ, Filho PM. Investigation
Short and long sleep duration are associated
into sleep disturbance of patients suffering
with prevalent cardiovascular disease in
from cluster headache. Cephalalgia 2005;
Australian adults. J Sleep Res 2012;21(4):
25(7):488Y492.
441Y447.
52. Evers S. Sleep and headache: the biological
37. Watson NF. Stroke and sleep specialists: an
basis. Headache 2010;50(7):1246Y1251.
opportunity to intervene? J Clin Sleep Med
2010;6(2):138Y139. 53. Buechler RD. Rodriguez AJ, Lahr BD, So EL.
38. Trotti LM, Esper CD, Feustel PJ, et al. Ictal scalp EEG recording during sleep and
Excessive daytime sleepiness in cervical wakefulness: diagnostic implications for
seizure localization and lateralization.
dystonia. Parkinsonism Relat Disord 2009;
15(10):784Y786. Epilepsia 2008;49(2):340Y342.
39. Kuyper DJ, Parra V, Aerts S, et al. Nonmotor 54. Sinha S, Brady M, Scott CA, Walker MC. Do
manifestations of dystonia: a systematic seizures in patients with refractory epilepsy
review. Mov Disord 2011;26(7):1206Y1217. vary between wakefulness and sleep?
J Neurol Neurosurg Psychiatry 2006;77(9):
40. Taylor N, Bramble D. Sleep disturbance and 1076Y1078.
Huntingdons disease. Br J Psychiatry 1997;
171:393. 55. Derry CP. The sleep manifestations of frontal
lobe epilepsy. Curr Neurol Neurosci Rep
41. Goodman AO, Barker RA. How vital is sleep 2011;11(2):218Y226.
in Huntingtons disease? J Neurol 2010;
257(6):882Y897. 56. Eriksson SF. Epilepsy and sleep. Curr Opin
Neurol 2011;24(2):171Y176.
42. Arnulf I, Nielsen J, Lohmann E, et al. Rapid
eye movement sleep disturbances in 57. Sonka K, Juklickova M, Pretl M, et al.
Huntington disease. Arch Neurol 2008;65(4): Seizures in sleep apnea patients: occurrence
482Y488. and time distribution. Sb Lek 2000;101(3):
229Y232.
43. Chandran V, Pal PK, Reddy JY, et al.
Non-motor features in essential tremor. 58. Malow BA, Levy K, Maturen K, Bowes R.
Acta Neurol Scand 2012;125(5):332Y337. Obstructive sleep apnea is common in

medically refractory epilepsy patients. 73. Hukins CA, Hillman DR. Daytime predictors
Neurology 2000;55(7):1002Y1007. of sleep hypoventilation in Duchenne
muscular dystrophy. Am J Respir Crit Care
59. van Golde EG, Gutter T, de Weerd AW. Sleep
Med 2000;161(1):166Y170.
disturbances in people with epilepsy;
prevalence, impact and treatment. Sleep 74. Bourke SC, Bullock RE, Williams TL, et al.
Med Rev 2011;15(6):357Y368. Noninvasive ventilation in ALS: indications
and effect on quality of life. Neurology
60. Parhizgar F, Nugent K, Raj R. Obstructive
2003;61(2):171Y177.
sleep apnea and respiratory complications
associated with vagus nerve simulators. 75. Laberge L, Begin P, Dauvilliers Y, et al. A
J Clin Sleep Med 2011;7(4):401Y407. polysomnographic study of daytime sleepiness
in myotonic dystrophy type 1. J Neurol
61. Beran RG, Holland GJ, Yan KY. The use of
Neurosurg Psychiatry 2009;80(6):642Y646.
CPAP in patients with refractory epilepsy.
Seizure 1997;6(4):323Y325. 76. Prudlo J, Koenig J, Ermert S, et al. Sleep
disordered breathing in medically stable
62. Segal E, Vendrame M, Gregas M, et al. Effect
patients with myasthenia gravis. Eur J
of treatment of obstructive sleep apnea on
Neurol 2007;14(3):321Y326.
seizure outcomes in children with epilepsy.
Pediatr Neurol 2012;46(6):359Y362. 77. Romigi A, Izzi F, Pisani V, et al. Sleep
disorders in adult-onset myotonic dystrophy
63. Vitiello MV, Borson S. Sleep disturbances
type 1: a controlled polysomnographic
in patients with Alzheimers disease:
study. Eur J Neurol 2011;18(9):1139Y1145.
epidemiology, pathophysiology and
treatment. CNS Drugs 2001;15(10):777Y796. 78. Lo Coco D, Piccoli F, La Bella V. Restless legs
syndrome in patients with amyotrophic
64. Sukys-Claudino L, Moraes W, Guilleminault
lateral sclerosis. Mov Disord 2010;25(15):
C, et al. Beneficial effect of donepezil on
2658Y2661.
obstructive sleep apnea: a double-blind,
placebo-controlled clinical trial. Sleep Med 79. Bamer AM, Johnson KL, Amtmann D,
2012;13(3):290Y296. Kraft GH. Prevalence of sleep problems in
individuals with multiple sclerosis. Mult Scler
65. Benarroch EE, Schmeichel AM, Low PA,
2008;14(8):1127Y1130.
Parisi JE. Depletion of putative chemosensitive
respiratory neurons in the ventral medullary 80. Rammohan KW, Rosenberg JH, Lynn DJ,
surface in multiple system atrophy. Brain et al. Efficacy and safety of modafinil
2007;130(pt 2):469Y475. (Provigil) for the treatment of fatigue in
multiple sclerosis: a two centre phase 2
66. Gaig C, Iranzo A. Sleep-disordered breathing
study. J Neurol Neurosurg Psychiatry 2002;
in neurodegenerative diseases. Curr Neurol
72(2):179Y183.
Neurosci Rep 2012;12(2):205Y217.
81. Zifko UA, Rupp M, Schwarz S, et al.
67. Bonanni E, Maestri M, Tognoni G, et al. Daytime
Modafinil in treatment of fatigue in
sleepiness in mild and moderate Alzheimers
multiple sclerosis. Results of an open-label
disease and its relationship with cognitive
study. J Neurol 2002;249(8):983Y987.
impairment. J Sleep Res 2005;14(3):311Y317.
82. Heesen C, Nawrath L, Reich C, et al. Fatigue
68. Bhatt MH, Podder N, Chokroverty S. Sleep
and neurodegenerative diseases. Semin in multiple sclerosis: an example of cytokine
Neurol 2005;25(1):39Y51. mediated sickness behaviour? J Neurol
Neurosurg Psychiatry 2006;77(1):34Y39.
69. Comella CL. Sleep disturbances in
parkinsons disease. Curr Neurol Neurosci 83. Stanton BR, Barnes F, Silber E. Sleep and
Rep 2003;3(2):173Y180. fatigue in multiple sclerosis. Mult Scler 2006;
12(4):481Y486.
70. Postuma RB, Gagnon JF, Vendette M, et al.
Quantifying the risk of neurodegenerative 84. Kaynak H, Altintas A, Kaynak D, et al.
disease in idiopathic REM sleep behavior Fatigue and sleep disturbance in multiple
disorder. Neurology 2009;72(15):1296Y1300. sclerosis. Eur J Neurol 2006;13(12):1333Y1339.
71. Bliwise DL, Trotti LM, Yesavage JA, Rye DB. 85. Vetrugno R, Stecchi S, Scandellari C, et al.
Periodic leg movements in sleep in elderly SleepVwake and body core temperature
patients with Parkinsonism and Alzheimers rhythms in multiple sclerosis with fatigue.
disease. Eur J Neurol. 2012;19(6):918Y923. Clin Neurophysiol 2007;118(1):228Y234.
72. Benditt JO. Initiating noninvasive 86. Manconi M, Fabbrini M, Bonanni E, et al.
management of respiratory insufficiency in High prevalence of restless legs syndrome in
neuromuscular disease. Pediatrics 2009; multiple sclerosis. Eur J Neurol 2007;14(5):
123(suppl 4):S236YS238. 534Y539.

87. Bensmail D, Marquer A, Roche N, et al. 89. Dalmau J, Graus F, Villarejo A, et al. Clinical
Pilot study assessing the impact of analysis of anti-Ma2-associated encephalitis.
intrathecal baclofen administration mode Brain 2004;127(pt 2):1831Y1844.
on sleep-related respiratory parameters.
Arch Phys Med Rehabil 2012;93(1): 90. Glasauer FE, Egnatchick JE. Restless legs
96Y99. syndrome: an unusual cause for a perplexing
syndrome. Spinal Cord 1999;37(12):862Y865.
88. Merlino G, Fratticci L, Lenchig C, et al.
Prevalence of poor sleep among patients 91. Lee MS, Choi YC, Lee SH, Lee SB.
with multiple sclerosis: an independent Sleep-related periodic leg movements
predictor of mental and physical status. associated with spinal cord lesions. Mov
Sleep Med 2009;10(1):26Y34. Disord 1996;11(6):719Y722.

Review Article
Sleep-Related
Dr Michael H. Silber, Mayo
Clinic, Department of
Neurology, 200 1st Street SW,
Rochester, MN 55905,
msilber@mayo.edu.
Movement Disorders
Dr Silber reports no Michael H. Silber, MBChB, FAAN
disclosure.
Unlabeled Use of
Use Disclosure: Dr Silber ABSTRACT
gabapentin, pregabalin,
Purpose of Review: This article reviews the sleep-related movement disorders,
opioids, and benzodiazepines including restless legs syndrome (RLS; Willis-Ekbom disease), periodic limb move-
for the treatment of restless ment disorder, rhythmic movement disorders, sleep-related bruxism, and sleep-
legs syndrome.
related leg cramps.
of Neurology. Recent Findings: The prevalence of clinically significant RLS is 1.5% to 3.0%. The
pathophysiology of RLS may involve abnormal iron transport across the blood-brain
barrier and down-regulation of putaminal D2 receptors. The availability of the
rotigotine patch provides an additional form of dopaminergic therapy for RLS. Calcium
channel alpha-2-delta ligands (gabapentin, gabapentin enacarbil, and pregabalin)
provide alternative therapies for RLS especially in patients with augmentation, impulse
control disorders, or hypersomnia induced by dopamine agonists. Long-term use of
opioid medication is safe and effective for refractory cases of RLS.
Summary: RLS is a common disorder causing considerable morbidity. Accurate di-
agnosis and appropriate investigations are essential. Many effective therapies are
available, but the side effects of each class of medication should be considered in
determining optimal treatment. Periodic limb movements of sleep, bruxism, and
rhythmic movement disorders are sleep-related phenomena often accompanying other
sleep disorders and only sometimes requiring primary therapy. Sleep-related leg cramps
are generally idiopathic. Management is challenging with few effective therapies.
INTRODUCTION RESTLESS LEGS SYNDROME

Movement disorders and sleep are RLS, also known as Willis-Ekbom dis-
intimately related. Some abnormal move- ease, was accurately described by Tho-
ments are at least partially suppressed by mas Willis in 1685 but first delineated as
sleep, including tremor, chorea, dystonia, a unique condition by Dr Karl-Axel
and tics, while others are activated by Ekbom of Sweden in 1945 when he
sleep, including periodic limb move- described a hitherto overlooked dis-
Supplemental digital content: ments, rhythmic movement disorder, ease in the legs.1 Initially believed to
ticle are cited in the text as
bruxism, and REM sleep behavior disor- be a rare condition, later studies sug-
Supplemental Digital Content. der. This article focuses on the sleep- gested prevalence as high as 10% to
Videos may be accessed by related movement disorders as defined by 15%. However, recent large epidemio-
clicking on links provided in
the HTML, PDF, and iPad the International Classification of Sleep logic studies in Europe and the United
versions of this article; the Disorders, Second Edition: Diagnostic Sates have determined that the true
URLs are provided in the print
version. Video legends begin and Coding Manual. Restless legs syn- prevalence for RLS that causes moder-
on page 182. drome (RLS) will be emphasized, but ate distress and occurs at least twice a
periodic limb movement disorder, rhyth- week is in the range of 1.5% to 3.0%.2,3
mic movement disorder, sleep-related RLS is more common in women than
bruxism, and sleep-related leg cramps in men. It can commence in childhood,
will also be addressed. when it is often diagnosed as growing

KEY POINTS
TABLE 9-1 International Classification of Sleep Disorders, Second h Restless legs syndrome
Edition: Diagnostic and Coding Manual Diagnostic that is prominent
Criteria for Restless Legs Syndromea enough to occur at least
twice a week and cause
b An urge to move the legs that is usually, but not always, accompanied or moderate or severe
caused by uncomfortable and unpleasant leg sensations distress has a prevalence
b The symptoms begin or worsen during rest or inactivity of 1.5% to 3.0%.
b The symptoms are partially or totally relieved by movements such as walking h Restless legs syndrome
or stretching for at least as long as the activity continues is diagnosed clinically
b The symptoms only occur or are worse in the evening or night than during the day and requires a history of
b The symptoms are not solely accounted for as being primary to another an uncontrollable urge
condition, such as leg cramps or positional discomfort to move the legs while
a at rest that is worse in
Modified from American Academy of Sleep Disorders.4 Used with permission of the American
Academy of Sleep Medicine, Darien, IL, 2012. the evening or night
and is relieved by
movement such as
walking.
pains. The incidence increases with may be less evident but should have
age, and symptoms may progress with been present earlier. h Mimickers of restless
In a study of 788 patients who en- legs syndrome,
time; however, many patients experi-
especially sleep-related
ence unexplained remissions lasting at dorsed the first four criteria on a ques-
leg cramps relieved by
least a month. tionnaire, 15% were found to have an
stretching or massaging
alternative diagnosis after an interview the affected muscle and
Diagnosis of Restless Legs with an expert.6 Nocturnal leg cramps positional discomfort
Syndrome and positional discomfort were the most relieved by changing
The diagnosis of RLS is made clinically. common mimickers, and when addi- position rather than
All five of the essential diagnostic fea- tional questions were added to rule out walking, must be
tures must be present (Table 9-1),4 and these complaints, the specificity of the excluded.
care must be taken to exclude diagnos- questionnaire rose to 94%.7 Patients de-
tic mimickers (Table 9-2).5 The essen- scribe leg cramps as hardening of a mus-
tial features are an uncontrollable urge cle group, often gastrocnemius-soleus,
to move the legs while at rest (either
sitting or lying down), with at least
temporary relief obtained by movement TABLE 9-2 Diagnostic Mimickers
such as walking. The symptoms only of Restless Legs
Syndrome in
occur in the evening or night or are the Approximate Decreasing Order
worst at those times (Supplemental of Importance
Digital Content 9-1, links.lww.com/
CONT/A20). The urge to move is usu- b Leg cramps
ally, but not always, associated with b Positional discomfort
unpleasant leg sensations, variously b Habitual foot tapping
described as creepy, crawly, tingly, or a b Fibromyalgia
deep ache. Many patients find it hard to
b Arthritis
describe the nature of the discomfort.
b Venous stasis
RLS symptoms may alternate between
b Leg edema
legs and may be asymmetric. It is not
unusual for patients with severe RLS to b Painful peripheral neuropathy
describe similar symptoms in the arms b Painful legs and moving toes
syndrome
and occasionally the trunk. Later in the
disease course, the relief by movement

Sleep-Related Movement Disorders
KEY POINTS
h More than 50% of with intense pain relieved not by walking controls even in the absence of sys-
patients with restless but by massaging the muscle or standing temic iron deficiency. MRI and trans-
legs syndrome have a on the toes. Positional discomfort, such cranial sonography have shown
family history of the as paresthesia or pain in a leg, is relieved reduced iron stores in the basal ganglia,
disorder that is usually by changing position in bed, which alone and autopsy studies have demonstrated
inherited in an does not help RLS. Habitual foot tapping decreased substantia nigra iron, ferritin,
autosomal dominant during wakefulness or drowsiness is a and transferrin receptor concentrations
pattern. Multiple loci and learned behavior not associated with an with increased transferrin, a pattern
several polymorphisms urge to move and can easily be discon- suggestive of low iron stores. Abnor-
associated with restless tinued when attention is drawn to the malities in the transport of iron across
legs syndrome have been
activity. Discomfort from venous stasis, the blood-brain barrier in RLS may be
identified.
edema, peripheral neuropathy, or arthri- the underlying mechanism.11
h Low intracerebral iron, tis may need to be considered. Fibro- The excellent response of RLS to
especially in the basal myalgia or nonspecific myofascial leg dopaminergic medications and the exac-
ganglia, possibly related
pain may be worse at night, but the erbation of RLS with dopamine antago-
to abnormalities in iron
characteristics rarely fulfill all five RLS nists suggest that dopamine deficiency
transport across the
blood-brain barrier, may
diagnostic criteria. may be at the heart of the disorder. RLS
underlie restless legs is associated with down-regulation of
syndrome. Restless
Etiology and Pathophysiology dopamine D2 receptors in the putamen,
legs syndrome is also of Restless Legs Syndrome and the degree of loss of receptors in
associated with What causes RLS? Increasing evidence RLS correlates with severity of the
abnormalities in the exists to suggest an underlying genetic disorder.12 The levels of tyrosine
dopamine system, basis for the disorder. Over 50% of hydroxylase, the rate-limiting enzyme
possibly due to patients have a family history of RLS in for dopamine synthesis, are increased
down-regulation of D2 first-degree relatives, sometimes in in the substantia nigra in RLS, presum-
receptors. three or more generations. Inheritance ably as a compensatory mechanism to
is usually autosomal dominant. Linkage reduced dopamine receptors. Similar
studies have identified multiple loci on findings of reduced putaminal D2 re-
different chromosomes associated with ceptors are seen in iron deficiency in
RLS in North American, French Canadian, rats along with increased tyrosine
and Italian populations. Genomewide hydroxylase levels in the brain.12 These
association studies have found several findings suggest a possible link between
predisposing polymorphisms in a variety intracerebral iron deficiency and RLS.
of genes. The most frequently reported Secondary causes of RLS include
in multiple populations is BTBD9 on acquired iron deficiency, chronic renal
chromosome 6p with a protein prod- failure, peripheral neuropathy, and cer-
uct widely expressed in the brain.8 tain medications. These medications
Other clues to understanding RLS include most antidepressants (with the
involve disturbances in iron and dop- probable exception of bupropion), dop-
amine function. A link between RLS and amine antagonists (neuroleptic agents
iron deficiency was recognized by Dr used to treat psychoses and antinausea
Ekbom, and studies have confirmed that medications), and possibly antihist-
low systemic iron stores are associated amines. RLS is often precipitated or ex-
with increased RLS severity. Researchers acerbated by pregnancy.
and clinicians have shown considerable
interest in the possibility that RLS Consequences of Restless
may be a disorder characterized by low Legs Syndrome
intracerebral iron.9,10 CSF ferritin levels The clinical consequences of RLS can be
are lower in patients with RLS than in severe.13 Quality-of-life studies have

KEY POINTS
consistently demonstrated low question- iron stores. Symptoms and signs of a h Restless legs syndrome
naire scores for patients with moderate possible peripheral neuropathy should has profound effects on
to severe disease, equivalent to those be elicited. Medications that can cause quality of life, equivalent
seen with other chronic diseases, such as or exacerbate RLS should be noted, to those caused by other
osteoarthritis, rheumatoid arthritis, dia- and the temporal relationship between chronic medical
betes mellitus, and cardiac failure. Sleep- the onset of RLS and their use deter- illnesses, and is
onset insomnia and sleep-maintenance mined. Serum ferritin concentration is associated with insomnia,
insomnia are reported by 50% to 85% the most sensitive measure of iron depression, and anxiety.
of patients, which results in many hours stores and should be measured in h An association may exist
awake each night. Studies have shown patients with chronic RLS. Serum ferri- between restless legs
an increased prevalence of depression tin is an acute-phase reactant, and syndrome and vascular
and anxiety in patients with RLS com- therefore concentrations may be spu- disease, but more
pared to controls. Recently, a possible riously high in the setting of acute or research is needed to
relationship between RLS and vascular chronic inflammatory disorders. Under better define the degree
and nature of the
disease has been hypothesized.14 Many those circumstances, total iron-binding
relationship before
of the cross-sectional studies per- capacity and percent saturation should
basing therapeutic
formed have methodologic flaws, and also be measured. Nonpharmacologic decisions on concern for
the few prospective studies are contra- approaches and a number of classes of vascular risk.
dictory; some, but not all, suggest a drugs are available for the treatment of
h Serum ferritin should be
higher incidence of vascular disease RLS (Table 9-3).
measured in patients
after diagnosis of RLS or periodic limb Nonpharmacologic management. If with chronic persistent
movements of sleep, but with low the serum ferritin concentration is restless legs syndrome.
odds ratios. Proposed mechanisms for below the lower limit of normal for
h Oral iron replacement
such a relationship include the effects age, sex, and the specific laboratory,
should be administered
of sleep deprivation and arousals from then a cause should be sought and iron with vitamin C if serum
periodic limb movements causing ex- supplementation prescribed. If the level ferritin levels are
cessive sympathetic stimulation. Be- is between the lower level of normal abnormally low and
cause of the uncertainty of the findings, and 50 2g/L, then iron therapy can be should be considered if
the relatively low increased risk, and considered, especially in patients who levels are low normal
the lack of interventional studies, cur- prefer natural therapies or appear resist- (G50 2/L).
rent therapeutic decisions should not ant to drug treatment, as several studies
be made based on concern about vas- have shown that levels G50 2g/L corre-
cular risk. late with RLS severity. Many iron prep-
arations, such as ferrous sulfate or
Investigation and Management ferrous gluconate, are available. Iron
of Restless Legs Syndrome should be administered apart from
The diagnosis of RLS is made clinically food, generally in two doses, with a
on history. Polysomnography (PSG) is total daily amount of elemental iron of
not routinely indicated unless an addi- 150 mg to 200 mg. Vitamin C (200 mg)
tional sleep disorder such as obstructive should be added to each dose to
sleep apnea is suspected. Although 85% enhance absorption. Serum ferritin con-
of patients with RLS will have periodic centration should be rechecked every 6
limb movements of sleep on PSG,15 months. Open-label studies of IV iron
such a finding is nonspecific, especially dextran showed some promise, but two
in older people. Secondary causes of controlled trials using iron sucrose have
RLS should be considered. A history of been negative.16,17 A recent small trial
menorrhagia, gastrointestinal hemor- of ferric carboxymaltose (currently un-
rhage, anemia, or frequent blood don- available in the United States but under
ation should prompt measurement of review by the US Food and Drug

TABLE 9-3 Selected Medications for Management of Restless Legs Syndrome
Daily Dosage
Drug and Type Indications (mg) Side Effects
Dopaminergic agents
Pramipexole Chronic-persistent restless 0.125Y0.75 Nausea, augmentation, impulse
legs syndrome (RLS)a control disorders, hypersomnia
Ropinirole Chronic-persistent RLSa 0.25Y4 Nausea, augmentation, impulse
control disorders, hypersomnia
Rotigotine patch Chronic-persistent RLSa 1Y3 Nausea, augmentation, impulse
control disorders, hypersomnia,
patch-related skin reactions
Carbidopa/levodopa Intermittent RLS 25/100 Nausea, lightheadedness,
augmentation
Calcium channel alpha-2-delta ligands
Gabapentin Chronic-persistent RLS 600Y2400 Hypersomnia, dizziness,
unsteadiness, weight gain
Gabapentin Chronic-persistent RLSa 600 Hypersomnia, dizziness,
enacarbil unsteadiness, weight gain
Pregabalin Chronic-persistent RLS 100Y300 Hypersomnia, dizziness,
unsteadiness, weight gain
Benzodiazepines
Clonazepam Intermittent or refractory 0.25Y1 Hypersomnia, unsteadiness,
RLS cognitive dysfunction
Temazepam Intermittent or refractory 7.5Y30 Hypersomnia, unsteadiness,
RLS cognitive dysfunction
Zolpidem Intermittent or refractory 5Y10 Amnestic reactions,
RLS sleepwalking or sleep eating
Opioids
Codeine Intermittent RLS 15Y60 Nausea, constipation
Tramadol Intermittent RLS 25Y100 Nausea, constipation,
augmentation, seizures
Oxycodone Refractory RLS 10Y20 Nausea, constipation,
hypersomnia, cognitive
dysfunction, unsteadiness,
itch, sleep apnea
Methadone Refractory RLS 5Y15 Nausea, constipation,
hypersomnia, cognitive
dysfunction, unsteadiness,
itch, sleep apnea
a
US Food and Drug Administration-approved for RLS.
Administration [FDA]) showed modest tion state or complete intolerance to

but significant benefit in reducing RLS oral iron preparations. Iron gluconate
severity.18 At present IV iron therapy or iron sucrose should be used, as iron
should be restricted to patients with dextran carries a risk of anaphylactic
low iron stores and either a malabsorp- reactions.

KEY POINTS
Other preventive nonpharmacologic by more serious side effects, such as h Nonergot dopamine
approaches that can be considered augmentation, impulse control disor- agonists (ropinirole,
include practicing regular moderate ders, and daytime sleepiness. pramipexole, and
exercise; reducing caffeine, alcohol, or Augmentation, as illustrated by rotigotine transdermal
nicotine use; and considering with- Case 9-1, is the development of wor- patch) are highly
drawal of predisposing medications. sening RLS progressively earlier in the effective treatments for
For management of the symptoms, tech- day after administration of dopaminer- restless legs syndrome
niques such as walking, bicycling, mas- gic medication in the afternoon or but are associated
saging, or soaking the affected limbs, or evening.19 It may take the form of ear- with augmentation
practicing mind-alerting techniques (eg, lier onset of symptoms, worsening of (worsening of restless
legs syndrome earlier
working on a computer or doing a preexisting symptoms, or spread of
in the day), impulse
crossword puzzle) can be helpful. Useful symptoms to the arms. In one study, control disorders, and
patient information can be found on the augmentation developed in at least 42% hypersomnia.
websites of the RLS Foundation (rls.org), of patients treated with pramipexole
the American Academy of Sleep Medi- h Impulse control
who were followed for a median of 9.7
disorders, including
cine ( yoursleep.aasmnet.org), and the years,20 and other studies have shown pathologic gambling
American Academy of Neurologys similar frequencies.21 Initially augmen- and compulsive
patient magazine NeurologyNow tation from dopamine agonists can be shopping, occur in 6%
(neurologynow.com). managed by adding a supplementary to 17% of patients
Dopaminergic agents. The nonergot dose of medication earlier in the day, taking dopamine
dopaminergic agonists pramipexole, but in many patients worsening aug- agonists for restless legs
ropinirole, and rotigotine are approved mentation will eventually develop, ne- syndrome and may only
by the FDA for the treatment of RLS. cessitating discontinuation of the drug. manifest 9 months or
Extensive controlled trials have demon- Impulse control disorders (ICD) longer after starting
strated their effectiveness. It is impor- include pathologic gambling, compul- treatment.
tant to understand that the milligram sive shopping, and hypersexuality. A
equivalents of pramipexole and ropinir- case-control study showed a frequency
ole are different: ropinirole doses of 17% in patients with RLS treated with
should be approximately 4 times higher dopamine agonists,22 whereas other
than those of pramipexole. Doses used studies have shown frequencies be-
are considerably lower than those used tween 6% and 12%.23Y25 Serious finan-
in Parkinson disease (maximum ap- cial, social, and legal consequences of
proved doses for RLS are 0.75 mg for these disorders can occur. All patients
pramipexole and 4 mg for ropinirole). treated with these agents should be
Generally treatment should be started warned of their risks, and these warnings
with 0.125 mg pramipexole or 0.25 mg should be repeated at each subsequent
to 0.5 mg ropinirole about 2 hours visit as the mean time from starting
before symptoms start and increased the medication to onset of an ICD is
every few days until relief is obtained. 9 months.22 In almost every case,
Some patients will require a dose of however, the ICD resolves promptly
medication in the afternoon as well as after discontinuing the drug. Excessive
the evening. Rotigotine is supplied as a daytime sleepiness develops in about
once daily transdermal patch with doses 50% of patients, and sleep attacks have
of 1 mg to 3 mg. Lightheadedness, nau- been reported in about 10%, especially
sea, nasal congestion, and leg edema when taking higher doses.20
may occur with any dopamine agonist, Levodopa in combination with a dopa
and rotigotine may result in skin irrita- decarboxylase inhibitor such as carbi-
tion under the patch. However, long- dopa is very effective in relieving RLS;
term use of these drugs is often limited however, an augmentation rate of up to

KEY POINT
h Calcium channel
alpha-2-delta ligands
Case 9-1
A 45-year-old woman had restless legs syndrome (RLS) for 6 years. At the
(gabapentin, pregabalin,
time of first presentation her symptoms were present nightly, delaying
and gabapentin
sleep onset by 1 to 2 hours. Serum ferritin was 65 2g/L. She was prescribed
enacarbil) are all effective
pramipexole, which relieved restless legs at a dose of 0.5 mg taken at
in restless legs syndrome
8:00 PM. About a year later, RLS recurred in the evening after 7:00 PM, and
but can cause dizziness,
an additional 0.25 mg pramipexole was prescribed at 6:00 PM. Over the
unsteadiness,
next 5 years, RLS began intruding daily from 1:00 PM onward whenever she
hypersomnia, and
sat down, and over the past 6 months also began waking her at 1:00 AM.
weight gain.
Restlessness developed in her arms at the same time as her legs. Her
dose of pramipexole had been increased to 0.5 mg 4 times a day at noon,
6:00 PM, 8:00 PM, and 11:00 PM. She became excessively sleepy in the
afternoon and evening, dozing while driving home from work and while
watching TV or talking to her husband after dinner. Pregabalin was
added in increasing doses, and pramipexole was withdrawn over a week.
Initially her symptoms worsened during the transition, but within 2 weeks
they had all resolved on a pregabalin dose of 100 mg 3 times a day. Her
sleepiness improved.
Comment. This patients history illustrates some of the difficulties using
long-term dopamine agonists. The patient developed typical augmentation
with the symptoms moving earlier in the day and spreading to the arms.
As more frequent doses of medication were added progressively earlier in the
day, her symptoms worsened, and she developed daytime sleepiness. Under
these circumstances, the dopamine agonist medication should be slowly
withdrawn, and a calcium channel alpha-2-delta ligand, such as gabapentin,
gabapentin enacarbil, or pregabalin, substituted. If these are ineffective,
an opioid may be needed.
80%26 limits its use, and it should only hypersomnia, dizziness, unsteadiness,
be prescribed for occasional use with weight gain, and edema. Augmentation
intermittent RLS. has not been reported.
Calcium channel alpha-2-delta Opioids. Opioid medication is highly
ligands. The drugs gabapentin,27 pre- effective in RLS. Low- to intermediate-
gabalin,28 and gabapentin enacarbil (a potency drugs, such as codeine, may be
gabapentin prodrug) have all been useful in intermittent RLS, whereas
shown to be effective in the manage- high-potency agents may be needed in
ment of RLS,29 but only gabapentin RLS refractory to other medications.
enacarbil has been approved by the Oxycodone, hydrocodone, and metha-
FDA for this purpose. The mechanism done have been used successfully.
of action in RLS has not been clearly Tramadol is the only opioid agent in
established. The mean effective total which augmentation has been reported,
daily dose of gabapentin is 1800 mg and and it carries a slight risk of seizures. A
pregabalin 300 mg. Doses should be long-term follow-up study of 76 patients
slowly increased based on effectiveness using methadone for RLS showed a
and patient tolerance. They can be ad- discontinuation rate of 15% in the first
ministered 1 to 3 times a day, depend- year and then continued efficacy with-
ing on the time of RLS symptoms. out development of tolerance for the
Gabapentin enacarbil is administered remainder over 10 years.21 Usual doses
in a dose of 600 mg once daily in the needed are approximately 10 mg to
late afternoon. Class side effects include 20 mg for oxycodone and 5 mg to

KEY POINT
h High-potency opioids,
such as oxycodone,
hydrocodone, and
methadone, are highly
effective for refractory
restless legs syndrome
but are addictive and
may exacerbate sleep
apnea. In most patients
they can be used for
prolonged periods with
no tolerance and
continued effectiveness.
FIGURE 9-1 A 60-second polysomnography fragment showing four periodic limb movements of
sleep associated with arousals.
30
Reprinted from Krahn LE, et al, Informa Healthcare. B 2011, with permission from Informa Healthcare.
15 mg for methadone. Side effects dem, may induce amnestic reactions

include itch (due to mast cell degranu- and episodes of walking, eating, and
lation and not allergy), nausea, constipa- occasionally driving while asleep.
tion, sleepiness, cognitive impairment, Practical approach to treatment. A
and gait unsteadiness. Obstructive sleep practical approach to RLS management
apnea can be exacerbated, and central is based on dividing the disorder into
sleep apnea can develop. The risk of three categories: intermittent, chronic-
dependance must be considered. persistent, and refractory. Intermittent
Benzodiazepines and benzodiaze- RLS occurs less than twice a week,
pine agonists. Clonazepam was among whereas chronic-persistent RLS occurs
the earliest drugs reported to be suc- at least twice a week and causes suf-
cessful in treating RLS; however, few ficient distress to warrant daily preven-
clinical trials of benzodiazepine and tive therapy. Refractory RLS is RLS
benzodiazepine agonist agents have treated with a dopamine agonist and
been conducted, and it seems likely an alpha-2-delta ligand with inadequate
they work by inducing sleep rather than response or intolerable side effects.
by specifically targeting the symptoms Intermittent RLS can be treated with
of RLS. They may be helpful in patients nonpharmacologic measures or inter-
with intermittent RLS at night, especially mittent use of levodopa, codeine, or a
if insomnia disorder is also present, and benzodiazepine. Chronic-persistent RLS
they may be used to supplement other should be treated with either a dopa-
agents in refractory RLS. The longer- mine agonist or a calcium channel
acting agents, such as clonazepam and calcium channel alpha-2-delta ligand. If
temazepam, may induce sleepiness, the drug chosen is ineffective or its use
unsteadiness at night in the elderly, is limited by side effects, an agent of the
cognitive symptoms, and potential other class should be tried. Iron status
dependance. The newer shorter-acting should be checked. For refractory RLS,
benzodiazepine agonists, such as zolpi- other agents in the dopamine agonist or

calcium channel alpha-2-delta agonist leg movements separated by 5 to 90

class can be considered, as well as the seconds between onsets of successive
addition of a benzodiazepine at night; movements must occur in succession
however, most patients at this stage of to be scored as PLMS (Figure 9-1).30 Leg
the disorder will require long-term movements associated with arousals
opioid therapy. from respiratory events during sleep are
excluded. PLMS occur more in the first
PERIODIC LIMB MOVEMENT half of the night than the second and
DISORDER usually do not persist into REM sleep.
Periodic limb movements of sleep The significance of PLMS has been
(PLMS), originally called nocturnal myo- debated ever since the movements were
clonus, were first described almost 50 first identified. It is known that PLMS
years ago. Bed partners notice rhythmic occur in 80% to 88% of patients with
jerking of the legs during sleep with the RLS,15 but most patients with PLMS on
sleeper generally unaware of the motor a PSG do not have RLS. PLMS are
activity. Formal PSG criteria were first common in patients with obstructive
suggested in 1980 and have since been sleep apnea. They are found in 80% of
refined. A periodic limb movement patients with narcolepsy and 71% of
(PLM) lasts 0.5 to 10 seconds with min- patients with REM sleep behavior dis-
imum amplitude of 8-2V increase in order.15 They occur more frequently in
anterior tibial surface EMG voltage Parkinson disease than in controls.31
above the resting EMG.4 At least four The prevalence of PLMS increases with
Case 9-2
A 54-year-old woman presented with problems sleeping during the past
3 years. She initiated sleep without difficulty at 11:00 PM but awoke 4 to
5 times during the night for uncertain reasons. Once awake she had
difficulty returning to sleep, sometimes lying awake for up to an hour.
During this time she thought about the next days activities and worried
about not being able to sleep. She woke with an alarm at 6:45 AM feeling
unrefreshed. Her husband described regular leg kicking throughout the
night without arm movements or vocalization, but she was unaware of the
movements. She denied any discomfort in her legs or any urge to move
while lying in bed or sitting in a chair. During the day she felt fatigued but
did not fall asleep inappropriately. She denied symptoms of depression but
felt mildly anxious. A polysomnogram showed a respiratory disturbance
index of 4 per hour and a periodic limb movement index of 26 per hour,
14 of which were associated with arousals. Sleep efficiency was 69% because
of 2 hours wake time after sleep onset. A diagnosis of psychophysiologic
insomnia was made, and cognitive behavioral therapy for insomnia was
instituted. Over the next few months her sleep maintenance problems
markedly improved.
Comment. This case history illustrates how periodic limb movements of
sleep are often an epiphenomenon related to other sleep disturbances
rather than their cause. This patient did not have restless legs, and her
primary complaint was remaining awake for prolonged periods during the
night. Her symptoms responded to treatment for psychophysiologic
insomnia. Institution of medication to treat her periodic limb movements
would have been inappropriate.

KEY POINTS
h Periodic limb movements
of sleep occur in 80%
to 88% of patients with
restless legs syndrome
and are also frequent in
narcolepsy, REM sleep
behavior disorder,
obstructive sleep apnea,
and normal people
60 years of age or older.
h In the absence of
restless legs syndrome,
periodic limb movements
of sleep are generally
nonspecific
epiphenomena that
accompany fragmented
FIGURE 9-2 A 30-second polysomnography fragment showing typical EMG activity at about 1 Hz sleep with arousals and
in the electrooculogram and EEG derivations typical of the masseter contractions only rarely require
of bruxism.
30 treatment as a specific
disorder.
age. A study of 100 normal subjects the leg movement in 49.2%, simulta-
found that no subjects aged below 30 neous with the leg movement in 30.6%,
years, 5.2% of subjects aged 30 to 49 and after the leg movement in 23.2%.38
years, and 29.0% of subjects aged more Treatment of PLMS with levodopa elim-
than 49 years had 30 or more PLMS inates the movements, but the arousals
over the course of a night.32 Studies of persist.39 Transient increases in heart
community-dwelling subjects aged 60 rate and blood pressure40Y42 can occur
years or older have found that 45% to in association with PLMS, even when
58% had five or more PLMS per unaccompanied by EEG arousals, but
hour.33,34 The nonspecific nature of the changes in heart rate and blood
the movements, occurring in associa- pressure often precede the onset of the
tion with a wide range of other disor- leg movement. These findings suggest
ders as well as in normal older people, that PLMS may be a response to non-
raises questions as to whether they specific arousals rather than their cause.
have any clinical significance of their This is illustrated by Case 9-2.
own or are simply an epiphenomenon As a result of these considerations,
of other disorders. the entity of periodic limb movement
No definite relationship has been disorder (PLMD), as opposed to the PSG
detected between the presence of PLMS finding of PLMS, is strictly defined.4 In
and symptoms of insomnia or hyper- order for a diagnosis of PLMD to be
somnia. Similarly, no association has made, PLMS must be present on PSG at
been found between PLMS and PSG a frequency of more than 5 per hour in
measures such as total sleep time, wake children and more than 15 per hour in
time after sleep onset, arousal index, and most adults. In addition, a clinical sleep
sleep efficiency.35Y37 In a study of 3916 disturbance or complaint of daytime fa-
EEG arousals associated with PLMS in tigue attributable to PLMS must be
10 patients, the arousal occurred before present and not better explained by

KEY POINT
h Sleep-related bruxism
occurs in 8% of
people, with highest
prevalence in young
adults. It can cause
tooth damage and jaw
discomfort but does not
usually result in
disrupted sleep.
FIGURE 9-3 Polysomnography fragment showing the typical movement artifact in the EEG and
respiratory channels at about 1.5 Hz typical of rhythmic movement disorder.
30
any other current sleep, medical, neuro- very typical, but audiovisual recordings
logic, mental, or substance use disorder are needed to definitively identify the
or the use of medications. A diagnosis phenomenon (Supplemental Digital
of PLMD is thus not used for RLS with Content 9-2, links.lww.com/CONT/
PLMS, and considerable caution should A21). Bruxism is seen most frequently
be exercised in diagnosing PLMD in the in light non-REM (NREM) sleep but may
setting of sleep apnea or narcolepsy. occur in any stage. It occurs in about 8%
When defined in this way, PLMD is a of people with prevalence highest in
rare disorder. young adults and falling with age.43
The optimal treatment of PLMD is Consequences of bruxism must be pre-
uncertain. Extrapolating from RLS, dop- sent before it is considered a disorder.
aminergic agonists may be the drugs of These include damage to the teeth, jaw
choice, and a sustained improvement discomfort, fatigue or pain or temporal
in insomnia or hypersomnia with the headaches on wakening. Rarely mass-
use of dopaminergic agonists can help eter or temporalis muscle hypertrophy
establish the correctness of the diagno- can ensue.
sis. No controlled clinical trials of any Apart from the physical effects
agents for pure PLMD have been re- described, there is little evidence for
ported, however, beyond single night other adverse consequences of bruxism.
studies. PSG studies have not demonstrated any
significant effects on total sleep time,
SLEEP-RELATED BRUXISM wake time after sleep onset, sleep
In sleep-related bruxism (ie, tooth grind- efficiency, sleep latency, or arousals.
ing or clenching), tonic contraction of Subjectively, bruxism has been associ-
the masseter muscles lasting at least 2 ated with perception of disrupted sleep,
seconds, or trains of rhythmic masseter but the abnormal movements may be
contraction at about 1 Hz are observed the result of sleep fragmentation rather
(Figure 9-2).30 The PSG appearance is than the cause. EEG alpha activity and

KEY POINTS
heart rate increase before the onset of movements start in drowsiness and then h Rhythmic movement
bruxism,44 and the movements are persist into light sleep. Patients with disorder, including head
frequently seen on PSG following RMD often have sleep-onset insomnia, banging and body
arousals from obstructive apneas. Ther- but it is not clear that sleep difficulties rocking, is common in
apy generally involves the use of oral are induced by the movements rather infancy and early
appliances to protect the teeth rather than accompany them. Generally RMD childhood but may
than medications aimed specifically at only requires specific treatment if risk of persist into adulthood.
eliminating the jaw contractions. bodily injury or severe disruption to the h Insomnia accompanying
sleep of a bed partner exists, but insom- rhythmic movement
RHYTHMIC MOVEMENT nia may need to be independently disorder should be
DISORDER managed. In young children, protective treated, but specific
The movements of rhythmic movement head gear or padding of cribs may treatment for the
disorder (RMD) consist of stereotyped prevent injuries from violent head move- movements is only
contractions of large muscle groups at 0.5 ments. No clinical trials of medications needed if risk of bodily
injury or severe
Hz to 2 Hz during drowsiness or sleep45 for RMD have been reported, although
disruption to sleep of a
(Figure 9-330; Supplemental Digital the use of benzodiazepines such as
bed partner exists.
Content 9-3, links.lww.com/CONT/ clonazepam has been suggested.
A22). They are most frequent in light h Nocturnal leg cramps are
SLEEP-RELATED LEG CRAMPS usually idiopathic, and
NREM sleep but may sometimes be
treatment is difficult;
seen during REM sleep. The head or Leg cramps are painful contractions of
quinine should generally
trunk may rock from side to side or muscles of the leg or foot with resultant not be used because of
back to front, and occasionally the legs tightness or hardness. They occur most serious potential side
may flex and extend. Subtypes, such as frequently at night, waking the patient effects, including
head banging (Supplemental Digital from sleep. They are generally helped by thrombocytopenia and
Content 9-4, links.lww.com/CONT/ stretching the affected muscle, often by cardiac arrhythmias.
A23; Supplemental Digital Content 9- standing. Most cramps are idiopathic,
5, links.lww.com/CONT/A24) and body but they may occur in the setting of
rocking (Supplemental Digital Content neuromuscular disorders such as radicu-
9-6, links.lww.com/CONT/A25), have lopathies, myopathies, ALS, and disor-
been named but no evidence exists to ders of neuromuscular hyperexcitability
suggest that the different phenotypes such as Isaac syndrome. Hypocalcemia
have any specific significance. In order and other electrolyte disorders are rare
for the movements to be classified as a causes. Nocturnal leg cramps are com-
disorder, they must cause interference mon and, when frequent, can result in
with normal sleep, impairment in day- sleep maintenance insomnia.
time functioning, or bodily injury. RMD Treatment of leg cramps is difficult.46
is common in infancy and early child- Quinine is probably effective, but the
hood (Supplemental Digital Content benefits are modest (about 20% to 25%
9-7, links.lww.com/CONT/A26) but can reduction in number of cramps). It
persist into adulthood (Supplemental should not be used in most cases
Digital Content 9-8, links.lww.com/ because the risk of severe side effects
CONT/A27). Intellectually handicapped (including thrombocytopenia and car-
children may be especially prone to diac arrhythmias) outweigh the poten-
injury from RMD. tial benefits. Diltiazem may be effective,
The nature of RMD is controversial. although supporting data are limited.
Patients frequently explain that they No evidence indicates that magnesium
have used the soothing and rhythmic is helpful. Anticonvulsants, such as
nature of the movements to induce gabapentin or levetiracetam, have not
sleep from childhood, and often the been adequately assessed.

VIDEO LEGENDS Supplemental Digital Content 9-5

Supplemental Digital Content 9-1 Rhythmic movement disorder. Video dem-
Restless legs syndrome with obstructive sleep onstrates head banging in an adult.
apnea. Video demonstrates restless legs syndrome links.lww.com/CONT/A24
(RLS) in a 72-year-old man. Note the severe kicking B 2013 Sona Nevsmalova, MD, DSc. Used with
of the legs against one another. Polysomnography permission.
is not required for the diagnosis of RLS in adults
but may be useful if other comorbidities are Supplemental Digital Content 9-6
thought to exacerbate the condition. This patient Rhythmic movement disorder. Video demon-
presented with RLS symptoms and apneic spells strates body rocking in an adult leading to 1 Hz to
and was subsequently diagnosed and treated for 2 Hz movement artifact in the polysomnogram.
obstructive sleep apnea, which resulted in some Body rocking is a sleep-related rhythmic move-
improvement of his RLS symptoms. The patients ment disorder that interferes with normal sleep
RLS symptoms did not respond to traditional and can result in self-inflicted bodily injury.
first-line agents (dopamine agonists and gaba- links.lww.com/CONT/A25
pentin enacarbil) but responded well to opioid B 2013 Geert Mayer, MD, PhD. Used with
therapy, which resulted in some improvement. permission.
B 2013 Alon Y. Avidan, MD, MPH, FAASM. Used Supplemental Digital Content 9-7
with permission. Rhythmic movement disorder. Video demonstrates
rhythmic stereotyped body rocking in a child.
Supplemental Digital Content 9-2 Rhythmic movement disorders usually begin in
Catathrenia and bruxism. Catathrenia (ie, sleep- the first year of life and spontaneously remit by
related groaning) consists of sleep-related respi- 4 years of age.
ratory noises that occur predominantly during links.lww.com/CONT/A26
REM sleep. The typical respiratory noise in a B 2013 Sona Nevsmalova, MD, DSc. Used with
patient with catathrenia has an expiratory quality permission.
and responds well to therapy with continuous
positive airway pressure, which suggests that Supplemental Digital Content 9-8
catathrenia may result from upper airway restric- Rhythmic movement disorder. Video demon-
tion. Between events, the patient in this video strates head rocking movements in a 55-year-old
also exhibits bruxism (ie, grinding of the teeth), woman with severe pulmonary sarcoidosis who
which is a movement disorder of sleep and may was also diagnosed with obstructive sleep apnea
also represent an oral parafunctional activity. and referred for a continuous positive airway
links.lww.com/CONT/A21 pressure titration. During the study she was dis-
B 2013 Sona Nevsmalova, MD, DSc. Used with covered to have these head rocking movements
permission. that arose out of N1 sleep. The results of her
neurologic workup were normal. On subsequent
Supplemental Digital Content 9-3 history she mentioned that she has always
Rhythmic movement disorder. Video demon- rocked herself to sleep.
strates the often-stereotyped rhythmic move- links.lww.com/CONT/A27
ment of body rocking in a child. Body rocking B 2013 Hrayr Attarian, MD, FAASM, FCCP. Used
tends to have a frequency of 1 Hz to 3 Hz and with permission.
creates noise that sometimes awakens family
members or bed partners. REFERENCES
links.lww.com/CONT/A22 1. Ekbom KA. Restless legs. Stockholm,
B 2013 Sona Nevsmalova, MD, DSc. Used with Sweden: Ivar Hoeggstroms; 1945.
permission.
2. Allen R, Bharmal M, Calloway M. Prevalence
Supplemental Digital Content 9-4 and disease burden of primary restless legs
syndrome: results of a general population
Rhythmic movement disorder. Video demon- survey in the United States. Mov Disord
strates head banging in a child. Head banging 2011;26(1):114Y120.
consists of stereotyped and repetitive rhythmic
3. Allen RP, Stillman P, Myers AJ.
movements of the head that occur during wake-
Physician-diagnosed restless legs syndrome
to-sleep transitions and wakefulness. in a large sample of primary medical care
links.lww.com/CONT/A23 patients in western Europe: prevalence and
B 2013 Rama Maganti, MD. Used with permission. characteristics. Sleep Med 2010;11(1):31Y37.

4. American Academy of Sleep Medicine. standard criteria. Mov Disord 1997;12(1):
International classification of sleep 61Y65.
disorders: diagnostic and coding manual.
16. Earley CJ, Horska A, Mohamed MA, et al.
2nd ed. Westchester, IL: American Academy
A randomized, double-blind,
of Sleep Medicine, 2005.
placebo-controlled trial of intravenous iron
5. Allen RP, Picchietti D, Hening WA, et al. sucrose in restless legs syndrome. Sleep Med
Restless legs syndrome: diagnostic criteria, 2009;10(2):206Y211.
special considerations, and epidemiology. A
17. Grote L, Leissner L, Hedner J, Ulfberg J. A
report from the restless legs syndrome
randomized, double-blind, placebo
diagnosis and epidemiology workshop at
controlled, multi-center study of intravenous
the National Institutes of Health. Sleep Med
iron sucrose and placebo in the treatment
2003;4(2):101Y119.
of restless legs syndrome. Mov Disord 2009;
6. Hening WA, Allen RP, Washburn M, et al. 24(10):1445Y1452.
The four diagnostic criteria for restless legs
18. Allen RP, Adler CH, Du W, et al. Clinical
syndrome are unable to exclude
efficacy and safety of IV ferric
confounding conditions (mimics). Sleep
carboxymaltose (FCM) treatment of RLS: a
Med 2009;10(9):976Y981.
multi-centred, placebo-controlled
7. Allen RP, Burchell BJ, MacDonald B, et al. preliminary clinical trial. Sleep Med 2011;
Validation of the self-completed 12(9):906Y913.
Cambridge-Hopkins questionnaire (CH-RLSq)
19. Garca-Borreguero D, Williams A.
for ascertainment of restless legs syndrome
Dopaminergic augmentation of restless legs
(RLS) in a population survey. Sleep Med
syndrome. Sleep Med Rev 2010;14(5):339Y346.
2009;10(10):1097Y1100.
20. Lipford MC, Silber MH. Long-term use of
8. Trenkwalder C, Hogl B, Winkelmann J.
pramipexole in the mangement of restless
Recent advances in the diagnosis, genetics
legs syndrome. Sleep 2011;34:A202.
and treatment of restless legs syndrome.
J Neurol 2009;256(4):539Y553. 21. Silver N, Allen RP, Senerth J, Earley CJ. A
10-year, longitudinal assessment of
9. Connor JR, Boyer PJ, Menzies SL, et al.
dopamine agonists and methadone in the
Neuropathological examination suggests
treatment of restless legs syndrome. Sleep
impaired brain iron acquisition in restless legs
Med 2011;12(5):440Y444.
syndrome. Neurology 2003;61(3):304Y309.
22. Cornelius JR, Tippmann-Peikert M, Slocumb
10. Schmidauer C, Sojer M, Seppi K, et al.
NL, et al. Impulse control disorders with the
Transcranial ultrasound shows nigral
use of dopaminergic agents in restless legs
hypoechogenicity in restless legs syndrome.
syndrome: a case-control study. Sleep
Ann Neurol 2005;58(4):630Y634.
2010;33(1):81Y87.
11. Connor JR, Ponnuru P, Wang X-S, et al.
Profile of altered brain iron acquisition in 23. Ondo WG, Lai D. Predictors of impulsivity
restless legs syndrome. Brain 2011;134(pt 4): and reward seeking behavior with
959Y968. dopamine agonists. Parkinsonism Relat
Disord 2008;14(1):28Y32.
12. Connor JR, Wang X-S, Allen RP, et al.
Altered dopaminergic profile in the putamen 24. Pourcher E, Remillard S, Cohen H.
and substantia nigra in restless leg syndrome. Compulsive habits in restless legs syndrome
Brain 2009;132(pt 9):2403Y2412. patients under dopaminergic treatment.
J Neurol Sci 2010;290(1Y2):52Y56.
13. Earley C, Silber MH. Restless legs syndrome:
understanding its consequences and the 25. Voon V, Schoerling A, Wenzel S, et al.
need for better treatment. Sleep Med Frequency of impulse control behaviours
2010;11(9):807Y815. associated with dopaminergic therapy in
restless legs syndrome. BMC Neurol 2011;
14. Innes KE, Selfe TK, Agarwal P. Restless legs
11:117.
syndrome and conditions associated with
metabolic dysregulation, sympathoadrenal 26. Hogl B, Garcia-Borreguero D, Kohnen R,
dysfunction, and cardiovascular disease risk: et al. Progressive development of
a systematic review. Sleep Med Rev 2012; augmentation during long-term treatment
16(4):309Y339. with levodopa in restless legs syndrome:
results of a prospective multi-center study.
15. Montplaisir J, Boucher S, Poirier G, et al.
J Neurol 2010;257(2):230Y237.
Clinical, polysomnographic, and genetic
characteristics of restless legs syndrome: a 27. Garcia-Borreguero D, Larrosa E, De la Llave Y,
study of 133 patients diagnosed with new et al. Treatment of restless legs syndrome

with gabapentin: a double-blind, cross-over 37. Carrier J, Frenette S, Montplaisir J, et al.

study. Neurology 2002;59(10):1573Y1579. Effects of periodic leg movements during
sleep in middle-aged subjects without
28. Garcia-Borreguero D, Larrosa O, Williams
sleep complaints. Mov Disord 2005;20(9):
AM, et al. Treatment of restless legs
1127Y1132.
syndrome with pregabalin: a double-blind,
placebo-controlled study. Neurology 2010; 38. Karadeniz D, Ondze B, Besset A, Billiard M.
74(23):1897Y1904. EEG arousals and awakenings in relation
with periodic leg movements during sleep.
29. Lee DO, Ziman RB, Perkins AT, et al.
J Sleep Res 2000;9(3):273Y277.
A randomized, double-blind,
placebo-controlled study to assess the 39. Montplaisir J, Boucher S, Gosselin A, et al.
efficacy and tolerability of gabapentin Persistence of repetitive EEG arousals
enacarbil in subjects with restless legs (K-alpha complexes) in RLS patients treated
syndrome. J Clin Sleep Med 2011;7(3):282Y292. with L-dopa. Sleep 1996;19(3):196Y199.
30. Silber MH. Movement disorders and 40. Pennestri MH, Montplaisir J, Colombo R,
parasomnias. In: Krahn LE, Silber MH, et al. Nocturnal blood pressure changes in
Morgenthaler TI, eds. Atlas of sleep patients with restless legs syndrome.
medicine. London, UK: Informa Healthcare; Neurology 2007;68(15):1213Y1218.
2011:117Y130.
41. Siddiqui F, Strus J, Ming X, et al.
31. Wetter TC, Collado-Seidel V, Pollmacher T, Rise of blood pressure with periodic
et al. Sleep and periodic leg movement limb movements in sleep and wakefulness.
patterns in drug-free patients with Clin Neurophysiol 2007;118(9):1923Y1930.
Parkinsons disease and multiple system
42. Winkelman JW. The evoked heart rate
atrophy. Sleep 2000;23(3):361Y367.
response to periodic leg movements of
32. Bixler EO. Nocturnal myoclonus and sleep. Sleep 1999;22(5):575Y580.
nocturnal myoclonic activity in the normal
43. Lavigne GJ, Montplaisir JY. Restless legs
population. Res Commun Chem Pathol
syndrome and sleep bruxism: prevalence
Pharmacol 1982;36(1):129Y140.
and association among Canadians. Sleep
33. Ancoli-Israel S, Kripke DF, Klauber MR, et al. 1994;17(8):739Y743.
Periodic limb movements in sleep in
44. Huynh N, Kato T, Rompre PH, et al. Sleep
community-dwelling elderly. Sleep 1991;
bruxism is associated to micro-arousals and
14(6):496Y500.
an increase in cardiac sympathetic activity.
34. Dickel MJ, Mosko SS. Morbidity cut-offs for J Sleep Res 2006;15(3):339Y346.
sleep apnea and periodic leg movements in
45. Vetrugno R, Montagna P. Sleep-to-wake
predicting subjective complaints in seniors.
transition movement disorders. Sleep Med
Sleep 1990;13(2):155Y166.
2011;12(suppl 2):S11YS16.
35. Mendelson W. Are periodic limb movements
46. Katzberg HD, Khan AH, So YT. Assessment:
associated with clinical sleep disturbance?
symptomatic treatment for muscle cramps
Sleep 1996;19(3):219Y223.
(an evidence-based review): report of the
36. Youngstedt SW, Kripke DF, Klauber MR, therapeutics and technology assessment
et al. Periodic leg movements during sleep subcommittee of the American Academy
and sleep disturbances in elders. J Gerontol of Neurology. Neurology 2010;74(8):
A Biol Sci Med Sci 1998;53(5):M391YM394. 691Y696.

Review Article
Sleep Disorders in
Dr Timothy F. Hoban, L3221
Womens Hospital, 1500 East
Medical Center Dr, SPC 5203,
Children Ann Arbor, MI 48109-5203,

thoban@umich.edu.
Timothy F. Hoban, MD Dr Hoban has performed
medicolegal review of
pediatric neurology-related
cases.
Unlabeled Use of
ABSTRACT Products/Investigational
Purpose of Review: The purpose of this review is to examine how sleep disorders in Use Disclosure: Dr Hoban
discusses the use of
children are affected by age and comorbid medical influences, and to discuss current treatments for sleep apnea in
understanding of how the clinical manifestations, pathophysiology, and treatment of children, including nasal
common childhood sleep disorders differ from those of the adult population. steroids and maxillary
expansion devices,
Recent Findings: Recently established age-specific norms are required for accurate which are unlabeled.
interpretation of polysomnograms and multiple sleep latency tests in children. * 2013, American Academy
Summary: Sleep disorders such as insomnia, obstructive sleep apnea, and excessive of Neurology.
daytime somnolence are common in both children and adults, but the clinical mani-
festations and underlying pathophysiology of these disorders vary substantially with
age. For example, the bedtime struggles of a temperamental toddler are associated
with different symptoms and causative factors compared to psychophysiologic
insomnia affecting a middle-aged person. Similarly, a 6-year-old child with obstructive
sleep apnea is more likely to exhibit daytime inattention and hyperactivity as a referable
daytime symptom than the clear-cut lethargy or sleepiness that most affected adults
experience. This review will examine how insomnia, excessive sleepiness, and ob-
structive sleep apnea differ in children compared to adults.
SLEEPLESSNESS IN INFANTS comes longer and more continuous

AND YOUNGER CHILDREN and daytime napping diminishes via a
Determining whether night waking in process called settling. Although most
an infant or young child represents a infants settle during the first year of
clinically significant problem sometimes life, about 10% do not achieve con-
requires careful comparison of the childs solidated nighttime sleep by the age of
sleep patterns and sleep duration to 12 months.2 Brief waking, up to several
highly variable and age-dependent nor- times nightly, persists as a normal
mative data (Figure 10-1).1 Most new- phenomenon for many toddlers with-
borns and younger infants initially sleep out clinical sleep problems, usually at a Supplemental digital content:
in brief 2- to 4-hour periods equally dis- level not noticed by parents and care- ticle are cited in the text as
tributed across the daytime and night- givers.3 Night waking is considered Supplemental Digital Content.
time hours and affected by the need for abnormal when it is disproportionately clicking on links provided in
frequent feedings during early infancy. frequent, prolonged, or disruptive for the HTML, PDF, and iPad
As a result, frequent night waking is the persons age. Problematic night wak- URLs are provided in the print
considered entirely normal for younger ing is estimated to affect 20% of infants version. Video legends begin
infants. and toddlers.4 on page 196.
As circadian regulatory mechanisms Night waking in infants and younger

grow stronger and become entrained to children is frequently associated with
recurring behavioral and environmental bedtime struggles, which may take the
cues, nighttime sleep gradually be- form of crying in infants, tantrums or

Sleep Disorders in Children
FIGURE 10-1 Percentiles for total nighttime (A) and daytime (B) sleep duration during childhood.
Reprinted with permission from Iglowstein I, et al, Pediatrics.1 B 2003, by the AAP. pediatrics.aappublications.org/content/111/2/
302.abstract?sid=8cea3a74-5f1c-4356-9d03-57d1cf604c90.
KEY POINTS curtain calls in toddlers, and other including anxiety, lack of sleepiness, a
h The symptoms, forms of bedtime resistance that vary desire to engage the parent, or delib-
pathophysiology, and with age (Case 10-1). Problematic erate effort to forestall sleep onset.
treatments for some
behaviors at bedtime may reflect a Although bedtime struggles may occur
sleep disorders are
variety of underlying influences, on an occasional basis in healthy
substantially different
for children compared
to adults.
Case 10-1
h Ten percent of children A 12-month-old infant was referred by his pediatrician for evaluation of
do not achieve long-standing difficulties settling to sleep at bedtime, associated with
consolidated nighttime frequent night waking. The childs mother reported that he had always
sleep by 1 year of age. had difficulty settling to sleep unless she was with him. On most nights, he
would fall asleep near 9:00 PM while being held by his mother, who was
usually watching television. Although he would initially remain asleep
upon being transferred to his crib, on most nights he would awaken
2 hours after sleep onset, crying, fully awake, and difficult to console. He
would return to sleep after 30 to 60 minutes only if held by his mother
until asleep. Night waking of similar duration and character would recur
during the remainder of the night at intervals of about 90 minutes until
morning waking at or before 7:00 AM. The mother reported similar
difficulties and circumstances settling her son for his 90-minute midday
nap. The familys attempts to let the child settle to sleep alone were
unsuccessful, as he would cry unabated until picked up and held, typically
after 20 to 40 minutes.
No obstructive symptoms or restlessness was reported during nighttime
sleep, but daytime irritability was consistently observed when night waking
was worse. The child was developmentally normal and otherwise healthy
apart from allergic rhinitis. Physical examination results were notable for mild
nasal congestion and 2+ tonsillar size (Figure 2-4), but otherwise normal.
Comment. This case illustrates a typical example of behavioral insomnia
of childhood, a disorder in which a childs difficulty falling asleep or
staying asleep is secondary to inappropriate sleep-onset associationsVin
this case a habitual need to have his mother present while falling
asleepVor inconsistent limit setting.5

KEY POINTS
younger children, more substantial children with sleep problems. To the h Sleep-onset association
bedtime resistance is estimated to extent possible, the child should be disorder is one of the
affect 10% to 20% of toddlers and provided with an age-appropriate crib most common underlying
preschool-aged children.6 or bed in a quiet and comfortable en- or contributing causes
In the sleep-onset association type vironment. Exposure to ambient light for insomnia and night
of behavioral insomnia, a child habitu- at bedtime and during the night should waking in infants and
ally settles to sleep via circumstances be minimized apart from judicious use younger children.
that cannot be independently sus- of small night lights for children who h Many families try
tained, such as being rocked or having are afraid of the dark. Maintaining a extinction-based
a parent present. Affected children regular sleep schedule can promote interventions for only a
become so dependent on these rou- circadian entrainment, which often few nights, encounter an
tines for transition to sleep that they facilitates sleep onset close to the ha- extinction burst of
are unable to settle to sleep without bitual bedtime. temporarily worse
them. Attempts to do so result in in- Structured behavioral interventions symptoms, and abandon
somnia or distress at bedtime, and the technique before it
are often additionally necessary for
has had time to be
inability to return to sleep following effective treatment of behavioral in-
effective.
the physiologic awakenings normally somnia of childhood. Well-established
occurs during the middle and latter methods include extinction (systematic
portions of the nighttime sleep period. ignoring of crying or other behaviors
The limit-setting type of behavioral until the child eventually falls asleep)
insomnia is characterized by inconsis- and graduated extinction (a variation
tent limit setting by parents or care- in which extinction techniques are
givers in response to a childs bedtime applied for progressively increasing
struggles or night waking. Whereas intervals before parents are allowed to
consistent limit-setting reduces the briefly resettle their child).7,8 Bedtime
frequency and severity of problematic fading involves transiently moving a
behaviors at these times, inconsistent childs bedtime later, ie, closer to the
or suboptimal responses to a childs time of actual sleep onset, with even-
inappropriate behavior tend to perpet- tual return to an earlier, age-appropri-
uate the sleep problem. ate bedtime after the child is falling
Treatment of insomnia and night asleep more quickly.9 Consistent and
waking for infants and young children sustained application of these interven-
begins with optimization of sleep tions is usually necessary to achieve
hygiene, practices that promote opti- sustained clinical improvement in chil-
mal nighttime sleep. Structured bed- dren with more severe forms of bed-
time routines appropriate for age help time struggles and night waking.
many younger children transition from Drug treatment of insomnia in in-
a higher level of daytime activity to a fants and younger children has received
quieter and more relaxed state that scant formal study and is not routinely
facilitates sleep onset. Routines for recommended.
younger children often include bathing,
tooth-brushing, changing clothes, read- INSOMNIA IN OLDER CHILDREN
ing stories, and being tucked in. AND ADOLESCENTS
Potentially stimulating activities such Insomnia remains common as children
as vigorous play or watching television grow older, affecting at least 10% of
are best avoided in children who have adolescents,10 but underlying causes
difficulty with settling at bedtime. change substantially with advancing
Establishing an optimal sleep envi- age. Older children and adolescents
ronment is also important for younger have increasing autonomy with respect

KEY POINTS
h Delayed sleep phase is to bedtime and sleep schedule as they of other sleep disorders such as restless
an extremely common grow older, often resulting in bedtimes legs syndrome.
cause or contributing that are too late to permit habitually Treatment of insomnia for older
factor to insomnia in sufficient nighttime sleep. Evening- children and adolescents is seldom suc-
adolescent or older time use of electronic devices such as cessful unless all pertinent influences
preadolescent children. computers, smart phones, televisions, are addressed and the child is moti-
When present, or video games can delay bedtime or vated enough to make the lifestyle and
medication treatment be sufficiently stimulating to delay sleep schedule changes that are usually
alone is unlikely to be sleep onset even after cessation of necessary to correct the problem.
effective. the activity.11 Consumption of caffei- Sleep hygiene should be examined
h Sleeping in late on nated beverages, particularly late in the and optimized before more specific
weekend and day, may also be associated with and labor-intensive treatments are im-
nonYschool days can insomnia and sleep problems in this plemented. Any excessive consumption
reduce the effectiveness age group.12 of caffeinated beverages should be
of other interventions
One of the most important influen- normalized on a gradual basis to avoid
for delayed sleep phase.
ces that affect insomnia in older chil- withdrawal symptoms and any late-day
dren and adolescents is the well- intake should be eliminated. Potentially
recognized tendency for many children stimulating activities, including home-
in this age range to become night work, vigorous exercise, or use of elec-
owls who gravitate toward later bed- tronic devices, should be moved to
times and waking times.13 Circadian alternative times and optimally replaced
rhythm disorder, delayed sleep-phase with a structured prebedtime routine
type, can be diagnosed when a ten- incorporating less stimulating activities.
dency toward delayed sleep phase is A target weekday sleep schedule
associated with habitual inability to fall should be identified based on the
asleep and/or wake up at desired or childs age, school schedule, individual
socially acceptable times. Some pa- sleep needs, and family needs. Efforts
tients with this disorder compensate should be made to keep bedtime and
for insufficient nighttime sleep with waking time on nonYschool days con-
daytime naps, which may lead to sistent with those on school days to
further difficulties falling asleep at a eliminate irregularity of sleep schedule.
conventional bedtime. The common Any daytime napping should be elimi-
adolescent practice of habitually later nated. Sleep schedule goals should be
bedtime and waking time on nonY negotiated with the family in a prag-
school nights can lead to worsening matic fashion, which sometimes re-
of the sleep-phase delay and result in quires that initial targets be achievable,
additional irregularity of sleep sched- although perhaps not ideal.
ule compared to school nights.14 When insomnia related primarily to
Other forms of insomnia, such as delayed sleep phase is mild, consis-
psychophysiologic insomnia and in- tent implementation of the measures
somnia due to drug or substance, can described above are sufficient to alle-
also affect older children and teenagers, viate insomnia and permit adequate
with symptoms and contributory influ- nighttime sleep duration. Gradual but
ences similar to those of affected adults. consistent advancement of the childs
Insomnia may occur secondary to bedtime and waking time toward the
underlying medical conditions such as earlier times of the target schedule
attention deficit hyperactivity disorder may be additionally necessary.
or developmental disabilities. Insomnia Chronotherapy is a useful method
can also represent an associated feature for treating severe or resistant forms

KEY POINTS
of insomnia related to delayed sleep that childhood OSA is more commonly h Obstructive sleep apnea
phase. This treatment entails pro- characterized by intermittent or sus- is underdiagnosed in
gressive delays of the childs bedtime tained partial obstruction during sleep children in part because
and waking time by 2 to 3 hours daily as opposed to recurrent episodes of the lack of observed
until the target sleep schedule complete obstruction (Supplemental respiratory pauses and
is attained, typically within 5 to 7 Digital Content 10-1, links.lww.com/ obvious daytime
days.15,16 The technique is rapid, safe, CONT/A28). sleepiness in most
and effective, but benefits are only Daytime symptoms of OSA in chil- affected children limit
sustained when the target sleep dren may be more subtle or variable parent and medical
schedule is rigorously maintained fol- compared to adults. Children with OSA practitioner recognition
that the condition might
lowing the initial treatment. Light are seldom obviously sleepy during the
be present.
therapy using carefully timed expo- day unless nighttime airway obstruction
sure to high-intensity full-spectrum is severe. Daytime sleepiness in af- h Although obesity
sources following morning waking is fected children is more commonly in- represents a risk factor
for childhood
also sometimes used for treatment of termittent or mild, sometimes evident
obstructive sleep apnea,
delayed sleep phase in children and only during sustained sedentary activ-
children with low or
adolescents.16 ities such as riding in an automobile. normal body weight can
Drug treatment of insomnia in older Disturbances in attention, behavior, have substantial
children and adolescents has not been and academic performance represent obstructive sleep apnea,
rigorously studied despite seemingly more common and prominent daytime particularly when
widespread use of homeopathic, non- symptoms in children with OSA, but underlying adenotonsillar
prescription, and off-label prescription these are frequently misattributed to hypertrophy is present.
agents in this population.17,18 Several alternative causes, such as attention
studies have reported melatonin to be deficit hyperactivity disorder (ADHD).
effective in treating insomnia for A small proportion of children with
school-aged children.19,20 OSA may present with isolated systemic
or constitutional symptoms such as
OBSTRUCTIVE SLEEP APNEA failure to thrive or unexplained hyper-
IN CHILDREN tension.23 A variety of medical condi-
Obstructive sleep apnea (OSA) is tions may be associated with increased
estimated to affect about 2% of chil- risk for childhood OSA (Table 10-2),24
dren, with peak incidence thought to including Down syndrome, Prader-Willi
occur between 3 and 8 years of age.21 syndrome, cleft palate repair, and cra-
Clinical features of OSA in children niofacial disorders characterized by
compared to adults are summarized micrognathia, such as Pierre Robin
in Table 10-1.22 syndrome (Figure 10-2).25,26 Obesity
The nighttime symptoms exhibited represents an increasingly prevalent
by affected children are similar to, but risk factor for OSA in children, partic-
often milder than, those exhibited by ularly during adolescence.27
adults. Most children with OSA have Although the physical examination
some degree of snoring or noisy respi- findings of children with OSA are fre-
ration during sleep, but this may be mild quently normal, some children exhibit
or intermittent. Other common but characteristic findings associated with
variable nighttime symptoms include increased risk for upper airway obstruc-
mouth breathing, restlessness, and dia- tion during sleep, including mouth
phoresis. Dramatic pauses in respiration breathing, tonsillar hypertrophy, nar-
during sleep are observed by parents row upper palate, and maxillary or man-
and caregivers only when OSA is severe, dibular hypoplasia. Although tonsillar
consistent with current understanding hypertrophy is common among children

TABLE 10-1 Comparative Features of Obstructive Sleep Apnea in

Children Compared to Adultsa
Features Children Adults

Physical characteristics
Gender Younger children: sexes Primarily males,
equally affected postmenopausal females
Adolescents: males9females
Peak age 2Y8 Years Middle aged and older
Body weight Usually normal, occasionally Most often obese
overweight
Upper airway Adenotonsillar enlargement Adenotonsillar
frequent enlargement occasional
Redundant soft tissue Redundant soft tissue
occasional frequent
Symptoms during sleep
Snoring Frequent, continuous, Frequent, often
or intermittent interrupted by pauses
Witnessed apnea Occasional Frequent
Polysomnographic characteristics
Obstruction Prolonged partial Cyclical intermittent
obstruction9intermittent obstruction
Sleep architecture Normal9fragmented Frequent arousals with
sleep fragmentation
Secondary symptoms
Daytime sleepiness Most often absent or Frequent, usually
intermittent prominent
Neurobehavioral Inattention, hyperkinesis, Cognitive slowing,
disturbed behavior increased accident risk
Cardiovascular Hypertension, cor pulmonale Hypertension, heart
disease, stroke
a
Reprinted with permission from Hoban T, Ann N Y Acad Sci.22 onlinelibrary.wiley.com/doi/10.1111/
j.1749-6632.2009.05112.x/abstract.
with OSA (Figure 2-4 in Approach to ciated with symptomatic OSA (eg, snor-
and Evaluation of Sleep Disorders), ing, diaphoresis, daytime hyperactivity,
its presence is neither necessary nor or behavior problems) and polysomno-
sufficient for the diagnosis of child- graphic confirmation that airway ob-
hood OSA. struction associated with disturbed
Current criteria for the diagnosis of gas exchange or sleep architecture is
OSA in children were established in 2005 present. Whereas the diagnostic criteria
by the International Classification of for adult OSA require that at least five
Sleep Disorders, Second Edition: Diag- respiratory disturbances per hour be
nostic and Coding Manual.1 Definitive present during polysomnography
diagnosis of the disorder requires a (PSG), pediatric criteria require a mini-
combination of clinical criteria asso- mum of only one disturbance per hour,

KEY POINT
TABLE 10-2 Medical Conditions Associated With Increased Risk for h Of children undergoing
Childhood Obstructive Sleep Apneaa adenotonsillectomy for
treatment of obstructive
b Craniofacial Syndromes Featuring Prominent Maxillary or Mandibular Hypoplasia sleep apnea, 50% to
Apert syndrome 75% may still have
Crouzon syndrome some degree of
obstructive sleep apnea
Pierre Robin syndrome
postoperatively (usually
Saethre-Chotzen syndrome
milder).
Treacher Collins syndrome
b Other Skeletal and Craniofacial Disorders
Achondroplasia
Choanal atresia
Cleft palate, especially following surgical repair
Velocardiofacial syndrome
b Systemic Genetic and Metabolic Disorders
Down syndrome
Hypothyroidism
Mucopolysaccharide storage disorders (eg, Hunter syndrome, Hurler syndrome)
Prader-Willi syndrome
b Other Medical and Neurologic Conditions
Brainstem and cranial nerve disorders (eg, syringobulbia, Chiari malformation)
Chronic nasal obstruction (eg, septal deviation, allergic rhinitis, polyp, infections)
Obesity
Sickle cell disease
a
Reprinted from Hoban TF, Chervin RD, Sleep Med Clin.24 B 2007, with permission from Elsevier.
www.sciencedirect.com/science/article/pii/S1556407X07000550.
reflecting the increased vulnerability of tomy nevertheless experienced signifi-

children to the effects of mild noc- cant partial improvement of their OSA,
turnal airway obstruction compared to these and other reports suggest that
adults.28
Adenotonsillectomy represents the
most commonly used treatment for
OSA in children. Although this proce-
dure had historically been considered to
be highly effective in treating childhood
OSA,29 recent studies using contempo-
rary diagnostic criteria and PSG have
suggested that respiratory parameters
during sleep fully normalize in only
25% to 50% of children with OSA who
undergo adenotonsillectomy.30,31 Al-
though these studies should be inter- Child with Pierre Robin syndrome and
FIGURE 10-2
preted with due recognition that many micrognathia.
of the children whose OSA was not Reprinted from Tewfik TL, Der Kaloustian VM, Oxford University Press.
25
By permission of Oxford University Press, USA.

completely cured by adenotonsillec-

KEY POINT
h Continuous positive clinicians must remain vigilant for re- Continuous positive airway pressure
airway pressure is sidual or recurrent OSA following ade- (CPAP) is also considered a first-line
considered a first-line notonsillectomy in children.32,33 treatment for childhood OSA. Although
treatment for obstructive Most children with OSA who undergo used less frequently than adenotonsil-
sleep apnea in children. adenotonsillectomy exhibit tangible lectomy for the pediatric population,
improvements in obstructive symptoms CPAP is particularly useful in children
during sleep and in overall sleep quality. whose OSA persists despite adenoton-
The impact on daytime symptoms may sillectomy and in children who are not
be variable, especially when comorbid appropriate candidates for adenotonsil-
non-OSA influences are present, but lectomy (eg, morbid obesity, craniofa-
multiple studies have reported im- cial disorders, and other conditions in
proved academic performance or ADHD which airway obstruction is not primar-
symptoms in children whose OSA was ily related to adenotonsillar obstruc-
treated via adenotonsillectomy.34,35 tion) (Case 10-2).
Case 10-2
An 8-year-old boy with a history of autoimmune hepatitis and recent
liver transplantation was referred for evaluation of snoring and daytime
sleepiness. Snoring had become severe since liver transplantation and was
associated with mouth breathing and significant restlessness during sleep.
The family also reported substantial daytime tiredness for at least 1 year
despite 10 hours of sleep per night on average. The child typically napped
after school 2 to 3 days weekly and would fall asleep quickly during
automobile rides. His teachers at school reported substantial problems
with drowsiness, inattention, oppositional behavior, and poor academic
performance. Initial examination was notable for obesity (body mass index
of 34 kg/m2) and noisy mouth breathing. Examination of the oropharynx
was significant for a Mallampati class IV airway, large scalloped tongue,
mildly high-arched palate, and 2+ tonsillar size.
A baseline polysomnogram confirmed the presence of severe obstructive
sleep apnea (OSA), characterized by frequent obstructive apneas and
hypopneas associated with marked sleep fragmentation and prominent
desaturation of SpO2. The apnea-hypopnea index was 86.7 events/h and
9.7% of total sleep time spent with SpO2 levels below 90.0%. End-tidal
carbon dioxide monitoring demonstrated no sleep-related hypoventilation.
The patient underwent adenotonsillectomy and was admitted overnight
for postoperative respiratory monitoring (as is standard practice for children
with severe sleep apnea undergoing this procedure). Following the childs
recovery from surgery, his family reported that his snoring and restlessness
during sleep had improved substantially and become mild in severity.
Daytime somnolence and napping had nearly resolved. The childs teachers
reported little improvement with respect to inattention and distractibility at
school, however, and told the childs mother that he was at risk of not being
promoted to the next grade.
A postoperative polysomnogram demonstrated mild OSA, characterized
by hypopneas associated with mild desaturation of SpO2 and slight
fragmentation of sleep architecture. The apnea-hypopnea index was

KEY POINTS
Continued from page 192 h Nasal steroids and rapid
maxillary expansion
1.9 events/h, rising to 6.2 during REM sleep. A subsequent continuous represent promising
positive airway pressure trial demonstrated that pressure settings of 7 cm alternative techniques
and 9 cm of water provided good control of obstructive respiratory for treatment of
disturbances during sleep. childhood obstructive
The child was highly compliant with home CPAP use, and the family sleep apnea.
reported that snoring and restlessness during sleep resolved completely
when it was initiated. Inattention and distractibility at school improved h Some pediatric studies
suggest that mild
moderately after CPAP was started, and the family reported no substantial
obstructive sleep apnea is
academic concerns at their last appointment.
more likely to be
Comment. This case illustrates several important clinical aspects of
associated with symptoms
childhood OSA, including the facts that severe OSA frequently persists in a
suggestive of attention
milder form following adenotonsillectomy, that mild OSA without daytime
deficit hyperactivity
somnolence may still be associated with neurobehavioral sequelae that benefit
disorder than more severe
from treatment, and that CPAP can successfully be implemented as long-term
forms are.
treatment for OSA in a relatively young child with complex medical needs.
h The presence of
significant sleepiness in
a child with snoring is
CPAP is generally considered to be times benefit from alternative surgical
concerning for the
both safe and effective for the treatment interventions, such as uvulopalato-
presence of severe
of childhood OSA, although acquired pharyngoplasty, maxillary or mandibular underlying obstructive
maxillary hypoplasia has been reported advancement, or even tracheostomy, sleep apnea.
as a rare complication of long-term although pediatric data regarding these
treatment.36 Limitations of this treat- procedures are extremely limited.
ment in children relate primarily to
the fact that not all children success- EXCESSIVE DAYTIME
fully acclimate to use of the device or SOMNOLENCE IN CHILDREN
achieve long-term compliance with its
Healthy children and adolescents
use. Use of CPAP may be especially chal-
who receive sufficient nighttime sleep
lenging in young or developmentally
normally exhibit excellent levels of
disabled children, although structured
daytime alertness and seldom nap dur-
desensitization techniques are some-
ing the day. The presence of persis-
times effective in helping these patients
tently excessive sleepiness in a child
achieve successful long-term use.
generally signifies one of three major
Alternative treatments for childhood
possibilities:
OSA are considered when the first-line
treatments are either ineffective or not 1. That the child is not receiving
feasible. Several studies have suggested sufficient nighttime sleep
that use of nasal steroids or maxillary 2. That an underlying sleep disorder
expansion devices may help alleviate has severely disrupted nighttime
upper airway obstruction for some chil- sleep
dren with OSA, but the overall effec- 3. That a sleep or medical disorder
tiveness and safety of these treatments that may cause sleepiness even in
have not been well established.37,38 Use the absence of disrupted nighttime
of supplemental oxygen or positional sleep (eg, narcolepsy, anemia,
therapy during sleep may provide hypothyroidism) is present
some (often partial) benefit for chil- Determining whether a young
dren with OSA. Children with severe patient is receiving habitually sufficient
and otherwise refractory OSA some- nighttime sleep requires careful review

KEY POINT
h Chronically insufficient TABLE 10-3 Ontogeny of Sleep EEG Background and Sleep
nighttime sleep Architecture During Infancy and Childhood
represents a very
common cause of b Primary EEG Background Activity During Sleep in Premature Infants
sleepiness and poor 26Y30 Weeks postconceptional age: trace discontinue
academic performance 28Y30 Weeks postconceptional age: delta brushes (disappear by term)
in children.
32Y36 Weeks postconceptional age: trace alternant (disappears by 12
weeks postterm)
b Ontogeny of Key Sleep-Staging Landmarks
30 Weeks postconceptional age: REMs apparent
2 Months postterm: sleep spindles apparent
4Y6 Months: K complexes and well-differentiated non-REM stages
b Development of the Waking Posterior Dominant Rhythm
2 Months: Q4 Hz
6 Months: Q6 Hz
3 Years: Q8 Hz
9 Years: Q9 Hz
b Ontogeny of Sleep Architecture
Term neonates: 50% REM; 50% non-REM (sleep-onset REM common)
6Y12 Months: 30%Y35% REM; 65%Y70% non-REM
3Y5 Years: 25% REM; 75% non-REM
of the childs sleep schedule and com- be explored. A detailed medical history
parison to age-appropriate norms often identifies symptoms and risk
(Table 10-1).1 If daytime sleepiness factors that guide further investigation,
resolves after nighttime sleep is length- such as symptoms of nocturnal sleep
ened, additional investigation and disruption (eg, snoring, restlessness), a
treatment are often unnecessary. history of medical disorders that can be
When excessive sleepiness persists associated with fatigue and sleepiness
despite adequate or lengthened night- (eg, depression, Epstein-Barr virus in-
time sleep, other potential causes must fection), or use of potentially sedating
TABLE 10-4 Pediatric Norms for Multiple Sleep Latency Testinga,b
Tanner Stage Mean Sleep Latency (Minutes)c SD

Stage 1 19.0 1.6
Stage 2 18.5 1.9
Stage 3 16.1 3.8
Stage 4 15.8 3.4
Stage 5 16.6 2.1
Older adolescents 15.7 3.4
SD = standard deviations.
a
Adapted from Carskadon MA, Addison-Wesley.43
b
Reprinted from Hoban TF, Chervin RD, Semin Pediatr Neurol.44 B 2001, with permission from Elsevier.
c
Data averaged from tests performed on 3 successive days of recording.

medications. Physical examination Kleine-Levin syndrome is a rare con-
sometimes identifies additional clues, dition characterized by recurrent epi-
such as anatomic features associated sodes of sleepiness, encephalopathy, and
with increased risk for OSA or physical altered appetite that last days to
findings suggestive of underlying ane- weeks.5,39 Behavioral disturbances dur-
mia or hypothyroidism. ing episodes may include aggression or
Although sleepiness in children is inappropriate sexual behaviors that re-
most often secondary to insufficient quire additional treatment and safety pre-
nighttime sleep or another underlying cautions beyond symptomatic treatment
sleep disorder, such symptoms are of the hypersomnia. This disorder most
occasionally the result of hypersom- often affects adolescent boys and some-
nias of central origin, such as recurrent times remits spontaneously with time.
hypersomnia (Kleine-Levin syndrome) Narcolepsy in children is character-
or narcolepsy. ized by the same clinical manifestations
Case 10-3
An 8-year-old girl was referred by another neurologist for further evaluation of pervasive daytime
sleepiness and intermittent weakness sometimes associated with loss of posture. The family reported
that her pervasive sleepiness had been noted during the prior school year, when the child had
occasionally fallen asleep in school. Sleepiness at the time of initial evaluation was described as
substantial, with the child sleeping almost constantly on automobile rides and napping for up to 90
minutes daily despite 10 to 11 hours of sleep during most nights.
Episodic weakness was first noted at 2 years of age and became gradually more prominent with
advancing age. Events were reported to occur almost exclusively during giggling or laughter, persisting
for several seconds to several minutes before subsiding. Milder episodes were characterized only
by brief, subtle dipping of the head, whereas more severe events were characterized by diffuse weakness
and loss of postural tone. (The accompanying video [Supplemental Digital Content 10-2, links.lww.com/
CONT/A29] depicts a different patient with a similar condition.) Several spells had been associated with
falls resulting in broken bones.
The family reported no snoring or significant nighttime sleep problems apart from brief partial
awakenings and mild restlessness during sleep. They observed no hallucinatory events or sleep
paralysis near sleep onset or offset. Episodes of weakness and loss of posture were not associated with
any impairment of consciousness, and an extensive prior workup for seizures had been negative. The
initial examination was remarkable only for mouth breathing, a mildly narrow upper palate, and
equivocal limitation of upward gaze.
A nocturnal PSG was essentially normal, recording 458.5 minutes of sleep and no significant
respiratory disturbances. A multiple sleep latency test performed the next day recorded sleep during
all five nap opportunities, with mean sleep-onset latency of 0.7 minutes and four sleep-onset REM
periods. Findings were interpreted as supporting the presence of severe sleepiness and compatible
with the diagnosis of narcolepsy.
Daytime sleepiness and cataplectic episodes improved considerably following initiation of treatment
with modafinil and tricyclic agents. School performance also improved, but declined several months later
despite continued good control of sleep-related symptoms. This prompted further diagnostic
investigation. A skin biopsy and cholesterol esterification studies demonstrated findings consistent with
Niemann-Pick disease type C.
Comment. This case illustrates several important clinical aspects of childhood narcolepsy, including
multiple sleep latency test findings that were strongly indicative of childhood narcolepsy, the fact that
narcolepsy often responds well to off-label treatment using modafinil, and that children who present with
narcolepsy at a younger-than-typical age or experience progressive symptoms despite treatment may
require screening for other underlying disorders.

experienced by adults: daytime somno- dary basis. Children with hypersomnias

lence, sleep paralysis, hypnagogic and of central origin such as narcolepsy,
hypnopompic hallucinations, and some- however, usually benefit from treat-
times cataplexy. Onset of the condition ment with wake-promoting medica-
is occasionally abrupt, but symptoms tions, such as modafinil, stimulants, or
more commonly evolve in an insidious sodium oxybate, which are used cau-
fashion over time. Clinical manifestations tiously on an off-label basis in this
most commonly begin during the sec- population. Off-label use of selective
ond decade of life, and onset at younger serotonin reuptake inhibitors or tricy-
ages is sometimes associated with the clic agents is sometimes effective in
presence of additional underlying con- controlling cataplexy for children with
ditions such as Niemann-Pick disease narcolepsy (Case 10-3).
type C or Prader-Willi syndrome.40,41
Sleep laboratory assessment of exces- VIDEO LEGENDS
sive sleepiness in children often requires Supplemental Digital Content 10-1
both PSG and multiple sleep latency Sleep apnea syndrome in a child. Video dem-
onstrates sleep apnea syndrome in a child. This
testing (MSLT). Investigation commen- child is overweight and has grade 4+ tonsils,
ces with nocturnal PSG, which docu- which has led to complete cyclical airway oc-
ments the duration of nighttime sleep clusion and resuscitative arousals. Obstructive
and screens for OSA and other potential sleep apnea in children may have different causes
disruptors of nighttime sleep. The noc- and consequences than in adults. Children with
untreated obstructive sleep apnea may experi-
turnal PSG should be interpreted using
ence neurocognitive decline, hyperactivity,
pediatric norms42 (Table 10-3), which hypersomnolence, and decline in IQ scores.
differ substantially for children com- links.lww.com/CONT/A28
pared to adults. MSLT is performed B 2013 Sona Nevsmalova, MD, DSc. Used with
the next day to objectively assess the permission.
severity of daytime somnolence and Supplemental Digital Content 10-2
screen for sleep-onset REM periods and Child cataplexy. Video demonstrates cataplexy
other findings that help differentiate in a child, depicting loss of muscle tone triggered
between narcolepsy and other potential by laughter.
causes of excessive sleepiness. Because links.lww.com/CONT/A29
mean sleep latency scores for healthy B 2013 Sona Nevsmalova, MD, DSc. Used with
children undergoing MSLT are signifi- permission.
cantly longer than those for adults, it
REFERENCES
is essential that the nap study also
1. Iglowstein I, Jenni OG, Molinari L, Largo RH.
be interpreted using pediatric norms Sleep duration from infancy to adolescence:
(Table 10-4).43,44 Most children with reference values and generational trends.
narcolepsy demonstrate multiple sleep- Pediatrics 2003;111(2):302Y307.
onset REM periods and mean sleep 2. Guilleminault C, Anders TF. The
latency of less than 5 minutes on MSLT. pathophysiology of sleep disorders in
pediatrics. Part II. Sleep disorders in children.
Treatment of excessive daytime Adv Pediatr 1976;22:151Y174.
sleepiness in children is customized
3. Sadeh A, Lavie P, Scher A, et al. Actigraphic
based on the severity of somnolence home monitoring of sleep-disturbed and
and the nature of the associated clinical control infants and young children: a
circumstances. Some sleepy children new method for pediatric assessment of
sleep-wake patterns. Pediatrics
require nothing more than lengthening 1991;87(4):494Y499.
nighttime sleep or treatment of an
4. Sheldon SH. Disorders of initiating and
associated medical or sleep disorder maintaining sleep. In: Sheldon SH, Ferber R,
that is causing sleepiness on a secon- Kryger MH, eds. Principles and practice of

pediatric sleep medicine. Philadelphia, PA: 18. Owens JA, Rosen CL, Mindell JA. Medication
Saunders, 2005. use in the treatment of pediatric insomnia:
results of a survey of community-based
5. Anonymous. The international classification
pediatricians. Pediatrics 2003;111(5 pt 1):
of sleep disorders. 2nd ed. Westchester, NY:
e628Ye635.
19. Smits M, Van Stel H, Van der Heijen K, et al.
6. Ramchandani P, Wiggs L, Webb V, et al. A
Melatonin improves health status and
systematic review of treatments for settling
sleep in children with idiopathic chronic
problems and night waking in young
sleep-onset insomnia: a randomized,
children. BMJ 2000;320(7229):209Y213.
placebo-controlled trial. J Am Acad Child
7. Mindell JA, Kuhn B, Lewin DS, et al. Adolesc Psychiatry 2003;42(11):1286Y1293.
Behavioral treatment of bedtime problems
20. van Geijlswijk IM, Mol RH, Egberts TCG,
and night wakings in infants and young
Smits MG. Evaluation of sleep, puberty and
children [published erratum in Sleep.
mental health in children with long-term
2006;29(11):1380]. Sleep 2006;29(10):
melatonin treatment for chronic idiopathic
1263Y1276.
childhood sleep onset insomnia.
8. Morgenthaler TI, Owens J, Alessi C, et al. Psychopharmacology (Berl) 2011;216(1):
Practice parameters for behavioral 111Y120.
treatment of bedtime problems and night
21. Marcus CL. Sleep-disordered breathing in
wakings in infants and young children.
children. Am J Respir Critical Care Med
Sleep 2006;29(10):1277Y1281.
2001;164(1):16Y30.
9. Taylor DJ, Roane BM. Treatment of
22. Hoban TF. Sleep disorders in children. Ann N
insomnia in adults and children: a
Y Acad Sci 2010;1184:1Y14.
practice-friendly review of research. J Clin
Psychol 2010;66(11):1137Y1147. 23. Li AM, Au CT, Sung RY, et al. Ambulatory
blood pressure in children with obstructive
10. Roberts RE, Roberts CR, Chan W. Persistence
sleep apnoea: a community based study.
and change in symptoms of insomnia among
Thorax 2008;63(9):803Y809.x
adolescents. Sleep 2008;31(2):177Y184.
24. Hoban TF, Chervin RD. Sleep-related
11. Cain N, Gradisar M. Electronic media use
breathing disorders of childhood:
and sleep in school-aged children and
description and clinical picture, diagnosis,
adolescents: a review. Sleep Med 2010;
and treatment approaches. Sleep Med Clin
11(8):735Y742.
2007;2:445Y462.
12. Bryant Ludden A, Wolfson AR.
25. Tewfik TL, Der Kaloustian VM. Congenital
Understanding adolescent caffeine use:
anomalies of the ear, nose, and throat. New
connecting use patterns with expectancies,
York, NY: Oxford University Press, 1997:517.
reasons, and sleep. Health Educ Behav
2010;37(3):330Y342. 26. Shott SR, Amin R, Chini B, et al. Obstructive
sleep apnea: should all children with Down
13. Carskadon MA. The second decade. In:
syndrome be tested? Arch Otolaryngol Head
Guilleminault C, ed. Sleeping and waking
Neck Surg 2006;132(4):432Y436.
disorders: indications and techniques.
Menlo Park, CA: Addison Wesley, 1982: 27. Kalra M, Inge T, Garcia V, et al. Obstructive
99Y125. sleep apnea in extremely overweight
14. Crowley SJ, Acebo C, Carskadon MA. adolescents undergoing bariatric surgery.
Sleep, circadian rhythms, and delayed phase Obes Res 2005;13(7):1175Y1179.
in adolescence. Sleep Med 2007;8(6):602Y612. 28. Rosen CL, DAndrea L, Haddad GG. Adult
15. Czeisler C, Richardson G, Coleman R, et al. criteria for obstructive sleep apnea do not
Chronotherapy: resetting the circadian identify children with serious obstruction.
clocks of patients with delayed sleep phase Am Rev Respir Dis 1992;146(5 pt 1):
insomnia. Sleep 1981;4(1):1Y21. 1231Y1234.
16. Okawa M, Uchiyama M, Ozaki S, et al. 29. Brietzke SE, Gallagher D, Brietzke SE, et al.
Circadian rhythm sleep disorders in The effectiveness of tonsillectomy and
adolescents: clinical trials of combined adenoidectomy in the treatment of
treatments based on chronobiology. pediatric obstructive sleep apnea/hypopnea
Psychiatry Clin Neurosci 1998;52(5):483Y490. syndrome: a meta-analysis. Otolaryngol
Head Neck Surg 2006;134(6):979Y984.
17. Pelayo R, Dubik M. Pediatric sleep
pharmacology. Semin Pediatr Neurol 30. Tauman R, Gulliver TE, Krishna J, et al.
2008;15(2):79Y90. Persistence of obstructive sleep apnea

syndrome in children after adenotonsillectomy. 37. Kheirandish-Gozal L, Gozal D. Intranasal

J Pediatr 2006;149(6):803Y808. budesonide treatment for children with
mild obstructive sleep apnea syndrome.
31. Guilleminault C, Huang YS, Glamann C,
Pediatrics 2008;122(1):e149Ye155.
et al. Adenotonsillectomy and obstructive
sleep apnea in children: a prospective survey. 38. Villa MP, Malagola C, Pagani J, et al. Rapid
Otolaryngol Head Neck Surg 2007;136(2): maxillary expansion in children with
169Y175. obstructive sleep apnea syndrome: 12-month
follow-up. Sleep Med 2007;8(2):128Y134.
32. Amin R, Anthony L, Somers V, et al.
Growth velocity predicts recurrence of 39. Arnulf I, Lin L, Gadoth N, et al. Kleine-Levin
sleep-disordered breathing 1 year after syndrome: a systematic study of 108
adenotonsillectomy. Am J Respir Crit Care patients. Ann Neurol 2008;63(4):482Y493.
Med 2008;177(6):654Y659.
40. Kotagal S. Narcolepsy in children. Semin
33. Mitchell RB. Adenotonsillectomy for Pediatr Neurol 1996;3(1):36Y43.
obstructive sleep apnea in children:
outcome evaluated by pre- and 41. Smit LS, Lammers GJ, Catsman-Berrevoets
postoperative polysomnography. CE. Cataplexy leading to the diagnosis of
Laryngoscope 2007;117(10):1844Y1854. Niemann-Pick disease type C. Pediatr Neurol
2006;35(1):82Y84.
34. Chervin RD, Ruzicka DL, Giordani BJ, et al.
Sleep-disordered breathing, behavior, and 42. Iber C, Ancoli-Israel S, Chesson A, Quan SF.
cognition in children before and after The AASM manual for the scoring of
adenotonsillectomy. Pediatrics sleep and associated events. Westchester,
2006;117(4):e769Ye778. NY: American Academy of Sleep Medicine,
2007.
35. Gozal D. Sleep-disordered breathing and
school performance in children. Pediatrics 43. Carskadon MA. The second decade. In:
1998;102(3 pt 1):616Y620. Guilleminault C, ed. Sleeping and waking
disorders: indications and techniques. Menlo
36. Li KK, Riley RW, Guilleminault C. An Park, CA: Addison-Wesley, 1982.
unreported risk in the use of home nasal
continuous positive airway pressure and 44. Hoban TF, Chervin RD. Assessment of
home nasal ventilation in children: mid-face sleepiness in children. Semin Pediatr Neurol
hypoplasia. Chest 2000;117(3):916Y918. 2001;8(4):216Y228.

\
The Neurobiology of Sleep

Saper, Clifford B. MD, PhD, FAAN, FRCP. CONTINUUM: Lifelong Learning in Neurology.
Volume 19(1) Sleep Disorders. February 2013: p 19Y31.
Abstract
ABSTRACT:
Purpose of Review:
The basic circuitries that regulate wake-sleep cycles are described, along with how these are
affected by different disease states and how those alterations lead to the clinical manifestations of
those disorders.
Recent Findings:
The discovery of both sleep-promoting neurons in the ventrolateral preoptic nucleus and
wake-promoting neurons, such as the lateral hypothalamic orexin (also called hypocretin)
neurons, has allowed us to recognize that these two populations of neurons are mutually
antagonistic (ie, inhibit each other) and form a flip-flop switch, a type of circuit that results in
rapid and complete transition in behavioral state. The same principle applies to the circuitry
controlling transitions between REM sleep and non-REM (NREM) sleep.
Summary:
The flip-flop switch circuitry of the wake-sleep regulatory system produces the typical sleep
pattern seen in healthy adults, with consolidated waking during the day and alternation between
NREM and REM sleep at night. Breakdown in this circuitry both results in and explains the
manifestations of a variety of sleep disorders including insomnia, narcolepsy with cataplexy, and
REM sleep behavior disorder.
Key Points
& von Economo was the first neurologist to recognize that specific brain lesions could
identify brain circuitry controlling wake-sleep cycles.
& The ascending arousal system begins in the upper pons and contains two branches, one to
the thalamus and the other through the hypothalamus and basal forebrain, both of which
activate the cerebral cortex.
& Sleep-promoting neurons in the preoptic area, posterior lateral hypothalamus, and
possibly the lower brainstem inhibit the neurons in the arousal areas during sleep.
Copyright * 2013, American Academy of Neurology. All rights reserved.

& The mutual inhibition between the wake-promoting and sleep-promoting circuits
produces a flip-flop switch, which ensures rapid and complete transitions between sleep
and wakefulness.
& Sleep is divided into REM sleep, characterized by a fast EEG and muscle atonia, and
non-REM sleep, during which the EEG is slow and high voltage, and muscle tone is
present but low.
& Primary insomnia is associated with a state of coactivation of both arousal- and
sleep-promoting systems, resulting in a different state in which the EEG simultaneously
shows both the slowing of non-REM sleep and the fast frequencies associated with active
wakefulness.
& REM sleep behavior disorder is due to a failure of atonia circuitry during REM sleep,
allowing the patient to act out dreams, which often are violent.
& REM generator neurons in the upper pons are tonically inhibited by REM-off neurons in
the lower midbrain, which gate the entry into REM sleep.
& Orexin neurons in the posterior lateral hypothalamus stabilize the sleep-wake and the
REM switches.
& The loss of orexin neurons produces narcolepsy, which is characterized by state
instability: falling asleep too often when awake, waking up too often when asleep, and
falling into partial REM states such as atonia (cataplexy) or dreaming (hypnagogic or
hypnopompic hallucinations).
Approach to and Evaluation of Sleep

Disorders
Shelgikar, Anita Valanju MD; Chervin, Ronald MD, MS, FAASM, FAAN. CONTINUUM:
Lifelong Learning in Neurology. Volume 19(1) Sleep Disorders. February 2013: p 32Y49.
Abstract
ABSTRACT:
Purpose of Review:
This article provides a framework for the clinical assessment of patients with sleep-related
complaints and outlines a systematic approach to a sleep-specific history and physical
examination, subjective assessment tools, and diagnostic testing modalities.
Recent Findings:
Physical examination findings may suggest the presence of a sleep disorder, and obstructive sleep
apnea in particular, but the clinical history remains the most important element of the assessment
for most sleep problems. While nocturnal polysomnography in a sleep laboratory remains the
gold standard for diagnosis of sleep-disordered breathing, out-of-center testing may be
considered when the clinician has a high pretest suspicion for obstructive sleep apnea and the
patient has no significant cardiopulmonary, neuromuscular, or other sleep disorders.
Summary:
Sleep-related symptoms are common in adult and pediatric patients. A comprehensive sleep
history, physical examination with detailed evaluation of the head and neck, and judicious use of

sleep-specific questionnaires guide the decision to pursue diagnostic testing. Understanding of
the benefits and limitations of various diagnostic modalities is important as the spectrum of
testing options increases.
Key Points
& Information from the patient, medical record, and any available bed partner, friend, or
family member can clarify the extent and consequences of the patients sleep-related
symptoms.
& The 3P framework of insomnia comprises predisposing, precipitating, and perpetuating
factors. Discussion of all factors facilitates identification of potential treatment targets.
& Details of facial morphology, nasal airway patency, and oral airway crowding are key
features of the sleep-specific examination.
& Classification of the patients dentition helps to evaluate the position of the maxillary arch
relative to the mandibular arch.
& The Epworth Sleepiness Scale, a patient-completed questionnaire, assesses the patients
subjective tendency to doze during sedentary situations in recent times, not only at the
moment the questionnaire is completed.
& The Epworth Sleepiness Scale should not be used in lieu of diagnostic testing but may be
a valuable component of ongoing clinical evaluation.
& A daily sleep diary helps to summarize a patients sleep-wake schedule more accurately
than memory often allows and can facilitate construction of personalized plans for
management of circadian rhythm sleep disorders and insomnia.
& The complex classification of portable testing devices reflects the multitude of designs
available to clinicians and will undoubtedly change as technology advances.
& Careful consideration should be given to the indications for out-of-center testing.
Attended nocturnal polysomnography is indicated if a portable study yields a negative or
technically inadequate result.
& The multiple sleep latency test is the gold standard for objective assessment of daytime
sleepiness, but interpretation of the results must be made within the clinical context of the
patients history.
& In the multiple sleep latency test, the patient is instructed to try to sleep during each nap
trial. In the maintenance of wakefulness test, the patient is instructed to try to remain
awake during the nap trial.
& A baseline nocturnal polysomnogram is required before a multiple sleep latency test and
considered, but not required, before a maintenance of wakefulness test.
& Actigraphy can be useful in evaluation and treatment of circadian rhythm sleep disorders
and in management of insomnia.
& Neuroimaging is not routinely indicated in the clinical evaluation of sleep disorders and
should be pursued on a case-by-case basis.
& Careful assimilation of the clinical history, the sleep-specific physical examination,
patient questionnaires, and diagnostic test results leads to the most accurate assessment of
patients with symptoms related to sleep or alertness.
Chronic Insomnia
Neubauer, David N. MD. CONTINUUM: Lifelong Learning in Neurology. Volume 19(1)
Sleep Disorders. February 2013: p 50Y66.

Abstract
ABSTRACT:
Purpose of Review:
This article provides an overview of current strategies for evaluating and treating patients who
experience chronic insomnia.
Recent Findings:
The US Food and Drug Administration (FDA) has approved several medications for the treatment
of insomnia that incorporate a variety of pharmacodynamics and pharmacokinetic properties,
thus allowing the development of a customized therapeutic approach. FDA-approved
medications include F-aminobutyric acid-modulating benzodiazepine receptor agonists, a
melatonin receptor agonist, and a histamine receptor agonist. Psychological and behavioral
techniques combined as cognitive-behavioral therapy also have been shown to be effective in the
treatment of chronic insomnia.
Summary:
Insomnia is the most common sleep disturbance and represents a chronic condition for many
people. Difficulty falling asleep and maintaining sleep are highly prevalent problems in patients
with neurologic disorders. Multiple factors typically contribute to insomnia. Accordingly, a rather
broad approach to evaluating patients is warranted. Evidence-based guidelines support the use of
cognitive and behavioral strategies and selected medications in the treatment of patients with
chronic insomnia.
Key Points
& Poor sleep, whether due to inadequate quality or quantity, increases the risk for multiple
chronic comorbid health conditions.
& Wellness promotion should include good quality sleep along with a healthy diet and
exercise plan.
& The diagnosis of insomnia requires some degree of daytime impairment in addition to
persistent difficulty falling asleep or remaining asleep.
& Insomnia currently is conceptualized as a disorder of the wake system resulting in
round-the-clock hyperarousal.
& During the daytime most patients with chronic insomnia feel fatigued but not sleepy.
& Chronic insomnia associated with daytime consequences affects about one in 10 adults.
& Patients with chronic insomnia frequently have comorbid conditions associated with their
sleep disturbance.
& Use a comprehensive approach in evaluating chronic insomnia; the etiology is
multifactorial for most patients.
& Sleep logs and questionnaires completed by patients are very helpful in the insomnia
evaluation process.
& Sleep laboratory studies are not routinely performed in the insomnia evaluation, but they
are invaluable for selected patients with risk factors for comorbid sleep disorders.
& It is useful to establish clear goals with patients when treating their insomnia symptoms.
& Always consider the potential influences of sleep-disordered breathing and circadian
rhythm sleep disorders when evaluating insomnia symptoms.

& Be sure to review the complete list of a patients medications to identify possible
sleep-disturbing effects.
& Strongly encourage healthy sleep habits for all patients. Primary treatment modalities
may fail if patients have irregular bedtime hours or drink excessive caffeinated beverages.
& Psychological and behavioral strategies combined as cognitive-behavioral therapy for
insomnia have been shown to be effective in numerous well-controlled studies.
& Insomnia medications approved by the US Food and Drug Administration include
F-aminobutyric acid response modulators, a melatonin receptor agonist, and a histamine
H1 receptor antagonist.
& Benzodiazepine receptor agonist hypnotics all are allosteric modulators of
F-aminobutyric acid responses at the GABAA receptor complex.
& In addition to immediate-release and extended-release pill and tablet formulations,
benzodiazepine receptor agonist hypnotics are available in oral spray and sublingual
dissolvable formulations.
& Low-dose doxepin is approved for the treatment of insomnia characterized by difficulty
with sleep maintenance.
& Beware of the anticholinergic effects associated with over-the-counter antihistamines
people often use as sleep aids.
& Melatonin, which is unregulated in the United States, may be beneficial in the treatment of
certain circadian rhythm sleep disorders, especially in people with a phase-delay pattern.
& Currently the most promising novel pipeline compounds are orexin receptor antagonists.
Primary Hypersomnias of Central Origin

Malhotra, Samit MD; Kushida, Clete A. MD, PhD, RPSGT. CONTINUUM: Lifelong Learning
in Neurology. Volume 19(1) Sleep Disorders. February 2013: p 67Y85.
Abstract
ABSTRACT:
Purpose of Review:
This review discusses the various causes of primary hypersomnias with emphasis on clinical
recognition, diagnosis, and treatment options.
Recent Findings:
Narcolepsy is probably the most fascinating syndrome causing excessive daytime sleepiness.
With increasing understanding of the hypocretin/orexin pathways and the neurotransmitters that
subserve the role of wakefulness and sleep, newer therapeutic modalities with promising results
are being investigated and opening new frontiers in the treatment of this rare but devastating
disease.
Summary:
This article reviews the primary hypersomnias of central origin. Where possible, clinical cases
that highlight and explain the clinical syndromes are included. Treatment modalities and future
directions are also discussed to help the clinician identify and treat the underlying disorder.

Key Points
& Most whites and African Americans who have narcolepsy with cataplexy are positive for
HLA-DQB1*0602, showing a strong association with this human leukocyte antigen type.
& Naps are usually refreshing and often recommended as part of the treatment plan for
narcolepsy. Short daytime naps lasting about 30 minutes can result in the attenuation of
the sleep drive for a few hours.
& Symptoms of subtle muscle weakness in cataplexy include slurring of speech, buckling of
knees, jaw dropping, or even nodding of the head and should be specifically elicited
during history taking.
& A rare sustained cataplectic episode, status cataplecticus, may occur following abrupt
discontinuation of medications used to treat cataplexy. This is also referred to as rebound
cataplexy.
& The presence of a sleep-onset REM period on an overnight sleep study of a patient with a
history of excessive daytime sleepiness and muscle atonia that occurs in the setting of an
emotional outburst may be suggestive of a diagnosis of narcolepsy with cataplexy.
& Hypocretin-1 and hypocretin-2 are the two peptides that result from the splitting of their
precursor, preprohypocretin. Hypocretin-1 is implicated in human narcolepsy.
& A finding of low (less than 110 pg/mL) or undetectable CSF hypocretin levels will nearly
always be seen in patients with true narcolepsy with cataplexy.
& Various medications treat the individual symptoms of narcolepsy with cataplexy, but
sodium oxybate is favored over the others because of its effectiveness in treating the
primary symptoms, including excessive daytime sleepiness and REM-related atonia
(cataplexy), simultaneously.
& Idiopathic hypersomnia has an unknown etiology and is typified by symptoms of
nonrefreshing sleep with difficulty waking up, which could either be in the morning or
after a nap.
& Naps are usually not refreshing in patients with idiopathic hypersomnia, in contrast to
patients with narcolepsy, who find scheduled naps very rewarding.
& Kleine-Levin syndrome consists of symptoms of hyperphagia, hypersomnia, and
hypersexuality.
& Kleine-Levin syndrome is a clinical diagnosis, and the investigations are done merely to
rule out other causes of hypersomnia.
& Most episodes of Kleine-Levin syndrome resolve spontaneously within a 30-day period,
and the interepisode hiatus almost never surpasses 15 months.
& SPECT has demonstrated a reduced perfusion of the thalamus during an active
Kleine-Levin syndrome episode that eventually reversed to normal as the symptoms
resolved.
& Women with menstrual-related hypersomnia experience episodes of recurrent sleepiness
coinciding with their menstrual cycles.
& Posttraumatic hypersomnia is prevalent and often missed as a cause of unexplained
hypersomnia.
Panossian, Lori MD, MS; Daley, Joseph MD, PhD. CONTINUUM: Lifelong Learning in
Neurology. Volume 19(1) Sleep Disorders. February 2013: p 86Y103.

Abstract
ABSTRACT:
Purpose of Review:
This article introduces readers to the clinical presentation, diagnosis, and treatment of
sleep-disordered breathing and reviews the associated risk factors and health consequences.
Recent Findings:
Sleep-disordered breathing is associated with significant impairments in daytime alertness
and cognitive function as well as adverse health outcomes. The initial treatment of choice is
positive airway pressure. Improvements in technology and mask delivery systems have helped to
make this treatment more comfortable and convenient for many patients.
Summary:
Sleep-disordered breathing, particularly in the form of obstructive sleep apnea, is highly prevalent
in the general population and has important implications for neurology patients. Sleep-disordered
breathing is characterized by repetitive periods of cessation in breathing, termed apneas, or
reductions in the amplitude of a breath, known as hypopneas, that occur during sleep. These
events are frequently associated with fragmentation of sleep, declines in oxygen saturation, and
sympathetic nervous system activation with heart rate and blood pressure elevation. Obstructive
sleep apnea, which represents cessation of airflow, develops because of factors such as anatomic
obstruction of the upper airway related to obesity, excess tissue bulk in the pharynx, and changes
in muscle tone and nerve activity during sleep. Central sleep apnea represents cessation of airflow
along with absence or significant reduction in respiratory effort during sleep and is more
commonly found in the setting of congestive heart failure, neurologic disorders, or
cardiopulmonary disease.
Key Points
& An obstructive apnea is defined as cessation of airflow with continued respiratory effort
due to complete upper airway occlusion.
& A hypopnea is a partial decrement in airflow with an associated physiologic consequence,
either an arousal or oxygen desaturation, due to partial upper airway collapse.
& A mixed apnea is defined as a period of airflow cessation without respiratory effort
followed by a period of resumed effort with continued decrements in airflow.
& Obstructive sleep apnea is a highly prevalent condition that occurs predominantly in
middle-aged or older men and postmenopausal women.
& Obstructive sleep apnea is viewed as a primarily mechanical problem of the upper airway,
with both neuronal and anatomic factors contributing to increased collapsibility.
& Symptoms suggestive of obstructive sleep apnea include snoring; witnessed apneas;
arousals associated with choking, gasping, and diaphoretic awakenings from sleep; and
excessive daytime sleepiness.
& Polysomnography is the diagnostic modality of choice for obstructive sleep apnea and
other sleep disorders, although monitors with fewer channels have been validated in
certain populations for obstructive sleep apnea detection.
& The apnea-hypopnea index is the measure used to define the severity of sleep apnea; 5 or
greater is considered to be abnormal.

& Continuous positive airway pressure uses forced air to stent the airway open and reduce
obstructive events.
& A central apnea is defined by cessation of airflow without evidence of respiratory effort.
& Central sleep apnea can be seen in a variety of conditions, including congestive heart
failure, medullary lesions, and autonomic dysregulation.
& Successful treatment of central sleep apnea associated with heart failure is associated with
improved cardiac function and survival.
Complex Nocturnal Behaviors:

Nocturnal Seizures and Parasomnias
Foldvary-Schaefer, Nancy DO, MS, FAASM; Alsheikhtaha, Zahreddin MBBS, RPSGT.
CONTINUUM: Lifelong Learning in Neurology. Volume 19(1) Sleep Disorders. February
2013: p 104Y131.
Abstract
ABSTRACT:
Purpose of Review:
This article summarizes the clinical and electrophysiologic manifestations of nocturnal seizures,
particularly nocturnal frontal lobe epilepsy (NFLE), parasomnias, and other disorders presenting
with complex behaviors in sleep. The evaluation and treatment of patients with complex
nocturnal behaviors can be challenging. While the differential diagnosis of sleep-related
movements, including physiologic and pathologic phenomena, is extensive, the focus of
evaluation in patients with complex nocturnal behaviors distinguishes between nocturnal seizures
and parasomnias.
Recent Findings:
Seizures in NFLE have a wide range of complexity and severity, overlapping considerably with
the disorders of arousal from non-REM (NREM) sleep. Video polysomnography with EEG
(VPSG-EEG) has identified key clinical features useful in differentiating these disorders. A
dysfunctional arousal mechanism involving the cholinergic system is involved in the
pathophysiology of the autosomal dominant form of NFLE and NREM parasomnias. The high
prevalence of parasomnias in NFLE families further confounds their distinction. VPSG-EEG
combines PSG with comprehensive EEG to evaluate unexplained nocturnal behaviors when
epileptic seizures are suspected. This procedure provides improved detection of interictal and
ictal EEG abnormalities and time-synchronized correlation of clinical and neurophysiologic
phenomena.
Summary:
The diagnosis of complex nocturnal behaviors is among the most difficult to establish in sleep
medicine clinics and laboratories. VPSG-EEG is indicated in the evaluation of patients with
complex nocturnal behaviors when routine EEG is nondiagnostic. Ongoing research is necessary

to fully elucidate the pathophysiology of these disorders, which share a host of clinical
manifestations.
Key Points
& Sleep is an important modulator of EEG abnormalities and seizures in patients with
epilepsy; non-REM sleep activates and REM sleep inhibits epileptic discharges and
seizures.
& The differential diagnosis of complex nocturnal behaviors includes nocturnal seizures,
non-REM arousal disorders, REM sleep behavior disorder, and other parasomnias such as
sleep-related dissociative disorders.
& Seizures in nocturnal frontal lobe epilepsy consist of hypermotor activity involving
complex movements of the trunk and proximal extremities that are repetitive, high
amplitude, and high velocity and asymmetric tonic seizures having dystonic, dyskinetic,
and repetitive proximal movements that are highly stereotyped and frequent, often with
preserved consciousness.
& Sudden, brief, and asymmetric tonic posturing of one or more extremities, commonly
with both sides affected simultaneously, suggests early activation of the supplementary
sensorimotor area.
& Autosomal dominant nocturnal frontal lobe epilepsy is associated with mutations in the
transmembrane region of the neuronal nicotinic acetylcholine receptor alpha-4 subunit
(CHRNA4), beta-2 subunit (CHRNB2), and alpha-2 subunit (CHRNA2) and
corticotrophin-releasing hormone.
& While sleep-related complex motor seizures have been considered pathognomonic for
nocturnal frontal lobe epilepsy, extrafrontal origin is observed in up to 30% of patients,
most often from the temporal and insular regions but also from the posterior cortex.
& Parasomnias are undesirable physical events or experiences that occur during entry into
sleep, within sleep, or during arousals from sleep and involve complex, seemingly
purposeful, goal-directed behaviors without consciousness.
& Arousal disorders can be precipitated by sleep deprivation and recovery from sleep
deprivation due to slow-wave sleep rebound; mental and physical stress; fever; menses;
environmental stimuli; sleep disorderYproducing arousals, including sleep apnea and
periodic limb movements; neurologic and psychiatric comorbid conditions; alcohol; and
medications, particularly psychotropic drugs.
& The non-REM parasomnias include confusional arousals, sleep terrors, and sleepwalking,
classified as distinct entities but in reality representing a spectrum of behaviors produced
by a faulty arousal system.
& The presenting complaint in REM sleep behavior disorder is recurrent dream-enacting
behaviors, including vocalizations and motor activity in relation to altered dream
mentation. Sleep-related injuries to the affected person or bed partner occur in
approximately one-third of cases.
& REM sleep behavior disorder usually emerges later in life, typically after age 50, and
has a striking male predominance. The condition is frequently associated with the
>-synucleinopathies, which include Parkinson disease, dementia with Lewy bodies,
and multiple system atrophy.
& Activation of common pattern generators is responsible for the overlapping semiology of
nocturnal seizures and arousal disorders.
& Video polysomnogram-EEG has several advantages over routine polysomnogram,
including the improved ability to identify interictal and ictal EEG abnormalities and
correlate clinical behaviors with neurophysiologic parameters.

& Complex nocturnal behaviors can be differentiated by the state from which episodes
emerge. Nocturnal seizures typically arise from light non-REM sleep often during
sleep-wake transitions, while arousal disorders arise from slow-wave sleep preferentially
during the first third of the sleep period, and REM sleep behavior disorder episodes
present from REM sleep preferentially during the last third of the sleep period.
& REM sleep behavior disorder is the only parasomnia that requires diagnostic confirmation
by polysomnography. The pathognomonic polysomnographic finding in patients with
clinical suspicion of REM sleep behavior disorder is REM sleep without atonia.

Zee, Phyllis C. MD, PhD; Attarian, Hrayr MD, FAASM, FCCP;
Videnovic, Aleksandar MD, MSc. CONTINUUM: Lifelong Learning in Neurology. Volume
19(1) Sleep Disorders. February 2013: p 132Y147.
Abstract
ABSTRACT:
Purpose:
This article reviews the recent advances in understanding of the fundamental properties of
circadian rhythms and discusses the clinical features, diagnosis, and treatment of circadian
rhythm sleep disorders (CRSDs).
Recent Findings:
Recent evidence strongly points to the ubiquitous influence of circadian timing in nearly all
physiologic functions. Thus, in addition to the prominent sleep and wake disturbances, circadian
rhythm disorders are associated with cognitive impairment, mood disturbances, and increased
risk of cardiometabolic disorders. The recent availability of biomarkers of circadian timing in
clinical practice has improved our ability to identify and treat these CRSDs.
Summary:
Circadian rhythms are endogenous rhythms with a periodicity of approximately 24 hours. These
rhythms are synchronized to the physical environment by social and work schedules by various
photic and nonphotic stimuli. CRSDs result from a misalignment between the timing of the
circadian rhythm and the external environment (eg, jet lag and shift work) or a dysfunction of the
circadian clock or its afferent and efferent pathways (eg, delayed sleep-phase, advanced
sleep-phase, nonY24-hour, and irregular sleep-wake rhythm disorders). The most common
symptoms of these disorders are difficulties with sleep onset and/or sleep maintenance and
excessive sleepiness that are associated with impaired social and occupational functioning.
Effective treatment for most of the CRSDs requires a multimodal approach to accelerate circadian
realignment with timed exposure to light, avoidance of bright light at inappropriate times, and
adherence to scheduled sleep and wake times. In addition, pharmacologic agents are
recommended for some of the CRSDs. For delayed sleep-phase, nonY24-hour, and shift work
disorders, timed low-dose melatonin can help advance or entrain circadian rhythms; and for shift
work disorder, wakeenhancing agents such as caffeine, modafinil, and armodafinil are options for
the management of excessive sleepiness.

Key Points
& Circadian rhythms are physiologic and behavioral cycles with a recurring periodicity of
approximately 24 hours, generated by the endogenous biological pacemaker, the
suprachiasmatic nucleus, located in the anterior hypothalamus.
& Circadian rhythms are synchronized with the earths rotation by daily adjustments in the
timing of the suprachiasmatic nucleus, following the exposure to stimuli that signal the
time of day. These stimuli are known as zeitgebers (German for time-giver), of
which light is the most important and potent stimulus. The magnitude and direction of the
change in phase depends on when within the circadian system the light pulse is presented.
& Delayed sleep-phase disorder is characterized by chronic or recurrent inability to fall
asleep and wake up at socially acceptable times, resulting in symptoms of difficulty
falling asleep and excessive daytime sleepiness, particularly in the morning.
& Diagnosis of delayed sleep-phase disorder is made by careful history and well-kept sleep
diaries with or without actigraphy for a minimum of 7 days (preferably 14 days).
& Bright light (full spectrum or blue enriched) in the morning for 2 hours shortly after the
minimum of the core body temperature rhythm (typically occurring 2 to 3 hours before
natural wake-up time) has been shown to successfully advance circadian rhythms in
patients with delayed sleep-phase disorder.
& Patients with advanced sleep-phase disorder typically present with symptoms of daytime
sleepiness (most prominent in the late afternoon or early evening hours) sleep
maintenance difficulty, and early morning awakening.
& Practical therapeutic approaches for advanced sleep-phase disorder include timed light
exposure in the evening and avoiding light in early morning hours. Melatonin or
hypnotics may be beneficial for sleep-maintenance insomnia.
& Creating a cognitively enriched environment with structured social and physical activity
during the day is an important therapeutic modality for patients with irregular sleep-wake
rhythm disorder, especially if combined with a healthy bedtime routine and a nocturnal
environment conducive to sleep.
& NonY24-hour sleep-wake disorder is characterized by a chronic or recurrent pattern of
sleep and wake cycles that are not synchronized to the 24-hour environment. Typically a
consistent daily drift (usually to later and later times) of sleep-onset and wake-up times
occurs.
& In blind patients with nonY24-hour sleep-wake disorder, melatonin is the therapeutic
mainstay together with strong structured behavioral and social cues such as timing of
meals, planned activities, and regular physical exercise. This same approach is
recommended for sighted persons, with the additional option of bright light exposure in
the morning shortly after awakening.
& Internal desynchronization of physiologic rhythms resulting from time-zone changes is
responsible for most of the symptoms of jet-lag disorder. The severity of jet lag depends
on several variables, including the number of time zones crossed and the direction of
travel.
& Nonpharmacologic treatment approaches are important in the management of jet-lag
disorder. Strategic exposure and avoidance of exposure to light have been utilized as an
effective treatment approach.
& Based on the American Academy of Sleep Medicine practice parameters, timed
melatonin administration is recommended as treatment for jet-lag disorder.
& Night shift workers and rotating shift workers get less sleep than day workers or evening
shift workers.

& Shift work disorder is accompanied by significant social and economic burdens in the
form of accidents, lost days of work, poorer performance, and increased health care use.
& For night shift workers, bright light exposure ranging from 1000 lux to 10,000 lux either
in 3- to 6-hour blocks or in 20-minute to 1-hour blocks (ending 2 hours before the end of
the shift) has been shown to accelerate circadian adaptation to night work and improve
both alertness and performance.
Sleep and Comorbid Neurologic

Disorders
Watson, Nathaniel F. MD, MSc; Viola-Saltzman, Mari DO. CONTINUUM: Lifelong Learning
in Neurology. Volume 19(1) Sleep Disorders. February 2013: p 148Y169.
Abstract
ABSTRACT:
Purpose of Review:
An understanding of the impact of sleep on neurologic disorders, and the impact of neurologic
disorders on sleep, provides fresh opportunities for neurologists to improve the quality of life and
functioning of their patients.
Recent Findings:
Sleep-disordered breathing (SDB) is a risk factor for cerebrovascular disease and should be
considered in all TIA and stroke patients. Sleep disorders can amplify nociception and worsen
headache disorders; and some headaches, including those related to SDB and hypnic headache,
are sleep specific. REM sleep behavior disorder may be an early sign of neurodegenerative
disease. Focal lesions of almost any etiology (eg, multiple sclerosis and CNS malignancies) in the
hypothalamus, basal forebrain, or brainstem may result in sleep disturbance, sleepiness, and
insomnia. Sleep-related hypoventilation and fatigue are common in neuromuscular disease. SDB
and epilepsy are mutually facilitatory, and poor sleep can exacerbate epilepsy.
Summary:
Continued surveillance for sleep disorders by neurologists is rewarded by new treatment avenues
in their patients with the possibility of improved clinical outcomes.
Key Points
& Sleep-disordered breathing is a term that encompasses all breathing disturbances in sleep,
including obstructive sleep apnea, central sleep apnea, Cheyne-Stokes respirations, and
upper airway resistance syndrome.
& Sleep-disordered breathing is an independent risk factor for stroke.
& Sleep-disordered breathing should be considered in all stroke and TIA patients.
& Cervical dystonia is associated with reduced sleep quality and sleepiness, even when
compared to patients with other focal movement disorders.

& Sleep disturbance is present in nearly 90% of patients with Huntington disease, with most
rating it a significantly important factor in overall health impairment.
& Sleep is impaired in 20% to 50% of children and young adults with Tourette syndrome.
& Obstructive sleep apnea is a common cause for headache upon awakening, particularly if
it dissipates during the course of the day.
& Bruxism should be considered as a potential cause for headache upon wakening.
& Patients with cluster headache have an eightfold increased risk of obstructive sleep apnea
when compared to age- and sex-matched controls.
& Hypnic headache is sleep specific, occurring relative to REM sleep at a consistent time of
the night.
& Epilepsy and sleep-disordered breathing are mutually facilitatory, with higher rates of
each disorder observed in patients with the other disorder when compared to the general
population.
& One in five patients with epilepsy has seizures exclusively during sleep.
& Most sleep-related seizures occur out of non-REM sleep, most often non-REM sleep
stage N2.
& Nocturnal frontal lobe epilepsy can be difficult to distinguish from parasomnias, with
stereotypia, minimal postevent confusion, and shorter duration providing clues that the
event was epileptic in nature.
& Medication side effects should always be considered as a cause of sleepiness in a patient
with epilepsy.
& When approaching a sleep problem in a patient with neurodegenerative disease,
medication side effects should always be considered as a causative factor, particularly
with cholinergic, antipsychotic, and sedative hypnotic medications.
& Sundowning is common in patients with neurodegenerative diseases; treatment is best
focused on nonpharmacologic measures, such as improved sleep hygiene and a consistent
daytime schedule, that include light exposure and regular physical activity.
& REM sleep behavior disorder can herald preclinical synucleinopathies, and as such
patients with REM sleep behavior disorder should be followed for signs and symptoms
of these diseases over time.
& Indicators of sleep-disordered breathing in patients with neuromuscular disorders include
disrupted nocturnal sleep, daytime sleepiness and fatigue, morning headache, and trouble
concentrating.
& Objective tests indicating nocturnal hypoventilation in neuromuscular disease include
daytime PaCO2 greater than 45 mm Hg, nocturnal oximetry showing oxygen saturation
of 88% or less for 5 consecutive minutes, nocturnal PaCO2 of greater than 55 mm Hg
for 10 minutes or more or a 10 mm Hg or greater increase in PaCO2 during sleep
(compared to wake) to a value exceeding 50 mm Hg for 10 minutes or more, maximal
inspiratory pressure of less than 60-cm water, and forced vital capacity of less than
50% predicted.
& When treating patients with neuromuscular disorders with bilevel positive airway
pressure, improving ventilation is often more important than relieving airway obstruction,
and wide pressure-support windows may be necessary.
& Multiple sclerosis lesions in brain areas subserving sleep onset, alertness, and REM sleep
paralysis can precipitate insomnia, sleepiness, and REM sleep behavior disorder.
& Insomnia is common in multiple sclerosis and likely due to many disease-related
factors, such as pain, spasticity, bladder dysfunction, depression, anxiety, and medication
side effects.
& Sellar or suprasellar malignancies can indirectly cause sleep-disordered breathing by
endocrinologic dysfunction causing obesity.

& Secondary narcolepsy can occur from treatment of CNS malignancies with surgical
resection or radiation therapy in the perihypothalamic region.

Silber, Michael H. MBChB, FAAN. CONTINUUM: Lifelong Learning in Neurology. Volume
19(1) Sleep Disorders. February 2013: p 170Y184.
Abstract
ABSTRACT:
Purpose of Review:
This article reviews the sleep-related movement disorders, including restless legs syndrome
(RLS; Willis-Ekbom disease), periodic limb movement disorder, rhythmic movement disorders,
sleep-related bruxism, and sleep-related leg cramps.
Recent Findings:
The prevalence of clinically significant RLS is 1.5% to 3.0%. The pathophysiology of RLS may
involve abnormal iron transport across the blood-brain barrier and down-regulation of putaminal
D2 receptors. The availability of the rotigotine patch provides an additional form of dopaminergic
therapy for RLS. Calcium channel alpha-2-delta ligands (gabapentin, gabapentin enacarbil, and
pregabalin) provide alternative therapies for RLS especially in patients with augmentation,
impulse control disorders, or hypersomnia induced by dopamine agonists. Long-term use of
opioid medication is safe and effective for refractory cases of RLS.
Summary:
RLS is a common disorder causing considerable morbidity. Accurate diagnosis and appropriate
investigations are essential. Many effective therapies are available, but the side effects of each
class of medication should be considered in determining optimal treatment. Periodic limb
movements of sleep, bruxism, and rhythmic movement disorders are sleep-related phenomena
often accompanying other sleep disorders and only sometimes requiring primary therapy.
Sleep-related leg cramps are generally idiopathic. Management is challenging with few effective
therapies.
Key Points
& Restless legs syndrome that is prominent enough to occur at least twice a week and cause
moderate or severe distress has a prevalence of 1.5% to 3.0%.
& Restless legs syndrome is diagnosed clinically and requires a history of an uncontrollable
urge to move the legs while at rest that is worse in the evening or night and is relieved by
movement such as walking.
& Mimickers of restless legs syndrome, especially sleep-related leg cramps relieved by
stretching or massaging the affected muscle and positional discomfort relieved by
changing position rather than walking, must be excluded.

& More than 50% of patients with restless legs syndrome have a family history of the
disorder that is usually inherited in an autosomal dominant pattern. Multiple loci and
several polymorphisms associated with restless legs syndrome have been identified.
& Low intracerebral iron, especially in the basal ganglia, possibly related to abnormalities in
iron transport across the blood-brain barrier, may underlie restless legs syndrome.
Restless legs syndrome is also associated with abnormalities in the dopamine system,
possibly due to down-regulation of D2 receptors.
& Restless legs syndrome has profound effects on quality of life, equivalent to those
caused by other chronic medical illnesses, and is associated with insomnia, depression,
and anxiety.
& An association may exist between restless legs syndrome and vascular disease, but more
research is needed to better define the degree and nature of the relationship before basing
therapeutic decisions on concern for vascular risk.
& Serum ferritin should be measured in patients with chronic persistent restless legs
syndrome.
& Oral iron replacement should be administered with vitamin C if serum ferritin levels are
abnormally low and should be considered if levels are low normal (G50 K/L).
& Nonergot dopamine agonists (ropinirole, pramipexole, and rotigotine transdermal patch)
are highly effective treatments for restless legs syndrome but are associated with
augmentation (worsening of restless legs syndrome earlier in the day), impulse control
disorders, and hypersomnia.
& Impulse control disorders, including pathologic gambling and compulsive shopping,
occur in 6% to 17% of patients taking dopamine agonists for restless legs syndrome and
may only manifest 9 months or longer after starting treatment.
& Calcium channel alpha-2-delta ligands (gabapentin, pregabalin, and gabapentin
enacarbil) are all effective in restless legs syndrome but can cause dizziness, unsteadiness,
hypersomnia, and weight gain.
& High-potency opioids, such as oxycodone, hydrocodone, and methadone, are highly
effective for refractory restless legs syndrome but are addictive and may exacerbate sleep
apnea. In most patients they can be used for prolonged periods with no tolerance and
continued effectiveness.
& Periodic limb movements of sleep occur in 80% to 88% of patients with restless legs
syndrome and are also frequent in narcolepsy, REM sleep behavior disorder, obstructive
sleep apnea, and normal people 60 years of age or older.
& In the absence of restless legs syndrome, periodic limb movements of sleep are generally
nonspecific epiphenomena that accompany fragmented sleep with arousals and only
rarely require treatment as a specific disorder.
& Sleep-related bruxism occurs in 8% of people, with highest prevalence in young adults.
It can cause tooth damage and jaw discomfort but does not usually result in
disrupted sleep.
& Rhythmic movement disorder, including head banging and body rocking, is common in
infancy and early childhood but may persist into adulthood.
& Insomnia accompanying rhythmic movement disorder should be treated, but specific
treatment for the movements is only needed if risk of bodily injury or severe disruption to
sleep of a bed partner exists.
& Nocturnal leg cramps are usually idiopathic, and treatment is difficult; quinine should
generally not be used because of serious potential side effects, including
thrombocytopenia and cardiac arrhythmias.

Hoban, Timothy F. MD. CONTINUUM: Lifelong Learning in Neurology. Volume 19(1) Sleep
Disorders. February 2013: p 185Y198.
Abstract
ABSTRACT:
Purpose of Review:
The purpose of this review is to examine how sleep disorders in children are affected by age and
comorbid medical influences, and to discuss current understanding of how the clinical
manifestations, pathophysiology, and treatment of common childhood sleep disorders differ from
those of the adult population.
Recent Findings:
Recently established age-specific norms are required for accurate interpretation of
polysomnograms and multiple sleep latency tests in children.
Summary:
Sleep disorders such as insomnia, obstructive sleep apnea, and excessive daytime somnolence are
common in both children and adults, but the clinical manifestations and underlying
pathophysiology of these disorders vary substantially with age. For example, the bedtime
struggles of a temperamental toddler are associated with different symptoms and causative factors
compared to psychophysiologic insomnia affecting a middle-aged person. Similarly, a 6-year-old
child with obstructive sleep apnea is more likely to exhibit daytime inattention and hyperactivity
as a referable daytime symptom than the clear-cut lethargy or sleepiness that most affected adults
experience. This review will examine how insomnia, excessive sleepiness, and obstructive sleep
apnea differ in children compared to adults.
Key Points
& The symptoms, pathophysiology, and treatments for some sleep disorders are
substantially different for children compared to adults.
& Ten percent of children do not achieve consolidated nighttime sleep by 1 year of age.
& Sleep-onset association disorder is one of the most common underlying or contributing
causes for insomnia and night waking in infants and younger children.
& Many families try extinction-based interventions for only a few nights, encounter an
extinction burst of temporarily worse symptoms, and abandon the technique before it
has had time to be effective.
& Delayed sleep phase is an extremely common cause or contributing factor to insomnia in
adolescent or older preadolescent children. When present, medication treatment alone is
unlikely to be effective.
& Sleeping in late on weekend and nonYschool days can reduce the effectiveness of
other interventions for delayed sleep phase.

& Obstructive sleep apnea is underdiagnosed in children in part because the lack of
observed respiratory pauses and obvious daytime sleepiness in most affected
children limit parent and medical practitioner recognition that the condition might
be present.
& Although obesity represents a risk factor for childhood obstructive sleep apnea, children
with low or normal body weight can have substantial obstructive sleep apnea, particularly
when underlying adenotonsillar hypertrophy is present.
& Of children undergoing adenotonsillectomy for treatment of obstructive sleep apnea,
50% to 75% may still have some degree of obstructive sleep apnea postoperatively
(usually milder).
& Continuous positive airway pressure is considered a first-line treatment for obstructive
sleep apnea in children.
& Nasal steroids and rapid maxillary expansion represent promising alternative techniques
for treatment of childhood obstructive sleep apnea.
& Some pediatric studies suggest that mild obstructive sleep apnea is more likely to be
associated with symptoms suggestive of attention deficit hyperactivity disorder than more
severe forms are.
& The presence of significant sleepiness in a child with snoring is concerning for the
presence of severe underlying obstructive sleep apnea.
& Chronically insufficient nighttime sleep represents a very common cause of sleepiness
and poor academic performance in children.
Sleep and Fatigue Countermeasures for

the Neurology Resident and Physician
Avidan, Alon Y. MD, MPH, FAASM. CONTINUUM: Lifelong Learning in Neurology.
Volume 19(1) Sleep Disorders. February 2013: p 204Y222.
Abstract
ABSTRACT:
Purpose of Review:
Fragmented sleep, prolonged work hours, misalignment of sleep-wake cycles, and an expectation
to make medical decisions when alertness levels are reduced are pervasive in neurology residency
training. Sleep loss in residency training can lead to cognitive and psychosocial impairment and
accidents, compromise patient care, and reduce the trainees quality of life. Neurology residents
experience levels of hypersomnolence similar to residents in surgical specialties and have
comparable subjective levels of sleepiness as persons with pathologic sleep disorders such as
narcolepsy and obstructive sleep apnea. Over the past 2 decades, work-hour limitations were
established to alleviate fatigue and sleepiness. However, the implementation of work-hour
limitations alone does not guarantee alleviation of fatigue and may be insufficient without
additional key measures to prevent, counteract, and control sleepiness when it strikes. This article
provides effective strategies to combat sleepiness, such as modification of the on-call structure
(night float), power naps, and caffeine, in neurologists in training and those who are at risk for
excessive sleepiness.

Recent Findings:
Despite two specific work-hour restrictions set by the Accreditation Council for Graduate
Medical Education, the most recent in July 2011, little data exist about the efficacy of work-hour
restrictions alone in improving fatigue and sleepiness. Curtailed work hours, while appearing
attractive on the surface, have important financial, educational, and patient care imperfections and
fail to address the core issueVsleepiness.
Summary:
Historically, sleepiness and fatigue place both residents and patients at risk. Excessive sleepiness
in residency training occurs because of sleep deprivation and a spectrum of other factors, such as
mood disorders or even the anxiety of anticipating being woken up. An effective model to
counteract sleep deprivation and its consequences is a multiplayer approach that uniquely targets
and addresses the needs of all the stakeholders. A sleep medicine perspective is proposed along
with other interventions to prevent adverse consequences.
Key Points
& Historically, residents have faced sleep loss and fatigue related to long working hours at
the hospital. Recent regulations restrict on-duty scheduling in an effort to reduce
sleepiness and improve safety.
& While data regarding ACGME work-hour stipulations among neurology trainees seem to
trend toward improved quality of life in trainees, this comes at the cost of degradation of
education opportunities and patient care.
& Subjective sleepiness in residents is alarming as it is similar to that found in cohorts of
sleep patientsVparticularly those with narcolepsy and sleep apneaVwho exhibit
pathologic levels of hypersomnolence.
& Causes of hypersomnolence in residents are most likely circadian factors leading to
diminished alertness during the nighttime; insufficient sleep; interrupted and fragmented
sleep when on call; and comorbid medical, psychiatric, and primary sleep disorders.
& Consequences of sleep loss in residency training include disturbances in neurocognitive
and psychomotor functioning as well as reduced satisfaction with work experience,
increased stress, weight gain, pregnancy-related complications, and increased risk of
accidents inside and outside the hospital.
& In neurology residencies, implementation of a night-float system may be operationally
difficult, and data about its efficacy in improving sleepiness are equivocal.
& The only reliable way to counteract and reverse the physiologic need for sleep is to sleep.
& Countermeasures for sleep and fatigue in residency training consist of a number of
interventions focusing on strategies to improve alertness, such as strategically placed
15- to 20-minute short naps (also known as power naps), caffeine intake, and
light exposure.
& In neurology residencies, integration of a standardized sleep medicine curriculum,
including teaching modules on fatigue countermeasures, may assist residents in
managing excessive sleepiness when it occurs.
& The Swiss cheese model attempts to intercept sleepiness-related errors by supporting the
integration of a comprehensive multifaceted approach, including the use of alerting
techniques such as power naps, sleep education, and operational measures to curtail work
hours.

Ethical Perspectives
Ethical Considerations
Dr Stephanie Vertrees, Austin
Neurology and Sleep
Associates, 711-E1 West 38th St,
in REM Sleep Behavior Austin, TX 78705, svertrees@

austinneurosleep.com.
Disorder Dr Vertrees reports no

disclosure. Dr Greenough has
received a grant from
Dartmouth Center for Clinical
Stephanie Vertrees, MD; Glen P. Greenough, MD, FAASM and Translational Science
Pilot and Collaborative Studies
Program.
Unlabeled Use of
ABSTRACT Products/Investigational
Use Disclosure:
A patient diagnosed with REM behavior sleep disorder (RBD) has as much as a 65% risk Drs Vertrees and Greenough
of developing an !-synucleinopathy. Currently, it is not possible to predict whether an report no disclosures.
individual will develop a disease, or, if so, which disease.The neurologist treating the * 2013, American Academy
patient must consider (1) the difference between disclosing a diagnosis and disclosing of Neurology.
the risk of a diagnosis; (2) whether to disclose this risk to patients; and (3) if deciding
to disclose the risk, the appropriate timing of such a conversation.
Case
Note: This is a hypothetical case.
A 70-year-old man presented to the clinic at the insistence of his wife,
who noted the gradual development of strange behaviors at night, including
shouting, swearing, kicking, and punching. Her husband had been a
sleeptalker and restless sleeper for many years. More recently, the episodes
had become more violent, and his wife had bruises on her left arm and leg as
a result of his nocturnal movements. She now slept in a different room.
The patient was somewhat embarrassed. He was aware of nightmares and
reported dreaming of muggers attacking him and his wife. In the dream,
he would fight the assailants. Much to his chagrin, when he would awaken he
would find he had been punching his wife. He had also injured himself,
recently falling out of bed and sustaining a laceration over his eyebrow.
Polysomnography revealed frequent periodic limb movements in
non-REM sleep and elevated motor tone in REM sleep, which in
conjunction with the history were consistent with the diagnosis of REM
sleep behavior disorder (RBD). Because RBD is associated with an increased
risk of developing a neurodegenerative disease, the neurologist felt that
the risk should be disclosed to the patient and his wife, but a colleague
advised that this would be unwarranted as it would only cause worry for
them. This case raises the following ethical questions:
1. Should the physician disclose the risk of neurodegenerative disease in
patients with RBD? If so, how? If not, why?
2. Does the disclosure of a diagnosis differ from the disclosure of a risk?

REM Sleep Behavior Disorder
DISCUSSION
RBD is a parasomnia characterized by dream enactment behaviors during REM
sleep, including excessive motor activity and vocalizations. RBD is known to be a
common clinical feature in the !-synucleinopathies (including Parkinson disease
[PD], dementia with Lewy bodies, and multiple system atrophy), and it can also be
seen in spinocerebellar ataxia type 3, Huntington disease (HD), and other neu-
rologic conditions. Several reports have shown that patients who are diagnosed
with idiopathic RBD (iRBD) and who have no clinical signs or symptoms of the
!-synucleinopathies are at a significantly increased risk of developing one of
the !-synucleinopathies later in life. Schenck and colleagues first reported the
development of PD in 38% of patients originally diagnosed with iRBD.1 Later
studies show the risk of developing neurodegenerative disease ranges from 45%
to 65%, with higher rates seen the longer patients are followed.2Y4
A significant delay from the onset of the RBD symptoms to the onset of the
!-synucleinopathy exists. For men initially diagnosed with iRBD over the age of
50, the mean time to onset of the !-synucleinopathy is 13 years.5 The link
between neurodegenerative disease and RBD may be related to the pathologic
involvement of common brainstem structures, including the nigrostriatal com-
plex, locus coeruleus, raphe nucleus, and others.6 Furthermore, approximately
50% of patients with RBD have mild cognitive impairment, and RBD is asso-
ciated with cognitive decline in PD.7
The association between RBD and neurodegenerative disorders raises the
issue of disclosure of potential risk for patients presenting with RBD who have
no signs or symptoms of neurodegenerative disorders, an issue that has not
been addressed in the peer-reviewed literature. The difficulty lies in the dif-
ference between disclosing a diagnosis versus disclosing the risk of a diagnosis.
The diagnosis of RBD is not absolutely predictive of the development of a
neurodegenerative disease, but rather suggests an increased susceptibility or
probability (compared to the general population) that the patient will develop
such a disorder in the future. Clinical examples with similar characteristics
include genetic susceptibilities toward dementia and for sudden unexplained
death in epilepsy (SUDEP).8,9
The ethical principles of autonomy, informed consent, and respect for
persons support disclosure of information to patients.10 In RBD, however, a
patients individual risk of developing a neurodegenerative disorder is
uncertain, and physicians are unable to provide definitive information. By shar-
ing the implications of the diagnosis of RBD with patients, physicians enable
them to make an informed decision, thus preserving patients autonomy.
Because decisions are based on general rather than specific probabilities, both
patient and physician may be frustrated, but the potential frustration from
uncertainty is an inadequate justification for withholding information the
patient needs to make an informed decision. Furthermore, withholding infor-
mation may harm the doctor-patient relationship, which relies on veracity, the
ethical principle, and the physicians duty to tell the truth.10
Does disclosing the risk to the patient benefit the management or pre-
vention of the disorder for which the patient is at risk? With SUDEP, disclosure
of the risk may help prevent sudden death by promoting compliance in taking
antiepileptic medications.9 With RBD and neurodegenerative diseases, however,
some physicians may find it pointless to disclose the risk of developing disease

because no interventions exist to prevent or delay disease development, and
no definitive disease-altering treatments exist. Thus, some physicians argue
against disclosing information that would disturb a patients current life unless
and until signs of neurodegenerative disease develop. The patient might live
many years awaiting the onset of a disorder that may never occur. By sharing
the risk of developing an !-synucleinopathy, they would argue, the patient may
experience years of needless worry or anxiety as they anticipate developing a
neurodegenerative disease. Many physicians seem to share this view, as de-
mentia diagnoses are withheld from patients in about 50% of cases.11 This is in
part done to shield patients from worry about developing a dementia.
Recent data support disclosure of probabilities of a diagnosis on the basis of
the principle of beneficence. Up to 92% of patients with dementia and their
family members desire to know diagnoses as soon as possible.12,13 Reasons
include putting affairs in order, such as wills and advance directives; arranging
for assistance with housing, caregiving, and finances; initiating treatment as
soon as possible; and indicating preferences for treatments and research par-
ticipation. The aforementioned actions are best done while the patient retains
decision-making capacity.12Y15 Similar benefits would be found with early dis-
closure of the risk of iRBD. The physician, patient, and family can discuss the
implications of developing an !-synucleinopathy, and if desired the patient can
seek a second opinion or referral to a subspecialist.
In addition, disclosure to patients and family members alerts them to watch
for the onset of symptoms such as tremor, bradykinesia, memory impairment,
or orthostasis, which may allow for early diagnosis. If neurodegenerative disease
is diagnosed, therapies can be initiated for enhancing quality of life. If a
definitive neuroprotective agent for !-synucleinopathies was identified, this is a
population that might benefit from early treatment with this therapy. The
knowledge that most patients have a desire to know what is wrong with them
and that beneficial interventions exist if an !-synucleinopathy develops may
sway physicians to disclose the risk of a neurodegenerative disorder. The phy-
sicians might otherwise be reluctant to disclose information, believing that pa-
tients have little to gain.15
Even if the physician chooses not to discuss the association of iRBD and !-
synucleinopathies, the patient and family are likely to discover this information
on the Internet (eg, www.scientificamerican.com/blog/post.cfm?id=is-rem-
sleep-disorder-early-sign-of-2008-12-24), which would also likely lead them to
conclude correctly that the physician had withheld important information from
them, which violates the principles of truth telling and respect for autonomy.
Patients may have grounds for legal action against physicians if information is
withheld, unless there is overwhelming evidence that receiving such informa-
tion is harmful, invoking the so-called therapeutic privilege.10 Depending on the
website, the patient may be exposed to misinformation.
Could disclosure of the future risk of neurodegenerative disease be harmful?
The risks of stigmatization, developing hopelessness and despair, suicidality, or
losing personal identity have been claimed as reasons not to disclose the
diagnosis of Alzheimer dementia.16 One model for disclosure of neurodegener-
ative processes has been with HD, which has been associated with RBD;
however, the paradigm of disclosure is different from iRBD because the risk can
be more accurately estimated based on HDs genetic nature and available

REM Sleep Behavior Disorder
testing.6,8 Disclosure of HD genetic status and disease risk has been known to
cause anxiety, depression, and disruption of marriages and interpersonal re-
lationships in presymptomatic HD patients as well as in undiagnosed individuals
who have been notified of the risk of developing disease before genetic testing
is performed.17Y19 Research in HD and dementia has shown that the harmful
effects of disclosure are short-lived and that patients lacked signs of long-term
psychological distress.12,19
Whether to break such news to patients should not be the question. Instead,
the determination of when and how to do it is important.8,20 Early disclosure
appears to be the best approach rather than waiting until symptoms develop.
But how early? This may depend on the individual patient. Disclosures should
always occur in a patient-centered manner. The physician should determine
what the patient knows about the disease and the risks it poses, and then build
on the patients knowledge and address any misconceptions. The conversation
should focus on the goals of care. Emphasis should be placed on the availability
of the physician for regular monitoring and, should disease develop, for
symptomatic treatment and disease management.14,21 Patients are likely to be
reassured when physicians express their availability to care for them if an
!-synucleinopathy were to develop. This approach, consistent with the principle
of nonabandonment, is key. Neurologists should commit to closely follow
patients to look for signs of neurodegenerative disease, allowing for early di-
agnosis and initiation of available therapies.
Finally, some patients may not want bad news shared with them. An ap-
propriate approach would be to first ask patients if they want to know the future
implications of their RBD diagnosis. If the patient expresses a desire to be
informed, a discussion of neurodegenerative disease risk is relevant, and pa-
tients should be warned that bad news is coming. Patients may decline such a
discussion when first offered. Patients have an autonomous right to refuse to
hear this bad news.22 If the patient initially declines such a discussion, the issue
can be raised at a future visit once the patient has had time to digest the
diagnosis of RBD. If the patient continues to decline, expressing ones avail-
ability to have such a discussion in the future when and if the patient so desires
might be a reasonable next step.
RECOMMENDATIONS
Based on ethical principles and experience with other diseases, the patient in
the case would benefit from the disclosure of the risk of developing neu-
rodegenerative disease when informed of his RBD diagnosis. Telling the truth
about the future risk of neurodegenerative disease with RBD while being hon-
est about the uncertainty of the risk promotes his autonomy, is beneficent, and
will engender the patients trust in the physician. Furthermore, discussing the
diagnosis of RBD and offering to discuss the potential long-term implications
would be appropriate.
REFERENCES
1. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38%
of 29 older men diagnosed with idiopathic rapid eye movement sleep behaviour disorder.
Neurology 1996;46(2):388Y393.

2. Schenck CH, Bundlie SR, Mahowald MW. REM sleep behavior disorder (RBD): delayed emergence
of parkinsonism and/or dementia in 65% of older men initially diagnosed with idiopathic RBD,
and an analysis of the maximum and minimum tonic and/or phasic electromyographic
abnormalities found during REM sleep. Sleep 2003;26(suppl):A316.
3. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behaviour disorder as an
early marker for neurodegenerative disease: a descriptive study. Lancet Neurol 2006;5(7):
572Y577.
4. Postuma RB, Gagnon JF, Vendette M, et al. Quantifying the risk of neurodegenerative disease in
idiopathic REM sleep behavior disorder. Neurology 2009;72(15):1296Y1300.
5. American Academy of Sleep Medicine. The international classification of sleep disorders, second
edition: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine,
2005.
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(6):385Y401.
7. Gagnon JF, Bertrand JA, Genier Marchand D. Cognition in rapid eye movement sleep behavior
disorder. Front Neurol 2012;3(82). Epub 2012 May 17. doi: 10.3389/fneur.2012.00082.
8. Arribas-Ayllon M. The ethics of disclosing genetic diagnosis for Alzheimers disease: do we need
a new paradigm? Br Med Bull 2011;100:7Y21.
9. Hamada H, Nass R. Ethical perspectives in neurology: ethical considerations in sudden
unexplained death in epilepsy. Continuum Lifelong Learning Neurol 2010;16(3):242Y245.
10. Beauchamp TL, Childress JF. Principles of biomedical ethics, 6thed. New York: Oxford University
Press, 2008.
11. Carpenter B, Dave J. Disclosing a dementia diagnosis: a review of opinion and practice, and a
proposed research agenda. Gerontologist 2004:44(2):149Y158.
12. Erde EL, Nadal EC, Scholl TO. On truth telling and the diagnosis of Alzheimers disease.
J Fam Pract 1988;26(4):401Y406.
13. Robinson L, Gemski A, Abley C, et al. The transition to dementiaVindividual and family
experiences of receiving a diagnosis: a review. Int Psychogeriatr 2011;23(7):1026Y1043.
14. Holt GR. Timely diagnosis and disclosure of Alzheimer disease gives patients opportunities to
make choices. South Med J 2011;104(12):779Y780.
15. Connell CM, Roberts JS, McLaughlin SJ, Carpenter BD. Black and white adult family members
attitudes toward a dementia diagnosis. J Am Geriatr Soc 2009;57(9):1562Y1568.
16. Mattsson N, Brax D, Zetterberg H. To know or not to know: ethical issues related to early
diagnosis of Alzheimers disease. Int J Alzheimers Dis 2010;4:doi:10.4061/2010/841941.
17. Robins Wahlin TB. To know or not to know: a review of behaviour and suicidal ideation in
preclinical Huntingtons disease. Patient Educ Couns 2007;65(3):279Y287.
18. Hakimian R. Disclosure of Huntingtons disease to family members: the dilemma of known but
unknowing parties. Genet Test 2000;4(4):359Y364.
19. Tibben A, Duivenvoorden HJ, Niermeijer MF, et al. Psychological effects of presymptomatic DNA
testing for Huntingtons disease in the Dutch program. Psychosom Med 1994;56(6):526Y532.
20. Fisk JD, Beattie BL, Donnelly M, et al. Disclosure of the diagnosis of dementia. Alzheimers
Dement 2007;3(4):404Y410.
21. Lee L, Weston WW. Disclosing a diagnosis of dementia: helping learners to break bad news.
Can Fam Physician 2011;57(7):851Y852.
22. Marzanski M. Would you like to know what is wrong with you? On telling the truth to patients
with dementia. J Med Ethics 2000;26(2):108Y113.

Practice
Sleep and Fatigue

Dr Alon Y. Avidan, UCLA
Department of Neurology,
710 Westwood Blvd, Room
1-169 RNRC, Los Angeles,
CA 90095-6975,
avidan@mednet.ucla.edu.
Countermeasures for
Dr Avidan is a member of
the speakers bureaus of
the Neurology Resident
GlaxoSmithKline, Purdue
Pharma, Teva Pharmaceuticals,
and UCB, and serves as a
consultant for Merck & Co. Inc.
and Physician
Unlabeled Use of Alon Y. Avidan, MD, MPH, FAASM
Use Disclosure:
Dr Avidan reports
no disclosure. ABSTRACT
* 2013, American Academy Purpose of Review: Fragmented sleep, prolonged work hours, misalignment of
of Neurology. sleep-wake cycles, and an expectation to make medical decisions when alertness
levels are reduced are pervasive in neurology residency training. Sleep loss in resi-
dency training can lead to cognitive and psychosocial impairment and accidents,
compromise patient care, and reduce the trainees quality of life. Neurology resi-
dents experience levels of hypersomnolence similar to residents in surgical special-
ties and have comparable subjective levels of sleepiness as persons with pathologic
sleep disorders such as narcolepsy and obstructive sleep apnea. Over the past 2
decades, work-hour limitations were established to alleviate fatigue and sleepiness.
However, the implementation of work-hour limitations alone does not guarantee
alleviation of fatigue and may be insufficient without additional key measures to
prevent, counteract, and control sleepiness when it strikes. This article provides ef-
fective strategies to combat sleepiness, such as modification of the on-call structure
(night float), power naps, and caffeine, in neurologists in training and those who are at
risk for excessive sleepiness.
Recent Findings: Despite two specific work-hour restrictions set by the Accreditation
Council for Graduate Medical Education, the most recent in July 2011, little data exist
about the efficacy of work-hour restrictions alone in improving fatigue and sleepiness.
Curtailed work hours, while appearing attractive on the surface, have important
financial, educational, and patient care imperfections and fail to address the core
issueVsleepiness.
Summary: Historically, sleepiness and fatigue place both residents and patients at
risk. Excessive sleepiness in residency training occurs because of sleep deprivation and
a spectrum of other factors, such as mood disorders or even the anxiety of an-
ticipating being woken up. An effective model to counteract sleep deprivation and its
consequences is a multiplayer approach that uniquely targets and addresses the
needs of all the stakeholders. A sleep medicine perspective is proposed along with
other interventions to prevent adverse consequences.
INTRODUCTION AND prolonged, variable training period

HISTORICAL ANECDOTES and restrictive lifestyle in which resi-
During his tenure as the first surgeon- dents literally lived in the hospital and
in-chief at the Johns Hopkins Medical worked around the clock with mini-
School in the 1800s, William Stewart mal opportunities for sleep and rest.1
Halsted (Figure 11-1) introduced a Two centuries later, serious questions

investigate the death of a young woman
named Libby Zion at a New York City
teaching hospital in 1988.4 At the time
that these political developments
were occurring in New York, public
interest in the issue of sleep loss and
fatigue in medical training was galvan-
ized by the National Academy of
Sciences Institute of Medicine report
To Err is Human, released in the
spring of 2000, which stressed the need
to investigate and address human fac-
tors, such as sleep deprivation, that are
potentially involved in violations of
patient safety.5 Political pressure and
FIGURE 11-1 William Stewart Halsted,
first surgeon-in-chief at public concern alone, however, could
Johns Hopkins Medical not form the basis for a rational and
School in the 1800s, who introduced the informed discussion of the issue of
concept of intense apprenticeship around
the clock without work-hour regulations. sleep and fatigue in medical training
Until the 1980s, this was the structure of without the addition of a third ele-
most residency training programs in the
United States. ment, namely, an expanded under-
Photograph courtesy of the Yale University
standing of the science of sleep loss
Manuscripts & Archives Digital Images and fatigue. The existence of ample
Database, Yale University, New Haven, CT.
en.wikipedia.org/wiki/File:William_Stewart_ supporting data from research regard-
Halsted_Yale_College_class_of_1874.jpg. ing the effects of sleep loss and fatigue
in humans from field studies in other
have arisen about this traditional prac- occupations and from studies directly
tice. Specifically, emerging data have addressing residency training, was crit-
begun to raise questions about the ical to the formulation of an empirically
impact of sleep loss and fatigue on based approach to this issue.
patient safety and trainees lives and Reports of widespread violations of
learning opportunities. the New York regulations and concern
We now recognize that the relentless about the ability of medical education
hospital shifts, decreased opportunities and professional organizations to enforce
for sleep, and minimal recuperation compliance with Resident Review Com-
time traditionally experienced by train- mittee work-hour standards helped pro-
ees as well as physicians in practice can pel the filing of a petition with the
impact health and well-being, increase Occupational Health and Safety Admin-
the likelihood of medical errors, reduce istration by several trainee groups in the
the quality of the educational experi- spring of 2001. Similar requirements
ence, and lead to poor quality of life.2,3 were incorporated into legislative bills,
These findings have been the impetus introduced by Rep John Conyers in the
for policy development regarding this House of Representatives (HR 3236) and
issue. New York was the first state to Sen Jon Corzine in the Senate (S 2614).
ratify resident work-hour legislation, an In response to mounting pressure, in
action that evolved from the 1989 September 2001, the Accreditation
recommendations of the Bell Commis- Council for Graduate Medical Education
sion, a task force established by the New (ACGME) charged its Work Group on
York State Commissioner of Health to Resident Duty Hours and the Learning

Sleep and Fatigue Countermeasures
KEY POINTS
h Historically, residents Environment with developing a set of The ACGME solicited comments re-
have faced sleep loss recommendations regarding common garding the policy15 and eventually
and fatigue related to requirements for resident duty hours adopted these new changes in July
long working hours at across accredited programs in all medi- 2011. Since then, stakeholders, includ-
the hospital. Recent cal specialties. These recommendations, ing program directors and residents,
regulations restrict which went into effect on July 1, 2003, have had discussions about where ex-
on-duty scheduling in included an 80-hour workweek, contin- actly to set the bar when balancing
an effort to reduce uous duty hours limited to 24, and 1 day training requirements and educational
sleepiness and improve in 7 free of patient duties, and they were opportunities with the assurance of pa-
safety. inspected, discussed, and interpreted in tient safety and sleepiness and fatigue
h While data regarding the community of neurologists.6Y11 Re- countermeasures.16Y22
ACGME work-hour cent data suggest a trend toward im-
stipulations among proved quality of life, but a sense of EXTENT OF EXCESSIVE
neurology trainees discontent about the repercussions SLEEPINESS IN RESIDENTS
seem to trend toward
on patient care and education has The Epworth Sleepiness Scale (ESS)
improved quality of life
arisen.12,13 (Appendix A), an eight-item question-
in trainees, this comes
at the cost of degradation
In 2008, coinciding with the 5-year naire, asks respondents to rate their
of education anniversary of the previous ACGME likelihood of dozing from 0 to 3
opportunities and work-hours standards, the Institute of under several specific conditions, with
patient care. Medicine published a manuscript, Resi- 3 indicating the highest likelihood of
dent Duty Hours: Enhancing Sleep, sleepiness. The highest possible score
Supervision, and Safety, providing for is 24. The generally accepted value for
additional changes, including new work- the upper limit of normal is 10 to 11.
load limits, greater supervision require- Values between 11 and 13 are consid-
ments and on-call duty restrictions.14 ered to be mild sleepiness; between 14
and 17, moderate sleepiness; and over
17, severe sleepiness.23,24
When compared to the general
population, residents exhibited sleepi-
ness indices that are equivalent to those
found in some clinical populations of
patients with sleep apnea and narco-
lepsy (Figure 11-2, Figure 11-3).26,27
CAUSES OF EXCESSIVE
SLEEPINESS IN RESIDENTS
Wakefulness and sleep are states that
are regulated by a balance of the ho-
meostatic drive for sleep and circadian
influences on alertness and controlled
by an interaction of external and inter-
FIGURE 11-2 Data representing mean values for the
Epworth Sleepiness Scale (ESS) for nal stimuli (Figure 11-4).28 Appropriate
normal people and patients with sleep duration and proper circadian
a variety of sleep disorders (eg, insomnia, sleep apnea,
and narcolepsy) compared with data reporting ESS wakefulness contribute to optimal men-
values obtained in a multicenter survey of medical tal performance.29 When residents do
residents. An ESS score above 10 suggests clinically
significant excessive sleepiness. not attain sufficient sleep (ie, less than
26 5 hours of sleep per night), the homeo-
Data from Papp KK, Stoller EP, Sage P, et al. Acad Med.
journals.lww.com/academicmedicine/pages/articleviewer.aspx? static drive to sleep increases precip-
year=2004&issue=05000&article=00007&type=abstract.
itously, inducing increased susceptibility

KEY POINT
h Subjective sleepiness
in residents is
alarming as it is similar
to that found in
cohorts of sleep
patientsVparticularly
those with
narcolepsy and sleep
apneaVwho exhibit
pathologic levels of
hypersomnolence.
FIGURE 11-3 Specialties most likely to report

experiences of sleep deprivation.
Sleepiness in neurology residents is
comparable to that of surgical specialties such as orthopedic
surgery. Specialties associated with the least amount of
sleepiness include dermatology, pathology, and radiology.
27
Data from Baldwin DC Jr, Daugherty SR. Sleep. www.journalsleep.
org/ViewAbstract.aspx?pid=25943.
FIGURE 11-4 Two-process model depicting how the sleep-wake cycle is driven by a
gradually increasing sleep load that is being concurrently opposed by
alerting signals generated by the suprachiasmatic nuclei. During the day,
the sleep drive accumulates until it reaches a critical threshold. Wake propensity is the
integrated function of the homeostatic sleep load and the opposing circadian alerting
signal. The drive for wakefulness increases throughout the day, with a midafternoon dip
( ), until about 9:00 PM or 10:00 PM, when it drops during the normal sleep time (j).
For on-call residents, who need to sleep during the day, the drive for wakefulness can
result in difficulties falling asleep and maintaining sleep and in fragmented sleep. Residents
are at risk for sleepiness during the night as the normal circadian drive for wakefulness
decreases at 9:00 PM or 10:00 PM, when they are expected to be awake and at work.

KEY POINT
h Causes of hypersomnolence to sleep30 and diminution in cognitive causes include insufficient sleep and frag-
in residents are most functioning. The end result is an mented sleep on call nights (Figure 11-6).
likely circadian factors increased tendency to fall asleep in An insufficient sleep quantity may result
leading to diminished improper situations, including morning when the resident obtains less sleep
alertness during the rounds, lectures, and driving home than is sufficient for optimal rest (8 hours
nighttime; insufficient at the conclusion of the call duty. As a night). Insufficient sleep represents
sleep; interrupted and shown in Figure 11-4, the circadian the most important primary cause for
fragmented sleep when drive for wakefulness increases through- sleepiness in neurology residency train-
on call; and comorbid out the daytime, with a midafternoon ing. Yet, even when sleep duration is
medical, psychiatric, and decline, until the late evening hours sufficient, residents may still experience
primary sleep disorders.
(9:00 PM to 10:00 PM), when it dips excessive sleepiness if their sleep is of
down during the habitual sleep time. poor quality. Fragmented sleep in resi-
Residents who are on call at night or dents during on-call nights may be
during the night-float rotation and caused by interruptions from repeated
need to sleep during the day may phone calls, pager beeping, and even the
experience a drive for wakefulness that anticipation of being on call despite
leads to difficulties initiating and main- sufficient opportunities to sleep.
taining sleep, as well as fragmented Comorbid sleep disturbances may
sleep. During the night while the resi- be due to primary sleep disorders, such
dent is awake and at work, the normal as obstructive sleep apnea, delayed sleep-
circadian drive for wakefulness is low. phase syndrome, narcolepsy, restless legs
Excessive daytime sleepiness in resi- syndrome, and insomnia.33 Residents
dency training may be a consequence of may also be taking CNS-acting medi-
a spectrum of underlying factors that cations, which cause sleepiness. Mood
occur independently or as comorbidi- disorder is an important contributor to
ties (Figure 11-5) (Case 11-1). Primary daytime sleepiness and every resident
FIGURE 11-5 Potential causes of excessive sleepiness in resident physicians.

Case 11-1
A 30-year-old neurology resident on the stroke service was noted to be late to morning report
on a daily basis for 2 weeks. She had difficulty remembering details about her patients and
often failed to note important facts relating to their care. During the didactic sessions, she
rarely participated and became confused when quizzed about cases presented. This behavior
was out of character for her as she had an excellent neurology foundation as a neuroscience
PhD student and received honors during her neurology acting internship as a medical student.
On several occasions, she was noted to make judgment errors when administering tissue
plasminogen activator to her patients without following protocol. These errors were
intercepted by the senior resident on the team but were brought to the attention of the
inpatient attending neurologist, who discussed these issues with the neurology residency
program director.
The program director met with the resident, who arrived to the appointment tearful. She
reported that she was exhausted from being on call and felt overwhelmed. As this was the
fourth month of her residency, she was eager to identify solutions to remedy the difficulties.
She indicated that she felt dejected because she did not have enough time to spend with her
two children and husband. She reported a 13.6-kg (30-lb) weight gain since beginning her
residency training and had the sensation of choking and shortness of breath at night. Upon
awakening in the morning, she was very sleepy and often had a headache. She craved
chocolate and other candy and described consuming up to five cups of coffee per day. She
reported problems falling asleep at night and was worried about her performance. She rarely
had time to read about her patients and felt that her knowledge base was below what was
expected of her. She was afraid to ask for help because she did not want to appear weak
in the eyes of her classmates. She lived about 30 miles from the hospital and often spent 1.0 to
1.5 hours each day commuting. Over the past few weeks she had begun using caffeine tablets and
energy drinks that helped address her sleepiness, but she would crash 2 to 3 hours later. She
made up for lost sleep on the weekends, taking 3- to 4-hour naps on Saturdays and Sundays
when finishing rounds in the hospital, but she could not fall asleep until 1:00 AM or 2:00 AM on
these days. She was contemplating quitting residency because these difficulties were causing
marital discord, depression, and a poor quality of life. She was no longer enthusiastic about a
profession in neurology.
Comment. This hypothetical case summarizes a number of key issues leading to fatigue
and burnout in neurology residency training. It draws attention to key domains affected by
sleep deprivation: professional, educational, psychosocial, lifestyle, and quality of life.
Causes of sleepiness in this resident could be related to (1) sleep deprivation, (2) possible
untreated sleep apnea, (2) delayed sleep-phase circadian rhythm disorder, (3) depression, and
(4) poor sleep hygiene. Even when not on call, this resident is at risk for sleepiness, highlighting the
argument that work-hour limitations by themselves have not helped curtail sleepiness in this
individual. Her sleep deprivation is likely leading to endocrine dysregulation of energy
homeostasis, which may lead to weight gain and obesity31 and could play a role in the emergence
of sleep-disordered breathing.32 The resident should have a formal sleep clinic evaluation,
undergo a sleep study since obstructive sleep apnea is suspected, work with a clinical psychologist
on improving her sleep hygiene and identifying relaxation techniques at bedtime, limit
caffeine consumption, and take strategic power naps. The resident may also be referred to
the graduate medical education office to see an educational counselor who could assist in
remedying her educational techniques and in finding strategies to help her spend more time
with her family. The program director, together with the residency program, is responsible for
identifying other measures to assist the resident through this difficult period by tailoring
remedial educational sessions, altering her schedule to allow for more elective time as
treatment is underway, and encouraging the chief residents to continue to support and
monitor her progress.

FIGURE 11-6 Sleep fragmentation during on-call night. Two hypnograms, a graphic representations of sleep
stages as a function of time of night, are shown. Hypnogram A shows the sleep hypnogram of a
normal sleeper. The Y axis depicts stages of sleep as the individual falls into deeper sleep
proceeding from wake into stage 1 and 2 (light sleep), and stages 3 and 4 (non-REM sleep stage
N3 or deep/slow-wave sleep). Hypnogram B shows the sleep hypnogram of a typical resident on call. Sleep is
very fragmented by frequent interruptions during the night. As a result, the resident does not obtain an adequate
period of consolidated sleep, spends very little time in the restorative stages of sleep (slow-wave and REM),
and wakes up very sleepy just in time for morning rounds.
reporting sleepiness should be screened the population studied because they

for it. are designed for patients with neuro-
psychiatric syndromes.34
CONSEQUENCES OF SLEEP LOSS Numerous reports on sleep loss and
Sleep deprivation in neurology residents fatigue in medical training are available,
may be caused by a number of fac- including performance studies that
tors and has important consequences, evaluate specific effects on a variety of
as described in Table 11-1. Specific performance measures. These out-
domains impacted include personal, come variables may be broadly catego-
health, cognitive and neurobehavioral, rized as effects on neurocognitive and
professional, and patient care. Inter- psychomotor functioning in the labora-
estingly however, one recent article tory setting, performance of simulated
found that sleep-deprived neurology work-related and occupational tasks in
residents did not experience signifi- actual work settings, and mood and
cant cognitive impairment related to psychological state. The design of most
tasks of short duration.34 The authors of these studies involves comparisons
note that stressful work environments between precall (ie, rested) and postcall
(as those on the neurology ward) may (ie, sleep deprived) performance in a
promote partial adaptation, and the group of residents. Other interventions
methods used for the assessment of include the comparison of schedule
performance may not be applicable in types from a study by Landrigan and

TABLE 11-1 Consequences of Sleep Loss in Neurology Residency Training
b Personal
Less time with family and loved ones leading to depression and stress
b Health
Substances to counteract sleepiness/sleeplessness leading to substance use, misuse, or abuse
Increased likelihood for weight gain because of chronic sleep deprivation
Pregnancy-related complications (eg, pregnancy-induced hypertension, abruptio placentae and
preterm labor, and adverse fetal outcomes)
Increased risk of morbidity and mortality related to drowsy driving accidents
b Cognitive and Neurobehavioral
Inattention
Reduced reaction time
Decreased vigilance
Impaired memory
Decreased motivation
b Professional Duties
Impaired ability to perform procedures
Reduced ability to interpret data
Loss of professionalism
Degradation of communication skills when interacting with patients, colleagues, and staff
b Medical Education and Professional Development
Impaired retention of information
Reduced information processing and medical decision making
Decline in the motivation to learn
b Patient Care
Decreased quality of patient care
Increased likelihood for diagnostic and therapeutic errors
colleagues35 as is illustrated in Figure 11-7. impaired state, and fears of feeling

Baldwin and Daughertys study data belittled or humiliated. These mea-
depict the troubling correlation be- sures as well as learning improved in a
tween reduced sleep time and error dose-response fashion when sleep
and adverse event reporting in their time increased. Table 11-227,36 depicts
cohort of a national random sample of trends surrounding a number of im-
postgraduate year (PGY) 1 and PGY2 portant variables affecting patient care
residents (Figure 11-8).27 Despite the and safety reported by residents aver-
fact that their study was conducted aging 5 hours or less per night.27
before the ACGME work-hour regula- When reviewing the current liter-
tions of 2003 and 2011 went into effect, ature describing sleep deprivation in
it depicts a correlation between sleep physicians in training the following may
loss and less optimal residency training be concluded:
experience. As shown in Figure 11-9,27 1. Physicians in training, particularly
satisfaction with overall residency ex- those at more junior levels of
perience is reduced when total sleep training and in the surgical specialties,
time is diminished. This dissatisfaction regularly experience high levels of
with the residency experience is prob- sleep deprivation in the hospital
ably driven by an increased stress rating setting. These individuals are
during residency, working in an regularly asked to function and

FIGURE 11-7 Intern sleep and patient safety study. Landrigan and colleagues studied a
group of 20 interns under two conditions: a traditional schedule with
30-hour shifts scheduled every other shift, and an intervention schedule
in which shifts were limited to 16 hours. Medical errors were determined
by direct observation of interns and chart review, voluntary reports, and computerized
event-detection monitoring. Errors were categorized as including procedural, medication,
and diagnostic errors. The study included 2203 patient-days, 634 admissions, and
5888 hours of direct observation. The number of serious errors made by the interns was
35.9% higher during the traditional schedule than during the intervention schedule. The
rate of diagnostic (Dx) errors was 5.6 times higher during the traditional schedule than
during the intervention schedule.
FIGURE 11-8 Self-reported resident errors by average daily hours of sleep. This
national multispecialty survey demonstrates that reduced sleep hours
correlated with increased error reporting and greater likelihood of
having caused an adverse event.
Data from Baldwin DC Jr, Daugherty SR. Sleep.27 www.journalsleep.org/
ViewAbstract.aspx?pid=25943.

FIGURE 11-9 Average hours of sleep per night impacts residency experience. In this
large, national multispecialty survey, a dose-response relationship was
found between average hours of sleep per night and key subjective
parameters. Reported satisfaction with overall residency experience increased with
improved sleep time: ratings of personal stress, reports of working while personally
impaired, and experiences of feeling belittled and humiliated at work decreased with
greater hours of sleep. The opposite trend is seen with less sleep time.
27
Data from Baldwin DC Jr, Daugherty SR. Sleep. www.journalsleep.org/ViewAbstract.aspx?pid=25943.
work in circumstances that could psychomotor task completion

lead to impaired levels of alertness. to a greater extent than the accuracy
2. In general, restricted sleep of performance. In surgical
compromises the efficiency or specialties, this is termed the
speed of neurocognitive and operative inefficiency. Interestingly,
TABLE 11-2 Odds Ratio of Adverse Consequences Associated With

Insufficient Sleepa
Residents Averaging Fewer Than 5 Hours of Sleep Odds

Per Night Were Significantly More Likely to Report Ratio
Involvement in a malpractice case 2.02
Use of medication to stay awake 1.91
Serious conflict with others 1.86
Accidents or injuries 1.84
Making a serious medical error 1.74
Noticeable weight change 1.59
Increased use of alcohol 1.52
Serious conflict with other residents, attending or supervising 1.47
physicians, and nursing staff
a
Data from Baldwin DC Jr, Daugherty SR. Sleep.27 www.journalsleep.org/ViewAbstract.aspx?pid=
25943; Baldwin DC Jr, et al. Acad Med.36 journals.lww.com/academicmedicine/pages/articleviewer.
aspx?year=2003&issue=11000&article=00018&type=abstract.

KEY POINT
h Consequences of sleep in the short term, increased mental steps in rectifying these concerns; how-
loss in residency training effort appears to diminish these effects. ever, this is not the case.
include disturbances in 3. Residents, unfortunately, do not Literature on sleep deprivation based
neurocognitive and develop tolerance, immunity, on anecdotal and empiric evidence sug-
psychomotor functioning resistance, or adaptation to chronic gests that operational or systems
as well as reduced sleep loss over time. Specifically, changes in and of themselves neither
satisfaction with work studies of medical residents that correct nor guarantee well-rested and
experience, increased have focused on the relative impact optimally functioning residents.
stress, weight gain, of fatigue in different populations A number of key reasons for this
pregnancy-related did not demonstrate any improvement observation are as follows:
complications, and
or stabilization of impairment with 1. It is evident from recent experiences
increased risk of accidents
advancing levels of training. that operational or systems changes
inside and outside the
hospital.
4. One of the key findings and may be very difficult to execute
perhaps the most consistent and maintain.
conclusion in the literature on this 2. Despite the ACGME work-hour
topic is the impact of sleep deprivation stipulations in 2003 and 2011, no
on mood in resident physicians, evidence documents that the
which mirrors what is understood protection of residents from longer
about the impact of sleep hours at work translates to more-rested
deprivation in humans in general. residents and fewer medical errors.
5. Adverse physical health consequences 3. The culture of medical training
associated with sleep deprivation in continues to advocate that residents
residents consist of increased learn to adapt to the fatigue and
somatic complaints; changes in rigor of being on call with no formal
weight; and self-reported increases teaching of countermeasures in
in stress level, accidents and injuries, residency training or in medical
and alcohol and stimulant use.37 school. The requirement by the
Pregnancy-related complications ACGME that faculty and residents
include pregnancy-induced must be educated to recognize the
hypertension, abruptio placenta signs of fatigue and sleep deprivation
and preterm labor, and adverse fetal and must adopt and apply policies to
outcomes (low birth weight and prevent and counteract its potential
intrauterine growth retardation).38 negative effects on patient care and
The data also confirm an increased risk learning implies that that these
of morbidity and mortality related to resources are available in every
drowsy driving accidents in residents.39 residency program. In fact, a
recent study by Avidan and Silber40
COUNTERMEASURES FOR demonstrates that as many as 40%
SLEEPINESS AND FATIGUE IN of US neurology residency programs
RESIDENCY TRAINING do not have a board-certified sleep
As already discussed, data confirm the neurologist in their program and up
important relationship between cumu- to 7% of programs do not provide
lative sleep deprivation and patient care, lectures on sleep disorders in their
medical error, accidents, professional- curriculum. Without standardized
ism, and the well-being of trainees them- requirements for sleep lectures in
selves. Regulation of work hours and the curriculum or formal teaching
other operational changes such as sched- modules on fatigue countermeasures,
uling adjustments would therefore programs may send an implicit
seem to be sufficient and appropriate message to their trainees that sleep

KEY POINTS
countermeasures have to be learned didactic conferences take place when the h In neurology residencies,
independently or perhaps are not covering resident would be required to implementation of a
sufficiently important to be included leave the hospital. night-float system may
in the curriculum. be operationally difficult,
4. Work-hour regulations, stipulations, COUNTERMEASURES and data about its
rulings, and other operational Table 11-342Y53 provides a summary of efficacy in improving
changes cannot by definition govern the literature based on the focus of sleepiness are equivocal.
residents autonomy or behavior the intervention to counteract fatigue h The only reliable way to
outside of the workplace or dictate and sleepiness, examples of specific counteract and reverse
personal priorities regarding interventions, and potential barriers. the physiologic need for
adequate sleep and, therefore, Historically, industries such as sleep is to sleep.
cannot ensure that trainees are transportation and aviation, whose h Countermeasures for
protected from insufficient sleep. employees face similar challenges in sleep and fatigue in
5. Creative solutions, such as the fatigue management, have evaluated residency training
night-float on-call coverage system, and adopted strategically placed consist of a number of
have not been established to fatigue management strategies or interventions focusing
counteract fatigue. countermeasures in an effort to lessen on strategies to improve
the potential effects of sleep loss on alertness, such as
Interestingly, studies on resident per- strategically placed
formance found that, contrary to the employees. The most effective univer-
15- to 20-minute short
presumed expectations, residents who sal countermeasure that targets sleepi-
naps (also known as
were provided with an intervention ness is to obtain more sleep or to nap. power naps), caffeine
consisting of protected coverage time Sleep-related behavioral strategies to intake, and light
for sleep (lasting 4 hours) did not obtain enhance alertness in occupational set- exposure.
more sleep, as measured by ambulatory tings have included use of a variety of
EEG recording, than residents who were sleep schedules, including fixed and
not given this protected sleep time.41 split-sleep periods, on-demand and
The authors concluded that the resi- carefully timed consumption of caf-
dents in the intervention group used feine, timed light therapy, and teaching
their protected time to catch up on the principles of sleep hygiene.44,54
work, but not to sleep. Night-float sys- The principal objective of any rec-
tems are operationally difficult to ommendations to counteract sleepi-
achieve in smaller neurology programs ness and fatigue in residency training
or programs in which the residents are is to ensure that trainees consistently
required to cover a number of teaching obtain sufficient sleep to allow them
hospitals. For example, at UCLA, our to assume their duties and learn at an
residents rotate and take call at three optimal level. Neurology residency
different hospitals and have two programs need to provide educational
different services at the main teaching opportunities to teach their trainees
hospital. When we last examined the as well as faculty about interventions
night-float option, we realized that it regarding the consequences of sleep
would be difficult to integrate, espe- loss and fatigue. All stakeholders, in-
cially given that our internal review of cluding residents, program directors,
the neurology residency program and attending physicians, as well as
occurred concurrently with the ACGME medical school faculty, hospital
work-hour stipulations of July 2011. administrators, and hospital person-
Other concerns raised included the risk nel, should be provided with resour-
of intellectual isolation during the ces and tools focusing on alertness
night-float rotation and loss of edu- management strategies at a variety of
cational opportunities, given that our recurring venues. Education is key in

a
TABLE 11-3 Sleepiness and Fatigue Countermeasures
Focus of
Intervention Intervention Comments and Examples Potential Barriers
Improved Power naps Short prophylactic naps (before Work schedule may not be
alertness and during night shift) lasting conducive to incorporate
15Y20 min are therapeutic and power naps.
can ameliorate performance
decrement.
Caffeine Readily available. Strategic Diuretic action, tolerance,
consumption is the key. Effects dependence, mood disturbances,
appear within 15Y30 min; unpredictable gastrointestinal
half-life is 3Y7 h. May be used absorption, may erode sleep
for temporary relief of sleepiness quality and cause arousals
(initial 1Y3 h of work time). at night.
Caffeine (4 mg/kg) 30 min before
night shift in combination
with napping can be very helpful.
Drip coffee (7 oz), 110Y175 mg;
cola (8 oz), 30Y45 mg; tea (8 oz ),
10Y70 mg; Starbucks Grande,
320 mg; Mountain Dew (8 oz),
57 mg; Red Bull (331 mL), 80 mg.
Light exposure Bright light exposure has an Light exposure in the hospital
immediate alerting effect and setting is highly variable, and
should be maximized during consistent results may not be
work time. Exposure to bright achieved.
light should be minimized during
the day in residents on night-float
rotations, especially when driving
or walking home in the morning.
Wake-promoting Approved to treat excessive The use of wake-promoting agents
agents sleepiness in shift work schedule in residency training has not been
disorder. Role in residency clearly established and may infringe
training has not been established. on physician autonomy.
Increased sleep Educational The only way to definitively Physicians receive little
duration programs to reverse the physiologic education on normal sleep
improve sleep need for sleep is to sleep. and sleep hygiene.
knowledge
A notion exists that physicians
need to learn how to manage
without sleep.
Improved Maintain a regular Sleep hygiene may not be
sleep hygiene sleep-wake cycle. optimal because of the demands
Regularly exercise early in of the residency program and
the day. family obligations.
Increase exposure to bright
light during the day.

TABLE 11-3 Continued
Focus of Intervention Intervention Comments and Examples Potential Barriers

Increased sleep Improved sleep Avoid exposure to bright
duration hygiene light during the night.
(continued) (continued)
Avoid heavy meals within
3 h of bedtime.
Enhance the sleep environment.
Avoid caffeine, alcohol,
and nicotine.
Keep a relaxing routine.
When appropriate, Address comorbid insomnia. Certain hypnotics, especially
hypnotic therapy sedating antidepressants,
Ensure short-acting agents
at night may lead to sedation in
as opposed to hypnotics
the morning.
with long half-lives.
Avoidance of sleep Always try to obtain 7.5Y8.0 h Personal and educational
deprivation of sleep before on-call duty. responsibilities and time
before on-call with family and loved ones
responsibilities sometimes lead to sleep deficit.
Optimized sleep Protect sleep environment; Call rooms are sometimes
environment reduce noises; noisy. Custodian schedule
darken room, set a comfortable may not consistently allow
temperature. preparation of clean call
Ensure call rooms are protected, room around the clock.
cleaned, and available for
power naps.
Safety measures Safety measures Recognize the warning signs of Persons with moderate to
in the hospital sleepiness: falling asleep on severe sleep debt may fall
rounds; inattention; forgetfulness; asleep even while rating
difficulty focusing; restlessness; themselves quite alert.
irritability; inefficiency at work
(in surgical specialties, operative
inefficiency); conflicts with staff,
colleagues, family, and friends.
Warning signs include microsleeps
(brief intrusions of EEG harbingers
of sleep into wakefulness).
Safety measures Avoid driving when sleepy. Living within close proximity
outside the Nap or have a cup of coffee to a training hospital is not
hospital before driving. Live within close always possible when
proximity to the hospital to multiple training sites are
avoid opportunities for drowsy involved. Sometimes it is not
driving. Use public transportation, practical to share a ride or
car pool, or taxi to and from the take public transportation.
hospital for on-call duty. Cost can be a significant
issue for far-away sites.

TABLE 11-3 Continued
Focus of
Intervention Intervention Comments and Examples Potential Barriers
Circadian Maximize exposure Align circadian rhythm Nighttime illumination is usually
realignment to bright light at work; of alertness with the suboptimal to impact alertness.
on night float avoid exposure in the night work and
morning following the sleepiness with daytime
night shift sleep schedule.
Avoidance of sleep Avoid starting night Residents on jeopardy rotation
debt at the start of float duty following or those who cross-cover for sick
the night float insufficient sleep colleagues may be at risk for
recovery. sleep deprivation before their
expected call time.
Melatonin Improves duration Consistent data (dose, timing)
of daytime sleep in resident physicians have
not been clearly established.
Guidelines and Ensures that residents Operational or system changes
standardization of are able to perform that place limits on work hours
work-hour limitations at their optimal level in and of themselves do not
on a consistent basis guarantee well-rested and
across all programs. optimally functioning residents.
Restricted work hours Work-hour stipulations cannot
improve residents by definition govern residents
quality of life. behavior outside of the workplace.
Definitive support that improved
work hours translate to increased
sleep time is lacking.
Maximize Videotaped lectures Take advantage of May be associated with increased
educational and grand rounds technology to provide cost. Not available at all programs.
opportunities conferences at different
times (eg, video recording,
recording PowerPoint slides
with audio/notes online,
podcasts of grand rounds).
Rotating curriculum Structure the educational
curriculum to repeat and
reinforce material at different
venues using a variety of
approaches. Help protect
resident education time
whenever possible.
a
Data from Caldwell JA, et al, Aviat Space Environ Med.42 ingentaconnect.com/content/asma/asem/2009/00000080/00000001/
art00007; Rose SH, Curry TB, Mayo Clin Proc.43 www.ncbi.nlm.nih.gov/pmc/articles/PMC2770906/; Rosekind MR, et al, Behav Med.44
www.tandfonline.com/doi/abs/10.1080/08964289.1996.9933753?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_
pub%3dpubmed; Russo MB, Aviat Space Environ Med.45 Scott LD, et al, Nurs Res.46 journals.lww.com/nursingresearchonline/pages/
articleviewer.aspx?year=2010&issue=07000&article=00004&type=abstract; Balkin TJ, et al, Aviat Space Environ Med.47 ingentaconnect.
com/search/download?pub=infobike%3a%2f%2fasma%2fasem%2f2004%2f00000075%2fA00103s1%2fart00026&mimetype=
text%2fhtml; Batejat DM, Lagarde DP, Aviat Space Environ Med.48; Kushida CA, Curr Treat Options Neurol.49 link.springer.com/article/
10.1007/s11940-006-0025-7; Schweitzer PK, et al, Sleep.50 www.journalsleep.org/ViewAbstract.aspx?pid=26415; Walsh JK,et al,
J Sleep Res.51 onlinelibrary.wiley.com/doi/10.1111/j.1365-2869.1995.tb00233.x/abstract; Zee PC, Roth T, Potomac Center for Medical
Education and Rockpointe Corporation.52; Owens J AA, et al, American Academy of Sleep Medicine.53

addressing behavioral change on the Despite the call for enhanced sleep
individual level. The trainee needs to education, residents typically receive
not only comprehend the reasoning little or no formal teaching about
for the changes in order to buy into normal sleep and circadian rhythms
them but also accept personal re- or the essential role of sleep in main-
sponsibility for instituting them. Edu- taining adequate health and perform-
cation regarding sleep deprivation and ance in graduate medical education.
countermeasures needs to be em- Finding time to teach new fields,
braced at the institutional and system- such as sleep medicine, is difficult when
wide levels as it represents a critical medical school curricula are already
force driving change. From a social overcrowded.55,56 Despite the high
dynamic position, a key identified bar- prevalence of sleep disorders, many
rier to enhancing compliance with physicians fail to diagnose and some-
work-hour stipulations is the culture times misdiagnose sleep disorders in
of the workplace, which needs to sup- their patients.57,58 One community-
port and motivate the changes in in- based study reported rates as low as
dividuals. Education, an important 0.1% in the recognition and diagno-
vehicle for driving changes in lifestyle sis of sleep disorders.59 While sleep
or personal behaviors that impact knowledge surveys demonstrate a pos-
alertness, can attain the objective in a itive attitude toward sleep medicine,
collaborative as opposed to a regula- the data demonstrate that knowledge
tory approach. about sleep disorders is lacking among
FIGURE 11-10 Application of the Swiss cheese model to the sleep deprivationYrelated
consequences. The risk in this diagram is the sleep-deprived neurology
resident, while the potential harm represents possible consequences
related to the risk. The model shows that alignment of multiple layers (Swiss cheese)
of protection are more effective in prevention of harm as opposed to one layer (eg,
limiting work hours).
ACGME = Accreditation Council for Graduate Medical Education.

KEY POINTS
h In neurology residencies, medical students and physicians residency who take care of many of
integration of a alike.60Y63 Up to 90% of physicians rate them, all stakeholders must take effec-
standardized sleep their knowledge of sleep disorders as tive action toward a resolution.
medicine curriculum, fair or poor.64,65 A study by the
including teaching author reveals that medical textbooks REFERENCES
modules on fatigue available to physicians in practice fail to 1. Killelea BK, Chao L, Scarpinato V, Wallack
countermeasures, may provide sufficient sleep content rela- MK. The 80-hour workweek. Surg Clin North
assist residents in tive to other topics.66 It may therefore Am 2004;84(6):1557Y1572, x.
managing excessive be argued that to better manage sleep 2. Veasey S, Rosen R, Barzansky B, et al. Sleep
sleepiness when it disorders in residency training, pro- loss and fatigue in residency training: a
occurs. reappraisal. JAMA 2002;288(9):1116Y1124.
grams should set as a priority the
h The Swiss cheese model enhancement of sleep medicine con- 3. Howard SK, Gaba DM, Rosekind MR,
attempts to intercept Zarcone VP. The risks and implications of
tent in the curriculum, providing excessive daytime sleepiness in resident
sleepiness-related errors modules on basic principles of sleep physicians. Acad Med 2002;77(10):1019Y1025.
by supporting the
and chronobiology; the impact of 4. Asch DA, Parker RM. The Libby Zion case:
integration of a
sleep deprivation; common myths one step forward or two steps backward?
comprehensive N Engl J Med 1988;318(12):771Y775.
multifaceted approach,
and misconceptions about sleep loss
and fatigue; an outline of the basic 5. Committee on Quality of Care; Kohn LT,
including the use of Corrigan J, Donaldson MS, eds. To err is
alerting techniques such principles of sleep hygiene; implemen- human: building a safer health system.
as power naps, sleep tation and use of well-established coun- Washington, DC: National Academies Press,
education, and termeasures; and specific systemwide 2000.
operational measures operational changes. Application of 6. Watson JC. Impact of the ACGME work hour
to curtail work hours. the Swiss cheese model (Figure 11-10) requirements: a neurology resident and
program director survey. Neurology
to counteract the possibility that sleep 2005;64(2):E11YE15.
deprivation will result in injury is a use-
7. Kissela B, Peltier W. ACGME work hours
ful representation of the argument, regulations: a perspective from neurology
provided that the management of the program directors. Neurology 2004;62(1):E3YE4.
sleep-deprived neurologist must in- 8. Larriviere D. Duty hours vs professional
clude a comprehensive multilayered ethics: ACGME rules create conflicts.
approach using a number of specific Neurology 2004;63(1):E4YE5.
countermeasures as described in 9. Dodick DW, Capobianco D, Kash K, et al.

Table 11-3.42Y53 Acgme, test thyself! Neurology 2009;73(21):
1811; author reply 1811.
CONCLUSION 10. Feske S. ACGME, test thyself! Neurology

2009;72(4):302Y303.
Several solutions and countermeas-
11. Govindarajan R, Salgado E. New ACGME
ures have been proposed to mitigate resident duty hour impacts neurology and
the problem of fatigue in neurology family medicine residents alike. Fam Med
residency. At present, work-hour lim- 2011;43(10):745Y746.
itation remains the only consistent 12. Schuh LA, Adair JC, Drogan O, et al.
and universal approach that is adopted Education research: neurology residency
training in the new millennium. Neurology
and adhered to by residency programs. 2009;72(4):e15Ye20.
Because sleepiness may persist despite
13. Freeman WD, Nolte CM, Matthews BR, et al.
modification of work-hour schedules, Results of the American Academy of
all stakeholders need to ensure that ef- Neurology resident survey. Neurology
fective countermeasures are integrated 2011;76(13):e61Ye67.
in a collaborative manner. Given that 14. Ulmer C, Wolman DM, Johns MME, eds.
Committee on Optimizing Graduate Medical
sleep disturbances are ubiquitous in neu-
Trainee (Resident) Hours and Work Schedule
rology patients and, to a large extent, to Improve Patient Safety, National Research
the physicians during their first years of Council. Resident duty hours enhancing sleep,

supervision, and safety. Washington, DC: mixed-method study. Acad Med 2004;
The National Academies Press, 2009. 79(5):394Y406.
psnet.ahrq.gov/resource.aspx?resourceID=8815.
27. Baldwin DC Jr, Daugherty SR. Sleep
Accessed October 5, 2012.
deprivation and fatigue in residency
15. Nasca TJ, Day SH, Amis ES Jr; ACGME Duty training: results of a national survey of
Hour Task Force. The new recommendations first- and second-year residents. Sleep
on duty hours from the ACGME Task Force. 2004;27(2):217Y223.
N Engl J Med 2010;363(2):e3.
28. Borbely AA, Achermann P. Sleep
16. De Martino RR, Brewster LP, Kokkosis AA, homeostasis and models of sleep regulation.
et al. The perspective of the vascular surgery [see comment]. J Biol Rhythms 1999;14(6):
trainee on new ACGME regulations, fatigue, 557Y568.
resident training, and patient safety. Vasc
Endovascular Surg 2011;45(8):697Y702. 29. Carrier J, Monk T. Circadian rhythms of
performance: new trends. Chronobiol Int
17. Flynn TC. Invited comment on: the surgical 2000;17(6):719Y732.
residency and ACGME reform: steep
learning or sleep learning? Am J Surg 30. Jewett M, Dijk D, Kronauer R, Dinges D.
Dose-response relationship between sleep
2011;202(3):372Y373.
duration and human psychomotor vigilance
18. Alpert JS, Frishman WH. A bridge too far: and subjective alertness. Sleep 1999;22(2):
a critique of the new ACGME duty hour 171Y179.
requirements. Am J Med 2012;125(1):1Y2.
31. Schmid SM, Hallschmid M, Jauch-Chara K,
19. Brown NM, Helmer SD, Yates CL, Osland JS. et al. A single night of sleep deprivation
The revised ACGME laparoscopic operative increases ghrelin levels and feelings of
requirements: how have they impacted hunger in normal-weight healthy men.
resident education? Surg Endosc J Sleep Res 2008;17(3):331Y334.
2012;26(6):1737Y1743.
32. Ursavas A, Ilcol YO, Nalci N, et al. Ghrelin,
20. Hoh BL, Neal DW, Kleinhenz DT, et al. leptin, adiponectin, and resistin levels in
Higher complications and no improvement sleep apnea syndrome: role of obesity. Ann
in mortality in the ACGME resident Thorac Med 2010;5(3):161Y165.
duty-hour restriction era: an analysis of
more than 107,000 neurosurgical trauma
International classification of sleep
patients in the Nationwide Inpatient
disorders, second edition: diagnostic and
Sample database. Neurosurgery
2012;70(6):1369Y1381; discussion 1381Y1362.
21. Navathe AS, Silber JH, Small DS, et al.
34. Reimann M, Manz R, Prieur S, et al.
Teaching hospital financial status and
Education research: cognitive performance
patient outcomes following acgme duty
is preserved in sleep-deprived neurology
hour reform [published online ahead of
residents. Neurology 2009;73(21):e99Ye103.
print]. Health Serv Res Aug 2 2012.
doi:10.1111/j.1475-6773.2012.01453.x. 35. Landrigan CP, Rothschild JM, Cronin JW, et
al. Effect of reducing interns work hours on
22. Waterman B. ACGME work-hour restrictions:
serious medical errors in intensive care units.
a better quality of life, but at what cost?
N Engl J Med 2004;351:1838Y1848.
Am J Orthop (Belle Mead NJ) 2012;41(7):
36. Baldwin DC Jr, Daugherty SR, Tsai R, Scotti
E102YE103.
MJ Jr. A national survey of residents
23. Johns MW. Sleepiness in different situations self-reported work hours: thinking beyond
measured by the Epworth Sleepiness Scale. specialty. Acad Med 2003;78(11):1154Y63.
Sleep 1994;17(8):703Y710.
37. Daugherty SR, Baldwin DC Jr, Rowley BD.
24. Johns MW. Sleep propensity varies with Learning, satisfaction, and mistreatment
behaviour and the situation in which it is during medical internship: a national survey
measured: the concept of somnificity. of working conditions. JAMA 1998;279(15):
J Sleep Res 2002;11(1):61Y67. 1194Y1199.
25. Mustafa M, Erokwu N, Ebose I, Strohl K. 38. Klebanoff MA, Shiono PH, Rhoads GG.
Sleep problems and the risk for sleep Outcomes of pregnancy in a national sample
disorders in an outpatient veteran of resident physicians. N Engl J Med
population. Sleep Breath 2005;9(2):57Y63. 1990;323(15):1040Y1045.
26. Papp KK, Stoller EP, Sage P, et al. The 39. Mansukhani MP, Kolla BP, Surani S, et al.
effects of sleep loss and fatigue on Sleep deprivation in resident physicians,
resident-physicians: a multi-institutional, work hour limitations, and related outcomes:

a systematic review of the literature. Postgrad Potomac Center for Medical Education
Med 2012;124(4):241Y249. and Rockpointe Corporation; 2011.
40. Avidan A, Vaughn B, Silber MH. The current 53. Owens J AA, et al. Alertness and fatigue
state of sleep medicine education in US education in residency esentation.
neurology residency training programs: where PowerPoint presentation. 2003. American
do we go from here? J Clin Sleep Med, In press. Academy of Sleep Medicine MEDSleep
Education Products, Educational,
41. Richardson GS, Wyatt JK, Sullivan JP, et al.
PowerPoint Presentations; 2006.
Objective assessment of sleep and alertness
in medical house staff and the impact of 54. Rosekind MR, Gander PH, Gregory KB, et al.
protected time for sleep. Sleep 1996;19(9): Managing fatigue in operational settings
718Y726. 2: an integrated approach. Behav Med
1996;21(4):166Y170.
42. Caldwell JA, Mallis MM, Caldwell JL, et al;
Aerospace Medical Association Fatigue 55. Ozuah PO. Undergraduate medical
Countermeasures Subcommittee of the education: thoughts on future challenges.
Aerospace Human Factors Committee. BMC Med Educ 2002;2:8.
Fatigue countermeasures in aviation. Aviat
56. Rosen RC, Rosekind M, Rosevear C, et al
Space Environ Med 2009;80(1):29Y59.
Physician education in sleep and sleep
43. Rose SH, Curry TB. Fatigue, disorders: a national survey of U.S. medical
countermeasures, and performance schools. Sleep 1993;16:249(3)Y254.
enhancement in resident physicians. Mayo
57. BaHammam AS. Knowledge and attitude of
Clin Proc 2009;84(11):955Y957.
primary health care physicians towards sleep
44. Rosekind MR, Gander PH, Gregory KB, et al. disorders. Saudi Med J 2000;21(12):1164Y1167.
Managing fatigue in operational settings.
58. Owens J. Introduction to special section:
1: physiological considerations and
NIH Sleep Academic Award program. Sleep
countermeasures. Behav Med 1996;21(4):157Y165.
Med 2005;6(1):45Y46.
45. Russo MB. Recommendations for the
59. Rosen RC, Zozula R, Jahn EG, Carson JL.
ethical use of pharmacologic fatigue
Low rates of recognition of sleep disorders
countermeasures in the U.S. military. Aviat
in primary care: comparison of a
Space Environ Med 2007;78(5 Suppl):
community-based versus clinical academic
B119YB127; discussion B128YB137.
setting. Sleep Med 2001;2(1):47Y55.
46. Scott LD, Hofmeister N, Rogness N, Rogers
60. Kovaci Z, Marendi M, Solji M, et al.
AE. An interventional approach for patient
Knowledge and attitude regarding sleep
and nurse safety: a fatigue countermeasures
medicine of medical students and physicians
feasibility study. Nurs Res 2010;59(4):250Y258.
in Split, Croatia. Croat Med J 2002;43(1):71Y74.
47. Balkin TJ, Kamimori GH, Redmond DP, et al.
61. Mahendran R, Subramaniam M, Chan YH.
On the importance of countermeasures in
Medical students behaviour, attitudes and
sleep and performance models. Aviat Space
knowledge of sleep medicine. Singapore
Environ Med 2004;75(3 Suppl):A155YA157.
Med J 2004;45(12):587Y589.
48. Batejat DM, Lagarde DP. Naps and modafinil 62. Mindell JA, Moline ML, Zendell SM, et al.
as countermeasures for the effects of sleep Pediatricians and sleep disorders: training and
deprivation on cognitive performance. Aviat
practice. Pediatrics 1994;94(2 Pt 1):194Y200.
Space Environ Med 1999;70(5):493Y498.
63. Orr WC, Stahl ML, Dement WC, Reddington
49. Kushida CA. Countermeasures for sleep loss D. Physician education in sleep disorders.
and deprivation. Curr Treat Options Neurol J Med Educ 1980;55(4):367Y369.
2006;8(5):361Y366.
64. Papp KK, Penrod CE, Strohl KP. Knowledge
50. Schweitzer PK, Randazzo AC, Stone K, et al. and attitudes of primary care physicians
Laboratory and field studies of naps and toward sleep and sleep disorders. Sleep
caffeine as practical countermeasures for Breath 2002;6(3):103Y109.
sleep-wake problems associated with night
work. Sleep 2006;29(1):39Y50. 65. Sateia MJ, Reed VA, Christian Jernstedt G.
The Dartmouth sleep knowledge and attitude
51. Walsh JK, Muehlbach MJ, Schweitzer PK. survey: development and validation. Sleep
Hypnotics and caffeine as countermeasures Med 2005;6(1):47Y54. Epub 2004 Dec 25.
for shiftwork-related sleepiness and sleep
66. Teodorescu MC, Avidan AY, Teodorescu M,
disturbance. J Sleep Res 1995;4(S2):80Y83.
et al. Sleep medicine content of major
52. Zee PC, Roth T. Shift work sleep disorders medical textbooks continues to be
in hospitals: reducing risk and improving underrepresented. Sleep Med 2007;8(3):
outcome. Slide Set CME sponsored by 271Y276. Epub 2007 Mar 21.

Practice
Coding for Sleep

Dr Jennifer R. Molano,
University of Cincinnati
Academic Health Center, 260
Disorders Stetson St, Ste 2300,

Cincinnati, OH 45267,
molanoje@ucmail.uc.edu.
Jennifer Rose V. Molano, MD Relationship Disclosure:
Dr Molano reports no
disclosure.
Unlabeled Use of
Use Disclosure:
Dr Molano reports no
Accurate coding is an important function of neurologic practice. This section disclosure.
of is part of an ongoing series that presents helpful coding in- * 2013, American Academy
formation along with examples related to the issue topic. Tips for diagnosis coding, of Neurology.
evaluation and management coding, procedure coding, or a combination are
presented, depending on which are most useful for the subject area of the issue.
DIAGNOSTIC CODING
The International Classification of Sleep Disorders, Second Edition: Diagnostic
and Coding Manual (ICSD-2)1 has the following main categories for sleep
disorders in adults: insomnia, sleep-related breathing disorders, hypersomnias,
circadian rhythm sleep disorders, parasomnias, sleep-related movement disorders,
and other sleep disorders. Coding for these disorders is disseminated in multiple
sections of the International Classification of Diseases, Ninth Revision, Clinical
Modification (ICD-9-CM).2 A full list of codes can be found at the following
website: www.cdc.gov/nchs/icd/icd9cm.htm
General ICD-9-CM Sections and Categories Associated with ICSD-2

Diagnoses
Sections Categories
Diseases of the Nervous System and Sense Organs 307, 327, 333, 347, 368
Mental Disorders 291, 292, 300, 307
Persons Encountering Health Services in Other V69
Circumstances
Symptoms, Signs, and Ill-Defined Conditions 780, 786
Primary sleep disorders, such as obstructive sleep apnea (OSA) or narcolepsy,

should not be used as codes until a diagnosis has been made after a formal
evaluation and symptoms can be used to order diagnostic testing. For example, in
a patient with symptoms of sleep-disordered breathing, symptoms such as snor-
ing (ICD-9-CM code 786.09 other respiratory abnormalities) and hypersomnia
(ICD-9-CM code 780.54) can be used to order the initial diagnostic polysomnog-
raphy for suspected OSA.
For sleep disorders due to a secondary cause, general guidelines are as follows:
1. If any sleep diagnosis is due to a mental disorder or a medical condition,
the underlying condition should be coded first.

Coding for Sleep Disorders
2. Any diagnosis associated with a drug or substance is coded as 292.85.

3. Any diagnosis associated with alcohol use is coded as 291.82.
For example, if a patient has either insomnia or hypersomnia due to a drug
or substance, the code 292.85 for drug-induced sleep disorders should be used.
If the patient has sleep difficulties due to alcohol use, then the code 291.82 for
alcohol-induced sleep disorders should be used.
Similar to the ICD-9-CM, the International Classification of Diseases, Tenth
Edition, Clinical Modification (ICD-10-CM) codes for sleep symptoms and
disorders can be found in various sections.2 A partial list of these sections is
included below.
General ICD-10-CM Sections Associated with Sleep Symptoms and

Disorders
Sleep Symptoms and Disorders Section

Sleep disorders not due to a substance or known F51
physiological condition
Sleep disorders G47
Abnormalities of breathing R06
Problems related to sleep Z72
Restless legs syndrome (G25.81) and somnolence (R40.0) are not included in
this table. Specific ICD-10-CM codes have been made for sleep disorders
associated not only with alcohol abuse or dependence (F10.182 or F10.282), but
also with individual drugs and substances, such as opioid use unspecified with
opioid-induced sleep disorder (F11.982) and other stimulant abuse with
stimulant-induced sleep disorder (F15.182).
CURRENT PROCEDURAL TERMINOLOGY CODES

Current Procedural Terminology (CPT) codes for commonly ordered studies in
sleep medicine are described below.3
Code Type of Study

95800 Sleep study, unattended, simultaneous recording of heart rate, oxygen
saturation, respiratory analysis (eg, by airflow or peripheral arterial
tone), and sleep time
95801 Sleep study, unattended, minimum of heart rate, oxygen saturation,
and respiratory analysis (eg, by airflow or peripheral arterial tone)
95803 Actigraphy testing, recording, analysis, interpretation, and report
(minimum of 72 hours to 14 consecutive days of recording)
95805 Multiple sleep latency or maintenance of wakefulness testing,
recording, analysis and interpretation of physiological measurements
of sleep during multiple trials to assess sleepiness

Continued
95806 Sleep study, unattended, simultaneous recording of heart rate,

oxygen saturation, respiratory airflow, and respiratory effort
(eg, thoracoabdominal movement)
95807 Sleep study, simultaneous recording of ventilation, respiratory effort,
ECG or heart rate, and oxygen saturation, attended by a technologist
95808 Polysomnography, any age, sleep staging with 1-3 additional
parameters of sleep, attended by a technologist
95810 Polysomnography, age 6 years or older, sleep staging with 4 or more
parameters of sleep, attended by a technologist
95811 Polysomnography, age 6 years or older, sleep staging with 4 or
more parameters of sleep and positive airway pressure, attended by
a technologist
95872 Polysomnography, younger than 6 years, sleep staging with 4 or more
additional parameters of sleep, attended by a technologist
95873 Polysomnography, younger than 6 years, sleep staging with 4 or
more additional parameters of sleep, with initiation of continuous
positive airway pressure therapy or bi-level ventilation, attended by
a technologist
CPT B 2010 American Medical Association. All rights reserved.

CPT is a registered trademark of the American Medical Association.
POLYSOMNOGRAPHY AND OTHER TYPES OF STUDIES

Both sleep study and polysomnography refer to the recording of various sleep
parameters for at least 6 hours. Polysomnography includes sleep staging with EEG,
submental EMG, and electrooculogram (EOC). Other sleep parameters can in-
clude heart rate with an ECG, respiratory effort, pulse oximetry or other measures
of gas exchange, limb movements with bilateral anterior tibialis EMG, extended
EEG monitoring, snoring, body position, and esophageal monitoring. A sleep study
does not include sleep staging in the analysis.
Polysomnography
Polysomnography performed in a sleep laboratory and attended by a technologist
is billed as 95810 if it is a diagnostic study and 95811 if it is a titration study with
continuous positive airway pressure after OSA has been diagnosed. Both codes
include sleep staging with at least four additional sleep parameters. Poly-
somnography that is attended by a technologist is billed as 95808 if only one to
three other sleep parameters are included.
The American Academy of Sleep Medicine (AASM) has published practice
guidelines for polysomnography and sleep studies.4 Polysomnography is rec-
ommended for the following indications:
1. To diagnose sleep-related breathing disorders especially in those with
congestive heart failure and symptoms of sleep-disordered breathing
2. To be used as a preoperative evaluation before upper airway surgery in
those with snoring or symptoms of OSA

3. To be performed as a part of a titration study for continuous positive airway

pressure treatment in those diagnosed with a sleep-related breathing disorder
4. To evaluate for sleep disturbance in patients with neuromuscular disorders
if a diagnosis has not been made after clinical assessment of sleep hygiene
and sleep schedules
5. To diagnose narcolepsy (must be performed on the evening before a
multiple sleep latency test)
6. To diagnose periodic limb movement disorder in those with repetitive leg
movements and associated symptoms such as nonrestorative sleep or
excessive daytime sleepiness.
Polysomnography can be considered in those with coronary artery disease
or stroke who have symptoms of sleep-disordered breathing, in those with sleep-
related behaviors that are potentially injurious, as well as in those with parasomnias
and seizures that are refractory to conventional treatment. Polysomnography is not
recommended to diagnose circadian rhythm disorders, chronic lung disease, rest-
less legs syndrome, depression, or common, uncomplicated, noninjurious para-
somnias, such as typical disorders of arousals, nightmares, enuresis, sleeptalking,
and bruxism.4 The study is also not recommended for the routine evaluation
for insomnia but can be considered if symptoms of sleep-disordered breathing
are present or if insomnia is refractory to treatment.5
Current national coverage guidelines from the Centers for Medicare and
Medicaid Services (CMS) only address the use of polysomnography in the
evaluation for OSA and provide coverage for polysomnography performed in a
dedicated sleep study laboratory.6 As a result, approval for polysomnography may
vary by Medicare carrier, and those ordering polysomnography should refer to
local Medicare guidelines to determine whether the test is covered for the
evaluation of narcolepsy, parasomnias, periodic limb movement disorder, and
other sleep disturbances.
Portable Monitoring
In addition to polysomnography that is performed in a sleep laboratory,
portable monitoring studies can be used to determine the presence of OSA.
Given recent discussions of changes that support the ordering of more out-of-
center testing, the AASM is currently in the process of determining not only the
types of portable monitors that are appropriate for the diagnosis of OSA but
also the patients who would be appropriate for these out-of-center studies.7
Portable monitoring studies have been categorized into three types. Type II
studies are portable monitors that include sleep staging and therefore can be
considered as unattended polysomnography that is not performed in a sleep
medicine laboratory. Type III studies are portable monitors that include at least
four channels measuring airflow or respiratory effort, heart rate, and oxygen
saturation. Type IV studies are portable monitors that use at least one channel
and typically include oximetry but do not meet criteria for the other types of
studies. Of note, a type I study is not associated with portable monitoring and
refers to polysomnography that is performed in a sleep medicine laboratory and
attended by a technologist.
Sleep studies associated with codes 95806 and 95807 refer to studies with
four channels that monitor ventilation, heart rate, oxygen saturation, and
respiratory effort (type III studies). Code 95806 should be used if the study is

not attended by a technologist, and code 95807 should be used if the study is
attended by a technologist.
The 95800 and 95801 codes were added in 2011 and refer to unattended out-
of-clinic sleep studies with three channels that monitor heart rate, oxygen
saturation, and respiratory analysis (type IV studies). Either airflow or peripheral
arterial tone can be used for respiratory analysis; respiratory effort is not
included. Code 95800 should be used if sleep time is recorded, and code 95801
should be used if sleep time is not recorded. G codes also have been used to
report home sleep studies as seen below.
G Code Type of Study

G0398 Type II Portable Monitor
G0399 Type III Portable Monitor
G0400 Type IV Portable Monitor
According to CMS national guidelines, type II or type III portable monitoring

can be covered to diagnose OSA.6 Type IV portable monitoring can also be
covered if at least three channels are used.6 However, the AASM recommends
that portable monitoring only be performed with a comprehensive sleep medi-
cine evaluation by a board-certified or board-eligible sleep medicine specialist
and should include airflow, respiratory effort, and heart rate.
Portable monitoring can be considered in those without significant medical
comorbidities who are at high risk for having OSA and also can be considered to
evaluate response to nonYcontinuous positive airway pressure treatments for
OSA. Portable monitoring is not recommended for those with significant
medical comorbidities such as neuromuscular disease, pulmonary disease, or
congestive heart failure, as well as for those with other sleep disorders.
Actigraphy, Multiple Sleep Latency Test, and Maintenance

of Wakefulness Test
There are no CMS national-coverage documents for actigraphy, the multiple
sleep latency test (MSLT) or the maintenance of wakefulness test (MWT); those
ordering sleep studies should refer to local guidelines to determine whether the
test is covered.6 However, guidelines from the AASM have been published.
MSLT is indicated as a part of the workup for narcolepsy and may be useful in
the diagnosis for idiopathic hypersomnia, but is not recommended to diagnose
OSA, hypersomnia due to secondary causes, insomnia, or circadian rhythm
disorders. MWT can be used to determine effectiveness of treatment for nar-
colepsy or idiopathic hypersomnia and to determine safety issues depending on
clinical judgment.9 Actigraphy may be used to evaluate circadian rhythm
disorders and insomnia, to determine total sleep time in patients with OSA
when polysomnography cannot be performed, and to document treatment
response for those with circadian rhythm disorders or insomnia.10
Pediatric Polysomnography
For children 6 years of age and older, polysomnography performed in a sleep
laboratory and attended by a technologist is billed as a 95810 if it is a diagnostic

study and 95811 if it is a titration study with continuous positive airway pres-
sure after OSA has been diagnosed. For children under 6 years of age,
polysomnography performed in a sleep laboratory and attended by a technologist
is billed as 95872 if it is a diagnostic study and 95873 if it is a titration study with
continuous positive airway pressure (CPAP) after OSA has been diagnosed.
AASM practice guidelines for respiratory indications for polysomnography in
children have been published. Polysomnography is indicated in children who
have symptoms of sleep-disordered breathing. It is indicated to determine the
presence of residual OSA after treatmentVtypically adenotonsillectomy in
childrenVin those with persistent symptoms of sleep-disordered breathing; in
those with mild OSA; or in those with craniofacial abnormalities, moderate to
severe OSA, obesity, or neurologic conditions. It also is indicated as a part of a
titration study with CPAP treatment if there is residual OSA. Polysomnography
can be used in those with congenital central alveolar hypoventilation, sleep-
related hypoventilation, or an apparent life-threatening event.11
OTHER CONSIDERATIONS
Coverage for Continuous Positive Airway Pressure Treatment
Once OSA has been diagnosed, national coverage guidelines by the CMS currently
cover the use of CPAP for an initial 12-week period in those who have an apnea-
hypopnea index (AHI) of at least 15 events/h or in those with an AHI between five
events/h and 15 events/h with the following documented symptoms or comor-
bidities: excessive daytime sleepiness, cognitive impairment, insomnia, mood dis-
orders, hypertension, ischemic heart disease, or stroke.6 The AHI should have
been determined based on recommended AASM scoring criteria.6,8
Coverage for CPAP would continue if the patient were found to benefit
from CPAP during the initial 12-week period. In addition to documentation of
improved symptoms of OSA and a follow-up clinical evaluation, physicians should
also document whether the patient is compliant to CPAP. This compliance data can
be downloaded from the CPAP machine and must show that the patient used the
device at least 4 hours a night over 70% of nights in a 30-day period.6 Other local
coverage guidelines may apply.
CONCLUSION
Diagnostic codes in the clinical evaluation of sleep disorders can be found in various
sections of the ICD-9-CM and ICD-10-CM.Polysomnography refers to tests that
include sleep staging, and sleep studies are tests that do not include sleep
staging. National CMS guidelines currently address the use of polysomnography
and portable monitoring (type II and type III studies) in the diagnosis of
obstructive sleep apnea, and clinicians should review local Medicare guidelines
before ordering studies in the evaluation of other sleep disorders. Changes for
coding in sleep medicine, not only for diagnosing a patient with a sleep disorder
but in ordering tests to evaluate for sleep disturbances, will continue to occur.
REFERENCES
1. American Academy of Sleep Medicine. International classification of sleep disorders, second edition:
diagnostic and coding manual. Westchester, IL: American of Academy of Sleep Medicine, 2005.
2. Centers for Medicare & Medicaid Services, National Center for Health Statistics. ICD-9-CM
official guidelines for coding and reporting. www.cdc.gov/nchs/data/icd9/icdguide10.pdf.
Accessed October 18, 2012.

3. American Medical Association. CPT: current procedural terminology 2012. Chicago, IL: American
Medical Association Press, 2011.
4. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indication of
polysomnography and related procedures: an update for 2005. Sleep 2005;28(4):499Y521.
5. Littner M, Hirschkowitz M, Kramer M, et al; American Academy of Sleep Medicine Standards of
Practice Committee. Practice parameters for using polysomnography to evaluate insomnia: an
update. Sleep 2003;26(6):754Y760.
6. Centers for Medicare & Medicaid Services. Medicare coverage database.
www.cms.gov/medicare-coverage-database/. Accessed October 18, 2012.
7. Collop N, Tracy S, Kapur V, et al. Obstructive sleep apnea devices for out-of-center (OOC) testing:
technology evaluation. J Clin Sleep Med 2011;7(5):531Y548.
8. Iber C, Ancoli-Israel S, Chesson A, et al. The AASM scoring manual for the scoring of sleep and
associated events: rules, terminology and technical specifications. 1st ed. Westchester, IL:
9. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep
latency test and the maintenance of wakefulness test. Sleep 2005;28(1):113Y121.
10. Morganthaler T, Alessi C, Friedman L, et al; American Academy of Sleep Medicine Standards and
Practice Committee. Practice parameters for the use of actigraphy in the assessment of sleep
and sleep disorders: an update for 2007. Sleep 2007;30(4):519Y529.
11. Aurora RN, Zak RS, Karippot A, et al. Practice parameters for the respiratory indications for
polysomnography in children. Sleep 2011;34(3):379Y388.

Vol 19.1 - Sleep Disorders.2013

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Vol 19.1 - Sleep Disorders.2013

Transféré par

Droits d'auteur :

Formats disponibles

Continuum: Lifelong Learning in NeurologySleep Disorders, Volume 19, Issue 1,

Sleep Disorders, February 2013;19(1)

Continuum: Lifelong Learning in Neurology is designed to help practicing neurologists stay

participants will be able to:

circadian rhythm abnormalities, restless legs syndrome, and parasomnias

likely to be encountered by neurologists

who present with hypersomnia, insomnia, and abnormal nighttime behaviors

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

countermeasures to help alleviate fatigue

Practice-Based Learning and Improvement

Interpersonal and Communication Skills

Alon Y. Avidan, MD, MPH, FAASM, Guest Editor

Zahreddin Alsheikhtaha, MBBS, RPSGT

Hyrar Attarian, MD, FAASM, FCCP

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Joseph Daley, MD, PhD

Nancy Foldvary-Schaefer, DO, MS, FAASM

Glen P. Greenough, MD, FAASM

Douglas Kirsch, MD, FAASM

Clete A. Kushida, MD, PhD

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Jennifer Rose V. Molano, MD

Lori Panossian, MD, MS

Clifford B. Saper, MD, PhD, FAAN, FRCP

Anita Valanju Shelgikar, MD

Michael H. Silber, MBChB, FAAN

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Nathaniel F. Watson, MD, MSc

Phyllis C. Zee, MD, PhD

Marcel Hungs, MD, PhD

MULTIPLE-CHOICE QUESTION WRITERS

Douglas J. Gelb, MD, PhD, FAAN

Methods of Participation and Instructions for Use

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

as important as, if not more important than, the material itself.

The goals of Continuum include disseminating up-to-date information to the practicing

information, , and comprehensive CME and self-assessment offerings, including a self-

assessment pretest, multiple-choice questions with preferred responses, and a patient

activities, visit aan.com/continuum/cme.

issue topic accompanies issues when applicable.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Zahreddin Alsheikhtaha, MBBS, RPSGT

Hyrar Attarian, MD, FAASM, FCCP

Ronald D. Chervin, MD, MS, FAASM, FAAN

Joseph Daley, MD, PhD

Continuum (Minneap Minn) 2013;19(1) www.aan.com/continuum

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Glen P. Greenough, MD, FAASM

Douglas Kirsch, MD, FAASM

Clete A. Kushida, MD, PhD

www.aan.com/continuum February 2013

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Jennifer Rose V. Molano, MD

Lori Panossian, MD, MS

Clifford B. Saper, MD, PhD, FAAN, FRCP

Anita Valanju Shelgikar, MD

Continuum (Minneap Minn) 2013;19(1) www.aan.com/continuum

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Aleksandar Videnovic, MD, MSc

www.aan.com/continuum February 2013

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Phyllis C. Zee, MD, PhD

MULTIPLE-CHOICE QUESTION WRITERS