Principles and Practice of Sleep Medicine: Expert Consult - Online and Print, 5th Edition

Principles and Practice of

SLEEP MEDICINE

Fifth

Edition

Principles and Practice of

SLEEP MEDICINE Meir H. Kryger, MD, FRCPC

Clinical Professor of Medicine University of Connecticut Director of Research and Education Gaylord Sleep Medicine Wallingford, Connecticut

Thomas Roth, PhD

Professor, Department of Psychiatry Wayne State University School of Medicine Director and Division Head Sleep Disorders and Research Center Henry Ford Hospital Detroit, Michigan Clinical Professor, Department of Psychiatry University of Michigan Medical School Ann Arbor, Michigan

William C. Dement, MD, PhD

Lowell W. and Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences, and Director Sleep Disorders and Research Center Stanford University School of Medicine Palo Alto, California

3251 Riverport Lane St. Louis, Missouri 63043 PRINCIPLES AND PRACTICE OF SLEEP MEDICINE

Basic Edition: 978-1-4160-6645-3   Premium Edition: 978-1-4377-0731-1 Copyright © 2011, 2005, 2000, 1994, 1989 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Principles and practice of sleep medicine / [edited by] Meir H. Kryger, Thomas Roth, William C. Dement.—5th ed.     p. ; cm.   Includes bibliographical references and index.   ISBN 978-1-4160-6645-3   1.  Sleep disorders.  2.  Sleep.  I.  Kryger, Meir H.  II.  Roth, T. (Tom)  III.  Dement, William C., 1928  [DNLM:  1.  Sleep Disorders.  2.  Sleep–physiology. WM 188 P957 2011] RC547.P75 2011 616.8′498–dc22                      2010002721

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But the tigers come at night, With their voices soft as thunder, As they tear your hope apart, As they turn your dream to shame. From I Dreamed a Dream, LES MISÉRABLES, with permission, Cameron Mackintosh, producer © 1985 Alain Boublil Music Ltd. Used by permission 1991, CMI.

Blessings on him who first invented sleep.—It covers a man all over, thoughts and all, like a cloak.—It is meat for the hungry, drink for the thirsty, heat for the cold, and cold for the hot.—It makes the shepherd equal to the monarch, and the fool to the wise.—There is but one evil in it, and that is that it resembles death, since between a dead man and a sleeping man there is but little difference. From DON QUIXOTE By Saavedra M. de Cervantes

“To sleep! To forget!” he said to himself with the serene confidence of a healthy man that if he is tired and sleepy, he will go to sleep at once. And the same instant his head did begin to feel drowsy and he began to drop off into forgetfulness. The waves of the sea of unconsciousness had begun to meet over his head, when all at once—it was as though a violent shock of electricity had passed over him. He started so that he leapt up on the springs of the sofa, and leaning on his arms got in a panic on to his knees. His eyes were wide open as though he had never been asleep. The heaviness in his head and the weariness in his limbs that he had felt a minute before had suddenly gone. From ANNA KARENINA, Part IV, Chapter XVIII By Leo Tolstoy

Contributors  ix

Contributors

Peter Achermann, PhD Professor, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

Sleep Homeostasis and Models of Sleep Regulation

Alon Y. Avidan, MD, MPH Associate Professor of Neurology; Associate Director, Sleep Disorders Program; Director, UCLA Neurology Residency Program; Director, UCLA Neurology Clinic, Department of Neurology, University of California, Los Angeles, Los Angeles, California Physical Examination in Sleep Medicine

Torbjörn Åkerstedt, PhD Head Professor, Stress Research Institute, Stockholm University; Affiliated Professor, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden Introduction Sleep, Stress, and Burnout

Ravi Allada, MD Associate Professor, Neurobiology and Physiology, Associate Director, Center for Sleep and Circadian Biology, Northwestern University, Evanston, Illinois

Genetic Basis of Sleep in a Simple Model Organism: Drosophila

Richard P. Allen, PhD, FAASM Associate Professor, Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland Restless Legs Syndrome and Periodic Limb Movements during Sleep

Sonia Ancoli-Israel, PhD Professor of Psychiatry, University of California, San Diego, La Jolla, California Sleep and Fatigue in Cancer Patients Insomnia in Older Adults Actigraphy

Roseanne Armitage, PhD Professor of Psychiatry, Adjunct Professor of Psychology, Director, Sleep and Chronophysiology Laboratory, University of Michigan Medical School, Ann Arbor, Michigan Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms

Isabelle Arnulf, MD, PhD Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Paris, France Parkinsonism

Charles W. Atwood, Jr., MD Associate Professor and Director, Sleep Medicine Fellowship, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine; Assistant Chief of Medicine and Sleep Laboratory Director, Department of Medicine, Pulmonary and Sleep Medicine Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Medical Therapy for Obstructive Sleep Apnea

Fiona C. Baker, PhD Honorary Senior Research Fellow, Brain Function Research Group, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa; Sleep Physiologist, Center for Health Sciences, SRI International, Menlo Park, California Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms

Thomas J. Balkin, PhD Director, Behavioral Biology Branch Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland Performance Deficits during Sleep Loss: Effects of Time Awake, Time of Day, and Time on Task

Bilgay Izci Balserak, BA, MA, PhD Division of Sleep Medicine and Center for Sleep and Respiratory Neurobiology, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Sleep Disturbances and Sleep-Related Disorders in Pregnancy

Siobhan Banks, PhD Research Fellow, Centre for Sleep Research, University of South Australia, Adelaide, Australia Chronic Sleep Deprivation

Steven R. Barczi, MD, FAASM Associate Professor of Medicine, Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health; Associate Director, Education and Evaluation, Madison VA Geriatric Research, Education & Clinical Center, Wm. S. Middleton Veterans Memorial Hospital, Director of Education, University of Wisconsin Center for Sleep Medicine and Sleep Research, Madison, Wisconsin Medical and Psychiatric Disorders and the Medications Used to Treat Them

ix

x  Contributors

Joseph T. Bass, MD, PhD Associate Professor, Department of Medicine and Neurology, Northwest University, Evanston, Illinois

Animal Models for Disorders of Chronobiology: Cell and Tissue

Claudio L. Bassetti, MD Director, Neurocenter of Southern Switzerland, Lugano; Chairman, Neurology Department, Professor of Neurology, University Hospital, Zürich, Switzerland Idiopathic Hypersomnia Sleep and Stroke

Gregory Belenky, MD Research Professor and Director, Sleep and Performance Research Center, Washington State University, Spokane, Washington Introduction Fatigue Risk Management Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management

Ruth M. Benca, MD, PhD Professor, Department of Psychiatry, University of Wisconsin-Madison School of Medicine, Madison, Wisconsin Mood Disorders

Kathleen L. Benson, PhD Brain Imaging Center, McLean Hospital, Belmont, Massachusetts; Associate Clinical Professor (retired), Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Director, Sleep Disorders Program (retired), Psychiatry Service, VA Palo Alto Health Care System, Palo Alto, California Schizophrenia

Donald L. Bliwise, PhD Professor of Neurology, Psychiatry, Behavioral Sciences and Nursing; Director, Program in Sleep, Aging and Chronobiology, Emory University School of Medicine, Atlanta, Georgia Normal Aging Sleep in Independently Living and Institutionalized Elderly

Bradley F. Boeve, MD Professor of Neurology, Mayo College of Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota Alzheimer’s Disease and Other Dementias

Michael H. Bonnet, PhD Professor, Department of Neurology, Wright State University, Director of Sleep Laboratory; Neurology, Dayton Department of Veterans Affairs Medical Center, Dayton, Ohio Acute Sleep Deprivation Shift Work, Shift Work Disorder, and Jet Lag

Alexander A. Borbély, MD Professor Emeritus of Pharmacology, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland Sleep Homeostasis and Models of Sleep Regulation

Michel A. Cramer Bornemann, MD, D-ABSM, FAASM Director, Minnesota Regional Sleep Disorders Center; Lead Investigator, Sleep Forensics Associates, Hennepin County Medical Center; Assistant Professor, Department of Neurology, Department of Medicine, University of Minnesota School of Medicine; Faculty Instructor, Department of Biomedical Engineering, Bakken/MIND Laboratory, University of Minnesota Graduate School, Minneapolis, Minnesota Sleep Forensics Non-REM Arousal Parasomnias

Peter Buchanan, MB, ChB, MD, FRACP Senior Clinical Research Fellow, Sleep & Circadian Group, Woolcock Institute of Medical Research; Senior Staff Specialist, Department of Respiratory Medicine, Liverpool Hospital; Consultant Sleep Medicine Physician, St. Vincent’s Clinic, Sydney, Australia

Positive Airway Pressure Treatment for Obstructive Sleep Apnea-Hypopnea Syndrome

Orfeu M. Buxton, PhD Instructor in Medicine, Division of Sleep Medicine, Harvard Medical School; Associate Neuroscientist, Department of Medicine, Brigham and Women’s Hospital, Boston Massachusetts

The Human Circadian Timing System and Sleep−Wake Regulation

Daniel J. Buysse, MD Professor, Psychiatry, Clinical, and Translational Science, University of Pittsburgh School of Medicine; Director, Neuroscience Clinical and Translational Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Clinical Pharmacology of Other Drugs Used as Hypnotics Insomnia: Recent Developments and Future Directions Treatment Guidelines for Insomnia

Georgina Cano, PhD Research Assistant Professor, Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania Models of Insomnia

Michelle T. Cao, DO Clinical Instructor, Division of Sleep Medicine, Stanford University School of Medicine, Palo Alto, California. Narcolepsy: Diagnosis and Management Sleep Neuromuscular Diseases Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome

Colleen E. Carney, PhD Assistant Professor, Department of Psychology, Ryerson University, Toronto, Ontario, Canada Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations

Contributors  xi

Mary A. Carskadon, PhD Professor, Psychiatry and Human Behavior, Alpert Medical School of Brown University; Director of Chronobiology and Sleep Research, Child and Adolescent Psychiatry, E.P. Bradley Hospital, Providence, Rhode Island Normal Human Sleep: An Overview Daytime Sleepiness and Alertness

Rosalind Cartwright, PhD, FAASM Professor Emeritus, Neuroscience Program, Graduate College, Rush University Medical Center, Chicago, Illinois Dreaming as a Mood-Regulation System

Chien Lin Chen, MD Lecturer, Department of Medicine, Tzu Chi University, School of Medicine; Director, Gastrointestinal Motility, Laboratory; Attending Physician, Division of Gastroenterology and Hepatology, Tzu Chi General Hospital, Hualien, Taiwan Gastrointestinal Monitoring Techniques

Ronald D. Chervin, MD, MS Professor of Neurology, Michael S. Aldrich Collegiate Professor of Sleep Medicine, Department of Neurology and Sleep Disorders Center, University of Michigan Medical School; Director, Sleep Disorders Center; Co-Director, Center for Sleep Science, University of Michigan Health System, Ann Arbor, Michigan Use of Clinical Tools and Tests in Sleep Medicine

Peter A. Cistulli, MBBS, PhD, MBA, FRACP, FCCP Professor, Respiratory Medicine, Head of Discipline of Sleep Medicine, Sydney Medical School, University of Sydney; Director, Centre for Sleep Health & Research, Department of Respiratory Medicine, Royal North Shore Hospital; Research Leader, Sleep & Circadian Group, Woolcock Institute of Medical Research, Sydney, Australia Oral Appliances for Sleep-Disordered Breathing

Anita P. Courcoulas, MD, MPH, FACS Chief, Minimally Invasive Bariatric and General Surgery; Associate Professor of Surgery, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Obstructive Sleep Apnea, Obesity, and Bariatric Surgery

Yves Dauvilliers, MD, PhD Professor, Neurology, Guide Chauliac Hospital, Montpellier, France Idiopathic Hypersomnia

Alec J. Davidson, PhD Assistant Professor, Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia

Animal Models for Disorders of Circadian Functions: Whole Organism

O’Neill F. D’Cruz, MD, MBA Medical Director, Neurology, UCB Pharma, Raleigh, North Carolina Cardinal Manifestations of Sleep Disorders

Tom de Boer, PhD Assistant Professor, Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands Body Temperature, Sleep, and Hibernation

William C. Dement, MD, PhD Lowell W. and Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences; Director, Sleep Disorders and Research Center, Stanford University School of Medicine, Palo Alto, California History of Sleep Physiology and Medicine Normal Human Sleep: An Overview Daytime Sleepiness and Alertness Sleep Medicine, Public Policy, and Public Health

Ronald Denis, MD Faculty of Dental Medicine, Université de Montréal, Montréal, Québec, Canada Pain and Sleep

Derk-Jan Dijk, PhD Professor of Sleep and Physiology, Surrey Sleep Research Centre, University of Surrey, Guildford, United Kingdom Genetic Basis of Sleep in Healthy Humans

David F. Dinges, PhD Professor and Chief, Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Chronic Sleep Deprivation Circadian Rhythms in Sleepiness, Alertness, and Performance Sleep Medicine, Public Policy, and Public Health

Antonio Culebras, MD, FAAN, FAHA Professor, Neurology, SUNY Upstate Medical University; Consultant, The Sleep Center, Community General Hospital, Syracuse, New York.

G. William Domhoff, PhD Research Professor of Psychology, Department of Psychology, University of California, Santa Cruz, Santa Cruz, California

Charles A. Czeisler, PhD, MD, FRCP Baldino Professor of Sleep Medicine and Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep Medicine, Senior Physician, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

Neil J. Douglas, Kt, MD, DSc, FRCP, FRCPE Professor of Respiratory and Sleep Medicine, Respiratory Medicine, University of Edinburgh; Consultant Physician, Sleep Department, Royal Infirmary of Edinburgh, United Kingdom

Other Neurological Disorders

The Human Circadian Timing System and Sleep−Wake Regulation

Dream Content: Quantitative Findings

Respiratory Physiology: Understanding the Control of Ventilation Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease

xii  Contributors

Christopher L. Drake, PhD Bioscientific Staff Investigator, Sleep Disorders and Research Center, Henry Ford Hospital; Associate Professor, Department of Psychiatry and Behavioral Neuroscience, Wayne State University, Detroit, Michigan Shift Work, Shift-Work Disorder, and Jet Lag

Jack D. Edinger, PhD Clinical Professor, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine; Senior Psychologist, Durham VA Medical Center, Durham, North Carolina Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations

Mark W. Elliott, MD, FRCP Senior Lecturer, Clinical Medicine, University of Leeds, Department of Respiratory Medicine, St. James’s University Hospital, Leeds, West Yorkshire, England Noninvasive Ventilation to Treat Chronic Ventilatory Failure

Colin A. Espie, MappSci, PhD FBPsS, CPsychol Director, University of Glasgow Sleep Centre; Head, Section of Psychological Medicine, Section of Psychological Medicine, Faculty of Medicine, University of Glasgow; Professor, Clinical Psychology, University of Glasgow Sleep Centre, Sackler Institute of Psychobiological Research, Southern General Hospital, Glasgow, Scotland, United Kingdom Models of Insomnia

Juliette H. Faraco, PhD Senior Research Scientist, Stanford Center for Narcolepsy Research, Stanford University, Palo Alto, California Genetics of Sleep and Sleep Disorders in Humans

Irwin Feinberg, MD Psychiatry and Behavioral Sciences, University of California, Davis, Davis, California Schizophrenia

Kathleen A. Ferguson, BSc, MD, FRCPC Associate Professor of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada Oral Appliances for Sleep-Disordered Breathing

Luigi Ferini-Strambi, MD Associate Professor, General Psychology, Universita Vita-Salve San Raffaele; Director, Sleep Disorders Center, Department of Neuroscience, Milan, Italy Restless Legs Syndrome and Periodic Limb Movements during Sleep

Paul Franken, PhD Maître d’Enseignement et de Recherche, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Genetic Basis of Sleep in Rodents

Karl A. Franklin, MD Associate professor, Surgery and Respiratory Medicine, Umeå University, Umeå, Sweden Coronary Artery Disease and Obstructive Sleep Apnea

Philippa Gander, PhD Professor and Centre Director, Sleep/Wake Research Centre, Massey University, Wellington, New Zealand Fatigue Risk Management

Charles F.P. George, MD, FRCPC Professor of Medicine, University of Western Ontario; Director, Sleep Medicine Clinic and Laboratory, London Health Sciences Centre, London, Ontario, Canada Sleep and Stroke Cognition and Performance in Patients with Obstructive Sleep Apnea

Rachel Givelber, MD Assistant Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Medical Therapy for Obstructive Sleep Apnea

Shelagh K. Gleeson, MD Staff Physician, Pulmonary, Critical Care & Sleep Disorders, Sentara Pulmonary and Critical Care Specialists, Norfolk, Virginia

Wake-Promoting Medications: Efficacy and Adverse Effects

Paul B. Glovinsky, PhD Clinical Director, St. Peter’s Sleep Center, St. Peter’s Hospital, Albany, New York Assessment Techniques for Insomnia

Namni Goel, PhD Research Assistant Professor, Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Circadian Rhythms in Sleepiness, Alertness, and Performance

Joshua J. Gooley, PhD Assistant Professor, Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore; Instructor of Medicine, Harvard Medical School, Boston, Massachusetts Anatomy of the Mammalian Circadian System

R. Curtis Graeber, PhD President, The Graeber Group, Ltd., Kirkland, Washington Fatigue Risk Management

Contributors  xiii

Ronald Grunstein, MB, BS, MD, PhD, FRACP Professor of Sleep Medicine, Woolcock Institute of Medical Research, The University of Sydney Medical School; Head and Senior Staff Specialist, Centre for Respiratory Failure and Sleep Disorders, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, Australia; Chief Investigator, NHMRC, Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Glebe, Sydney, Australia Positive Airway Pressure Treatment for Obstructive Sleep Apnea-Hypopnea Syndrome Endocrine Disorders

Béatrice Guardiola-Lemaître, PhD Scientific Director, R & D, Scientific Direction, ADIR, Servier International Research Institute, Courbevoie, France

Melatonin and the Regulation of Sleep and Circadian Rhythms

Christian Guilleminault, MD, DM, DBiol Professor, Division of Sleep Medicine, Stanford University School of Medicine, Palo Alto, California

Narcolepsy: Diagnosis and Management Sleep and Neuromuscular Diseases Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome

Ronald M. Harper, PhD Department of Neurobiology and the Brain Research Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, California Cardiovascular Physiology: Central and Autonomic Regulation

Allison G. Harvey, PhD Professor of Clinical Psychology, Department of Psychology; Director, Golden Bear Sleep and Mood Clinic, University of California, Berkeley, Berkeley, California Insomnia: Diagnosis, Assessment, and Outcomes

Jan Hedner, MD, PhD Professor, Sleep Medicine, Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden

Coronary Artery Disease and Obstructive Sleep Apnea

Raphael C. Heinzer, MD, MPH Senior Lecturer and Researcher, Pulmonary Department; Co-Director, Center for Investigation and Research in Sleep, Lausanne University Hospital, Lausanne, Switzerland Normal Physiology of the Upper and Lower Airways

John H. Herman, PhD Professor, Departments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center at Dallas; Director, Sleep Disorders Center for Children, Children’s Medical Center, Dallas, Texas; Associate Professor, Departments of Psychiatry and Medicine, Baylor College of Medicine; Director, Sleep Disorders and Research Center, Michael E. DeBakey VA Medical Center; Clinical Director, Methodist Hospital Diagnostic Sleep Laboratory, VA Medical Center Sleep Center, Houston, Texas Chronobiologic Monitoring Techniques

Victor Hoffstein, PhD, MD, FRCP(C), FCCP Professor of Medicine, Department of Medicine, University of Toronto; Staff Respirologist, Department of Medicine, St. Michael’s Hospital, Toronto, Canada Snoring

Max Hirshkowitz, PhD Tenured Associate Professor, Medicine, Baylor College of Medicine, Houston, Texas; Sleep Center Director, Sleep Disorders and Research Center, Michael E. DeBakey VA Medical Center, Houston, Texas Monitoring and Staging Human Sleep Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing Evaluating Sleepiness

Richard L. Horner, PhD Canada Research Chair in Sleep and Respiratory Neurobiology, Associate Professor, Departments of Medicine and Physiology, University of Toronto, Toronto, Canada Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep

Christer Hublin, MD, PhD Adjunct Professor, Neurology, Helsinki University; Assistant Chief Medical Officer, Brain@Work Research Center, Finnish Institute of Occupational Health, Helsinki, Finland Epidemiology of Sleep Disorders

Steven R. Hursh, PhD Adjunct Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; President, Institutes for Behavior Resources, Inc., Baltimore, Maryland Fatigue and Performance Modeling Fatigue, Performance, Errors, and Accidents

Nelly T. Huynh, PhD Faculty of Dentistry, Université de Montréal, Centre d’Etude du Sommeil, Hôpital du Sacré-Coeur, Montréal, Québec, Canada Sleep Bruxism

xiv  Contributors

Shahrokh Javaheri, MD Professor Emeritus of Medicine, University of Cincinnati College of Medicine; Medical Director of Sleepcare Diagnostics, Cincinnati, Ohio Sleep and Cardiovascular Disease: Present and Future Cardiovascular Effects of Sleep-Related Breathing Disorders Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea Heart Failure

Mark E. Josephson, MD Herman Dana Professor of Medicine, Department of Medicine, Harvard Medical School; Chief, Division of Cardiovascular Medicine; Director, HarvardThorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, Massachusetts Jonathan Jun, MD Post-Doctoral Fellow, Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland Obstructive Sleep Apnea and Metabolic Dysfunction

Göran Kecklund, PhD National Institute for Psychosocial Medicine, Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden Sleep, Stress, and Burnout

Sharon Keenan, PhD, REEGT, RPSGT, D-ABSM Director, The School of Sleep Medicine, Inc., Palo Alto, California Monitoring and Staging Human Sleep

Kurt Kräuchi Head, Thermophysiological Chronobiology, Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland Body Temperature, Sleep, and Hibernation

James M. Krueger, PhD, MDHC Regents Professor, Sleep and Performance Research Center, Washington State University, Pullman, Washington Sleep and Host Defense

Meir H. Kryger, MD, FRCPC Clinical Professor of Medicine, University of Connecticut; Director of Research and Education, Gaylord Hospital, Sleep Medicine, Wallingford, Connecticut

Management of Obstructive Sleep Apnea-Hypopnea Syndrome Restrictive Lung Disorders Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing

Andrew D. Krystal, MD, MS Professor, Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina Pharmacologic Treatment: Other Medications

Samuel T. Kuna, MD Associate Professor of Medicine, Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania; Chief, Pulmonary, Critical Care and Sleep Section, Philadelphia VA Medical Center Sleep Center, Philadelphia, Pennsylvania Anatomy and Physiology of Upper Airway Obstruction

Clete A. Kushida, MD, PhD, RPSGT Professor, Division of Sleep Medicine; Acting Medical Director, Stanford Sleep Medicine Center; Director, Stanford Center for Human Sleep Research, Palo Alto, California Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome

Hans-Peter Landolt, PhD Professor, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland Genetic Basis of Sleep in Healthy Humans

Paola A. Lanfranchi, MD Assistant Professor, Medicine, Université de Montréal; Cardiologist, Department of Medicine, Division of Cardiology, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders

Gilles Lavigne, DMD, FRCD, PhD, HC Dean, Faculty of Dental Medicine, Université de Montreal; Scientist Clinician, Surgery, Trauma and Sleep, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Relevance of Sleep Physiology for Sleep Medicine Clinicians Sleep Bruxism Pain and Sleep

Kathryn Lee, RN, PhD, FAAN, CBSM Professor and Associate Dean for Research; James & Marjorie Livingston Endowed Chair; Director, T32 Nurse Research Training in Symptom Management, School of Nursing, University of California, San Francisco Department of Family Health Care Nursing, San Francisco, California Sleep Disturbances and Sleep-Related Disorders in Pregnancy Menopause

Patrick Leger, MD, FCCP Laboratoire du Sommeil, Service de Pneumologie, Pierre Bénite, Lyon, France Noninvasive Ventilation to Treat Chronic Ventilatory Failure

Christopher Li, MD, FRCP (C), DABSM Assistant Professor, Department of Medicine, University of Toronto; Staff Respirologist, Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada Snoring

Contributors  xv

Kenneth L. Lichstein, PhD Professor, Department of Psychology, The University of Alabama, Tuscaloosa, Alabama Insomnia: Epidemiology and Risk Factors

Alan A. Lowe, DMD, PhD, FRCD(C) Professor and Chair, Division of Orthodontics, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada Oral Appliances for Sleep-Disordered Breathing

James G. MacFarlane, PhD Assistant Professor of Pediatrics and Psychiatry, University of Toronto; Research Associate (Neurology), The Hospital for Sick Children; Director of Education, MedSleep (Network of Clinics), Toronto, Ontario, Canada Fibromyalgia and Chronic Fatigue Syndromes

Mark W. Mahowald, MD Professor, Neurology, University of Minnesota Medical School; Co-Director, Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, Minnesota Sleep Forensics Epilepsy, Sleep, and Sleep Disorders Non-REM Arousal Parasomnias REM Sleep Parasomnias Other Parasomnias

Jeannine A. Majde, PhD Adjunct Professor, College of Veterinary Medicine, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington Sleep and Host Defense

Beth A. Malow, MD, MS Professor and Director, Sleep Disorders Division, Neurology; Director, Vanderbilt Sleep Disorders Center, Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee Approach to the Patient with Disordered Sleep Neurologic Monitoring Techniques Physical Examination in Sleep Medicine

Juan F. Masa, MD Head of Respiratory Research in Centro de Investigación Biomédica en Red de Enfermedades Respiratorias; (CIBERES); Head of Pulmonary Division, Pulmonary Unit, San Pedro de Alcántara Hospital, Cáceres, Spain Restrictive Lung Disorders

Christina S. McCrae, PhD Associate Professor, Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida Insomnia: Epidemiology and Risk Factors

Jennifer McDonald, PhD Postdoctoral Fellow, Center for Behavioral Health Research and Services, University of Alaska Anchorage, Anchorage, Alaska

Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management

Dennis McGinty, PhD Adjunct Professor, University of California Los Angeles; Chief, Neurophysiology Research, VA Greater Los Angeles Healthcare System, Los Angeles, California Neural Control of Sleep in Mammals

Melanie K. Means, PhD Staff Psychologist, Veterans Affairs Medical Center; Assistant Professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations

Thomas A. Mellman, MD Professor, Psychiatry, Howard University, Washington, DC Dreams and Nightmares in Posttraumatic Stress Disorder Anxiety Disorders

Wallace Mendelson, MD Professor of Psychiatry and Clinical Pharmacology, University of Chicago, Chicago, Illinois

Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects

Rachel Manber, PhD Professor, Psychiatry and Behavioral Science, Stanford Sleep Medicine Center, Stanford School of Medicine, Stanford University, Palo Alto, California

Emmanuel Mignot, MD, PhD Director, Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, California

Christiane Manzini Research Assistant, University of Montreal Faculty of Medicine and Dentistry; Center for the Study of Sleep and Biological Rhythms, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada

Ralph E. Mistlberger, PhD Professor, Psychology, Simon Fraser University, Burnaby, British Columbia, Canada

Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations

Sleep Bruxism

Pierre Maquet, MD, PhD Research Director FNRS, Cyclotron Research Centre, University of Liège, Liège, Belgium

What Brain Imaging Reveals about Sleep Generation and Maintenance

Genetics of Sleep and Sleep Disorders in Humans Wake-Promoting Medications: Basic Mechanisms and Pharmacology Narcolepsy: Pathophysiology and Genetic Predisposition

Circadian Rhythms in Mammals: Formal Properties and Environmental Influences

xvi  Contributors

Murray A. Mittleman, MD, DrPH Associate Professor of Medicine and Epidemiology, Harvard Schools of Medicine and Public Health; Director, Cardiovascular Epidemiology Research Unit, Medicine, Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Seiji Nishino, MD Professor, Psychiatry and Behavioral Sciences, Stanford University School of Medicine; Director, Sleep and Circadian Neurobiology Laboratory, Stanford University School of Medicine, Palo Alto, California

Karen E. Moe, PhD Research Associate Professor and Assistant Vice Provost for Research, Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington

Eric A. Nofzinger, MD Director, Sleep Neuroimaging Research Program, Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Sleep-Related Cardiac Risk

Menopause

Harvey Moldofsky, MD, Dip Psych, FRCPC Professor Emeritus, Department of Psychiatry; Member Emeritus, Institute of Medical Science, School of Graduate Studies, University of Toronto; Honorary Staff, Department of Psychiatry, Toronto Western Hospital, University Health Network; President and Medical Director, Sleep Disorders Clinics, Centre for Sleep and Chronobiology, Toronto, Ontario, Canada Fibromyalgia

Jacques Montplaisir, MD, PhD, CRCP Professor, Psychiatry and Neuroscience, Université de Montréal; Director, Center for Advanced Studies in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada Restless Legs Syndrome and Periodic Limb Movements during Sleep Alzheimer’s Disease and Other Dementias

Charles M. Morin, PhD Professor, Psychology, Université Laval; Director, Sleep Research Center, Centre de Recherche Université Laval Robert-Giffard, Québec, Québec, Canada Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy

Tore Nielsen, PhD Professor, Psychiatry, Université de Montréal; Director, Dream & Nightmare Laboratory, Sleep Research Center, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Introduction: The Changing Historical Context of Dream Research Ultradian, Circadian, and Sleep-Dependent Features of Dreaming Dream Analysis and Classification: The Reality Simulation Perspective Idiopathic Nightmares and Dream Disturbances Associated with Sleep−Wake Transitions Disturbed Dreaming as a Factor in Medical Conditions

F. Javier Nieto, MPH, MD, PhD Helfaer Professor of Public Health; Professor and Chair of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea

Wake-Promoting Medications: Basic Mechanisms and Pharmacology

What Brain Imaging Reveals about Sleep Generation and Maintenance

Louise M. O’Brien, PhD Assistant Professor, Sleep Disorders Center, Department of Neurology; Assistant Research Scientist, Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, Michigan Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms

Bruce F. O’Hara, PhD Associate Professor, Biology, University of Kentucky, Lexington, Kentucky Genetic Basis of Sleep in Rodents

Eric J. Olson, MD Associate Professor, Medicine, College of Medicine; Co-Director, Center for Sleep Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota Obstructive Sleep Apnea, Obesity, and Bariatric Surgery

Mary B. O’Malley, MD, PhD Private Practice Great Barrington, Massachusetts

Wake-Promoting Medications: Efficacy and Adverse Effects

William C. Orr, PhD President and CEO, Lynn Health Science Institute; Clinical Professor of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Gastrointestinal Physiology in Relation to Sleep Gastrointestinal Disorders Gastrointestinal Monitoring Techniques

Edward F. Pace-Schott, PhD Postdoctoral Fellow, Psychology, University of Massachusetts, Amherst, Massachusetts; Associate Researcher, Psychiatry, Massachusetts General Hospital; Faculty, Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts The Neurobiology of Dreaming

Markku Partinen, MD, PhD Adjunct Professor, Department of Clinical Neurosciences, University of Helsinki; Director, Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland Epidemiology of Sleep Disorders

Contributors  xvii

Dipali Patel, BSc (Hons)

Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management

John H. Peever, PhD Associate Professor, Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada Sensory and Motor Processing during Sleep and Wakefulness

Philippe Peigneux, PhD Professor, Chair Clinical Neuropsychology, Neuropsychology and Functional Neuroimaging Research Unit, Université Libre de Bruxelles, Bruxelles, Belgium; Scientific Collaborator, Cyclotron Research Centre, Université de Liège, Liège, Belgium Memory Processing in Relation to Sleep

Yüksel Peker, MD, PhD Associate Professor, Pulmonary Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Medical Doctor, Neurology, Rehabilitation and Sleep Medicine, Skaraborg County Hospital, Skövde, Sweden Coronary Artery Disease and Obstructive Sleep Apnea

Michael Perlis, PhD Associate Professor, Psychiatry; Director, Behavioral Sleep Medicine Program, University of Pennsylvania, Philadelphia, Pennsylvania Models of Insomnia

Aleksander Perski, PhD Assistant Professor, Stress Research Institute, Stockholm University, Stockholm, Sweden Sleep, Stress, and Burnout

Michael J. Peterson, MD, PhD Assistant Professor, Psychiatry, University of Wisconsin, School of Medicine and Public Health; Director of Consultation and Liaison Psychiatry, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Mood Disorders

Dominique Petit, PhD Research Assistant, Psychiatry, Université de Montréal; Senior Research Assistant, Center for Advanced Studies in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada Alzheimer’s Disease and Other Dementias

Pierre Philip, MD, PhD Université Bordeaux 2, GENPPHASS, Clinique du Sommeil, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France Drowsy Driving

Barbara A. Phillips, MD, MSPH, FCCP Professor, Division of Pulmonary, Critical Care and Sleep Medicine; Internal Medicine, University of Kentucky College of Medicine; Medical Director, University of Kentucky Good Samaritan Sleep Center, Lexington, Kentucky Management of Obstructive Sleep Apnea-Hypopnea Syndrome Obstructive Sleep Apnea in the Elderly

Wilfred R. Pigeon, PhD, CBSM Assistant Professor; Director, Sleep and Neurophysiology Research Laboratory, Psychiatry, University of Rochester Medical Center, Rochester, New York Dreams and Nightmares in Posttraumatic Stress Disorder

Vsevolod Y. Polotsky, MD, PhD Associate Professor, Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Obstructive Sleep Apnea and Metabolic Dysfunction

Nelson B. Powell, MD, DDS, FACS Department of Otolaryngology Head and Neck Surgery and Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Palo Alto, California Surgical Management for Obstructive SleepDisordered Breathing

Naresh M. Punjabi, MD, PhD Associate Professor of Medicine and Epidemiology, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland Obstructive Sleep Apnea and Metabolic Dysfunction

Maria Antonia Quera-Salva, MD Director of Sleep Unit, Hôpital Raymond Poincaré APHP, Paris Ouest University, Paris, France

Melatonin and the Regulation of Sleep and Circadian Rhythms

Holly Ramsawh, PhD Assistant Project Scientist, Psychiatry, University of California, San Diego, La Jolla, California Anxiety Disorders

Kathryn Moynihan Ramsey, PhD Post Doctoral Fellow, Departments of Neurobiology & Physiology and Medicine, Northwestern University, Evanston, Illinois Animal Models for Disorders of Chronobiology: Cell and Tissue

Susan Redline, MD, MPH Professor, Medicine and Center of Clinical Investigation, Case Western Reserve University, Cleveland, Ohio Genetics of Obstructive Sleep Apnea

Kathryn J. Reid, PhD Research Assistant Professor, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Circadian Disorders of the Sleep–Wake Cycle

xviii  Contributors

John E. Remmers, MD Professor, Internal Medicine and of Physiology and Biophysics, University of Calgary Faculty of Medicine; Physician, Foothills Hospital, Calgary, Alberta, Canada Anatomy and Physiology of Upper Airway Obstruction

Robert W. Riley, DDS, MD, FACS Adjunct Clinical Professor, Surgery, Department of Otolaryngology Head and Neck Surgery; Adjunct Clinical Associate Professor, Sleep Disorders Medicine, Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford University Sleep and Research Center, Palo Alto, California Surgical Management for Obstructive SleepDisordered Breathing

Dominique Robert, PUPH Professor, Claude Bernard University; Medical Doctor, Intensive Care, Hospices Civils de Lyon; President, Home Care Program, Association Lyonnaise de Logistique Post-hospitalière, Lyon, France

Noninvasive Ventilation to Treat Chronic Ventilatory Failure

Timothy Roehrs, PhD Professor, Department of Psychiatry and Behavioral Neuroscience, Wayne State University, School of Medicine; Director of Research, Sleep Disorders of Research Center, Henry Ford Hospital, Detroit, Michigan Daytime Sleepiness and Alertness Medication and Substance Abuse

Alan M. Rosenwasser, PhD Professor, Department of Psychology, University of Maine; Cooperating Professor, School of Biology and Ecology, University of Maine, Orono, Maine Physiology of the Mammalian Circadian System

Thomas Roth, PhD Professor, Department of Psychiatry, Wayne State University School of Medicine; Director and Division Head, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan; Clinical Professor, Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan Daytime Sleepiness and Alertness Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists Medication and Substance Abuse

Megan E. Ruiter, MA Graduate Student, Department of Psychology, The University of Alabama, Tuscaloosa, Alabama Insomnia: Epidemiology and Risk Factors

Benjamin Rusak, PhD, FRSC Professor and Director of Research, Psychiatry, Dalhousie University; Director, Chronobiology and Sleep Program, Capital District Health Authority; Professor, Psychology, Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

Circadian Rhythms in Mammals: Formal Properties and Environmental Influences

Patricia Sagaspe, PhD Genpphass, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France; Laboratoire Exploitation, Perception, Simulateurs et Simulations; Institut National de Recherche sur les Transports et leur Sécurité; Laboratoire Central des Ponts et Chaussées, Paris, France Drowsy Driving

Charles Samuels, MD Medical Director, Centre for Sleep and Human Performance; Clinical Assistant Professor, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

Sleep Problems in First Responders and the Military

Mark H. Sanders, MD, FCCP, D’ABSM Professor of Medicine (retired), Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Sleep in Chronic Kidney Disease

Clifford B. Saper, MD, PhD James Jackson Putnam Professor, Department of Neurology, Program in Neuroscience, and Division of Sleep Medicine, Harvard Medical School; Chairman, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Anatomy of the Mammalian Circadian System

Aliya Sarwar, MD Assistant Professor of Neurology, Baylor College of Medicine; Associate Director, Clinical Care, Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Michael E. DeBakey VA Medical Center, Houston, Texas Evaluating Sleepiness

Michael J. Sateia, MD Professor of Psychiatry, Sleep Medicine, Dartmouth Medical School; Chief, Section of Sleep Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Treatment Guidelines for Insomnia

Josée Savard, PhD Professor, School of Psychology, Université Laval; Researcher, Laval University Cancer Research Center, Québec, Québec, Canada Sleep and Fatigue in Cancer Patients

Carlos H. Schenck, MD Professor, Department of Psychiatry, University of Minnesota Medical School; Staff Psychiatrist, Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, Minnesota REM Sleep Parasomnias

Michael Schredl, PhD Head of Research, Sleep Laboratory, Central Institute of Mental Health; Associate Professor, Department of Psychology, Fakultät für Sozialwissenschaften, University of Mannheim, Mannheim, Germany Dreams in Patients with Sleep Disorders

Contributors  xix

Richard J. Schwab, MD Professor, Department of Medicine, Division of Sleep Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Carlyle Smith, PhD Lifetime Professor Emeritus, Psychology, Trent University, Peterborough, Ontario, Canada; Adjunct Professor, Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada

Paula K. Schweitzer, PhD Director of Research, Sleep Medicine and Research Center, St. Luke’s Hospital, St. Louis, Missouri

Michael T. Smith, PhD Associate Professor, Psychiatry and Behavioral Sciences; Director, Behavioral Sleep Medicine Program, The Johns Hopkins Bayview Medical Center, Baltimore, Maryland

Anatomy and Physiology of Upper Airway Obstruction

Drugs That Disturb Sleep and Wakefulness

Frédéric Sériès, MD Professor, Department of Medicine, Laval University; Director, Sleep Laboratory, Pneumology, Institut de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada

Normal Physiology of the Upper and Lower Airways

Barry J. Sessle, MDS, PhD, DSc(hc), FRSC Professor, Canada Research Chair, Faculty of Dentistry, University of Toronto; Consultant, Wasser Pain Management Centre, Mount Sinai Hospital, Toronto, Ontario, Canada; Adjunct Professor of Dentistry, School of Medicine and Dentistry, University of Rochester, Rochester, New York Sensory and Motor Processing during Sleep and Wakefulness

Amir Sharafkhaneh, MD, PhD, DABSM Associate Professor of Medicine, Baylor College of Medicine, Baylor University; Medical Director, Sleep Disorders and Research Center, Michael E. DeBakey VA Medical Center, Houston, Texas Evaluating Sleepiness

Paul J. Shaw, PhD Assistant Professor, Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri Models of Insomnia

Tamar Shochat, DSc Associate Professor, Nursing, University of Haifa, Haifa, Israel Insomnia in Older Adults

Margaret Shouse, PhD Professor, Neurobiology, School of Medicine, University of California, Los Angeles, Los Angeles, California Epilepsy, Sleep, and Sleep Disorders

Jerome M. Siegel, PhD Professor, Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California; Chief, Neurobiology Research, VA Greater Los Angeles Healthcare System-Sepulveda, Center for Sleep Research, North Hills, California REM Sleep Sleep in Animals: A State of Adaptive Inactivity

Memory Processing in Relation to Sleep

Pain and Sleep

Virend K. Somers, MD, PhD Professor of Medicine, Cardiovascular Division, Department of Internal Medicine; Consultant, Division of Cardiology Department of Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders Cardiovascular Effects of Sleep-Related Breathing Disorders

Arthur J. Spielman, PhD Professor, Psychology, The City College of the City University of New York; Associate Director, Center for Sleep Medicine, Weill Cornell Medical College, Cornell University, New York, New York; Director of Research, Center for Sleep Disorders Medicine and Research, New York Methodist Hospital, Brooklyn, New York Assessment Techniques for Insomnia Insomnia: Diagnosis, Assessment, and Outcomes

Murray B. Stein, MD, MPH Professor, Psychiatry and Family and Preventive Medicine, University of California, San Diego, La Jolla, California; Staff Psychiatrist, Psychiatry, VA San Diego Healthcare System, San Diego, California Anxiety Disorders

Robert Stickgold, PhD Associate Professor, Psychiatry, Harvard Medical School; Associate Professor, Psychiatry, Beth Israel-Deaconess Medical Center, Boston, Massachusetts Why We Dream

Katie L. Stone, MA, PhD Senior Scientist, Research Institute, California Pacific Medical Center, San Francisco, California Actigraphy

Robyn Stremler, RN, PhD Assistant Professor, Lawrence S. Bloomberg Faculty of Nursing, University of Toronto; Adjunct Scientist, The Hospital for Sick Children, Toronto, Ontario, Canada The Postpartum Period

xx  Contributors

Patrick J. Strollo, Jr., MD Associate Professor, Medicine and Clinical and Translational Research, Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Medical Therapy for Obstructive Sleep Apnea

Ronald Szymusiak, PhD Adjunct Professor, Departments of Medicine and Neurobiology, David Geffen School of Medicine at UCLA; Research Scientist, VA Greater Los Angeles Healthcare System, Los Angeles, California Neural Control of Sleep in Mammals

J. Taillard, MD, PhD Université Bordeaux 2, GENPPHASS, Clinique du Sommeil, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France Drowsy Driving

Esra Tasali, MD Assistant Professor, Medicine, Pulmonary & Critical Care Medicine, University of Chicago Medical Center, Chicago, Illinois Endocrine Physiology in Relation to Sleep and Sleep Disturbances

Daniel J. Taylor, PhD Associate Professor, Department of Psychology, University of North Texas, Denton, Texas Insomnia: Epidemiology and Risk Factors

Mihai Teodorescu, MD Clinical Assistant Professor of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Medical and Psychiatric Disorders and the Medications Used to Treat Them

Jiuan Su Terman, PhD Clinical Coordinator, Center for Light Treatment and Biological Rhythms, Columbia University Medical Center, New York, New York Light Therapy

Michael Terman, PhD Professor, Psychiatry, College of Physicians & Surgeons, Columbia University; Research Scientist VI, Clinical Chronobiology, New York State Psychiatric Institute; Director, Center for Light Treatment and Biological Rhythms, New York Presbyterian Hospital, Columbia University Medical Center; President, Center for Environmental Therapeutics, New York, New York Light Therapy

Michael J. Thorpy, MD Director, Sleep/Wake Disorders Center, Montefiore Medical Center, and Albert Einstein College of Medicine New York, New York Classification of Sleep Disorders

Irene Tobler, PhD Professor, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland Phylogeny of Sleep Regulation

Claudia Trenkwalder, MD Paracelsus Elena Hospital Kassel, Professor of Neurology, Department of Clinical Neurophysiology, University of Gottingen, Gottingen, Germany; Chair, Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel, Germany Parkinsonism

Fred W. Turek, PhD Charles E. and Emma H. Mison Professor, Biology, Center for Sleep and Circadian Biology, Northwestern University, Evanston, Illinois Introduction, Section 3 Circadian Clock Genes Genetic Basis of Sleep in Rodents Introduction: Master Circadian Clock and Master Circadian Rhythm Gastrointestinal Physiology in Relation to Sleep Physiology of the Mammalian Circadian System Animal Models for Disorders of Circadian Functions: Whole Organism

Mark L. Unruh, MD, MSc Assistant Professor, Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Sleep in Chronic Kidney Disease

Eve Van Cauter, PhD Professor, Department of Medicine, Chicago, Illinois

Endocrine Physiology in Relation to Sleep and Sleep Disturbances

Hans P.A. Van Dongen, MS, PhD Research Professor and Assistant Director, Sleep and Performance Research Center, Washington State University, Spokane, Washington Circadian Rhythms in Sleepiness, Alertness, and Performance Fatigue and Performance Modeling Fatigue, Performance, Errors, and Accidents

Bradley V. Vaughn, MD Professor, Neurology and Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina Cardinal Manifestations of Sleep Disorders

Richard L. Verrier, PhD, FACC Associate Professor of Medicine, Harvard Medical School, Department of Medicine, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Cardiovascular Physiology: Central and Autonomic Regulation Sleep-Related Cardiac Risk Cardiac Arrhythmogenesis during Sleep: Mechanisms, Diagnosis, and Therapy

Contributors  xxi

Bryan Vila, PhD Professor and Director, Simulated Hazardous Operational Tasks Laboratory, Sleep and Performance Research Center, Washington State University, Spokane, Washington Sleep Problems in First Responders and the Military

Martha Hotz Vitaterna, PhD Research Associate Professor, Center for Functional Genomics, Northwestern University Center for Functional Genomics, Evanston, Illinois Circadian Clock Genes

James K. Walsh, PhD Visiting Professor, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California; Executive Director and Senior Scientist, Sleep Medicine and Research Center, St. Luke’s Hospital; Adjunct Professor, Department of Psychology, Saint Louis University, St. Louis, Missouri Sleep Medicine, Public Policy, and Public Health Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists

Arthur S. Walters, MD Professor and Associate Director, Sleep Medicine, Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee Restless Legs Syndrome and Periodic Limb Movements during Sleep

Erin J. Wamsley, PhD Instructor, Psychiatry, Harvard Medical School; Instructor, Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts Why We Dream

Terri E. Weaver, PhD, RN, FAAN Professor and Dean, University of Illinois at Chicago College of Nursing, Chicago, Illinois Cognition and Performance in Patients with Obstructive Sleep Apnea

John V. Weil, MD Emeritus Professor, Medicine, University of Colorado School of Medicine, Denver, Colorado Respiratory Physiology: Sleep at High Altitudes

Ian D. Weir, DO Associate Director, the Sleep Disorders Center; Director of the Insomnia Center, Norwalk Hospital, Norwalk, Connecticut Wake-Promoting Medications: Efficacy and Adverse Effects

Andrew Wellman, MD Instructor, Medicine, Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts Central Sleep Apnea and Periodic Breathing

Nancy J. Wesensten, PhD Behavioral Biology Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland

Pharmacologic Management of Performance Deficits Resulting from Sleep Loss and Circadian Desynchrony

David P. White, MD Clinical Professor, Medicine, Harvard Medical School; Clinical Professor of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Central Sleep Apnea and Periodic Breathing

Amy R. Wolfson, PhD Professor of Psychology; Associate Dean for Faculty Development, Office of the Dean, College of the Holy Cross, Worcester, Massachusetts The Postpartum Period

Kenneth P. Wright, Jr., PhD Assistant Professor, University of Colorado, Boulder, Colorado Shift Work, Shift-Work Disorder, and Jet Lag

Chien-Ming Yang, PhD Assistant Professor, Department of Psychology, National Chengchi University, Taipei, Taiwan Assessment Techniques for Insomnia

Terry Young, MS, PhD Professor, Department of Population Health Sciences, Epidemiology Section, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea

Antonio Zadra, PhD Professor, Psychology, Université de Montréal; Research Professor, Centre d’Etude du Sommeil et des Rythmes Biologiques, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Dream Content: Quantitative Findings Idiopathic Nightmares and Dream Disturbances Associated with Sleep−Wake Transitions

Phyllis C. Zee, MD, PhD Professor, Neurology; Director, Sleep Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois Circadian Disorders of the Sleep−Wake Cycle

Marco Zucconi, MD Professor, Department of Neurology, Sleep Disorders Center, H San Raffaele Scientific Institute and Hospital, Università Vita-Salute San Raffaele, Milan, Italy Pain and Sleep

Foreword  xxiii

Foreword

Medicine has only recently discovered the importance of sleep, and how sleep symptoms can be the canary in the mine of serious medical and psychiatric problems that can affect all people. I can attest firsthand about the importance of sleep, and how symptoms affecting sleep can impact a person’s life. I was the Canadian Force Commander of the United Nations Assistance Mission for Rwanda between October 1993 and August 1994. During that time, a genocide resulted in the deaths of 800,000 people and I was an eyewitness having heard, smelled, seen, and touched thousands and thousands of mutilated bloated bodies of innocent civilians while trying to arrange a peace during a civil war while much of the world stood idly by. My sleep suffered, my health suffered, and I developed the symptoms of posttraumatic stress disorder. As the mission was winding down … “After prayers, I climbed into my vehicle and took off without telling anyone. It wasn’t the first time. I had begun to suffocate in the headquarters, with its endless stream of problems and demands. I had been inventing trips to get me away from it, deciding that I had to see the troops in the field or just tour the country. In every village, along every road, in every church, in every school were unburied corpses. My dreams at night became my reality of the day, and increasingly I could not distinguish between the two. By this point, I wasn’t bothering to make excuses anymore to disguise my quest for solitude. I would just sneak away and then drive around thinking all manner of black thoughts that I couldn’t permit myself to say to anyone for fear of the effect on the morale of my troops. Without my marking the moment, death became a desired option. I hoped I would hit a mine or run into an ambush and just end it all. I think some part of me wanted to join the legions of the dead, whom I felt I had failed. I could not face the thought of leaving Rwanda alive after so many people had died. On my travels around the country, whole roads and villages were empty, as if they’d been hit by a nuclear bomb or the bubonic plague. You could drive for miles without seeing a single human being or a single living creature. Everything seemed so dead.” From, Roméo A. Dallaire, Shake Hands with the Devil: The Failure of Humanity in Rwanda. Carroll & Graf Publishers, New York. 2003. pp 499-500. This is the first medical textbook that focuses on the sleep disorders that affect everyone, and that also includes the problems of first responders and the military and teaches doctors about how post traumatic stress disorder impacts sleep. I congratulate the editors.

It is an honor for us, representing the Sleep Research Society, to help introduce the 5th edition of Principles and Practice of Sleep Medicine. This volume appears nearly fifty years after the first professional sleep research meeting in the United States on March 25 and 26, 1961, a meeting which directly led to the formation of the Sleep Research Society. According to records of Al Rechtschaffen, maintained in the University of Chicago Library, the first meeting was titled the “Conference on Research in EEG, Sleep and Dreams.” Two days of scientific sessions included topics such as: “Methods and Merits of Various Systems of Scoring,” “Equipment and Technical Problems” and “The Relation of EEG to Verbal Report.” As the session titles suggest, in 1961 sleep scientists were necessarily focused upon some of the most basic tenants of research: observation, measurement, standardization, and tech­ nology. It seems very unlikely that any of the thirty-six scientists in attendance, including Bill Dement, would have envisioned the exponential growth of knowledge about sleep and its disorders represented in the many pages of the current volume. Sleep research has evolved to include the breadth of modern scientific approaches, and sleep medicine is germane to most medical specialties and public health concerns. In the 149 chapters of this text (including more than 50 new chapters and new sections on Genetics, Occupational Sleep Medicine, Sleep Medicine in Older People) experts describe the intricate mechanisms of biological timing, the genetic polymorphisms conferring risk for sleep disorders, sleep-immune interactions, the morbidity and mortality risks of sleep apnea, and the impact of sleep disturbance on workplace and transportation safety, just to highlight as few areas. We commend the authors on their excellent contributions which will serve to educate and inspire practitioners, researchers and students for years to come. The Sleep Research Society congratulates Drs. Kryger, Roth, and Dement on the publication of this very impressive 5th edition of Principles and Practice of Sleep Medicine and thanks them for undertaking the important service of identifying the latest advances in the field and compiling the body of knowledge represented herein.

—Lt. Gen the Hon. Roméo Dallaire, OC, CMM,

—Clifford B. Saper, MD, PhD

GOQ, MSC, CD, (Ret’d), Senator, Canada

—James K. Walsh, PhD President, Sleep Research Society Executive Director and Senior Scientist Sleep Medicine and Research Center St. Luke’s Hospital Chesterfield, Missouri Past-president, Sleep Research Society James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center Boston, Massachusetts

xxiii

xxiv  Foreword

The success of any field of medicine is often directly proportional to the scope and comprehensiveness of the knowledge base available to physicians, scientists, trainees, and the general public. For the field of sleep medicine, we are fortunate in that there continues to be dramatic growth in this knowledge, derived from both patient care and clinical/basic research. It is revealing when we step back and reflect on how this knowledge base has developed in so short a time: It has been less than 60 years since the discovery of rapid eye movement (REM) sleep, which initiated the organized, scientific study of sleep, and barely 25 years since the invention of continuous positive airway pressure (CPAP), which comprised the first effective treatment for obstructive sleep apnea. In this short time, the sleep field has expanded to the point where we have almost 1,900 accredited sleep centers and laboratories in the United States and over 9,000 members of the American Academy of Sleep Medicine. Our field has blossomed to the point where it is truly interdisciplinary, comprising specialists from the areas of pulmonary medicine, neurology, psychiatry, internal and family medicine, pediatrics, psychology, otolaryngology, and others. Exciting breakthroughs in sleep research have impacted other disciplines of science and research as well, and it is not unusual for sleep medicine specialists to collaborate with other diverse fields of medicine such as cardiology, endocrinology, and immunology. Despite our amazing growth, there are still many questions yet to be answered, including the holy grail of our field: the function of sleep. To explore these questions, the field requires a continued supply of dedicated and talented researchers in both the clinical and basic sciences. In addition, funding from the government, industry, and foundations; support from institutions; and strong mentorship by experienced investigators are important cornerstones to a successful independent research career. As members of the field, we must collectively strive to ensure that funding, support, and mentorship continues in order to ensure success of our field, even in times of economic downturns and increased competition from other fields. For without breakthroughs in research, there won’t be new diagnostic tools, medications, or treatments to help us manage the nearly 90 different sleep disorders that we have identified thus far. The growth of our field and the exploration of critical research areas cannot exist without adequate education and training of our young clinicians and investigators. We are indeed privileged that we have excellent resources available that enable trainees to learn more about sleep and sleep medicine. For countless numbers of students, Principles and Practice of Sleep Medicine has served as the primary textbook, study material for the sleep medicine board certification examination, and/or the basic resource for any sleep-related condition or question about sleep. Often fondly referred to simply as “P&P”, it continues to rise in prominence and demand. I’ve had the great pleasure to learn from and collaborate with Drs. Kryger, Roth, and Dement, and not only are they among the top clinicians and scientists within our field, but they have continued to produce a sleep medicine reference that has remained the

gold standard over the span of 20 years. Our field is deeply indebted to their dedication, hard work, and diligence. —Clete A. Kushida, MD, PhD, RPSGT

President, American Academy of Sleep Medicine Director, Stanford Center for Human Sleep Research Stanford University, California

The American Sleep Apnea Association (ASAA) congratulates the editors of the Principles and Practice of Sleep Medicine on the publication of the fifth edition of this invaluable guide for those practicing sleep medicine. As the field evolves, it has become a key resource for those responsible for diagnosing and treating those with sleep disorders like sleep apnea. The long-term management of patients requires a partnership between the doctor who will learn from this volume the scientific basis of the field and the patient with a chronic illness who must also learn about their condition. For the patient and their families seeking to understand sleep apnea prior to diagnosis, and often once they are treated, they frequently turn to the ASAA, since 1990 the only patient interest organization in the USA dedicated to sleep apnea education, support and advocacy. The ASAA produces educational materials and includes support groups for sleep apnea patients and their families operating under the name A.W.A.K.E. that stands for Alert, Well, And Keep Energetic. The network of the more than 300 A.W.A.K.E. groups has locations around the United States, Canada and overseas. As elucidated in this book sleep apnea is associated with several important comorbidities and thus the ASAA will expand contacts with other patient groups concerned such as heart disease and type 2 diabetes. The fifth edition of Practice and Principles of Sleep Medicine is for the education and support of the caregiver and the American Sleep Apnea Association for the education and support of the apnea patient and their family. —Edward Grandi

Executive Director American Sleep Apnea Association

On behalf of the National Sleep Foundation, it is my pleasure and honor to help introduce the fifth edition of Principles and Practice of Sleep Medicine, the latest update to what has over the past 21 years properly come to be regarded as the preeminent reference text on sleep medicine. I congratulate the editors, Drs. Kryger, Roth, and Dement, for this new edition – representing as it does their long-standing and continuing commitment to the expansion of the field of sleep medicine and science, and their collective talent for presentation and dissemination of sleep-related knowledge. When the first edition was published, the discipline of sleep medicine was in its infancy. Today, perusing previous editions of PPSM is akin to marveling over the growth of a child by leafing through old family photo albums: Although it is understood on an intellectual level that growth and maturation have been occurring continuously, the intermittent nature of the photographic record serves to crystallize those changes in startlingly sharp relief. So it

Foreword  xxv

is with PPSM and the history of our field. Each successive edition of PPSM has faithfully reflected the progress made in the intervening years, in a narrative manner that makes clear the process by which high-quality scientific research on sleep and its disorders accrues and is translated into the practice of sleep medicine. Perusal of the current edition will, I think, make it apparent that our field has now grown past infancy, spurted through childhood, and entered its adolescence: to be sure,

a phase of high energy and escalating complexity with a few early hints of maturity, but a phase primarily characterized by the exhilaration of a future that still seems horizonless. For those wishing an understanding of the roots of sleep science, desiring a comprehensive overview of the current ‘state of the art’ of sleep medicine, or yearning for a glimpse of what the future of sleep science holds, just start turning the pages. … —Thomas J. Balkin, Ph.D.

Chairman of the Board of Directors National Sleep Foundation Washington, DC

Preface It has been a quarter century since we started work on the first edition of Principles and Practice of Sleep Medicine. At that time there was a great deal of concern from colleagues that there simply wasn’t enough information available for a book, and there simply wasn’t enough of a market to justify all that effort. In fact, several colleagues whom we respect a great deal tried to talk us out of a textbook because they felt it would have been a waste of time. At that time there were roughly 2000 members of the American Sleep Disorders Association (now the American Academy of Sleep Medicine). Information about sleep medicine was transmitted and shared via telephone (almost everybody knew everybody practicing sleep medicine), articles, scientific meetings and one or two journals that regularly published articles about sleep. How things have changed. In the United States of America, within about 25 miles of anybody’s home there are about 5 to 10 accredited sleep disorders centers, and also some unaccredited centers. There are about 1900 accredited sleep disorders centers. The American Academy of Sleep medicine has approximately 9000 members and counting. The number of doctors who practice sleep medicine is unknown, but there are 3,445 who have specialty certification in sleep awarded by the American Board of Sleep Medicine. This has been supplanted by a new certification exam administered by the American Board of Medical Specialties. The first time the exam was given, 724 physicians passed the examination. In addition, doctors from other specialties who may not have had any training in sleep medicine (for example those trained in pulmonary, neurology, otolaryngology) frequently evaluate and manage patients with sleep disorders. There are now eleven journals that publish articles exclusively about sleep. Whereas in 1985 there were about

Thomas Roth

400 articles published using the keywords “sleep apnea” or “sleep apnoea,” by 2010 about 4000 articles are being published per year. Entirely new fields now have important sleep components including geriatrics, occupational health, women’s health, and there has been an explosion of knowledge just in the past few years in the genetics, molecular biology, and neuroanatomy and neurochemistry of sleep. To ensure that the information is up-to-date, this edition has five entirely new sections (“Sleep Medicine in the Elderly,” “Occupational Sleep Medicine,” “Physiology in Sleep,” “Genetics of Sleep,” and “Sleep Mechanisms and Phylogeny”). There are more than 50 brand new chapters and the remaining chapters have all been updated. There are new sleep stage and respiratory event scoring rules and this is perhaps the first major sleep textbook that incorporates these rules. A companion volume, Atlas of Clinical Sleep Medicine, contains hundreds of examples of polysomnographic data, and videos of interviews with patients with sleep disorders. Besides the dramatic increase in content, we had to deal with the changes in the delivery of information. Books were the way to go in the 1980s, content on CDs were the rage in the 1990s, but web-enabled books appear to be what people want beyond 2010. The third edition almost came out solely on a CD. It turned out that CDs were a passing trend and people hated reading large amounts of text on a computer screen. What doctors want now is a book that they can access in their library, via the internet and even on their handheld device and tablet. We have been listening to caregivers who use this content to help them better care for their patients and hope that you will continue to provide feedback.

Meir H. Kryger

William C. Dement

xxvii

Acknowledgments

This is now about the 25th year since the editors started to work on the first edition of the Principles and Practice of Sleep Medicine. Twenty-five years is a generation and during that time it is safe to say that thousands of professionals and editorial staff have worked on this book, and it is impossible to thank each and every one, as much as we would love to. We would like to thank the current and previous section editors. They are the leaders in their fields and they bring their vision to the book. They fashioned the content so it is of greatest value and relevance to the reader, and ultimately the patient. We would like to thank all the chapter contributors for their hard work. Producing a new chapter or refreshing and updating a previous one is not easy because scientific papers on sleep are published daily and it is a difficult task to remain completely up-to-date.

We would also like to thank the staff at Elsevier who have been so supportive of sleep medicine. Dolores Meloni has been fabulous and supportive of the book. Angela Norton and Anne Snyder shepherded the production of content for the book and Bob Browne has quietly and efficiently managed the web content. We especially wish to thank Sarah Wunderly who took over production of the book at the home stretch and calmly, expertly, and patiently delivered it to the printers. We want to thank the book designers and the production staff for producing such an elegant volume. Finally, we want to thank the many people, readers, who have given us such excellent ideas and feedback. —Meir H. Kryger, Thomas Roth, and William C. Dement

xxix

Abbreviations  xxxi

Abbreviations

AASM: American Academy of Sleep Medicine ACC: anterior cingulate cortex Ach: acetylcholine ACTH: adrenocorticotropic hormone AD-ACL: Activation-Deactivation Adjective Check List ADHD: attention-deficit-hyperactivity disorder AHI: apnea-hypopnea index AIM: ancestry informative marker AMPA: α-amino-3hydroxy-5-methylisozazole-4propionic acid AMPK: adenosine-monophosphate-activated protein kinase AMS: acute mountain sickness ANS: autonomic nervous system ASPS: advanced sleep phase syndrome ASPT: advanced sleep phase type AW: active wakefulness BA: Brodman area BAC: blood alcohol content BCOPS: Buffalo Cardio-Metabolic occupational Police Stress BF: basal forebrain BMAL1: brain and muscle ARNT-like BMI: body mass index BNST: bed nucleus of the stria terminalis BPD: biliopancreatic diversion BPDDS: Biliopancreatic diversion with duodenal switch BzRA: benzodiazepine receptor agonist CAD: coronary artery disease CAPS: cyclic alternating pattern sequence(s) CBT: cognitive behavior therapy CHF: congestive heart failure CI: confidence interval CPS/HHPRI: Calgary Police Service Health and Human Performance Research Initiative COMT: catechol-O-methyltransferase COPD: chronic obstructive pulmonary disease CPAP: continuous positive airway pressure CRP: C-reactive protein CRY: cryptochrome CSN: cold-sensitive neuron CYP: cytochrome P-450 DA: dopamine DAT: dopamine transporter DBP: D-element binding protein DD: constant dark DIM: digital integration mode DLMO: dim-light melatonin onset DLPFC: dorsolateral prefrontal cortex DMD: Duchenne’s muscular dystrophy DSISD: Duke Structured Interview for Sleep Disorders

DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition DSPS: delayed sleep phase syndrome DSPT: delayed sleep phase type DTs: delirium tremens DU: duodenal ulcer ECG: electrocardiogram/electrocardiographic EDS: excessive daytime sleepiness EEG: electroencephalogram, electroencephalographic EMG: electromyogram ENS: enteric nervous system EOG: electrooculogram EPS: extrapyramidal side effects (s) EPSP: excitatory postsynaptic potential ERP: event-related potential ESS: Epworth Sleepiness Scale FAID: Fatigue Audit InterDyne 18 FDG: 2-deoxy-2-[18F]fluoro-d-glucose F-DOPA: 6-[18F]fluoro-l-dopa FEV1: forced expiratory volume in 1 second FIRST: Ford Insomnia Response to Stress Test fMRI: functional magnetic resonance imaging FOQA: flight operations quality assurance FOSQ: Functional Outcomes of Sleep Questionnaire FRA: Federal Railroad Administration FRC: functional residual capacity FSIVGTT: frequently sampled intravenous glucose tolerance test GABA: gamma-aminobutyric acid GAD: generalized anxiety disorder GAHMS: genioglossus advancement, hyoid myotomy, and suspension GCD: global cessation of dreaming GER: gastroesophageal reflux GHB: gamma-hydroxybutyrate GHRH: growth hormone-releasing hormone GWA: genome wide association 5-HIAA: 5-hydroxyindole acetic acid 5-HT: hydroxytryptamine (serotonin) HAPE: high-altitude pulmonary edema Hcrt: hypocretin HDI: hypnotic-dependent insomnia HDL: high density lipoprotein HIF: hypoxia inducible factor HIV: human immunodeficiency virus HLA: human leukocyte antigen HOMA: homeostasis model assessment HPA: hypothalamic-pituitary-adrenal axis HRV: heart rate variability HVA: homovanillic acid HWHSGPS: Harvard Work Hours and Safety Group Police Study xxxi

xxxii  Abbreviations

ICD: International Classification of Diseases ICD-9-CM: International Classification of Diseases, 9th revision, Clinical Modification ICS-10: International Classification of Diseases, 10th revision ICSD-2: International Classification of Sleep Disorders, Revised ICV: intracerebroventricular IEG: immediate early gene IGL: intergeniculate leaflet IL: interleukin ILD: interstitial lung disease IPSP: inhibitory postsynaptic potential ISI: Insomnia Severity Index kd: kilodalton KSS: Karolinska Sleepiness Scale LAUP: laser-assisted uvulopalatoplasty LD: light-dark LDL: low density lipoprotein l-dopa: l-dihydroxyphenylalanine, levodopa LG: lateral geniculate LL: constant light LOC: left outer canthus LPA (or LPOA): lateral preoptic area LSAT: lowest oxyhemoglobin saturation LTIH: long-term intermittent hypoxia MAO: monoamine oxidase MAOI: monamine oxidase inhibitor MDA: methylenedioxyamphetamine MDD: major depressive disorder MDMA: methylenedioxymethamphetamine (“ecstasy”) MDP-LD: muramyl dipeptide N-actyl-muramyl-l-alanyl-d-isoglutamine MEG: magnetoencephalography MI: myocardial infarction MMC: migrating motor complex MMO: maxillary and mandibular osteotomy MnPN: median preoptic nucleus MNSA: muscle nerve sympathetic vasomotor activity MPA or (MPOA): medial preoptic area MPA: medroxyprogesterone acetate MRA: mandibular repositioning appliance MSLT: Multiple Sleep Latency Test MWT: Maintenance of Wakefulness Test NAD: nicotinamide adenine nucleotide NAMPT: nicotinamide phosphoribosyltransferase NASH: nonalcoholic steatohepatitis NCEP: National Cholesterol Education Program NCSDR: National Center on Sleep Disorders Research NE: norepinephrine NET: norepinephrine transporter NFLD: nonalcoholic fatty liver disease NFκB: nuclear factor kappa B NHANES: national Health and Nutrition Examination Survey NIH: National Institutes of Health NIPPV: nasal intermittent positive-pressure ventilation NK: natural killer [cell] NMDA: N-methyl-d-aspartate NO: nitric oxide NPPV: noninvasive positive-pressure ventilation NPT: nocturnal penile tumescence

NREM: non–rapid eye movement, non-REM OCD: obsessive-compulsive disorder OFC: orbitofrontal cortex 6-OHDA: 6-hydroxydopamine OHS: obesity-hypoventilation syndrome OR: odds ratio OSA: obstructive sleep apnea OSAHS: obstructive sleep apnea–hypopnea syndrome OSAS: obstructive sleep apnea syndrome PACU: postanesthesia care unit PCOS: polycystic ovary syndrome PEEP: positive end-expiratory pressure PER: period PET: positron emission tomography PGO: ponto-geniculo-occipital [spike] PIA: pontine inhibitory area PLMS: periodic limb movements during sleep (or PLM) PMDD: premenstrual dysphoric disorder PNI: people not having insomnia POA: preoptic area POMS: Profile of Mood States POSSR: Patrol Officers Shift Schedule Review PR: prevalence ratio PRC: phase–response curve PSG: polysomnography, polysomnographic PSQI: Pittsburgh Sleep Quality Index PTSD: posttraumatic stress disorder PVN: paraventricular nucleus PVT: psychomotor vigilance test PWI: people with insomnia PWOP: people who did not report having the medical problem PWP: people who reported have the medical problem QTL: quantitative trait loci (or locus) QW: quiet wakefulness RBD: REM sleep behavior disorder RDC: research diagnostic criteria RDI: respiratory disturbance index REM: rapid eye movement RERA: respiratory effort related arousal RFA: radiofrequency ablation RHT: retinohypothalamic tract RI: recombinant inbred Rin: membrane input resistance RIP: respiratory inductive plethysmography RLS: restless legs syndrome RMMA: rhythmic masticatory motor activity ROC: right outer canthus ROS: reactive oxygen species (sing. and pl.) RR: risk ratio RT: reaction time RYGB: Roux-en-Y gastric bypass SAFTE: Sleep, Activity, Fatigue, and Task Effectiveness (model) SCD: stearoyl coenzyme A desaturase SCID: Structured Clinical Interview for Diagnosis SCN: suprachiasmatic nucleus SCT: sleep compression therapy SDB: sleep-disordered breathing SE%: sleep efficiency percentage SEMs: small eye movements SIDS: sudden infant death syndrome

Abbreviations  xxxiii

SIT: suggested immobilization test SND: synucleinopathic disorders SNP: single nucleotide polymorphism SOL: sleep-onset latency SOREM: sleep-onset REM SOREMP: sleep-onset REM period SP: sleep paralysis SPM: statistical parametric mapping SRE: sleep-related erection SREBP: sterol regulatory element binding proteinSRED: sleep-related eating disorder SRT: sleep restriction therapy SSEP: somatosensory evoked potential SSS: Stanford Sleepiness Scale SSRI: selective serotonin reuptake inhibitor SWA: slow wave activity SWD: shift work disorder/shift work sleep disorder SWS: slow wave sleep Ta: ambient temperature

TAT: time above threshold TCA: tricyclic antidepressant THH: terrifying hypnagogic hallucination TLR: Toll-like receptor TMJ: temporomandibular joint TNF: tumor necrosis factor TRD: tongue-retaining device UARS: upper airway resistance syndrome UNS: Ullanlinna Narcolepsy Scale UPF: uvulopalatal flap UPPP: uvulopalatopharyngoplasty VIP: vasoactive intestinal peptide VLDL: very low density lipoprotein VLPO: ventrolateral POA (preoptic area) VMAT2: vascular monoamine transporter-2 VTA: ventral tegmental area WASO: wake after sleep onset WSN: warm-sensitive neuron ZCM: zero crossing mode

Normal Sleep and Its Variations

Section

1

Timothy Roehrs 1  History of Sleep Physiology and Medicine 2  Normal Human Sleep: An Overview 3  Normal Aging

4  Daytime Sleepiness and Alertness 5  Acute Sleep Deprivation 6  Chronic Sleep Deprivation

History of Sleep Physiology and Medicine William C. Dement Abstract There has been great scientific interest in sleep for well over a century, with the discoveries of the electrical activity of the brain, the arousal systems, the circadian system, and rapid eye movement sleep. In spite of these discoveries, the field of sleep medicine has existed for only about 4 decades. The evolution of the field required clinical research, development of clinical services, and changes in society and public policy that recognized the impact of sleep disorders on society. The field is still evolving as new disorders are being discovered, new treatments are being delivered, and basic science is helping us understand the complexity of sleep and its disorders. Interest in sleep and dreams has existed since the dawn of history. Perhaps only love and human conflict have received

SLEEP AS A PASSIVE STATE “Sleep is the intermediate state between wakefulness and death; wakefulness being regarded as the active state of all the animal and intellectual functions, and death as that of their total suspension.”2 The foregoing is the first sentence of The Philosophy of Sleep, a book by Robert MacNish, a member of the faculty of physicians and surgeons of Glasgow; the first American edition was published in 1834 and the Scottish edition somewhat earlier. This sentence exemplifies the overarching historical conceptual dichotomy of sleep research and sleep medicine, which is sleep as a passive process versus sleep as an active process. Until the discovery of rapid eye movements and the duality of sleep, sleep was universally regarded as an inactive state of the brain. With one or two exceptions, most thinkers regarded sleep as the inevitable result of reduced sensory input with the consequent diminishment of brain activity and the occurrence of sleep. Waking up and being awake were considered a reversal of this process, mainly as a result of bombardment of the brain by stimulation from the envi-

Chapter

1

more attention from poets and writers. Some of the world’s greatest thinkers, such as Aristotle, Hippocrates, Freud, and Pavlov, have attempted to explain the physiologic and psychological bases of sleep and dreaming. However, it is not the purpose of this chapter to present a scholarly review across the ages about prehistoric, biblical, and Elizabethan thoughts and concerns regarding sleep or the history of man’s enthrallment with dreams and nightmares. This has been reviewed by others.1 What is emphasized here for the benefit of the student and the practitioner is the evolution of the key concepts that define and differentiate sleep research and sleep medicine, crucial discoveries and developments in the formative years of the field, and those principles and practices that have stood the test of time.

ronment. No real distinction was seen between sleep and other states of quiescence such as coma, stupor, intoxication, hypnosis, anesthesia, and hibernation. The passive to active historical dichotomy is also given great weight by the modern investigator J. Allan Hobson.3 In the first sentence of his book, Sleep, published in 1989, he stated that “more has been learned about sleep in the past 60 years than in the preceding 6,000.” He went on, “In this short period of time, researchers have discovered that sleep is a dynamic behavior. Not simply the absence of waking, sleep is a special activity of the brain, controlled by elaborate and precise mechanisms.” Dreams and dreaming were regarded as transient, fleeting interruptions of this quiescent state. Because dreams seem to occur spontaneously and sometimes in response to environmental stimulation (e.g., the well-known alarm clock dreams), the notion of a stimulus that produces the dream was generalized by postulating internal stimulation from the digestive tract or some other internal source. Some anthropologists have suggested that notions of spirituality and the soul arose from primitive peoples’ need to 3

4  PART I / Section 1  •  Normal Sleep and Its Variations

explain how their essence could leave the body temporarily at night in a dream and permanently at death. In addition to the mere reduction of stimulation, a host of less popular theories were espoused to account for the onset of sleep. Vascular theories were proposed from the notion that the blood left the brain to accumulate in the digestive tract, and from the opposite idea that sleep was due to pressure on the brain by blood. Around the end of the 19th century, various versions of a “hypnotoxin” theory were formulated in which fatigue products (toxins and the like) were accumulated during the day, finally causing sleep, during which they were gradually eliminated. It had, of course, been observed since biblical times that alcohol would induce a sleeplike state. More recently, these observations included other compounds such as opium. Finally, it was noted that caffeine had the power to prevent sleep. The hypnotoxin theory reached its zenith in 1907 when French physiologists, Legendre and Pieron,4 did experiments showing that blood serum from sleep-deprived dogs could induce sleep in dogs that were not sleep deprived. The notion of a toxin causing the brain to sleep has gradually given way to the notion that there are a number of endogenous “sleep factors” that actively induce sleep by specific mechanisms. In the 1920s, the University of Chicago physiologist Nathaniel Kleitman carried out a series of sleep-deprivation studies and made the simple but brilliant observation that individuals who stayed up all night were generally less sleepy and impaired the next morning than in the middle of their sleepless night. Kleitman argued that this observation was incompatible with the notion of a continual buildup of a hypnotoxin in the brain or blood. In addition, he felt that humans were about as impaired as they would get, that is, very impaired, after about 60 hours of wakefulness, and that longer periods of sleep deprivation would produce little additional change. In the 1939 (first) edition of his comprehensive landmark monograph “Sleep and Wakefulness” Kleitman5 summed up by saying, “It is perhaps not sleep that needs to be explained, but wakefulness, and indeed, there may be different kinds of wakefulness at different stages of phylogenetic and ontogenetic development. In spite of sleep being frequently designated as an instinct, or global reaction, an actively initiated process, by excitation or inhibition of cortical or subcortical structures, there is not a single fact about sleep that cannot be equally well interpreted as a let down of the waking activity.”

THE ELECTRICAL ACTIVITY OF THE BRAIN As the 20th century got under way, Camillo Golgi and Santiago Ramón y Cajal had demonstrated that the nervous system was not a mass of fused cells sharing a common cytoplasm but rather a highly intricate network of discrete cells that had the key property of signaling to one another. Luigi Galvani had discovered that the nerve cells of animals produce electricity, and Emil duBois-Reymond and Hermann von Helmholtz found that nerve cells use their electrical capabilities for signaling information to one another. In 1875, the Scottish physiologist Richard Caton

demonstrated electrical rhythms in the brains of animals. The centennial of his discovery was commemorated at the 15th annual meeting of the Association for the Psychophysiological Study of Sleep convening at the site of the discovery, Edinburgh, Scotland. However, it was not until 1928 when the German psychiatrist Hans Berger6 recorded electrical activity of the human brain and clearly demonstrated differences in these rhythms when subjects were awake or asleep that a real scientific interest commenced. Berger correctly inferred that the signals he recorded, which he called “electroencephalograms,” were of brain origin. For the first time, the presence of sleep could be conclusively established without disturbing the sleeper, and, more important, sleep could be continuously and quantitatively measured without disturbing the sleeper. All the major elements of sleep brain wave patterns were described by Harvey, Hobart, Davis, and others7-9 at Harvard University in a series of extraordinary papers published in 1937, 1938, and 1939. Blake, Gerard, and Kleitman10,11 added to this from their studies at the University of Chicago. On the human electroencephalogram (EEG), sleep was characterized by high-amplitude slow waves and spindles, whereas wakefulness was characterized by low-amplitude waves and alpha rhythm. The image of the sleeping brain completely “turned off ” gave way to the image of the sleeping brain engaged in slow, synchronized, “idling” neuronal activity. Although it was not widely recognized at the time, these studies were some of the most critical turning points in sleep research. Indeed, Hobson3 dated the turning point of sleep research to 1928, when Berger began his work on the human EEG. Used today in much the same way as they were in the 1930s, brain wave recordings with paper and ink, or more recently on computer screens, have been extraordinarily important to sleep research and sleep medicine. The 1930s also saw one series of investigations that seemed to establish conclusively both the passive theory of sleep and the notion that it occurred in response to reduction of stimulation and activity. These were the investigations of Frederick Bremer,12,13 reported in 1935 and 1936. These investigations were made possible by the aforementioned development of electroencephalography. Bremer studied brain wave patterns in two cat preparations. One, which Bremer called encéphale isolé, was made by cutting a section through the lower part of the medulla. The other, cerveau isolé, was made by cutting the midbrain just behind the origin of the oculomotor nerves. The first preparation permitted the study of cortical electrical rhythms under the influence of olfactory, visual, auditory, vestibular, and musculocutaneous impulses; in the second preparation, the field was narrowed almost entirely to the influence of olfactory and visual impulses. In the first preparation, the brain continued to present manifestations of wakeful activity alternating with phases of sleep as indicated by the EEG. In the second preparation, however, the EEG assumed a definite deep sleep character and remained in this condition. In addition, the eyeballs immediately turned downward with a progressive miosis. Bremer concluded that in sleep there occurs a functional (reversible, of course) deafferentation of the cerebral



cortex. The cerveau isolé preparation results in a suppression of the incessant influx of nerve impulses, particularly cutaneous and proprioceptive, which are essential for the maintenance of the waking state of the telencephalon. Apparently, olfactory and visual impulses are insufficient to keep the cortex awake. It is probably misleading to assert that physiologists assumed the brain was completely turned off, whatever this metaphor might have meant, because blood flow and, presumably, metabolism continued. However, Bremer and others certainly favored the concept of sleep as a reduction of activity-idling, slow, synchronized, “resting” neuronal activity.

THE ASCENDING RETICULAR SYSTEM After World War II, insulated, implantable electrodes were developed, and sleep research on animals began in earnest. In 1949, one of the most important and influential studies dealing with sleep and wakefulness was published: Moruzzi and Magoun’s classic paper “Brain Stem Reticular Formation and Activation of the EEG.”14 These authors concluded that “transitions from sleep to wakefulness or from the less extreme states of relaxation and drowsiness to alertness and attention are all characterized by an apparent breaking up of the synchronization of discharge of the elements of the cerebral cortex, an alteration marked in the EEG by the replacement of high voltage, slow waves with low-voltage fast activity” (p. 455). High-frequency electrical stimulation through electrodes implanted in the brainstem reticular formation produced EEG activation and behavioral arousal. Thus, EEG activation, wakefulness, and consciousness were at one end of the continuum; sleep, EEG synchronization, and lack of consciousness were at the other end. This view, as can be seen, is hardly different from the statement by MacNish quoted at the beginning of this chapter. The demonstration by Starzl and coworkers15 that sensory collaterals discharge into the reticular formation suggested that a mechanism was present by which sensory stimulation could be transduced into prolonged activation of the brain and sustained wakefulness. By attributing an amplifying and maintaining role to the brainstem core and the conceptual ascending reticular activating system, it was possible to account for the fact that wakefulness outlasts, or is occasionally maintained in the absence of, sensory stimulation. Chronic lesions in the brainstem reticular formation produced persisting slow waves in the EEG and immobility. The usual animal for this research was the cat because excellent stereotaxic coordinates of brain structures had become available in this model.16 These findings appeared to confirm and extend Bremer’s observations. The theory of the reticular activating system was an anatomically based passive theory of sleep or an active theory of wakefulness. Figure 1-1 is from the published proceedings of a symposium entitled Brain Mechanisms and Consciousness, which published in 1954 and is probably the first genuine neuroscience bestseller.17 Horace Magoun had extended his studies to the monkey, and the illustration represents the full flowering of the ascending reticular activating system theory.

CHAPTER 1  •  History of Sleep Physiology and Medicine  5

EARLY OBSERVATIONS OF SLEEP PATHOLOGY Insomnia has been described since the dawn of history and attributed to many causes, including a recognition of the association between emotional disturbance and sleep disturbance. Scholars and historians have a duty to bestow credit accurately. However, many discoveries lie fallow for want of a contextual soil in which they may be properly understood and in which they may extend the understanding of more general phenomena. Important early observations were those of von Economo on “sleeping sickness” and of Pavlov, who observed dogs falling asleep during conditioned reflex experiments. Two early observations about sleep research and sleep medicine stand out. The first is the description in 1880 of narcolepsy by Jean Baptiste Edouard Gélineau (18591906), who derived the name narcolepsy from the Greek words narkosis (a benumbing) and lepsis (to overtake). He was the first to clearly describe the collection of components that constitute the syndrome, although the term cataplexy for the emotionally induced muscle weakness was subsequently coined in 1916 by Richard Henneberg. Obstructive sleep apnea syndrome (OSAS), which may be called the leading sleep disorder of the 20th century, was described in 1836, not by a clinician but by the novelist Charles Dickens. In a series of papers entitled the “Posthumous Papers of the Pickwick Club,” Dickens described Joe, a boy who was obese and always excessively sleepy. Joe, a loud snorer, was called Young Dropsy, possibly as a result of having right-sided heart failure. Meir Kryger18 and Peretz Lavie19,20 published scholarly accounts of many early references to snoring and conditions that were most certainly manifestations of OSAS. Professor Pierre Passouant21 provided an account of the

Figure 1-1  Lateral view of the monkey’s brain, showing the ascending reticular activating system in the brainstem receiving collaterals from direct afferent paths and projecting primarily to the associational areas of the hemisphere. (Redrawn from Magoun HW: The ascending reticular system and wakefulness. In Adrian ED, Bremer F, Jasper HH [eds]. Brain mechanisms and consciousness. A symposium organized by the Council for International Organizations of Medical Sciences, 1954. (Courtesy of Charles C Thomas, Publisher, Springfield, Ill.)

6  PART I / Section 1  •  Normal Sleep and Its Variations

life of Gélineau and his landmark description of the narcolepsy syndrome.

SIGMUND FREUD AND THE INTERPRETATION OF DREAMS By far the most widespread interest in sleep by health professionals was engendered by the theories of Sigmund Freud, specifically about dreams. Of course, the interest was really in dreaming, with sleep as the necessary concomitant. Freud developed psychoanalysis, the technique of dream interpretation, as part of his therapeutic approach to emotional and mental problems. As the concept of the ascending reticular activating system dominated behavioral neurophysiology, so the psychoanalytic theories about dreams dominated the psychological side of the coin. Dreams were thought to be the guardians of sleep and to occur in response to a disturbance in order to obviate waking up, as exemplified in the classic alarm clock dream. Freud’s concept that dreaming discharged instinctual energy led directly to the notion of dreaming as a safety valve of the mind. At the time of the discovery of rapid eye movements during sleep (circa 1952), academic psychiatry was dominated by psychoanalysts, and medical students all over America were interpreting one another’s dreams. From the vantage point of today’s world, the dream deprivation studies of the early 1960s, engendered and reified by the belief in psychoanalysis, may be regarded by some as a digression from the mainstream of sleep medicine. On the other hand, because the medical–psychiatric establishment had begun to take dreams seriously, it was also ready to support sleep research fairly generously under the guise of dream research. CHRONOBIOLOGY Most, but not all, sleep specialists share the opinion that what has been called chronobiology or the study of biologic rhythms is a legitimate part of sleep research and sleep medicine. The 24-hour rhythms in the activities of plants and animals have been recognized for centuries. These biologic 24-hour rhythms were quite reasonably assumed to be a direct consequence of the periodic environmental fluctuation of light and darkness. However, in 1729, Jean Jacques d’Ortous de Mairan described a heliotrope plant that opened its leaves during the day even after de Mairan had moved the plant so that sunlight could not reach it. The plant opened its leaves during the day and folded them for the entire night even though the environment was constant. This was the first demonstration of the persistence of circadian rhythms in the absence of environmental time cues. Figure 1-2, which represents de Mairan’s original experiment, is reproduced from The Clocks That Time Us by Moore-Ede and colleagues.22 Chronobiology and sleep research developed separately. The following three factors appear to have contributed to this: 1. The long-term studies commonly used in biologic rhythm research precluded continuous recording of brain wave activity. Certainly, in the early days, the latter was far too difficult and not really necessary. The measurement of wheel-running activity was a conve-

Figure 1-2  Representation of de Mairan’s original experiment. When exposed to sunlight during the day (upper left), the leaves of the plant were open; during the night (upper right), the leaves were folded. De Mairan showed that sunlight was not necessary for these leaf movements by placing the plant in total darkness. Even under these constant conditions, the leaves opened during the day (lower left) and folded during the night (lower right). (Redrawn from Moore-Ede MC, Sulzman FM, Fuller CA. The clocks that time us: physiology of the circadian timing system. Cambridge, Mass: Harvard University Press; 1982. p. 7.)

nient and widely used method for demonstrating circadian rhythmicity. 2. The favorite animal of sleep research from the 1930s through the 1970s was the cat, and neither cats nor dogs demonstrate clearly defined circadian activity rhythms. 3. The separation between chronobiology and sleep research was further maintained by the tendency for chronobiologists to know very little about sleep, and for sleep researchers to remain ignorant of such biological clock mysteries as phase response curves, entrainment, and internal desynchronization.

THE DISCOVERY OF REM SLEEP The characterization of rapid eye movement (REM) sleep as a discrete organismic state should be distinguished from the discovery that rapid eye movements occur during sleep. The historical threads of the discovery of rapid eye movements can be identified. Nathaniel Kleitman (Fig. 1-3, Video 1-1), a professor of physiology at the University of Chicago, had long been interested in cycles of activity and inactivity in infants and in the possibility that this cycle ensured that an infant would have an opportunity to



Figure 1-3  Nathaniel Kleitman (circa 1938), Professor of Physiology, University of Chicago, School of Medicine.

respond to hunger. He postulated that the times infants awakened to nurse on a self-demand schedule would be integral multiples of a basic rest-activity cycle. The second thread was Kleitman’s interest in eye motility as a possible measure of “depth” of sleep. The reasoning for this was that eye movements had a much greater cortical representation than did almost any other observable motor activity, and that slow, rolling, or pendular eye movements had been described at the onset of sleep with a gradual slowing and disappearance as sleep “deepened.”23 In 1951, Kleitman assigned the task of observing eye movement to a graduate student in physiology named Eugene Aserinsky. Watching the closed eyes of sleeping infants was tedious, and Aserinsky soon found that it was easier to designate successive 5-minute epochs as “periods of motility” if he observed any movement at all, usually a writhing or twitching of the eyelids, versus “periods of no motility.” After describing an apparent rhythm in eye motility, Kleitman and Aserinsky decided to look for a similar phenomenon in adults. Again, watching the eyes during the day was tedious, and at night it was even worse. Casting about, they came upon the method of electrooculography and decided (correctly) that this would be a good way to measure eye motility continuously and would relieve the human observer of the tedium of direct observations. Sometimes in the course of recording electrooculograms (EOGs) during sleep, they saw bursts of electrical potential changes that were quite different from the slow movements at sleep onset. When they were observing infants, Aserinsky and Kleitman had not differentiated between slow and rapid movements. However, on the EOG, the difference between the slow eye movements at sleep onset and the newly discovered rapid motility was obvious. Initially, there was a

CHAPTER 1  •  History of Sleep Physiology and Medicine  7

great deal of concern that these potentials were electrical artifacts. With their presence on the EOG as a signal, however, it was possible to watch the subject’s eyes simultaneously, and when this was done, the distinct rapid movement of the eyes beneath the closed lids was extremely easy to see. At this point, Aserinsky and Kleitman made two assumptions: 1. These eye movements represented a “lightening” of sleep. 2. Because they were associated with irregular respiration and accelerated heart rate, they might represent dreaming. The basic sleep cycle was not identified at this time, primarily because the EOG and other physiologic measures, notably the EEG, were not recorded continuously but rather by sampling a few minutes of each hour or halfhour. The sampling strategy was done to conserve paper (there was no research grant) and because there was not a clear reason to record continuously. Also, the schedule made it possible for the researcher to nap between sampling episodes. Aserinsky and Kleitman initiated a small series of awakenings, both when rapid eye movements were present and when rapid eye movements were not present, for the purpose of eliciting dream recall. They did not apply sophisticated methods of dream content analysis, but the descriptions of dream content from the two conditions were generally quite different with REM awakenings yielding vivid complex stories and non-REM (NREM) awakenings often yielding nothing at all or very sparse accounts. This made it possible to conclude that rapid eye movements were associated with dreaming. This was, indeed, a breakthrough in sleep research.24,25 The occurrence of the eye movements was quite compatible with the contemporary dream theories that dreams occurred when sleep lightened in order to prevent or delay awakening. In other words, dreaming could still be regarded as the “guardian” of sleep. However, it could no longer be assumed that dreams were fleeting and evanescent.

ALL-NIGHT SLEEP RECORDINGS AND THE BASIC SLEEP CYCLE The seminal Aserinsky and Kleitman paper was published in 1953. It attracted little attention, and no publications on the subject appeared from any other laboratory until 1959. Staying up at night to study sleep remained an undesirable occupation by anyone’s standards. In the early 1950s, most previous research on the EEG patterns of sleep, like most approaches to sleep physiology generally, had either equated short periods of sleep with all sleep or relied on intermittent time sampling during the night. The notion of obtaining continuous records throughout typical nights of sleep would have seemed highly extravagant. However, motivated by the desire to expand and quantify the description of rapid eye movements, then graduate student William Dement and Kleitman26 did just this over a total of 126 nights with 33 subjects and, by means of a simplified categorization of EEG patterns, scored the paper recordings in their entirety. When they examined these 126 records, they found that there was a predictable

8  PART I / Section 1  •  Normal Sleep and Its Variations

sequence of patterns over the course of the night, such as had been hinted at by Aserinsky’s study but entirely overlooked in all previous EEG studies of sleep. Although this sequence of regular variations has now been observed tens of thousands of times in hundreds of laboratories, the original description remains essentially unchanged. The usual sequence was that after the onset of sleep, the EEG progressed fairly rapidly to stage 4, which persisted for varying amounts of time, generally about 30 minutes, and then a “lightening” took place. Whereas the progression from wakefulness to stage 4 at the beginning of the cycle was almost invariable through a continuum of change, the lightening was usually abrupt and coincident with a body movement or series of body movements. After the termination of stage 4, there was generally a short period of stage 2 or stage 3 which gave way to stage 1 and rapid eye movements. When the first eye movement period ended, the EEG again progressed through a continuum of change to stage 3 or 4, which persisted for a time and then lightened, often abruptly, with body movement to stage 2, which again gave way to stage 1 and the second rapid eye movement period (see p. 679 of Dement and Kleitman26). Dement and Kleitman found that this cyclical variation of EEG patterns occurred repeatedly throughout the night at intervals of 90 to 100 minutes from the end of one eye movement period to the end of the next. The regular occurrences of REM periods and dreaming strongly suggested that dreams did not occur in response to chance disturbances. At the time of these observations, sleep was still considered to be a single state. Dement and Kleitman characterized the EEG during REM periods as “emergent stage 1” as opposed to “descending stage 1” at the onset of sleep. The percentage of the total sleep time occupied by REM sleep was between 20% and 25%, and the periods of REM sleep tended to be shorter in the early cycles of the night. This pattern of all-night sleep has been seen over and over in normal humans of both sexes, in widely varying environments and cultures, and across the life span.

REM SLEEP IN ANIMALS The developing knowledge of the nature of sleep with rapid eye movements was in direct opposition to the ascending reticular activating system theory and constituted a paradigmatic crisis. The following observations were crucial: • Arousal thresholds in humans were much higher during periods of REM sleep that had a low-amplitude, relatively fast (stage 1) EEG pattern than during similar “light sleep” periods at the onset of sleep. • Rapid eye movements during sleep were discovered in cats; the concomitant brain wave patterns (lowamplitude, fast) were indistinguishable from active wakefulness. • By discarding the sampling approach and recording continuously, a basic 90-minute cycle of sleep without rapid eye movements, alternating with sleep with rapid eye movements, was discovered. This basic sleep-cycle characterized all episodes of nocturnal sleep. Continuous recording also revealed a consistent, low-amplitude

EEG pattern during a precise interval of sleep always associated with bursts of REM, which were additionally established as periods of vivid dreaming. • Observations of motor activity in both humans and animals revealed the unique occurrence of an active suppression of spinal motor activity and muscle reflexes. Thus, sleep consists not of one state but rather of two distinct organismic states, as different from one another as both are from wakefulness. It had to be conceded that sleep could no longer be thought of as a time of brain inactivity and EEG slowing. By 1960, this fundamental change in our thinking about the nature of sleep was well established; it exists as fact that has not changed in any way since that time. The discovery of rapid eye movements during sleep in humans, plus the all-night sleep recordings that revealed the regular recurrence of lengthy periods during which rapid eye movements occurred and during which brain wave patterns resembled light sleep, prepared the way for the discovery of REM sleep in cats, in spite of the extremely powerful bias that an “activated” EEG could not be associated with sleep. In the first study of cats, maintaining the insulation and, therefore, the integrity of implanted electrodes had not yet been solved, so an alternative, small pins in the scalp, was used. With this approach, the waking EEG was totally obscured by the electromyogram from the large temporal muscles of the cat. However, when the cat fell asleep, slow waves could be seen, and the transition to REM sleep was clearly observed because muscle potentials were completely suppressed. The cat’s rapid eye movements and also the twitching of the whiskers and paws could be directly observed. It is very difficult today, in 2010, to understand and appreciate the exceedingly controversial nature of these findings. The following note from a more personal account27 illustrates both the power and the danger of scientific dogma. “I wrote them [the findings] up, but the paper was nearly impossible to publish because it was completely contradictory to the totally dominant neurophysiological theory of the time. The assertion by me that an activated EEG could be associated with unambiguous sleep was considered to be absurd. As it turned out, previous investigators had observed an activated EEG during sleep in cats28,29 but simply could not believe it and ascribed it to arousing influences during sleep. A colleague who was assisting me was sufficiently skeptical that he preferred I publish the paper as sole author. After four or five rejections, to my everlasting gratitude, Editor-in-Chief Herbert Jasper accepted the paper without revision for publication in Electroencephalography and Clinical Neurophysiology.” (see p. 23 of Dement30) It is notable, however, that I did not appreciate the significance of the absence of muscle potentials during the REM periods in cats. It remained for Michel Jouvet, working in Lyon, France, to insist on the importance of electromyographic suppression in his early papers,31,32 the first of which was published in 1959. Hodes and Dement began to study the “H” reflex in humans in 1960, finding complete suppression of reflexes during REM sleep,33 and Octavio Pompeiano and others in Pisa, Italy, worked out the basic mechanisms of REM atonia in the cat.34



THE DUALITY OF SLEEP Even though the basic NREM sleep cycle was well established, the realization that REM sleep was qualitatively different from the remainder of sleep took years to evolve. Jouvet35 and his colleagues performed an elegant series of investigations on the brainstem mechanisms of sleep that forced the inescapable conclusion that sleep consists of two fundamentally different organismic states. Among his many early contributions were clarification of the role of pontine brainstem systems as the primary anatomic site for REM sleep mechanisms and the clear demonstration that electromyographic activity and muscle tonus are completely suppressed during REM periods and only during REM periods. These investigations began in 1958 and were carried out during 1959 and 1960. It is now an established fact that atonia is a fundamental characteristic of REM sleep and that it is mediated by an active and highly specialized neuronal system. The pioneering microelectrode studies of Edward Evarts36 in cats and monkeys, and observations on cerebral blood flow in the cat by Reivich and Kety37 provided convincing evidence that the brain during REM sleep is very active. Certain areas of the brain appear to be more active in REM sleep than in wakefulness. By now, the notion of sleep as a passive process was totally demolished although for many years there was a lingering attitude that NREM sleep was essentially inactive and quiet. By 1960, it was possible to define REM sleep as a completely separate organismic state characterized by cerebral activation, active motor inhibition, and, of course, an association with dreaming. The fundamental duality of sleep was an established fact. PREMONITIONS OF SLEEP MEDICINE Sleep research, which emphasized all-night sleep recordings, burgeoned in the 1960s and was the legitimate precursor of sleep medicine and particularly of its core clinical test, polysomnography. Much of the research at this time emphasized studies of dreaming and REM sleep and had its roots in a psychoanalytic approach to mental illness which strongly implicated dreaming in the psychotic process. After sufficient numbers of all-night sleep recordings had been carried out in humans to demonstrate a highly characteristic “normal” sleep architecture, investigators noted a significantly shortened REM latency in association with endogenous depression.38 This phenomenon has been intensively investigated ever since. Other important precursors of sleep medicine were the following: 1. Discovery of sleep-onset REM periods in patients with narcolepsy 2. Interest in sleep, epilepsy, and abnormal movement– primarily in France 3. Introduction of benzodiazepines and the use of sleep laboratory studies in defining hypnotic efficacy SLEEP-ONSET REM PERIODS AND CATAPLEXY In 1959, a patient with narcolepsy came to the Mount Sinai Hospital in New York City to see Dr. Charles Fisher. At

CHAPTER 1  •  History of Sleep Physiology and Medicine  9

Fisher’s suggestion, a sleep recording was begun. Within seconds after he fell asleep, the patient was showing the dramatic, characteristic rapid eye movements of REM sleep, and sawtooth waves as well, in the EEG. The first paper documenting sleep-onset REM periods in a single patient was published in 1960 by Gerald Vogel.39 In a collaborative study between the University of Chicago and the Mount Sinai Hospital, nine patients were studied, and the important sleep-onset REM periods at night were described in a 1963 paper.40 Subsequent research showed that sleepy patients who did not have cataplexy did not have sleep-onset REM periods (SOREMPs), and those with cataplexy always had SOREMPs.41 It was clear that the best explanation for cataplexy was the normal motor inhibitory mechanisms of REM sleep occurring during wakefulness in a precocious or abnormal way.

THE NARCOLEPSY CLINIC: A FALSE START In January 1963, after moving to Stanford University, Dement was eager to test the hypothesis of an association between cataplexy and SOREMPs. However, not a single narcoleptic patient could be identified. A final attempt was made by placing a “want ad,” a few words about an inch high, in a daily newspaper, the San Francisco Chronicle. More than 100 people responded! About 50 of these patients were bona fide narcoleptics having both sleepiness and cataplexy. The response to the ad was a noteworthy event in the development of sleep disorders medicine. With one or two exceptions, none of the narcoleptics had ever been diagnosed correctly. A responsibility for their clinical management had to be assumed in order to facilitate their participation in the research. The late Dr. Stephen Mitchell, who had completed his neurology training and was entering a psychiatry residency at Stanford University, joined Dement in creating a narcolepsy clinic in 1964, and they were soon managing well over 100 patients. Mostly, this involved seeing the patients at regular intervals and adjusting their medication. Nonetheless, the seeds of the typical sleep disorders clinic were sowed because at least one daytime polygraphic sleep recording was performed on all patients to establish the presence of SOREMPs, and patients were questioned exhaustively about their sleep. If possible, an all-night sleep recording was carried out. Unfortunately, most of the patients were unable to pay cash to cover their bills, and insurance companies declared that the recordings of narcoleptic patients were experimental. Because the clinic was unable to generate sufficient income, it was discontinued and most of the patients were referred back to local physicians with instructions about treatment. EUROPEAN INTEREST In Europe, a genuine clinical interest in sleep problems had arisen, and it achieved its clearest expression in a 1963 symposium held in Paris, organized by Professor H. Fischgold, and published as La Sommeil de Nuit Normal et Pathologique in 1965.42 The primary clinical emphasis in this symposium was the documentation of sleep-related

10  PART I / Section 1  •  Normal Sleep and Its Variations

epileptic seizures and a number of related studies on sleepwalking and night terrors. Investigators from France, Italy, Belgium, Germany, and the Netherlands took part.

BENZODIAZEPINES AND HYPNOTIC EFFICACY STUDIES Benzodiazepines were introduced in 1960 with the marketing of chlordiazepoxide (Librium). This compound offered a significant advance in terms of safety over barbiturates for the purpose of tranquilizing and sedating. It was quickly followed by diazepam (Valium) and the first benzodiazepine introduced specifically as a hypnotic, flurazepam (Dalmane). Although a number of studies had been done on the effects of drugs on sleep, usually to answer theoretical questions, the first use of the sleep laboratory to evaluate sleeping pills was the 1965 study by Oswald and Priest.43 An important series of studies establishing the role of the sleep laboratory in the evaluation of hypnotic efficacy was carried out by Anthony Kales and his colleagues at the University of California, Los Angeles.44 The group also carried out studies of patients with hypothyroidism, asthma, Parkinson’s disease, and somnambulism.45-48 THE DISCOVERY OF SLEEP APNEA One of the most important events in the history of sleep disorders medicine occurred in Europe. Sleep apnea was discovered independently by Gastaut, Tassinari, and Duron49 in France and by Jung and Kuhlo in Germany.50 Both these groups reported their findings in 1965. As noted earlier, scholars have found references to this pheno­ menon in many places, but this was the first clear-cut recognition and description that had a direct causal continuity to sleep disorders medicine as we know it today. Peretz Lavie has detailed the historical contributions made by scientists and clinicians around the world in helping to describe and understand this disorder.20 These important findings were widely ignored in America (Video 1-2). What should have been an almost inevitable discovery by either the otolaryngologic surgery community or the pulmonary medicine community did not occur because there was no tradition in either specialty for carefully observing breathing during sleep. The wellknown and frequently cited study of Burwell and colleagues51—although impressive in a literary sense in its evoking of the somnolent boy, Joe, from the “Posthumous Papers of the Pickwick Club”—erred badly in evaluating their somnolent obese patients only during waking and attributing the cause of the somnolence to hypercapnia. The popularity of this paper further reduced the likelihood of discovery of sleep apnea by the pulmonary community. To this day, there is no evidence that hypercapnia causes true somnolence, although, of course, high levels of PCO2 are associated with impaired cerebral function. Nonetheless, the term “pickwickian” became an instant success as a neologism and may have played a role in stimulating interest in this syndrome by the European neurologists who were also interested in sleep. A small group of French neurologists who specialized in clinical neurophysiology and electroencephalography were in the vanguard of sleep research. One of the collaborators

in the French discovery of sleep apnea, C. Alberto Tassinari, joined the Italian neurologist Elio Lugaresi in Bologna in 1970. These clinical investigators along with Giorgio Coccagna and a host of others over the years performed a crucial series of clinical sleep investigations and, indeed, provided a complete description of the sleep apnea syndrome, including the first observations of the occurrence of sleep apnea in nonobese patients, an account of the cardiovascular correlates, and a clear identification of the importance of snoring and hypersomnolence as diagnostic indicators. These studies are recounted in Lugaresi’s book, Hypersomnia with Periodic Apneas, published in 1978.52

ITALIAN SYMPOSIA In 1967, Henri Gastaut and Elio Lugaresi (Fig. 1-4) organized a symposium, published as The Abnormalities of Sleep in Man,53 which encompassed issues across a full range of pathologic sleep in humans. This meeting took place in Bologna, Italy, and the papers presented covered many of what are now major topics in the sleep medicine field: insomnia, sleep apnea, narcolepsy, and periodic leg movements during sleep. It was an epic meeting from the point of view of the clinical investigation of sleep; the only major issues not represented were clear concepts of clinical practice models and clear visions of the high population prevalence of sleep disorders. However, the event that may have finally triggered a serious international interest in sleep apnea syndromes was organized by Lugaresi in 1972 and took place in Rimini, a small resort on the Adriatic coast.54 BIRTH PANGS In spite of all the clinical research, the concept of all-night sleep recordings as a clinical diagnostic test did not emerge unambiguously. It is worth considering the reasons for this failure, partly because they continue to operate today as impediments to the expansion of the field, and partly to understand the field’s long overdue development. The first important reason was the unprecedented nature of an all-night diagnostic test, particularly if it was conducted on outpatients. The cost of all-night

Figure 1-4  Elio Lugaresi, Professor of Neurology, University of Bologna, at the 1972 Rimini symposium.



polygraphic recording, in terms of its basic expense, was high enough without adding the cost of hospitalization although hospitalization would have legitimized a patient’s spending the night in a testing facility. To sleep in an outpatient clinic for a diagnostic test was a totally unprecedented, time-intensive, and labor-intensive enterprise and completely in conflict with the brief time required to go to the chemistry laboratory to give a blood sample, to breathe into a pulmonary function apparatus, to undergo a radiographic examination, and so forth. A second important barrier was the reluctance of nonhospital clinical professionals to work at night. Although medical house staff are very familiar with night work, they do not generally enjoy it; furthermore, clinicians could not work 24-hour days, first seeing patients and ordering tests, and then conducting the tests themselves. Finally, only a very small number of people understood that complaints of daytime sleepiness and nocturnal sleep disturbance represented something of clinical significance. Even narcolepsy, which was by the early 1970s fully characterized as an interesting and disabling clinical syndrome requiring sleep recordings for diagnosis, was not recognized in the larger medical community and had too low a prevalence to warrant creating a medical subspecialty. A study carried out in 1972 documented a mean of 15 years from onset of the characteristic symptoms of excessive daytime sleepiness and cataplexy to diagnosis and treatment by a clinician. The study also showed that a mean of 5.5 different physicians were consulted without benefit throughout that long interval.55

THE EARLY DEVELOPMENT OF SLEEP MEDICINE CLINICAL PRACTICE The practice of sleep medicine developed in many centers in the 1970s, often as a function of the original research interests of the center. The sleep disorders clinic at Stanford University is in many ways a microcosm of how sleep medicine evolved throughout the world. Patients complaining of insomnia were enrolled in hypnotic efficacy research studies. This brought the Stanford group into contact with many insomnia patients and demolished the notion that the majority of such patients had psychiatric problems. An early question was how reliable the descriptions of their sleep by these patients were. The classic all-night sleep recording gave an answer and yielded a great deal of information. Throughout the second half of the 1960s, as a part of their research, the Stanford group continued to manage patients with narcolepsy. As the group’s reputation for expertise in narcolepsy grew, it began to receive referrals for evaluation from physicians all over the United States. Although sleep apnea had not yet been identified (or treated) as a frequent cause of severe daytime sleepiness, it was clear that a number of patients referred with the presumptive diagnosis of narcolepsy certainly did not possess narcolepsy’s two cardinal signs, SOREMPs and cataplexy, and actually suffered from obstructive sleep apnea. True pickwickians were an infrequent referral at this time. In January 1972, Christian Guilleminault, a French neurologist and psychiatrist, joined the Stanford group. He

CHAPTER 1  •  History of Sleep Physiology and Medicine  11

had extensive knowledge of the European studies of sleep apnea. Until his arrival, the Stanford group had not routinely used respiratory and cardiac sensors in their allnight sleep studies. Starting in 1972, these measurements became a routine part of the all-night diagnostic test. This test was given the permanent name of polysomnography in 1974 by Dr. Jerome Holland, a member of the Stanford group. Publicity about narcolepsy and excessive sleepiness resulted in a small flow of referrals to the Stanford sleep clinic, usually with the presumptive diagnosis of narcolepsy. During the first year or two, the goal for the Stanford practice was to see at least five new patients per week. To foster financial viability, the group did as much as possible (within ethical limits) to publicize its services. As a result, there was also a sprinkling of patients, often self-referred, with chronic insomnia. The diagnosis of obstructive sleep apnea in patients with profound excessive daytime sleepiness was nearly always completely unambiguous. During 1972, the search for sleep abnormality in patients with sleep-related complaints continued; an attempt was made as well to conceptualize the pathophysiologic process both as an entity and as the cause of the presenting symptom. With this approach, a number of phenomena seen during sleep were rapidly linked to the fundamental sleep-related presenting complaints. Toward the end of 1972, the basic concepts and formats of sleep disorders medicine were sculpted to the extent that it was possible to offer a daylong course through Stanford University’s Division of Postgraduate Medicine. The course was titled “The Diagnosis and Treatment of Sleep Disorders.” The topics covered were normal sleep architecture; the diagnosis and treatment of insomnia with drug-dependent insomnia, pseudoinsomnia, central sleep apnea, and periodic leg movement as diagnostic entities; and the diagnosis and treatment of excessive daytime sleepiness or hypersomnia, with narcolepsy, NREM narcolepsy, and obstructive sleep apnea as diagnostic entities. The disability and cardiovascular complications of severe sleep apnea were severe and alarming. Unfortunately, the treatment options at this time were limited to usually ineffective attempts to lose weight and chronic tracheostomy. The dramatic results of chronic tracheostomy in ameliorating the symptoms and complications of obstructive sleep apnea had been reported by Lugaresi and coworkers56 in 1970. However, the notion of using such a treatment was strongly resisted at the time by the medical community, both in the Stanford University medical community and elsewhere. One of the first patients referred to the Stanford sleep clinic for investigation of this severe somnolence and who eventually had a tracheostomy was a 10-year-old boy. The challenges that were met to secure the proper management of this patient can be seen in this account by Christian Guilleminault (personal communication, 1990). In addition to medical skepticism, a major obstacle to the practice of sleep disorders medicine was the retroactive denial of payment by insurance companies, including the largest one in the United States. A 3-year period of educational efforts directed toward third-party carriers finally culminated in the recognition of polysomnography as a reimbursable diagnostic test in 1974. Another issue was

12  PART I / Section 1  •  Normal Sleep and Its Variations

that outpatient clinics that offered overnight testing in polysomnographic testing bedrooms needed to obtain state licensure in order to avoid the licensing requirements of hospitals. This, too, was finally accomplished in 1974.

CLINICAL SIGNIFICANCE OF EXCESSIVE DAYTIME SLEEPINESS Christian Guilleminault, in a series of studies, had clearly shown that excessive daytime sleepiness was a major presenting complaint of several sleep disorders as well as a pathologic phenomenon unto itself.57 However, it was recognized that methods to quantify this symptom and the underlying condition were not adequate to document the degree of improvement as a result of treatment. The subjective Stanford Sleepiness Scale, developed by Hoddes and colleagues,58 did not give reliable results. The problem was not a crisis, however, because patients with severe apnea and overwhelming daytime sleepiness improved dramatically after tracheostomy, and the reduction in daytime sleepiness was unambiguous. Nonetheless, the less urgent need to document the pharmacologic treatment of narcolepsy and the objective improvement of sleepiness in patients with less severe sleep apnea continued to be a problem. The apparent lack of interest in daytime sleepiness by individuals who were devoting their careers to the investigation of sleep at that time has always been puzzling. There is no question but that the current active investigation of this phenomenon is the result of the early interest of sleep disorders specialists. The early neglect of sleepiness is all the more difficult to understand because it is now widely recognized that sleepiness and the tendency to fall asleep during the performance of hazardous tasks is one of the most important problems in our society. A number of reasons have been put forward. One is that sleepiness and drowsiness are negative qualities. A second is that the societal failure to confront the issue was fostered by language ambiguities in identifying sleepiness. A third is that the early sleep laboratory studies focused almost exclusively on REM sleep and other nighttime procedures with little concern for the daytime except for psychopathology. Finally, the focus with regard to sleep deprivation was on performance from the perspective of human factors rather than on sleepiness as representing a homeostatic response to sleep reduction. An early attempt to develop an objective measure of sleepiness was that of Yoss and coworkers59 who observed pupil diameter directly by video monitoring and described changes in sleep deprivation and narcolepsy. Subsequently designated pupillometry, this technique has not been widely accepted. Dr. Mary Carskadon deserves most of the credit for the development of the latter-day standard approach to the measurement of sleepiness called the Multiple Sleep Latency Test (MSLT). She noted that subjective ratings of sleepiness made before a sleep recording not infrequently predicted the sleep latency. In the spring of 1976, she undertook to establish sleep latency as an objective measurement of the state of sleepiness-alertness by measuring sleep tendency before, during, and after 2 days of total sleep deprivation.60 The protocol designed for this study has become the standard protocol for the MSLT.

The choices of a 20-minute duration of a single test and a 2-hour interval between tests were essentially arbitrary and dictated by the practical demands of that study. This test was then formally applied to the clinical evaluation of sleepiness in patients with narcolepsy61 and, later, in patients with OSAS.62 Carskadon and her colleagues then undertook a monumental study of sleepiness in children by following them longitudinally across the second decade of life, which happens to also be the decade of highest risk for the development of narcolepsy. Using the new MSLT measure, she found that 10-year-old children were completely alert in the daytime, but by the time they reached sexual maturity, they were no longer fully alert even though they obtained almost the same amount of sleep at night as at age ten. Results of this remarkable decade of work and other studies are summarized in an important review.63 Early MSLT research established the following important advances in thinking: 1. Daytime sleepiness and nighttime sleep are an inter­ active continuum, and the adequacy of nighttime sleep absolutely cannot be understood without a complementary measurement of the level of daytime sleepiness or its antonym, alertness. 2. Excessive sleepiness, also known as impaired alertness, was sleep medicine’s most important symptom.

FURTHER DEVELOPMENT OF SLEEP MEDICINE As the decade of the 1970s drew to a close, the consolidation and formalization of the practice of sleep disorders medicine was largely completed. What is now the American Academy of Sleep Medicine was formed and provided a home for professionals interested in sleep and, particularly, in the diagnosis and treatment of sleep disorders. This organization began as the Association of Sleep Disorders Centers with five members in 1975. The organization then was responsible for the initiation of the scientific journal Sleep, and it fostered the setting of standards through center accreditation and an examination for practitioners by which they were designated Accredited Clinical Polysomnographers. The first international symposium on narcolepsy took place in the French Languedoc in the summer of 1975, immediately after the Second International Congress of the Association for the Physiological Study of Sleep in Edinburgh. The former meeting, in addition to being scientifically productive, had landmark significance because it produced the first consensus definition of a specific sleep disorder,64 drafted, revised, and unanimously endorsed by 65 narcoleptologists of international reputation. The first sleep disorders patient volunteer organization, the American Narcolepsy Association, was also formed in 1975. The ASDC/APSS Diagnostic Classification of Sleep and Arousal Disorders was published in fall 1979 after 3 years of extraordinary effort by a small group of dedicated individuals who composed the “nosology” committee chaired by Howard Roffwarg.65 Before the 1980s, the only effective treatment for severe OSAS was chronic tracheostomy. This highly effective but personally undesirable approach was replaced by two new



CHAPTER 1  •  History of Sleep Physiology and Medicine  13

procedures—one surgical,66 the other mechanical.67 The first was uvulopalatopharyngoplasty, which is giving way to more complex and effective approaches. The second was the widely used and highly effective continuous positive nasal airway pressure technique introduced by the Australian pulmonologist Colin Sullivan (Video 1-3). The combination of the high prevalence of OSAS and effective treatments fueled a strong expansion of centers and individuals offering the diagnosis and treatment of sleep disorders to patients. The decade of the 1980s was capped by the publication of sleep medicine’s first textbook, Principles and Practice of Sleep Medicine.68 For many years there was only one medical journal devoted to sleep; by 2004 there were seven: Sleep, Journal of Sleep Research, Sleep and Biological Rhythms, Sleep & Breathing, Sleep Medicine, Sleep Medicine Reviews, and Sleep Research Online. Articles about sleep are now routinely published in the major pulmonary, neurology, and psychiatric journals. The 1990s saw an acceleration in the acceptance of sleep medicine throughout the world.69 In spite of that, adequate sleep medicine services are still not readily available everywhere.70 In the United States, the National Center on Sleep Disorders Research (NCSDR) was established by statute as part of the National Heart, Lung, and Blood Institute of the National Institutes of Health.71,72 The mandate of NCSDR is to support research, promote educational activities, and coordinate sleep-related activities throughout various branches of the U.S. government. This initiative led to the development of large research projects dealing with various aspects of sleep disorders and the establishment of awards to develop educational materials at all levels of training. The 1990s also saw the establishment of the National Sleep Foundation73 as well as other organizations for patients. This foundation points out to the public the dangers of sleepiness, and sponsors the annual National Sleep Awareness Week. As the Internet increases exponentially in size, so does the availability of sleep knowledge for physicians, patients, and the general public. The average

person today knows a great deal more about sleep and its disorders than the average person did at the end of the 1980s.

THE TURN OF THE CENTURY AND BEYOND Chapter 62 of this volume deals with public policy and public health issues. From today’s vantage, the greatest challenge for the future is the cost-effective expansion of sleep medicine so that its benefits will be readily available. The major barrier to this availability is the continuing failure of sleep research and sleep medicine to effectively penetrate the educational system at any level. As a consequence, the majority of individuals remain unaware of important facts of sleep and wakefulness, biologic rhythms, and sleep disorders, and particularly of the symptoms that suggest a serious pathologic process. The management of sleep deprivation and its serious consequences in the workplace, particularly in those industries that depend on sustained operations, continue to need increased attention. Finally, the education and training of all health professionals, including nurses, has far to go. This situation was highlighted by the recently published report of the Institute of Medicine.74 Take heart! These problems are grand opportunities. Sleep medicine has come into its own (Videos 1-4 and 1-5). It has made concern for health a truly 24-hours-a-day enterprise, and it has energized a new effort to reveal the secrets of the healthy and unhealthy sleeping brain. ❖  Clinical Pearl Recent advances in sleep science, sleep medicine, public policy, and communications will foster an educated public that will know a great deal about sleep and its disorders. Clinicians should expect that their patients may have already learned about their sleep disorders from the information sources that are readily available.

Case History Raymond M. was a 10 12 -year-old boy referred to the pediatrics clinic in 1971 for evaluation of unexplained hypertension, which had developed progressively over the preceding 6 months. There was a positive family history of high blood pressure, but never so early in life. Raymond was hospitalized and had determination of renin, angiotensin, and aldosterone, renal function studies including contrast radiographs, and extensive cardiac evaluation. All results had been normal except that his blood pressure oscillated between 140-170/90100. It was noticed that he was somnolent during the daytime and Dr. S. suggested that I see him for this “unrelated” symptom. I reviewed Raymond’s history with his mother. Raymond had been abnormally sleepy “all his life.” However, during the past 2 to 3 years, his schoolteachers were complaining that he would fall asleep in class and was at times a “behavioral problem” because he

was not paying attention and was hyperactive and aggressive. His mother confirmed that he had been a very loud snorer since he was very young, at least since age 2, perhaps before. Physical examination revealed an obese boy with a short neck and a very narrow airway. I recommended a sleep evaluation, which was accepted. An esophageal balloon and measurement of end-tidal CO2 was added to the usual array. His esophageal pressure reached 80 to 120  cm H2O, he had values of 6% end-tidal CO2 at end of apnea, apneic events lasted between 25 and 65 seconds, and the apnea index was 55. His SaO2 [oxygen saturation, arterial] was frequently below 60%. I called the pediatric resident and informed him that the sleep problem was serious. I also suggested that the sleep problem might be the cause of the unexplained hypertension. The resident could not make Continued

14  PART I / Section 1  •  Normal Sleep and Its Variations sense of my information and passed it to the attending physician. I was finally asked to present my findings at the pediatric case conference, which was led by Dr. S. I came with the recordings, showed the results, and explained why I believed that there was a relationship between the hypertension and the sleep problem. There were a lot of questions. They simply could not believe it. I was asked what treatment I would recommend, and I suggested a tracheostomy. I was asked how many patients had this treatment in the United States, and how many children had ever been treated with tracheostomy. When I had to answer “zero” to both questions, the audience was somewhat shocked. It was decided that such an approach was doubtful at best, and com-

REFERENCES 1. Thorpy M. History of sleep and man. In: Thorpy M, Yager J, editors. The encyclopedia of sleep and sleep disorders. New York: Facts on File; 1991. 2. MacNish R. The philosophy of sleep. New York: D Appleton; 1834. 3. Hobson J. Sleep. New York: Scientific American Library; 1989. 4. Legendre R, Pieron H. Le probleme des facteurs du sommeil: resultats d’injections vasculaires et intracerebrales de liquides insomniques. C R Soc Biol 1910;68:1077-1079. 5. Kleitman N. Sleep and wakefulness. Chicago: University of Chicago Press; 1939. 6. Berger H. Ueber das Elektroenkephalogramm des Menschen. J Psychol Neurol 1930;40:160-179. 7. Davis H, Davis PA, Loomis AL, et al. Changes in human brain potentials during the onset of sleep. Science 1937;86:448-450. 8. Davis H, Davis PA, Loomis AL, et al. Human brain potentials during the onset of sleep. J Neurophysiol 1938;1:24-38. 9. Harvey EN, Loomis AL, Hobart GA. Cerebral states during sleep as studied by human brain potentials. Science 1937;85:443-444. 10. Blake H, Gerard RW. Brain potentials during sleep. Am J Physiol 1937;119:692-703. 11. Blake H, Gerard RW, Kleitman N. Factors influencing brain potentials during sleep. J Neurophysiol 1939;2:48-60. 12. Bremer F. Cerveau “isolé” et physiologie du sommeil. C R Soc Biol 1935;118:1235-1241. 13. Bremer F. Cerveau. Nouvelles recherches sur le mecanisme du sommeil. C R Soc Biol 1936;122:460-464. 14. Moruzzi G, Magoun H. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949;1:455-473. 15. Starzl TE, Taylor CW, Magoun HW. Collateral afferent excitation of reticular formation of brain stem. J Neurophysiol 1951;14:479. 16. Jasper H, Ajmone-Marsan C. A Stereotaxic Atlas of the Diencephalon of the Cat. Ottawa, Ontario, Canada: The National Research Council of Canada; 1954. 17. Magoun HW. The ascending reticular system and wakefulness. In: Adrian ED, Bremer F, Jasper HH, editors. Brain mechanisms and consciousness: a symposium organized by the council for international organizations of medical sciences. Springfield, Ill: Charles C Thomas; 1954. 18. Kryger MH. Sleep apnea: From the needles of Dionysius to continuous positive airway pressure. Arch Intern Med 1983;143:2301-2308. 19. Lavie P. Nothing new under the moon: historical accounts of sleep apnea syndrome. Arch Intern Med 1986;144:2025-2028. 20. Lavie P. Restless Nights: Understanding Snoring and Sleep Apnea. New Haven, Conn: Yale University Press; 2003. 21. Passouant P. Doctor Gélineau (1828-1906): narcolepsy centennial. Sleep 1981;3:241-246. 22. Moore-Ede M, Sulzman F, Fuller C. The clocks that time us: Physiology of the circadian timing system. Cambridge, Mass: Harvard University Press; 1982. 23. de Toni G. I movimenti pendolari dei bulbi oculari dei bambini durante il sonno fisiologico, ed in alcuni stati morbosi. Pediatria 1933;41:489-498.

pletely unacceptable in a child. However, they did concede that if no improvement was achieved by medical management, Raymond would be reinvestigated, including sleep studies. That was spring 1972. In the fall, he was, if anything, worse in spite of vigorous medical treatment. At the end of 1972, Raymond finally had his tracheostomy. His blood pressure went down to 90/60 within 10 days, and he was no longer sleepy. During the 5 years we were able to follow Raymond, he remained normotensive and alert, but I had to fight continuously to prevent outside doctors from closing his tracheostomy. I do not know what has happened to him since then.

24. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953;118: 273-274. 25. Aserinsky E, Kleitman N. Two types of ocular motility occurring in sleep. J Appl Physiol 1955;8:11-18. 26. Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol 1957;9:673-690. 27. Dement W. A personal history of sleep disorders medicine. J Clin Neurophysiol 1990;1:17-47. 28. Derbyshire AJ, Rempel B, Forbes A, et al. The effects of anesthetics on action potentials in the cerebral cortex of the cat. Am J Physiol 1936;116:577-596. 29. Hess R, Koella WP, Akert K. Cortical and subcortical recordings in natural and artificially induced sleep in cats. Electroencephalogr Clin Neurophysiol 1953;5:75-90. 30. Dement W. The occurrence of low voltage, fast electroencephalogram patterns during behavioral sleep in the cat. Electroencephalogr Clin Neurophysiol 1958;10:291-296. 31. Jouvet M, Michel F, Courjon J. Sur un stade d’activite electrique cerebrale rapide au cours du sommeil physiologique. C R Soc Biol 1959;153:1024-1028. 32. Jouvet M, Mounier D. Effects des lesions de la formation reticulaire pontique sur le sommeil du chat. C R Soc Biol 1960;154:2301-2305. 33. Hodes R, Dement W. Depression of electrically induced reflexes (“H-reflexes”) in man during low voltage EEG “sleep.” Electroencephalogr Clin Neurophysiol 1964;17:617-629. 34. Pompeiano O. Mechanisms responsible for spinal inhibition during desynchronized sleep: Experimental study. In: Guilleminault C, Dement WC, Passouant P, editors. Advances in Sleep Research, vol 3: Narcolepsy. New York: Spectrum; 1976. p. 411-449. 35. Jouvet M. Recherches sur les structures nerveuses et les mecanismes responsales des differentes phases du sommeil physiologique. Arch Ital Biol 1962;100:125-206. 36. Evarts E. Effects of sleep and waking on spontaneous and evoked discharge of single units in visual cortex. Fed Proc 1960;4 (Suppl.):828-837. 37. Reivich M, Kety S. Blood flow and metabolism in the sleeping brain. In: Plum F, editor. Brain Dysfunction in Metabolic Disorders. New York: Raven Press; 1968. p. 125-140. 38. Kupfer D, Foster F. Interval between onset of sleep and rapid eye movement sleep as an indicator of depression. Lancet 1972;2:684686. 39. Vogel G. Studies in psychophysiology of dreams, III: The dream of narcolepsy. Arch Gen Psychiatry 1960;3:421-428. 40. Rechtschaffen A, Wolpert E, Dement W, et al. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;15: 599-609. 41. Dement W, Rechtschaffen A, Gulevich G. The nature of the narcoleptic sleep attack. Neurology 1966;16:18-33. 42. Fischgold H, editor. La Sommeil de Nuit Normal et Pathologique: Etudes Electroencephalographiques. Paris, France: Masson et Cie; 1965. 43. Oswald I, Priest R. Five weeks to escape the sleeping pill habit. Br Med J 1965;2:1093-1095.

44. Kales A, Malmstrom EJ, Scharf MB, et al. Psychophysiological and biochemical changes following use and withdrawal of hypnotics. In: Kales A, editor. Sleep: Physiology and Pathology. Philadelphia: JB Lippincott; 1969. p. 331-343. 45. Kales A, Beall GN, Bajor GF, et al. Sleep studies in asthmatic adults: Relationship of attacks to sleep stage and time of night. J Allergy 1968;41:164-173. 46. Kales A, Heuser G, Jacobson A, et al. All night sleep studies in hypothyroid patients, before and after treatment. J Clin Endocrinol Metab 1967;27:1593-1599. 47. Kales A, Ansel RD, Markham CH, et al. Sleep in patients with Parkinson’s disease and normal subjects prior to and following levodopa administration. Clin Pharmacol Ther 1971;12:397-406. 48. Kales A, Jacobson A, Paulson NJ, et al. Somnambulism: Psychophysiological correlates, I: All-night EEG studies. Arch Gen Psychiatry 1966;14:586-594. 49. Gastaut H, Tassinari C, Duron B. Etude polygraphique des manifestations episodiques (hypniques et respiratoires) du syndrome de Pickwick. Rev Neurol 1965;112:568-579. 50. Jung R, Kuhlo W. Neurophysiological studies of abnormal night sleep and the pickwickian syndrome. Prog Brain Res 1965;18: 140-159. 51. Burwell CS, Robin ED, Whaley RD, et al. Extreme obesity associated with alveolar hypoventilation: a pickwickian syndrome. Am J Med 1956;21:811-818. 52. Lugaresi E, Coccagna G, Mantovani M. Hypersomnia with Periodic Apneas. New York: Spectrum; 1978. 53. Gastaut H, Lugaresi E, Berti-Ceroni G, et al, editors. The Abnormalities of Sleep in Man. Bologna, Italy: Aulo Gaggi Editore; 1968. 54. Gastaut H, Lugaresi E, Berti-Ceroni G, et al. Pathophysiological, clinical, and nosographic considerations regarding hypersomnia with periodic breathing. Bull Physiopathol Resp 1972;8:12491256. 55. Dement W, Guilleminault C, Zarcone V, et al. The narcolepsy syndrome. In: Conn H, Conn R, editors. Current diagnosis, vol. 2. Philadelphia: WB Saunders; 1974. p. 917-921. 56. Lugaresi E, Coccagna G, Mantovani M, et al. Effects de la trachéotomie dans les hypersomnies avec respiration periodique. Rev Neurol 1970;123:267-268. 57. Guilleminault C, Dement W. 235 cases of excessive daytime sleepiness: Diagnosis and tentative classification. J Neurol Sci 1977;31: 13-27. 58. Hoddes E, Zarcone V, Smythe H, et al. Quantification of sleepiness: A new approach. Psychophysiology 1973;10:431-436.

CHAPTER 1  •  History of Sleep Physiology and Medicine  15 59. Yoss R, Moyer N, Hollenhorst R. Pupil size and spontaneous pupillary waves associated with alertness, drowsiness, and sleep. Neurology 1970;20:545-554. 60. Carskadon M, Dement W. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48:495-506. 61. Richardson G, Carskadon M, Flagg W, et al. Excessive daytime sleepiness in man: Multiple sleep latency measurements in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 1978;45:621-627. 62. Dement W, Carskadon M, Richardson G. Excessive daytime sleepiness in the sleep apnea syndromes. In: Guilleminault C, Dement W, editors. Sleep Apnea Syndromes. New York: Alan R Liss. 1978. p. 23-46. 63. Carskadon M, Dement W. Daytime sleepiness: Quantification of a behavioral state. Neurosci Biobehav Rev 1987;11:307-317. 64. Guilleminault C, Dement W, Passouant P, editors. Narcolepsy. New York: Spectrum; 1976. 65. Sleep Disorders Classification Committee. Diagnostic classification of sleep and arousal disorders, 1st ed. Association of Sleep Disorders Centers and the Association for the Psychophysiological Study of Sleep. Sleep 1979;2:1-137. 66. Fujita S, Conway W, Zorick F, et al. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: Uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg 1981; 89:923-934. 67. Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862-865. 68. Kryger M, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: WB Saunders; 1989. 69. International Sleep Medicine Societies. Available at http://dev.ersnet. org/uploads/Document/15/WEB_CHEMIN_743_11654189 26.pdf, accessed September 2010. 70. Flemons WW, Douglas NJ, Kuna ST, et al. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med 2004;169:668-672. 71. Lefant C, Kiley JP. Sleep research: Celebration and opportunity. Sleep 1998;21:665-669. 72. National Heart, Lung, and Blood Institute. Sleep Disorders Information. Available at http://www.nhlbi.nih.gov/about/ncsdr/. Accessed September 2010. 73. National Sleep Foundation. Available at http://www.sleepfound ation.org. Accessed September 2010. 74. Colten H, Altevogt B, editors. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington DC: National Academies Press; 2006.

Normal Human Sleep: An Overview Mary A. Carskadon and William C. Dement Abstract Normal human sleep comprises two states—rapid eye movement (REM) and non–REM (NREM) sleep—that alternate cyclically across a sleep episode. State characteristics are well defined: NREM sleep includes a variably synchronous cortical electroencephalogram (EEG; including sleep spindles, Kcomplexes, and slow waves) associated with low muscle tonus and minimal psychological activity; the REM sleep EEG is desynchronized, muscles are atonic, and dreaming is typical. A nightly pattern of sleep in mature humans sleeping on a regular schedule includes several reliable characteristics: Sleep begins in NREM and progresses through deeper NREM stages (stages 2, 3, and 4 using the classic definitions, or stages N2 and N3 using the updated definitions) before the first episode of REM sleep occurs approximately 80 to 100 minutes later. Thereafter, NREM sleep and REM sleep cycle with a period of approximately 90 minutes. NREM stages 3 and 4 (or stage N3) concentrate in the early NREM cycles, and REM sleep episodes lengthen across the night. Age-related changes are also predictable: Newborn humans enter REM sleep (called active sleep) before NREM (called quiet sleep) and have a shorter sleep cycle (approximately 50

SLEEP DEFINITIONS According to a simple behavioral definition, sleep is a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment. It is also true that sleep is a complex amalgam of physiologic and behavioral processes. Sleep is typically (but not necessarily) accompanied by postural recumbence, behavioral quiescence, closed eyes, and all the other indicators one commonly associates with sleeping. In the unusual circumstance, other behaviors can occur during sleep. These behaviors can include sleepwalking, sleeptalking, teeth grinding, and other physical activities. Anomalies involving sleep processes also include intrusions of sleep—sleep itself, dream imagery, or muscle weakness—into wakefulness, for example (Box 2-1). Within sleep, two separate states have been defined on the basis of a constellation of physiologic parameters. These two states, rapid eye movement (REM) and non-REM (NREM), exist in virtually all mammals and birds yet studied, and they are as distinct from one another as each is from wakefulness. NREM (pronounced “non-REM”) sleep is conventionally subdivided into four stages defined along one measurement axis, the electroencephalogram (EEG). The EEG pattern in NREM sleep is commonly described as synchronous, with such characteristic waveforms as sleep spindles, K-complexes, and high-voltage slow waves (Fig. 2-1). The four NREM stages (stages 1, 2, 3, and 4) roughly parallel a depth-of-sleep continuum, with arousal thresholds generally lowest in stage 1 and highest in stage 4 sleep. NREM 16

Chapter

2

minutes); coherent sleep stages emerge as the brain matures during the first year. At birth, active sleep is approximately 50% of total sleep and declines over the first 2 years to approximately 20% to 25%. NREM sleep slow waves are not present at birth but emerge in the first 2 years. Slow-wave sleep (stages 3 and 4) decreases across adolescence by 40% from preteen years and continues a slower decline into old age, particularly in men and less so in women. REM sleep as a percentage of total sleep is approximately 20% to 25% across childhood, adolescence, adulthood, and into old age except in dementia. Other factors predictably alter sleep, such as previous sleep-wake history (e.g., homeostatic load), phase of the circadian timing system, ambient temperature, drugs, and sleep disorders. A clear appreciation of the normal characteristics of sleep provides a strong background and template for understanding clinical conditions in which “normal” characteristics are altered, as well as for interpreting certain consequences of sleep disorders. In this chapter, the normal young adult sleep pattern is described as a working baseline pattern. Normative changes due to aging and other factors are described with that background in mind. Several major sleep disorders are highlighted by their differences from the normative pattern.

sleep is usually associated with minimal or fragmentary mental activity. A shorthand definition of NREM sleep is a relatively inactive yet actively regulating brain in a movable body. REM sleep, by contrast, is defined by EEG activation, muscle atonia, and episodic bursts of rapid eye movements. REM sleep usually is not divided into stages, although tonic and phasic types of REM sleep are occasionally distinguished for certain research purposes. The distinction of tonic versus phasic is based on short-lived events such as eye movements that tend to occur in clusters separated by episodes of relative quiescence. In cats, REM sleep phasic activity is epitomized by bursts of ponto-geniculooccipital (PGO) waves, which are accompanied peripherally by rapid eye movements, twitching of distal muscles, middle ear muscle activity, and other phasic events that correspond to the phasic event markers easily measurable in human beings. As described in Chapter 141, PGO waves are not usually detectable in human beings. Thus, the most commonly used marker of REM sleep phasic activity in human beings is, of course, the bursts of rapid eye movements (Fig. 2-2); muscle twitches and cardiorespiratory irregularities often accompany the REM bursts. The mental activity of human REM sleep is associated with dreaming, based on vivid dream recall reported after approximately 80% of arousals from this state of sleep.1 Inhibition of spinal motor neurons by brainstem mechanisms mediates suppression of postural motor tonus in REM sleep. A shorthand definition of REM sleep, therefore, is an activated brain in a paralyzed body.



CHAPTER 2  •  Normal Human Sleep: An Overview  17

Box 2-1  Sleep Medicine Methodology and Nomenclature In 2007, the American Academy of Sleep Medicine (AASM) published a new manual (see reference 50) for scoring sleep and associated events. This manual recommends alterations to recording methodology and terminology that the Academy will demand of clinical laboratories in the future. Although specification of arousal, cardiac, movement, and respiratory rules appear to be value added to the assessment of sleep-related events, the new rules, terminology, and technical specifications for recording and scoring sleep are not without controversy. The current chapter uses the traditional terminology and definitions, upon which most descriptive and experimental research has been based since the 1960s.17 Hence, where the AASM terminology uses the term N for NREM sleep stages and R for REM sleep stages, N1 and N2 are used instead of stage 1 and stage 2; N3 is used to indicate the sum of stage 3 and stage 4 (often called slow-wave sleep in human literature); R is used to name REM sleep. Another change is to the nomenclature for the recording placements. Hence, calling the auricular placements M1 and M2 (rather than A1 and A2) is unnecessary and places the sleep EEG recording terminology outside the pale for EEG recording terminology in other disciplines. Although these are somewhat trivial changes, changes in nomenclature can result in confusion when attempting to compare to previous literature and established data sets and are of concern for clinicians and investigators who communicate with other fields. Of greater concern are changes to the core recording and scoring recommendations that the AASM manual recommends. For example, the recommended scoring montage requires using a frontal (F3 or F4) EEG placement for use with visual scoring of the recordings, rather than the central (C3 or C4) EEG placements recommended in the standard manual. The rationale for the change is that the frontal placements pick up more slow-wave activity during sleep. The consequence, however, is that sleep studies performed and scored with the frontal EEG cannot be compared to normative or clinical data and the frontal placements also truncate the ability to visualize sleep spindles. Furthermore, developmental changes to the regional EEG preclude the universal assumption that sleep slow-wave activity is a frontal event. Other issues are present in this new AASM approach to human sleep; however, this is not the venue for a complete description of such concerns. In summary, the AASM scoring manual has not yet become the universal standard for assessing human sleep and might not achieve that status in its current form. Specifications for recording and scoring sleep are not without controversy.51-56

SLEEP ONSET The onset of sleep under normal circumstances in normal adult humans is through NREM sleep. This fundamental principle of normal human sleep reflects a highly reliable finding and is important in considering normal versus pathologic sleep. For example, the abnormal entry into

Stage 1

Stage 2

Stage 3

Stage 4

100 µV 5 sec Figure 2-1  The stages of non–rapid eye movement sleep. The four electroencephalogram tracings depicted here are from a 19-year-old female volunteer. Each tracing was recorded from a referential lead (C3/A2) recorded on a Grass Instruments Co. (West Warwick, R.I.) Model 7D polygraph with a paper speed of 10 mm/sec, time constant of 0.3 sec, and 12 -amplitude highfrequency setting of 30 Hz. On the second tracing, the arrow indicates a K-complex and the underlining shows two sleep spindles.

C3/A2 ROC/A1 LOC/A2 50 µV

3 sec

CHIN EMG

Figure 2-2  Phasic events in human rapid eye movement (REM) sleep. On the left side is a burst of several rapid eye movements (out-of-phase deflections in right outer canthus [ROC]/A1 and left outer canthus [LOC]/A2). On the right side, there are additional rapid eye movements as well as twitches on the electromyographic (EMG) lead. The interval between eye movement bursts and twitches illustrates tonic REM sleep.

sleep through REM sleep can be a diagnostic sign in adult patients with narcolepsy. Definition of Sleep Onset The precise definition of the onset of sleep has been a topic of debate, primarily because there is no single measure that is 100% clear-cut 100% of the time. For example, a change in EEG pattern is not always associated with a person’s perception of sleep, yet even when subjects report that they are still awake, clear behavioral changes can indicate the presence of sleep. To begin a consideration of this issue, let us examine the three basic polysomnographic measures of sleep and how they change with sleep onset. The electrode placements are described in Chapter 141. Electromyogram The electromyogram (EMG) may show a gradual diminution of muscle tonus as sleep approaches, but rarely does

18  PART I / Section 1  •  Normal Sleep and Its Variations

C3/A2

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Figure 2-3  The transition from wakefulness to stage 1 sleep. The most marked change is visible on the two electroencephalographic (EEG) channels (C3/A2 and O2/A1), where a clear pattern of rhythmic alpha activity (8 cps) changes to a relatively low-voltage, mixed- frequency pattern at about the middle of the figure. The level of electromyographic (EMG) activity does not change markedly. Slow eye movements (right outer canthus [ROC]/left outer canthus [LOC]) are present throughout this episode, preceding the EEG change by at least 20 seconds. In general, the change in EEG patterns to stage 1 as illustrated here is accepted as the onset of sleep.

a discrete EMG change pinpoint sleep onset. Furthermore, the presleep level of the EMG, particularly if the person is relaxed, can be entirely indistinguishable from that of unequivocal sleep (Fig. 2-3). Electrooculogram As sleep approaches, the electrooculogram (EOG) shows slow, possibly asynchronous eye movements (see Fig. 2-3) that usually disappear within several minutes of the EEG changes described next. Occasionally, the onset of these slow eye movements coincides with a person’s perceived sleep onset; more often, subjects report that they are still awake. Electroencephalogram In the simplest circumstance (see Fig. 2-3), the EEG changes from a pattern of clear rhythmic alpha (8 to 13 cycles per second [cps]) activity, particularly in the occipital region, to a relatively low-voltage, mixed-frequency pattern (stage 1 sleep). This EEG change usually occurs seconds to minutes after the start of slow eye movements. With regard to introspection, the onset of a stage 1 EEG pattern may or may not coincide with perceived sleep onset. For this reason, a number of investigators require the presence of specific EEG patterns—the K-complex or sleep spindle (i.e., stage 2 sleep)—to acknowledge sleep onset. Even these stage 2 EEG patterns, however, are not unequivocally associated with perceived sleep.2 A further complication is that sleep onset often does not occur all at once; instead, there may be a wavering of vigilance before “unequivocal” sleep ensues (Fig. 2-4). Thus, it is difficult to accept a single variable as marking sleep onset. As Davis and colleagues3 wrote many years ago (p. 35): Is “falling asleep” a unitary event? Our observations suggest that it is not. Different functions, such as sensory awareness, memory, self-consciousness, continuity of logical thought, latency of response to a stimulus, and alterations in the pattern of brain potentials all go in parallel in a general way, but there are exceptions to every rule. Nevertheless, a reasonable consensus exists that the EEG change to stage 1, usually heralded or accompanied by slow eye movements, identifies the transition to sleep, provided

50 µV

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Figure 2-4  A common wake- to-sleep transition pattern. Note that the electroencephalographic pattern changes from wake (rhythmic alpha) to stage 1 (relatively low-voltage, mixedfrequency) sleep twice during this attempt to fall asleep. EMG, electromyogram; LOC, left outer canthus; ROC, right outer canthus.

C3/A2 ROC/A1

SEMs

Asleep

SEMs

LOC/A2 SAT

Gap Gap

Figure 2-5  Failure to perform a simple behavioral task at the onset of sleep. The volunteer had been deprived of sleep overnight and was required to tap two switches alternately, shown as pen deflections of opposite polarity on the channel labeled SAT. When the electroencephalographic (EEG; C3/A2) pattern changes to stage 1 sleep, the behavior stops, returning when the EEG pattern reverts to wakefulness. LOC, left outer canthus; ROC, right outer canthus; SEMs, slow eye movements. (From Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48:495-506. © Perceptual and Motor Skills, 1979.)

that another EEG sleep pattern does not intervene. One might not always be able to pinpoint this transition to the millisecond, but it is usually possible to determine the change reliably within several seconds. Behavioral Concomitants of Sleep Onset Given the changes in the EEG that accompany the onset of sleep, what are the behavioral correlates of the wake-tosleep transition? The following material reviews a few common behavioral concomitants of sleep onset. Keep in mind that “different functions may be depressed in different sequence and to different degrees in different subjects and on different occasions” (p. 35).3 Simple Behavioral Task In the first example, volunteers were asked to tap two switches alternately at a steady pace. As shown in Figure 2-5, this simple behavior continues after the onset of slow eye movements and may persist for several seconds after the EEG changes to a stage 1 sleep pattern.4 The behavior then ceases, usually to recur only after the EEG reverts to a waking pattern. This is an example of what one may think of as the simplest kind of “automatic” behavior pattern. Because such simple behavior can persist past sleep onset



and as one passes in and out of sleep, it might explain how impaired, drowsy drivers are able to continue down the highway. Visual Response A second example of behavioral change at sleep onset derives from an experiment in which a bright light is placed in front of the subject’s eyes, and the subject is asked to respond when a light flash is seen by pressing a sensitive microswitch taped to the hand.5 When the EEG pattern is stage 1 or stage 2 sleep, the response is absent more than 85% of the time. When volunteers are queried afterward, they report that they did not see the light flash, not that they saw the flash but the response was inhibited. This is one example of the perceptual disengagement from the environment that accompanies sleep onset. Auditory Response In another sensory domain, the response to sleep onset is examined with a series of tones played over earphones to a subject who is instructed to respond each time a tone is heard. One study of this phenomenon showed that reaction times became longer in proximity to the onset of stage 1 sleep, and responses were absent coincident with a change in EEG to unequivocal sleep.6 For responses in both visual and auditory modalities, the return of the response after its sleep-related disappearance typically requires the resumption of a waking EEG pattern. Olfactory Response When sleeping humans are tasked to respond when they smell something, the response depends in part on sleep state and in part on the particular odorant. In contrast to visual responses, one study showed that responses to graded strengths of peppermint (strong trigeminal stimulant usually perceived as pleasant) and pyridine (strong trigeminal stimulant usually perceived as extremely unpleasant) were well maintained during initial stage 1 sleep.7 As with other modalities, the response in other sleep stages was significantly poorer: Peppermint simply was not consciously smelled in stages 2 and 4 NREM sleep or in REM sleep; pyridine was never smelled in stage 4 sleep, and only occasionally in stage 2 NREM and in REM sleep.7 On the other hand, a tone successfully aroused the young adult participants in every stage. One conclusion of this report was that the olfactory system of humans is not a good sentinel system during sleep. Response to Meaningful Stimuli One should not infer from the preceding studies that the mind becomes an impenetrable barrier to sensory input at the onset of sleep. Indeed, one of the earliest modern studies of arousability during sleep showed that sleeping human beings were differentially responsive to auditory stimuli of graded intensity.8 Another way of illustrating sensory sensitivity is shown in experiments that have assessed discriminant responses during sleep to meaningful versus nonmeaningful stimuli, with meaning supplied in a number of ways and response usually measured as evoked K-complexes or arousal. The following are examples. • A person tends to have a lower arousal threshold for his or her own name versus someone else’s name.9 In light

CHAPTER 2  •  Normal Human Sleep: An Overview  19

sleep, for example, one’s own name spoken softly will produce an arousal; a similarly applied nonmeaningful stimulus will not. Similarly, a sleeping mother is more likely to hear her own baby’s cry than the cry of an unrelated infant. • Williams and colleagues10 showed that the likelihood of an appropriate response during sleep was improved when an otherwise nonmeaningful stimulus was made meaningful by linking the absence of response to punishment (a loud siren, flashing light, and the threat of an electric shock). From these examples and others, it seems clear that sensory processing at some level does continue after the onset of sleep. Indeed, one study has shown with functional magnetic resonance imaging that regional brain activation occurs in response to stimuli during sleep and that different brain regions (middle temporal gyrus and bilateral orbitofrontal cortex) are activated in response to meaningful (person’s own name) versus nonmeaningful (beep) stimuli.11 Hypnic Myoclonia What other behaviors accompany the onset of sleep? If you awaken and query someone shortly after the stage 1 sleep EEG pattern appears, the person usually reports the mental experience as one of losing a direct train of thought and of experiencing vague and fragmentary imagery, usually visual.12 Another fairly common sleep-onset experience is hypnic myoclonia, which is experienced as a general or localized muscle contraction very often associated with rather vivid visual imagery. Hypnic myoclonias are not pathologic events, although they tend to occur more commonly in association with stress or with unusual or irregular sleep schedules. The precise nature of hypnic myoclonias is not clearly understood. According to one hypothesis, the onset of sleep in these instances is marked by a dissociation of REM sleep components, wherein a breakthrough of the imagery component of REM sleep (hypnagogic hallucination) occurs in the absence of the REM motor inhibitory component. A response by the individual to the image, therefore, results in a movement or jerk. The increased frequency of these events in association with irregular sleep schedules is consistent with the increased probability of REM sleep occurring at the wake-to-sleep transition under such conditions (see later). Although the usual transition in adult human beings is to NREM sleep, the REM portal into sleep, which is the norm in infancy, can become partially opened under unusual circumstances. Memory Near Sleep Onset What happens to memory at the onset of sleep? The transition from wake to sleep tends to produce a memory impairment. One view is that it is as if sleep closes the gate between short-term and long-term memory stores. This phenomenon is best described by the following experiment.13 During a presleep testing session, word pairs were presented to volunteers over a loudspeaker at 1-minute intervals. The subjects were then awakened either 30 seconds or 10 minutes after the onset of sleep (defined as EEG stage 1) and asked to recall the words presented before sleep onset. As illustrated in Figure 2-6, the

20  PART I / Section 1  •  Normal Sleep and Its Variations

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Figure 2-7  The progression of sleep stages across a single night in a normal young adult volunteer is illustrated in this sleep histogram. The text describes the ideal or average pattern. This histogram was drawn on the basis of a continuous overnight recording of electroencephalogram, electrooculogram, and electromyogram in a normal 19-year-old man. The record was assessed in 30-second epochs for the various sleep stages. REM, rapid eye movement.

Figure 2-6  Memory is impaired by sleep, as shown by the study results illustrated in this graph. See text for explanation.

30-second condition was associated with a consistent level of recall from the entire 10 minutes before sleep onset. (Primacy and recency effects are apparent, although not large.) In the 10-minute condition, however, recall paralleled that in the 30-second group for only the 10 to 4 minutes before sleep onset and then fell abruptly from that point until sleep onset. In the 30-second condition, therefore, both longer-term (4 to 10 minutes) and shorter-term (0 to 3 minutes) memory stores remained accessible. In the 10-minute condition, by contrast, words that were in longer-term stores (4 to 10 minutes) before sleep onset were accessible, whereas words that were still in shorter-term stores (0 to 3 minutes) at sleep onset were no longer accessible; that is, they had not been consolidated into longer-term memory stores. One conclusion of this experiment is that sleep inactivates the transfer of storage from short- to long-term memory. Another interpretation is that encoding of the material before sleep onset is of insufficient strength to allow recall. The precise moment at which this deficit occurs is not known and may be a continuing process, perhaps reflecting anterograde amnesia. Nevertheless, one may infer that if sleep persists for approximately 10 minutes, memory is lost for the few minutes before sleep. The following experiences represent a few familiar examples of this phenomenon: • Inability to grasp the instant of sleep onset in your memory. • Forgetting a telephone call that had come in the middle of the night. • Forgetting the news you were told when awakened in the night. • Not remembering the ringing of your alarm clock. • Experiencing morning amnesia for coherent sleeptalking. • Having fleeting dream recall. Patients with syndromes of excessive sleepiness can experience similar memory problems in the daytime if sleep becomes intrusive.

Learning and Sleep In contrast to this immediate sleep-related “forgetting,” the relevance for sleep to human learning—particularly for consolidation of perceptual and motor learning—is of growing interest.14,15 The importance of this association has also generated some debate and skepticism.16 Nevertheless, a spate of recent research is awakening renewed interest in the topic, and mechanistic studies explaining the roles of REM and NREM sleep more precisely are under examination (see Chapter 29).

PROGRESSION OF SLEEP ACROSS THE NIGHT Pattern of Sleep in a Normal Young Adult The simplest description of sleep begins with the ideal case, the normal young adult who is sleeping well and on a fixed schedule of about 8 hours per night (Fig. 2-7). In general, no consistent male versus female distinctions have been found in the normal pattern of sleep in young adults. In briefest summary, the normal human adult enters sleep through NREM sleep, REM sleep does not occur until 80 minutes or longer thereafter, and NREM sleep and REM sleep alternate through the night, with an approximately 90-minute cycle (see Chapter 141 for a full description of sleep stages). First Sleep Cycle The first cycle of sleep in the normal young adult begins with stage 1 sleep, which usually persists for only a few (1 to 7) minutes at the onset of sleep. Sleep is easily dis­ continued during stage 1 by, for example, softly calling a person’s name, touching the person lightly, quietly closing a door, and so forth. Thus, stage 1 sleep is associated with a low arousal threshold. In addition to its role in the initial wake-to-sleep transition, stage 1 sleep occurs as a transitional stage throughout the night. A common sign of severely disrupted sleep is an increase in the amount and percentage of stage 1 sleep. Stage 2 NREM sleep, signaled by sleep spindles or K-complexes in the EEG (see Fig. 2-1), follows this brief



episode of stage 1 sleep and continues for approximately 10 to 25 minutes. In stage 2 sleep, a more intense stimulus is required to produce arousal. The same stimulus that produced arousal from stage 1 sleep often results in an evoked K-complex but no awakening in stage 2 sleep. As stage 2 sleep progresses, high-voltage slow-wave activity gradually appears in the EEG. Eventually, this activity meets the criteria17 for stage 3 NREM sleep, that is, high-voltage (at least 75 µV) slow-wave (2 cps) activity accounting for more than 20% but less than 50% of the EEG activity. Stage 3 sleep usually lasts only a few minutes in the first cycle and is transitional to stage 4 as more and more high-voltage slow-wave activity occurs. Stage 4 NREM sleep—identified when the high-voltage slowwave activity comprises more than 50% of the record— usually lasts approximately 20 to 40 minutes in the first cycle. An incrementally larger stimulus is usually required to produce an arousal from stage 3 or 4 sleep than from stage 1 or 2 sleep. (Investigators often refer to the combined stages 3 and 4 sleep as slow-wave sleep [SWS], delta sleep, or deep sleep.) A series of body movements usually signals an “ascent” to lighter NREM sleep stages. A brief (1- or 2-minute) episode of stage 3 sleep might occur, followed by perhaps 5 to 10 minutes of stage 2 sleep interrupted by body movements preceding the initial REM episode. REM sleep in the first cycle of the night is usually short-lived (1 to 5 minutes). The arousal threshold in this REM episode is variable, as is true for REM sleep throughout the night. Theories to explain the variable arousal threshold of REM sleep have suggested that at times, the person’s selective attention to internal stimuli precludes a response or that the arousal stimulus is incorporated into the ongoing dream story rather than producing an awakening. Certain early experiments examining arousal thresholds in cats found highest thresholds in REM sleep, which was then termed deep sleep in this species. Although this terminology is still often used in publications about sleep in animals, it should not be confused with human NREM stages 3 plus 4 sleep, which is also often called deep sleep. One should also note that SWS is sometimes used (as is synchronized sleep) as a synonym for all of NREM sleep in other species and is thus distinct from SWS (stages 3 plus 4 NREM) in human beings. NREM-REM Cycle NREM sleep and REM sleep continue to alternate through the night in cyclic fashion. REM sleep episodes usually become longer across the night. Stages 3 and 4 sleep occupy less time in the second cycle and might disappear altogether from later cycles, as stage 2 sleep expands to occupy the NREM portion of the cycle. The average length of the first NREM-REM sleep cycle is approximately 70 to 100 minutes; the average length of the second and later cycles is approximately 90 to 120 minutes. Across the night, the average period of the NREM-REM cycle is approximately 90 to 110 minutes. Distribution of Sleep Stages across the Night In the young adult, SWS dominates the NREM portion of the sleep cycle toward the beginning of the night (the

CHAPTER 2  •  Normal Human Sleep: An Overview  21

first one third); REM sleep episodes are longest in the last one third of the night. Brief episodes of wakefulness tend to intrude later in the night, usually near REM sleep transitions, and they usually do not last long enough to be remembered in the morning. The preferential distribution of REM sleep toward the latter portion of the night in normal human adults is thought to be linked to a circadian oscillator, which can be gauged by the oscillation of body temperature.18,19 The preferential distribution of SWS toward the beginning of a sleep episode is not thought to be mediated by circadian processes but shows a marked response to the length of prior wakefulness.20 The SWS pattern reflects the homeostatic sleep system, highest at sleep onset and diminishing across the night as sleep pressure wanes. Thus, these aspects of the normal sleep pattern highlight features of the two-process model of sleep as elaborated on in Chapter 37. Length of Sleep The length of nocturnal sleep depends on a great number of factors—of which volitional control is among the most significant in human beings—and it is thus difficult to characterize a “normal” pattern. Most young adults report sleeping approximately 7.5 hours a night on weekday nights and slightly longer, 8.5 hours, on weekend nights. The variability of these figures from person to person and from night to night, however, is quite high. Sleep length also depends on genetic determinants,21 and one may think of the volitional determinants (staying up late, waking by alarm, and so on) superimposed on the background of a genetic sleep need. Length of prior waking also affects how much sleeps, although not in a one-for-one manner. Indeed, the length of sleep is also determined by processes associated with circadian rhythms. Thus, when one sleeps helps to determine how long one sleeps. In addition, as sleep is extended, the amount of REM sleep increases, because REM sleep depends on the persistence of sleep into the peak circadian time in order to occur. Generalizations about Sleep in the Normal Young Adult A number of general statements can be made regarding sleep in the normal young adult who is living on a conventional sleep-wake schedule and who is without sleep complaints: • Sleep is entered through NREM sleep. • NREM sleep and REM sleep alternate with a period near 90 minutes. • SWS predominates in the first third of the night and is linked to the initiation of sleep and the length of time awake. • REM sleep predominates in the last third of the night and is linked to the circadian rhythm of body temperature. • Wakefulness in sleep usually accounts for less than 5% of the night. • Stage 1 sleep generally constitutes approximately 2% to 5% of sleep. • Stage 2 sleep generally constitutes approximately 45% to 55% of sleep. • Stage 3 sleep generally constitutes approximately 3% to 8% of sleep.

22  PART I / Section 1  •  Normal Sleep and Its Variations

• Stage 4 sleep generally constitutes approximately 10% to 15% of sleep. • NREM sleep, therefore, is usually 75% to 80% of sleep. • REM sleep is usually 20% to 25% of sleep, occurring in four to six discrete episodes. Factors Modifying Sleep Stage Distribution Age The strongest and most consistent factor affecting the pattern of sleep stages across the night is age (Fig. 2-8). The most marked age-related differences in sleep from the patterns described earlier are found in newborn infants. For the first year of life, the transition from wake to sleep is often accomplished through REM sleep (called active sleep in newborns). The cyclic alternation of NREM-REM sleep is present from birth but has a period of approximately 50 to 60 minutes in the newborn compared with approximately 90 minutes in the adult. Infants also only gradually acquire a consolidated nocturnal sleep cycle, and the fully developed EEG patterns of the NREM sleep stages are not present at birth but emerge over the first 2 to 6 months of life. When brain structure and function achieve a level that can support high-voltage slowwave EEG activity, NREM stages 3 and 4 sleep become prominent. SWS is maximal in young children and decreases markedly with age. The SWS of young children is both qualitatively and quantitatively different from that of older adults. For example, it is nearly impossible to wake youngsters in the SWS of the night’s first sleep cycle. In one study,22 a 123-dB tone failed to produce any sign of arousal in a group of children whose mean age was 10 years. In addition, children up to midadolescence often “skip” their first REM episode, perhaps due to the quantity and inten-

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Figure 2-8  Changes in sleep with age. Time (in minutes) for sleep latency and wake time after sleep onset (WASO) and for rapid eye movement (REM) sleep and non-REM (NREM) sleep stages 1, 2, and slow wave sleep (SWS). Summary values are given for ages 5 to 85 years. (Ohayon M, Carskadon MA, Guilleminault C, et al. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. Sleep 2004;27:1255-1273.)

sity of slow-wave activity early in the night. A similar, although less profound qualitative difference distinguishes SWS occurring in the first and later cycles of the night in a given person. The quantitative change in SWS may best be seen across adolescence, when SWS decreases by nearly 40% during the second decade, even when length of nocturnal sleep remains constant.23 Feinberg24 hypothesized that the age-related decline in nocturnal SWS might parallel loss of cortical synaptic density. By midadolescence, youngsters no longer typically skip their first REM, and their sleep resembles that described earlier for young adults. By age 60 years, SWS might no longer be present, particularly in men. Women appear to maintain SWS later into life than men. REM sleep as a percentage of total sleep is maintained well into healthy old age; the absolute amount of REM sleep at night has been correlated with intellectual functioning25 and declines markedly in the case of organic brain dysfunctions of the elderly.26 Arousals during sleep increase markedly with age. Extended wake episodes of which the individual is aware and can report, as well as brief and probably unremembered arousals, increase with aging.27 The latter type of transient arousals may occur with no known correlate but are often associated with occult sleep disturbances, such as periodic limb movements during sleep (PLMS) and sleeprelated respiratory irregularities, which also become more prevalent in later life.28,29 Perhaps the most notable finding regarding sleep in the elderly is the profound increase in interindividual variability,30 which thus precludes generalizations such as those made for young adults. Prior Sleep History A person who has experienced sleep loss on one or more nights shows a sleep pattern that favors SWS during recovery (Fig. 2-9). Recovery sleep is also usually prolonged and deeper—that is, having a higher arousal threshold throughout—than basal sleep. REM sleep tends to show a rebound on the second or subsequent recovery nights after an episode of sleep loss. Therefore, with total sleep loss, SWS tends to be preferentially recovered compared with REM sleep, which tends to recover only after the recuperation of SWS. Cases in which a person is differentially deprived of REM or SWS—either operationally, by being awakened each time the sleep pattern occurs, or pharmacologically (see later)—show a preferential rebound of that stage of sleep when natural sleep is resumed. This phenomenon has particular relevance in a clinical setting, in which abrupt withdrawal from a therapeutic regimen can result in misleading diagnostic findings (e.g., sleep-onset REM periods [SOREMPs] as a result of a REM sleep rebound) or could conceivably exacerbate a sleep disorder (e.g., if sleep apneas tend to occur preferentially or with greater intensity in the rebounding stage of sleep). Chronic restriction of nocturnal sleep, an irregular sleep schedule, or frequent disturbance of nocturnal sleep can result in a peculiar distribution of sleep states, most commonly characterized by premature REM sleep, that is, SOREMPs. Such episodes can be associated with hypnagogic hallucinations, sleep paralysis, or an increased



CHAPTER 2  •  Normal Human Sleep: An Overview  23

circadian body temperature phase position shows that sleep onset is likeliest to occur on the falling limb of the temperature cycle. A secondary peak of sleep onsets, corresponding to afternoon napping, also occurs; the offset of sleep occurs most often on the rising limb of the circadian body temperature curve.34

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Figure 2-9  The upper histogram shows the baseline sleep pattern of a normal 14-year-old female volunteer. The lower histogram illustrates the sleep pattern in this volunteer for the first recovery night after 38 hours without sleep. Note that the amount of stage 4 sleep on the lower graph is greater than on baseline, and the first rapid eye movement (REM) sleep episode is markedly delayed.

incidence of hypnic myoclonia in persons with no organic sleep disorder. Although not strictly related to prior sleep history, the first night of a laboratory sleep evaluation is commonly associated with a disruption of the normal distribution of sleep states, characterized chiefly by a delayed onset of REM sleep.31 Often this delay takes the form of skipping the first REM episode of the night. In other words, the NREM sleep stages progress in a normal fashion, but the first cycle ends with an episode of stage 1 or a brief arousal instead of the expected brief REM sleep episode. In addition, REM sleep episodes are often disrupted, and the total amount of REM sleep on the first night in the sleep laboratory is also usually reduced from the normal value. Circadian Rhythms The circadian phase at which sleep occurs affects the distribution of sleep stages. REM sleep, in particular, occurs with a circadian distribution that peaks in the morning hours coincident with the trough of the core body temperature rhythm.18,19 Thus, if sleep onset is delayed until the peak REM phase of the circadian rhythm—that is, the early morning—REM sleep tends to predominate and can even occur at the onset of sleep. This reversal of the normal sleep-onset pattern is commonly seen in a normal person who acutely undergoes a phase shift, either as a result of a work shift change or as a change resulting from jet travel across a number of time zones. Studies of persons sleeping in environments free of all cues to time have shown that the timing of sleep onset and the length of sleep occur as a function of circadian phase.32,33 Under these conditions, sleep distribution with reference to the

Temperature Extremes of temperature in the sleeping environment tend to disrupt sleep. REM sleep is commonly more sensitive to temperature-related disruption than is NREM sleep. Accumulated evidence from human beings and other species suggests that mammals have only minimal ability to thermoregulate during REM sleep; in other words, the control of body temperature is virtually poikilothermic in REM sleep.35 This inability to thermoregulate in REM sleep probably affects the response to temperature extremes and suggests that such conditions are less of a problem early during a night than late, when REM sleep tends to predominate. It should be clear, as well, that such responses as sweating or shivering during sleep under ambient temperature extremes occur in NREM sleep and are limited in REM sleep. Drug Ingestion The distribution of sleep states and stages is affected by many common drugs, including those typically prescribed in the treatment of sleep disorders as well as those not specifically related to the pharmacotherapy of sleep dis­ orders and those used socially or recreationally. Whether changes in sleep stage distribution have any relevance to health, illness, or psychological well-being is unknown; however, particularly in the context of specific sleep dis­ orders that differentially affect one sleep stage or another, such distinctions may be relevant to diagnosis or treatment. A number of generalizations regarding the effects of certain of the more commonly used compounds on sleep stage distribution can be made. • Benzodiazepines tend to suppress SWS and have no consistent effect on REM sleep. • Tricyclic antidepressants, monoamine oxidase inhibitors, and certain selective serotonin reuptake inhibitors tend to suppress REM sleep. An increased level of motor activity during sleep occurs with certain of these compounds, leading to a pattern of REM sleep without motor inhibition or an increased incidence of PLMS. Fluoxetine is also associated with rapid eye movements across all sleep stages (“Prozac eyes”). • Withdrawal from drugs that selectively suppress a stage of sleep tends to be associated with a rebound of that sleep stage. Thus, acute withdrawal from a benzodiazepine compound is likely to produce an increase of SWS; acute withdrawal from a tricyclic antidepressant or monoamine oxidase inhibitor is likely to produce an increase of REM sleep. In the latter case, this REM rebound could result in abnormal SOREMPs in the absence of an organic sleep disorder, perhaps leading to an incorrect diagnosis of narcolepsy. • Acute presleep alcohol intake can produce an increase in SWS and REM sleep suppression early in the night, which can be followed by REM sleep rebound in the latter portion of the night as the alcohol is metabolized.

24  PART I / Section 1  •  Normal Sleep and Its Variations Wake

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Figure 2-10  These sleep histograms depict the sleep of a 64-year-old male patient with obstructive sleep apnea syndrome. The let graph shows the sleep pattern before treatment. Note the absence of slow-wave sleep, the preponderance of stage 1 (S1), and the very frequent disruptions. The right graph shows the sleep pattern in this patient during the second night of treatment with continuous positive airway pressure (CPAP). Note that sleep is much deeper (more SWS) and more consolidated, and rapid eye movement (REM) sleep in particular is abnormally increased. The pretreatment REM percentage of sleep was only 10%, versus nearly 40% with treatment. (Data supplied by G. Nino-Murcia, Stanford University Sleep Disorders Center, Stanford, Calif.)

Low doses of alcohol have minimal effects on sleep stages, but they can increase sleepiness late at night.36,37 • Acute effects of marijuana (tetrahydrocannabinol [THC]) include minimal sleep disruption, characterized by a slight reduction of REM sleep. Chronic ingestion of THC produces a long-term suppression of SWS.38

have indicated a relatively high prevalence of REM sleep onsets in young adults40 and in adolescents with early rise times.41 In the latter, the REM sleep onsets on morning (8:30 am and 10:30 am) naps were related to a delayed circadian phase as indicated by later onset of melatonin secretion.

Pathology Sleep disorders, as well as other nonsleep problems, have an impact on the structure and distribution of sleep. As suggested before, these distinctions appear to be more important in diagnosis and in the consideration of treatments than for any implications about general health or illness resulting from specific sleep stage alterations. A number of common sleep-stage anomalies are commonly associated with sleep disorders.

S LEEP APNEA SYNDROMES Sleep apnea syndromes may be associated with suppression of SWS or REM sleep secondary to the sleep-related breathing problem. Successful treatment of this sleep disorder, as with nocturnal continuous positive airway pressure, can produce large rebounds of SWS or REM sleep (Fig. 2-10).

N ARCOLEPSY Narcolepsy is characterized by an abnormally short delay to REM sleep, marked by SOREMPs. This abnormal sleep-onset pattern occurs with some consistency, but not exclusively; that is, NREM sleep onset can also occur. Thus, the preferred diagnostic test consists of several opportunities to fall asleep across a day (see Chapter 143). If REM sleep occurs abnormally on two or more such opportunities, narcolepsy is extremely probable. The occurrence of this abnormal sleep pattern in narcolepsy is thought to be responsible for the rather unusual symptoms of this disorder. In other words, dissociation of components of REM sleep into the waking state results in hypnagogic hallucinations, sleep paralysis, and, most dramatically, cataplexy. Other conditions in which a short REM sleep latency can occur include infancy, in which sleep-onset REM sleep is normal; sleep reversal or jet lag; acute withdrawal from REM-suppressant compounds; chronic restriction or disruption of sleep; and endogenous depression.39 Reports

S LEEP FRAGMENTATION Fragmentation of sleep and increased frequency of arousals occur in association with a number of sleep disorders as well as with medical disorders involving physical pain or discomfort. PLMS, sleep apnea syndromes, chronic fibrositis, and so forth may be associated with tens to hundreds of arousals each night. Brief arousals are prominent in such conditions as allergic rhinitis,42,43 juvenile rheumatoid arthritis,44 and Parkinson’s disease.45 In upper airway resistance syndrome,46 EEG arousals are important markers because the respiratory signs of this syndrome are less obvious than in frank obstructive sleep apnea syndrome, and only subtle indicators may be available.47 In specific situations, autonomic changes, such as transient changes of blood pressure,48 can signify arousals; Lofaso and colleagues49 indicated that autonomic changes are highly correlated with the extent of EEG arousals. Less well studied is the possibility that sleep fragmentation may be associated with subcortical events not visible in the cortical EEG signal. These disorders also often involve an increase in the absolute amount of and the proportion of stage 1 sleep.



CHAPTER 2  •  Normal Human Sleep: An Overview  25

Acknowledgments The authors thank Joan Mancuso for preparing the figures.

❖  Clinical Pearls The clinician should expect to see less slow-wave sleep (stages 3 and 4) in older persons, particularly men. Clinicians or colleagues might find themselves denying mid-night communications (nighttime calls) because of memory deficits that occur for events proximal to sleep onset. This phenomenon might also account for memory deficits in excessively sleepy patients. Many medications (even if not prescribed for sleep) can affect sleep stages, and their use or discontinuation alters sleep. Thus, REM-suppressant medications, for example, can result in a rebound of REM sleep when they are discontinued. Certain patients have sleep complaints (insomnia, hypersomnia) that result from attempts to sleep or be awake at times not in synchrony with their circadian phase. Patients who wake with events early in the night might have a disorder affecting NREM sleep; patients who wake with events late in the night may have a disorder affecting REM sleep. When using sleep restriction to build sleep pressure, treatment will be more effective if sleep is scheduled at the correct circadian phase. The problem of napping in patients with insomnia is that naps diminish the homeostatic drive to sleep.

REFERENCES 1. Dement W, Kleitman N. The relation of eye movements during sleep to dream activity: an objective method for the study of dreaming. J Exp Psychol 1957;53:339-346. 2. Agnew HW, Webb WB. Measurement of sleep onset by EEG criteria. Am J EEG Technol 1972;12:127-134. 3. Davis H, Davis PA, Loomis AL, et al. Human brain potentials during the onset of sleep. J Neurophysiol 1938;1:24-38. 4. Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48:495-506. 5. Guilleminault C, Phillips R, Dement WC. A syndrome of hypersomnia with automatic behavior. Electroencephalogr Clin Neurophysiol 1975;38:403-413. 6. Ogilvie RD, Wilkinson RT. The detection of sleep onset: behavioral and physiological convergence. Psychophysiology 1984;21:510-520. 7. Carskadon MA, Herz R. Minimal olfactory perception during sleep: why odor alarms will not work for humans. Sleep 2004;27:402-405. 8. Williams HL, Hammack JT, Daly RL, et al. Responses to auditory stimulation, sleep loss and the EEG stages of sleep. Electroencephalogr Clin Neurophysiol 1964;16:269-279. 9. Oswald I, Taylor AM, Treisman M. Discriminative responses to stimulation during human sleep. Brain 1960;83:440-453. 10. Williams HL, Morlock HC, Morlock JV. Instrumental behavior during sleep. Psychophysiology 1966;2:208-216. 11. Portas CM, Krakow K, Allen P, et al. Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans. Neuron 2000;28:991-999. 12. Foulkes D. The psychology of sleep. New York: Charles Scribner’s Sons; 1966. 13. Wyatt JK, Bootzin RR, Anthony J, et al. Does sleep onset produce retrograde amnesia? Sleep Res 1992;21:113. 14. Maquet P. The role of sleep in learning and memory. Science 2001;294:1048-1052.

15. Stickgold R, Hobson JA, Fosse R, et al. Sleep, learning and dreams: Off-line memory reprocessing. Science 2001;294:1052-1057. 16. Siegel J. The REM sleep-memory consolidation hypothesis. Science 2001;294:1058-1063. 17. Rechtschaffen A, Kales A, editors. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute; 1968. 18. Czeisler CA, Zimmerman JC, Ronda JM, et al. Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep 1980;2:329-346. 19. Zulley J. Distribution of REM sleep in entrained 24 hour and freerunning sleep-wake cycles. Sleep 1980;2:377-389. 20. Weitzman ED, Czeisler CA, Zimmerman JC, et al. Timing of REM and stages 3 + 4 sleep during temporal isolation in man. Sleep 1980;2:391-407. 21. Karacan I, Moore CA. Genetics and human sleep. Psychiatr Ann 1979;9:11-23. 22. Busby K, Pivik RT. Failure of high intensity auditory stimuli to affect behavioral arousal in children during the first sleep cycle. Pediatr Res 1983;17:802-805. 23. Carskadon MA, Dement WC. Sleepiness in the normal adolescent. In: Guilleminault C, editor. Sleep and its disorders in children. New York: Raven Press; 1987. p. 53-66. 24. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1983; 17:319-334. 25. Prinz P. Sleep patterns in the healthy aged: relationship with intellectual function. J Gerontol 1977;32:179-186. 26. Prinz PN, Peskind ER, Vitaliano PP, et al. Changes in the sleep and waking EEGs of nondemented and demented elderly subjects. J Am Geriatr Soc 1982;30:86-93. 27. Carskadon MA, Brown ED, Dement WC. Sleep fragmentation in the elderly: relationship to daytime sleep tendency. Neurobiol Aging 1982;3:321-327. 28. Ancoli-Israel S, Kripke DF, Mason W, et al. Sleep apnea and nocturnal myoclonus in a senior population. Sleep 1981;4:349-358. 29. Carskadon MA, Dement WC. Respiration during sleep in the aging human. J Gerontol 1981;36:420-423. 30. Williams RL, Karacan I, Hursch CJ. EEG of human sleep: clinical applications. New York: John Wiley & Sons; 1974. 31. Agnew HW, Webb WB, Williams RL. The first-night effect: an EEG study of sleep. Psychophysiology 1966;2:263-266. 32. Czeisler CA, Weitzman ED, Moore-Ede MC, et al. Human sleep: Its duration and organization depend on its circadian phase. Science 1980;210:1264-1267. 33. Zulley J, Wever R, Aschoff J. The dependence of onset and duration of sleep on the circadian rhythm of rectal temperature. Pflugers Arch 1981;391:314-318. 34. Strogatz SH. The mathematical structure of the human sleep-wake cycle. New York: Springer-Verlag; 1986. 35. Parmeggiani PL. Temperature regulation during sleep: a study in homeostasis. In Orem J, Barnes CD, editors. Physiology in sleep. New York: Academic Press; 1980. p. 98-143. 36. Van Reen E, Jenni O, Carskadon MA. Effects of alcohol on sleep and the sleep electroencephalogram in healthy young women. Alcohol Clin Exp Res 2006;30(6):974-981. 37. Rupp TL, Acebo C, Van Reen E, Carskadon MA. Effects of a moderate evening dose of alcohol. I. Sleepiness. Alcohol Clin Exp Res 2007;31(8):1358-1364. 38. Freemon FR. The effect of chronically administered delta-9-tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers. Drug Alcohol Depend 1982;10:345-353. 39. Kupfer DJ. REM latency: a psychobiologic marker for primary depressive disease. Biol Psychiatry 1976;11:159-174. 40. Bishop C, Rosenthal L, Helmus T, et al. The frequency of multiple sleep onset REM periods among subjects with no excessive daytime sleepiness. Sleep 1996;19:727-730. 41. Carskadon MA, Wolfson AR, Acebo C, et al. Adolescent sleep patterns, circadian timing, and sleepiness at a transition to early school days. Sleep 1998;21:871-881. 42. Lavie P, Gertner R, Zomer J, et al. Breathing disorders in sleep associated with “microarousals” in patients with allergic rhinitis. Acta Otolaryngol 1981;92:529-533. 43. Craig TJ, Teets S, Lehman EB, et al. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue

26  PART I / Section 1  •  Normal Sleep and Its Variations and the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998;101:633-637. 44. Zamir G, Press J, Tal A, et al. Sleep fragmentation in children with juvenile rheumatoid arthritis. J Rheumatol 1998;25:1191-1197. 45. Stocchi F, Barbato L, Nordera G, et al. Sleep disorders in Parkinson’s disease. J Neurol 1998;245(Suppl. 1):S15-S18. 46. Guilleminault C, Stoohs R, Clerk A, et al. From obstructive sleep apnea syndrome to upper airway resistance syndrome—consistency of daytime sleepiness. Sleep 1992;15(6 Suppl.):S13-S16. 47. Hosselet JJ, Norman RG, Ayappa I, et al. Detection of flow limitation with a nasal cannula/pressure transducer system. Am J Respir Crit Care Med 1998;157:1461-1467. 48. Pitson DJ, Stradling JR. Autonomic markers of arousal during sleep in patients undergoing investigation for obstructive sleep apnoea, their relationship to EEG arousals, respiratory events and subjective sleepiness. J Sleep Res 1998;7:53-59. 49. Lofaso F, Goldenberg F, Dortho MP, et al. Arterial blood pressure response to transient arousals from NREM sleep in nonapneic snorers with sleep fragmentation. Chest 1998;113:985-991. 50. Iber C, Ancoli-Israel S, Quan SF, for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications.

1st ed. Westchester, Ill: American Academy of Sleep Medicine, 2007. 51. Moser D, Anderer P, Gruber G, et al. Sleep classification according to AASM and Rechtschaffen & Kales: effects on sleep scoring parameters. Sleep 2009;32:139-149. 52. Danker-Hopfe H, Anderer P, Zeitlhofer J, et al. Interrater reliability for sleep scoring according to the Rechtschaffen & Kales and the new AASM standard. J Sleep Res 2009;18:74-84. 53. Parrino L, Ferri R, Zucconi M, Fanfulla F. Commentary from the Italian Association of Sleep Medicine on the AASM manual for the scoring of sleep and associated events: for debate and discussion. Sleep Med 2009;10:799-808. 54. Grigg-Damberger MM. The AASM scoring manual: a critical appraisal. Curr Opin Pulm Med 2009;15:540-549. 55. Novelli L, Ferri R, Bruni O. Sleep classification according to AASM and Rechtschaffen and Kales: effects on sleep scoring parameters of children and adolescents. J Sleep Res 2010;19:238-247. 56. Miano S, Paolino MC, Castaldo R, Villa MP. Visual scoring of sleep: A comparison between the Rechtschaffen and Kales criteria and the American Academy of Sleep Medicine criteria in a pediatric population with obstructive sleep apnea syndrome. Clin Neurophysiol 2010;121:39-42.

Normal Aging Donald L. Bliwise Abstract Numerous factors challenge the integrity of sleep in the older human. Intrinsic lightening and fragmentation of sleep, reflecting changes in circadian and, even more so, homeostatic processes characterize aging, as do numerous medical and psychiatric comorbidities. Specific disorders such as sleep-disordered breathing and restless legs syndrome can

As the populations of industrialized societies age, knowledge of defining how sleep is affected by age will assume greater importance. Within the United States, the average current life expectancy of 77 years means that 80% of residents now live to be at least 65; the fastest growing segment of the population is those who are 85 years and older. These huge numbers force the sleep medicine specialist to confront the definition of what is normal. Researchers often use the term to connote a variety of meanings. In sleep medicine, confusion often occurs because the term is used descriptively, to indicate representativeness, as well as clinically, to indicate absence of disease. Aging is also subject to semantic confusion. Chronologic age has been shown repeatedly only to approximate physiologic (biological) age. The decline in slow-wave sleep, for example, can occur at a chronological age (at least in men) far earlier than most age-related declines in other biological functions. Some researchers in gerontology have noted that distance from death may be a far better approximation of the aging process, but too few longitudinal sleep studies in humans exist to yield these types of findings. However, studies of invertebrates and have shed new light on relationships between physiologic age and sleep that can affect the functional significance of age-dependent changes (see Basic Science Considerations, later). In addition to the issue of physiologic age, subjective age must be considered. Because the practice of sleep disorders medicine in geriatrics relies heavily on the increased self-reports of sleep disturbance seen in aging, subjective appraisal of the older person’s symptoms must be considered. Whether an aged person views 75% sleep efficiency as insomnia or merely accepts this as a normal part of aging may depend largely on that person’s perspective on growing old and what that means to him or her. It has been reported that older people are more likely to perceive themselves as having sleep problems if they have difficulty falling asleep rather than staying asleep, even though the latter continues to be a generally more commonly endorsed symptom.(See reference 1 for review) In addition, some have suggested that self-reports of sleep measured by polysomnography (PSG) are inherently less accurate and valid in older relative to younger subjects, although evidence for such age differences in other studies is decidedly mixed and varies according to the variables under consideration or the subject’s sex. Finally, normal aging must be viewed in counterpoint to pathologic aging (see Chapter 136). Although the preva-

Chapter

3

demonstrate age-dependence and contribute to sleep problems. Descriptive data continue to accrue to suggest that sleep disturbance in late life might carry its own morbidity and should not be dismissed by the sleep medicine specialist. New data suggest that the breakdown of sleep in the aged organism might reflect physiologic age and reflect alterations in function present at the genomic level.

lence of dementing illnesses is high in late life, determination of the number of normal elderly persons who may be in incipient stages of dementia has seldom been addressed. Additionally, recognition of mental impairments in the more limited domains of memory, executive function, language, attention, and visuospatial ability characterized as of lesser severity has led to the use of an intermediate diagnostic category termed mild cognitive impairment (MCI).2 Few sleep studies of normal aging rely on extensive diagnostic work to eliminate persons in the earliest stages of mental impairment, and polysomnographic studies in well-defined MCI patients have yet to occur. The point here is not to dismiss all that is known about sleep patterns in normal aging as inadequate but rather to point out the complexities of defining normal aging. Normal aging can never be defined without some arbitrary criteria. Throughout this chapter I will refer to aging across several species, encompassing both what in humans may be considered “middle-aged” (approximately 40 to 65 years) and “elderly” (older than 65 years). We recognize fully the otherwise arbitrary nature of these verbal and numeric descriptors of processes that are most assuredly gradual, are continuous, and vary widely across individuals. It is also important to recognize that the age-dependent alterations in sleep may simply be secondary manifestations of senescence.

SLEEP ARCHITECTURE Although age-dependent alterations in sleep architecture have been described for many years,3 only recently have attempts been made to summarize this large body of crosssectional data using meta-analytic techniques.4,5 Results from the first of these analyses4 indicated that although sleep efficiency showed clear age-dependent declines up to and beyond age 90 years, the vast majority of agedependent changes in sleep architecture occurred before age of 60 years, with few changes in slow-wave sleep (SWS, now referred to as N3 sleep in the revised American Academy of Sleep Medicine [AASM] nomenclature6; see later), rapid eye movement (REM) sleep, and stage 1 percentage (N1) occurring after that.4 Some variables (total sleep time, REM) appeared best characterized as linear decline, whereas others (SWS, wake after sleep onset) followed a more exponential course. Sleep latency showed no clear age effect after age 60 years, although it increased up 27

28  PART I / Section 1  •  Normal Sleep and Its Variations Table 3-1  Sleep Architecture as a Function of Age Percentage of Time Spent in Stage—Mean (95% CI) STAGE 1 AGE (YR)

STAGE 2

STAGE 3 + 4

REM SLEEP

MEN

WOMEN

MEN

WOMEN

MEN

WOMEN

MEN

WOMEN

37-54

5.8 (5.2-6.5)

4.6 (4.1-5.3)

61.4 (60.0-62.8)

58.5 (57.1-60.0)

11.2 (9.9-12.6)

14.2 (12.7-15.9)

19.5 (18.8-20.2)

20.9 (20.0-21.8)

55-60

6.3 (5.6-7.0)

5.0 (4.4-5.7)

64.5 (63.2-65.9)

56.2 (54.5-57.8)

8.2 (7.1-9.5)

17.0 (15.2-18.9)

19.1 (18.4-19.8)

20.2 (19.3-21.1)

61-70

7.1 (6.4-7.9)

5.0 (4.4-5.7)

65.2 (63.9-66.5)

57.3 (55.7-58.9)

6.7 (5.7-7.7)

16.7 (14.8-18.6)

18.4 (17.8-19.1)

19.3 (18.4-20.2)

>70

7.6 (6.8-8.5)

4.9 (4.3-5.6)

66.5 (65.1-67.8)

57.1 (55.6-58.7)

5.5 (4.5-6.5)

17.2 (15.5-19.1)

17.8 (17.1-18.5)

18.8 (18.0-19.6)

CI, confidence interval; REM, rapid eye movement. From Redline S, Kirchner HL, Quan SF, et al. The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406-418.

to that point. A second meta-analysis focused only on REM percentage and noted a cubic trend, with REM apparently increasing after age 75 years and then demonstrating an even steeper drop after age 90 years.5 The meaning of the latter data is unclear and raises many questions as to the extent of the precision of chronologic age to capture biological processes in these upper age ranges. Published population-based longitudinal data on sleep architecture would assist in addressing many of these uncertainties. Although meta-analyses can provide cumulative information on age-dependent values across many laboratories, enormous variability in parameter values exists across studies,4 and much of the sleep architecture was not scored blindly to the patient’s chronologic age or sex. This might limit the value of meta-analytic approaches for extrapolation of readily usable, age-dependent laboratory norms. By contrast, the systematically collected, rigorously acquired data derived from the centralized scoring center for the Sleep Heart Health Study (SHHS), although subject to survivor effects and based on single-night data derived from composite cohorts, offer detailed appreciation of how comorbidities, demographics, and sleep-disordered breathing (SDB) can affect observed sleep architecture values employing traditional Rechtschaffen and Kales rules.7 Some have viewed the SHHS sleep architecture data as broadly representative of the elderly population generally because persons with a wide variety of medical conditions were not excluded.8 Percentage of Time Spent in Each Sleep Stage Table 3-1 provides sleep architecture values for 2685 SHHS participants ages 37 to 92 years, excluding persons who use psychotropic medications and who have high alcohol intake, restless legs syndrome symptoms and systemic pain conditions. About a third of these participants were hypertensive and about 10% had histories of cardiovascular disease or chronic pulmonary disease. Results clearly show that although age effects are apparent in some measures, gender occupied a far more dramatic role in sleep architecture, in some cases showing considerable

divergence when comparing women and men. Most notable in this regard is percentage of time spent in sleep stages 3 plus 4, which shows enormous gender differences at every age and, in fact, shows no appreciable decline with aging in women, relative to men. Men demonstrate a marked cross-sectional decline with aging, as well as huge individual differences in every age group. In fact, the extent of these individual differences is emphasized by the fact that even within men as a group, coefficients of variation (ratio of variance to mean) in percentage of time spent in sleep stages 3 plus 4 far exceeded those for all other sleep variables in both men and women. Although gender differences in SWS have been noted previously (see reference 3 for review), the fact that the agedependent decline may be confined only to men suggests a more limited utility of this often-characterized aging biomarker for women. In contrast to the results of the SHHS, these gender differences in SWS were not confirmed meta-analytically.4 At least one study has proposed that gender differences in delta activity are more likely to be a function of overall lower EEG amplitude in men relative to women.9 When corrected for overall amplitude, the decreased growth hormone secretion seen in postmenopausal women was accompanied by lower delta amplitude than in comparably aged men.10 A decline in the amplitude and the incidence of the evoked K-complex over the age range of 19 to 78 years has been reported in both women and men, suggesting that similar deficits in delta synchronization processes operate equally in both sexes.11 Gender did not play a significant role when assessed as the homeostatic response of nighttime delta power to daytime napping in either young or elderly subjects.12 Percentage of time spent in sleep stage 1 also showed similar gender-related effects in SHHS, and agedependent increases in this sleep stage, usually considered to represent a feature of fragmented, transitional sleep, were confined only to men. By contrast, percentage of time spent in REM sleep showed a modest decline with age, but the effect was detected in both men and women. REM percentages of 18% to 20% in 75- to 85-year-olds were derived from curve smoothing in another meta-analysis



focused on only REM sleep measures in normal aging,5 which were slightly lower than, but essentially similar to, SHHS data (see Table 3-1). In SHHS, sleep efficiency also declined with age, with mean values of 85.7 (standard deviation [SD] = 8.3) in the 37- to 54-year-old group, 83.3 (SD = 8.9) in the 55- to 60-year-old group, 80.6 (SD = 11.7) in the 61- to 70-year-old group, and 79.2 (SD = 10.1), in the over-70-year-old group, but without differential effects of gender, findings corroborated metaanalytically in persons older than 60 years.4 However, the declines in percentage of time spent in REM sleep and the (male-specific) increases in percentage of time spent in sleep stage 1 seen in SHHS were not confirmed metaanalytically in persons older than 60 years.4 The density of eye movements in REM is reduced with aging,13 but lack of standardization across laboratories precludes examination of this aspect of REM using meta-analytic techniques. Arousals during Sleep Brief arousals during sleep, representing one component of the microarchitecture of sleep, continues to attract considerable interest as a metric, with particular relevance for the aged population. When examined in the laboratory, healthy older persons wake up from sleep more frequently than younger persons do, regardless of circadian phase, but they have no greater difficulty falling back to sleep.14 Failure to maintain continuous sleep has, as its basic science counterpart, short bout lengths, a feature highly characteristic of sleep in many aged mammalian species.3 In elderly humans without SDB, arousal indices from 18 to 27 events per hour have been reported.15 Among the predominantly elderly subjects (mean age, 61 years) in SHHS, the mean (SD) Arousal Index showed significant but relatively small increases with age: 16.0 (8.2) for 37- to 54-year-olds, 18.4 (10.0) for 55- to 61-year-olds, 20.3 (10.5) for 62- to 70-year-olds, and 21.0 (11.6) for subjects older than 70 years.7 Values approximating these have been reported16 in another group of subjects without sleep apnea or periodic leg movements, thus further corroborating these SHHS values. Other phasic events of non-REM (NREM) sleep, such as K-complex and spindle density, also decrease with age.17 Spindle density is thought to reflect, at least partially, the corticothalamic functional integrity of gammaaminobutyric acid–ergic (GABAergic) systems. Although, like other metrics of impaired sleep quality, brief arousals show a male predominance (also seen metaanalytically using Wake after Sleep Onset4), the influences of age and gender are not as pronounced as the effects of breathing events (Table 3-2). In fact, when accounting for the presence of brief arousals in the elderly, the Respiratory Disturbance Index (RDI) predicts 10-fold more variance than age and 5-fold more variance than gender. Higher levels of RDI were also associated with slightly lower percentage of time spent in REM sleep in both men and women and with lower percentages of time spent in sleep stages 3 plus 4 in men. The latter result is consistent with the hypothesis that at least some SDB in both elderly men and women might reflect ventilatory control instability and that SWS may be protective (see the later section on SDB).

CHAPTER 3  •  Normal Aging  29

Table 3-2  Brief Arousal Index in Elderly Subjects as a Function of Sleep-Disordered Breathing Arousal Index: Brief Arousals per Hour of Sleep (±SD) RDI

MEN

WOMEN

≤5

16.7 (7.7)

14.7 (7.1)

>5 to 15

20.5 (8.7)

17.9 (7.8)

>15 to 30

25.2 (10.3)

23.2 (10.4)

>30*

39.4 (14.7)

29.7 (13.6)

*Estimated weighted values. RDI, respiratory disturbance index (apneas plus hypopneas per hour of sleep), a measure of sleep-disordered breathing; SD, standard deviation. From Redline S, Kirchner HL, Quan SF, et al. The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406-418.

Comorbidities Insofar as comorbidities are concerned, SHHS sleep architecture data showed substantial convergence with metaanalytically derived data. In SHHS, selected medical comorbidities (a positive history of cardiovascular disease, hypertension, and stroke) were associated with disturbed sleep architecture, as was smoking, although, curiously, these results were not seen with chronic obstructive pulmonary disease. Consistent with results suggesting that reduced sleep amounts or quality might predispose to the metabolic syndrome in old age, diabetic patients had smaller percentages of time in stages 3 plus 4 sleep, lower sleep efficiencies, and higher numbers of brief arousals and percentage of time spent in sleep stage 1. In most cases, however, these effects appeared to less salient (i.e., predicted less variance) for sleep architecture than demographic variables such as gender, age (to a lesser extent), and, in some cases, ethnicity,7 except for the arousal index, where RDI was by far the single most powerful predictor. Less-disease-specific moderator effects from meta-analytic approaches also suggested that across the entire life span, age effects were reduced substantially when persons with medical and psychiatric conditions were included.4 The inclusion of persons with sleep apnea showed some evidence of reducing the effects of age in sleep efficiency, wake after sleep onset, and SWS when considered across the entire adult life span,4 data that are compatible with SHHS. Slow-Wave Sleep The gender differences in SWS reported by SHHS notwithstanding, several aspects of these data must be viewed in the context of prior literature on age-dependent changes in architecture. When analyzed with period-amplitude analyses, the major change in SWS ascribed to aging has been a decline in delta wave amplitude rather than wavelength (Fig. 3-1).(See reference 3 for review) The decrease in delta amplitude simply may be a more readily identifiable visual change of the sleep EEG, which is present at frequencies up to about 10 Hz, though it is difficult to see above this.18 When scored visually using central derivations and

30  PART I / Section 1  •  Normal Sleep and Its Variations

Delta activity of a 15-year-old male

Well-preserved delta activity, 65-year-old male

Typical delta activity of older men (age 64)

50 µV 1 sec

Figure 3-1  Age differences in delta activity. The top tracing shows typically abundant high-amplitude delta in an adolescent. The middle tracing shows particularly well-preserved delta in an older man. Note the marked decrease in amplitude relative to the adolescent. The bottom tracing is a more typical example of delta activity in an older man. Note the number of waves failing to meet the 75-µV amplitude criterion. (From Zepelin H. Normal age related change in sleep. In: Chase MH, Weitzman ED, editors. Sleep disorders: basic and clinical research. New York: Spectrum; 1983. pp. 431-445.)

employing a 75-µV threshold, typical figures for the amount stages 3 plus 4 sleep in the elderly have often been considered to fall in the 5% to 10% range. Thus, the figures reported by SHHS, particularly for women, are somewhat higher than these conventionally accepted figures. Whether these values represent a more precise rendering of delta activity within sleep, perhaps engendered by the visual analyses of EEG waveforms on digital display or the simultaneous availability of precise calibration of the 75 microvolt criterion for delta waves stipulated by the Rechtschaffen and Kales guidelines, is unclear. Nonetheless, the strictly controlled and exquisitely refined visual analyses conducted by SHHS are likely to represent a standard of polysomnographic technology aspired to by the field of sleep medicine, thus arguing that these newly published metrics may well replace existing data and supplant our current understanding of how sleep architecture measures should be benchmarked. Given the new AASM guidelines for sleep stage scoring,6 much of the foregoing normative data on sleep architecture may have limited relevance for laboratories that elect to adopt such changes. For example, slow-wave activity has higher amplitude when recorded from frontal derivations relative to central derivations. This would be expected to result in increased levels of visually scored slow-wave (i.e., N3) sleep. Indeed a recent study comparing recordings scored with both revised AASM and traditional Rechtschaffen and Kales criteria have shown a number of significant differences in resulting measures.19 Predictably, particularly in older persons, the revised scoring system resulted in higher percentages in N3 sleep. Beyond creating the need to establish new normative data, the mechanistic and functional significance or the diagnostic and

therapeutic importance of such a revisionary approach remain obscure. Much the same effect could be obtained by adopting alternative scoring thresholds of less than 75 µV for defining delta wave activity. Such proposals were put forth in the 1990s(See reference 3 for review) but have not led to enhanced understanding of the age-dependent changes in SWS. Eventually, digitized indices of delta activity (e.g., fast Fourier transform, zero-crossing, or hybrid techniques) might come to replace such conventional measures; however, considerable controversy regarding filtering, sampling rates, and data-storage formatting leaves formal adoption of such approaches dubious for routine clinical purposes at this time,20 though such efforts at signal processing are yielding important new clues regarding the significance of sleep-related delta activity for aging. Slow-wave activity during sleep is thought to represent synaptic downscaling, which is viewed as critical for forming memories.21 Broadly viewed, given at least some data suggesting decreased SWS with age, such findings might fit with mild impairments in cognition that characterize normal aging. Extremely low frequency (10).3 Prevalence rates for sleepiness of 15% and greater also have been found for specific age groups that are consistent with smaller laboratory studies using the physiological measure of sleepiness, the Multiple Sleep Latency Test (MSLT), which is described later. Young adults were sleepier, on average, than a comparison group of middle-aged adults, and about 20% of the young adults had mean daily sleep latencies of less than 5 minutes, a level of sleepiness considered pathological.4 Healthy elderly also were found to be physiologically sleepier than middle-aged adults.5 In surveys of the work force engaged in shift or night work, complaints of excessive sleepiness during waking hours are more frequent than among day workers, and continuous ambulatory electroencephalographic (EEG) field monitoring has confirmed the sleepiness.6 Sleepiness in Representative Populations Representative survey studies of national populations  have been done. In a study representative of the Finnish



CHAPTER 4  •  Daytime Sleepiness and Alertness  43

population, 11% of women and 7% of men reported daytime sleepiness almost every day.7 In another survey, representative of a large geographical area in Sweden, 12% of respondents thought their sleep was insufficient.8 In that survey, insufficient sleep, and not its consequent daytime sleepiness, was the focus of the questions. Two studies representative of the United States population used the MSLT to assess sleepiness. Given the necessary time commitment required of participants in MSLT studies, the representative integrity of study results is critically dependent on the recruitment response rate. From a large southeastern Michigan random sample (n = 1648) representative of the U.S. population, a subsample (n = 259) with a 68% response rate was recruited to undergo a nocturnal polysomnogram (NPSG) and MSLT the following day. The prevalence of excessive sleepiness, defined as a MSLT average sleep latency of less than 6 minutes, was 13%.9 In another probability sample of 6,947 Wisconsin state employees, a subsample (n = 632), collected with a 52% response rate, slept at home and then completed a MSLT in the laboratory the next day. Twenty-five percent had an average sleep latency of less than 5 minutes.10 These two studies also used the ESS to assess sleepiness; in the Michigan study 20% had ESS scores greater than 10, and in the Wisconsin study 25% had scores greater than 11. The higher prevalence in the Wisconsin study, despite the more stringent definition of sleepiness (MSLT of 5 vs. 6 minutes and ESS of 11 vs. 10), could be attributed to an age difference in the samples (51 vs. 42 yr on average) or the previous night’s sleep time and circumstances (habitual

at home, on average 7.1 hr vs. standard laboratory 8.5 hr). In Figure 4-1 the distribution of sleepiness, defined as average sleep latency on the MSLT, is illustrated for the Michigan population representative sample. The average sleep latency of various clinical samples and experimental sleep time manipulations is provided for comparisons. Risk Factors for Sleepiness The risk factors for sleepiness identified in the various surveys includes hours of daily sleep, employment status, marital status, snoring, and depression. Among 26- to 35-year-old members of a large health maintenance organization in Michigan, respondents reported 6.7 hours of sleep on weekdays and 7.4 hours on weekend days, on average.11 The hours of sleep were inversely related to daytime sleepiness scores on the Sleep–Wake Activity Inventory (SWAI). Both these variables were related to employment and marital status, with full employment and being single predictive of less sleep time and more sleepiness. Self-reported snoring and depression, as measured by a structured diagnostic interview, were also associated with increased sleepiness. In the Finnish study cited earlier, sleepiness was associated with moderate to severe depression and with snoring more than three times per week.7

NATURE OF SLEEPINESS Physiological Need State Sleepiness, according to a consensus among sleep researchers and clinicians, is a basic physiological need state.12

7.7%

29.0%

Excessive daytime sleepiness

Moderate sleepiness

10%

Anesthesia Residents Sleep apnea

Mean = 11.4

8 hr TIB x 5 nights

6 hr TIB x 4 nights

0 hr TIB x 1 night 7.5%

10 hr TIB x 14 nights (full alertness) Narcolepsy

5%

2.5%

0% 0

5

10

15

20

MSLT mean sleep latency (min) Figure 4-1  The distribution of mean daily sleep latency (min) on the multiple sleep latency test in a subsample (n = 259) recruited (68% response rate) from a large Southeastern Michigan random sample (N = 1648) representative of the U.S. population. The population mean is 11.4 minutes and this is compared to means reported for various patient groups60,70,71 and the means found in healthy normals after various bedtime manipulations.23,62 TIB, time in bed.

44  PART I / Section 1  •  Normal Sleep and Its Variations

It may be likened to hunger or thirst, which are physiological need states basic to the survival of the individual organism. The presence and intensity of this state can be inferred by how readily sleep onset occurs, how easily sleep is disrupted, and how long sleep endures. Deprivation or restriction of sleep increases sleepiness, and as hunger or thirst is reversible by eating or drinking, sleep reverses sleepiness. In the organism’s daily homeostatic economy, severe deprivation states do not normally occur and hence are not routinely responsible for regulating eating or drinking; other factors (i.e., taste, smell, time-of-day, social factors, biological variables) modulate these behaviors before severe deprivation states develop. Similarly, routine consumption of sleep is not purely homeostatic, but is greatly influenced by social (i.e., job, family, and friends) and environmental (i.e., noise, light, and bed) factors. The subjective experience of sleepiness and its behavioral indicators (yawning, eye rubbing, nodding) can be reduced under conditions of high motivation, excitement, exercise, and competing needs (e.g., hunger, thirst); that is, physiological sleepiness may not necessarily be manifest. The expression of mild to moderate sleepiness can be masked by any number of factors that are alerting, including motivation, environment, posture, activity, light, or food intake. Studies have shown that average sleep latency on the MSLT is increased by 6 minutes when sitting versus lying in bed and also by 6 minutes when immediately preceded by a 5-minute walk.13 However, when physiological sleepiness is most severe and persistent, the ability to reduce its impact on overt behavior wanes. The likelihood of sleep onset increases and the intrusion of microsleeps into ongoing behavior occurs. On the other hand, a physiologically alert (sleepiness and alertness are used here as antonyms) person does not experience sleepiness or appear sleepy even in the most soporific situations. Heavy meals, warm rooms, boring lectures, and the monotony of longdistance automobile driving unmask physiological sleepiness when it is present, but they do not cause it. Within a conventional 24-hour sleep and wake schedule, maximum sleepiness ordinarily occurs in the middle of the night when the individual is sleeping, and consequently this sleepiness typically is not experienced or remembered. When forced to be awake in the middle of the night, one experiences loss of energy, fatigue, weariness, difficulty concentrating, and memory lapses. When significant physiological sleepiness (as a result of reduced sleep quantity or quality) intrudes on one’s usual waking activities during the day, similar symptoms are experienced. Adaptation to the chronic experience of sleepiness most probably occurs. Clinicians have reported anecdotally that successfully treated patients will frequently comment that they had forgotten the experience of complete alertness. Reduced sensitivity to chronic sleepiness is a likely explanation for the disparities between subjective assessments, even when done with validated scales and the MSLT.5,14 Typically, it is the most sleepy individuals that show the greatest disparity in subjective versus objective assessments.5,14 Such individuals deny sleepiness despite significant objective indicators of sleepiness. On the other hand, basally alert individuals (ESS mean 5.6, SEM 0.3) after a one night acute sleep restriction were quite accurate in estimating their sleepiness relative to the increases in EEG

theta activity shown during a simulated driving task.15 Studies have also shown that compensation occurs to the cognitive and behavioral effects of experimental sleep restriction and increased sleepiness, particularly when the sleep loss is mild and accumulates at a slow rate.16 The absence of a readily apparent behavioral deficiency probably also contributes to the subjective-objective disparity seen in chronically sleepy individuals. Finally, findings from a general population study suggest that subjective sleepiness has multiple dimensions, beyond an increased tendency to fall asleep.17 Consequently, patients often mistake chronic debilitating fatigue for sleepiness.18 The specific nature of this physiological need state is unclear. Whether sleepiness is one-dimensional, varying only in severity, or multidimensional, varying as to etiology or chronicity, has been discussed.19 If it is one-dimensional, whether or not sleepiness and alertness are at opposite poles of the dimension is also an issue. Earlier, it was noted that sleepiness and alertness are being used as antonyms, which suggests a unipolar state. However, it is possible that sleepiness varies from presence to absence and is distinct from alertness. It was noted that sleepiness may be multidimensional, and among the different types of sleepiness cited are rapid eye movement (REM) versus non–rapid eye movement (NREM) and core versus optional sleepiness.19 A complete discussion of the heuristic value and evidence to support these distinctions is beyond the scope of this chapter. Nonetheless, the point must be made that these theoretical perspectives may be colored by different measures, experimental demands, populations studied, and subject or patient motivations (i.e., sensitivity to and capacity to counteract sleepiness). Neural Substrates of Sleepiness The substrates of sleepiness have yet to be determined. It is assumed that sleepiness is a central nervous system (CNS) phenomenon with identifiable neural mechanisms and neurochemical correlates. Various electrophysiological events suggestive of incipient sleep processes appear in behaviorally awake organisms undergoing sleep deprivation. In sleep-deprived animals, ventral hippocampal spike activity, which normally is a characteristic of NREM sleep, increases during behavioral wakefulness and in the absence of the usual changes in cortical EEG indicative of sleep.20 Human beings deprived, or restricted, of sleep show identifiable microsleep episodes (brief intrusions of EEG indications of sleep) and increased amounts of alpha and theta activity while behaviorally awake.21 The evidence suggests that these electrophysiological events are indicants of sleepiness. An emerging literature of neuroimaging studies, both structural and functional, have suggested specific brain systems that may be involved in sleepiness. Sleep deprivation in young healthy volunteers reduced regional cerebral glucose metabolism, as assessed by positron emission tomography, in thalamic, basal ganglia, and limbic regions of the brain.22 Functional magnetic resonance imaging (fMRI) after chlorpheniramine (a sedating antihistamine) compared with placebo showed increased frontal and temporal activation.23 Because fMRI was conducted while the subject was performing cognitive tasks, the authors interpreted the observed brain activation to have resulted from



the increased mental effort, due to sleepiness, required to perform the task. Two groups of patients with severe or slight hypersomnia associated with paramedian thalamic stroke on an MRI showed lesions involving dorso- and centromedial thalamic nuclei, bilateral lesions in the severe group and unilateral in the slight group.24 As yet, these imaging data are not conclusive. They do suggest it may be possible to identify brain regions and functions that vary with sleepiness. But the nature of the alteration may depend on the behavioral load imposed on the sleepy subject as well as the cause of the sleepiness. The neurochemistry of sleepiness and alertness involves critical and complex issues that have not yet been fully untangled (see Chapters 18, 37, 42, and 44). First, a basic issue concerns whether sleepiness and alertness have a neurochemistry specific and unique from that associated with the sleep process, per se. Second, it is not clear whether sleepiness and alertness are controlled by separate neurochemicals or by a single substance or system. Third, the relation of the neurochemistry of sleepiness and alertness to circadian mechanisms has not yet been determined. Given the number of questions, it should be of no surprise that these are areas of active research. Neurophysiological studies of sleep and wake mechanisms have implicated histamine, serotonin, the catecholamines, and acetylcholine in control of wake and gamma-aminobutyric acid (GABA) for sleep.25 Evidence from animal studies is emerging that suggests extracellular adenosine is the homeostatic sleep factor, with brain levels accumulating during prolonged wakefulness and declining during sleep.26 The peptide hypocretin/orexin has received much attention for its role in the pathophysiology of narcolepsy.27 It is considered to be a major wake-promoting hypothalamic neuropeptide and a hypocretin/orexin deficiency has been found in human narcolepsy. Its interactive role in the homeostatic control of sleep and sleepiness has yet to be determined. It is discussed in greater detail in Chapters 18, 37, 42, and 44. Pharmacological studies provide other interesting hypotheses regarding the neurochemistry of sleepinessalertness. For example, the benzodiazepines induce sleepiness and facilitate GABA function at the GABAA receptor complex, thus implicating this important and diffuse  inhibitory neurotransmitter.25 Another example involves histamine, which is now considered to be a CNS neurotransmitter and is thought to have CNS-arousing activity.25 Antihistamines that penetrate the CNS produce sleepiness.28 A functional neuroimaging study of histamine H1 receptors in human brain found that the degree of sleepiness associated with cetirizine (20 mg) was correlated to the degree of H1 receptor occupancy.29 Stimulant drugs suggest several other transmitters and neuromodulators. The mechanism of action of one class of drugs producing psychomotor stimulation and arousal, the amphetamines, is blockade of catecholamine uptake.30 Another class of stimulants, the methylxanthines, which include caffeine and theophylline, are adenosine receptor antagonists. Adenosine, considered the key neurochemical in the homeostatic regulation of sleep, has inhibitory activity on the two major excitatory neurotransmitters acetylcholine and glutamate. It may be a biomarker of sleepiness.26 On the other hand, some contradictory evi-

CHAPTER 4  •  Daytime Sleepiness and Alertness  45

dence limits making definitive conclusions. The space here is too limited to discuss all the evidence in detail. In conclusion, although it is widely held that sleepiness is a physiological state, its physiological substrates are as yet not fully defined.

ASSESSMENT OF SLEEPINESS Quantifying Sleepiness The behavioral signs of sleepiness include yawning, ptosis, reduced activity, lapses in attention, and head nodding. An individual’s subjective report of his or her level of sleepiness also can be elicited. As noted earlier, a number of factors such as motivation, stimulation, and competing needs can reduce the behavioral manifestation of sleepiness. Thus, behavioral and subjective indicators often underestimate physiological sleepiness. Assessment problems were evident early in research on the daytime consequences of sleep loss. Sleep loss compromises daytime functions; virtually everyone experiences dysphoria and reduced performance efficiency when not sleeping adequately. But a majority of the tasks used to assess the effects of sleep loss are insensitive.31 In general, only long and monotonous tasks are reliably sensitive to changes in the quantity and quality of nocturnal sleep. An exception is a 10-minute visual vigilance task, completed repeatedly across the day, during which lapses (response times greater than or equal to 500 milliseconds) and declines in the best response times are increasingly observed as sleep is lost, either during total deprivation or cumulatively over nights of restricted bedtimes.32 In various measures of mood, including factor analytic scales, visual analogue scales, and scales for specific aspects of mood, subjects have shown increased fatigue or sleepiness with sleep loss. Among the various subjective measures of sleepiness, the Stanford Sleepiness Scale (SSS) is the best validated.33 Yet clinicians have found that chronically sleepy patients may rate themselves alert on the SSS even while they are falling asleep behaviorally.34 Such scales are state measures that query individuals about how they feel at the present moment. Another perspective is to view sleepiness behaviorally, as in the likelihood of falling asleep, and thus ask individuals to rate that likelihood in different social circumstances and over longer periods. The Epworth Sleepiness Scale (ESS) has been validated in clinical populations showing a 74% sensitivity and 50% specificity relative to the MSLT in a study of sleep disorders patients.35 It asks about falling asleep in settings in which patients typically report falling asleep (e.g., while driving, at church, in social conversation). The time frame over which ratings are to be made is 2 to 4 weeks. The standard physiological measure of sleepiness, the MSLT, similarly conceptualizes sleepiness as the tendency to fall asleep by measuring the speed of falling asleep. The MSLT has gained wide acceptance within the field of sleep and sleep disorders as the standard method of quantifying sleepiness.36 Using standard polysomnographic techniques, this test measures, on repeated opportunities at 2-hour intervals throughout the day, the latency to fall asleep while lying in a quiet, dark bedroom. The MSLT is based on the assumption, as outlined earlier, that sleepiness is a

46  PART I / Section 1  •  Normal Sleep and Its Variations

physiological need state that leads to an increased tendency to fall asleep. The metric typically used to express sleepiness has been average daily sleep latency (i.e., mean of the four or five tests conducted), but survival analyses have also been successfully used.37 The reliability and validity of this measure have been documented in a variety of experimental and clinical situations.38 In contrast to tests of performance, motivation does not seem to reduce the impact of sleep loss as measured by the MSLT. After total sleep deprivation, subjects can compensate for impaired performance, but they cannot stay awake long while in bed in a darkened room, even if they are instructed to do so.39 An alternative to the MSLT, suggested by some clinical investigators, is the Maintenance of Wakefulness Test (MWT). This test requires that subjects lie in bed or sit in a chair in a darkened room and try to remain awake.40 Like the MSLT, the measure of ability to remain awake is the latency to sleep onset. The test has not been standardized: there are 20-minute and 40-minute versions, and the subject is variously sitting upright in a chair, lying in bed, or semirecumbent in bed. The reliability of the MWT has not been established either. One study reported sensitivity to the therapeutic effects of continuous positive airway pressure (CPAP) in patients with sleep apnea,41 and several studies reported sensitivity to the therapeutic effects of stimulants in narcolepsy.42 A study attempted to tease apart the critical factors being measured by the MWT and concluded that, unlike the MSLT which measures level of sleepiness, the MWT measures the combined effects of level of sleepiness and the degree of arousal as defined by heart rate.43 The rationale for the MWT is that clinically the critical issue for patients is how long wakefulness can be maintained. A basic assumption underlying this rationale, however, may not be valid: it assumes that a set of circumstances can be evaluated in the laboratory that will reflect an individual’s probability of staying awake in the real world. Such a circumstance is not likely because environment, motivation, circadian phase, and any competing drive states all affect an individual’s tendency to remain awake. Stated simply, an individual crossing a congested intersection at midday is more likely to stay awake than an individual driving on an isolated highway in the middle of the night. The MSLT, on the other hand, addresses the question of the individual’s risk of falling asleep by establishing a setting to maximize the likelihood of sleep onset: all factors competing with falling asleep are removed from the test situation. Thus, the MSLT identifies sleep tendency or clinically identifies maximum risk for the patient. Obviously, the actual risk will vary from individual to individual, from hour to hour, and from environment to environment. Relation of Sleepiness to Behavioral Functioning Given that the MSLT is a valid and reliable measure of sleepiness, the question arises as to how this measure relates to an individual’s capacity to function. Direct correlations of the MSLT with other measures of performance under normal conditions have not been too robust. Several studies have found, however, that when sleepiness is at maximum levels, correlations with performance are

high. For example, MSLT scores after sleep deprivation,44 after administration of sedating antihistamines,45 and after benzodiazepine administration46 correlate with measures of performance and even prove to be the most sensitive measure. Studies also have compared levels of sleepiness to the known performance-impairing effects of alcohol.47 A study relating performance lapses on a vigilance task to the cumulative effects of sleep restriction found a function comparable to that of the MSLT under a similar cumulative sleep restriction (Fig. 4-2).48 The reason many studies have found weak correlations between performance and MSLT at normal or moderate levels of sleepiness is that laboratory performance and MSLT are differentially affected by variables such as age, education, and motivation. For the most part, the literature relating sleepiness and behavioral functioning has focused on psychomotor and attention behaviors with the major outcomes being response slowing and attentional lapses. These impairments can be attributed to slowed processing of information and microsleeps, that is intrusion of sleep preparation and sleep onset behaviors. Research has focused on other behavioral domains not as clearly associated with sleepmediated behaviors, including decision-making and pain sensation. Several studies have shown that increased sleepiness is associated with poor risk-taking decisions.49 Sleep loss and its associated sleepiness have also been shown to increase pain sensitivity.50

16 14 12 10 8 6 4 PVT lapses 2

Sleep latency (min)

0 B

P1

P2

P3

P4

P5

P6

P7

Day Figure 4-2  Similar functions relating mean daily sleep latency on the multiple sleep latency test (MSLT) and mean daily lapses on the visual psychomotor vigilance test (PVT) to the cumulative effects of sleep restriction (about 5 hours of bedtime nightly) across 7 consecutive nights (P1 to P7). (Redrawn from Dinges DF, Pack F, Williams K, et al. Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. Sleep 1997;20:275.)



CHAPTER 4  •  Daytime Sleepiness and Alertness  47

Clinical Assessment of Sleepiness Assessing the clinical significance of a patient’s complaint of excessive sleepiness can be complex for an inexperienced clinician. The assessment depends on two important factors: chronicity and reversibility. Chronicity can be explained simply. Although a healthy normal individual may be acutely sleepy, the patient’s sleepiness is persistent and unremitting. As to reversibility, unlike the healthy normal person, increased sleep time may not completely or consistently ameliorate a patient’s sleepiness. Patients with excessive sleepiness may not complain of sleepiness per se, but rather its consequences: loss of energy, fatigue, lethargy, weariness, lack of initiative, memory lapses, or difficulty concentrating. To clarify the patient complaint, it is important to focus on soporific situations in which physiological sleepiness is more likely to be manifest, as was discussed earlier. Such situations might include watching television, reading, riding in a car, listening to a lecture, or sitting in a warm room. Table 4-1 presents the commonly reported “sleepinducing” situations for a large sample of patients with sleep apnea syndrome. After clarifying the complaint, one should ask the patient about the entire day: morning, midday, and evening. In the next section, it will become clear that most adults experience sleepiness over the midday. However, patients experience sleepiness at other times of the day as well, and often throughout the day. Whenever possible, objective documentation of sleepiness and its severity should be sought. As indicated earlier, the standard and accepted method to document sleepiness objectively is the MSLT. Guidelines for interpreting the results of the MSLT are available (see Fig. 4-1).36 A number of case series of patients with disorders of excessive sleepiness have been published with accompanying MSLT data for each diagnostic classification.51 These data provide the clinician with guidelines for evaluating the clinical significance of a given patient’s MSLT results. Although these data cannot be considered norms, a scheme for ranking MSLT scores to indicate degree of pathology has been suggested.41 An average daily MSLT score of 5 minutes or fewer suggests pathological sleepiness, a score of more than 5 minutes but fewer than 10 minutes is considered a diagnostic gray area,

Table 4-1  Sleep-Inducing Situations for Patients with Apnea* SITUATION

PERCENTAGE OF PATIENTS

Watching television

91

Reading

85

Riding in a car

71

Attending church

57

Visiting friends and   relatives

54

Driving

50

Working

43

Waiting for a red light

32

*N = 384 patients.

and a score of more than 10 minutes is considered to be in the normal range (see Fig. 4-1 for MSLT results in the general population). The MSLT is also useful in identifying sleep-onset REM periods (SOREMPs), which are common in patients with narcolepsy.52 The American Academy of Sleep Medicine Standards of Practice Committee has concluded that the MSLT is indicated in the evaluation of patients with suspected narcolepsy.52 MSLT results, however, must also be evaluated with respect to  the conditions under which the testing was conducted. Standards have been published for administering the MSLT, which must be followed to obtain a valid, interpretable result.36

DETERMINANTS OF SLEEPINESS Quantity of Sleep The degree of daytime sleepiness is directly related to the amount of nocturnal sleep. The performance effects of acute and chronic sleep deprivation are discussed in Chapters 5 and 6. As to sleepiness, partial or total sleep deprivation in healthy normal subjects is followed by increased daytime sleepiness the following day.38 Therefore, modest nightly sleep restriction accumulates over nights to progressively increase daytime sleepiness and performance lapses (see Fig. 4-1).53 However, the speed at which sleep loss is accumulated is critical, as studies have shown adaptation to a slow accumulation of 1 to 2 hours nightly occurs, which then increases the duration of the subsequent recovery process.23 Increased sleep time in healthy, but sleepy, young adults by extending bedtime beyond the usual 7 to 8 hours per night produces an increase in alertness (i.e., reduction in sleepiness).54 Further, the pharmacological extension of sleep time by an average of 1 hour in elderly people produces an increase in mean sleep latency on the MSLT (i.e., increased alertness).55 Reduced sleep time explains the excessive sleepiness of several patient and nonpatient groups. For example, a subgroup of sleep clinic patients has been identified whose excessive daytime sleepiness can be attributed to chronic insufficient sleep.56 These patients show objectively documented excessive sleepiness, “normal” nocturnal sleep with unusually high sleep efficiency (time asleep–time in bed), and report about 2 hours more sleep on each weekend day than each weekday. Regularizing bedtime and increasing time in bed produces a resolution of their symptoms and normalized MSLT results.57 The increased sleepiness of healthy young adults also can be attributed to insufficient nocturnal sleep. When the sleepiest 25% of a sample of young adults is given extended time in bed (10 hours) for as long as 5 to 14 consecutive nights, their sleepiness is reduced to a level resembling the general population mean.54 Individual differences in tolerability to sleep loss have been reported.58 These differences can be attributed to a number of possible factors. A difference in the basal level of sleepiness at the start of a sleep time manipulation is quite possible given the range of sleepiness in the general population (see Fig. 4-1). The basal differences may reflect insufficient nightly sleep relative to ones’ sleep need.54 There also may be differences in the sensitivity and responsivity of the sleep homeostat to sleep loss, that is how large

48  PART I / Section 1  •  Normal Sleep and Its Variations

a sleep deficit the system can tolerate and how robustly the sleep homeostat produces sleep when detecting deficiency. Finally, genetic differences in sleep need, the set point around which the sleep homeostat regulates daily sleep time, have long been hypothesized and one study has suggested a gene polymorphism may mediate vulnerability to sleep loss.59 These all are fertile areas for research. Quality of Sleep Daytime sleepiness also relates to the quality and the continuity of a previous night’s sleep. Sleep in patients with a number of sleep disorders is punctuated by frequent, brief arousals of 3 to 15 second durations. These arousals are characterized by bursts of EEG speeding or alpha activity and, occasionally, transient increases in skeletal muscle tone. Standard scoring rules for transient EEG arousals have been developed.60 A transient arousal is illustrated in Figure 4-3. These arousals typically do not result in awakening by either Rechtschaffen and Kales sleep staging criteria or behavioral indicators, and the arousals recur in some conditions as often as 1 to 4 times per minute. The arousing stimulus differs in the various disorders and can be identified in some cases (apneas, leg movements, pain) but not in others. Regardless of etiology, the arousals generally do not result in shortened sleep but rather in fragmented or discontinuous sleep, and this fragmentation produces daytime sleepiness.61 Correlational evidence suggests a relation between sleep fragmentation and daytime sleepiness. Fragmentation, as indexed by number of brief EEG arousals, number of shifts from other sleep stages to stage 1 sleep or wake, and the percentage of stage 1 sleep correlates with EDS in various patient groups.61 Treatment studies also link sleep fragmentation and excessive sleepiness. Patients with sleep apnea syndrome who are successfully treated by surgery (i.e., number of apneas are reduced) show a reduced frequency of arousals from sleep as well as a reduced level of sleepiness, whereas those who do not benefit from the

surgery (i.e., apneas remain) show no decrease in arousals or sleepiness, despite improved sleeping oxygenation.62 Similarly, CPAP, by providing a pneumatic airway splint, reduces breathing disturbances and consequent arousals from sleep and reverses EDS.63 The reversal of daytime sleepiness following CPAP treatment of sleep apnea syndrome is presented in Figure 4-4. The hours of nightly CPAP use predicts both subjective and objective measures of sleepiness.64 Experimental fragmentation of the sleep of healthy normal subjects has been produced by inducing arousals with an auditory stimulus. Several studies have shown that subjects awakened at various intervals during the night demonstrate performance decrements and increased sleepiness on the following day.65 Studies have also fragmented sleep without awakening subjects by terminating the stimulus on EEG signs of arousal rather than on behavioral response. Increased daytime sleepiness (shortened latencies on the MSLT) resulted from nocturnal sleep fragmentation in one study,66 and in a second study, the recuperative effects (measured as increased latencies on the MSLT) of a nap following sleep deprivation were compromised by fragmenting the sleep on the nap.67 One nonclinical population in which sleep fragmentation is an important determinant of excessive sleepiness is the elderly. Many studies have shown that even elderly people without sleep complaints show an increased number of apneas and periodic leg movements during sleep.68 As noted earlier, the elderly as a group are sleepier than other groups.5 Furthermore, it has been demonstrated that elderly people with the highest frequency of arousal during sleep have the greatest daytime sleepiness.69 Circadian Rhythms A biphasic pattern of objective sleep tendency was observed when healthy, normal young adult and elderly subjects were tested every 2 hours over a complete 24-hour day.70 During the sleep period (11:30 pm to 8:00 am) the latency

15 Latency to sleep (min)

LE – A1 RE – A1 EMG (submental) C4 – A1 Oz – A1 V5 50 µV

12 9

1 night 14 nights

*,**

*,**

42 nights *

6 3

1 sec

Figure 4-3  A transient arousal (on right side of figure) fragmenting sleep. The preexistence of sleep is evident by the K-complex at second 9 of the epoch preceding the arousal. LE-A1, Left electrooculogram referenced to A1; RE-A1, right electrooculogram referenced to A1; EMG, electromyogram from submental muscle; C4-A1, electroencephalogram referenced to A1 from C4 placement; Oz-A1, electroencephalogram referenced to A1 from Oz placement; V5, electrocardiogram from V5 placement. (Redrawn from American Sleep Disorders Association. EEG arousals: scoring rules and examples. Sleep 1992;  15:173-184.)

0 Pre

Post CPAP treatment

Figure 4-4  Mean daily sleep latency on the multiple sleep latency test (MSLT) in patients with obstructive sleep apnea syndrome before (pre) and after (post) 1, 14, and 42 nights of continuous positive airway pressure (CPAP) treatment. *, P < .05; **, P < .01. (Redrawn from Lamphere J, Roehrs T, Wittig R, et al. Recovery of alertness after CPAP in apnea. Chest 1989;96:1364-1367.)

Mean latency to sleep onset (min)

CHAPTER 4  •  Daytime Sleepiness and Alertness  49

25 20 15 10 5

Elderly

Young adult

0 0930

1330

1730

2130

0130

0530

0930

Time of day Figure 4-5  Latency to sleep at 4-hour intervals across the 24-hour day. Testing during the daytime followed standard multiple sleep latency test (MSLT) procedures. During the night, from 11:30 PM to 8:00 AM (shaded area), subjects were awakened every 2 hours for 15 minutes, and latency of return to sleep was measured. Elderly subjects (n = 10) were 60 to 83 years old; young subjects (n = 8) were 19 to 23 years old. (Redrawn from Carskadon MA, Dement WC: Daytime sleepiness: Quantification of a behavioral state. Neurosci Biobehav Rev 1987;111:307-317. Copyright 1987, Elsevier Science.)

testing was accomplished by awakening subjects for 15 minutes and then allowing them to return to sleep. Two troughs of alertness—one during the nocturnal hours (about 2:00 to 6:00 am) and another during the daytime hours (about 2:00 to 6:00 pm)—were observed. Figure 4-5 shows the biphasic pattern of sleepiness–alertness. Other research protocols have yielded similar results. In constant routine studies, where external environmental stimulation is minimized and subjects remain awake, superimposed on the expected increase in self-rated fatigue resulting from the deprivation of sleep is a biphasic circadian rhythmicity of self-rated fatigue similar to that seen for sleep latency.71 In another constant routine study in which EEG was continuously monitored, a biphasic pattern of “unintentional sleep” was observed.72 In studies with sleep scheduled at unusual times, the duration of sleep periods has been used as an index of the level of sleepiness. A pronounced circadian variation in sleep duration is found with the termination of sleep periods closely related to the biphasic sleep latency function in the studies cited earlier.73 If individuals are permitted to nap when they are placed in time-free environments, this biphasic pattern becomes quite apparent in the form of a midcycle nap.74 This circadian rhythm in sleepiness is part of a circadian system in which many biological processes vary rhythmically over 24 hours. The sleepiness rhythm parallels the circadian variation in body temperature, with shortened latencies occurring in conjunction with temperature troughs.70 But these two functions, sleep latency and body temperature, are not mirror images of each other; the midday body temperature decline is relatively small compared with that of sleep latency. Furthermore, under freerunning conditions, the two functions become dissociated.75 However, no other biological rhythm is as closely associated with the circadian rhythm of sleepiness as is body temperature.

Earlier, it was noted that shift workers are unusually sleepy, and jet travelers experience sleepiness acutely in a new time zone. The sleepiness in these two conditions results from the placement of sleep and wakefulness at times that are out of phase with the existing circadian rhythms. Thus, not only is daytime sleep shortened and fragmented but also wakefulness occurs at the peak of sleepiness or trough of alertness. Several studies have shown that pharmacological extension and consolidation of out-of-phase sleep can improve daytime sleepiness (see Chapters 42, 73, and 81 for more detail).76 Yet, the basal circadian rhythm of sleepiness remains, although the overall level of sleepiness has been reduced. In other words, the synchronization of circadian rhythms to the new sleep– wake schedule is not hastened. CNS Drugs Sedating Drug Effects Central nervous system (CNS) depressant drugs, as expected, increase sleepiness. Most of these drugs act as agonists at the GABAA receptor complex. The benzodiazepine hypnotics hasten sleep onset at bedtime and shorten the latency to return to sleep after an awakening during the night (which is their therapeutic purpose), as demonstrated by a number of objective studies.77 Long-acting benzodiazepines continue to shorten sleep latency on the MSLT the day following bedtime administration.77 Finally, ethanol administered during the daytime (9:00 am) reduces sleep latency in a dose-related manner as measured by the MSLT.78 Second generation antiepileptic drugs, including gabapentin, tiagabine, vigabatrin, pregabalin, and others, enhance GABA activity through various mechanisms that directly or indirectly involve the GABAA receptor.79 The sedating effects of these various drugs have not been thoroughly documented, but some evidence indicates they do have sedative activity. GABAB receptor agonists are being investigated as treatments for drug addictions and the preclinical animal research suggests these drugs may have sedative activity as well.80 Antagonists acting at the histamine H1 receptor also have sedating effects. One of the most commonly reported side effects associated with the use of H1 antihistamines is daytime sleepiness. Several double-blind, placebo-controlled studies have shown that certain H1 antihistamines, such as diphenhydramine, increase sleepiness using sleep latency as the objective measure of sleepiness, whereas others, such as terfenadine or loratadine do not.81 The difference among these compounds relates to their differential CNS penetration and binding. Others of the H1 antihistamines (e.g., tazifylline) are thought to have a greater peripheral compared with central H1 affinity, and, consequently, effects on daytime sleep latency are found only at relatively high doses.81 Antihypertensives, particularly beta adrenoreceptor blockers, are also reported to produce sedation during the daytime.82 These CNS effects are thought to be related to the differential liposolubility of the various compounds. However, we are unaware of any studies that directly measure the daytime sleepiness produced by beta-blockers; the information is derived from reports of side effects. As noted earlier, it is important to differentiate sleepiness

50  PART I / Section 1  •  Normal Sleep and Its Variations

from tiredness or fatigue. Patients may be describing tiredness or fatigue resulting from the drugs’ peripheral effects (i.e., lowered cardiac output and blood pressure), not sleepiness, a presumed central effect. Sedative effects of dopaminergic agonists used in treating Parkinson’s disease have been reported as adverse events in clinical trials and in case reports as “sleep attacks” while driving.83 It is now clear these “sleep attacks” are not attacks per se, but are the expression of excessive sleepiness. Whereas the dose-related sedative effect of these drugs has been established, the mechanism by which the sedative effects occur is unknown. The dopaminergic agonists are also known to disrupt and fragment sleep.84 Thus, the excessive sleepiness may be secondary to disturbed sleep, or to a combination of disturbed sleep and direct sedative effects. Alerting Drug Effects Stimulant drugs reduce sleepiness and increase alertness. The drugs in this group differ in their mechanisms of action. Amphetamine, methylphenidate, and pemoline block dopamine reuptake and to a lesser extent enhance the release of norepinephrine, dopamine, and serotonin. The mechanism of modafinil is not established; some evidence suggests that modafinil has a mechanism distinct from the classical stimulants. Amphetamine, methylphenidate, pemoline, and modafinil are used to treat the EDS associated with narcolepsy and some have been studied as medications to maintain alertness and vigilance in normal subjects under conditions of sustained sleep loss (e.g., military operations). Studies in patients with narcolepsy using MSLT or MWT have shown improved alertness with amphetamine, methylphenidate, modafinil, and pemoline.85 There is dispute as to the extent to which the excessive sleepiness of narcoleptics is reversed and the comparative efficacy of the various drugs. In healthy normal persons restricted or deprived of sleep, both amphetamine and methylphenidate increase alertness on the MSLT and improve psychomotor performance.86,87 Caffeine is an adenosine receptor antagonist. Caffeine, in doses equivalent to 1 to 3 cups of coffee, reduced daytime sleepiness on the MSLT in normal subjects after 5 hours of sleep the previous night.88 Influence of Basal Sleepiness The preexisting level of sleepiness–alertness interacts with a drug to influence the drug’s behavioral effect. In other words, a drug’s effect differs when sleepiness is at its maximum compared to its minimum. As noted previously, the basal level of daytime sleepiness can be altered by restricting or extending time in bed58; this in turn alters the usual effects of a stimulating versus a sedating drug. A study showed comparable levels of sleepiness–alertness during the day following 5 hours in bed and morning (9:00 am) caffeine consumption compared to 11 hours in bed and morning (9:00 am) ethanol ingestion. Follow-up studies explored the dose relations of ethanol’s interaction with basal sleepiness.89 Dose-related differences in daytime sleepiness following ethanol and 8 hours of sleep were diminished after even 1 night of 5 hour sleep, although the measured levels of ethanol in breath were consistent day to day. In other words, sleepiness enhanced the sedative

effects of ethanol. In contrast, caffeine and methylphenidate produced a similar increase in alertness, regardless of the basal level of sleepiness. Clinically, these findings imply, for example, that a sleepy driver with minimal blood ethanol levels may be as dangerous as an alert driver who is legally intoxicated.89 The basal state of sleepiness also influences drug-seeking behavior. The likelihood that a healthy normal person without a drug abuse history will self-administer methylphenidate is greatly enhanced after 4 hours of sleep the previous night compared to 8 hours of sleep (see Fig. 4-4). Though not experimentally demonstrated as yet, self administration of caffeine also is probably influenced by basal state of sleepiness. The high volume of caffeine use in the population probably relates to the high rate of self medication for sleepiness due to chronic insufficient sleep in the population. CNS Pathologies Pathology of the CNS is another determinant of daytime sleepiness. The previously noted hypocretin/orexin deficiency is thought to cause excessive sleepiness in patients with narcolepsy.90 Another sleep disorder associated with excessive sleepiness due to an unknown pathology of the CNS is idiopathic CNS hypersomnolence. A report of a series of rigorously diagnosed cases (n = 77) found moderate MSLT scores (8.5 minutes mean latency) relative to narcoleptics (4.1 minutes mean latency).91 As yet hypocretin/orexin deficiency has not been shown in this disorder. These two conditions are described in detail in Chapters 84 and 86. Excessive sleepiness is reported in other neurological diseases. A study in patients with myotonic dystrophy, type 1 reported excessive sleepiness on the MSLT and reduced cerebrospinal levels of hypocretin/orexin.92 “Sleep attacks” have been reported in Parkinson’s disease and assessment with the MSLT suggests these attacks are the expression of excessive daytime sleepiness.93 What remains unresolved in the excessive sleepiness of Parkinson’s disease is the relative contribution of the disease itself, the fragmentation of sleep due to periodic leg movement or apnea , and the dopaminergic drugs used in treating Parkinson’s disease.94 The previously cited study found no differences in sleepiness as a function of prescribed drug or sleep fragmentation, although further assessment in larger samples is necessary to confirm this finding. Sleepiness may be prominent after traumatic brain injury.94a,94b

CLINICAL AND PUBLIC HEALTH SIGNIFICANCE OF SLEEPINESS Although the patients at sleep disorders centers are not representative of the general population, they do provide some indications regarding the clinical significance of sleepiness. Their sleep–wake histories directly indicate the serious impact excessive sleepiness has on their lives.95 Nearly half the patients with excessive sleepiness report automobile accidents; half report occupational accidents, some life threatening; and many have lost jobs because of their sleepiness. In addition, sleepiness is considerably disruptive of family life.96 An elevated automobile accident rate (i.e., sevenfold) among patients with excessive sleepi-



ness has been verified through driving records obtained from motor vehicle agencies.97 Population-based information regarding traffic and industrial accidents also suggests a link between sleepiness and life-threatening events. Verified automobile accidents occurred more frequently in a representative sample of people with MSLT scores of 5 minutes or less.98 The highest rate of automobile accidents occurs in the early morning hours, which is notable because the fewest automobiles are on the road during these hours. Also during these early morning hours, the greatest degree of sleepiness is experienced.99 Long-haul truck drivers have accidents most frequently (even corrected for hours driving before the accident) during the early morning hours, again when sleepiness reaches its zenith.100 Workers on the graveyard shift were identified as a particularly sleepy subpopulation. In 24-hour ambulatory EEG recordings of sleep and wakefulness, workers (20% in one study) were found to actually fall asleep during the night shift.8 Not surprisingly, the poorest job performance consistently occurs on the night shift, and the highest rate of industrial accidents is usually found among workers on this shift.101 Medical residents are another particularly sleepy subpopulation. In surveys those reporting five or fewer hours of sleep per night were more likely to make medical errors, report serious accidents, and were two times more likely to be named in medical malpractice suits.102,103 In a survey of medical house-staff, 49% reported falling asleep while driving and 90% of the episodes occurred postcall compared to 13% fall-asleep episodes reported by the medical faculty and 20 of the 70 housestaff were involved in automobile accidents compared to 11 of the 85 faculty.104 Cognitive function is also impaired by sleepiness. Adults with various disorders of excessive sleepiness have cognitive and memory problems.105 The memory deficiencies are not specific to a certain sleep disorder but rather specific to the sleepiness associated with the disorder. When treated adequately, sleepiness is rectified and the memory and cognitive deficits similarly improve.106 Results of sleep deprivation studies in healthy normal patients support the relation between sleepiness and memory deficiency. Even modest reductions of sleep time are associated with cognitive deficiencies.107 Sleepiness also depresses arousability to physiological challenges: 24-hour sleep deprivation decreases upper airway dilator muscle activity108 and decreases ventilatory responses to hypercapnia and hypoxia.109 In a canine model of sleep apnea, periodic disruption of sleep with acoustic stimuli (i.e., sleep fragmentation, in contrast to sleep deprivation) resulted in lengthened response times to airway occlusion, greater oxygen desaturation, increases in inspiratory pressures, and surges in blood pressure.110 Depressed physiological responsivity due to sleepiness is clinically significant for patients with sleep apnea and other breathing disorders as they are all exacerbated by sleepiness. The emerging data on sleepiness and pain threshold, cited earlier, is also clinically significant in the management of both acute and chronic pain conditions. Finally, life expectancy data directly link excessive sleep (not specifically sleepiness) and mortality. A 1976 study found that men and women who reported sleeping more

CHAPTER 4  •  Daytime Sleepiness and Alertness  51

than 10 hours of sleep a day were about 1.8 times more likely to die prematurely than those sleeping between 7 and 8 hours daily.111 This survey, however, associated hypersomnia and increased mortality and not necessarily EDS, for which the relation is currently unknown. ❖  Clinical Pearl Sleepiness, when most excessive and persistent, is a signal to the individual to stop operating because it is dangerous and life-threatening to continue without sleep. It is also a signal to the clinician that there may be some underlying pathology that can be successfully treated, or in the very least minimized, as to its vital, life-threatening impact.

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editors. Sleep 1976. Basel, Switzerland: Karger; 1977. pp. 95-  100. 96. Broughton R, Ghanem Q, Hishikawa Y, et al. Life effects of  narcolepsy in 180 patients from North America, Asia and  Europe compared to matched controls. J Can Sci Neurol 1981;8:  299-304. 97. Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive apnea. Am Rev Respir Dis 1988;138:337-340. 98. Drake C, Scofield H, Jefferson C, et al. MSLT defined sleepiness predicts verified automotive crashes in the general population. Sleep 2007;30:A131 [abstract]. 99. Mitler MM, Carskadon MA, Czeisler CA, et al. Catastrophes, sleep, and public policy: consensus report. Sleep 1988;11:100-109. 100. Mackie RR, Miller JC. Effects of hours of service, regularity of schedules, and cargo loading on truck and bus driver fatigue. Washington, DC: US Government Printing Office; 1978. Technical Report 1765-F DOT-HS-5-01142. 101. Dorrian J, Tolley C, Lamond N, et al. Sleep and errors in a group of Australian hospital nurses at work and during the commute. App Ergon 2008;39:605-613. 102. Baldwin DC, Daugherty SR. Sleep deprivation and fatigue in residency training: results of a national survey of first- and second-year residents. Sleep 2004;27:217-223. 103. Marcus CL, Loughlin GM. Effect of sleep deprivation on driving safety in housestaff. Sleep 1996;19:763-766. 104. Roehrs TA, Merrion M, Pedrosi B, et al. Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD). Sleep 1995;18:  382-388. 105. Rao V, Spiro J, Samus QM, et al. Insomnia and anytime sleepiness in people with dementia residing in assisted living: finding from the Maryland Assisted Living Study. Int J Ger Psychiat 2008;23:199-  206. 106. Aguirre M, Broughton RJ, Stuss D. Does memory impairment  exist in narcolepsy-cataplexy? J Clin Exp Neuropsychol 1985;7:  14-24. 107. Blagrove M, Alexander C, Horne JA. The effects of chronic sleep reduction on the performance of cognitive tasks sensitive to sleep deprivation. Appl Cogn Psychol 1994;9:21-40. 108. Leiter JC, Knuth SL, Barlett D. The effect of sleep deprivation on activity of the genioglossus muscle. Am Rev Respir Dis 1985;  132:1242-1245. 109. White DP, Douglas NJ, Pickett CK, et al. Sleep deprivation and control of ventilation. Am Rev Respir Dis 1983;128:984-986. 110. Brooks D, Horner RL, Kimoff RJ, et al. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Respir Crit Care Med 1997;155:1609-1617. 111. Kripke DF, Simons NR, Garfinkel L, et al. Short and long sleep and sleeping pills. Is increased mortality associated? Arch Gen Psychiatry 1979;36:103-116.

Acute Sleep Deprivation Michael H. Bonnet Abstract Sleep deprivation is extremely common in modern society. Sleep loss is accompanied by significant and increasingly apparent alterations in mood, alertness, and performance. This chapter reviews the behavioral effects of sleep deprivation, including both sleep/circadian influences and arousal system influences such as activity, light, noise, posture, motivation, and drugs. The effects of sleep loss are broad, and numerous systems are affected. Work showing similar changes after alcohol ingestion provides one means of comparatively describing the effects of sleep loss. A number of relatively mild physiologic changes accompany total sleep deprivation in

Sleep deprivation is both extremely common and critically relevant in our society. As a clinical entity, sleep deprivation is recognized by the diagnosis of insufficient sleep syndrome (International Classification of Diseases [ICD]2, #307.44). As an experimental methodology, sleep deprivation serves as a major tool in understanding the function of sleep. A broad range of physiologic responses and behavioral abilities have been examined after varying periods without sleep, and lawful relationships have been described. These relationships and the theory they represent are important in their own right, but the findings also serve as an extensive guide to symptoms associated with insufficient sleep. Furthermore, methods developed to lessen the impact of sleep deprivation also serve as possible clinical treatments for disorders related to insufficient sleep or excessive sleepiness. This chapter will review behavioral, physiologic, and theoretical implications of acute sleep deprivation. Chronic partial sleep deprivation is examined in Chapter 6. Studies of sleep deprivation can suffer from some common methodological problems that require consideration. The most important control issue is that one cannot perform a blinded sleep deprivation study. Both experimenter and subject motivation can have an impact on results, particularly in the behavioral and subjective domains. Motivation effects are frequently apparent near the end of sleep deprivation studies (where performance improvement is sometimes found) and may account for the difficulty in showing early decrements. Animal studies are less susceptible to subject expectation effects, but they may contain additional elements of stress that may interact with sleep loss, so these studies may not be directly comparable with stress control conditions. In addition, almost all sleep loss experiments involve more than simple loss of sleep. Maintenance of wakefulness usually includes upright posture, light, movement, cognition, and all the underlying physiologic processes implied by these activities. The experimental setting itself is usually far from routine. Some studies have attempted to control some of these factors during sleep loss, but trying to control all variables in a single experiment is daunting. 54

Chapter

5

man. However, several new means of assessing sleep deprivation effects, including brain scans, genetic assessment, and animal models, show promise for a better understanding of sleep and sleep loss. Studies have also shown that highfrequency periodic sleep fragmentation produces nonrestorative sleep that results in a state of sleepiness and decreased performance that is similar in many dimensions to sleepiness after total sleep deprivation. Recovery sleep after sleep loss or sleep fragmentation shows a characteristic pattern of elevated slow-wave sleep (SWS) with elevated sensory thresholds followed by elevated rapid eye movement (REM) sleep.

Over a thousand studies of sleep deprivation have been published during the past 10 years, and the resulting knowledge database has been remarkably consistent. However, new techniques and increasingly sensitive tests continue to add both theoretical and practical understanding of the impact of sleep loss. This review includes sections on total sleep deprivation, sleep fragmentation, and recovery from sleep deprivation.

TOTAL SLEEP DEPRIVATION The first published studies of total sleep loss date to 1894 for puppies1 and 1896 for humans.2 The puppy study indicated that prolonged sleep loss in animals could be fatal, an idea reinforced by numerous, more recent animal studies. The human study included a range of physiologic and behavioral measurements and remains a model study. Behavioral Effects The most striking effect of sleep loss is sleepiness, and this can be inferred from subjective reports, the multiple sleep latency test (MSLT), electroencephalographic (EEG) change, or simply looking at the face of the participant. The variables that determine the impact of sleep loss can be divided into four categories: sleep/circadian influences, arousal system influences, individual characteristics, and test characteristics (Box 5-1). Sleep/Circadian Influences Sleep deprivation, like nutritional status, is a relative concept. How an individual responds to sleep loss depends on the prior sleep amount and distribution. Performance during a period of sleep loss is also directly dependent on the length of time awake and the circadian time, and predictive models support these factors. Experiments usually try to control prior wakefulness and sleep amount by requiring “normal” nights of sleep before initiation of a sleep loss episode. Data from multiple regression analyses of behavioral and EEG data during 64 hours of sleep loss3 suggest that time awake accounts for 25% to 30% of the variance in alertness, and that circadian time



CHAPTER 5  •  Acute Sleep Deprivation  55

1.3

Sleep/Circadian Influences •  Prior sleep amount and distribution •  Length of time awake •  Circadian time

1.1

Individual Characteristics •  Age •  Individual sensitivity •  Personality and psychopathology Test Characteristics and Types •  Length of test •  Knowledge of results •  Test pacing •  Proficiency level •  Difficulty or complexity of test •  Memory requirement •  Executive function measures •  Subjective (versus objective) measures •  Electroencephalographic measures—multiple sleep latency test (MSLT)

accounts for about 6% of the variance. When prophylactic naps of varying length were interjected early in a period of sleep loss, it was found that the prophylactic nap sleep accounted for about 5% of the variance in alertness during the sleep deprivation period. In terms of reducing the effect of sleep loss, the overall effect of increasing the prophylactic nap period was linear for additional sleep amounts ranging up to 8 hours in length. Figure 5-1 displays the effects of time awake and the circadian rhythm on objective alertness as measured by the MSLT and the ability to complete correct symbol substitutions during 64 hours of sleep loss. Arousal Influences Environmental and emotional surroundings have a large impact on the course of a period of sleep loss. In early stages of sleep deprivation, many intervening variables can easily reverse all measurable sleep loss decrements. These influences include activity, bright light, noise, temperature, posture, stress, and drugs. A CTIVITY A 5-minute walk immediately preceding MSLT evaluations had a large impact (about 6 minutes) on MSLT values, which masked the impact of a 50% reduction of nocturnal sleep (about a 2-minute reduction on MSLT) and continued for at least 90 minutes.4 Exercise before

MSLT DSST

0.9 0.7 0.5 0.3

:0 1: 0 0 4: 0 0 7: 0 0 10 0 :0 13 0 : 16 00 :0 19 0 :0 22 0 :0 1: 0 0 4: 0 0 7: 0 0 10 0 :0 13 0 :0 16 0 :0 19 0 :0 0

0.1

22

Arousal Influences •  Activity •  Bright light •  Noise •  Temperature •  Posture •  Motivation or interest •  Drugs •  Group effects •  Repeated exposure to sleep loss

Proportion of baseline

Box 5-1  Determinants of the Impact of Sleep Loss

Time of day Figure 5-1  Latency to stage 2 sleep (boxes) and number of correctly completed symbol substitutions in repeated 5-minute test sessions (dots) over a period of 64 hours of sleep deprivation, both expressed as a proportion of baseline values. (Data from Bonnet MH, Gomez S, Wirth O, et al. The use of caffeine versus prophylactic naps in sustained performance. Sleep 1995;18:97-104.) DSST, digit symbol substitution task; MSLT multiple sleep latency test.

performing tasks provided transient reversal of some psychomotor decrements resulting from sleep loss. However, more ambitious studies comparing high activity and low activity that continued over 40 to 64 hours of sleep deprivation have shown no beneficial effects of exercise on overall performance.5 Perhaps, arousing stimuli act for only a discrete period of time that is decreased by increasing sleep loss.6 There may also be a trade-off between production of arousal and production of physical fatigue. B RIGHT LIGHT Bright light can shift circadian rhythms. Some controversy exists concerning whether bright light can also act as a source of stimulation during a sleep-loss state to help to maintain alertness. Two of five studies found that periods of bright light immediately before sleep onset significantly increased sleep latencies. Other studies found improved nocturnal performance during bright light conditions, with elevated heart rate as a probable correlate.7 N OISE Noise, despite complex and occasionally negative effects on the performance of well-rested individuals, may produce small beneficial effects during sleep deprivation.8 It is generally assumed that noise increases arousal level, and this may provide maximal benefit during sleep loss. T EMPERATURE Although temperature variation is commonly used as an acute stimulus to maintain alertness, little research supports ambient temperature as a large modulator of alertness. One study has shown that heat (92° F) was effective in improving performance during the initial minutes of a vigilance task during sleep deprivation.9 However, another

56  PART I / Section 1  •  Normal Sleep and Its Variations

study10 showed only a small decrease in subjectively rated sleepiness for about 15 minutes after a car air-conditioner was turned on during simulated driving. P OSTURE One study has shown a significant increase in sleep latency, as a measure of alertness, when subjects were asked to fall asleep in the sitting position (60-degree angle) as opposed to lying down.11 Such a difference could be accounted for by increasing sympathetic nervous system activity, which occurs as one moves to the upright posture. D RUGS Many drugs have been studied in conjunction with sleep loss, and an extensive review by the American Academy of Sleep Medicine has been published.12 Most studies have examined stimulants, including amphetamine, caffeine, methylphenidate, modafinil, armodafinil, nicotine, and cocaine. Numerous studies have shown that caffeine (dosages of 200 to 600 mg), modafinil (100 to 400 mg), and amphetamine (5 to 20 mg) can improve objective alertness and psychomotor performance for periods of time related to dosage, half-life, and hours of total sleep deprivation. However, head-to-head studies often provide the clearest comparison of compounds. One study13 examined alertness and response speed hourly for 12 hours during the first night of sleep deprivation after administration of modafinil (100, 200, and 400 mg) in comparison with caffeine 600 mg. In that study, modafinil dosages of 200 and 400 mg were shown to be equivalent to caffeine (600 mg) in maintaining response speed consistently above placebo levels for 12 hours. The same group compared modafinil (400 mg), caffeine (600 mg), and dextroamphetamine (20 mg) given just before midnight of the second night of total sleep loss.14 In this study, caffeine and dextroamphetamine significantly improved response speed only at midnight, 2:00 am, and 4:00 am, whereas modafinil improved response speed through 10 am. The decreased sensitivity to caffeine probably reflects both the half-life of caffeine and the increased sleep pressure from the second night of deprivation. Side effects were fewest after modafinil at 400 mg. However, the authors concluded that (1) these stimulants all provided some benefits and had some associated costs, (2) caffeine, with efficacy, availability, and low cost, can be a first choice for alertness, and (3) modafinil, with good efficacy and few side effects, would be a good substitute if caffeine were ineffective (related to time course of available administration, tolerance, side effects, or degree of sleep loss). Effects of stimulants can be enhanced by the use of naps or other sources of arousal. The beneficial effect of caffeine (300 mg) during periods of sleep loss was approximately equivalent to that seen after a 3- to 4-hour prophylactic nap before the sleep loss period.15 The combination of a 4-hour prophylactic nap followed by 200 mg of caffeine at 1:30 am and 7:30 am resulted in significantly improved performance (remaining at baseline levels) compared with the nap alone, for 24 hours.16 The combination of naps and caffeine was additive16 and superior to the provision of 4 hours of nocturnal naps. The combination of 200 mg of caffeine administered at 10:00 pm and 2:00 am and expo-

sure to 2500-lux bright light had no impact beyond the effect of caffeine alone on the maintenance of wakefulness test but did provide significant benefit above caffeine alone on a vigilance task.17 Recent work has shown that armodafinil (the levorotatory R-enantiomer of modafinil), which has a 10- to 14-hour half-life, is effective in maintaining alertness and performance throughout 1 night of sleep deprivation.18 Results with armodafinil (200  mg) appeared to be similar to those with modafinil (200  mg) but may have provided some additional benefit 11 to 13 hours after administration.18 Nicotine, infused intravenously at dosages of 0.25, 0.37 and 0.5 mg after 48 hours of wakefulness, had no significant impact on MSLT or psychomotor performance.19 Cocaine (96 mg), like amphetamine, did not improve performance in subjects before sleep loss. However, reaction time and alertness, as measured by the Profile of Mood States, was improved after 24 and 48 hours of sleep loss.20 Alcohol use has been found to consistently reduce alertness.21 Subjects were tested with the MSLT and simulated driving after 0.6  g/kg alcohol or placebo following normal sleep or 4 hours of sleep. There was a significant main effect for condition, and MSLT latencies were 10.7, 6.3, 6.1, and 4.7 minutes after placebo (normal sleep), placebo (4 hours sleep), ethanol (normal sleep), and ethanol (4 hours sleep), respectively. Similar results were found in the driving simulator, where there were three “crashes”— all in the reduced-sleep-with-ethanol condition. One difficulty in assessing the magnitude of performance effects associated with sleep loss is the lack of a clear standard of pathology for most measures. The fact that society has established very specific rules for blood alcohol content with respect to driving has led to the use of impairment associated with blood alcohol level as a standard reference for sleep deprivation as well. Several studies of alcohol use in direct comparison with sleep deprivation have shown decrements on different tasks. Response speed on the Mackworth task was reduced by approximately half a second by 3:45 am (i.e., with sleep loss) and to a similar extent by a blood alcohol content (BAC) of 0.1%. Also, hand–eye coordination (in a visual tracking task) declined in a linear fashion during sleep loss and with increasing BAC, such that performance was equivalent at 3:00 am to a blood alcohol level of 0.05% and equivalent at 8:00 am (after a full night of sleep loss) to a blood alcohol level of 0.1%. In a third study,22 performance was measured in a driving simulator after alcohol use or sleep deprivation. After a night of sleep deprivation (at 7:30 am), subjects averaged one off-road (i.e., vehicle driving off the road) incident every 5 minutes. This same level of off-road driving was reached with a BAC of 0.08%. These studies suggest that the changes in response speed, visual tracking, and driving commonly found during the first night of total sleep deprivation are equivalent to changes associated with legal intoxication. Such metrics provide useful understanding of the consequences associated with short periods of sleep loss. M OTIVATION OR INTEREST Motivation is relatively easy to vary by paying subjects and has therefore received attention. In one study, monetary



rewards for “hits” on a vigilance task and “fines” for false alarms23 resulted in performance being maintained at baseline levels for the first 36 hours of sleep loss in the highincentive group. Performance began to decline during the following 24 hours but remained significantly better than in the “no incentive” group. However, the incentive was ineffective in maintaining performance at a higher level during the third day of sleep loss. Knowledge of results— for example, the publication of daily test results—was sufficient to remove the effects of 1 night of sleep loss. In another variation, simple knowledge that a prolonged episode of sleep deprivation was going to end in a few hours was sufficient for performance to improve by 30% in a group of soldiers.24 G ROUP EFFECTS There are few studies, but interest is growing in how groups perform during sleep deprivation. Such studies are difficult because groups of individuals interact in many ways. One early study suggested that, if all group members were working at a similar task, greater deficits were seen as sleep deprivation progressed, compared with individual work. However, a more recent study that distributed work so that each individual added a unique component to task completion found that the deficits that accumulated during sleep deprivation were less pronounced in the group task.25 R EPEATED PERIODS OF SLEEP LOSS Studies of repeated episodes of sleep loss have agreed that the magnitude of performance loss increases as a function of the number of exposures to sleep loss.26 Increasingly poor performance may be secondary to decreased motivation or to familiarity with the sleep deprivation paradigm (resulting in decreased arousal). Individual Characteristics The impact of sleep loss on a given individual depends on characteristics that each participant brings to the sleep loss situation. For example, age and personality represent differences in physiologic or psychological function that may interact with the sleep loss event. A GE Tests of performance and alertness in older subjects undergoing sleep loss reveal a decrease in performance and alertness similar to that seen in younger individuals. If anything, older men had a smaller decrease in psychomotor performance ability at nocturnal times during sleep loss27,28 than younger men. Older individuals perform more poorly than young adults on a broad range of tasks, but, because of decreased amplitude of the circadian body temperature rhythm, this relationship may not be maintained across the night or during sleep loss.27 The same flattened curve associated with lower temperatures and decreased performance during the day also produces relatively elevated temperatures that could be related to improved performance at night. S ENSITIVITY TO SLEEP LOSS A number of studies have now demonstrated consistent individual differences in both alertness and performance during sleep deprivation.29 The studies have also shown

CHAPTER 5  •  Acute Sleep Deprivation  57

that the reliable changes in subjective alertness, objective alertness, and performance are not related to one another. Performance consistently declined in the same subjects when sleep loss was repeated, but decrements did not generalize across performance tasks. This has led some to speculate that different brain areas could be responsible for different tasks. Some studies have begun to look for central predictors of performance loss. Early functional magnetic resonance imaging (fMRI) studies showed that subjects with higher levels of global brain activation (consistent at both baseline and during sleep loss) maintained better performance on a working memory task,30 and a more recent study linked working memory during sleep loss with left frontal and parietal brain areas.31 Other studies have shown that extroverts and caffeine-sensitive individuals were more sensitive to sleep loss.32 Such findings imply individual trait ability to maintain higher levels of arousal in specific brain areas or systems to help to maintain performance during sleep loss. In another approach, over 400 potential subjects were screened genetically, and groups were formed on the basis of the PER3 polymorphism (PER3[5/5] versus PER3[4/4]) before a 40-hour constant routine. The PER3(5/5) group appeared sleepier by all measures (significantly shorter sleep latency, more slow-wave sleep (SWS), greater slow eye movements during sleep loss, and significantly worse performance during sleep loss, particularly on executive tasks done early in the morning [0600 to 0800]).33,34 P ERSONALITY AND PSYCHOPATHOLOGY Mood changes, including increased sleepiness, fatigue, irritability, difficulty in concentrating, and disorientation, are commonly reported during periods of sleep loss. Perceptual distortions and hallucinations, primarily of a visual nature, occur in up to 80% of normal individuals, depending on work load, visual demands, and length of deprivation.35 Such misperceptions are normally quite easy to differentiate from the primarily auditory hallucinations of a schizophrenic patient, but normal individuals undergoing sleep loss may express paranoid thoughts. Two percent of 350 individuals sleep deprived for 112 hours experienced temporary states resembling acute paranoid schizophrenia. Some predisposition toward psychotic behavior existed in individuals who experienced significant paranoia during sleep loss, and the paranoid behavior tended to become more pronounced during the night, with partial recovery during the day and disappearance after recovery sleep. In a review of the area, Johnson concluded, “Each subject’s response to sleep loss will depend on his age, physical condition, the stability of his mental health, expectations of those around him, and the support he receives.”36, p. 208 At a more general level, normal adults undergoing sleep deprivation typically express some increase in somatic complaints, anxiety, depression, and paranoia that do not reach clinical levels.37 In view of the commonly reported effects of sleep deprivation, it seems quite unusual that one would seek to treat depression by sleep deprivation. However, sleep deprivation has been used as a successful treatment for depression in 40% to 60% of cases for over 30 years. Imaging studies have shown that depressed patients have elevated metabolism in the prefrontal cortex and ventral anterior cingulate

58  PART I / Section 1  •  Normal Sleep and Its Variations

cortex (possibly related to reduced transmission of dopamine and serotonin) that is normalized by sleep deprivation.38 One theory proposes that sleep deprivation is more effective in depressed patients with high levels of activation or high central noradrenergic activity because it limits the effects of chronic hyperarousal. As a result, patients felt tired but also had improved mood and energy. Test Characteristics and Types Two meta-analyses of subtopics of sleep deprivation have been published.39 Both analyses indicated that sleep deprivation has a significant impact on psychomotor performance. In general, longer periods of sleep loss had greater impact on performance, and decrements in speed of performance were greater than decreases in accuracy. Also, mood measures were more sensitive than cognitive tasks, which were more sensitive than motor tasks,39 during sleep loss. Therefore, the measured response to sleep deprivation is critically dependent on the characteristics of the test used. To some extent, the type of test has also been used to infer specific brain area dysfunction. Sleep-deprived individuals appear most sensitive to the following dimensions. L ENGTH OF TEST Individuals undergoing sleep loss can usually rally momentarily to perform at their non–sleep-deprived levels, but their ability to maintain that performance decreases as the length of the task increases. For example, subjects attempted significantly fewer addition problems than baseline after 10 minutes of testing following 1 night of sleep loss but reached the same criterion after 6 minutes of testing following the second night of sleep loss. It took 50 minutes of testing to show a significant decrease in percentage of correct problems after 1 night of sleep loss, and 10 minutes of testing to reach that criterion after the second night.40 It is frequently difficult to show reliable differences during short-term sleep loss from almost any test that is shorter than 10 minutes in duration. Momentary arousal, even as minor as an indication that 5 minutes remained on a task, was sufficient to reverse 75% of the decrement accumulated over 30 minutes of testing. K NOWLEDGE OF RESULTS Immediate performance feedback, possibly acting through motivation, has been shown to improve performance during sleep deprivation.41 Simply not giving knowledge of results to subjects with normal sleep doubled their number of very long responses (“gaps”) on a serial-reaction time test. One night of total sleep loss increased the number of gaps by 9.3 times the baseline level, but provision of immediate knowledge of results decreased the number of gaps back to baseline levels.41 T EST PACING Self-paced tasks are usually more resistant to the effects of sleep loss than tasks that are timed or in which items are presented by the experimenter. In a self-paced task, the subject can concentrate long enough to complete items correctly and not be penalized for lapses in attention that occur between items. When tasks are externally

paced, errors occur if items are presented during lapses in attention. P ROFICIENCY LEVEL Sleep loss is likely to affect newly learned skills more than well-known activities, as long as arousal level remains constant. For example, in a study of the effects of sleep loss on doctors in training, significant performance decrements were found in postgraduate year (PGY)-1 surgical residents but not in PGY-2 to -5 surgical residents.42 D IFFICULTY OR COMPLEXITY Performance on simple tasks such as monitoring a light on a control panel (on/off) declines less than performance on more complex tasks such as mental subtraction43 during sleep loss. Task difficulty can also be adjusted by increasing the speed at which the work must be performed. When 2 seconds was allowed to complete mental arithmetic problems, no significant performance decline was found after 2 nights of sleep loss, but when the rate of presentation was increased to 1.25 seconds, significant performance decline was found. M EMORY REQUIREMENT Impairment of immediate recall for elements placed in short-term memory is a classic finding in sleep deprivation studies. Because subjects are usually required to write down each item as presented, the observed decrements, which can usually be seen after 1 night of sleep loss, do not result from impaired sensory registration of items. Observed decrements may result from decreased ability to encode,44 from an increasing inability to rehearse old items (due to lapses) while the items are being presented, or from a combination of memory effects with reduced ability to respond. Deficits have been shown in both explicit/declarative memory and procedural/implicit memory.44 E XECUTIVE FUNCTION Increasing behavioral and physiologic data implicate loss of function in prefrontal brain areas during sleep loss. Prefrontal areas are heavily involved in divergent thinking, temporal memory (planning, prioritization, organization), and novelty. Numerous studies have shown deficits on these tasks during sleep loss. One study45 has shown decreased ability to make emotional judgments after total sleep loss. Another aspect of prefrontal behavior is related to risk taking. Studies have shown a shift toward accepting short-term rewards even when long-term consequences were more severe after sleep loss.46 S UBJECTIVE (VERSUS OBJECTIVE) MEASURES Measures of mood such as sleepiness, fatigue, and ability to think or concentrate are inversely correlated with performance and body temperature during sleep loss. Mood changes occur early, are easy to measure, and are prominent. E EG MEASURES Clear EEG changes are seen during sleep loss (see Neurologic Changes, later). The MSLT, a standard test developed as an objective measure of sleepiness, was validated,



in part, by being shown to be sensitive to several types of partial and total sleep loss.47 That the MSLT is more sensitive than psychomotor tasks can be seen in Figure 5-1, which displays performance changes in terms of the number of symbol substitutions correctly completed in 5-minute test periods and MSLT data.15 Summary Tasks most affected by sleep loss are long, monotonous, without feedback, externally paced, newly learned, and have a memory component. One example of a task containing many of these elements is driving, which was discussed earlier in reference to the effects of alcohol. Since 1994, more than 20 studies have examined the impact of reduced sleep on various measures of driving ability or safety. One study,48 for example, found that 49% of medical residents who worked on call and averaged 2.7 hours of sleep reported falling asleep at the wheel (90% of the episodes were after being on call). The residents also had 67% more citations for moving violations and 82% more car accidents than the control group.48

PHYSIOLOGIC EFFECTS OF SLEEP DEPRIVATION Physiologic changes that occur during sleep loss can be categorized into neurologic (including EEG), autonomic, genetic, biochemical, and clinical changes. Physiologic and biochemical effects of sleep deprivation were extensively reviewed by Horne.49 Neurologic Changes Although it is easy to identify a sleep-deprived individual by appearance and to demonstrate obvious behavioral changes, measurable neurologic changes during sleep loss are relatively minor and quickly reversible. In extended sleep loss studies (205 or more hours), mild nystagmus, hand tremor, intermittent slurring of speech, and ptosis have been noted.50 Sluggish corneal reflexes, hyperactive gag reflex, hyperactive deep tendon reflexes, and increased sensitivity to pain were reported after deprivation that is more extensive. All of these changes reversed immediately after recovery sleep. Sleep loss is consistently accompanied by characteristic EEG changes.51 In careful studies, subjects have been required to stand or to be involved in tasks in an attempt to stabilize arousal level. Several studies have reported a generally linear decrease in alpha activity during sleep loss. Subjects were unable to sustain alpha activity for longer than 10 seconds after 24 hours of sleep loss, and this ability continued to decline to 4 to 6 seconds after 72 hours, and 1 to 3 seconds after 120 hours of sleep loss.52 After 115 hours of sleep loss, eye closure failed to produce alpha activity. In another study, in which individuals were recorded standing with their eyes closed, the percentage of time spent with an alpha pattern in the EEG decreased from 65% in the early deprivation period to about 30% after 100 hours of sleep loss.53 Delta and theta activity in the waking EEG were increased from 17% and 12% of the time to 38% and 26% of the time, respectively.53 The increase in delta activity was most pronounced in frontal areas in younger subjects. Performance errors during sleep

CHAPTER 5  •  Acute Sleep Deprivation  59

loss were usually accompanied by a slowing of the EEG54 that was labeled a “microsleep.” Imaging Studies Global decreases in brain activation correlated with increasing sleep loss have been found using positron emission tomography (PET). Larger decreases were found in prefrontal, parietal, and thalamic areas.55 Several fMRI studies have examined the activity in prefrontal cortex and parietal lobes after sleep loss56 that was measured while subjects performed various tasks. In some studies of verbal tasks, activity in these areas increases with task difficulty and after sleep loss as long as performance level is maintained, which has been interpreted as representing increased effort after sleep loss.56 However, studies that have found declines in performance or examined subjects with poor performance after sleep loss have reported decreases in parietal activation during the performance.31,57 These fMRI results suggest that imaging patterns could predict performance deficits during sleep loss. Clinical EEG Although the neurologic changes associated with significant sleep loss are relatively minor in normal young adults, sleep loss has repeatedly been shown to be a highly activating stress in individuals suffering seizure disorders, perhaps by reduction of central motor inhibition.58 Using a period of sleep loss as a “challenge” to elicit abnormal EEG events is currently a standard neurologic test.58 Autonomic Changes In humans, autonomic changes, even during prolonged periods of sleep loss, are relatively minor. Individual studies have reported either increases or decreases in systolic blood pressure, diastolic blood pressure, finger pulse volume, heart rate, respiration rate, and tonic and phasic skin conductance. However, the majority of 10 to 15 studies have reported no change in these variables during sleep loss in humans.49 It has been suggested that these variable findings could be explained in part by measurement circumstances. Those studies that have had more strict activity controls and have made measurements from recumbent subjects have been more likely to find evidence for decreased or no change in activation, whereas studies of sitting or more active participants have tended to find increases in these parameters.59 There may be about a 20% reduction in response to hypoxia and hypercapnia60 during sleep deprivation. However, this reduction was suggestive of a transient setpoint change rather than system failure. Sleep deprivation has been associated with small decreases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in patients with pulmonary disease.61 Both a study of infants61a and one of adults62 have shown more apneic events61a and longer apneic events after sleep loss. Brooks and colleagues63 have shown that apneas become longer as a function of the sleep fragmentation produced by the apneas (as opposed to the respiratory pathology). Several studies in humans have found a small overall decrease (0.3° to 0.4° C) in body temperature during sleep loss.2,64 Changes in thermoregulation have been described as heat retention deficits. Much larger changes

60  PART I / Section 1  •  Normal Sleep and Its Variations

in thermoregulation producing huge increases in energy expenditure have been found in rats after longer periods of sleep deprivation (see Chapter 28).65 No sleep deprivation–related changes in whole-body metabolism were found at normal temperatures and in a cold-stress situation.66 This finding in humans is of particular interest because a series of elegant studies in rats has shown that after a week of sleep loss, metabolic levels are greatly increased, increased food consumption is accompanied by significant weight loss, and significant difficulty with thermoregulation is apparent.65 Several studies have examined aspects of brain metabolism in animals during short periods of sleep deprivation. Direct measures of brain metabolic rate were not different after a short period of sleep deprivation,67 although several related enzymes did differ. However, some of the noted differences could have been related to stress rather than sleep deprivation. Biochemical Changes Several studies (10 or more for some variables) have examined various biochemical changes in humans during sleep loss. There is generally no significant change in cortisol,68 adrenaline and related compounds, catecholamine output,66,69 hematocrit,70 plasma glucose,70 creatinine,66 or magnesium66 during sleep loss. Results from analyses of blood components largely parallel the results found in urine components. None of the adrenal or sex hormones (including cortisol, adrenaline, noradrenaline, luteinizing hormone, follicle-stimulating hormone, variants of testosterone, and progesterone) rises during sleep deprivation in humans.68 Some of these hormones actually decreased somewhat during sleep loss, perhaps as a result of sleepiness and decreased physiologic activation. Thyroid activity, as indexed by thyrotropin, thyroxine, and triiodothyronine, was increased, probably as a result of the increased energy requirements of continuous wakefulness.71 Studies appear about equally divided between those showing an increase in melatonin and no change in melatonin during sleep deprivation.72 A finding of decreased melatonin in young adults after sleep deprivation suggested that earlier findings of increased melatonin may have been related to lack of control for posture, activity, and light.73 Most studies have concluded that there is no significant change in hematocrit levels,66 erythrocyte count, or plasma glucose during total sleep deprivation in humans.70 As would be expected, hormones such as noradrenaline, prolactin, ghrelin, and growth hormone, which are dependent on sleep for their circadian rhythmicity or appearance, lose their periodic pattern of excretion during sleep loss (see reference 74 for review). Rebounds in growth hormone and adrenocorticotropic hormone (ACTH) during recovery sleep are seen after sleep loss or SWS deprivation.75 Gene Studies A recent review of gene expression has described a number of changes that occur during wakefulness and extended wakefulness76 (see Chapter 15). A number of genes expressed during wakefulness that regulate mitochondrial activity and glucose transport probably reflect increased energy use while awake. However, as sleep

deprivation progresses, one gene, for the enzyme arylsulfotransferase (AST), showed stronger induction as a function of length of sleep deprivation. AST induction could reflect a homeostatic response to continuing central noradrenergic activity during sleep loss,76 and this might imply a role for sleep in reversing activity of brain catecholaminergic systems.77 In another approach, a gene named Sleepless was identified as required for sleep in Drosophila. Flies with significant reduction in Sleepless protein had reduced sleep and sleepiness before and after sleep deprivation.78 Clinical Changes Immune Function A number of studies in humans have examined various aspects of immune function after varying periods of partial or total sleep loss (see Chapter 25). Several studies have found decreases in natural killer (NK) cell numbers after short periods of sleep deprivation,79 but increases after longer periods of sleep loss. Some studies have shown increases in interleukin (IL)-179 and IL-680 during total sleep loss. In general, immune function studies are difficult to compare because parameters measured, time and number of blood draws, and degree of sleep deprivation vary across studies. At a more macroscopic level, one study reported the development of respiratory illness or asthma in three subjects after a 64-hour sleep deprivation protocol,81 whereas another reported no incidence of illness after a similar protocol.79 In longer studies involving strenuous exercise and other factors along with sleep loss, increased infection rates are reported about 50% of the time.82 One animal study has suggested that mice immunized against a respiratory influenza virus responded to that virus as if they had never been immunized, only when exposed after sleep loss.83 However, in another study,84 total sleep loss actually slowed the progression of a viral infection in mice. An extensive study of sleep loss in rats (7 to 49 days) was unable to show significant changes in spleen cell numbers, mitogen responses, or in vivo or in vitro splenic antibody-secreting cell responses.85 Pain Increased sensitivity to pain has been an incidental finding in sleep deprivation research for many years, but 10 studies have now made specific pain measurements in several conditions of partial, sleep stage, or total sleep deprivation. Initial studies linked increased pain to SWS but not rapid eye movement (REM) deprivation. Later studies showed that total sleep deprivation decreased pressure pain or heat pain tolerance. However, the most recent studies86,87 found effects for REM-stage deprivation not found earlier, and they split on the effectiveness of total sleep deprivation. One study,87 which found increased pain sensitivity after disturbed sleep compared with reduced sleep, suggested that all of the pain findings associated with sleepstage deprivation may actually have been caused by the sleep fragmentation necessary to produce sleep-stage deprivation. Another study has reported increased pain sensitivity to esophageal acid perfusion, specifically in patients with gastroesophageal reflux disease (but not controls) after sleep reduced to 3 hours or less for 1 night.88



Weight Control and Insulin There are numerous reports of increased sympathetic activity, impaired glucose tolerance, and weight gain associated with chronic partial sleep deprivation (see Chapter 6), but, remarkably, these effects have not been replicated following total sleep deprivation. One study, in a small group of subjects, before and after 1 night of total sleep deprivation found no increase in cortisol, blood glucose, insulin, ACTH, catecholamines, or lactate.90 This study did report a decrease in basal glucagon, possibly linked to pancreatic islet secretion and increased hunger. From such reports, it is unclear whether the results reported from chronic partial sleep deprivation are related to increased or chronic stress or whether time of sampling may play a role. Exercise Effects of sleep loss on the ability to perform exercise are subtle. Animal studies have consistently shown that sleep deprivation decreases spontaneous activity by up to 40%,91 but most human studies have focused on maximal exercise ability, where large differences as a function of sleep loss are more difficult to demonstrate. For example, one study92 reported a 7% decrease in maximum oxygen  O 2max ) during 64 hours of sleep loss. This uptake ( V change was not associated with heart rate, respiratory exchange ratio, or blood lactate, which remained unchanged. Recovery from exercise may be slowed by sleep loss. Studies are evenly divided between claims that the amplitude of the circadian rhythm of temperature is increased, decreased, or unchanged during sleep loss.49 Summary A large number of studies have reported autonomic, biochemical, and immune function variables during sleep loss. Many of the older studies were based on single observation points before and after sleep loss. Many studies suffer from poor activity controls (use of activity to maintain wakefulness may produce or mask changes in underlying variables of interest). More recent studies have been able to make use of sampling as often as once per hour and have begun to consider circadian and activity effects. For example, NK cell numbers were increased93 during the night when subjects remained awake (compared with a sleep control) but were then decreased on the following afternoon, with the result that numbers averaged across the entire study were the same in sleep loss and baseline conditions. This means that a study could find an increase, a decrease, or the same number of NK cells based on the time of sampling. In a similar manner, it has been found that IL-6 was decreased during a night of sleep deprivation compared with the sleep control but increased compared with control during the next day, so that numbers averaged across the entire study were, again, about the same.

SLEEP FRAGMENTATION Sleep is a time-based cumulative process that can be impeded both by deprivation and by systematic disturbance. A number of studies have shown that very brief periodic arousals from sleep reduce the restorative power of sleep and leave deficits similar to those seen after total sleep deprivation.94 Experimental Sleep Fragmentation Many studies have examined the relationship between various empiric schedules of sleep fragmentation and residual sleepiness on the following day. Data from eight studies are plotted in Figure 5-2. There is a strong relationship (r = .775, P < .01) between rate of fragmentation (plotted as minutes of sleep allowed between disturbances) and decrease in sleep latency on the following day as measured by MSLT.94 As expected, increased sleepiness after sleep fragmentation was also associated with decreased psychomotor performance on a broad range of tasks,95 and with degraded mood.94 Studies have been carefully designed to produce brief EEG arousals or even “nonvisible” EEG sleep disturbance, with the result that there are few96 in standard sleep EEG parameters despite the periodic sleep fragmentation. With preservation of normal-EEG sleep amounts, participants were still significantly sleepier on the day after sleep fragmentation. In another approach, fragmentation rates, consolidated sleep periods, and SWS amounts were experimentally varied in participants in an attempt to tease out sleep stage versus fragmentation effects, with similar

1.1 1.0 Proportion of baseline MSLT

This suggests that individual differences could also play a role in the modulation of pain. Animal studies have replicated findings of increasing pain sensitivity after REM deprivation and showed that pain sensitivity remained elevated even after low dosages of morphine and 24 hours of recovery sleep.89

CHAPTER 5  •  Acute Sleep Deprivation  61

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0

2

4

6

8

10

12

14

16

18

20

Length of sleep allowed (min) Figure 5-2  Proportion of baseline multiple sleep latency test (MSLT) value (i.e., sleep latency after fragmentation nights divided by sleep latency after baseline) in eight sleep fragmentation studies (two separate fragmentation conditions were identified in three studies), plotted as a function the amount of sleep time allowed until disturbance (e.g., “2” means that subjects were aroused briefly after each 2 minutes of sleep). (From Bonnet MH, Arand DL. Clinical effects of sleep fragmentation versus sleep deprivation. Sleep Med Rev 2003;7:297-310.)

62  PART I / Section 1  •  Normal Sleep and Its Variations

conclusions—residual sleepiness was more related to the sleep fragmentation than to sleep-stage parameters.94 Other studies have directly compared the impact of relatively high rates of sleep fragmentation (usually disturbance every 1 to 2 minutes) with the effect of total sleep deprivation in the same study. In one study, profiles of cortisol and ACTH were similar during total sleep deprivation and sleep fragmentation.97 In other studies,94 MSLT was decreased to similar low values after both total sleep deprivation and high-frequency sleep fragmentation. A significant increase in apnea-hypopnea index was found after both sleep fragmentation and sleep deprivation, and this increase was actually greater after sleep fragmentation.94 These findings of similar impacts on hormones, respiratory parameters, psychomotor performance, and objective sleepiness after similar periods of sleep deprivation and sleep fragmentation indicate that there is much in common between the high-frequency sleep fragmentation and total sleep deprivation. Clearly, the restorative function of sleep is impaired by high rates of sleep fragmentation. However, as indicated by Figure 5-2, the impact of periodic sleep fragmentation decreases rapidly as the intervals between arousals increase, and this may imply that normal restoration during sleep requires periods of consolidated sleep of 10 to 20 minutes.94 Recovery sleep following high rates of sleep fragmentation is characterized by rebounds of SWS and REM sleep like that seen after total sleep deprivation. In addition, recovery sleep after sleep fragmentation and sleep deprivation is notable for decreased arousals.98 A broad range of physiologic indices have been examined as possible measures of sleep fragmentation.94 A number of respiratory, cardiac, and alternative EEG measures have been examined, with the general conclusion that most of these physiologic measures, including traditional arousals, are moderately correlated with daytime sleepiness. However, much empirical work needs to be done to determine the extent to which these other physiologic measures are simply correlates of EEG arousals rather than new measures of sleep continuity. A physiologic event more specific than the EEG arousal remains to be identified. New animal models of sleep fragmentation in rats have revealed decreases in hippocampal neurogenesis and increases in basal forebrain adenosine to levels found after similar amounts of total sleep deprivation.99 Sleep Disorders and Fragmentation The earliest study of sleep fragmentation in dogs documented impaired arousal responses to hypercapnia and hypoxia during sleep.100 Further studies following dogs with experimentally produced apnea or sleep fragmentation for periods of more than 4 months showed that both the sleep fragmentation procedure and the experimentally produced apnea produced increased time to arousal as well as greater oxygen desaturation, greater peak inspiratory pressure, and greater surges in blood pressure in response to airway occlusion. It was concluded that the sleep fragmentation alone was responsible for the sleepiness symptoms associated with sleep apnea, and “the changes in the acute responses to airway occlusion resulting from OSA (obstructive sleep apnea) are

primarily the result of the associated sleep fragmentation.”63, p. 1609 Other clinical studies have documented that the number of brief arousals is significantly correlated with the magnitude of daytime sleepiness in groups of patients.94 Traditional sleep-stage rebounds (see Recovery Sleep, next) are seen when the pathology is corrected. After effective treatment of sleep apnea and the corresponding decrease in frequency of arousals during sleep, alertness was improved as measured by either MSLT or reduction in traffic accidents.101 There are many other instances of sleep fragmentation as a component in both medical illnesses (such as fibrositis, intensive-care-unit syndrome, chronic movement disorders, and chronic pain disorders) and life requirements (infant care, medical residents). Some of these impositions may not produce the critical number of arousals required for significant decrements in the apnea patients and in sleep fragmentation studies. However, most of these situations are a combination of chronic partial sleep loss and chronic sleep fragmentation.

RECOVERY SLEEP Sleep is all that is required to reverse the effects of sleep deprivation in almost all circumstances. The EEG characteristics of recovery sleep depend on the amount of prior wakefulness and the circadian time. These effects have been successfully modeled (see Chapter 37). Performance Effects Several efforts have been made to assess recovery of performance after sleep deprivation. It is commonly reported that recovery from periods of sleep loss of up to 10 days and nights is rapid and can occur within 1 to 3 nights. Several studies have reported recovery of performance after a single night (usually 8 hours) of sleep following anywhere from 40 to 110 hours of continuous wakefulness.5 Such experiments suggest that an equal amount of sleep is not required to recover from sleep lost. However, sleep deprivation itself was typically the main concern of these studies and, therefore, recovery was given minimal attention. One study specifically examined the rate of performance recovery during sleep in young adults, normal older subjects, and insomniacs after 40- and 64-hour sleep loss periods.27 Participants were awakened from stage 2 sleep for 20-minute test batteries approximately every 2 hours during baseline and recovery nights. Therefore, it was possible to follow the time course of return to baseline performance during recovery sleep in the three groups. In normal young adults, reaction time returned to levels not significantly less than baseline after 4 hours of sleep during recovery sleep following 40 hours of sleep loss. However, reaction time remained significantly slower than baseline in young adults throughout the first night of recovery sleep (including the postsleep morning test) following 64 hours of sleep loss. In contrast, reaction time in both older normal sleeper and insomniac groups was significantly slower than baseline at 5:30 am but had returned to baseline levels by 8:00 am after the first recovery night after 64 hours of sleep loss. The young adults not only recovered more slowly from sleep loss on the initial recovery night



CHAPTER 5  •  Acute Sleep Deprivation  63

Table 5-1  Effects of Sleep Loss on Stages of Recovery Sleep SLEEP LOSS: 40 HR YOUNG ADULTS (SD) Sleep latency

0.38 (0.09)

OLDER ADULTS (SD) —

DEPRESSED ADULTS

DEMENTED ADULTS

0.22

0.14

SLEEP LOSS: 64 HR SHORT SLEEPERS —

LONG SLEEPERS —

OLDER NORMAL SUBJECTS —

OLDER INSOMNIAC PATIENTS —

Wake time

0.44 (0.19)

0.51 (0.11)

—

—

0.13

0.48

—

—

Stage 1

0.42 (0.12)

0.59 (0.14)

0.61

0.68

0.98

0.60

0.56

0.52 1.20

Stage 2

0.87 (0.10)

0.95 (0.07)

1.06

1.08

1.38

0.99

1.07

Stage 3

0.98

1.32 (0.25)

1.14

1.16

—

—

2.36

3.00

Stage 4

2.40

2.06 (0.45)

1.35

1.12

—

—

7.00

5.25

Slow-wave sleep stage

1.53 (0.11)

1.56 (0.23)

1.23

1.15

1.37

1.52

2.56

3.30

REM sleep stage

0.89 (0.13)

1.04 (0.09)

0.84

0.78

1.26

1.03

0.26

0.92

REM sleep latency

1.01 (0.20)

0.77 (0.20)

2.2

2.0

1.13

1.26

0.35

0.96

The values presented in this table are the mean percentages of baseline levels of the indicated sleep stages for the indicated groups during the first sleep recovery night. Where sufficient studies were available, the standard deviation around the mean percentage is also given (SD). For example, on their recovery night after 1 night of sleep loss, young adults have a sleep latency that is 38% ± 9% of their baseline sleep latency. (See text for references.)

but also had some decrease in their reaction times that extended into the second recovery night. This result is consistent with other data showing that older subjects had daytime MSLT values at baseline levels following sleep loss and a single night of recovery sleep, whereas shorterthan-normal latencies continued in young adults.102 EEG Effects A large number of studies have reported consistent effects on sleep EEG when totally sleep deprived individuals are finally allowed to sleep. If undisturbed, young adults typically sleep only 12 to 15 hours, even after 264 hours of sleep loss.103 If sleep times are held to 8 hours on recovery nights, effects on sleep stages may be seen for 2 or more nights. The effects of 40 and 64 hours of sleep loss on recovery sleep stages during the initial recovery night are summarized in Table 5-1 for normal young adults,47,104-107 young adult short sleepers,108 young adult long sleepers,108 60- to 80-year-old normal sleepers,102,109,110 60- to 70-year-old chronic insomniacs,109,111 and 60- to 80-year-old depressed and demented patients.112,113 The table presents percentage change from baseline data, with an indication of studyto-study variability where the number of studies allowed computation. The table is presented as a summary device so that EEG effects of sleep deprivation can be predicted (roughly by multiplying population baseline values by figures presented in the table), and so that the potential differential effects of sleep deprivation on EEG recovery sleep as a function of group can be more clearly seen. The results of these several studies indicate that recovery sleep EEG changes that occur as a function of sleep deprivation are remarkably consistent across studies and across several experimental groups including men, women, older subjects, and older insomniacs. Significant deviations from population recovery values are seen primarily in REM latency changes in depressed and demented patients, and

secondarily in some less robust differences found in small groups of long and short sleepers. These latter findings might be related to differential sleep-stage distributions secondary to long or short sleep times. On the first recovery night after total sleep loss, there is a large increase in SWS over baseline amounts.70,111 As would be expected, wake time and stage 1 sleep are usually reduced. Stage 2 and REM sleep may both be decreased on the first recovery night after 64 hours of sleep loss,27,47 at least in young adults, as a function of increased SWS. In older normal sleepers and insomniacs, there is less absolute increase in SWS than in young adults on the first recovery night, although the percentage increase in SWS may be as great. Because there is less SWS rebound, there may be no change (geriatric normals) or even an increase in stage 2.27,113 Normal older individuals had a decrease in REM latency during recovery sleep102,109,113 rather than the increased REM latency common in young adults. It was found that REM latency in the older population was positively correlated with baseline SWS amounts109,113 and that sleep-onset REM periods occurred in about 20% of those carefully screened normal subjects.109,113 These REM changes were interpreted to be the result of decreased pressure for SWS in older humans. The REM latency findings did not apply to older depressed or demented individuals. REM rebound effects appear to be related to the amount of lost SWS, so that REM rebound is more likely on an early recovery night when there is less SWS loss as a function of either a shorter period of sleep loss or age. On the second recovery night after total sleep loss, SWS amounts approached normal values, and an increase in REM sleep was found in young adults.47 Total sleep time was still elevated. By the third recovery night, all sleep EEG values approached baseline. In situations where REM rebounds on the first sleep-recovery night, sleep EEG values may normalize by the second recovery night.

64  PART I / Section 1  •  Normal Sleep and Its Variations

Exceptions to these general rules may include older insomniacs, who have increased total sleep for at least 3 nights after 64 hours of sleep loss27 and individuals who have had significant selective REM deprivation. Relationship between EEG and Psychomotor Performance Recovery Effects The increase in SWS during recovery from sleep loss leads to the speculation that SWS is implicated in the sleep recovery process. Unfortunately, human studies designed to test this hypothesis directly by experimentally varying the amount of SWS during the recovery sleep period or during a sleep fragmentation period have not implicated any sleep stages as central in the recovery process.114 However, these studies were not designed to look for more subtle effects that might have occurred in the initial recovery night. Studies have also examined recovery of alertness and performance after total sleep deprivation for 1 or 2 nights. An early study that examined performance recovery in the sleep period found recovery of response speed to baseline levels after 1 night of recovery sleep following 40 hours of sleep loss and recovery to baseline levels during the second night of recovery sleep following 64 hours of sleep loss.115 More recent studies with larger groups of subjects have reported that simple response speed had recovered to baseline levels after 1 night of recovery sleep following 64 hours of sleep loss in one study116 but did not recover to baseline levels even after 5 recovery nights in a second study.117 MSLT was still significantly shorter after 1 night of recovery sleep following both 1 and 2 nights of total sleep loss.116,117 One study reported recovery for the MSLT after a second night of recovery sleep following 64 hours of sleep loss,116 but the second study did not.117

CONCLUSIONS The physiologic and behavioral effects of sleep loss in humans are consistent and well defined. There is a physiologic imperative to sleep in man and other mammals, and the drive to sleep can be as strong as the drive to breathe. Future work should (1) examine in more detail the physiologic microstructure of the sleep process and its relationship to sleep restoration, (2) reconcile response differences among species, (3) examine differences in response to sleep deprivation in normal and depressed humans, and (4) further explore the interaction of the sleep and the arousal systems, (5) examine impact in specific occupations.118

❖  Clinical Pearl The impact of sleep deprivation on performance and physiology has been examined in thousands of studies for over a hundred years. These findings might not seem directly relevant in a clinical sense, but it should be remembered that the clinical diagnosis of insufficient sleep syndrome is based on sleep deprivation. Sleepiness symptoms secondary to sleep apnea and periodic limb movements (sleep fragmentation) also evolve from sleep deprivation.

Acknowledgements Supported by the Medical Research Service of the Dayton Department of Veterans Affairs Medical Center and Wright State University, Dayton, Ohio. Literature searches were supported by the Sleep-Wake Disorders Research Institute, Dayton, Ohio. REFERENCES 1. Manaceine M. Quelques observations experimentales sur l’influence de l’insomnie absolue. Arch Ital Biol 1894;21:322-325. 2. Patrick GTW, Gilbert JA. On the effect of loss of sleep. Psychol Rev 1896;3:469-483. 3. Mikulincer M, Babkoff H, Caspy T, Sing H. The effects of 72 hours of sleep loss on psychological variables. Br J Psychol 1989;80: 145-162. 4. Bonnet MH, Arand DL. Sleep latency testing as a time course measure of state arousal. J Sleep Res 2005;14:387-392. 5. Lubin A, Hord DJ, Tracy ML, et al. Effects of exercise, bedrest and napping on performance decrement during 40 hours. Psychophysiology 1976;13:334-339. 6. Bonnet MH, Arand DL. Level of arousal and the ability to maintain wakefulness. J Sleep Res 1999;8:247-254. 7. Yokoi M, Aoki K, Shimomura Y, et al. Exposure to bright light modifies HRV responses to mental tasks during nocturnal sleep deprivation. J Physiol Anthropol 2006;25:153-161. 8. Wilkinson RT. Interaction of noise with knowledge of results and sleep deprivation. J Exp Psychol 1963;66:332-337. 9. Poulton EC, Edwards RS, Colquhoun WP. The interaction of the loss of a night’s sleep with mild heat: task variables. Ergonomics 1974;17:59-73. 10. Reyner LA, Horne JA. Evaluation of “in-car” countermeasures to sleepiness: cold air and radio. Sleep 1998;21:46-50. 11. Bonnet MH, Arand DL. Arousal components which differentiate the MWT from the MSLT. Sleep 2001;24:441-450. 12. Bonnet MH, Balkin TJ, Dinges DF, et al. The use of stimulants to modify performance during sleep loss: a review by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep 2005;28:1163-1187. 13. Wesensten J, Belenky G, Kautz MA, et al. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 2002;159:238-247. 14. Wesensten NJ, Killgore WD, Balkin TJ. Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. J Sleep Res 2005;14:255-266. 15. Bonnet MH, Gomez S, Wirth O, et al. The use of caffeine versus prophylactic naps in sustained performance. Sleep 1995;18:97-104. 16. Bonnet MH, Arand DL. The use of prophylactic naps and caffeine to maintain performance during a continuous operation. Ergonomics 1994;37:1009-1020. 17. Wright KP, Badia P, Myers BL, et al. Combination of bright light and caffeine as a countermeasure for impaired alertness and performance during extended sleep deprivation. J Sleep Res 1997; 6:26-35. 18. Dinges DF, Arora S, Darwish M, et al. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin 2006;22:159-167. 19. Newhouse PA, Penetar DM, Fertig JB, et al. Stimulant drug effects on performance and behavior after prolonged sleep deprivation: a comparison of amphetamine, nicotine, and deprenyl. Mil Psychology 1992;4:207-233. 20. Fischman MW, Schuster CR. Cocaine effects in sleep-deprived humans. Psychopharmacology 1980;72:1-8. 21. Roehrs T, Beare D, Zorick F, et al. Sleepiness and ethanol effects on simulated driving. Alcohol Clin Exp Res 1994;18:154-158. 22. Arnedt JT, Wilde GJ, Munt PW, et al. How do prolonged wakefulness and alcohol compare in the decrements they produce on a simulated driving task? Accid Anal Prev 2001;33:337-344. 23. Horne JA, Pettitt AN. High incentive effects on vigilance performance during 72 hours of total sleep deprivation. Acta Psychologica 1985;58:123-139. 24. Haslam DR. The incentive effect and sleep deprivation. Sleep 1983;6:362-368.



CHAPTER 5  •  Acute Sleep Deprivation  65 25. Baranski JV, Thompson MM, Lichacz FM, et al. Effects of sleep loss on team decision making: motivational loss or motivational gain? Hum Factors 2007;49:646-660. 26. Webb WB, Levy CM. Effects of spaced and repeated total sleep deprivation. Ergonomics 1984;27:45-58. 27. Bonnet MH, Rosa RR. Sleep and performance in young adults and older insomniacs and normals during acute sleep loss and recovery. Biol Psychol 1987;25:153-172. 28. Adam M, Retey JV, Khatami R, et al. Age-related changes in the time course of vigilant attention during 40 hours without sleep in men. Sleep 2006;29:55-57. 29. Leproult R, Colecchia EF, Berardi AM, et al. Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated. Am J Physiol Regul Integr Comp Physiol 2003;284:R280-R290. 30. Mu Q, Mishory A, Johnson KA, et al. Decreased brain activation during a working memory task at rested baseline is associated with vulnerability to sleep deprivation. Sleep 2005;28:433-446. 31. Chee MW, Chuah LY, Venkatraman V, et al. Functional imaging of working memory following normal sleep and after 24 and 35 h of sleep deprivation: correlations of fronto-parietal activation with performance. Neuroimage 2006;31:419-428. 32. Retey JV, Adam M, Gottselig JM, et al. Adenosinergic mechanisms contribute to individual differences in sleep deprivation-induced changes in neurobehavioral function and brain rhythmic activity. J Neurosci 2006;26:10472-10479. 33. Viola AU, Archer SN, James LM, et al. PER3 Polymorphism predicts sleep structure and waking performance. Curr Biol 2007; 17:613-618. 34. Groeger JA, Viola AU, Lo JCY, et al. Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. Sleep 2008;31:1159-1167. 35. Mullaney DJ, Kripke DF, Fleck PA, et al. Sleep loss and nap effects on sustained continuous performance. Psychophysiol 1983;20: 643-651. 36. Johnson LC. Physiological and psychological changes following total sleep deprivation. In: Kales A, editor. Sleep physiology and pathology. Philadelphia: JB Lippincott; 1969. p. 206-220. 37. Kahn-Greene ET, Killgore DB, Kamimori GH, et al. The effects of sleep deprivation on symptoms of psychopathology in healthy adults. Sleep Med 2007;8:215-221. 38. Wu JC, Buchsbaum M, Bunney W, et al. Antidepressant effects. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 421-430. 39. Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: a meta-analysis. Sleep 1996;19:318-326. 40. Donnell JM. Performance decrement as a function of total sleep loss and task duration. Percept Mot Skills 1969;29:711-714. 41. Wilkinson RT. Interaction of lack of sleep with knowledge of results, repeated testing, and individual differences. J Exp Psychol 1961;62:263-271. 42. Light AI, Sun JH, McCool C, et al. The effects of acute sleep deprivation on level of resident training. Curr Surg 1989;46:29-30. 43. Alluisi EA, Coates GD, Morgan BBJ. Effects of temporal stressors on vigilance and information processing. In: Mackie RR, editor. Vigilance: theory, operational performance, and physiological correlates. New York: Plenum Press; 1977. p. 361-421. 44. Forest G, Godbout R. Attention and memory changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 199-222. 45. Killgore WD, Killgore DB, Day LM, et al. The effects of 53 hours of sleep deprivation on moral judgment. Sleep 2007;30:345-352. 46. McKenna BS, Dicjinson DL, Orff HJ, Drummond SP. The effects of one night of sleep deprivation on known-risk and ambiguous-risk decisions. J Sleep Res 2007;16:245-252. 47. Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skill 1979;48:495-506. 48. Marcus CL, Loughlin GM. Effect of sleep deprivation on driving safety in housestaff. Sleep 1996;19:763-766. 49. Horne JA. A review of the biological effects of total sleep deprivation in man. Biol Psychol 1978;7:55-102. 50. Kollar EJ, Namerow N, Pasnau RO, et al. Neurological findings during prolonged sleep deprivation. Neurology 1968;18:836-840. 51. Finelli LA. Cortical and electroencephalographic changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 223-264.

52. Rodin EA, Luby ED, Gottleib JS. The EEG during prolonged experimental sleep deprivation. Electroencephalogr Clin Neurophysiol 1962;14:544-551. 53. Naitoh P, Pasnau RO, Kollar EJ. Psychophysiological changes after prolonged deprivation of sleep. Biol Psychiatry 1971;3:309-320. 54. Williams HL, Granda AM, Jones RC, et al. EEG frequency and finger pulse volume as predictors of reaction time during sleep loss. Electroencephalogr Clin Neurophysiol 1962;14:64-70. 55. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335-352. 56. Drummond SP, Brown GG, Salamat JS, et al. Increasing task difficulty facilitates the cerebral compensatory response to total sleep deprivation. Sleep 2004;27:445-451. 57. Lim J, Choo WC, Chee MW. Reproducibility of changes in behaviour and fMRI activation associated with sleep deprivation in a working memory task. Sleep 2007;30:61-70. 58. Scalise A, Desiato MT, Gigli GL, et al. Increasing cortical excitability: a possible explanation for the proconvulsant role of sleep deprivation. Sleep 2006;29:1595-1598. 59. Zhong X, Hilton HJ, Gates GJ, et al. Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol 2005;98: 2024-2032. 60. White DP, Douglas NJ, Pickett CK, et al. Sleep deprivation and the control of ventilation. Am Rev Respir Dis 1983;128:984-986. 61. Phillips BA, Cooper KR, Burke TV. The effect of sleep loss on breathing in chronic obstructive pulmonary disease. Chest 1987; 91:29-32. 61a.  Canet E, Gaultier C, D’Allest AM, et al. Effects of sleep deprivation on respiratory events during sleep in healthy infants. J Appl Physiol 1989;66:1158-1163. 62. Persson HE, Svanborg E. Sleep deprivation worsens obstructive sleep apnea. Comparison between diurnal and nocturnal polysomnography. Chest 1996;109:645-650. 63. Brooks D, Horner RL, Kimoff RJ, et al. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Respir Crit Care Med 1997;155:1609-1617. 64. Minors D, Waterhouse J, Akerstedt T, et al. Effect of sleep loss on core temperature when movement is controlled. Ergonomics 1999;42:647-656. 65. Shaw PJ. Thermoregulaory changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 319-338. 66. Fiorica V, Higgins EA, Iampietro PF, et al. Physiological responses of men during sleep deprivation. J Appl Physiol 1968;24:167-176. 67. Van Den Noort S, Brine K. Effect of sleep on brain labile phosphates and metabolic rate. Am J Physiol 1970;218:1434-1439. 68. Akerstedt T, Palmblad J, de la Torre B, et al. Adrenocortical and gonadal steroids during sleep deprivation. Sleep 1980;3:23-30. 69. Froberg JE. Twenty-four-hour patterns in human performance, subjective and physiological variables and differences between morning and evening active subjects. Biol Psychol 1977;5:119-134. 70. Kollar EJ, Slater GG, Palmer JO, et al. Stress in subjects undergoing sleep deprivation. Psychosom Med 1966;28:101-113. 71. Gary KA, Winokur A, Douglas SD, et al. Total sleep deprivation and the thyroid axis: effects of sleep and waking activity. Aviat Space Environ Med 1996;67:513-519. 72. Goh VH, Tong TY, Lim C, et al. Effects of one night of sleep deprivation on hormone profiles and performance efficiency. Mil Med 2001;166:427-431. 73. Zeitzer JM, Duffy JF, Lockley SW, et al. Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake. Sleep 2007;30:1437-1443. 74. Spiegel K, Leproult R, Van Cauter E. Metabolic and endocrine changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 293-318. 75. Schussler P, Uhr M, Ising M, et al. Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans. Psychoneuroendocrinology 2006;31:915-923. 76. Cirelli C. Functional genomic of sleep and circadian rhythm Invited review: how sleep deprivation affects gene expression in the brain: a review of recent findings. J Appl Physiol 2002;92: 394-400.

66  PART I / Section 1  •  Normal Sleep and Its Variations 77. Cirelli C. Changes in gene expression. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 387-397. 78. Koh K, Joiner WJ, Wu MN, et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 2008;321:372-376. 79. Dinges DF, Douglas SD, Zaugg L, et al. Leukocytosis and natural killer cell function parallel neurobehavioral fatigue induced by 64 hours of sleep deprivation. J Clin Invest 1994;93:1930-1939. 80. Irwin MR, Wang M, Campomayor CO, et al. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 2006;166:1756-1762. 81. Moldofsky H. Central nervous system and peripheral immune functions and the sleep-wake system. J Psychiatr Neurosci 1994;19: 368-374. 82. Boyum A, Wiik P, Gustavsson E, et al. The effect of strenuous exercise, calorie deficiency and sleep deprivation on white blood cells, plasma immunoglobulins and cytokines. Scand J Immunol 1996;43:228-235. 83. Brown R, Pang G, Husband AJ, et al. Suppression of immunity to influenza virus infection in the respiratory tract following sleep disturbance. Regional Immunology 1989;2:321-325. 84. Renegar KB, Crouse D, Floyd RA, et al. Progression of influenza viral infection through the murine respiratory tract: the protective role of sleep deprivation. Sleep 2000;23:859-863. 85. Benca RM, Kushida CA, Everson CA, et al. Sleep deprivation in the rat: VII. Immune function. Sleep 1989;12:47-52. 86. Roehrs T, Hyde M, Blaisdell B, et al. Sleep loss and REM sleep loss are hyperalgesic. Sleep 2006;29:145-151. 87. Smith MT, Edwards RR, McCann UD, et al. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep 2007;30:494-505. 88. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787-1795. 89. Nascimento DC, Andersen ML, Hipolide DC, et al. Pain hypersensitivity induced by paradoxical sleep deprivation is not due to altered binding to brain mu-opioid receptors. Behav Brain Res 2007;178:216-220. 90. Schmid SM, Hallschmid M, Jauch-Chara K, et al. Sleep loss alters basal metabolic hormone secretion and modulates the dynamic counterregulatory response to hypoglycemia. J Clin Endocrinol Metab 2007;92:3044-3051. 91. Tobler I, Sigg H. Long-term motor activity recording of dogs and the effect of sleep deprivation. Experientia 1986;42:987991. 92. Plyley MJ, Shephard RJ, Davis GM, et al. Sleep deprivation and cardiorespiratory function. Influence of intermittent submaximal exercise. Eur J Appl Physiol 1987;56:338-344. 93. Born J, Lange T, Hansen K, et al. Effects of sleep and circadian rhythm on human circulating immune cells. J Immunol 1997; 158:4454-4464. 94. Bonnet M. Sleep fragmentation. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 503-513. 95. Stepanski E. The effect of sleep fragmentation on daytime function. Sleep 2002;25:268-276. 96. Martin SE, Wraith PK, Deary IJ, et al. The effect of nonvisible sleep fragmentation on daytime function. Am J Respir Crit Care Med 1997;155:1596-1601.

97. Spath-Schwalbe E, Gofferje M, Kern W, et al. Sleep disruption alters nocturnal ACTH and cortisol secretory patterns. Biol Psychiatry 1991;29:575-584. 98. Sforza E, Chapotot F, Pigeau R, et al. Effects of sleep deprivation on spontaneous arousals in humans. Sleep 2004;27:1068-1075. 99. Guzman-Marin R, Bashir T, Suntsova N, et al. Hippocampal neurogenesis is reduced by sleep fragmentation in the adult rat. Neuroscience 2007;148:325-333. 100. Phillipson EA, Bowes G, Sullivan CE, et al. The influence of sleep fragmentation on arousal and ventilatory responses to respiratory stimuli. Sleep 1980;3:281-288. 101. Cassel W, Ploch T, Becker C, et al. Risk of traffic accidents in patients with sleep-disordered breathing: reduction with nasal CPAP. Eur Respir J 1996;9:2606-2611. 102. Carskadon MA, Dement WC. Sleep loss in elderly volunteers. Sleep 1985;8:207-221. 103. Johnson LC, Slye ES, Dement WC. Electroencephalographic and autonomic activity during and after prolonged sleep deprivation. Psychosom Med 1965;27:415-423. 104. Bonnet MH. The effect of varying prophylactic naps on performance, alertness and mood throughout a 52-hour continuous operation. Sleep 1991;14:307-315. 105. Borbely AA, Baumann F, Brandeis D, et al. Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol 1981;51:483-495. 106. Moses J, Lubin A, Naitoh P, et al. Exercise and sleep loss: effects on recovery sleep. Psychophysiol 1977;14:414-416. 107. Nakazawa Y, Kotorii M, Ohshima M, et al. Changes in sleep pattern after sleep deprivation. Folia Psychiatr Neurol Jpn 1978;32: 85-93. 108. Benoit O, Foret J, Bouard G, et al. Habitual sleep length and patterns of recovery sleep after 24 hour and 36 hour sleep deprivation. Electroencephalogr Clin Neurophysiol 1980;50:477-485. 109. Bonnet MH. Effect of 64 hours of sleep deprivation upon sleep in geriatric normals and insomniacs. Neurobiol Aging 1986;7:89-96. 110. Reynolds CFd, Kupfer DJ, Hoch CC, et al. Sleep deprivation in healthy elderly men and women: effects on mood and on sleep during recovery. Sleep 1986;9:492-501. 111. Bonnet MH, Arand DL. Sleep loss in aging. In: Roth T, Roehrs T, editors. Clinics in geriatric medicine. 1989. p. 405-420. 112. Reynolds CFd, Kupfer DJ, Hoch CC, et al. Sleep deprivation effects in older endogenous depressed patients. Psychiatry Res 1987;21: 95-109. 113. Reynolds CF 3rd, Kupfer DJ, Hoch CC, et al. Sleep deprivation as a probe in the elderly. Arch Gen Psychiatry 1987;44:982-990. 114. Bonnet MH. Performance and sleepiness following moderate sleep disruption and slow wave sleep deprivation. Physiol Behav 1986; 37:915-918. 115. Rosa RR, Bonnet MH, Warm JS. Recovery of performance during sleep following sleep deprivation. Psychophysiol 1983;20:152-159. 116. Beaumont M, Batejat D, Coste O, et al. Recovery after prolonged sleep deprivation: residual effects of slow-release caffeine on recovery sleep, sleepiness and cognitive functions. Neuropsychobiology 2005;51:16-27. 117. Lamond N, Jay SM, Dorrian J, et al. The dynamics of neurobehavioural recovery following sleep loss. J Sleep Res 2007;16:33-41. 118. Malmberg B, Kecklund G, Karlson B, et al. Sleep and recovery in physicians on night call: a longitudinal field study. BMC Health Serv Res 2010;10(1):239.

Chronic Sleep Deprivation Siobhan Banks and David F. Dinges Abstract Chronic sleep deprivation, also referred to as chronic sleep restriction, is common, with a wide range of causes including shift work and other occupational and economic demands, medical conditions and sleep disorders, and social and domestic responsibilities. Sleep dose–response experiments have found that chronic sleep restriction to less than 7 hours per night resulted in cognitive deficits that (1) accumulate (i.e., become progressively worse over time as sleep restriction persists), (2) are sleep-dose sensitive (i.e., the less sleep that is obtained, the faster the rate at which deficits develop), and

Chronic sleep restriction occurs frequently and results from a number of factors, including medical conditions (e.g., pain), sleep disorders, work demands (including extended work hours and shift work), and social and domestic responsibilities. Adverse effects on neurobehavioral functioning accumulate as the magnitude of sleep loss escalates, and the result is an increased risk of on-the-job errors, injuries, traffic accidents, personal conflicts, health complaints, and drug use. Chronic sleep restriction, or partial sleep deprivation, has been thought to occur when one fails to obtain a usual amount of sleep.1,2 Half a century ago, Kleitman first used the phrase sleep debt to describe the circumstances of delaying sleep onset time while holding sleep termination time constant.3 He described the increased sleepiness and decreased alertness in individuals on such a sleep–wake pattern, and proposed that those subjects who were able to reverse these effects by extending their sleep on weekends were able to “liquidate the debt.”3, p. 317 The term sleep debt is usually synonymous with chronic sleep restriction because it refers to the increased pressure for sleep that results from an inadequate amount of physiologically normal sleep.4 To determine the effects of chronic sleep loss on a range of neurobehavioral and physiologic variables, a variety of paradigms have been used, including controlled, restricted time in bed for sleep opportunities in both continuous and distributed schedules,5 gradual reductions in sleep duration over time,6 selective deprivation of specific sleep stages,7 and limiting the time in bed to a percentage of the individual’s habitual time in bed.8 These studies have ranged from 24 hours9 to 8 months6 in length. Many reports published before 1997 concluded that chronic sleep restriction in the range commonly experienced by the general population (i.e., sleep durations of less than 7 hours per night but greater than 4 hours per night) resulted in some increased subjective sleepiness but had little or no effect on cognitive performance capabilities. Consequently, there was a widely held belief that individuals could “adapt” to chronic reductions in sleep duration, down to 4 to 5 hours per day. However, nearly all of these reports of adaptation to sleep loss were limited

Chapter

6

(3) do not result in profound subjective sleepiness or full selfawareness of the cumulative deficits from sleep restriction. The mechanisms underlying the sleep dose–response cumulative neurobehavioral and physiologic alterations during chronic sleep restriction remain unknown. Individual variability in neurobehavioral responses to sleep restriction appear to be as large as those in response to total sleep deprivation and as stable over time, suggesting a traitlike (possibly genetic) differential vulnerability to the effects of chronic sleep restriction or differences in the nature of compensatory brain responses to the growing sleep loss.

by problems in experimental design.8 Since 1997, experiments that have corrected for these methodological weaknesses have found markedly different results from those earlier studies, and have documented cumulative objective changes in neurobehavioral outcomes as sleep restriction progressed.10 This chapter reviews the cognitive and neurobehavioral consequences of chronic sleep restriction in healthy individuals.

INCIDENCE OF CHRONIC SLEEP RESTRICTION Human sleep need, or, more precisely, the duration of sleep needed to prevent daytime sleepiness, elevated sleep propensity, and cognitive deficits, has been a long-standing controversy central to whether chronic sleep restriction may compromise health and behavioral functions. Selfreported sleep durations are frequently less than 8 hours per night. For example, approximately 20% of more than 1.1 million Americans indicated that they slept 6.5 hours or less each night.11 Similarly, in polls of 1000 American adults by the National Sleep Foundation, 15% of subjects (aged 18 to 84 years) reported sleeping less than 6 hours on weekdays, and 10% reported sleeping less than 6 hours on weekends over the past year.12 Scientific perspectives on the duration of sleep that defines chronic sleep restriction have come from a number of theories. THEORETICAL PERSPECTIVES ON SLEEP NEED AND SLEEP DEBT Basal Sleep Need The amount of sleep habitually obtained by an individual is determined by a variety of factors. Epidemiologic and experimental studies point to a high between-subjects variance in sleep duration, influenced by environmental, genetic, and societal factors. Although not clearly defined in the literature, the concept of basal sleep need has been described as habitual sleep duration in the absence of preexisting sleep debt.13 Sleep restriction has been defined as the fundamental duration of sleep below which waking deficits begin to accumulate.14 Given these definitions, the 67

68  PART I / Section 1  •  Normal Sleep and Its Variations

basal need for sleep appears to be between 7.5 and 8.5 hours per day in healthy adult humans. This number was based on a study in which prior sleep debt was completely eliminated through repeated nights of long-duration sleep that stabilized at a mean of 8.17 hours.15 A similar value was obtained from a large-scale dose–response experiment on chronic sleep restriction that statistically estimated daily sleep need to average 8.16 hours per night to avoid detrimental effects on waking functions.4 Core Sleep versus Optional Sleep In the 1980s, it was proposed that a normal nocturnal sleep period was composed of two types of sleep relative to functional adaptation: core and optional sleep.16,17 The initial duration of sleep in the sleep period was referred to as core, or “obligatory,” sleep, which was posited to “repair the effects of waking wear and tear on the cerebrum.”16, p. 57 Initially, the duration of required core sleep was defined as 4 to 5 hours of sleep per night, depending on the duration of the sleep restriction.16 The duration of core sleep has subsequently been redefined as 6 hours of (good-quality, uninterrupted) sleep for most adults.14 Additional sleep obtained beyond the period of core sleep was considered to be optional, or luxury, sleep, which “fills the tedious hours of darkness until sunrise.”16, p. 57 This core versus optional theory of sleep need is often presented as analogous to the concept of appetite: Hunger drives one to eat until satiated, but additional food can still be consumed beyond what the body requires. It is unknown whether the so-called optional sleep serves any function. According to the core sleep theory, only the core portion of sleep—which is dominated by slow-wave sleep (SWS) and slow-wave activity (SWA) on an electroencephalogram (EEG)—is required to maintain adequate levels of daytime alertness and cognitive functioning.16 The optional sleep does not contribute to this recovery or maintenance of neurobehavioral capability. This theory was strengthened by results from a mathematical model of sleep and waking functions (the three-process model) that predicted that waking neurobehavioral functions were primarily restored during SWS,18 which makes up only a portion of total sleep time. However, if only the core portion of sleep is required, it would be reasonable to predict that there would be no waking neurobehavioral consequences of chronically restricting sleep to 6 hours per night, and that cognitive deficits would be evident only when sleep durations were reduced below this amount. Experimental data have not supported this prediction.10 For example, findings from the largest sleep dose–response study to date, which examined the effects of sleep chronically restricted to 4, 6, or 8 hours of time in bed per night,4 found that cognitive performance measures were stable across 14 days of sleep restriction to 8 hours time in bed, but when sleep was reduced to either 6 or 4 hours per night, significant cumulative (dose-dependent) decreases in cognitive performance functions and increases in sleepiness were observed.4 It appears, therefore, that the “core” sleep needed to maintain stable waking neurobehavioral functions in healthy adults aged 22 to 45 years is in the range of 7 to 8 hours on average.18 Moreover, because extended sleep is thought to dissipate sleep debt caused by chronic sleep restriction,3 it is not clear that there is such a thing as

“optional” sleep. There is, instead, recovery sleep, which may or may not be optional, although there have very few studies of the sleep needed to recover from varying degrees of chronic sleep restriction. Adaptation to Sleep Restriction One popular belief is that subjects may be acutely affected after initial restriction of sleep length and may then be able to adapt to the reduced sleep amount, with waking neurocognitive functions unaffected further or returned to baseline levels. Although several studies have suggested that this is the case when sleep duration is restricted to approximately 4 to 6 hours per night for up to 8 months,6,9 there is also evidence indicating that the adaptation is largely confined to subjective reports of sleepiness but not objective cognitive performance parameters.4 This suggests that the presumed adaptation effect is actually a misperception on the part of chronically sleep-restricted people regarding how sleep restriction has affected their cognitive capability. One factor thought to be important in adaptation to chronic sleep restriction is the abruptness of the sleep curtailment. One study examined the relationship between rate of accumulation of sleep loss, to a total of 8 hours, and neurobehavioral performance levels.19 After 1 night of total sleep deprivation (i.e., a rapid accumulation of 8 hours of sleep loss), neurobehavioral capabilities were significantly reduced. When the accumulation of sleep loss was slower, achieved by chronically restricting sleep to 4 hours per night for 2 nights or 6 hours per night for 4 nights, neurobehavioral performance deficits were evident, but they were of a smaller magnitude than those following the night of total sleep loss. A greater degree of neurobehavioral impairment was evident in those subjects restricted to 4 hours for 2 nights than in those subjects allowed 6 hours per night, leading to the conclusion that during the slowest accumulation of sleep debt (i.e., 6 hours per night for 4 nights), there was evidence of a compensatory adaptive mechanism.19 It is possible but not scientifically resolved that different objective neurobehavioral measures may show different degrees of sensitivity and adaptation to chronic sleep restriction. For example, in the largest controlled study to date with statistical modeling of adaptation curves, cognitive performance measures showed little adaptation across 14 days of sleep restriction to 4 or 6 hours per night, compared with 8 hours per night,4 whereas waking EEG measures of alpha and theta frequencies showed no systematic sleep dose–dependent changes over days.14 Consequently, different neurobehavioral outcomes showed markedly different responses to chronic sleep restriction, with neurocognitive functions showing the least adaptation, subjective sleepiness measures showing more adaptation, and waking EEG measures as well as non–rapid eye movement (nonREM), SWS measures showing little or no response.4,14 The reliability of the latter findings may depend on the dose of restricted sleep and other factors. Two-Process Model Predictions of Sleep Restriction Biomathematical models of sleep–wake regulation have been used to make predictions about recovery in response



to various sleep durations. The basis of almost all current biomathematical models of sleep–wake regulation is the two-process model of sleep regulation.20 This model proposes that two primary components regulate sleep: (1) a homeostatic process that builds up exponentially during wakefulness and declines exponentially during sleep (as measured by slow-wave energy or delta power in the non-REM sleep EEG), and (2) a circadian process, with near–24-hour periodicity. Since its inception, the two-process model has gained widespread acceptance for its explanation of the timing and structure of sleep. Its use has extended to predictions of waking alertness and neurobehavioral functions in response to different sleep–wake scenarios.21 This extension of the two-process model was based on observations that as sleep pressure accumulated with increasing time awake, so did waking neurobehavioral or neurocognitive impairment, and as sleep pressure dissipated with time asleep, performance capability improved during the following period of wakefulness. In addition, forced-desynchrony experiments revealed that the sleep homeostatic and circadian processes interacted to create periods of stable wakefulness and consolidated sleep during normal 24-hour days.22 Hence, it was postulated that waking cognitive function (alertness variable A) could be mathematically modeled as the difference between the quantitative state for the homeostatic process (S) and the quantitative state for the circadian process (C), and thus A = S − C. Accordingly, predictions for changes in the neurobehavioral recovery afforded by chronically restricted sleep of varying durations could be made on the basis of sleep–wake times and circadian phase estimates, using the quantitative version of the two-process model. The validity of the various biomathematical models based on the two-process model, and their ability to predict actual experimental results of the neurobehavioral effects of chronic sleep restriction have been evaluated in a blind test.23 Because all current models are based on the same underlying principles as the two-process model, all yielded comparable predictions for neurobehavioral functioning in scenarios involving total sleep deprivation or chronic partial sleep restriction. All models accurately predicted waking neurobehavioral responses to total sleep deprivation. However, they all failed to adequately predict sleepiness and cognitive performance responses during chronic sleep restriction.4,23 Hence, it appears that the extension of the two-process model to prediction of waking alertness21 does not account for the results of chronic sleep restriction. Because the two-process model has had a profound theoretical influence on predictions of sleepiness based on total sleep deprivation data, its failure to capture the dynamic changes in neurobehavioral measures during chronic sleep restriction suggests that additional biological factors are relevant to the brain’s response to chronic sleep restriction.

EFFECTS OF CHRONIC SLEEP RESTRICTION The effects of sleep loss may be quantified in a number of different ways, using a wide range of physiologic, neurocognitive, behavioral, and subjective tools. Many early

CHAPTER 6  •  Chronic Sleep Deprivation  69

studies examining the effects of chronic sleep restriction on cognitive performance were conducted outside a controlled laboratory setting, with little or no control over potentially contaminating factors, such as the level of napping, extension of sleep periods, diet, stimulant use (e.g., caffeine, nicotine), activity, or exposure to zeitgebers (environmental time cues). The majority of these studies concluded that there were few or no detrimental effects on waking neurobehavioral capabilities, or subjective effects of the sleep restriction. For example, restriction of nocturnal sleep periods to between approximately 4 and 6 hours per night for up to 8 months produced no significant effects on a range of cognitive outcomes, including vigilance performance,9 psychomotor performance,6 logical reasoning, addition, or working memory.9 In addition, few effects on subjective assessments of sleepiness or mood were reported.9 Later studies, however, with far greater experimental control and appropriate control groups, have demonstrated significant cumulative sleep dose–response effects on a wide range of physiologic and neurobehavioral functions, which we summarize here. Sleep Architecture Sleep restriction alters sleep architecture, but it does not affect all sleep stages equally. Depending on the timing and duration of sleep, and the number of days it is reduced, some aspects of sleep are conserved, occur sooner, or intensify, and other aspects of sleep time are diminished. For example, studies examining sleep architecture during chronic periods of sleep restriction have demonstrated a consistent conservation of SWS at the expense of other non-REM and REM sleep stages.4,24,25 In addition, elevations in SWA, derived from spectral analysis of the sleep EEG in the range of 0.5 to 4.5 Hz, during non-REM sleep have also been reported during and after chronic sleep restriction.4,25 Because of the conservation of the amount of SWS and SWA during restricted sleep protocols, independent of sleep duration (e.g., 8 hours of time in bed or 4 hours of time in bed), it has been proposed that, with regard to behavioral and physiologic outcomes, these phenomena provide the recovery aspects of sleep. It remains to be determined whether the lack of SWS and SWA response to chronic restriction of sleep to 4 hours a night, relative to steady increases in physiologic and neurobehavioral measures of sleepiness,4 can account for the latter deficits. Consequently, although SWS and non-REM SWA may be conserved in chronic sleep restriction (to 4 to 7 hours per night), they do not appear to reflect the severity of daytime cognitive deficits or to protect against these deficits, raising serious doubts about SWS and non-REM SWA being the only aspects of sleep critical to waking functions in chronic sleep restriction.4 Sleep Propensity With the development and validation of sleep latency measures as sensitive indices of sleep propensity,26 the effects of chronic sleep restriction could be evaluated physiologically. Objective EEG measures of sleep propensity, such as the multiple sleep latency test26 (MSLT) and the

70  PART I / Section 1  •  Normal Sleep and Its Variations

maintenance of wakefulness test27 (MWT), are frequently used to evaluate sleepiness (see Chapters 4 and 143). The daytime MSLT26 has been shown to vary linearly after 1 night of sleep restricted to between 1 and 5 hours of time in bed.26 Progressive decreases in daytime sleep latency have been documented (i.e., increases in sleep propensity) across 7 days of sleep restricted to 5 hours per night in healthy young adults,28 a finding confirmed in a later study using the psychomotor vigilance test (PVT).8 Dose–response effects of chronic sleep restriction on daytime MSLT values have been reported in a controlled laboratory study in commercial truck drivers.24 A significant increase in sleep propensity across 7 days of sleep restricted to either 3 or 5 hours per night was observed, with no increase in sleep propensity found when sleep was restricted to 7 or 9 hours per night.24 Similarly, sleep propensity (as measured by the MWT29) during 7 days of sleep restriction to 4 hours per night was reported to increase, especially in subjects whose sleep was restricted by advancing sleep offset.30 An epidemiologic study of predictors of objective sleep tendency in the general population31 also found a dose– response relationship between self-reported nighttime sleep duration and objective sleep tendency as measured by the MSLT. Persons reporting more than 7.5 hours of sleep had significantly less probability of falling asleep on the MSLT than those reporting between 6.75 and 7.5 hours per night (27% risk of falling asleep), and than those reporting sleep durations less than 6.75 hours per night (73% risk of falling asleep).31 Although the MWT has been used less in experimental settings than the MSLT, it has also been found to increase in experiments in which adults were restricted to 4 hours for sleep for 7 nights,30 and for 5 nights.32 All of these studies suggest that chronic curtailment of nocturnal sleep increases daytime sleep propensity. Oculomotor responses have also been reported to be sensitive to sleep restriction.33 Eyelid closure and slow rolling eye movements are part of the initial transition from wakefulness to drowsiness. Eye movements and eye closures have been studied during sleep-loss protocols, under the premise that changes in the number and rate of movements and eyelid closures are a reflection of increased sleep propensity and precursors of the eventual onset of sleep.34 It has been demonstrated experimentally that slow eyelid closures during performance are associated with vigilance lapses and are sensitive indices of sleep deprivation, and slow eyelid closures have been found to be a sign of drowsiness while driving.33 Increased slow eye movements attributed to attentional failures have been reported to be increased by reduced sleep time in medical residents.35 Sleep restriction has also been found to decrease saccadic velocity and to increase the latency to pupil constriction in subjects allowed only 3 or 5 hours of time in bed for sleep over 7 nights.36 These changes in ocular activity were positively correlated with sleep latency, subjective sleepiness measures, and accidents on a simulated driving task.36 Waking Electroencephalogram Slowing in certain waking EEG frequencies has been thought to reflect the increased homeostatic pressure for

sleep during sleep restriction. EEG frequencies in the slower range (0.5 to 14 Hz)—in sleep-deprived individuals in particular—may herald an increased tendency for microsleeps. Significant increases in power densities in the delta range (3.75 to 4.5 Hz) and decreases in the alpha range (9.25 to 10 Hz) have been reported in subjects exposed to 4 hours of sleep restriction for 4 nights.25 In contrast, no effect on waking alpha power (8 to 12 Hz) across days of restriction was evident in subjects restricted to 4 or 6 hours of time in bed for sleep per night for 14 nights.14 An increase in theta power (4 to 8 Hz) across days of the sleep restriction protocol was evident; however, there was no significant difference in theta power changes between restriction conditions. It has been suggested that these changes in waking EEG frequency during sleep loss reflect “spectral leakage” indicative of elevated sleep pressure manifesting in wakefulness.37 Few studies have investigated the “leakage” of slower EEG activity in humans, but animal studies suggest that this process may enable the brain to discharge some of the accumulated homeostatic sleep drive without actually going to sleep.37 Cognitive Effects Reduced sleep time can adversely affect different aspects of waking cognitive performance, especially behavioral alertness, which is fundamental to many cognitive tasks. Behavioral alertness can be measured with the PVT, which requires vigilant attention and has proved to be very sensitive to any reduction in habitual sleep time.38,39 Studies have consistently shown that sleep restriction increases PVT response slowing40 and lapses,38 which are thought to reflect microsleeps.3,41 As loss of sleep accumulates, relatively brief lapses of a half second can increase to well over 10 seconds and longer.3,41,42 It is suggested that lapses produced by sleep loss involve shifts in neuronal activity in frontal, thalamic, and secondary sensory processing areas of the brain.43 Lapses of attention occur unpredictably throughout cognitive performance in sleep-restricted subjects, and they increase in frequency and duration as a function of the severity of sleep restriction, which has led to the idea that they reflect underlying “wake state instability.”38,42,43 This instability appears to involve moment-tomoment fluctuations in the relationship between neurobiological systems mediating wake maintenance and sleep initiation.43 One early study of chronic sleep restriction effects on cognitive performance examined the effects of reducing habitual sleep time by 40% for 5 nights.44 Decreases in performance on a vigilance and simple reaction time performance task were observed across the protocol with sleep restriction. Interestingly, however, there was no effect of sleep restriction on a choice reaction time task, suggesting that not all measures of performance are equally sensitive to chronic sleep restriction. This could result from any of a number of aspects of the psychometric properties of cognitive tests (e.g., learning curves) or from their neurobiological substrates; negative findings provide no insight into the reason for lack of sensitivity. Two large-scale experimental studies published in 2003 described dose-related effects of chronic sleep restriction on neurobehavioral performance measures.4,24 In one study, truck drivers were randomized to 7 nights of 3, 5,

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7, or 9 hours of time in bed for sleep per night.24 Cognitive performance was assessed using the PVT. Subjects in the 3- and 5-hour time-in-bed groups experienced a decrease in performance across days of the sleep restriction protocol, with increases in the mean reaction time, in the number of lapses, and in the speed of the fastest reaction on the PVT.24 In the subjects who were allowed 7 hours of time in bed per night, a significant decrease in mean response speed was also evident, although no effect on lapses was evident. Performance in the group allowed 9 hours of time in bed was stable across the 7 days. In an equally large experiment,4 young adults had their sleep duration restricted to 4, 6, or 8 hours of time in bed per night for 14 nights, and daytime deficits in cognitive functions were observed for lapses on the PVT (Fig. 6-1), for a memory task, and for a cognitive throughput task. These performance deficits accumulated across the experimental protocol in those subjects allowed less than 8 hours of sleep per night.4 Data from this study demonstrate that sleep restriction–induced deficits continued to accumulate beyond the 7 nights of restriction used in other experiments,8,24 with performance deficits still increasing at day 14 of the restricted sleep schedule. By the end of the 14-day chronic partial-sleep restriction period, the level of cognitive impairments recorded in subjects in the 4-hour sleep restriction condition was equivalent to the level of impairment seen after 1 to 2 nights without any sleep (see Fig. 6-1). To understand the relationship between the different sleep-loss conditions and the equivalence in performance impairment observed, the amount of cumulative sleep loss for subjects in each condition was calculated.4 The degree of sleep loss was greater in subjects allowed 4 hours of sleep each night for 14 nights (i.e., losing approximately 55 hours of sleep) than in subjects who remained awake for 88 hours (i.e., losing approximately 25 hours of sleep) (Fig. 6-2A), suggesting that impairments in waking performance should have been much worse in the 4-hour condition. However, this was not the case (see Fig. 6-1). To reconcile this paradox, wake time was defined as the difference between the duration of each continuous wake period and the duration of habitual wake time. Accordingly, cumulative wake-time extension was calculated as the sum of all consecutive hours of wakefulness extending beyond the habitual duration of wakefulness that each subject was accustomed to at home. In the 4-, 6-, and 8-hour sleep restriction conditions, this yielded the same results as for cumulative sleep loss, because the definitions of cumulative wake extension and cumulative sleep loss were arithmetically equivalent. However, for the 0-hour total sleep deprivation condition, each day without sleep added 24 hours to the cumulative wake extension. Thus, over 3 days with 0 hours of sleep, cumulative wake extension was equal to 72 hours for each subject (see Fig. 6-2B), whereas cumulative sleep loss was only 23 hours (see Fig. 6-2A). These results illustrate that cumulative sleep loss and cumulative wake extension are different constructs that can have different quantitative values, depending on the manner in which sleep loss occurs. They also suggest that sleep debt can also be understood as resulting in additional wakefulness beyond an average of approximately 16 hours a day, which has a neurobiological cost that accumulates over time.4

CHAPTER 6  •  Chronic Sleep Deprivation  71

Effect sizes 4 hr vs. 8 hr: 1.45 6 hr vs. 8 hr: 0.71 4 hr vs. 6 hr: 0.43

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Figure 6-1  Psychomotor vigilance task (PVT) performance lapses under varying dosages of daily sleep. Displayed are group averages for subjects in the 8-hour (diamond), 6-hour (light blue square), and 4-hour (circle) chronic sleep period time in bed (TIB) across 14 days, and in the 0-hour (green square) sleep condition across 3 days. Subjects were tested every 2 hours each day; data points represent the daily average (07:30 to 23:30) expressed relative to baseline (BL). The curves through the data points represent statistical nonlinear model-based best-fitting profiles of the response to sleep deprivation for subjects in each of the four experimental conditions. The ranges (mean ± SE) of neurobehavioral functions for 1 and 2 days of 0 hours of sleep (total sleep deprivation) are shown as light and dark bands, respectively, allowing comparison of the 3-day total sleep deprivation condition and the 14-day chronic sleep restriction conditions. (Redrawn from Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126.)

It appears that the neurocognitive effects of restricting nocturnal sleep to 6 or 4 hours per night on a chronic basis are fundamentally the same as when sleep is chronically restricted but split each day between a nighttime sleep and a daytime nap.45 Cognitive performance deficits also accumulate across consecutive days in which the restricted sleep occurs during the daytime and wakefulness occurs at night.46 The primary difference between the nocturnally4 and diurnally46 placed restricted sleep periods is that the magnitude of neurobehavioral impairment is significantly greater with daytime sleep compared with nighttime sleep, reflecting a combined influence of the homeostatic and circadian systems. In another experiment, when recovery periods after total sleep time were restricted to 6 hours versus 9 hours time in bed for sleep per night, neither PVT performance nor sleepiness recovered to baseline levels, suggesting that restricting sleep can also reduce its recovery potential.47 All these studies suggest that when time in bed for sleep is chronically restricted to less than 7 hours per night in healthy adults (aged 21 to 64 years), cumulative deficits in a variety of cognitive performance functions become evident. These deficits can accumulate to levels of impairment equivalent to those observed after 1 or even 2 nights of total sleep deprivation. These cognitive performance findings are consistent with those on the effects of sleep restriction on physiologic

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72  PART I / Section 1  •  Normal Sleep and Its Variations

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Figure 6-2  Cumulative buildup of sleep loss and wake time extension across days of sleep restriction and total sleep loss. A, Cumulative sleep loss relative to habitual sleep duration—that is, all hours of sleep habitually obtained (as measured at home during the 5 days prior to the experiment) but not received in the experiment because of sleep restriction. B, Cumulative wake extension relative to habitual wake duration—that is, all consecutive hours of wakefulness in excess of the habitual duration of a wakefulness period. Daily means are shown for subjects in the 8-hour (diamond), 6-hour (light blue square), 4-hour (circle), and 0-hour (green square) sleep period conditions. A also shows the range (orange band) of cumulative sleep loss (relative to habitual sleep duration) after 3 days in the 0-hour sleep condition, which was 23.1 ± 2.6 hours (mean ± SD). This was significantly less than the cumulative sleep loss after 14 days in the 4-hour sleep period condition (t20 = 10.58, P < .001). (Redrawn from Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126.)

sleep propensity measures (MSLT, MWT).24,28,30,32 Collectively, they suggest that there is a neurobiological integrator that accumulates either homeostatic sleep drive or the neurobiological consequences of excess wakefulness.4,24 There has as yet been no definitive evidence of what causes this destabilization of cognitive functions, but one intriguing line of evidence suggests that it may involve extracellular adenosine in the basal forebrain.48 Driving Performance There is an increased incidence of sleep-related motor vehicle crashes in drivers reporting less than 7 hours of sleep per night on average.49 Additional contributing factors to these sleep- or sleepiness-related crashes included poor sleep quality, dissatisfaction with sleep duration (i.e., undersleeping), daytime sleepiness, previous instances of driving drowsy, and time driving and time of day (driving late at night). It has been found that after 1 night of restricted sleep (5 hours), a decrease in performance on a driving simulator, with a concurrent increase in subjectively reported sleepiness, was found.50 In addition, during chronic sleep restriction in a controlled laboratory, with sleep durations reduced to between 4 and 6 hours per 24 hours, placed either nocturnally or diurnally, significant increases in the rate of accidents on a driving simulator occurred with decreased sleep durations, independent of the timing of the sleep period.51 Subjective Sleepiness and Mood In contrast to the continuing accumulation of cognitive performance deficits associated with nightly restriction of sleep to below 8 hours, subjective ratings of sleepiness, fatigue, and related factors repeatedly made by subjects on standardized sleepiness scales did not parallel performance deficits.4 As a consequence, after 2 weeks of sleep restricted to 4 or 6 hours per night, subjects were markedly impaired

and behaviorally less alert, but they thought themselves only moderately sleepy. This suggests that individuals frequently underestimate the actual cognitive impact of sleep restriction and believe themselves fit to perform. Experiments using driving simulators have found similar results, with drivers unable to accurately perceive their level of fatigue and cognitive impairment.50 Individual Differences in Responses to Chronic Sleep Restriction Although the majority of healthy adults develop cumulative cognitive deficits and sleepiness with chronic sleep restriction, interindividual variability in the neurobehavioral and physiologic responses to sleep restriction is substantial.3,38,39,42 Sleep restriction increases neurobehavioral performance variability in subjects,38,39,41 and it also reveals clear neurobehavioral differences between subjects. This interindividual variability is quite apparent in sleep restriction studies. For example, not everyone was affected to the same degree when sleep duration was limited to less than 7 hours per day in the studies described earlier.4,24 Some people experience very severe impairments even with modest sleep restriction, whereas others show little effect until sleep restriction is severe. However, this difference is not always apparent to the individual. It has been postulated that these individual differences are a result of state (basal level of sleepiness/alertness and basal differences in circadian phase) and trait differences (optimal circadian phase for sleep/wakefulness, sensitivity/responsiveness of sleep homeostat, and compensatory mechanisms),52 but these factors have not been widely researched. For studies of the possible genetic contributors to differential vulnerability to sleep loss, it is significant that the neurobehavioral responses to sleep deprivation have been found to be stable and consistent within subjects,23 suggesting they are traitlike.23



PHYSIOLOGIC EFFECTS There is increasing evidence of physiologic and healthrelated consequences of chronic sleep restriction. Alterations in other physiologic parameters, such as endocrine (see Chapter 125) and immune function (see Chapters 25 and 26), have been recognized and have implications for health status and risk. Several anecdotal and longitudinal studies have reported an increased incidence and risk of medical disorders and health dysfunction related to shift work schedules, which have been attributed to both circadian disruption and sleep disturbance. Further links between sleep disturbance and health effects have been reported in studies examining insomniac patients and patients with other sleep disorders and medical disorders that disturb sleep.53 In addition, an elevated mortality risk in those individuals who reported sleeping less than 6.5 hours per night has been found.11 One provocative discovery from this study was the finding that individuals sleeping more than 7.4 hours per night were also at an elevated risk of all-cause mortality. This finding is similar to that reported from the Nurses’ Health Study,54 where subjects reporting greater than 9 hours of sleep per night on average were at a higher risk for coronary events than those sleeping 8 hours per night. In addition, an increased risk of coronary events in women obtaining 7 hours of sleep or less per night was observed.55 Also, increasing epidemiologic, cross-sectional, and longitudinal data suggest that reduced sleep duration is associated with larger body mass index (BMI). A meta-analysis study found a consistent, increased risk of obesity among short sleepers—both children (sleeping less than 10 hours per night) and adults (sleeping less than 5 hours per night)—but, as the authors pointed out, causal inference was difficult because of the lack of control of confounders and inconsistency in the methodologies used.56 Endocrine and Metabolic Effects A number of studies have examined the effects of sleep loss on a range of neuroendocrine factors.57,57a Comparison of sleep restriction (4 hours per night for 6 nights) with sleep extension (12 hours per night for 6 nights) revealed an elevation in evening cortisol, increased sympathetic activation, decreased thyrotropin activity, and decreased glucose tolerance in the restricted as opposed to the extended sleep condition.55 Similarly, an elevation in evening cortisol levels and an advance in the timing of the morning peak in cortisol, so that the relationship between sleep termination and cortisol acrophase was maintained, were found after 10 nights of sleep restricted to 4.2 hours of time in bed for sleep each night compared with baseline measures and a control group allowed 8.2 hours of time in bed for sleep for 10 nights.58 Changes in the timing of the growth hormone secretory profile associated with sleep restriction to 4 hours per night for 6 nights, with a bimodal secretory pattern evolving, have also been reported.59 Immune and Inflammatory Effects The majority of studies examining sleep loss and immune function have concentrated on total sleep deprivation or 1 night of sleep restriction. Changes in natural killer cell activity,60,61 lymphokine-activated killer cell activity,60

CHAPTER 6  •  Chronic Sleep Deprivation  73

interleukin-6,62 and soluble tumor necrosis factor–alpha receptor 161 have all been reported with total sleep deprivation and sleep restriction. One study reported that antibody titers were decreased by more than 50% after 10 days in subjects who were vaccinated for influenza immediately after 6 nights of sleep restricted to 4 hours per night, compared with those who were vaccinated after habitual sleep duration.63 But by 3 to 4 weeks after the vaccination, there was no difference in antibody level between the two subject groups. Therefore, sleep loss appeared to alter the acute immune response to vaccination. Cardiovascular Effects Increased cardiovascular events and cardiovascular morbidity have been reported with reduced sleep durations.11,54 Additionally, this relationship has been found in a casecontrol study examining insufficient sleep resulting from work demands.64 In the Nurses’ Health Study, Ayas and colleagues54 reported that coronary events were increased in female subjects obtaining 7 hours of sleep or less per night compared with those averaging 8 hours per night, and Liu and associates64 reported a twofold to threefold increase in risk of cardiovascular events with an average sleep duration of 5 hours or less per night. Shift workers who typically experience chronic reductions in sleep time as well as circadian disruption have been found to have reduced cardiovascular health.65 The mechanism that links chronic sleep restriction and increased cardiovascular risk is unknown, but one potential pathway may be via activation of inflammatory processes during sleep loss. C-reactive protein (CRP) is a predictive inflammatory marker of increased risk for cardiovascular disease. Increased CRP levels have been found in patients with obstructive sleep apnea, who commonly experience reduced sleep time as well as hypoxia,66 and an increase in CRP levels was reported after both total sleep deprivation and sleep restriction (4 hours in bed for sleep per night) in healthy subjects.67 ❖  Clinical Pearl Chronic sleep deprivation can be caused by sleep disorders, work schedules, and modern lifestyles. Regardless of its cause, chronic sleep deprivation results in cumulative adverse effects in daytime awake functions, including sleep propensity, cognitive performance, driving safety, mood, and physiologic conditions.

Acknowledgments The substantive evaluation on which this chapter was based was supported by National Institutes of Health grants NR04281 and CTRC UL1RR024134, and by the National Space Biomedical Research Institute through NASA NCC 9-58. REFERENCES 1. Webb WB. Partial and differential sleep deprivation. In: Kales A, editor. Sleep: physiology and pathology—a symposium. Philadelphia: JB Lippincott; 1969. p. 221-231.

74  PART I / Section 1  •  Normal Sleep and Its Variations 2. Dement WC, Vaughan C. The promise of sleep. New York: Dell; 1999. 3. Kleitman N. Sleep and wakefulness. 2nd ed. Chicago: University of Chicago Press; 1963. 4. Van Dongen HPA, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26(2):117-126. 5. Hartley LR. Comparison of continuous and distributed reduced sleep schedules. Q J Exp Psychol 1974;26:8-14. 6. Friedmann J, Globus G, Huntley A, Mullaney D, et al. Performance and mood during and after gradual sleep reduction. Psychophysiology 1977;14:245-250. 7. Ferrara M, De Gennaro L, Bertini M. The effects of slow-wave sleep (SWS) deprivation and time of night on behavioral performance upon awakening. Physiol Behav 1999;68(1-2):55-61. 8. Dinges DF, Pack F, Williams K, Gillen KA, et al. Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. Sleep 1997;20(4):267-277. 9. Webb WB, Agnew HW. Effects of a chronic limitation of sleep length. Psychophysiology 1974;11(3):265-274. 10. Dinges DF. Sleep debt and scientific evidence. Sleep 2004;27(6): 1050-1052. 11. Kripke DF, Garfinkel L, Wingard DL, Klauber MR, et al. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 2002;59(2):131-136. 12. 2002 Sleep in America Poll—National Sleep Foundation. Washington DC: 2002. 13. Dement W, Greenber S. Changes in total amount of stage 4 sleep as a function of partial sleep deprivation. Electroencephalogr Clin Neurophysiol 1966;20(5):523-526. 14. Van Dongen HPA, Rogers NL, Dinges DF. Understanding sleep debt: Theoretical and empirical issues. Sleep and Biol Rhythms 2003; 1:4-12. 15. Wehr TA, Moul DE, Barbato G, Giesen HA, et al. Conservation of photoperiod-responsive mechanisms in humans. Am J Physiol 1993;265(4):R846-R857. 16. Horne J, editor. Why we sleep: the functions of sleep in humans and other mammals. Oxford: Oxford University Press; 1988. 17. Horne JA. Sleep function, with particular reference to sleepdeprivation. Ann Clin Res 1985;17(5):199-208. 18. Akerstedt T, Folkard S. The three-process model of alertness and its extension to performance, sleep latency, and sleep length. Chronobiol Int 1997;14(2):115-123. 19. Drake CL, Roehrs TA, Burduvali E, Bonahoom A, et al. Effects of rapid versus slow accumulation of eight hours of sleep loss. Psychophysiology 2001;38(6):979-987. 20. Borbely AA. A two process model of sleep regulation. Hum Neurobiol 1982;1(3):195-204. 21. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14(6):557-568. 22. Dijk DJ, Czeisler CA. Paradoxical timing of the circadian-rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Let 1994;166(1):63-68. 23. Van Dongen HPA. Comparison of mathematical model predictions to experimental data of fatigue and performance. Aviat Space Environ Med 2004;75(3):A15-A36. 24. Belenky G, Wesensten NJ, Thorne DR, Thomas ML, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003;12(1):1-12. 25. Brunner DP, Dijk DJ, Borbely AA. Repeated partial sleep-deprivation progressively changes the EEG during sleep and wakefulness. Sleep 1993;16(2):100-113. 26. Carskadon MA Dement WC. The multiple sleep latency test—what does it measure. Sleep 1982;5:S67-S72. 27. Mitler MM, Gujavarty KS, Browman CP. Maintenance of wakefulness test—a polysomnographic technique for evaluating treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 1982;53(6):658-661. 28. Carskadon MA, Dement WC. Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology 1981;18(2):107-113. 29. Banks S, Barnes M, Tarquinio N, Pierce RJ, et al. The maintenance of wakefulness test in normal healthy subjects. Sleep 2004;27(4): 799-802.

30. Guilleminault C, Powell NB, Martinez S, Kushida C, et al. Preliminary observations on the effects of sleep time in a sleep restriction paradigm. Sleep Med 2003;4(3):177-184. 31. Punjabi NM, Bandeen-Roche K, Young T. Predictors of objective sleep tendency in the general population. Sleep Med 2003;26(6):678683. 32. Banks S, Van Dongen H, Dinges DF. How much sleep is needed to recover from sleep debt?—the impact of sleep dose on recovery. Sleep 2005;28:A138. 33. Dinges DF, Mallis M, Maislin G, Powell JW. Evaluation of techniques for ocular measurement as an index of fatigue and the basis for alertness management. Final report for the U.S. Department of Transportation, National Highway Traffic Safety Administration. 1998;1-112. 34. Mallis MM, Dinges DF. Monitoring alertness by eyelid closure. In: Stanton N, Hedge A, Brookhuis K, Salas E, editors. The handbook of human factors and ergonomics methods. New York: CRC Press; 2005. p. 25. 35. Lockley SW, Cronin JW, Evans EE, Cade BE, et al. Effect of reducing interns’ weekly work hours on sleep and attentional failures. N Eng J Med 2004;351(18):1829-1837. 36. Russo M, Thomas M, Thorne D, Sing H, et al. Oculomotor impairment during chronic partial sleep deprivation. Clin Neurophysiol 2003;114(4):723-736. 37. Cirelli C, Tononi G. Is sleep essential? PLoS Biol 2008;6(8):e216. 38. Dorrian J, Dinges DF. Sleep deprivation and its effects on cognitive performance. In: Dorrian JS, Dinges DF, editors. Encyclopedia of sleep medicine. Hoboken, NJ:1 John Wiley & Sons; 2005. 39. Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol 2005;25:117-129. 40. Lim J, Dinges DF. Sleep deprivation and vigilant attention. Molecular and biophysical mechanisms of arousal, alertness, and attention. Ann N Y Acad Sci 2008;1129:305-322. 41. Dinges DF, Kribbs NB. Performing while sleepy: effects of experimentally-induced sleepiness. In: Monk TH, editor. Sleep, sleepiness and performance. Chichester: John Wiley & Sons; 1991. p. 97-128. 42. Doran SM, Van Dongen HPA, Dinges DF. Sustained attention performance during sleep deprivation: evidence of state instability. Arch Ital Biol 2001;139:253-267. 43. Chee MW, Tan JC, Zheng H, Parimal S, et al. Lapsing during sleep deprivation is associated with distributed changes in brain activation. J Neurosci 2008;28(21):5519-5528. 44. Herscovitch J, Broughton R. Performance deficits following shortterm partial sleep-deprivation and subsequent recovery oversleeping. Can J Psychol 1981;35(4):309-322. 45. Mollicone DJ, Van Dongen HPA, Rogers NL, Dinges DF. Response surface mapping of neurobehavioral performance: testing the feasibility of split sleep schedules for space operations. Acta Astronautica 2008;63(7):833-840. 46. Rogers NL, Van Dongen HPA, Powell JW, Carlin MM, et al. Neurobehavioural functioning during chronic sleep restriction at an adverse circadian phase. Sleep 2002;25(Abstract Suppl.):A126-A127. 47. Lamond N, Jay SM, Dorrian J, Ferguson SA, et al. The dynamics of neurobehavioural recovery following sleep loss. J Sleep Res 2007; 16(1):33-41. 48. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, et al. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 1997;276(5316):1265-1268. 49. Stutts JC, Wilkins JW, Osberg JS, Vaughn BV. Driver risk factors for sleep-related crashes. Accid Anal Prev 2003;35(3):321-331. 50. Banks S, Catcheside P, Lack L, Grunstein RR, et al. Low levels of alcohol impair driving simulator performance and reduce perception of crash risk in partially sleep deprived subjects. Sleep 2004; 27(6):1063-1067. 51. Dorrian J, Dinges DF, Rider RL, Price NJ, et al. Simulated driving performance during chronic partial sleep deprivation. Sleep 2003; 26:A182-A183. 52. Roth T, Roehrs T. The timing of sleep opportunities in a seven-night sleep restriction. Sleep Med 2003;4(3):169-170. 53. Bonnet MH. Sleep deprivation. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia: Saunders; 1994. p. 50-67. 54. Ayas NT, White DP, Manson JE, Stampfer MJ, et al. A prospective study of sleep duration and coronary heart disease in women. Arch Int Med 2003;163(2):205-209.

55. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354(9188):1435-1439. 56. Cappuccio FP, Taggart FM, Kandala NB, Currie A, et al. Metaanalysis of short sleep duration and obesity in children and adults. Sleep 2008;31(5):619-626. 57. Knutson KL, Van Cauter E. Associations between sleep loss and increased risk of obesity and diabetes. Ann N Y Acad Sci 2008; 1129:287-304. 57a.  Leproult R, Van Cauter E. Role of sleep and sleep loss in hormonal release and metabolism. Endocr Dev 2010;17:11-21. 58. Rogers NL, Price NJ, Mullington JM, Szuba MP, et al. Plasma cortisol changes following chronic sleep restriction. Sleep 2000;23: A70-A71. 59. Spiegel K, Leproult R, Colecchia EF, L’Hermite-Baleriaux M, et al. Adaptation of the 24-h growth hormone profile to a state of sleep debt. Ame J Physiol Regul Integr Comp Physiol 2000;279(3): R874-R883. 60. Irwin M, McClintick J, Costlow C, Fortner M, et al. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J 1996;10(5):643-653. 61. Shearer WT, Reuben JM, Mullington JM, Price NJ, et al. Soluble TNF alpha receptor 1 and IL-6 plasma levels in humans subjected

CHAPTER 6  •  Chronic Sleep Deprivation  75 to the sleep deprivation model of spaceflight. J Allergy Clin Immunol 2001;107(1):165-170. 62. Redwine L, Hauger RL, Gillin JC, Irwin M. Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab 2000; 85(10):3597-3603. 63. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immunization. JAMA 2002;288(12):1471-1472. 64. Liu Y, Tanaka H, the Fukuoka Heart Study Group. Overtime work, insufficient sleep, and risk of non-fatal acute myocardial infarction in Japanese men. Occup Environ Med 2002;59:447-451. 65. Knutsson A, Hallquist J, Reuterwall C, Theorell T, et al. Shiftwork and myocardial infarction: a case-control study. Occup Environ Med 1999;56(1):46-50. 66. Lee LA, Chen NH, Huang CG, et al. Patients with severe obstructive sleep apnea syndrome and elevated high-sensitivity C-reactive protein need priority treatment. Otolaryngol Head Neck Surg 2010;143(1):72-77. 67. van Leeuwen WM, Lehto M, Karisola P, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One 2009;4(2):e4589.

Sleep Mechanisms and Phylogeny

Section

2

Jerome M. Siegel 7  Neural Control of Sleep in Mammals 8  REM Sleep 9  Phylogeny of Sleep Regulation 10  Sleep in Animals: A State of Adaptive Inactivity

Neural Control of Sleep in Mammals Dennis McGinty and Ronald Szymusiak Abstract Mammalian sleep and wake states are facilitated by multiple brain regions. The lower brainstem is sufficient to generate wake, non–rapid eye movement (NREM)-like, and REM sleep states, but lesions in several brain regions, including sites in the medulla, mesencephalon, preoptic area (POA) of the hypothalamus, thalamus, and neocortex, all markedly reduce the amounts of NREM and REM sleep. Similarly, arousal and waking are facilitated by several chemically distinct neuronal groups localized in the midbrain, the posterior and lateral hypothalamus, and the basal forebrain. These include histaminergic, orexinergic, serotonergic, cholinergic, dopaminergic, and noradrenergic neurons. These arousal systems share the property of having long axons and extensive projections to widespread brain regions, including the diencephalon, limbic system, and neocortex. These widespread projections can account for the global aspect of arousal from sleep, characterized by concurrent changes in electroencephalographic (EEG), motor, sensory, autonomic, and integrative functions. Arousal systems also control the neuronal membrane potentials in thalamocortical neurons; these potentials, in turn, regulate the oscillatory mechanisms intrinsic to thalamocortical networks that underlie NREM or “synchronized” EEG patterns. Inhibition of arousal systems permits the emergence of synchronized EEG patterns.

DIVERSE BRAIN REGIONS MODULATE WAKING AND NREM SLEEP Isolated Forebrain The capacity of various brain regions to generate sleep and wake states was first studied by isolating or removing major regions. The physiology of the chronically maintained isolated forebrain or chronic cerveau isolé preparation can be examined in dogs and cats.1 Acutely after complete midbrain transections, the isolated forebrain exhibits continuous EEG slow waves and spindles. Thus, structures below the midbrain must normally facilitate awake-like EEG states. However, if a brainstem transection is made lower, at the 76

Chapter

7

Although several brain regions modulate sleep, the POA has a critical role in the control of NREM sleep. Groups of neurons in the POA exhibit increased activity during NREM and REM sleep and respond to physiologic signals, such as warming, that increase sleep. Several putative neurochemical sleep factors promote sleep through actions in the POA or adjacent basal forebrain. Signals from the circadian clock originating in the hypothalamic suprachiasmatic nucleus regulate the circadian timing of sleep through connections in this brain region. POA sleep-active neurons send inhibitory gamma-aminobutyric acid (GABA)ergic projections to the histaminergic, orexinergic, serotonergic, and noradrenergic arousal systems. Through coordinated inhibition of these arousal systems, the key elements of NREM sleep onset are enabled, including EEG synchronization and suppression of motor activity. We take it for granted that the brain controls sleep and waking, and this has been confirmed. Research spanning the past 80 years has identified specific groups of neurons and neurochemical mechanisms that carry out the control of sleep and waking and generate core aspects of the phenomena of sleep and waking, such as the electroencephalographic (EEG) patterns that define these states. Many methods have been used. The story is complex, but a surprisingly coherent picture of sleep–wake control has emerged.

mid-pontine level, an activated or wakelike forebrain EEG state becomes predominant immediately after the transection, but with some residual episodes of EEG slow-wave activity.2 In this preparation, the forebrain exhibits evidence of conditioning, and other signs of an integrated waking state. These studies argue that neuronal groups localized between the midpons and upper midbrain are important for generating a waking-like state. After 5 to 9 days of recovery from surgery, the chronic cerveau isolé rat preparation exhibits a circadian pattern of EEG activation and synchronization.3 In this preparation, preoptic area (POA) lesions are followed by a continuously activated EEG, abolishing the circadian facilitation of synchronization. Thus, the isolated forebrain can generate a sustained wake-



like state, and the POA must play a critical role in initiating the sleeplike EEG state of the isolated forebrain (see later). Wakelike and sleeplike EEG states appear to depend on a balance between wake-promoting and sleep-promoting systems. Diencephalon Chronic diencephalic cats, whose neocortex and striatum have been removed, exhibit behavioral waking with persistent locomotion and orientation to auditory stimuli, a quiet sleeplike or non–rapid eye movement (NREM)-like state with typical cat sleeping postures, and a REM-like state including antigravity muscle atonia, rapid eye movements, muscle twitches, and pontine EEG spikes.4 EEG patterns recorded in the thalamus showed increased amplitude in conjunction with the NREM-sleep–like state, although true spindles and slow waves are absent. The thalamic EEG exhibits desynchronization during the REM-like state. In summary, at least in the cat, the neocortex and striatum are not required for any behaviorally defined sleep– wake states, and an NREM-like state occurs in the absence of sleep spindles and slow waves. Thalamus Cats subjected to complete thalamectomy (athalamic cats) continue to exhibit episodes of EEG and behavioral sleep and waking, although there is an absence of spindles in the NREM sleep EEG,4 and they exhibit chronic insomnia, with reductions in both NREM and REM sleep. Fatal familial insomnia,5 a neurodegenerative disease characterized by progressive autonomic hyperactivation, motor disturbances, loss of sleep spindles, and severe NREM sleep insomnia, typically begins after age 40 years. Neuropathologic findings reveal initial severe cell loss and gliosis in the anterior medial thalamus, including the dorsomedial nucleus. However, patients with paramedian thalamic stroke, with magnetic resonance imaging (MRI)-verified damage to the dorsomedial and centromedial nuclei, present with either severe hypersomnolence or increased daytime sleepiness, not insomnia.6 In summary the thalamus plays a critical role in regulating cortical EEG patterns during waking and sleep, and portions of this structure appear to have hypnogenic functions. Lower Brainstem After recovery from the acute effects of the complete midbrain transections (described earlier), the lower brainstem can generate rudimentary behavioral waking, a NREMlike state, and a REM-like state.4 The behavior of the midbrain-transected cats could be characterized as having three states, including “waking” (identified by crouching, sitting, attempts to walk, dilated pupils, and head orientation to noises), and two sleeplike states. In the first sleeplike state, cats lay down in a random position, pupils exhibited reduced but variable miosis, and eyes exhibited slow and nonconjugate movements, and they could be aroused by auditory or other stimuli. If this stage is not disturbed, cats enter another stage, characterized by complete pupillary miosis, loss of neck muscle tone, and rapid eye movements, identifying a REM-like state. Additional studies support the hypothesis that the lower brainstem contains sleep-facilitating processes. Low-frequency electrical stimulation of the dorsal medullary reticular forma-

CHAPTER 7  •  Neural Control of Sleep in Mammals  77

tion in the nucleus of the solitary track produced neocortical EEG synchronization.7 Lesions or cooling of this site were followed by EEG activation.8 In summary, widespread structures in the mammalian nervous system, from the neocortex to the lower brainstem, have the capacity to facilitate both sleeplike and waking-like states and to modulate the amounts of sleep.

RETICULAR ACTIVATING SYSTEM AND DELINEATION OF AROUSAL SYSTEMS The transection studies just reviewed support the concept of a pontomesencephalic wake-promoting or arousal system. No discovery was historically more significant than the description of the reticular activating system (RAS) by Moruzzi.9 Large lesions of the core of the rostral pontine and mesencephalic tegmentum are followed by persistent somnolence and EEG synchronization, and electrical stimulation of this region induces arousal from sleep. Interruption of sensory pathways does not affect EEG activation. It was hypothesized that cells in the RAS generated forebrain activation and wakefulness. The concept of the RAS has been superseded by the finding that arousal is facilitated not by a single system but instead by several discrete neuronal groups localized within and adjacent to the pontine and midbrain reticular formation and its extension into the hypothalamus (Fig. 7-1). These discrete neuronal groups are identified and differentiated by their expression of molecular machinery that synthesizes and releases specific neurotransmitters and neuromodulators. These include neuronal groups that synthesize serotonin, noradrenalin, histamine, acetylcholine, and orexin/hypocretin (herein called orexin). Each of these systems has been studied extensively in the context of the control of specific aspects of waking behaviors. Here we will give only a brief overview of each, focusing on their contribution to generalized brain arousal or activation. Before proceeding, we point out certain general properties of these neuronal systems. 1. Arousal is a global process, characterized by concurrent changes in several physiologic systems, including autonomic, motor, endocrine, and sensory systems, and in EEG tracings. Thus, it is intriguing that most arousal systems share one critical property: the neurons give rise to long, projecting axons with extensive terminal fields that impinge on multiple regions of the brainstem and forebrain. These diffuse projections enable the systems to have multiple actions, as might be expected of arousal systems. In this review, we emphasize the ascending projections—that is, projections from the brainstem and hypothalamus to the diencephalon, limbic system, and neocortex, as these are particularly germane to the generation of cortical arousal. Some arousal systems also give rise to descending projections, which are also likely to play a role in regulating certain properties of sleep–wake states, such as changes in muscle tone. 2. The release of neurotransmitters and neuromodulators at nerve terminals is initiated by the propagation of action potentials to the terminals. Thus, neurotransmitter release is correlated with the discharge rate of

78  PART I / Section 2  •  Sleep Mechanisms and Phylogeny

Thalamus

BF (ACh)

TMN (HA) SN Raphe VTA (5-HT) (DA)

PPT (ACh) LDT LC (NE)

Reticular formation

A

Cortex Orexin BF TMN

SN VTA

PPT LDT

Raphe LC

B Figure 7-1  A, Sagittal view of a generic mammalian brain providing an overview of the wake-control networks described in the text. The upper brainstem, posterior and lateral hypothalamus, and basal forebrain contain several clusters of neuronal phenotypes, with arousal-inducing properties. These clusters include neurons expressing serotonin (5-HT), norepinephrine (NE), acetylcholine (ACh) in both pontomesencephalic and basal forebrain clusters, dopamine (DA), and histamine (HA). B, Sagittal view of brainstem and diencephalon showing localization of orexin-containing neurons and their projections to both forebrain and brainstem. All of these groups facilitate EEG arousal (waking and REM) and/ or motor-behavioral arousal (waking). The arousal systems facilitate forebrain EEG activation both through the thalamus and the basal forebrain and through direct projections to neocortex. Arousal systems also facilitate motor-behavioral arousal through descending pathways.

neurons. Most arousal systems have been studied by recording the discharge patterns of neurons in “freely moving” animals, in relationship to spontaneously occurring wake and sleep states. Increased discharge during arousal or wake compared with sleep constitutes part of the evidence for an arousal system. 3. The actions of a neurotransmitter on a target system are determined primarily by the properties of the receptors in the target. The neurotransmitters and neuromodulators underlying arousal systems each act on several distinct receptor types, with diverse actions. In addition, postsynaptic effects are regulated by transmitter-specific “reuptake” molecules, which transport the neurotransmitter out of the synaptic space, terminating

its action. Pharmacologic actions are usually mediated by actions on specific receptor types or transporters (see examples later). 4. Chronic lesions of individual arousal systems or genetic knockout (KO) of critical molecules have only small or sometimes no effect on sleep–wake patterns (with the exception of serotonin and orexin KOs; see later), even though acute manipulations of these same systems have strong effects on sleep–wake. The absence of chronic lesions or KO effects is probably explained by the redundancy of the arousal systems, such that, over time, deficiency in one system is compensated for by other systems or by changes in receptor sensitivity. Electrophysiologic studies show that the arousal systems are normally activated and deactivated within seconds or minutes. Thus, effects of acute experimental manipulations of particular arousal-related neurotransmitters, as with administration of a drug, may better mimic the normal physiologic pattern and be more informative as to their function. 5. REM sleep is, on one hand, a sleep state, but, on the other hand, it is associated with neocortical EEG characteristics of wake. In parallel with these two sides of REM, it has been shown that arousal systems can be classified into two types, ones that are “off” in REM, befitting the sleeplike property of REM, and others that are “on” in REM, befitting the wakelike properties of REM. Some arousal-promoting systems (summarized later) also play a role in REM control. Detailed analyses of the control of the role of these systems in REM sleep can be found in Chapters 8 and 9.

WAKE-ON, REM-OFF AROUSAL SYSTEMS Serotonin Neurons containing serotonin, or 5-hydroxytryptamine (5-HT), innervate the forebrain and are found in the dorsal raphe (DR) and median raphe (MR) nuclei of the midbrain. These neurons project to virtually all regions of the diencephalon, limbic system, and neocortex. Although it was initially hypothesized that serotonin might be a sleeppromoting substance,10 much evidence shows that the immediate effect of release of serotonin is arousal (reviewed in reference 11). Although there is some heterogeneity, the discharge rates of most DR and MR neurons are highest during waking, lower during NREM, and there is minimal discharge in REM; release of serotonin in the forebrain is highest in waking. Because of the great diversity of serotonin receptors (there are at least 14 types), the effects of serotonin on target neurons are complex. Some receptor types are inhibitory, some are excitatory. At least one class of receptors (5-HT2A) appears to facilitate NREM sleep; 5-HT2A KO mice have less NREM.12 Another type (5-HT1A) is inhibitory to REM sleep, as 5-HT1A KO mice have increased REM.13 Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are used to treat a variety of medical and psychiatric problems, and some drugs in this class have arousing or alerting properties. Serotonin has a wide range of functions in addition to the modulation of sleep–wake.



Norepinephrine Norepinephrine (NE)-containing neuronal groups in mammals are found throughout the brainstem, but the primary nucleus giving rise to ascending projections is the locus coeruleus (LC). NE neurons in the LC project throughout the diencephalon, forebrain, and cerebellum. LC neurons exhibit regular discharge during waking, reduced discharge during NREM sleep, and near-complete cessation of discharge in REM sleep, a pattern congruent with a role in behavioral arousal.14 Acute inactivation of the LC or a lesion in the ascending pathway from the LC increases slow-wave EEG activity during sleep.15 Distinct roles for alpha-1, alpha-2, and beta NE receptor types are established. Direct application of alpha-1 and beta agonists in preoptic area and adjacent basal forebrain sites induces increased wakefulness (reviewed in reference 16). The arousal-producing effects of psychostimulant drugs such as amphetamines depend partly on induction of increased NE release and inhibition of NE reuptake, as well as on enhanced dopamine action (see later). Histamine Histamine (HA)-containing neurons in mammals are discretely localized in the tuberomamillary nucleus (TMN) and adjacent posterior hypothalamus (PH). HA neurons project throughout the hypothalamus and forebrain, including the neocortex, as well as to the brainstem and spinal cord. Perhaps the most familiar evidence for an arousal-promoting action of central HA is that administration of histamine (H1)-receptor antagonists (antihistamines) that penetrate the blood–brain barrier cause sedation. Transient inactivation of the TMN region results in increased NREM sleep.17 HA neurons exhibit regular discharge during waking, greatly reduced discharge during NREM sleep, and cessation of discharge in REM sleep.18 HA neurons express the inhibitory H3-type autoreceptors. Administration of an antagonist of this receptor causes disinhibition and increased waking. Blockade of the critical HA-synthesizing enzyme increases NREM sleep.19 Orexin The loss of orexin neurons is known to underlie the human disease narcolepsy, whose major symptoms are cataplexy and excessive sleepiness.19-20a Orexin-containing neurons are localized in the midlateral hypothalamus, and like other arousal systems, they give rise to projections to all brain regions including the brainstem.21 Among the targets of orexin terminals are other arousal-promoting neurons including HA, 5-HT, and NE neurons. Orexin-containing neurons are active in waking, and they are “off” in both NREM and REM sleep.22,23 Local administration of orexin in several brain sites induces arousal.24 (See also Chapters 8 and 16.)

WAKE-ON, REM-ON AROUSAL SYSTEMS Acetylcholine Groups of acetylcholine (ACH)-containing neurons are localized in two regions: in the dorsolateral pontomesen-

CHAPTER 7  •  Neural Control of Sleep in Mammals  79

cephalic reticular formation (RF) (the pedunculopontine tegmental [PPT] and laterodorsal tegmental [LDT] nuclei) and in the basal forebrain.25 The pontomesencephalic ACH neuronal group projects to the thalamus, hypothalamus, and basal forebrain; the basal forebrain group projects to the limbic system and neocortex. Neurons in both groups exhibit higher rates of discharge in both waking and REM than in NREM sleep,26 and release of ACH is also increased in these states.27 Pharmacologic blockade of ACH receptors induces EEG synchrony and reduces vigilance, and inhibition of the ACH-degrading enzyme cholinesterase enhances arousal.28 Dopamine Dopamine (DA)-containing neurons are primarily localized in the substantia nigra and the adjacent ventral tegmental area of the midbrain and the basal and medial hypothalamus.29 Putative dopaminergic neurons exhibit highest activity in waking and REM sleep. Release of DA in the frontal cortex is higher during wakefulness than during sleep.30 DA is inactivated primarily through reuptake by the dopamine transporter. Stimulant drugs such as amphetamines and modafinil act primarily through DA receptors, particularly by binding to and suppressing the dopamine transporter, reducing reuptake.31 The degeneration of the nigrostriatal DA system is the primary neuropathologic basis of Parkinson’s disease, and excessive daytime sleepiness is one manifestation of it.32 DA agonists used to treat periodic limb movement in sleep and restless leg syndrome do not usually induce arousal, probably because they have effects on both presynaptic and postsynaptic DA receptors; presynaptic receptors inhibit transmitter release, counteracting postsynaptic stimulation. Glutamate Glutamate (Glu)-containing neurons are found throughout the brain, including in the core of the pontine and midbrain RF.33 However, the projections of the brainstem Glu system have not been described. Glu is the primary excitatory neurotransmitter of the brain. Arousal is increased by application of Glu to many sites.34 Glu actions are mediated by receptors controlling membrane ion flux, including the N-methyl-d-aspartate (NMDA) receptor, and “metabotrophic” receptors controlling intracellular processes. Humans may be exposed to systemic administration of NMDA receptor antagonists in the form of anesthetics (e.g., ketamine) or recreational drugs (PCP). The effects are dosage dependent: low dosages produce arousal, and high dosages produce sedation. In rats, exposure to NMDA antagonists induces a potent long-lasting enhancement of NREM slow-wave activity.35

SLEEP-PROMOTING MECHANISMS We have reviewed evidence for multiple neurochemically specific arousal systems and noted that the activity of each of these neuronal groups is reduced during NREM sleep. In most groups, the reduction in neuronal discharge precedes EEG changes that herald sleep onset. How is the process of sleep onset orchestrated?

80  PART I / Section 2  •  Sleep Mechanisms and Phylogeny

c-Fos Mapping Lesion and stimulation studies argue that the POA must contain sleep-active neurons. This has been confirmed in several species (reviewed in reference 38). The identification of sleep-active POA neurons was advanced by the application of the c-Fos immunostaining method.40 Rapid expression of the protooncogene c-fos has been identified as a marker of neuronal activation in many brain sites.41 Thus, c-Fos immunostaining permits functional mapping of neurons, identifying neurons that were activated in the preceding interval. After sustained sleep, but not waking, a discrete cluster of neurons exhibiting Fos immunoreactivity is found in the ventrolateral preoptic area (VLPO).40 The VLPO is located at the base of the brain, lateral to the optic chiasm. Sleep-related Fos immunoreactive neurons are also localized in the rostral and caudal median preoptic nucleus (MnPN).42 The MnPN is a midline cell group that widens to form a “cap” around the rostral end of the third ventricle. Examples of c-Fos immunostaining and the correlations between c-Fos counts and sleep amounts are shown in Figure 7-2. The number of sleeprelated Fos immunoreactive neurons in the MnPN is increased in rats exposed to a warm ambient temperature, in association with increased NREM sleep.42 The VLPO and the MnPN contain a high density of neurons with sleep-related discharge.43 Most sleep-active

CAUDAL MnPN SLEEP

ROSTRAL MnPN SLEEP

A

B WAKE

WAKE

600 µm

C

300 µm

D

160 120

r22 = 0.89 p2 5 on cardiorespiratory portable monitor

744 primary care patients

Martínez García et al.,104 2003

MODEL

GOLD STANDARD

SUBJECTS

255 patients referred for suspected SDB (training set); 150 similar patients (model testing)

102

Kirby et al.,103 1999

Netzer et al., 1999

REFERENCE

Table 59-2  Value of Historical or Questionnaire-Derived Diagnostic Information in the Diagnosis of Obstructive Sleep Apnea at Sleep Centers: Selected Studies Since 1990—cont’d

670  PART II / Section 8  •  Impact, Presentation, and Diagnosis



CHAPTER 59  •  Use of Clinical Tools and Tests in Sleep Medicine   671

Table 59-3  Estimated Clinical Values of Specific Symptoms in the Diagnosis of Obstructive Sleep Apnea Syndrome, with Reference to Patients Referred to a Sleep Clinic Effect on Probability of OSA SYMPTOM

SYMPTOM PRESENT

SYMPTOM ABSENT

↑↑

↓↓↓

Loud snoring

↑↑↑

↓↓

Observed apneas

↑↑↑

↓

Habitual snoring

Sleepy while driving

↑↑

↓

Sleepy while reading

↑

↓↓

↑

↓

Dry mouth on awakening

↑↑

↓

Nocturia (>1 episode/night)

↑↑

↓

Excessive sweating at night

↑↑

↓

Nocturnal reflux

↑↑

↓

Sleep maintenance insomnia

↑↑

↓↓

Nocturnal restlessness

↑

↓↓

History of hypertension

↑↑

↓

History of stroke

↑↑

↓

Morning headaches

↑ ↑ ↑, large increase; ↑ ↑, moderate increase; ↑, little or no increase. ↓ ↓ ↓, large decrease; ↓ ↓, moderate decrease; ↓, little or no decrease.

This model showed a PPV of 90% and an NPV of 67%. A third model is based on simple neck profile, pharyngeal, and overbite scores; OSA was identified with 40% sensitivity and 96% specificity, which produced a PPV of 95% and an NPV of 49%.24 The neck profile measurement alone accurately excluded OSA in about one quarter of referred patients. Direct comparison of these three models is difficult because the studies used different recording techniques and criteria for OSA. Some physical findings other than craniofacial features and obesity also have value in the diagnosis of OSA. High blood pressure increases the chance that OSA will be present, especially among those persons who are less obese.25 Signs of neuropathy or neuromuscular disease also may increase the likelihood of OSA. Nocturnal Polysomnography A nocturnal, laboratory-based polysomnogram (PSG) is the most commonly used test in the diagnosis of OSA. The PSG often is considered a gold standard for OSA diagnosis, assessment of severity, and identification of some other sleep disorders that can accompany OSA. The PSG allows direct monitoring and quantification of respiratory events and physiologic consequences—such as hypoxemia, arousals, and awakenings—that are believed to cause daytime symptoms. A single-night PSG is usually sufficient to diagnose or to exclude OSA. However, the test is not infallible. Accuracy may be reduced by variability in biologic severity, laboratory equipment, human scoring, or scoring protocols. Night-to-night variability may be particularly high in subjects with low but clinically significant rates of apneas and hypopneas during sleep. In one study, when 11 patients thought likely to have OSA on clinical grounds were restudied after initial normal PSGs, 6 had OSA.26

Although standards for scoring normal sleep were consistent and widely accepted for 4 decades,27 their widespread application to abnormal sleep probably did not serve patient care optimally well. Furthermore, standards for scoring sleep-related breathing abnormalities were not specified in the same document and became far from uniform between laboratories. Variations in practice made interpretation of unfamiliar reports difficult. Most important, the definition of hypopnea varied considerably between laboratories.28 The definition of apnea also varied to some extent. Publication by the American Academy of Sleep Medicine in 2007 of new sleep scoring guidelines also included recommendations for polysomnographic equipment; scoring of abnormal respiratory events, electrocardiographic findings, movements, and arousals during sleep; and modifications necessary for children.29 These guidelines are required for sleep laboratories accredited by the Academy and thereby are serving to increase uniformity of procedures between laboratories in the United States. For sleep-disordered breathing, these guidelines also specify rules for optional scoring of respiratory event– related arousals (RERAs), defined by nasal or esophageal pressure monitoring, in the absence of apneas or hypopneas. Most laboratories report a summary measure, called the apnea-hypopnea index (AHI) or the respiratory disturbance index, that represents the sum total of apneas, hypopneas, and—sometimes in the second case—RERAs per hour of sleep. An index of this type is often given the most weight in interpretation of whether the study shows significant sleep-disordered breathing. Other commonly used results, the extent and frequency of oxygen desaturations, are also tallied and reported. Although the 2007 Manual has greatly advanced clinical care, it does have

672  PART II / Section 8  •  Impact, Presentation, and Diagnosis

some limitations. The large majority of the recommendations were decided by consensus, in the absence of relevant published data, let alone outcome or evidence-based medicine. With respect to sleep-disordered breathing in particular, the hypopnea rule conforms to current Medicare billing requirements, but hypopneas leading to arousals or awakenings, in the absence of significant oxygen desaturation, are not recognized unless a rule labeled “alternative” is used. Furthermore, scoring of RERAs, by nasal or esophageal pressure monitoring, is “optional.” These multiple options, whether or not necessary given health care funding or widespread practice realities, leave significant disparities between laboratory practices, even among those accredited by the American Academy of Sleep Medicine. Furthermore, not all procedure details could be given in the Manual, and some are therefore left for individual laboratory directors to decide. As a result of this and also the imperfect reliability of PSGs, interpretation of PSG reports remains more complicated, especially when studies are performed by unfamiliar laboratories, and PSGs may not be definitive, particularly in borderline cases. Clinical information about the patient must still play an important role in establishing diagnoses and choosing appropriate management options. Specifically, despite researchers’ tendency to use a specified AHI threshold to define OSA, the clinician cannot succumb to the same temptation. An individual patient with an AHI of 40 is at risk for excessive daytime sleepiness and cardiovascular morbidity but may not have either. Conversely, a patient with an AHI of 2 may still have OSA (e.g., because of night-to-night variability in test results) or may have upper airway resistance syndrome with associated sleepiness and morbidity.13,14 Interpretation of a PSG without knowledge of the patient’s clinical presentation can lead to serious underdiagnosis and overdiagnosis. Many clinicians believe that an AHI above 5 suggests OSA, but a large population-based epidemiologic study found that only 22.6% of women and 15.5% of men who met this criterion clearly complained of daytime hypersomnolence.15 Some patients who meet polysomnographic criteria for OSA but do not complain of hypersomnolence have little to gain from treatment.30 Further research is needed to define and to improve the ability of PSGs to measure those aspects of sleepdisordered breathing that most affect health and daytime sleepiness. The AHI and minimum oxygen saturation do not correlate strongly with daytime sleepiness,31 although the AHI may correlate better with cardiovascular morbidity.25 Some patients with RERAs have excessive daytime sleepiness in the absence of a significant AHI.13 Esophageal pressure monitoring, a gold standard in assessment of respiratory effort, facilitates identification of such patients and is particularly helpful when sleep-disordered breathing is evaluated in patients who lack obvious symptoms and signs.12,32 However, criteria for abnormal esophageal pressure recordings, as defined by association with poor outcomes, remain to be studied more definitively. Nasal pressure monitoring may provide a well-tolerated alternative, but identification of more apneic events by this sensitive measure of airflow is not necessarily a diagnostic advantage; studies have yet to demonstrate improved prediction of outcomes, and initial comparisons to thermistor

results show correlations high enough (e.g., 0.90 or higher33) to suggest redundancy of information. Other polysomnographic measures that may (or may not) prove to enhance the ability of PSGs to predict outcomes of sleep-disordered breathing include end-tidal or transcutaneous carbon dioxide monitoring,34 pulse transit time,35 peripheral arterial tonometry,36 scoring of arousals,37 and analysis of respiratory cycle–related electroencephalographic changes.38 In short, the PSG is the single most useful and definitive test in the diagnosis of sleep-related breathing disorders, but the information it provides cannot be reliably interpreted by persons without experience in sleep medicine, summarized by any single number, or applied to patient care without careful use of additional clinical data. Failure to recognize these limitations, by health care policy makers or clinicians, could trigger unnecessary intervention or deprive a patient of effective treatment. Modified Forms of the Polysomnogram In comparison to the standard PSG, daytime nap studies and split-night studies may reduce costs and expedite evaluation. Studies of daytime PSGs have sometimes found a high NPV, with lower PPV, but inconsistent results and the lack of sufficient data explain why daytime PSGs have not generally been recommended.3 A successful split-night study may save a patient from a second night in the sleep laboratory. Initial studies of diagnostic accuracy and treatment outcomes appear promising.39 Although the preferred approach is separate, full night studies for diagnostic assessment and then positive airway pressure titration, split-night studies are now thought to be adequate alternatives in most cases.40 Portable Recording The wide range of recordings that can be performed during sleep in a patient’s home are designed primarily to test for OSA. Portable recordings usually are less costly than laboratory-based PSGs, and patients often prefer home studies to laboratory studies. However, the diagnostic value of unattended portable monitoring is reduced by the inability to make behavioral observations, to standardize recording conditions, to address technical problems, to make interventions during the night, or (in many cases) to monitor variables equivalent to those recorded in the laboratory setting. Portable studies that do not monitor signals necessary to identify sleep stages or leg movements may show respiratory events that cannot be assumed to have occurred during sleep and may fail to demonstrate disorders other than OSA. A Portable Monitoring Task Force of the American Academy of Sleep Medicine recommended home studies only after a comprehensive sleep evaluation by a clinician board eligible or certified in sleep medicine, and then supervised and interpreted by someone with the same level of specialty training.6 This is because published literature about the effectiveness of home studies usually included screening clinical evaluations, differential diagnoses can be broad, home studies must be interpreted with sufficient knowledge of their many limitations in addition to capabilities, and results must be integrated into the context of the patient’s history and physical examination. Under



CHAPTER 59  •  Use of Clinical Tools and Tests in Sleep Medicine   673

these conditions, home studies can be used as an alternative to laboratory-based PSGs when the clinical judgment suggests that pretest probability of moderate to severe OSA is high. Home studies should generally not be used when the patient is a child or older person, significant health comorbidities (such as severe pulmonary disease, neuromuscular disease, or congestive heart failure) are present, additional sleep disorders besides OSA are suspected, or a screening process is needed for asymptomatic individuals, even if at risk because of comorbidities such as hypertension or obesity.6 Home studies may be indicated for patients who do not have access to laboratory-based PSG, cannot tolerate the procedure, or need follow-up assessment of response to non–positive airway pressure treatments of OSA. A recent randomized but not blinded clinical trial supported use of home oximetry as an alternative to more elaborate studies, but only in combination with a sleep specialist evaluation, threshold scores on several screening surveys, absence of significant comorbidities, and other circumstances that in combination applied to less than 4% of referred patients.41 Published guidelines for home studies recommend that at minimum they monitor airflow, respiratory effort, and blood oxygenation, and the equipment should be applied by a sleep technologist or health care practitioner with appropriate training.6 A normal home study generally must be confirmed by a more definitive laboratory-based sleep study. A suggested algorithm for use of home studies is shown in Figure 59-1. Despite limited validation data for many portable recording devices, those that have low costs, high sensitivities, and high specificities have convinced some clinicians that portable studies are cost-effective in comparison to PSGs. However, cost-effectiveness analyses have been scarce (see later). In some situations, home studies could increase costs, delay confirmatory laboratory testing, encourage treatment of patients with false-positive results, or allow development of medical morbidity from undiagnosed and therefore untreated OSA. Nonetheless, Medicare recently approved home studies for justification of the need for home use of continuous positive airway pressure. Coverage of the expense of home studies was motivated in part by evidence that gold standard PSG measures do not necessarily predict symptoms or response to treatment accurately. Whether positive airway pressure is justified by findings of home or laboratory studies, Medicare now requires posttreatment clinical verification that positive airway pressure is used and helpful for the individual patient. Studies of Airway Morphology Although imaging of the upper airway for research purposes has led to a better understanding of OSA pathophysiology, such studies are not routinely performed in diagnostic evaluations of patients, in part because findings that predict OSA or its severity with sufficient accuracy to allow use in management of individual patients have not been identified. However, cephalometric radiography and pharyngoscopy may be useful in preoperative identification of sites of obstruction and in selection of appropriate surgical procedures. The diagnostic value of

PORTABLE MONITORING DECISION TREE Patient presents to BCSS for evaluation of suspected OSA

Does the patient have a high pretest probability of moderate to severe OSA?

Evaluate for other sleep disorders, consider in-lab PSG

No

Yes Does patient have symptoms or signs of comorbid medical disorders?

Yes No

No Does patient have symptoms or Yes In-lab signs of comorbid polysomnography sleep disorders?

OSA diagnosed?

No Sleep study (PM or in-lab PSG)

PM

No

OSA diagnosed?

Yes

Yes

Treatment

Figure 59-1  Recommended use of home studies. BCSS, Boardcatified sleep specialist; OSA, obstructive sleep apnea; PM, portable monitoring; PSG, polysomnography. (Reprinted with permission from Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737-747.)

cephalometrics may be limited in part because only sagittal plane dimensions are provided, and coronal plane dimensions or volume may be more pertinent to OSA.42 Pharyngoscopy allows three-dimensional anatomic characterization, but whether airway collapse with Müller’s maneuver predicts response to uvulopalatopharyngoplasty is debated. Pharyngoscopy may be particularly valuable if it is performed during supine sleep.43 Techniques for quantitative computer-assisted videoendoscopic airway analysis are also being developed and have shown, for example, correlation between the extent of anatomic change after uvulopalatopharyngoplasty and improvement in the AHI.44 Computed tomography and magnetic resonance imaging studies can show upper airway morphology,42 and some authors suggest the potential for clinical usefulness,45 but the value of these techniques in the clinical setting is not well defined. In particular, it is uncertain that imaging techniques more sophisticated and expensive than cephalometric radiographs and pharyngoscopy provide additional, valuable clinical information.

674  PART II / Section 8  •  Impact, Presentation, and Diagnosis

EVALUATION OF HYPERSOMNOLENCE History and Questionnaires The history provides important clues to the severity of hypersomnolence. Direct inquiry about sleepiness can be supplemented by questions about sleepiness in sedentary situations, such as driving, desk work, reading, or watching television. However, patients may report little of the excessive daytime sleepiness suggested by family members, clinical signs, or objective tests. Words other than sleepiness are often used by patients with sleep disorders to describe the chief complaint. Among 190 apneic subjects in one study, preferred terms included lack of energy (40%), tiredness (20%), fatigue (18%), and sleepiness (22%).46 Patients’ opinions about their own sleepiness sometimes show no significant association with results of the Multiple Sleep Latency Test (MSLT).47 Questionnaires such as the Epworth Sleepiness Scale48 and the Stanford Sleepiness Scale49 provide a more formal and perhaps reliable measure of excessive daytime sleepiness. The impact of sleepiness on activities of daily living can be assessed with the Functional Outcomes of Sleep Questionnaire.50 Epworth results correlate reasonably well with patients’ self-ratings for overall sleepiness but not well with MSLT results.51 Although the Epworth Sleepiness Scale and the Stanford Sleepiness Scale can have clinical utility, for example, in monitoring response to treatment over time, they do not substitute for well-validated objective measures of sleepiness. Unfortunately, the ability of subjective tests of sleepiness to predict future health outcomes remains largely unknown. Physical Examination Although the alerting effect of an examination obscures physical signs of sleepiness in most patients, overt signs of sleepiness—such as the inability to stay awake or to keep eyes open in the examination room—have high PPV and may obviate the need for additional tests. The examination may also help distinguish severe sleepiness from stupor due to neurologic impairment or drugs. Nocturnal Polysomnography Many patients referred to sleep centers for excessive daytime sleepiness have nocturnal sleep disorders, and polysomnography is often more notable for the manifestations of such disorders than for signs of excessive daytime sleepiness. Patients whose excessive daytime sleepiness is due to insufficient sleep can show shorter sleep latencies, increased sleep efficiency, decreased stage 1 sleep, and increased amounts of deep non–rapid eye movement (nonREM) sleep and REM sleep. The single polysomnographic variable that best reflects sleepiness, as measured by the mean sleep latency on the MSLT, is nocturnal sleep latency.52 Polysomnographic measures of sleep pathology, such as the AHI and minimum oxygen saturation, show only low magnitudes of correlation with MSLT results.53 Multiple Sleep Latency Test The mean sleep latency on the MSLT is the most commonly used objective measure in assessment of daytime sleepiness.54 The MSLT may contribute to diagnosis but

is usually not sufficient, alone, to establish a diagnosis. The mean sleep latency is most useful when it is clearly abnormally low. A patient with a mean sleep latency of 2 minutes on a properly performed MSLT is unlikely to be exaggerating a complaint of excessive daytime sleepiness, to suffer from fatigue rather than sleepiness, or to be free of any sleep disorder. The MSLT can help determine the clinical significance of a sleep disorder or assess response to treatment. As a general guideline, mean sleep latencies shorter than 8 minutes on a properly conducted MSLT are considered abnormal,54 and latencies shorter than 5 minutes are often taken to indicate severe excessive daytime sleepiness. However, proper interpretation of MSLT results requires integration of other factors and especially knowledge of the limitations of this test. Results may be misleading if they are affected by youth (different criteria apply for children), noise, anxiety, or atypical sleep on the previous night. Use of medications such as stimulants or antidepressants, their recent discontinuance, or inability to be weaned off them at least 10 days before testing can prevent administration of an MSLT or complicate interpretation of results. Sleep apnea and other sleep disorders may make sleep onset more difficult and thereby interfere with the test. In general, the NPV of a long mean sleep latency is less than the PPV of a particularly short mean sleep latency. When an MSLT is normal, clinicians must carefully consider other possible explanations before telling a subjectively sleepy patient that there is no objective evidence of excessive daytime sleepiness. Formal prospective studies of “real-life” outcomes associated with different mean sleep latencies are still needed, but until such data are available, clinicians should realize that MSLT results form a continuum without strictly interpretable cutoffs. Like most other physiologic tests, the MSLT is subject to test-retest biologic variation; a patient’s mean sleep latency may be 4 minutes on one day and 9 minutes on another without any intervening therapy. Communitybased samples of adults show mean sleep latencies of 8 minutes or less in well above 20% of subjects.55 High test-retest reliability among normal subjects56 does not necessarily generalize to patients.57 Interrater reliability can be excellent but adds another source of potential variation in test results. Finally, interpretation of the mean sleep latency on the MSLT must take into account available data on validity of the test. The most consistent data in support of the validity of the MSLT were generated in experiments with sleep deprivation, restriction, or fragmentation. However, in clinical practice, polysomnographic measures of the severity of sleep disorders may show small53,58 or insignificant52,59 correlation with MSLT results. A clinician should not be surprised when a patient with 8 apneic events per hour of sleep has a lower mean sleep latency than a patient who has 50 such events per hour of sleep. Furthermore, despite clear clinical improvement demonstrated by sleep apneic subjects and other patients treated for their sleep disorders, the MSLT does not always reflect the improvement.60,61 Evidence that mean sleep latency on the MSLT does not necessarily parallel other measures of sleepiness or reflect the patient’s symptoms may mean that the MSLT does not measure sleepiness precisely. However, the same



CHAPTER 59  •  Use of Clinical Tools and Tests in Sleep Medicine   675

evidence can also be used to support the importance of the MSLT, which provides unique data not generated by other methods. Sleepiness may have several aspects, some of which are measured better by the MSLT and some by other means.62 The investigators who developed the MSLT originally described it as a measure of physiologic sleep tendency rather than a direct measure of sleepiness.63 The narrower concept may define an important part of the neurophysiologic state of sleepiness without capturing the entire concept. Use of the MSLT in the Diagnosis of Narcolepsy The MSLT criteria for narcolepsy—two or more sleeponset REM periods (SOREMPs) and a short mean sleep latency—were once thought to have high sensitivity and specificity. Original case series suggested that all narcoleptic subjects and virtually no normal controls had two or more SOREMPs64; the PPV of two or more SOREMPs for the diagnosis of narcolepsy was 98%, and the NPV was 89%.65 More recent studies did not find the SOREMP criteria to provide such diagnostic accuracy, partly because the most common reasons for sleep laboratory referral evolved. Two or more SOREMPs were found in 25% of 187 sleep apneic subjects,66 17% of 139 normal subjects,67 and only 83% of 200 narcoleptic subjects who had cataplexy.68 Among 2083 patients evaluated with MSLTs at one sleep center, the PPV of two or more SOREMPs was 57% and the NPV was 98%.69 Other combinations of MSLT and polysomnographic criteria may have additional utility.69 A positive MSLT result is essential to establish a diagnosis of narcolepsy without cataplexy and useful also in making a diagnosis of narcolepsy with cataplexy.5 However, the MSLT results cannot be used alone to diagnose narcolepsy; the presence of SOREMPs must be interpreted in conjunction with other clinical and polysomnographic findings. In particular, the criterion of two or more SOREMPs cannot be used to diagnose narcolepsy when the patient has untreated OSA, upper airway resistance syndrome, or other sleep disorders associated with SOREMPs. As an alternative to the MSLT, cerebrospinal fluid hypocretin-1 levels can be used to confirm narcolepsy with cataplexy. These levels are low (≤110 pg/ mL or one third of the mean for controls) in more than 90% of affected patients but almost never among patients without this diagnosis.5 Variations of the Multiple Sleep Latency Test and Other Physiologic Tests Results of the Maintenance of Wakefulness Test (MWT) can differ markedly from those of the MSLT,70 but whether the MWT results are more predictive of adverse effects of sleepiness in daily life remains unknown. Results of both the MWT and MSLT can be influenced by the patient’s motivation.71 The MWT results correlate with measures of sleep apnea severity to about the same extent as MSLT results do72 but may better reflect improvement with treatment.70 Shorter sleep latencies on MWTs correlate with increased errors on driving simulation tests.73,74 However, until MWT and MSLT results are shown to differ in a clinically meaningful way, the MSLT continues to offer advantages of more published experience, familiarity among clinicians, and relevance to the diagnosis of narco-

lepsy. The Federal Aviation Administration and other agencies may at times request or require an MWT, but given the dearth of proven real-life predictive value, the role of this test or the MSLT in predicting workplace safety remains controversial.75,76 Other MSLT modifications, for which limited validity data exist, include the assignment of a simple performance task during the nap attempts77; a formula to combine quantities of sleep stages attained on naps into an overall polygraphic score of sleepiness78; calculation of mean wake efficiencies (100% minus time asleep during nap attempt) as an alternative to mean sleep latencies79; definition of sleep onset by a subject’s failure to respond to an intermittent light signal80; and use of survival analysis methods to better incorporate information from nap attempts on which no sleep was obtained.81 In the clinical setting, none of these modifications has a well-established role in the evaluation of hypersomnolence; neither do a range of other physiologic tests, including pupillometry and brainstem auditory evoked potentials. A variety of performancebased tests are used, usually in research settings, to assess variables related to sleepiness. Examples are the Psychomotor Vigilance Task82 and the Steer Clear driving simulation test.83

EVALUATION OF INSOMNIA Like excessive daytime sleepiness, the complaint of inadequate, insufficient, or nonrestorative sleep can have many different causes. However, causes of insomnia are often diagnosed by history alone.84 In part because the gold standard is not a physiologic test, few data are available with which to assess the relative value of individual symptoms. Predictive values for some symptoms are likely to be high because symptoms define the disorders. When a history does not reveal a cause of the insomnia, polysomnography may be useful (see later), but referral to an appropriate specialist for further history taking and evaluation is sometimes necessary. For example, if the sleep clinician cannot thoroughly evaluate a patient for depression, a psychiatrist or psychologist may be better able to establish a diagnosis and treatment regimen that will lead to resolution of the patient’s insomnia. Psychometric tests can reveal cognitive differences between insomniac subjects and normal controls,85 but these tests are not commonly used for diagnostic purposes in the clinical sleep medicine setting. Sleep logs are an important tool in the evaluation of insomnia,86 but data on their predictive value have not been published. Logs are not necessary to establish the presence of insomnia but can help define severity and facilitate identification of causes such as inadequate sleep hygiene, delayed sleep phase syndrome, or psychophysiologic insomnia. The physical and mental status examinations may provide clues that the cause of a patient’s insomnia is an underlying medical or psychiatric illness, such as hyperthyroidism, asthma, benign prostatic hypertrophy, painful lumbar radiculopathy, arthritis, depression, or anxiety. The importance and focus of an examination vary according to what is learned from the history. A patient’s history and physical examination sometimes suggest that insomnia

676  PART II / Section 8  •  Impact, Presentation, and Diagnosis

may be due to sleep-disordered breathing, periodic limb movement disorder, or uncertain causes. In such cases, polysomnography can be an important aid to diagnosis.87 If insomnia fails to respond to treatment for initial diagnoses, polysomnography also may be useful. Polysomnography may be indicated for patients who have precipitous arousals with violent or injurious behavior.84 Polysomnography may also be useful in some cases when sleep state misperception is suspected. However, injudicious use of polysomnography can sometimes enhance an insomniac person’s conviction that symptoms are due to physical rather than behavioral causes or lead to diagnoses that eventually prove irrelevant to the main complaint. Polysomnography is not indicated for routine evaluation of insomnia that is transient or chronic, due to psychiatric disorders, associated with dementia, or found in the many conditions (such as fibromyalgia) that are associated with the alpha-delta sleep pattern.84

EVALUATION FOR SUSPECTED PARASOMNIAS With the notable exception of REM sleep behavior disorder, parasomnias often can be diagnosed by history alone.5 Information obtained from a bed partner may contribute more than that obtained from the patient. Classic descriptions can be diagnostic for disorders such as sleep terrors, rhythmic movement disorder, sleep paralysis, sleep bruxism, and sleep enuresis. However, the history in such cases occasionally can be misleading, as when one patient’s nocturnal behaviors and bed wetting episodes were shown by polysomnography to occur only during wakefulness.88 Furthermore, some parasomnia presentations commonly lead to a differential diagnosis that frequently requires clarification by polysomnography. For example, the differential diagnosis for a middle-aged adult who presents with behavioral episodes at night may include not only sleepwalking but also REM sleep behavior disorder and complex partial seizures. The physical examination of patients evaluated for parasomnias can be useful, but its value is not well quantified. Some signs may suggest sleep apnea as an underlying trigger for confusional arousals, sleepwalking, sleep terrors, REM sleep behavior disorder, or nocturnal enuresis. Worn occlusive surfaces of molars can provide key evidence of sleep bruxism. The urogenital examination is important in patients thought to have impaired sleep-related penile erections, sleep-related painful erections, or sleep enuresis. Endocrine, cardiac, vascular, and neurologic examination findings can also show a cause of erectile dysfunction. A neurologic examination may suggest a primary cause of sleep enuresis or REM sleep behavior disorder. Similarly, appropriate laboratory findings may be helpful in some cases; for example, a urinalysis may reveal the cause of sleep enuresis. Few studies have examined the predictive value of polysomnography for parasomnia diagnoses. When the behavior in question occurs during polysomnography, the diagnostic value of the test is likely to be high, especially if appropriate additional recording devices, such as extra electroencephalographic leads, extra surface electromyographic leads, or video monitoring, are used.89 Unfortu-

nately, polysomnography often fails to document the behavior—especially in cases of suspected REM sleep behavior disorder, sleepwalking, night terrors, and epilepsy—either because the behavior does not occur on most nights or perhaps because the sleep laboratory is not an environment familiar to the patient. However, other findings during polysomnography can have positive predictive value. Examples include excessive limb twitching during REM sleep in a patient tested for REM sleep behavior disorder and spike and wave complexes in the electroencephalographic examination of a patient thought to have epilepsy. The electromyographic abnormalities in REM sleep behavior disorder can be quantified by eye or computer, in a manner that leads to good sensitivity (about 89% to 100% in a small series of patients with and without neurodegenerative disorders) and reasonable specificity (57% to 71%) against a clinical diagnosis based on accepted diagnostic criteria.90-92 For evaluation of parasomnias, the NPV of a completely normal study is less clear than the PPV of an abnormal study. In one series of 122 patients with suspected parasomnias, one or two nights of polysomnography with video monitoring contributed useful diagnostic information in more than 50% of the cases.89

BEYOND SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUE: DECISION AND COST-EFFECTIVENESS ANALYSES Data on sensitivity, specificity, pretest probability, and utility of outcomes can be used to construct a decision analysis. A clinical decision analysis typically models a choice between diagnostic and therapeutic alternatives. Logical rules are used to weigh information and to make the best decision for an individual patient.93 Decision analysis may be useful, for example, when one procedure has a high probability of a small benefit but an alternative has a low probability of a large benefit. Physicians often attempt a similar mental process but do not usually make optimal use of their own beliefs about probabilities and values of outcomes. Beyond utility, economic data on a procedure can include cost studies, cost-effectiveness analyses that compare different methods to achieve the same end, costutility analyses that compare costs per common unit of utility (often quality-adjusted life years), and cost-benefit analyses that compare monetary costs with monetary gains.94 Such studies require quantitative information on costs and outcomes, data that are not abundant for sleep disorders.95,96 Despite uncertainty of some important data points, one published cost-utility model focused on the decision of whether to diagnose OSA with the aid of a polysomnography, portable cardiorespiratory monitoring, or no ancillary test.97 Polysomnography generated higher utility than the other diagnostic options did, and the magnitude of the advantage of polysomnography easily justified the added initial expense. This result appeared to reflect the high utility of an OSA diagnosis and the expense of diagnostic mistakes. These findings highlight the importance of performing decision and cost-utility analyses before conclusions are made about relative values of diagnostic tests.



CHAPTER 59  •  Use of Clinical Tools and Tests in Sleep Medicine   677

❖  Clinical Pearl Evaluation of common sleep complaints is based on symptoms, signs, and test results, combined with an understanding of the diagnostic value that each type of data contributes.

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678  PART II / Section 8  •  Impact, Presentation, and Diagnosis 45. Suto Y, Matsuda E, Inoue Y, et al. Sleep apnea syndrome: comparison of MR imaging of the oropharynx with physiologic indexes. Radiology 1997;201:393-398. 46. Chervin RD. Sleepiness, fatigue, tiredness, and lack of energy in obstructive sleep apnea. Chest 2000;118:372-379. 47. Chervin RD, Aldrich MS, Pickett R, et al. Comparison of the results of the Epworth Sleepiness Scale and the multiple sleep latency test. J Psychosom Res 1997;42:145-155. 48. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540-545. 49. Hoddes E, Dement W, Zarcone V. The development and use of the Stanford Sleepiness Scale (SSS). Psychophysiology 1972;9: 150. 50. Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status outcomes for disorders of excessive sleepiness. Sleep 1997;20:835-843. 51. Chervin RD, Aldrich MS. The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea. Neurology 1999;52:125-131. 52. Chervin RD, Kraemer HC, Guilleminault C. Correlates of sleep latency on the multiple sleep latency test in a clinical population. Electroencephalogr Clin Neurophysiol 1995;95:147-153. 53. Chervin RD, Aldrich MS. The relation between MSLT findings and the frequency of apneic events in REM and NREM sleep. Chest 1998;113:980-984. 54. Littner MR, Kushida C, Wise M, et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28:113-121. 55. Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain 2006;129:1609-1623. 56. Zwyghuizen-Doorenbos A, Roehrs T, Schaefer M, et al. Test-retest reliability of the MSLT. Sleep 1988;11:562-565. 57. Roehrs T, Roth T. Multiple sleep latency test: technical aspects and normal values. J Clin Neurophysiol 1992;9:63-67. 58. Guilleminault C, Partinen M, Quera-Salva MA, et al. Determinants of daytime sleepiness in obstructive sleep apnea. Chest 1988;94: 32-37. 59. Cheshire K, Engleman H, Deary I, et al. Factors impairing daytime performance in patients with sleep apnea/hypopnea syndrome. Arch Intern Med 1992;152:538-541. 60. Engleman HM, Martin SE, Deary IJ, et al. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994;343:572-575. 61. Sangal RB, Thomas L, Mitler MM. Disorders of excessive sleepiness: treatment improves ability to stay awake but does not reduce sleepiness. Chest 1992;102:699-703. 62. Chervin RD, Guilleminault C. Assessment of sleepiness in clinical practice. Nat Med 1995;1:1252-1253. 63. Carskadon MA, Dement WC. The multiple sleep latency test: what does it measure? Sleep 1982;5:S67-S72. 64. Richardson GS, Carskadon MA, Flagg W, et al. Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 1978;45:621-627. 65. Amira SA, Johnson TS, Logowitz NB. Diagnosis of narcolepsy using the multiple sleep latency test: analysis of current laboratory criteria. Sleep 1985;8:325-331. 66. Biniaurishvili RG, Fry JM, DiPhillipo MA, et al. MSLT REM sleep episodes, excessive daytime sleepiness and sleep structure in obstructive sleep apnea patients. Sleep Res 1994;23:231. 67. Bishop C, Rosenthal L, Helmus T, et al. The frequency of multiple sleep onset REM periods among subjects with no excessive daytime sleepiness. Sleep 1996;19:727-730. 68. Moscovitch A, Partinen M, Guilleminault C. The positive diagnosis of narcolepsy and narcolepsy’s borderland. Neurology 1993;43: 55-60. 69. Aldrich MS, Chervin RD, Malow BA. Value of the Multiple Sleep Latency Test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620-629. 70. Sangal RB, Thomas L, Mitler MM. Maintenance of Wakefulness Test and Multiple Sleep Latency Test: measurement of different abilities in patients with sleep disorders. Chest 1992;101:898902.

71. Bonnet MH, Arand DL. Impact of motivation on Multiple Sleep Latency Test and Maintenance of Wakefulness Test measurements. J Clin Sleep Med 2005;1:386-390. 72. Poceta JS, Timms RM, Jeong DU, et al. Maintenance of wakefulness test in obstructive sleep apnea syndrome. Chest 1992;101: 893-897. 73. Sagaspe P, Taillard J, Chaumet G, et al. Maintenance of wakefulness test as a predictor of driving performance in patients with untreated obstructive sleep apnea. Sleep 2007;30:327-330. 74. Philip P, Sagaspe P, Taillard J, et al. Maintenance of Wakefulness Test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64:410-416. 75. Arand DL. The MSLT/MWT should be used for the assessment of workplace safety. J Clin Sleep Med 2006;2:124-127. 76. Bonnet MH. The MSLT and MWT should not be used for the assessment of workplace safety. J Clin Sleep Med 2006;2: 128-131. 77. Naitoh P, Kelly TL. Modification of the Multiple Sleep Latency Test. In: Ogilvie RD, Harsh JR, editors. Sleep onset: normal and abnormal processes. New York: Wiley; 1995. p. 327-338. 78. Roth B, Nevsimalova S, Sonka K, et al. An alternative to the multiple sleep latency test for determining sleepiness in narcolepsy and hypersomnia: polygraphic score of sleepiness. Sleep 1986;9: 243-245. 79. Pollak CP. How should the multiple sleep latency test be analyzed? Sleep 1997;20:34-39. 80. Bennett LS, Stradling JR, Davies RJ. A behavioural test to assess daytime sleepiness in obstructive sleep apnoea. J Sleep Res 1997;6:142-145. 81. Punjabi NM, O’Hearn DJ, Neubauer DN, et al. Modeling hypersomnolence in sleep-disordered breathing. Am J Respir Crit Care Med 1999;159:1703-1709. 82. Kribbs NB, Pack AI, Kline LR, et al. Effects of one night without nasal CPAP treatment on sleep and sleepiness in patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:1162-1168. 83. Findley L, Unverzagt M, Guchu R, et al. Vigilance and automobile accidents in patients with sleep apnea or narcolepsy. Chest 1995;108:619-624. 84. Littner M, Hirshkowitz M, Kramer M, et al. Practice parameters for using polysomnography to evaluate insomnia: an update. Sleep 2003;26:754-760. 85. Hauri PJ. Cognitive deficits in insomnia patients. Acta Neurol Belg 1997;97:113-117. 86. Spielman AJ, Nunes J, Glovinsky PB. Insomnia. Neurol Clin 1996; 14:513-543. 87. Reite M, Buysse D, Reynolds C, et al. The use of polysomnography in the evaluation of insomnia. Sleep 1996;18:58-70. 88. Molaie M, Deutsch GK. Psychogenic events presenting as parasomnias. Sleep 1997;20:402-405. 89. Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066. 90. Lapierre O, Montplaisir J. Polysomnographic features of REM sleep behavior disorder. Neurology 1992;42:1371-1374. 91. Consens FB, Chervin RD, Koeppe RA, et al. Validation of a polysomnographic score for REM sleep behavior disorder. Sleep 2005;28:993-997. 92. Burns JW, Consens FB, Little RJ, et al. EMG variance during polysomnography as an assessment for REM sleep behavior disorder. Sleep 2007;30:1771-1778. 93. Weinstein MC, Fineberg HV, Elstein AS, et al. Clinical decision analysis. Philadelphia: Saunders; 1980. 94. Crawford B. Clinical economics and sleep disorders. Sleep 1997;20:829-834. 95. Rodenstein DO. Sleep apnoea syndrome: the health economics point of view. Monaldi Arch Chest Dis 2003;55:404-410. 96. Martin SA, Aikens JE, Chervin RD. Toward cost-effectiveness analysis in the diagnosis and treatment of insomnia. Sleep Med Rev 2004;8:63-72. 97. Chervin RD, Murman DL, Malow BA, et al. Cost-utility of three approaches to the diagnosis of sleep apnea: polysomnography, home testing, and empirical therapy. Ann Intern Med 1999;130: 496-505. 98. Bliwise DL, Nekich JC, Dement WC. Relative validity of selfreported snoring as a symptom of sleep apnea in a sleep clinic population. Chest 1991;99:600-608.



CHAPTER 59  •  Use of Clinical Tools and Tests in Sleep Medicine   679

99. Rauscher H, Popp W, Zwick H. Model for investigating snorers with suspected sleep apnoea. Thorax 1993;48:275-279. 100. Douglass AB, Bornstein R, Nino-Murcia G, et al. The sleep disorders questionnaire I: creation and multivariate structure of SDQ. Sleep 1994;17:160-167. 101. American Sleep Disorders Association. International classification of sleep disorders, revised: diagnostic and coding manual. Rochester, Minn: American Sleep Disorders Association; 1997. 102. Netzer NC, Stoohs RA, Netzer CM, et al. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med 1999;131:485-491. 103. Kirby SD, Danter W, George CFP, et al. Neural network prediction of obstructive sleep apnea from clinical criteria. Chest 1999;116:409-415.

104. Martínez García MA, Soler Cataluña JJ, Román Sánchez P, et al. Clinical predictors of sleep apnea-hypopnea syndrome susceptible to treatment with continuous positive airway pressure. Arch Bronconeumol 2003;39:449-454. 105. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire—a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008;108:812-821. 106. Chung F, Yegneswaran B, Liao P, et al. Validation of the Berlin questionnaire and American Society of Anesthesiologists checklist as screening tools for obstructive sleep apnea in surgical patients. Anesthesiology 2008;108:822-830.

Classification of Sleep Disorders Michael J. Thorpy Abstract The classification of sleep disorders is necessary to discriminate between disorders and to facilitate an understanding of symptoms, etiology, pathophysiology, and treatment. The earliest classification systems were largely organized according to the major symptoms (insomnia, excessive sleepiness, and abnormal events that occur during sleep), because the pathophysiologic basis for many of the sleep disorders was unknown. These three categories provide a classification system that is easily understood by physicians and that is useful for developing a differential diagnosis. With the development of modern sleep research, some categories can now be based on patho-

The classification of sleep disorders has been of particular interest to clinicians ever since sleep disorders were first recognized. The first major classification, the Diagnostic Classification of Sleep and Arousal Disorders, published in 1979,1 organized the sleep disorders into categories that formed the basis of the current classification systems. In 1990, the International Classification of Sleep Disorders (ICSD) was produced after a 5-year process, initiated by the American Sleep Disorders Association (ASDA), that involved the three major international sleep societies at that time: the European Sleep Research Society, the Japanese Society of Sleep Research, and the Latin American Sleep Society. It resulted in the production of a diagnostic and coding manual, the International Classification of Sleep Disorders: Diagnostic and Coding Manual.2 The ICSD classification, developed primarily for diagnostic, epidemiologic, and research purposes, has been widely used by clinicians and has allowed better international communication in sleep disorder research. In 2003, the American Academy of Sleep Medicine, formerly the ASDA, began a complete revision and update of the ICSD. The resulting text, the International Classification of Sleep Disorders, version 2 (ICSD-2), was published in 2005 (Table 60-1).3 The ICSD-2 classification lists 85 sleep disorders, each presented in detail and with a descriptive diagnostic text that includes specific diagnostic criteria. The ICSD-2 has eight major categories: the insomnias, sleep-related breathing disorders, hypersomnias of central origin, circadian rhythm sleep disorders, the parasomnias, sleep-related movement disorders, isolated symptoms that are apparently normal variants and unresolved issues, and other sleep disorders. Most of the world uses the ICD-10 for classification of diseases. The ICD-10 transition date in the USA is October 1, 2013. This chapter includes these ICD-10 sleep codes.3a

INSOMNIAS The insomnias are defined by a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate time and opportunity for sleep, 680

Chapter

60

physiology. The International Classification of Sleep Disorders, version 2 (ICSD-2), published in 2005, combines a symptomatic presentation (e.g., insomnia) with one organized in part on pathophysiology (e.g., circadian rhythms) and in part on body systems (e.g., breathing disorders). This organization is necessary because of the varied nature of the sleep disorders and because the pathophysiology for many of the disorders is unknown. The ICSD-2 is not just a listing of the sleep disorders but is also a manual that lists relevant information on the diagnostic features and epidemiology to help the reader more easily differentiate between the disorders.

and they result in some form of daytime impairment (see Section 10). Insomnia complaints typically include difficulty initiating or maintaining sleep (or both), and they usually include extended periods of nocturnal wakefulness or insufficient amounts of nocturnal sleep. Occasionally, insomnia complaints are characterized by the perception of poor quality, or nonrestorative, sleep, even when the amount and quality of the usual sleep episode is considered to be normal or adequate. The insomnias can be either primary or secondary. Secondary forms can occur when the insomnia is a symptom of a medical or psychiatric illness, another sleep disorder, or substance abuse. Primary insomnias may have both intrinsic and extrinsic factors involved in their etiology, but they are not regarded as being secondary to another disorder. Primary Insomnia There are six types of primary insomnia. Psychophysiologic insomnia4,5 is a common form of insomnia that is present for at least 1 month and is characterized by a heightened level of arousal with learned sleep-preventing associations. There is an overconcern with the inability to sleep. Paradoxical insomnia (formerly known as sleep state misperception),6,7 is a complaint of severe insomnia that occurs without evidence of objective sleep disturbance and without daytime impairment to the extent that would be suggested by the amount of sleep disturbance reported. The patient often reports little or no sleep on most nights. It is thought to occur in up to 5% of insomniac patients. Adjustment sleep disorder8,9 is insomnia that is associated with a specific stressor. The stressor can be psychological, physiologic, environmental, or physical. This disorder exists for a short period, usually days to weeks, and usually resolves when the stressor is no longer present. Inadequate sleep hygiene10,11 is a disorder associated with common daily activities that are inconsistent with good-quality sleep and full daytime alertness. Such activities include irregular sleep onset and wake times, stimulating and alerting activities before bedtime, and substances (e.g., alcohol, caffeine, cigarette smoke) ingested around



CHAPTER 60  •  Classification of Sleep Disorders  681

Table 60-1  ICSD-2 Sleep Disorder Categories and Individual Sleep Disorders SLEEP DISORDERS

ICD-9-CM

ICD-10-CM

Adjustment sleep disorder (acute insomnia)

307.41

F 51.02

Psychophysiologic insomnia

307.42

F 51.04

Paradoxical insomnia (formerly sleep state misperception)

307.42

F 51.03

Idiopathic insomnia

307.42

F 51.01

Insomnia due to mental disorder

307.42

F 51.05

V69.4

Z72.821

Insomnias

Inadequate sleep hygiene

307.42

—

Sleep-onset association type

Behavioral insomnia of childhood

—

Z73.810

Limit-setting sleep type

—

Z73.811

Combined type

—

Z73.812

Insomnia due to drug or substance

292.85

G47.02

Insomnia due to medical condition (code also the associated medical condition)

327.01

G47.01

Insomnia not due to a substance or known physiologic condition, unspecified

780.52

F51.09

Physiologic (organic) insomnia, unspecified; (organic insomnia, NOS)

327.00

G47.09

Primary central sleep apnea

327.21

G47.31

Central sleep apnea due to Cheyne Stokes breathing pattern

768.04

R06.3

Central sleep apnea due to high altitude periodic breathing

327.22

G47.32

Central sleep apnea due to a medical condition, not Cheyne-Stokes

327.27

G47.31

Central sleep apnea due to a drug or substance

327.29

F10-19

Primary sleep apnea of infancy

770.81

P28.3

Obstructive sleep apnea, adult

327.23

G47.33

Obstructive sleep apnea, pediatric

327.23

G47.33

Sleep-related nonobstructive alveolar hypoventilation, idiopathic

327.24

G47.34

Congenital central alveolar hypoventilation syndrome

327.25

G47.35

Sleep-related hypoventilation or hypoxemia due to pulmonary parenchymal or vascular pathology

327.26

G47.36

Sleep-related hypoventilation or hypoxemia due to lower airways obstruction

327.26

G47.36

Sleep-related hypoventilation or hypoxemia due to neuromuscular or chest wall disorders

327.26

G47.36

320.20

G47.30

Narcolepsy with cataplexy

347.01

G47.411

Narcolepsy without cataplexy

347.00

G47.419

Narcolepsy due to medical condition

347.10

G47.421

Narcolepsy, unspecified

347.00

G47.43

Recurrent hypersomnia

780.54

G47.13

Kleine-Levin syndrome

327.13

G47.13

Menstrual-related hypersomnia

327.13

G47.13

Idiopathic hypersomnia with long sleep time

327.11

G47.11

Idiopathic hypersomnia without long sleep time

327.12

G47.12

Behaviorally induced insufficient sleep syndrome

307.44

F51.12

Hypersomnia due to medical condition

327.14

G47.14

Hypersomnia due to drug or substance

292.85

G47.14

Sleep-Related Breathing Disorders Central Sleep Apnea Syndromes

Obstructive Sleep Apnea Syndromes

Sleep-Related Hypoventilation and Hypoxemic Syndromes

Sleep-Related Hypoventilation and Hypoxemia Due to a Medical Condition

Other Sleep-Related Breathing Disorder Sleep apnea or sleep-related breathing disorder, unspecified Hypersomnias of Central Origin

Continued

682  PART II / Section 8  •  Impact, Presentation, and Diagnosis Table 60-1  ICSD-2 Sleep Disorder Categories and Individual Sleep Disorders—cont’d SLEEP DISORDERS

ICD-9-CM

ICD-10-CM

Hypersomnia not due to a substance or known physiologic condition

327.15

F51.1

Physiologic (organic) hypersomnia, unspecified (organic hypersomnia, NOS)

327.10

G47.10

Circadian rhythm sleep disorder, delayed sleep phase type

327.31

G47.21

Circadian rhythm sleep disorder, advanced sleep phase type

327.32

G47.22

Circadian rhythm sleep disorder, irregular sleep–wake type

327.33

G47.23

Circadian rhythm sleep disorder, free-running (nonentrained) type

327.34

G47.24

Circadian rhythm sleep disorder, jet lag type

327.35

G47.25

Circadian rhythm sleep disorder, shift-work type

327.36

G47.26

Circadian rhythm sleep disorders due to medical condition

327.37

G47.27

Other circadian rhythm sleep disorder

327.39

G47.29

Other circadian rhythm sleep disorder due to drug or substance

292.85

G47.27

Confusional arousals

327.41

G47.51

Sleepwalking

307.46

F51.3

Sleep terrors

307.46

F51.4

REM sleep behavior disorder (including parasomnia overlap disorder and status dissociatus)

327.42

G47.52

Recurrent isolated sleep paralysis

327.43

G47.53

Nightmare disorder

307.47

F51.5

Sleep-related dissociative disorders

300.15

F44.9

Sleep enuresis

788.36

N39.44

Sleep-related groaning (catathrenia)

327.49

G47.59

Exploding head syndrome

327.49

G47.59

Sleep-related hallucinations

368.16

R29.81

Sleep-related eating disorder

327.49

G47.59

Parasomnia, unspecified

227.40

G47.50

Parasomnia due to a drug or substance

292.85

G47.54

Parasomnia due to a medical condition

327.44

G47.54

Restless legs syndrome (including sleep-related growing pains)

333.49

G25.81

Periodic limb movement sleep disorder

327.51

G47.61

Sleep-related leg cramps

327.52

G47.62

Sleep-related bruxism

327.53

G47.63

Sleep-related rhythmic movement disorder

327.59

G47.69

Sleep-related movement disorder, unspecified

327.59

G47.90

Sleep-related movement disorder due to drug or substance

327.59

G47.67

Sleep-related movement disorder due to medical condition

327.59

G47.67

Long sleeper

307.49

R29.81

Short sleeper

307.49

R29.81

Snoring

786.09

R06.83

Sleeptalking

307.49

R29.81

Sleep starts, hypnic jerks

307.47

R25.8

Benign sleep myoclonus of infancy

781.01

R25.8

Circadian Rhythm Sleep Disorders

Parasomnias Disorders of Arousal (from Non-REM Sleep)

Parasomnias usually associated with REM sleep

Sleep-Related Movement Disorders

Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues

Hypnagogic foot tremor and alternating leg muscle activation during sleep

781.01

R25.8

Propriospinal myoclonus at sleep onset

781.01

R25.8

Excessive fragmentary myoclonus

781.01

R25.8 Continued



CHAPTER 60  •  Classification of Sleep Disorders  683

Table 60-1  ICSD-2 Sleep Disorder Categories and Individual Sleep Disorders—cont’d SLEEP DISORDERS

ICD-9-CM

ICD-10-CM

Other physiologic (organic) sleep disorder

327.8

G47.8

Other sleep disorder not due to a known substance or physiologic condition

327.8

G47.9

307.48

F51.8

Other Sleep Disorders

Environmental sleep disorder Sleep Disorders Associated with Conditions Classifiable Elsewhere Fatal familial insomnia

046.8

A81.8

Fibromyalgia

729.1

M79.7

345

G40.5

Sleep-related epilepsy Sleep-related headaches

784.0

R51

Sleep-related gastroesophageal reflux disease

530.1

K21.9

Sleep-related coronary artery ischemia

411.8

I25.6

Sleep-related abnormal swallowing, choking, and laryngospasm

787.2

R13.1

Other Psychiatric or Behavioral Disorders Commonly Encountered in the Differential Diagnosis of Sleep Disorders Mood disorders

—

—

Anxiety disorders

—

—

Somatoform disorders

—

—

Schizophrenia and other psychotic disorders

—

—

Disorders usually first diagnosed in infancy, childhood, or adolescence

—

—

Personality disorders

—

—

ICD-9, International Classification of Diseases, 9th Revision; ICD-10, International Classification of Diseases, 10th Revision; ICSD-2, International Classification of Sleep Disorders, Revised; NOS, not otherwise specified. Courtesy of the American Academy of Sleep Medicine, Chicago, Ill.

sleep time. These practices do not necessarily cause sleep disturbance in other people. For example, an irregular bedtime or wake time that produces insomnia in one person may not be important in another. Idiopathic insomnia12,13 is a long-standing form of insomnia that appears to date from childhood and has an insidious onset. Typically, there are no factors associated with the onset of the insomnia, which is persistent and without periods of remission. Behavioral insomnia of childhood14,15 includes limitsetting sleep disorder and sleep-onset association disorder. Limit-setting sleep disorder is a stalling or a refusing to go to sleep that is eliminated once a caretaker enforces limits on sleep times and other sleep-related behaviors. Sleeponset association disorder occurs when there is reliance on inappropriate sleep associations, such as rocking, watching television, holding a bottle or other object, or requiring environmental conditions such as a lighted room or an alternative place to sleep.

insomnia. The insomnia may be associated with the ingestion or discontinuation of the substance.20,21 Excessive use or dependency is not a feature of this diagnosis. Insomnia not due to a substance or known physiologic condition22,23 (formerly associated with other mental/behavioral factors) is the diagnosis applied when an underlying mental disorder is associated with the occurrence of the insomnia and when the insomnia constitutes a distinct complaint or focus of treatment. Differentiation between the two diagnoses, inadequate sleep hygiene and other insomnia due to a substance requires some elaboration. Caffeine ingestion in the form of coffee or soda can produce a disorder of inadequate sleep hygiene, if the intake amount is normal and within the limits of common use but the timing of ingestion is inappropriate. On the other hand, ingestion of caffeine in an amount that is considered excessive by normal standards can lead to a diagnosis of other insomnia due to a substance.

Secondary Insomnia The ICSD-2 classification lists several secondary insomnias. Insomnia due to medical condition16,17 is applied when a medical or neurologic disorder gives rise to the insomnia. The medical disorder and the insomnia type are given with the diagnosis. Insomnia due to drug or substance18,19 is applied when there is dependence on or excessive use of a substance such as alcohol, a recreational drug, or caffeine that is associated with the occurrence of the

SLEEP-RELATED BREATHING DISORDERS The disorders in this group are characterized by disordered respiration during sleep (see Section 13). Central apnea syndromes24,25 include those in which respiratory effort is diminished or absent in an intermittent or cyclic fashion as a result of central nervous system dysfunction. Other central sleep apnea forms are associated with

684  PART II / Section 8  •  Impact, Presentation, and Diagnosis

underlying pathologic or environmental causes, such as Cheyne–Stokes breathing pattern26,27 or high-altitude periodic breathing.28,29 Primary Sleep Apneas Primary central sleep apnea is a disorder of unknown cause characterized by recurrent episodes of cessation of breathing during sleep without associated ventilatory effort. A complaint of excessive daytime sleepiness, insomnia, or difficulty breathing during sleep is reported. The patient must not be hypercapnic (Pco2 greater than 45 mm Hg). This diagnosis requires that five or more apneic episodes per hour of sleep be seen by polysomnography. Central sleep apnea resulting from the Cheyne–Stokes breathing pattern is characterized by recurrent apneas or hypopneas alternating with prolonged hyperpnea in which tidal volume waxes and wanes in a crescendo–decrescendo pattern. This pattern does not occur in rapid eye movement (REM) sleep but is characteristically seen in non-REM (NREM) sleep. The pattern is typically seen in medical disorders such as heart failure, cerebrovascular disorders, and kidney failure. Central sleep apnea resulting from high-altitude periodic breathing30,31 is characterized by sleep disturbance that is caused by cycling periods of apnea and hyperpnea without ventilatory effort. The cycle length is typically between 12 and 34 seconds. Five or more central apneas per hour of sleep are required to make the diagnosis. Most people have this ventilatory pattern at elevations greater than 7600 meters, and some have it at lower altitudes. A secondary form of central sleep apnea resulting from drug or substance (substance abuse)30,32 is most commonly associated with long-term opioid use. The substance causes a respiratory depression by acting on the mu receptors of the ventral medulla. A central apnea index of greater than 5 is required for the diagnosis. Primary sleep apnea of infancy31,33 is a disorder of respiratory control most often seen in preterm infants (apnea of prematurity), but it can occur in predisposed infants (apnea of infancy). This may be a developmental pattern, or it may be secondary to other medical disorders. Respiratory pauses of 20 seconds or longer are required for the diagnosis. Obstructive Sleep Apneas The obstructive sleep apnea syndromes include those in which there is an obstruction in the airway resulting in increased breathing effort and inadequate ventilation. Upper airway resistance syndrome has been recognized as a manifestation of obstructive sleep apnea syndrome and therefore is not included as a separate diagnosis. Adult and pediatric forms of obstructive sleep apnea syndrome are discussed separately because the disorders have different methods of diagnosis and treatment. Adult obstructive sleep apnea34,35 is characterized by repetitive episodes of cessation of breathing (apneas) or partial upper airway obstruction (hypopneas). These events are often associated with reduced blood oxygen saturation. Snoring and sleep disruption are typical and common. Excessive daytime sleepiness or insomnia can result. Five or more respiratory events (apneas, hypopneas, or respiratory effort–related arousals) per hour of sleep are required

for diagnosis. Increased respiratory effort occurs during the respiratory event. Pediatric obstructive sleep apnea36,37 is characterized by features similar to those seen in the adult, but cortical arousals might not occur, possibly because of a higher arousal threshold. At least one obstructive event, of at least two respiratory cycles’ duration, per hour of sleep is required for diagnosis. Hypoventilation and Hypoxemia Sleep-related hypoventilation and hypoxemic syndromes comprise five disorders associated with hypoventilation or hypoxemia during sleep. Idiopathic sleep-related nonobstructive alveolar hypoventilation refers to decreased alveolar hypoventilation resulting in sleep-related arterial oxygen desaturation in patients with normal mechanical properties of the lungs. Congenital central alveolar hypoventilation syndrome (CCHS)38,39 is a failure of automatic central control of breathing in infants who do not breathe spontaneously or who breathe shallowly and erratically. It is a failure of central automatic control of breathing. The hypoventilation begins in infancy, and it is worse in sleep than wakefulness. Hypoventilation and hypoxemic disorders are related to elevated arterial carbon dioxide tension (Paco2) or reduced oxygen saturation during sleep. Sleep-related hypoventilation or hypoxemia due to a medical condition is a subgroup of three disorders of impaired lung function or chest wall mechanics. Hypoventilation or hypoxemia related to pulmonary parenchymal or vascular pathology40,41 is due to disorders of interstitial lung disease such as interstitial pneumonitis or disorders such as sickle-cell anemia or other hemoglobinopathies. Sleep-related hypoventilation or hypoxemia due to lower airways obstruction is seen in patients with lower airway disease such as chronic obstructive lung disease (COPD) and emphysema, bronchiectasis, or cystic fibrosis. Sleep-related hypoventilation or hypoxemia due to neuromuscular and chest wall disorders is seen in disorders such as neuromuscular disease or kyphoscoliosis.42-47

HYPERSOMNIA OF CENTRAL ORIGIN The hypersomnia disorders are those in which the primary complaint is daytime sleepiness and the cause of the primary symptom is not disturbed nocturnal sleep or misaligned circadian rhythms. Daytime sleepiness is defined as the inability to stay alert and awake during the major waking episodes of the day, resulting in unintended lapses into sleep. Other sleep disorders may be present, and they must first be effectively treated. These are the hypersomnias that are not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed nocturnal sleep. Narcolepsy with cataplexy48,49 requires the documentation of a definite history of cataplexy (see Chapter 85). Narcolepsy without cataplexy50,51 is the diagnosis when cataplexy is not present but when the patient has sleep paralysis and hypnagogic hallucinations, with supportive evidence in the form of a positive multiple sleep latency test with a mean sleep latency of no more than 8 minutes and two or more sleep-onset REM periods. Narcolepsy due to



medical condition52,53 is the diagnosis applied to a patient with sleepiness who has a significant neurologic or medical disorder that accounts for the daytime sleepiness. Recurrent hypersomnia,54,55 also known as periodic hypersomnia, comprises two subtypes: Kleine-Levin syndrome and menstrual-related hypersomnia. Kleine-Levin syndrome, is associated with episodes of sleepiness together with binge eating, hypersexuality, or mood changes. Menstrual-related hypersomnia is recurrent episodes of hypersomnia that occur in association with the menstrual cycle. Episodes usually last approximately 1 week and resolve at the time of menses. Idiopathic hypersomnia with long sleep time56,57 is the classic form of idiopathic hypersomnia, characterized by a major sleep episode that is at least 10 hours in duration, whereas idiopathic hypersomnia without long sleep time58,59 is the more commonly seen disorder of excessive sleepiness with unintended naps that are typically unrefreshing (see Chapter 86). Behaviorally induced insufficient sleep syndrome60,61 occurs in patients who have a habitual short sleep episode and who sleep considerably longer when the habitual sleep episode is not maintained. Hypersomnia due to medical condition62,63 is hypersomnia that is caused by a medical or neurologic disorder. Cataplexy or other diagnostic features of narcolepsy are not present. Hypersomnia due to drug or substance64-67 is diagnosed when the complaint is believed to be secondary to current or past use of drugs. Hypersomnia not due to a substance or known physiologic condition68,69 is excessive sleepiness that is temporally associated with a psychiatric diagnosis.

CIRCADIAN RHYTHM SLEEP DISORDERS The circadian rhythm sleep disorders share a common underlying chronophysiologic basis. The major feature of these disorders is a persistent or recurrent misalignment between the patient’s sleep pattern and the pattern that is desired or regarded as the societal norm (see Chapter 41). Maladaptive behaviors influence the presentation and severity of the circadian rhythm sleep disorders. The underlying problem in the majority of the circadian rhythm sleep disorders is that the patient cannot sleep when sleep is desired, needed, or expected. The wake episodes can occur at undesired times as a result of sleep episodes that occur at inappropriate times; therefore, the patient might complain of insomnia or excessive sleepiness. For several of the circadian rhythm sleep disorders, once sleep is initiated, the major sleep episode is of normal duration with normal REM–NREM cycling. Delayed sleep phase type,70,71 which is more commonly seen in adolescents, is characterized by a delay in the phase of the major sleep period in relation to the desired sleep time and wake time, whereas advanced sleep phase type,72,73 which is more commonly seen in older adults, is characterized by an advance in the phase of the major sleep period in relation to the desired sleep time and wake-up time. An alteration in the homeostatic regulation of sleep may be responsible. However, the delayed and advanced sleep phase types can have a predominant influence caused by the person’s choice to remain awake late into the night or

CHAPTER 60  •  Classification of Sleep Disorders  685

go to bed earlier associated with behavioral, social, or professional demands. The irregular sleep-wake type,74,75 a disorder that involves a lack of a clearly defined circadian rhythm of sleep and wakefulness, is most often seen in institutionalized older adults and is associated with a lack of synchronizing agents such as light, activity, and social activities. The free-running type76,77 or nonentrained type (formerly known as the non–24-hour sleep–wake syndrome) occurs because there is a lack of entrainment to the 24-hour period, and the sleep pattern often follows that of the underlying free-running pacemaker with a sequential shift in the daily sleep pattern. Circadian rhythm sleep disorders due to a medical condition78,79 are related to an underlying primary medical or neurologic disorder. A disrupted sleep–wake pattern leads to complaints of insomnia or excessive daytime sleepiness. Jet-lag type80,81 or jet-lag disorder, is related to a temporal mismatch between the timing of the sleep–wake cycle generated by the endogenous circadian clock produced by a rapid change in time zones. The severity of the disorder is influenced by the number of time zones crossed and the direction of travel, with eastward travel usually being more disruptive. Shift-work type82,83 is characterized by complaints of insomnia or excessive sleepiness that occur in relation to work hours that are scheduled during the usual sleep period. Other circadian rhythm sleep disorders not resulting from a known physiologic condition are irregular or unconventional sleep-wake patterns that can be the result of social, behavioral, or environmental factors.84,85 Noise, lighting, or other factors can predispose a person to develop this disorder. The appropriate timing of sleep within the 24-hour day can be disturbed in many other sleep disorders, particularly those associated with the complaint of insomnia. Patients with narcolepsy may have a pattern of sleepiness that is identical to that described as being caused by an irregular sleep-wake type. However, because the primary sleep diagnosis is narcolepsy, the patient should not receive a second diagnosis of a circadian rhythm sleep disorder unless the disorder is unrelated to the narcolepsy. For example, a diagnosis of jet-lag type could be stated along with a diagnosis of narcolepsy, if appropriate. Similarly, patients with mood disorders or psychoses can, at times, have a sleep pattern similar to that of delayed sleep phase type. A diagnosis of delayed sleep phase type would be coded only if the disorder is not directly associated with the psychiatric disorder. Some disturbance of sleep timing is a common feature in patients who have a diagnosis of inadequate sleep hygiene. Only if the timing of sleep is the predominant cause of the sleep disturbance and is outside the societal norm would the diagnosis be a circadian rhythm sleep disorder. Limit-setting sleep disorder is also associated with an altered time of sleep within the 24-hour day. If the setting of limits is a function of the caretaker, then the sleep disorder is more appropriately diagnosed as a limitsetting sleep disorder.

PARASOMNIAS The parasomnias are undesirable physical or experiential events that accompany sleep (see Section 12). These sleep

686  PART II / Section 8  •  Impact, Presentation, and Diagnosis

disorders are not abnormalities of the processes responsible for sleep and awake states per se but are undesirable phenomena that occur predominantly during sleep. The parasomnias consist of abnormal sleep-related movements, behaviors, emotions, perceptions, dreaming, and autonomic nervous system functioning. They are disorders of arousal, partial arousal, and sleep-stage transition. Many of the parasomnias are manifestations of central nervous system activation. Autonomic nervous system changes and skeletal muscle activity are the predominant features. The parasomnias often occur in conjunction with other sleep disorders such as obstructive sleep apnea syndrome. It is not uncommon for several parasomnias to occur in one patient. Three parasomnias have typically been associated with arousal from non-REM sleep, the disorders of arousal. Confusional arousals86,87 are characterized by mental confusion or confusional behavior that occurs during or after arousal from sleep. These arousals are common in children and can occur not only from nocturnal sleep but also from daytime naps. They sometimes occur in association with obstructive sleep apnea syndrome. Sleepwalking88,89 is a series of complex behaviors that occur from sudden arousals from slow-wave sleep and result in walking behavior during a state of altered consciousness. Sleep terrors90,91 also occur from slow-wave sleep and are associated with a cry or piercing scream accompanied by autonomic nervous system activation and behavioral manifestation of intense fear. Patients may be difficult to arouse from the episode and when aroused can be confused and subsequently amnestic for the episode. These two disorders, sleepwalking and sleep terrors, often coexist together, and sometimes one form blends into the other or is difficult to distinguish from the other. Several parasomnias are typically associated with the REM sleep stage. Some common underlying pathophysiologic mechanism related to REM sleep may underlie these disorders. REM sleep behavior disorder (RBD)92,93 involves abnormal behaviors that occur in REM sleep and result in injury or sleep disruption. The behaviors are often violent, with dream enactment that is action filled. The disorder can occur in narcolepsy, and many patients with Parkinson’s disease have RBD. The delayed emergence of a neurodegenerative disorder can occur, especially in men older than 50 years. Recurrent isolated sleep paralysis94,95 can occur at sleep onset or on awakening and is characterized by an inability to perform voluntary movements. Ventilation is usually unaffected. Hallucinatory experiences often accompany the paralysis. Nightmare disorder96,97 is characterized by recurrent nightmares that occur in REM sleep and result in an awakening with intense anxiety, fear, or other negative feelings. Sleep-related dissociative disorders98,99 involve a disruption of the integrative features of consciousness, memory, identity, or perception of the environment. This disorder can occur in the transition from wakefulness to sleep or after an awakening from stage 1 or 2 sleep. A history of physical or sexual abuse is common in such patients. These patients fulfill the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) criteria for dissociative disorder. Sleep enuresis100,101 is recurrent involuntary voiding that occurs during sleep. Enuresis

is considered primary in a child who has never been dry for 6 months or longer; otherwise, it is called secondary. Sleep-related groaning (catathrenia)102,103 is an unusual disorder in which there is a chronic, often nightly, expiratory groaning that occurs during sleep. The affected person is often unaware of the groaning. The disorder is rare and the pathophysiology is unknown. Exploding head syndrome104,105 is characterized by a loud imagined noise or sense of a violent explosion that occurs in the head as the patient is falling asleep or during waking in the night. Sleep-related hallucinations are hallucinatory experiences that occur at sleep onset or upon awakening. They may be difficult to distinguish from vivid dreams or nightmares but usually are complex images that occur when the patient is clearly awake. Sleep-related eating disorder106,107 involves recurrent eating and drinking episodes during arousals from nocturnal sleep. The eating behavior is uncontrollable, and often the patient is unaware of the behavior until the next morning. It can be associated with sleepwalking and can be induced by medication. Parasomnia due to a medical condition108,109 is the manifestation of a parasomnia associated with an underlying medical or neurologic disorder. Parasomnia due to a drug or substance110 is a parasomnia that has a close temporal relationship between exposure to a drug, medication, or biologic substance. Unspecified parasomnia111,112 is a parasomnia that occurs as a manifestation of an underlying psychiatric disorder.

SLEEP-RELATED MOVEMENT DISORDERS The sleep-related movement disorders are characterized by relatively simple, usually stereotyped movements that disturb sleep (see Chapter 90). Disorders such as periodic limb movement disorder and restless legs syndrome are classified in this section. Restless legs syndrome113,114 is characterized by a complaint of a strong, nearly irresistible urge to move the legs often accompanied by uncomfortable or painful symptoms. The sensations are worse at rest and occur more frequently in the evening or during the night. Walking or moving the legs relieves the sensation. Periodic limb movement disorder115,116 is an independent disorder of repetitive, highly stereotyped limb movements that occur during sleep. Periodic leg movements are often associated with restless legs syndrome. Sleep-related leg cramps117,118 are painful sensations that are associated with sudden intense muscle contractions, usually of the calves or small muscles of the feet. Episodes commonly occur during the sleep period and can lead to disrupted sleep. Relief is usually obtained by stretching the affected muscle. Sleeprelated bruxism119,120 is characterized by clenching of the teeth during sleep and can result in arousals. Often the activity is severe or frequent enough to result in symptoms of temporomandibular joint pain or wearing down of the teeth. Sleep-related rhythmic movement disorder121,122 is a stereotyped, repetitive rhythmic motor behavior that occurs during drowsiness or light sleep and results in large movements of the head, body, or limbs. The disorder is typically seen in children, but it can also be seen in adults. Head and limb injuries can result from violent movements.



Rhythmic movement disorder can also occur during full wakefulness and alertness, particularly in persons who are mentally retarded. Unspecified sleep-related movement disorder is a movement disorder that occurs during sleep and that is diagnosed before a psychiatric disorder can be ascertained. Sleep-related movement disorder due to a medical disorder appears to have a neurologic or medical basis. Sleeprelated movement disorder due to a drug or substance is a sleep disorder that appears to have a substance or drug as its basis.

OTHER SLEEP DISORDERS These disorders are difficult to fit into any other classification section. Environmental sleep disorder123,124 is a sleep disturbance that is caused by a disturbing environmental factor that disrupts sleep and leads to a complaint of either insomnia or excessive sleepiness. Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues This section lists sleep-related symptoms that are in the borderline between normal and abnormal sleep. Sleep length and snoring are two examples. A long sleeper125,126 is a person who sleeps more in the 24-hour day than the typical person. Sleep is normal in architecture and quality. Usually, sleep lengths of 10 hours or greater qualify for this diagnosis. Symptoms of excessive sleepiness occur if the person does not get that amount of sleep. A short sleeper125,126 is a person with a routine pattern of obtaining 5 hours or less of sleep in a 24-hour day. In children, this sleep length can be 3 hours or less than the norm for the age group. Snoring127,128 is diagnosed when a respiratory sound is disturbing to the patient, a bed partner, or others. This diagnosis is made when the snoring is not associated with either insomnia or excessive sleepiness. Not only can snoring lead to impaired health but also it may be a cause of social embarrassment and can disturb the sleep of a bed partner. Snoring associated with obstructive sleep apnea syndrome is not diagnosed as snoring. Sleep talking129,130 can be either idiopathic or associated with other disorders such as RBD or sleep-related eating disorder. Sleep starts (hypnic jerks)131,132 are sudden brief contractions of the body that occur at sleep onset. These movements are associated with a sensation of falling, a sensory flash, or a sleep-onset dream. Benign sleep myoclonus of infancy133,134 is a disorder of myoclonic jerks that occur during sleep in infants. It typically occurs from birth to age 6 months and is benign and resolves spontaneously. Hypnagogic foot tremor and alternating leg muscle activation135,136 occurs at the transition between wake and sleep or during light NREM sleep. It is demonstrated by recurrent electromyographic (EMG) potentials in one or both feet that are in the myoclonic range of longer than 250 msec. Propriospinal myoclonus at sleep onset137,138 is a disorder of recurrent sudden muscular jerks in the transition from wakefulness to sleep. The disorder may be associated with severe sleep-onset insomnia. Excessive fragmentary myoclonus139,140 is small muscle twitches in the fingers, toes, or the corner of the mouth that do not cause actual

CHAPTER 60  •  Classification of Sleep Disorders  687

movements across a joint. The myoclonus is often a finding during polysomnography that is often asymptomatic or can be associated with daytime sleepiness or fatigue. Other Organic Disorders Commonly Encountered in the Differential Diagnosis of Sleep Disorders Fatal familial insomnia141,142 is a progressive disorder characterized by difficulty in falling asleep and maintaining sleep that develops into enacted dreams or stupor. Autonomic hyperactivity with pyrexia, excessive salivation, and hyperhidrosis leads to cardiac and respiratory failure. The disease is caused by a prion and it leads eventually to death. Fibromyalgia is a disorder of widespread pain and muscle tenderness. It is usually associated with light and unrefreshing sleep. Sleep-related epilepsy143,144 is the diagnosis when epilepsy occurs during sleep. Several epilepsy types are associated with sleep, including nocturnal frontal lobe epilepsy, benign epilepsy of childhood with centrotemporal spikes, and juvenile myoclonic epilepsy. Sleep-related headaches145,146 are headaches that occur during sleep or on awakening from sleep. Chronic paroxysmal hemicrania, hypnic headache, or cluster headaches can all occur during sleep. Sleep-related gastroesophageal reflux147,148 is characterized by regurgitation of stomach contents into the esophagus during sleep. Shortness of breath or heartburn can result, but occasionally the disorder is asymptomatic. Sleep-related coronary artery ischemia149,150 is ischemia of the myocardium that occurs at night. Sleep-related abnormal swallowing, choking, and laryngospasm is a disorder in which patients report choking and difficulty breathing at night that may be due to pooling of saliva in the upper airway. Other Psychiatric or Behavioral Disorders Commonly Encountered in the Differential Diagnosis of Sleep Disorders This final section of the ICSD-2 lists the psychiatric diagnoses that are often encountered during an evaluation of sleep complaints. Many psychiatric disorders are associated with disturbances of sleep and wakefulness. The main sleep-related features are presented in this section. Psychiatric diagnoses that are discussed include mood disorders, anxiety disorders, somatoform disorders, schizophrenia and other psychotic disorders, disorders first diagnosed in childhood or adolescence, and personality disorders.151

CURRENT AND FUTURE CLASSIFICATION CONSIDERATIONS Comorbid Insomnia and Insomnia Research Criteria An outcome from the 2004 NIH consensus development conference on Insomnia was the promotion of the term, comorbid insomnia to distinguish insomnia due to other primary sleep disorders, medical, and psychiatric disorders and insomnia due to medication or drug use from primary insomnia.152,153 Primary insomnia is a term that has been used to apply to insomnia not due to another medical or psychiatric disorder, as compared to insomnia that is

688  PART II / Section 8  •  Impact, Presentation, and Diagnosis

secondary to other disorders. Comorbid insomnia does not indicate whether the associated medical disorder is causative or coincidental. The term, primary insomnia is used in the ICD-10-CM and DSM-IV-TR classifications and has the benefit of being a more global classification of insomnia (Table 60-2). The term is compatible with the ICSD-2, which uses a more detailed subtyping of the sleep

disorders. The term, secondary insomnia is still appropriate for use when there is a clear development of insomnia related to the underlying medical or psychiatric disorder, such as one might see in pain disorders. The definition of insomnia as being a complaint of sleep onset, sleep maintenance, waking too early, or unrestorative sleep is less precise than that required for research in

Table 60-2  ICD-10-CM Sleep Disorders CODE

DESCRIPTION

F51: Sleep Disorders Not Caused by a Substance or Known Physiologic Condition F51.01

Primary insomnia

F51.02

Adjustment insomnia

F51.03

Paradoxical insomnia

F51.04

Psychophysiologic insomnia

F51.05

Insomnia due to other mental disorder

F51.09

Other insomnia not due to a substance or known physiologic condition

F51.1

Hypersomnia not due to a substance or known physiologic condition

F51.11

Primary hypersomnia

F51.12

Insufficient sleep syndrome

F51.13

Hypersomnia due to other mental disorder

F51.19

Other hypersomnia not due to a substance or known physiologic condition

F51.3

Sleepwalking (somnambulism)

F51.4

Sleep terrors (night terrors)

F51.5

Nightmare disorder

F51.8

Other sleep disorders not due to a substance or known physiologic condition

F51.9

Sleep disorder not due to a substance or known physiologic condition, unspecified

G47: Organic Sleep Disorders G47.0

Insomnia, unspecified

G47.01

Insomnia due to medical condition

G47.09

Other insomnia

G47.1

Hypersomnia, unspecified

G47.11

Idiopathic hypersomnia with long sleep time

G47.12

Idiopathic hypersomnia without long sleep time

G47.13

Recurrent hypersomnia

G47.14

Hypersomnia due to medical condition

G47.19

Other hypersomnia

G47.20

Circadian rhythm sleep disorder, unspecified type

G47.21

Circadian rhythm sleep disorder, delayed sleep phase type

G47.22

Circadian rhythm sleep disorder, advanced sleep phase type

G47.23

Circadian rhythm sleep disorder, irregular sleep–wake type

G47.24

Circadian rhythm sleep disorder, free running type

G47.25

Circadian rhythm sleep disorder, jet lag type

G47.26

Circadian rhythm sleep disorder, shift-work type

G47.27

Circadian rhythm sleep disorder in conditions classified elsewhere

G47.29

Other circadian rhythm sleep disorder

G47.30

Sleep apnea, unspecified

G47.31

Primary central sleep apnea

G47.32

High-altitude periodic breathing

G47.33

Obstructive sleep apnea (adult) (pediatric)

G47.34

Idiopathic sleep-related nonobstructive alveolar hypoventilation

G47.35

Congenital central alveolar hypoventilation syndrome

G47.36

Sleep-related hypoventilation in conditions classified elsewhere Continued



CHAPTER 60  •  Classification of Sleep Disorders  689

Table 60-2  ICD-10-CM Sleep Disorders—cont’d CODE

DESCRIPTION

G47.37

Central sleep apnea in conditions classified elsewhere

G47.39

Other sleep apnea

G47.4

Narcolepsy and cataplexy

G47.41

Narcolepsy

G47.411

Narcolepsy with cataplexy

G47.419

Narcolepsy without cataplexy, NOS

G47.42

Narcolepsy in conditions classified elsewhere

G47.421

Narcolepsy in conditions classified elsewhere with cataplexy

G47.429

Narcolepsy in conditions classified elsewhere without cataplexy

G47.50

Parasomnia, unspecified

G47.51

Confusional arousals

G47.52

REM sleep behavior disorder

G47.53

Recurrent isolated sleep paralysis

G47.54

Parasomnia in conditions classified elsewhere

G47.59

Other parasomnia

G47.6

Sleep-related movement disorders

G47.61

Periodic limb movement disorder

G47.62

Sleep-related leg cramps

G47.63

Sleep-related bruxism

G47.69

Other sleep-related movement disorders

G47.8

Other sleep disorders

G47.9

Sleep disorder, unspecified

Z72.8: Problems Related to Sleep Z72.820

Sleep deprivation

Z72.821

Inadequate sleep hygiene

Z73.8: Other Problems Related to Life Management Difficulty Z73.810

Behavioral insomnia of childhood, sleep-onset association type

Z73.811

Behavioral insomnia of childhood, limit-setting type

Z73.812

Behavioral insomnia of childhood, combined type

Z73.819

Behavioral insomnia of childhood, unspecified type

insomnia. Specific research criteria have been developed for insomnia disorder.154 The criteria include a primary complaint of difficulty initiating sleep, maintaining sleep, waking too early, or unrestorative or poor quality sleep and a requirement that the sleep difficulty occurs despite adequate opportunity and circumstances for sleep, plus one or more complaints of daytime impairment due to the sleep difficulty. Specific research criteria have also been developed for primary insomnia, insomnia due to a mental disorder, psychophysiologic insomnia, paradoxical insomnia, idiopathic insomnia, insomnia related to periodic limb movement disorder, insomnia related to sleep apnea, insomnia due to medical condition and insomnia due to drug or substance, as well as diagnostic criteria for normal sleepers. Hypersomnia The diagnosis of narcolepsy with cataplexy is based upon the belief that most cases are due to loss of hypocretin possibly on an autoimmune basis.155 However, up to 10% of patients with narcolepsy and cataplexy have normal

hypocretin levels suggesting either a downstream problem with hypocretin, such as at the receptor level, or an alternative pathophysiologic mechanism.155 Another question is whether narcolepsy without cataplexy is the same disorder or a disorder based upon an entirely different pathophysiology. Most patients who have narcolepsy without cataplexy have intact hypocretin levels. Idiopathic hypersomnia, whether with or without long sleep time, is still poorly understood because there is no clear pathophysiologic mechanism.157 The genetic basis of the disorders needs to be determined. Whether idiopathic hypersomnia without long sleep time is a variant of narcolepsy without cataplexy is not yet determined. Parasomnia Catathrenia, a disorder with sleep-related moaning, has been suggested to be a variant of a sleep-related breathing disorder because treatment with continuous positive airway pressure has been reported to be successful.156 There has been described a classification of sleep-related sexual disorders and abnormal sexual behaviors.157 Many

690  PART II / Section 8  •  Impact, Presentation, and Diagnosis

of the disorders occur out of sleep and are related to the parasomnias, particularly confusional arousals; however, other sleep-related sexual behavior is associated with seizure disorders or other sleep disorders such as KleineLevin syndrome, insomnia, or restless legs syndrome. Some abnormal sexual behaviors occur in narcolepsy, sleep-related dissociative disorders, and nocturnal psychotic disorders. Sleep-related painful erection, which has been well described in the literature, and sleep exacerbation of persistent sexual arousal syndrome, which is a rare condition with widely diverse causes, are two other sexual disorders that are rare but not included in the ICSD-2. A study of the interobserver reliability of the diagnostic criteria included in the 1997 revised version of the ICSD-I showed that the diagnostic criteria were less precise for sleepwalking, sleep terrors, nightmares, RBD, and sleep starts.158 Sleep terrors, nightmares, and RBD had a weak agreement mainly because of the first criterion that defines the phenomenon. In sleepwalking, the disagreement was due to the inclusion of amnesia in the criteria. ❖  Clinical Pearl The classification of sleep disorders allows accurate diagnosis, improved communication among physicians, and the standardization of data for research purposes. New sleep disorders have been recognized, and previous sleep disorders have been clarified with a better understanding of their diagnostic and epidemiologic features. The International Classification of Sleep Disorders, version 2, increases the refinement of sleep disorder diagnoses because of recent advances in sleep research. Referring to the ICSD-2 helps clinicians establish a rational differential diagnosis when evaluating patients.

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Epidemiology of Sleep Disorders Markku Partinen and Christer Hublin Abstract Every day one third or more of the population suffers from some sleep disturbance and/or from abnormal daytime sleepiness. At least 10% of the population suffers from a sleep disorder that is clinically significant and of public health importance. Insomnia is the most common sleep disorder, followed by sleep-disordered breathing and restless legs syndrome. Sleep disorders are interrelated with medical and psychiatric disorders, such as arterial hypertension, cardiovascular and cerebrovascular diseases, morbid obesity, diabetes, metabolic syndrome, and depression. Many gender, socioeconomic, and also ethnic differences exist; and more epidemiologic and genetic epidemiologic studies are needed to understand reasons for these differences. In the 1980s, the large epidemiologic studies on sleep disorders were based on the 1979

Although sleep disorders are very common, rigorous epidemiologic studies in this field are fairly recent, in part because the discipline of sleep medicine is recent. In this chapter we present epidemiologic data important in the practice of sleep medicine. There are several excellent books of epidemiologic methods that are recommended.3-6

SLEEP DURATION Sleep duration is highly individual in all age groups, and it is clearly dependent on age. In the United States the relationship between age and the average sleep time is U-shaped, with a minimum 7.9 hours at age 45 to 54 years and a maximum (9.0 hours) at age 75 years or older.7 In addition to sleep disorders (e.g., insomniacs among short sleepers and hypersomniacs among long sleepers), there are also healthy subjects in the extreme groups: a few percent of the populations are so-called natural short sleepers or natural long sleepers (ICSD-2).2,8 Sleep duration can be considered as a lifestyle factor that is modulated by several background factors and by genotype. In a Finnish general-population study the most important and statistically independent determinants of short and long sleep duration were gender, physical tiredness, sleep problems, marital status, main occupation, and physical activity, but these accounted for only 16% of the variance in sleep duration.9 In the United States the largest reciprocal relationship to sleep was found for work time, followed by travel time, and only shorter than average (64 yr: 36.4 (m), 47.6 (f)

Morgan and Clarke69 1997 (England)

1042

Primary care (65-80+)

Patients with sleeping problems often or all the time

Questionnaire

65-69 yr: 33.2 (m), 44.1 (f) 70-74 yr: 39.4 (m), 44.4 (f) 75-79 yr: 11.2 (m), 30.8 (f)

982

Population sample (18+)

Insomnia (DSM-IV)

Telephone survey using Sleep-EVAL

DSM-IV: 11.7 Any type: 37.6

3030

Population sample (20+)

Insomnia of any type

Interview at home

22.3 (m), 20.5 (f) 20-39 yr: 18.1 40-59 yr: 18.9 60+ yr: 29.5 No stress: 15.9 Stress: 25.8

Population sample (20-100)

Insomnia Difficulty sleeping

Questionnaire (PSG in 1741)

Insomnia: 7.5 Difficulty sleeping: 22.4

Ohayon and Partinen43 2002 (Finland) Kim et al.70 2000 (Korea)

Bixler et al.41 2002 (USA)

16,583

Li et al.71 2002 (Hong Kong)

9851

Population sample Chinese (18-65)

Insomnia, DSM Preceding month ≥3 per week

Telephone survey

Insomnia: 11.9% Women: 1.6 × P (men) Increase with age

Morin et al.46 2006 (Canada)

2001

Population sample (18-91)

Insomnia, DSM-IV & ICD-10, ≥3 nights/wk

Telephone survey

Symptoms of insomnia: 29.9 Insomnia syndrome: 9.5

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed; f, female; m, male.



CHAPTER 61  •  Epidemiology of Sleep Disorders  697

Table 61-2  Occurrence of Symptoms of Insomnia Based on Different Types of Insomnia Complaints TROUBLE FALLING ASLEEP (%)

TROUBLE STAYING ASLEEP (%)

Questionnaire

1-2 nights/wk: 12.9 ≥3 nights/wk: 11.3

1-2 nights/wk: 6.0 ≥3 nights/wk: 6.5

Adolescents (13-15)

Interview

≥4 nights/wk: 9.1 (m), 10.0 (f)

≥4 nights/wk: 1.5 (m), 3.0 (f)

>4 nights/wk: 2.5 (m), 4.4 (f)

4972

Population sample (>14)

Telephone interview

Currently: 10.5 (m), 15.3 (f)

Currently: 16.4 (m), 24.8 (f)

Currently: 13.7(m), 17.8 (f)

Bixler et al.74 1979 (USA)

1006

Population sample (>18)

Sleep-EVAL questionnaire

Currently: 14.4 (about two thirds women)

Currently: 22.9 (about two thirds women)

Currently: 13.8 (about two thirds women)

Karacan et al.75 1983 (USA)

2347

Population sample (18-65+)

Interview

Often or always (no age effect): 6.0 (m), 11.2 (f)

Often or always Often or always (significant (significant increase with increase with age): 12.9 (m), age): 6.2 (m), 17.4 (f) 8.0 (f)

Ganguli et al.35 1996 (USA)

1050

Population sample (66-97)

Questionnaire

Sometimes or usually: 26.7 (m), 44.1 (f)

Sometimes or usually: 19.2 (m), 35.8 (f)

Sometimes or usually: 13.6 (m), 23.3 (f)

Blazer et al.76 1995 (USA)

3976

Population sample (≥65; EPESE)

Interview using a questionnaire

Blacks: 14.8 Whites: 16.3

Blacks: 19.9 Whites: 33.8

Blacks: 12.9 Whites: 16.0

Foley et al.77 1995 (USA)

9282

Population sample (≥65; EPESE)

Interview using a questionnaire

Most of the time: 19.2

Most of the time: 29.7

Most of the time: 18.8

Henderson et al.40 1995 (Australia)

869

Population sample (≥70)

Home interview, computer

Nearly every night over the previous 2 weeks: 5.1 algorithm

NA

Nearly every night over the previous 2 weeks: 2.6

Kim et al.70 2000 (Japan)

3030

Population sample (≥20)

Home interviews

7.0 (m) 9.4 (f) No stress: 4.1 Stress: 11.6

20-39 yr: 11.1 40-59 yr: 13.6 60+ yr: 22.6 No stress: 11.2 Stress: 18.3

20-39 yr: 5.1 40-59 yr: 6.7 60+ yr: 13.3 No stress: 6.0 Stress: 9.4

Ohayon and Partinen43 2002 (Finland)

982

Population sample (≥18)

Telephone survey using Sleep-EVAL questionnaire

≥3 nights/wk: 10.4 (m), 13.2 (f)

≥3 nights/wk: 30.2 (m), 33.0 (f)

≥3 nights/wk: 9.7 (m), 12.2 (f)

Li et al.71 2002 (Hong Kong)

9851

Population sample: Chinese (18-65)

Telephone survey Preceding month ≥ 3 nights/wk

≥3 nights/wk: 4.5 (4.1-5.0)

≥3 nights/wk: 6.9 (6.4-7.5)

≥3 nights/wk: 4.0 (3.6-4.4)

Morin et al.46 2006 (Canada)

2001

Population sample (18-91)

Telephone survey

≥3 nights/wk: 8.7 (7.4-9.9)

≥3 nights/wk: 6.4 (5.3-7.4)

≥3 nights/wk: 2.1 (1.5-2.8)

Gureje et al.78 2007 (Nigeria)

6752

Population sample (>18)

Face-to-face interviews

>2 wk/yr: 7.7

>2 wk/yr: 8.5

>2 wk/yr: 5.4

REFERENCE (COUNTRY)

NO. SUBJECTS

POPULATION (AGE RANGE, YR)

Blader et al.72 1997 (USA)

987

School-age children (5-12)

Morrison et al.73 1992 (Canada)

943

Ohayon et al.42 1997 (UK)

METHODS

EARLY MORNING AWAKENING (%)

EPESE, Established Populations for Epidemiologic Studes of the Elderly; f, female; m, male; NA, not applicable.

depression or anxiety, alcohol abuse, or both. Use of alcohol and over-the-counter medications to control insomnia is common. Also, somatic and psychological complaints as well as psychological stress are associated with a higher prevalence of insomnia.33,49-51 Fifth, social and occupational factors are important contributors to insomnia. Being unemployed or not married is associated with a higher prevalence of insomnia.14,52,53 In

a questionnaire survey of 6268 adults in 40 different occupations, 18.9% of bus drivers complained of having some or very much difficulty falling asleep. Among male executives and male physicians, the respective percentages were 3.7% and 4.9%. Disturbed nocturnal sleep was complained of the most often by male laborers (28.1% waking up at least three times a night) and female housekeepers (26.6%). Disturbed nocturnal sleep was rare among male physicians

698  PART II / Section 8  •  Impact, Presentation, and Diagnosis

(1.6%), male executives (7.4%), female head nurses (8.9%), and female social workers (9.4%).54 Symptoms of workrelated stress and mental exhaustion are associated with insomnia.46,55-57 Use of Hypnotics In a nationally representative probability sample survey of noninstitutionalized adults, 3161 people 18 to 79 years old were surveyed.58 Insomnia afflicted 35% of all adults during the course of 1 year. During the year before the survey, 2.6% of adults had used a medically prescribed hypnotic agent; 0.3% of all adults and 11% of all users of hypnotic agents reported using the medication regularly for 1 year or longer. When anxiolytic and antidepressant agents were excluded, 4.3% of adults had used a medically prescribed hypnotic for sleep and 3.1% had used an overthe-counter sleeping pill. In a reanalysis of several studies published in Finland between 1972-2005 (251,083 subjects) the prevalence figures concerning the use of sleeping medicine at least once a week among adult population did not show any clear trend of increase; the figures varied between 4% and 6% from 1982 to 2002.9 In Sweden, 10,216 members of the Swedish Pensioners’ Association were surveyed.59 Hypnotic agents were used by 13.5% of the men and 22.3% of the women. Of the men aged younger than 70 years, 7.9% were receiving such treatment; of those 70 to 80 years old, 14.4% were using hypnotic agents; and of those 80 years old or older, 21.8% were taking hypnotic agents (P < .0001). The corresponding frequencies among women were 15.0%, 23.0%, and 34.9%, respectively (P < .0001). Hypnotic agents are used by many institutionalized elderly subjects even without insomnia. This raises an ethical question because the chronic use of hypnotic agents is associated with excessive mortality rates.60 In a excellent meta-analytic study of risks and benefits of hypnotics among elderly persons the number needed to treat for improved sleep quality was 13 and the number needed to harm for any adverse event was 6.61 An excellent way of tracking the use of hypnotic medication of the population is to count unit defined daily doses (DDD) from the sales statistics. When one knows the assumed average dose per day for each drug, sales per year, and population of the country, one can calculate DDD per 1000 inhabitants per day. In Finland, for all hypnotic agents, the rate in 1994 was 38 DDD/1000 inhabitants/ day. In 2002 the rate had increased to 53.4 DDD/1000 inhabitants/day. Since that time the use of hypnotics has remained about the same. In 2007 the rate was 53.8 DDD/1000 inhabitants/day.62 Benzodiazepines are available in all Scandinavian countries, and in 2001 the consumption of benzodiazepines (in DDD/1000 inhabitants/ day) was 14.9 in Denmark, 21.5 in Finland, 20.8 in Iceland, 13.1 in Norway, and 11.7 in Sweden.63 Respectively, the consumption of cyclopyrrolones was 17.7 in Denmark, 29.5 in Finland, 34.5 in Iceland, 20.9 in Norway, and 24.3 in Sweden.63

CIRCADIAN RHYTHMS AND THEIR DISORDERS Morningness/eveningness or “chronotype” is dependent on genetic, environmental, and age-related factors. Using

the Munich ChronoType Questionnaire in more than 55,000 persons, it has been found that the most frequent (about 15%) type has midsleep on free days at 4:14 am and about 35% earlier and 50% later.79 (Midsleep is the halfway point between sleep onset and sleep end.) Women reach their maximum in lateness at around 19.5 years and men at 21 years, and this sex difference disappears around the age of 50; and people older than 60 years of age, on average, become even earlier chronotypes than they were as children.79 In a Finnish population, morning type increased from 16% among 25- to 29-year olds to about 50% among those 65 years and older.80 Respectively, evening type was observed in 11% to 12% among 25- to 29-year olds and the minimum (6%-7%) was found among 55- to 59-year olds. The estimate for overall genetic effect was 49.7%.80 Studies on the prevalences of circadian rhythm sleep disorders are scarce. Delayed sleep phase syndrome has been found in 0.17% among Norwegians aged 18 to 67 years81 and in 0.13% among Japanese aged 15 to 54 years,82 and the number of cases seems to have increased in the past few decades,83 being about 1.66% in Japanese university students.84 In Europeans aged 15 to 18 years a circadian rhythm disorder was found in fewer than 0.5%.85 One study has suggested that the prevalence of shift-work sleep disorder is about 10%.86

EXCESSIVE SLEEPINESS AND HYPERSOMNIA The feeling of not being alert is common, occurring both as a physiologic everyday phenomenon and as a symptom of sleep disorders.1,2 In spoken language, this feeling is probably most often called sleepiness but the actual meaning varies. By definition, sleepiness implies an increased risk of falling asleep,2 but the complaint of sleepiness is sometimes used to describe physical tiredness, fatigue, and loss of mental alertness without an increase in sleep behavior— conditions often associated with a decreased ability to fall asleep, contrary to true sleepiness. Abnormal sleepiness is often called excessive daytime sleepiness (EDS), but also this condition is difficult to be defined, because falling easily asleep or inability to stay awake may be normal and a desired everyday phenomenon (e.g., in the evening when going to bed). EDS has also been labeled as a disease or a disorder, although it is a symptom of a sleep disorder or of another disease. Our own studies exemplify these problems.87 Among those reporting daytime sleepiness every or almost every day, 19.5% of women and 42.3% of men were frequent snorers (snoring on at least 3 nights per week), 25% had scores suggesting moderate to severe depression, 25% had insomnia at least every other day, 10% were regular hypnotic or tranquilizer users, and 10% reported insufficient sleep. Thus, a “tired” or “sleepy” (in the patient’s words) person may have insomnia and not EDS or hypersomnia. In practice, it must be remembered that descriptions of the symptoms are related to the person’s feelings, emotions, level of education, and cultural background. Sleep researchers usually talk about sleepiness when referring to poor vigilance, lack of alertness, and tendency to fall asleep, but traffic researchers often use the terms, fatigue



CHAPTER 61  •  Epidemiology of Sleep Disorders  699

Table 61-3  Occurrence of Excessive Sleepiness REFERENCE (COUNTRY)

NO. SUBJECTS; AGE RANGE (YR)

DEFINITION OF SLEEPINESS (WORDING OF QUESTIONS)

METHODS

OCCURRENCE (%)

Excessive Sleep Time Karacan et al.99 1976 (USA)

1645; 18-70

Too much sleep

Questionnaire

0.3

Bixler et al.74 1979 (USA)

1006; 18-80

Sleeping too much

Questionnaire

Current: 4.2 (past 7.1) 18-30 yr: 9.9 31-50 yr: 2.3 51-80 yr: 1.8

Ford and Kamerow67 1989 (USA)

7954; 18-65

Ever a period of 2 wk or longer sleeping too much

Direct structured interview using diagnostic interview schedule

2.8 (m), 3.5 (f) 18-25 yr: 5.8 26-44 yr: 3.7 45-64 yr: 1.5 65+ yr: 1.6

Breslau et al.100 1996 (USA)

1007; 21-30

Definition and methods as in Ford and Kamerow67 (1989)

14.7 (m), 17.3 (f)

Ohayon et al.101 1997 (Great Britain)

4972; 15-100

Getting too much sleep

Telephone interview

3.2

Roberts et al.92 1999 (USA)

2730; 46-102

Sleeping too much nearly every day in the last 2 weeks

Questionnaire

6.0 and 1 year later 7.2, 7.4 (m) and 7.2 (f) 50-59-yr: 6.0 and 1 year later 7.1 60-69 yr: 5.5 and 5.2 70-79 yr: 8.4 and 10.3 80+ yr: 9.4 and 6.3

Saarenpää-Heikkilä et al.64 1995 (Finland)

574; 7-17

Sleeping in lessons often or always

Questionnaire (both subject and parents)

3 (m), 0 (f)

Partinen and Rimpelä66 1982 (Finland)

2016; 15-64

Involuntary sleep attacks daily or almost daily

Telephone interview

3.4 (m), 2.5 (f)

Kaneita et al.95 2005 (Japan)

28,714; 20-70+

Fall asleep when must not sleep

Questionnaire (e.g., when driving)

2.8 (m), 2.2 (f) 20-29 yr: 4.6 (m), 4.0 (f) 30-39 yr: 3.8 (m), 2.8 (f) 40-49 yr: 3.5 (m), 3.0 (f) 50-59 yr: 2.1 (m), 1.9 (f) 60-69 yr: 1.8 (m), 0.9 (f) 70+ yr: 0.9 (m), 0.7 (f)

Hays et al.96 1996 (USA)

3962; 65-85

Most of the time sleepiness, forcing to take a nap

Interview

25.2

Ganguli et al.35 1996 (USA)

1050; 66-97

Ever becoming uncontrollably sleepy so cannot help falling asleep

Interview

18.9 (no gender difference)

Saarenpää-Heikkilä et al.64 1995 (Finland)

574; 7-17

Sleepiness always or often

Questionnaire (both subject and parents)

20 (m), 22 (f)

Gaina et al.98 2007 (Japan)

9261; 12-13

Sleepiness

Questionnaire

Almost always: 20.7 (m), 29,6 (f) Often: 44.6 (m), 50.4 (f)

Chung and Cheung102 2008 (Hong Kong Chinese)

1629; 12-19

ESS >10

Questionnaire

41.9 (m < f)

Ohida et al.97 2004 (Japan)

106,297; 13-18

Excessively sleepy during the daytime always

Questionnaire

13-yr: 14-yr: 15-yr: 16-yr: 17-yr: 18-yr:

Sleep Attacks

Daytime Sleepiness

6.0 (m), 9.2 (f) 8.3 (m), 10.5 (f) 10.6 (m), 12.3 (f) 13.8 (m), 16.6 (f) 13.9 (m), 15.3 (f) 14.9 (m), 15.5 (f) Continued

700  PART II / Section 8  •  Impact, Presentation, and Diagnosis Table 61-3  Occurrence of Excessive Sleepiness—cont’d DEFINITION OF SLEEPINESS (WORDING OF QUESTIONS)

METHODS

OCCURRENCE (%)

3871; 15-18

ESS >10

Questionnaire

14.9 (m), 18.2 (f)

Ohayon et al.101 1997 (Great Britain)

4952; 15-100

Feeling greatly sleepy daily for at least 1 month

Telephone interview using Sleep-EVAL expert system

4.4 (m), 6.6 (f)

Souza et al.104 2002 (Brazil)

408; 18-60+

ESS >10

Interview

18.9 18-29 yr: 19.3 30-39 yr: 17.9 40-49 yr: 15.1 50-59 yr: 26.3 60+ yr: 19.6

Hara et al.105 2004 (Brazil)

1066; 18-60+

Sleepiness during the previous month ≥3 times per week

Interview

16.8 18-29 yr: 30.7 30-44 yr: 29.6 45-59 yr: 25.7 60+ yr: 14.0

Hublin et al.87 1996 (Finland)

11,354; 33-60

Sleepiness daily or almost daily

Questionnaire

6.7 (m), 11.0 (f)

Joo et al.106 2008 (Korea)

4405; 40-69

ESS >10

Questionnaire

10.7 (m), 13.7 (f) 40-49 yr: 10.2 (m), 11.2 (f) 50-59 yr: 13.1 (m), 20.5 (f) 60+ yr: 8.8 (m), 13.3 (f)

Tsuno et al.107 2007 (France)

2259; 65-96

ESS >10

Questionnaire and clinical evaluation

12.0 (m), 6.0 (f)

REFERENCE (COUNTRY) Joo et al. (Korea)

103

2005

NO. SUBJECTS; AGE RANGE (YR)

ESS, Epworth Sleepiness Scale; f, female; m, male.

or drowsiness.88 Sleeping alleviates sleepiness at least temporarily whereas resting without sleep does not. Fatigue, on the contrary, may be alleviated by having a pause, resting, physical exercise, and management of stress. Chronic fatigue is usually multifactorial in etiology, and it is generally not relieved by usual restorative techniques.88 Fatigue (57%), tiredness (61%), and lack of energy (62%) may be more frequent complaints than sleepiness (47%) in patients with sleep apnea.89 Also in primary care, complaints of chronic fatigue may be more common (20%-25%) than complaints of excessive sleepiness (5%-15%).90,91 Table 61-3 provides a summary of studies on daytime sleepiness.35,64,66,67,74,87,92,95-107 Depending on the wording, there is approximately a 100-fold difference in occurrence, ranging from 0.3% to more than 30%, and in most of the studies the range is from 5% to 15%. The prevalences of excessive sleep time or hypersomnia-like states are mostly around 5% in adults (no studies on children), with no clear gender difference. The prevalence may be age dependent, although the results are conflicting (decreases67,74 or increases92,93). In the classic study by Ford and Kamerow,67 64% of hypersomniacs had a psychiatric disorder in two interviews with a 1-year interval, most commonly an anxiety disorder or major depression. Similar findings are

reported from many European countries.94 Studies with two assessments of excessive sleep have shown stability of the symptom in less than one third.92 Sleep attacks (involuntary sleep episodes during awake periods) also mostly seem to occur in a few percent of the population in all age-groups, with no clear difference between the sexes and with conflicting results as to age-dependence (decreases95 or increases35,96 with age). Frequent or excessive (subjective) daytime sleepiness occurs in 10% to 15%. It occurs more often in school-aged children (with large differences between studies in the same country97,98) or young adults than in middle-aged or older adults. In most studies, sleepiness is more prevalent among women than among men. The variability of the results in different studies can be explained by differences in the definition of sleepiness and by other methodological aspects. Comparison of the results is difficult, but real differences in different populations probably exist. One problem is how “excessive” is understood in different studies. In questionnaires, the word “excessive” is subjective, and it should be compared with something that the responder considers normal for him or her. There are no studies on the population prevalences of recurrent hypersomnia or idiopathic hypersomnia.



CHAPTER 61  •  Epidemiology of Sleep Disorders  701

Table 61-4  Prevalence Studies on Narcolepsy-Cataplexy REFERENCE (COUNTRY)

FREQUENCY (PER 100,000)

95% CI*

BASE POPULATION (AGE RANGE, YR)

METHODS

Dement et al.123 1972 (USA)

50†

NA

NA (?) Bay area

Population sample Newspaper ad, telephone interview

Dement et al.124 1973 (USA)

67‡

NA

NA (?)

Population sample TV ad, telephone interview

9-230

12,469 (12-16)

Population sample Questionnaire, personal interview Personal interview

Honda109 1979, Honda et al.110 1983 (Japan)

160

Hublin et al.114 1994 (Finland)

26

0-56

11,354 (33-60) (Finnish twin cohort)

Population sample Questionnaire Ullanlinna Narcolepsy Scale Telephone interview Polygraphy HLA typing

Ohayon et al.118 1996 (UK)

40

0-96

4972 (15-100)

Population sample Telephone interview; Sleep-EVAL questionnaire

Silber et al.119 2002 (USA)

36

NC

97,667 (0-109) Olmsted County, Minnesota

Review of medical records covering 1960-1989

Wing et al.115 2002 (Hong Kong)

34

10-117

9851 (18-65)

Population sample (Chinese) as in Hublin et al.114 (1994)

Ohayon et al.94 2002 (five European countries)

47

NA

18,980 (15-100)

Population sample Telephone interview; Sleep-EVAL questionnaire

Shin et al.116 2008 (South Korea)

15

0-31

20,407 (14-19)

High school students as in Hublin et al.114 (1994)

Longstreth et al.120 2008 (USA)

22

19-25

1,366,417 (18 or more)

Physician-made diagnosis in one county covering 2001-2005

Heier et al.117 2009 (Norway)

22

6-80

8992 (20-60)

Population sample as in Hublin et al.114 (1994)

NA, not applicable; HLA, human leukocyte antigen. *95% confidence interval (CI) for the frequency of narcolepsy per 100,000 of population. † Estimated from San Francisco Bay area population (4 million), newspaper circulation (1.2 million), number of respondents (196) and interview-confirmed narcolepsy cases (114), and number of persons seeing/not seeing and responding/not responding to a control advertisement. ‡ Estimated from number of television homes in Los Angeles area (2,290,200), rating of number of viewers of the advertisement (56,576), number of respondents (165), and interview-confirmed narcolepsy cases (35); 30% sampling error and errors in making the diagnosis.

NARCOLEPSY AND NARCOLEPSY-LIKE SYMPTOMS There are about 30 studies published on the prevalence on narcolepsy (most of them on narcolepsy-cataplexy) with considerable differences in the figures. Highest prevalences (up to 30%) are based on questionnaire data without follow-up testing, and the next highest (0.2%-0.8%) on studies with self-reported diagnosis.108 In most studies with more intensive screening or clinical evaluation of suspected narcoleptics the prevalence of narcolepsy-cataplexy falls between 0.025% and 0.05%, or 25 to 50 per 100,000 population, and the 95% confidence intervals (CIs) for the frequencies overlap in the majority of them (Table 61-4). There are some exceptions. The highest figures are from Japan109,110 based on interviews of symptomatic schoolaged children selected by questionnaire, giving “a suspect

of narcolepsy” in 160 per 100,000 and a surprisingly high prevalence (7.6%) of “interview-confirmed cataplectic attacks,” which suggests criteria different from other studies. The lowest frequency (0.23 per 100,000) is found among Israeli Jews,111 but this was based on an extrapolation of sleep clinic samples to the entire population. However, narcolepsy is likely hugely underdiagnosed.111a The prevalence of narcolepsy-cataplexy seems to be consistent despite considerable differences methods, ethnic groups, and population frequencies of DQB1*0602, and so on between the studies.112 For example, there are three studies using a simple screening method called the Ullanlinna Narcolepsy Scale (UNS) developed and validated for population studies.113 It consists of 11 items assessing cataplexy-like symptoms and the tendency to fall asleep. Using the UNS, telephone interviews, and polygraphic confirmation of the diagnosis, the prevalence of narcolepsy

702  PART II / Section 8  •  Impact, Presentation, and Diagnosis

with clinically significant cataplexy has been found to be of same order among adult Finns (26 per 100,000),114 adult Chinese in Hong Kong (34 per 100,000),115 Korean adolescents (15 per 100,000),116 and adult Norwegians (22 per 100,000).117 Similar prevalences have been obtained in Europeans using telephone interviews (Sleep-EVAL questionnaire) without any other examinations (40 or 47 per 100,000)94,118 and in the United States using a review of medical records (36 per 100,000)119 and physician-made diagnoses (22 per 100,000).120 There are only a couple of studies on narcolepsy without cataplexy, giving a prevalence of 20 per 100,000 in adults in the United States119 and 34 per 100,000 in Korean adolescents,116 which may be gross underestimations.112 However, it can be difficult to assess the true prevalence because diagnostic Multiple Sleep Latency Test criteria may be 100 times more prevalent in a population than narcolepsy.121 One study gives an incidence rate of 1.37 (0.74 for narcolepsy with cataplexy) per 100,000 persons per year. Some studies suggest that narcolepsy may be slightly more common in men.108 Analytic epidemiologic studies have found associations between narcolepsy and body mass index (BMI), immune responses, and stressful life events, but these may rather reflect consequences than cause of disease.108 Although typical cataplexy is pathognomonic of narcolepsy, mild forms are difficult to separate from similar physiologic phenomena. As mentioned, reports of EDS in the population are common. In Finland, 29.3% of the people reported (at least once during his or her lifetime) feelings of limb weakness associated with emotions.114 If this is considered as evidence of cataplexy and combined with the occurrence of daytime sleep episodes at least 3 days per week, 6.5% of the population would have fulfilled the minimal diagnostic criteria for narcolepsy of the International Classification of Sleep Disorders.114,122 Therefore, using only questionnaires in population studies may increase the risk of too high prevalence rates.

SNORING, SLEEP-DISORDERED BREATHING, AND SLEEP APNEA SYNDROME Habitual snoring is defined as snoring almost every night or every night or as snoring at least 5 nights per week. It is almost always present in patients with obstructive sleep apnea syndrome (OSAS). In the first large-scale epidemiologic study on snoring, about 24% of San Marino men and 14% of San Marino women were reported to habitually snore (Table 61-5125-137). In Finland, 9% of adult men and 3.6% of adult women snore always or almost always when asleep.125 A Syndrome or a Disease? Obstructive sleep apnea syndrome is a public health disease. It is the most common organic sleep disorder causing excessive daytime somnolence. Sleep-related breathing disorders (SRBD) and sleep-disordered breathing (SDB) refer to the same clinical disorder. In this chapter, we still use the term OSAS, although hypopneas are now included in the syndrome.

According to various cross-sectional studies, the lowest rates for the prevalence of OSAS among adult men are 1% to 4%. There is an age relationship, so the prevalence of OSAS among men 40 to 59 years old may be greater than 4% or 8%.133 OSAS is less common is younger and older age groups. After menopause, up to the age of 65, OSAS is almost as common among women as among men. Obstructive sleep apneas are part of the complex of heavy snorer’s disease as defined by Lugaresi and colleagues.138 Heavy snoring (i.e., partial upper airway obstruction), even without apneas, is associated with higher pulmonary arterial pressure, daytime sleepiness, arterial hypertension, and insulin resistance.139-143 Heavy snoring is also associated with case-fatality and short-term mortality after a first acute myocardial infarction.144 Visceral central body obesity, measured by waist circumference, is strongly related to SBD.145 Among morbidly obese patients the proper diagnosis may be morbid obesity with obstructive sleep apnea.146 Another example is acromegaly with symptomatic sleep apnea. This is analogous to a patient with a brain tumor who has symptomatic epilepsy. The primary diagnosis is brain tumor (e.g., glioma), and epilepsy is a secondary symptom caused by the brain tumor. The severity of sleep apnea must be properly quantified, not only by indices (e.g., apnea index [AI], apnea-hypopnea index [AHI], or respiratory disturbance index [RDI]) but also by the number of oxygen desaturations, presence of cardiovascular effects, and degree of daytime sleepiness. Snoring and sleep apnea are more common in the supine sleeping position than in the lateral positions. It is therefore necessary to give indices separately for supine and lateral sleeping positions. In clinical studies, sequential apnea indices should always be compared relative to sleeping position. The diagnostic criteria should also be adjusted for age. Bixler and associates147 studied 20- to 100-year-old men. The criteria for OSAS were an AHI of at least 10 in the sleep laboratory and fulfillment of clinical criteria, including the presence of daytime symptoms. OSAS was found in 3.3% of the sample, with its maximum among 45- to 64-year-old men. Although the prevalence of sleep apnea increases with age the clinical impact of apnea seems to decrease among elderly people.148-150 Prevalence of Sleep Apnea The first large epidemiologic polysomnographic study was conducted in Madison, Wisconsin.133 The authors estimated that 2% of women and 4% of men in the middleaged work force met the minimal diagnostic criteria for the sleep apnea syndrome, defined as an AHI of 5 and daytime hypersomnolence.133 Up to 9% of women and 24% of men had an AHI of 5 without daytime somnolence. On examination of the subgroup of patients between the ages of 50 and 60, 4% of women and 9.1% of men were found to have an AHI exceeding 15.133 In a large U.S. population– based study,140,147 clinically defined sleep apnea (AHI ≥ 10 and daytime symptoms) occurred in 3.9% of men and 1.2% of women. The peak prevalence, 4.7% (95% CI, 3.1% to 7.1%), was found among men aged 45 to 64 years. Among the 20- to 44-year olds and those older than 65



CHAPTER 61  •  Epidemiology of Sleep Disorders  703

Table 61-5  Occurrence of Habitual Snoring

REFERENCE (POPULATION)

METHODS

1980 Lugaresi et al. (San Marino general population)

Interview

Partinen127 1982 (Army recruits)

DEFINITION/ WORDING OF HABITUAL SNORING

SEX

NO. SUBJECTS

AGE RANGE (YR)

PREVALENCE (%)

“Every night” (alternatives: no, sometimes, every

m

2858

3-94

24.1

f

2855

3-94

13.8

Questionnaire, clinical studies

Snoring always or almost always Snoring often or always

m

2537

18-29

Koskenvuo et al.125 1985 (Finnish population sample)

Postal questionnaire

“Snoring always or almost always”

m

3847

40-69

9

f

3864

40-69

3.6

Norton and Dunn 1985 (Canadian population sample)

Questionnaire filled during a medical visit

Snoring every night (reported by spouses)

m

1411 1211

3rd to 8th decade

13.2

f

Billiard et al.129 1987 (French army draftees)

Questionnaire completed under supervision

Snoring habitually

m

58,162

17-22

13.6

Gislason et al.130 1987 (Swedish men)

Postal questionnaire

“Loud and disturbing snoring” very often

m

4064

30-69

15.5

Cirignotta et al.131 1989 (Italian adults)

Postal questionnaire

Snoring always (alternatives: never, rarely,

m

1170

30-69

10.1

890

40-69

11.5

304

50-59

15.5

18 or older

10.2

126

128

2.9 9.5

5.6

Schmidt-Nowara et al.132 1990 (HispanicAmerican adults)

Interview using a questionnaire

“Regular and loud snoring” always (every night)

m

482

f

724

Young et al.133 1993 (state employees in Wisconsin)

Postal questionnaire (first stage of

Almost every night or every night snoring

m

1670

30-60

35

f

1843

30-60

28

Ali et al.134 1993 (English children)

Questionnaire filled by

“Snoring on most nights”

m, f

4-5

12.1

Jennum and Sjol135 1994 (Danish population sample)

Interview and clinical examinations

Snoring nightly (every night)

m

Total

30-60

19.1

f

1504

30-60

7.9

Kayukawa et al. (Japan, new outpatients)

Questionnaire, outpatient clinic visit

Habitual snoring

m

6445

Adults

16.0

Kaditis et al.136 2004 (Greek children and adolescents)

Questionnaire filled out by parents

Habitual snoring (snoring every night)

m, f

3680

1-18

1-6 yr: 5.3 7-12 yr: 4.0 13-18 yr: 3.8

Kuehni et al.137 2008 (English preschool children)

Population survey

Habitual snoring

m, f

6811

1-4

1 yr: 6.6 4 yr: 13.0

162

2000

782

5.4

f

years, the prevalence rate was 1.7%. Among women, the average prevalence was 1.2.140,147 In women, the prevalence of SDB increases after menopause; hormone replacement therapy is associated with lower occurrence of SDB.140,161 In the study by Bixler and coworkers.140 the prevalence of clinically defined sleep apnea among premenopausal women was 0.6%. Among postmenopausal women on hormone replacement therapy the prevalence was about the same (0.5%).140

6.5

The prevalence depends on the base population. OSAS is most frequent in persons 40 to 65 years old. One can safely estimate that the prevalence rate of OSAS in that age group is around 4% (3% to 8%) in men and 2% in women and that the absolute minimum prevalence of clinically significant OSAS is 1%. Among obese subjects, hypertensive persons, patients with adult-onset diabetes, and many patient groups with abnormal facial anatomy, the prevalence rates are significantly higher.

704  PART II / Section 8  •  Impact, Presentation, and Diagnosis Table 61-6  Occurrence of Obstructive Sleep Apnea Syndrome REFERENCE (COUNTRY)

METHODS

NO. SUBJECTS

AGE RANGE (YR)

CRITERIA

PREVALENCE (%)

Lavie151 1983 (Israel)

Questionnaire for industrial workers of whom 78 subjects had PSG

1262 (m)

18-67

AI ≥ 10, symptomatic

3.5 (1.0-5.9)

Telakivi et al.152 1987 (Finland)

Questionnaire. PSG recordings and clinical examination for potential subjects

1939 (m)

30-69

Snoring, EDS, and RDI > 10

0.4-1.4

Gislason et al.153 1988 (Sweden)

Questionnaire. PSG recordings and clinical examination for potential subjects

3201 (m)

30-69

Snoring, EDS, and AHI > 10

0.7-1.9

Cirignotta et al.131 1989 (Italy)

Questionnaire, telephone survey. PSG recordings and clinical examination for potential subjects Ambulatory oximetry recordings at home

1170 (m)

30-39

AI > 10, symptomatic

0.2-1.0

40-59

AI > 10, symptomatic

3.4-5.0

60-69

AI > 10, symptomatic

0.5-1.1

35-65

ODI4 > 20, symptomatic

0.3

ODI4 > 10

1.0

Stradling and Crosby154 1991 (Great Britain)

893 (m)

Young et al.133 1993 (Wisconsin, USA)

A sample of state employees. PSG recordings and clinical

352 (m)

30-60

250 (f)

30-60

Olson et al.155 1995 (Australia)

Questionnaire and home sleep recordings

1233 (m)

35-69

Bixler et al.147 1998 (USA)

Telephone survey. Random sample of men aged 20-100 yr A sleep laboratory study (PSG) for a subsample of men

4364 (m) Subsample: 741

20-100

Marin et al.156 1997 (Spain)

Personal interview, clinical examination, home oximetry A population sample

597 (m)

>18

Bixler et al.140 2001 (USA)

Telephone survey Random sample of women

12,219 (f)

A sleep laboratory study (PSG) for a subsample of women

Subsample: 1000

Male office workers

784 (m)

Ip et al.157 2001 (Hong Kong, China) Ip et al.158 2004 (Hong Kong, China)

969 (f)

625 (f) 20-100

30-60

Questionnaire and PSG in 153 Community samples of women

854 (f)

30-60

Questionnaire and PSG in 106

ODI4 > 5

4.6

Hypersomnia and RDI ≥ 5

4.0 (m) 2.0 (f)

AHI ≥ 15

4-18

AHI ≥ 10

7-35

AHI ≥ 5

14-69

AHI > 10 and clinical criteria fulfilled with daytime symptoms

All: 3.3 45-64 yr: 47

Loud snoring + EDS + abnormal home oximetry

2.2 (m)

AHI > 10 and clinical criteria fulfilled with presence of daytime symptoms

All (f): 1.2

0.8 (f)

Premenopause: 0.6 Postmenopause without HRT: 2.7 With HRT: 0.5

AHI ≥ 5 + EDS

4.1

AHI ≥ 15 + EDS

3.1

AHI ≥ 5 + EDS

2.1

AHI ≥ 15 + EDS

0.8

Kim et al.159 2004 (South Korea)

Examination of 5020 Korean subjects A subsample of 457 had PSG

5020

40-69

AHI ≥ 5 + EDS

4.5 (m); 3.2 (f)

Reddy et al.160 2009 (New Delhi, India)

Random community sample Questionnaire and PSG in 360

2505

≥ 18

AHI ≥ 5 + EDS

4 (m); 1.5 (f)

AHI, apnea–hypopnea index; AI, apnea index; EDS, excessive daytime sleepiness; f, female; HRT, hormone replacement therapy; m, male; NA, not applicable; ODI4, oxygen desaturation index (≥4% desaturation); OSAS, obstructive sleep apnea syndrome; PSG, polysomnography; RDI, respiratory disturbance index.



Role of Obesity as a Risk Factor for Snoring and Sleep Apnea Obesity is the most important risk factor for snoring and sleep apnea. The association is found without exceptions, which does not, naturally, mean that lean people could not have OSAS. Neck size162 and especially waist circumference145,163 are related to severity of sleep apnea and may be better indicators than BMI. Other Risk Factors for Snoring and Sleep Apnea Alcohol increases upper airway resistance and tends to induce obstructive sleep apnea in healthy people and especially among chronic snorers. In Great Britain, one drink per day increased the odds of mild or worse SDB by 25% (OR = 1.25; 95% CI, 1.07-1.46) among men. Among women, minimal to moderate alcohol consumption was not significantly associated with increased risk of SDB.164 Other risk factors include large adenoids or tonsils, rhinitis, and other abnormalities in the upper airways, such as those found in different syndromes of dysmorphia and in the mentally disabled. Also, smoking,165 acromegaly,166,167 and amyloidosis168 are known risk factors for SDB. Organic solvent use was associated with increased prevalence of SDB in Sweden169 but not in Germany.170 Snoring and Sleep Apnea in Children Habitual snoring and sleep apnea during childhood (see Tables 61-5 and 61-6125-137,140,147,151-160) may be associated with significant harmful effects on health. Childhood obesity and adenotonsillar hypertrophy are among the most common associated factors.171 In an Italian study, 118 (7.3%) of 1615 children 6 to 13 years of age were often snorers.172 Children with rhinitis were more than twice as likely to be habitual snorers than others. A positive correlation between parental smoking and snoring in children exists. In Singapore, 6% of children snore habitually.173 In Iceland,174 the minimal prevalence of obstructive sleep apnea among children 6 months to 6 years old was 3.2%. In another study, significant sleep and breathing disorders occurred in 0.7% of 4- to 5-year olds.134 The prevalence of SBD among adolescents aged 12 to 16 years was similar to that reported for younger children. In Greece, a survey of 3680 people aged 1 to 18 years revealed a prevalence of habitual (every night) snoring of 5.3%, 4%, and 3.8% among 1- to 6-, 7- to 12-, and 13- to 18-year-old subjects, respectively.136 Sleepiness at school was more common in habitual snorers than in nonhabitual snorers (4.6 vs. 2%, P = .03). Based on 70 random polysomnographic recordings among the 307 snorers without adenoidectomy and/or tonsillectomy the estimated prevalence of OSAS was 4.3%. In a population survey of 6811 children aged 1 to 4 years in the United Kingdom (from parent’s reports) the prevalence of habitual snoring was 7.9%, and 0.9% of children were reported to have habitual snoring and sleep disturbance. Habitual snoring increased with age from 6.6% in 1-year olds to 13.0% in 4-year olds. Habitual snoring was associated with parent’s smoking, road traffic, single parenthood, white but not South Asian children, and socioeconomic deprivation.137 Atopy and respiratory infections were strongly associated

CHAPTER 61  •  Epidemiology of Sleep Disorders  705

with snoring, but BMI was not,137 which shows that the association between childhood obesity and SBD is not simple.175 Sleep Apnea among Elderly People The prevalence of habitual snoring seems to decrease after the age of 65 or 70 years (see Table 61-5). According to Ancoli-Israel and colleagues,176 62% of elderly people have an RDI of at least 10. Bixler has emphasized the need to adjust the criteria for OSAS in elderly persons.147 A cohort of 198 noninstitutionalized elderly individuals (mean age at entry, 66 years) were followed up to 12 years.148 The mortality ratio for sleep apnea, defined as an RDI greater than 10, was 2.7 (95% CI, 0.95 to 7.47). In a cohort of 426 elderly people those with an RDI of 30 had significantly shorter survival. RDI was not an independent predictor of death among the elderly during 5 years follow-up after adjustment for age, cardiovascular disease, and pulmonary disease.149 The clinical significance of sleep apnea among elderly people remains open. Arterial Hypertension and Snoring An association between always or almost-always snoring and arterial hypertension exists. Among 41- to 60-year-old people in San Marino,126 hypertension was present in 15.2% of habitual snorers and in 7.5% of nonsnorers. In a cross-sectional study in Finland the odds of arterial hypertension were increased by 94% (OR 1.94) among habitual male snorers versus nonsnorers after adjustment for BMI and age.177 Case-control studies have shown that the prevalence of sleep apnea among patients with essential hypertension is around 30%. In another study,178 38% of the hypertensive subjects and 4% of normotensive subjects had an AHI of higher than 5.178 In middle-aged adults with drug-resistant hypertension the prevalence of OSA may be over 80%.179 There are now several studies, including prospective studies, showing that SDB in the form of habitual snoring or sleep apnea is a determinant of risk of arterial hypertension but occasional snoring is not associated with an increased risk.180-184 Snoring, Sleep Apnea, and Heart Disease An association of habitual snoring with electrocardiographic changes and arrhythmias has been reported.185 The association of snoring and ischemic heart disease was tested in a population consisting of 3847 men and 3664 women 40 to 69 years old. Reported angina pectoris was associated with habitual snoring among men (risk ratio, 1.9) but not among women (risk ratio, 1.2). The association was also found after adjustment for arterial hypertension and BMI.177 These results were confirmed in a prospective follow-up study of 4388 men 40 to 69 years old. The age-adjusted risk ratio of ischemic heart disease between often or always snorers and nonsnorers was 1.91 (1.18-3.09). An additional adjustment for BMI, history of arterial hypertension, smoking, and alcohol use decreased the risk ratio to 1.71 (0.96-3.05).186 In a casecontrol study with 50 patients with myocardial infarction and 100 control subjects, snoring every night was associated with myocardial infarction. The odds ratio was 2.35 (1.18-4.67) when patients were compared with both hospital control and population control subjects. Adjustment

706  PART II / Section 8  •  Impact, Presentation, and Diagnosis

by smoking, arterial hypertension, diabetes mellitus, and alcohol consumption did not change results.187 In Australia, men with an AI of more than 5.3 had a 23.3-fold (95% CI, 3.9 to 139.9) risk of myocardial infarction than men with an AI of less than 0.4. The mean AI was 6.9 in patients with myocardial infarction versus 1.4 in the control subjects.188 The association was independent of age, BMI, arterial hypertension, smoking, and cholesterol level. Fifty patients 61 ± 6 years old with coronary artery disease were investigated prospectively. In 25 patients (50%), the AI was more than 10/hour sleep. EDS was exhibited by 8 of the 25 patients.189 Several cross-sectional and prospective studies have now confirmed that there is an association between habitual snoring, sleep apnea, and ischemic heart disease142,144,190-193 or congestive heart failure.194,195 The minimum prevalence of OSAS among patients with coronary disease can be estimated as about 16%. Snoring, Sleep Apnea, and Brain Infarction An association between cerebral infarction and habitual snoring has been found in many studies.196 In a casecontrol study of 50 male patients with brain infarction and 100 male control subjects,197 the risk ratio of brain infarction between habitual or often snorers and occasional or never snorers was 2.8. Between habitual snorers and occasional or never snorers, the risk ratio of stroke was 10.3. After adjustments for several confounding variables among 177 male patients and control subjects matched for age and sex, the independent odds ratio relating to snoring and stroke remained at 2.13.198 Other studies have provided supporting results. In Italy,199 the adjusted (age, gender, obesity, diabetes, dyslipidemia, smoking, use of alcohol, and hypertension) odds ratio for “often or always snoring” in relation to ischemic brain infarction was 1.9 (1.2-2.9). Neau and associates200 studied 133 patients 45 to 75 years old and 133 control subjects matched for age and sex. The prevalence of habitual snoring was 23.3% among patients with stroke and 8.3% among their controls. The odds ratio for habitual snoring was 3.4 (1.5-7.6). The odds ratio for “often or always snoring” was 1.7 (1.03-2.93). After adjustment for age, sex, arterial hypertension, cardiac arrhythmia, and obesity, the odds ratio of habitual snoring for stroke remained statistically significant (2.9; 1.3-6.8). The risk of ischemic stroke seems to be especially high among habitually snoring men with arterial hypertension.200 A significant association between occurrence of sleep apnea and ischemic stroke exists.201-204 The causal relationships remain still somewhat open.196,205 Snoring and Sudden Death An autopsy was performed in 460 consecutive cases of sudden death among 35- to 76-year-old men. The closest cohabiting person to each deceased man was interviewed. The mean age was 55.4 years, and the mean BMI was 26.3 kg/m2. Among the obese snorers (N = 82), apneas had been observed “occasionally,” “often,” or “habitually” in 49 cases. Death was classified as cardiovascular in 186 cases (40.4%). The cardiovascular cause of death was more common among the habitual and often snorers than among

occasional or never snorers. Habitual snorers died more often while sleeping. Habitual snoring was found to be a risk (OR 4.07; 1.45-11.45) for cardiovascular early morning death between 4 and 8 am.206 In a follow-up study of 34 obese men, a history of obstructive sleep apnea was a strong risk factor for sudden cardiovascular death. On autopsy, the degree of atherosclerosis was moderate in all cases.207 Snoring and Dementia The occurrence of snoring was studied in 46 patients with Alzheimer’s disease, in 37 patients with multiinfarct dementia, and in a random sample of 124 elderly community residents.208 The demented patients snored twice as frequently as the control subjects. No difference in the occurrence of snoring was found between the two types of dementia. Among 235 nursing home residents 70% had an AHI of 5. The presence of sleep apnea correlated with results of dementia rating scales.209,210 Clinical reports exist about associations between sleep apnea and dementia,210,211 but larger epidemiologic studies are lacking. Evolution of Obstructive Sleep Apnea Syndrome Evolution of OSAS and the effects of treatment are handled in greater detail elsewhere in this textbook. OSAS may be a lethal disease if not treated. There are several studies showing an increased risk of cardiovascular complications and death in patients with at least moderate (AI > 20) or severe (AI > 40) OSAS.212-216 Mortality of mild sleep apnea, with AHI less than 15, does not seem to differ significantly from the mortality of the average population.216 The increased risk is found especially among middle-aged people with SDB, but not in the elderly, in whom several other risk factors for cardiovascular disease and death coexist with OSAS.216 In a Swedish study of 3100 men aged 30 to 69 followed for 10 years, 213 men died, 88 of cardiovascular diseases. In that study, those with isolated snoring or excessive daytime sleepiness (EDS) displayed no significantly increased mortality but the combination of snoring and EDS was associated with a significant increase in mortality. The relative rates decreased with increasing age as in other studies.217 Men younger than the age of 60 with both snoring and EDS had an age-adjusted total death rate that was 2.7 times higher than men with no snoring or EDS (95% CI 1.6 to 4.5). The corresponding age-adjusted hazard ratio for cardiovascular mortality was 2.9 (1.3-6.7) for subjects with both snoring and EDS. Further adjustment for BMI and reported hypertension, cardiac disease, and diabetes reduced the relative mortality risk associated with the combination of snoring and EDS to 2.2 (1.3-3.8) and the relative risk of cardiovascular mortality to 2.0 (0.8-4.7).217 Continuous positive airway pressure (CPAP) is an effective and life-saving treatment of severe OSAS.218-221 Studies show that CPAP is effective in short-term trials in the treatment of mild sleep apnea.222-224 A few prospective follow-up studies142,221,225,226 have been published, but more well-done prospective epidemiologic studies are still needed, especially based on intention to treat analysis. Different surgical methods (e.g., uvulopalatopharyngoplasty,



CHAPTER 61  •  Epidemiology of Sleep Disorders  707

Table 61-7  Prevalence of Restless Legs Syndrome REFERENCE (COUNTRY)

POPULATION; NO. SUBJECTS

METHODS, CRITERIA

PREVALENCE (%)

Ekbom230 1945 (Sweden)

Patients in a physician’s practice; N = 500

Presence of restless legs (original description)

5

Lavigne et al.233 1994 (Canada)

Population sample, age 18 yr+; N = 2019

Leg restlessness at bedtime, face-to-face interviews

10-15

Phillips et al.234 2000 (USA)

Kentucky random population of men and women, aged ≥ 18 yr, N = 1803

Telephone interview, presence of restless legs 5 or more times/month At least once per month

18-29 yr: 3 30-79 yr: 10 80+ yr: 19 All ages: 19.4

Rothdach et al.235 2000 and Berger et al.236 2002 (Germany)

German elderly population sample, age 65-83 years, N = 369

RLS-criteria and neurologic examination; IRLSSG criteria

Overall: 9.8 m: 6.1 f: 13.9 65-69 yr: 9.8 70-74 yr: 12.75 75+ yr: 7.4

Tan et al.237 2001 (Singapore)

General population sample, 155 subjects aged ≥ 55 yr and 1000 consecutive patients aged ≥ 21 yr in a health center

IRLSSG criteria

0.6 in the population; 0.1 among the patients

Ulfberg et al.238 2001 (Sweden)

A random sample of men in Sweden; N = 4000

IRLSSG criteria

5.8

Ulfberg et al.239 2001 (Sweden)

Random sample of women aged 18-64 yr in Sweden; N = 200

IRLSSG criteria

11.4

Ohayon and Roth240 2002 (5 European countries)

UK, Germany, Italy, Portugal, and Spain; N = 18,980; aged 15-100 yr

Telephone surveys, SleepEVAL questionnaire

RLS: 5.5 PLMD: 3.9 with ICSD criteria

Sevim et al.241 2003 (Turkey)

Turkish adults, N = 3234

IRLSSG criteria, face-to-face personal interviews

3.19

Bhowmik et al.242 2003 (India)

Case-control study. N = 121 hemodialysis patients and 99 control patients

Questionnaire with RLScriteria; ENMG

Patients on hemodialysis: 6.6 Control patients: 0.0

Nichols et al.243 2003 (USA)

A primary care patient population seen by family physicians, N = 2099

IRLSSG criteria, examined by family physicians

All 4 symptoms present: 24.0 Symptoms present at least weekly: 15.3

Suzuki et al.244 2003 (Japan)

Japanese pregnant women, N = 16,528

Questionnaire survey in 500 maternity services

19.9

Rijsman et al.245 2004 (The Netherlands)

Population of a health center in the Netherlands aged ≥ 50 yr; N = 1437

Questionnaire

7.1

Gigli et al.231 2004 (Italy)

N = 601 patients with endstage renal disease

IRLSSG criteria, questionnaire

21.5

Ulfberg, Nyström246 2004 (Sweden)

Blood donors, N = 946, aged 18-64 yr

IRLSSG criteria, questionnaire

f: 24.7 m: 14.7

Högl et al.247 2005 (Austria)

Population sample, aged 50-89 yr, N = 701

Interviews, clinical examination, laboratory

10.6

Allen et al.229 2005 (USA)

Population sample, aged > 18 yr, N = 15,391 (REST study)

IRLSSG criteria, questionnaire

RLS weekly: 5 RLS symptoms at least on 2 days per week: 2.7

Kim et al.248 2005 (South Korea)

Population sample, adults

IRLSSG criteria, questionnaire

f: 15.4 m: 8.5

Winkelman et al.249 2006 (USA)

Wisconsin Sleep Cohort, N = 2821

IRLSSG criteria, slightly modified, questionnaire

RLS at least weekly

Nomura et al.250 2008 (Japan)

N = 2812

Rural population telephone interview IRLSSG criteria, questionnaire

1.8

f: 14.2 m: 6.6

f: 11.2 m: 9.9 f: 2.3 m: 1.2

ICSD, International Classification of Sleep Disorders; IRLSSG, International Restless Legs Syndrome Study Group; PLMD, periodic limb movement disorder.

708  PART II / Section 8  •  Impact, Presentation, and Diagnosis Table 61-8  Population Prevalences of Parasomnias* Childhood

PARASOMNIA

OCCURRENCE (%) ALWAYS OR OFTEN/NOW AND THEN/EVER

Adulthood OCCURRENCE (%) ALWAYS OR OFTEN/NOW AND THEN/EVER

REFERENCES

REFERENCES

Sleep terrors

0.9-1.8/8.4/ 28-39.8

264, 271-273

–/–/ 30) presented an accident risk factor higher than that of the controls. In a third study,29 the investigators performed an integrated analysis of recordings of sleeprelated breathing disorders and self-reported automotive and company-recorded automotive accidents in 90 commercial long-haul truck drivers. In this study, truck drivers with sleep-disordered breathing had a twofold higher accident rate per mile than drivers without sleep-disordered breathing. In contrast to the study cited earlier,28 accident frequency was not dependent on the severity of the sleeprelated breathing disorder.30 In another study on professional drivers,8 over 20% of long-haul drivers reported having dozed off at least twice while driving. Near misses due to dozing off had occurred in 17% of these drivers. There is debate about

the best predictive symptom for risk of sleep-related accidents. Surprisingly, excessive daytime sleepiness per se as measured by the Epworth Sleepiness scale (ESS) has not been associated with accident risk in apneic patients.27 This finding could be explained by a low percentage of chronically sleepy drivers (9% scored themselves above 10 at the ESS) in the studied population. In a case-control study31 of a series of 189 consecutive patients and a control group of 40 hospital staff workers, the best predictors of traffic accidents were self-reported sleepiness while driving (odds ratio [OR] 5; 95% CI, 2.3-10.9), having quit driving because of sleepiness (OR 3; 95% CI, 1.1-8.6), and being currently working (OR 2.8; 95% CI, 1.1-7.7). In a similar vein, a sample of 4002 randomly selected drivers32 were interviewed to define the prevalence of drivers who are habitually sleepy while driving. The habitually sleepy drivers reported a significantly higher frequency of vehicular accidents than control subjects (adjusted OR 13.3; CI, 4.1-43.0) and had a significantly higher prevalence of respiratory sleep disorders than control subjects. The authors concluded that habitually sleepy drivers are a large group (1 in 30 drivers) who are involved in severalfold more vehicular accidents than control subjects. More recently, in a meta-analysis33 on sleep apnea and driving risk, 23 of 27 studies and 18 of 19 studies with control groups found a statistically significant increased risk, with many of the studies finding a twofold to threefold increased risk. Sleep apnea is not the only disease responsible for excessive daytime sleepiness. Narcolepsy is a major disorder responsible for excessive daytime sleepiness, and it has also been studied as a risk factor for traffic accidents. Narcoleptic patients present a higher risk of sleep-related accidents than apneic subjects.21 The proportion of individuals with sleep-related accidents are 1.5- to 4-fold greater in the hypersomnolent patients than in the control group. Apneic and narcoleptic individuals account for 71% of all sleep-related accidents. The results of multiple sleep latency tests (MSLT) did not correlate with the rate of accidents among sleepy patients. However, the number of patients in the study with MSLTs was quite limited (46 apneic, 22 narcoleptic, 17 other causes of excessive daytime sleepiness), which could explain the lack of power of the study. It is worth noting that in all sleep disorders, victims of accidents presented with sleep latencies shorter than those of controls. Elevated risks for motor vehicle accidents due to sleepiness and cataplexy have been reported for persons with untreated narcolepsy.34 In one study,35 researchers compared the performance on the Divided-Attention Driving Test (DADT) of 21 male patients with obstructive sleep apnea, 21 sex-matched controls, and 16 narcoleptic patients. Narcoleptic patients were younger and sleepier than the obstructive sleep apnea patients. The tracking error was much worse in patients than in control subjects (228 ± 145  cm for obstructive sleep apnea vs. 196 ± 146 for narcolepsy vs. 71 ± 31 for controls; P < .001). Further studies on narcolepsy and hypersomnia are urgently needed to improve the understanding of the driving risk of these patients.



EVALUATION OF RISK IN PATIENTS WITH SLEEPINESS WHILE DRIVING Two studies31,32 concluded that asking a subject about excessive sleepiness while driving may better predict which subjects with sleep-disordered breathing have accidents than asking about overall sleepiness. For this reason, a thorough clinical interview can usefully evaluate patients’ driving risks in a vast majority of cases. Nevertheless, this strategy relies on a truthful, subjective assessment by the driver talking to the physician. Deceit cannot be excluded, especially in drivers dependent on their driving license for their job. Very few studies have investigated the relationship between objective measurement of sleepiness (MSLT or MWT scores) and driving performance. In a study41 of the Wisconsin Sleep Cohort, the authors found a correlation between MSLT scores and driving accidents in male apneic drivers. One study42 compared the MWT score with performance on a driving simulator in healthy sleep-deprived volunteers and found the first evidence of the predictive value of the MWT for driving performances. When additional studies were performed in a driving simulator and in real driving experiments, they confirmed that MWT scores are significantly associated with impaired driving (i.e., inappropriate highway line crossings) (Fig. 69-1).43,44 Further data are needed to understand the predictive value of the MWT on accidental risk in large cohorts of apneic and narcoleptic patients. IMPACT OF TREATMENT AND COUNTERMEASURES ON ACCIDENT RISK Given the sleep-related risk, a major question is how can accidents involving these patients be reduced? Uvulopalatopharyngoplasty was evaluated as a therapeutic strategy to reduce accidental risk.45 The authors compared the car accident rate of 56 apneic patients for the first 5 years after this surgery with the rate of the 5 years immediately before the operation. The risk of accidents of apneic patients was compared with that of a control group of subjects followed for nasal surgery. The reported habitual sleepiness while driving had disappeared in 87% (P < .001) of drivers who had the problem preoperatively, and the accident risk reduction (corrected for mileage) in patients was almost four times greater than the reduction in control subjects (P < .001) after surgery. Several studies investigating the impact of continuous positive airway pressure (CPAP) on traffic accidents46-48

Mean number of inappropriate line crossings (ILC)

Drugs Even if many publications36-40 associate central nervous system drugs and risk of accidents, very few data show a link between sleep-related accidents and drug intake. Indirect factors such as the type of drugs responsible for traffic accidents (i.e., hypnotics and benzodiazepines) suggest that sleepiness could be the major cause for drug-related accidents, but further evidence is needed.

CHAPTER 69  •  Drowsy Driving  771

*

3 *

*

*

2

1

0 Very sleepy Sleepy Alert (0–19 min) (20–33 min) (34–40 min)

Controls

Maintenance of wakefulness test scores Figure 69-1  Mean number of inappropriate line crossings (ILC) during real driving (mean ± SE) in the three sleep latency groups on the Maintenance of Wakefulness Test (MWT) and in healthy controls. *P < .05. (From Philip P, Sagaspe P, Taillard J, et  al. Maintenance of Wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64:410-416.)

have confirmed that this therapy is associated with a reduction in the risk of motor vehicle accidents due to obstructive sleep apnea. No study has yet demonstrated in narcoleptics or hypersomnia patients the impact of drugs taken to promote alertness on accident rates. Although cold air or listening to the radio has not demonstrated any efficacy, coffee and naps are very efficient in combating sleepiness at the wheel.16,49-51 We have shown that subjects should select specific countermeasures according to their age or individual physiology.52 Indeed, a cup of coffee containing 200  mg of caffeine significantly improves performance in both young (20 to 25 years) and middle-aged participants (40 to 50 years) on nighttime highway driving performances, whereas a 30-minute nap is more efficient in younger than in middle-aged drivers.

DRIVING LICENSE REGULATIONS Excessive daytime sleepiness and several sleep disorders have been targeted by experts as medical conditions affecting driving skills. As part of the COST Action B-26, a review paper53 looked at driving license regulations in 25 European countries. Excessive daytime sleepiness is mentioned as a medical handicap for driving in 9 countries (Belgium, Finland, France, Germany, Hungary, the Netherlands, Spain, Sweden, the United Kingdom), whereas sleep apnea syndrome is mentioned in 10 countries (Belgium, Finland, France, Germany, Hungary, the Netherlands, Spain, Sweden, the United Kingdom, Poland). In all these European countries a patient with untreated obstructive sleep apnea syndrome is considered unfit to drive. However, even when excessive daytime sleepiness or sleep apnea is mentioned, no criteria for assessment of the sleep disorder are given. Finally, medical qualification of the physician applying the law is not clearly defined.

772  PART II / Section 9  •  Occupational Sleep Medicine

Implications for the patients and the physicians are also very different in each country. In the vast majority of European Union countries, once a diagnosis of sleep disorder is made it is the physician’s responsibility to inform the administrative authorities issuing driving licenses of the driver’s condition. This is not the case in 4 countries (Belgium, France, Germany, and The Netherlands), where the physician is expected to inform the patient, but not the authorities, that he or she is unfit to drive. Medicolegal authorizations for driving once diagnosed with a sleep disorder rely on a certificate delivered by a general practitioner or specialist (pulmonologist or neurologist) in 8 countries (Belgium, Finland, France, Germany, Hungary, Spain, the United Kingdom, Poland). This certificate is based on a patient’s clinical improvement and therapeutic compliance, but in 2 countries the final decision for fitness to drive relies on the patient’s self-evaluation. Despite available scientific evidence,33 many countries in Europe do not yet include sleep apnea or excessive daytime sleepiness as risk factors for traffic accidents. A unified European directive seems desirable and should include several sleep disorders and excessive daytime sleepiness in the list of medical conditions adversely affecting driving skills.54 Nonprofessional and professional drivers are not subjected to the same medical evaluations. Frequency and type of evaluation differ dramatically. Commercial drivers have a major motivation to keep their driving license, and this can affect their reports of symptoms during the medical evaluation. In addition, Europe and the United States differ in how the driver’s income is calculated. In Europe, drivers are paid by the hour with a limit on the number of hours that can be driven in a day. In the United States, although there is a daily limit on driving and on duty hours, drivers are paid by the mile and thus are effectively encouraged to achieve the longest distance per day to maximize their income. Thus, it would appear that the risk of fatigue is higher in the United States. In addition to these differences in calculating pay, health status is also approached differently. Several states within the United States require physicians to report if a professional driver is affected by a sleep disorder. Such a reporting requirement can have dramatic consequences for the driver’s continued employment. The 1991 U.S. Department of Transportation Federal Highway Administration Recommendations reference a 1988 conference on Neurological Disorders and Commercial Drivers that recommended that a person with a diagnosis of narcolepsy be disqualified from driving commercially.55 This restrictive attitude regarding clinical conditions and driving fitness is not followed in Europe. As recommended by the task force of the American College of Chest Physicians,56 apneic professional drivers are submitted to a more permissive regulation than narcoleptic drivers and can go back to work after appropriate treatment. An apneic driver should be diagnosed by a physician and the diagnosis confirmed by polysomnography, preferably in an accredited sleep laboratory and by a certified sleep specialist. A full-night study should be done unless a split-

night study is indicated (severe obstructive sleep apnea identified after at least 2 hours of sleep). Treatment (with CPAP) should be started as soon as possible (i.e., within 2 weeks of the sleep study). At a minimum of 2 weeks after initiating therapy, but within 4 weeks, the driver should be re-evaluated by the sleep specialist and compliance assessed. If the driver is compliant, the driver can return to work but should be initially certified for no longer than 3 months. Such an approach reduces health care and disability costs.57 In Europe, driving regulations are similar to U.S. recommendations for apneic commercial drivers with minor changes in terms of period of evaluation (e.g., 1 year in France). Finally, whereas some countries consider sleepiness while driving as the major problem regarding driver safety, only France requires an objective quantification of alertness (the Maintenance of Wakefulness Test) to evaluate fitness to drive. This specific position refers to the frequent combination of sleep disorders and poor sleep hygiene in truck drivers. To ensure legal protection for drivers and physicians, French experts estimated that it was mandatory to demonstrate objectively that patients respond to treatment before allowing them to drive again. In case of a sleep-related accident in treated drivers, physicians could not be sued for insufficient efficacy of treatment and patients should not be prosecuted for misreporting the beneficial effects of treatments.

FUTURE CONSIDERATIONS Although much has already been done in this field, many questions remain unanswered. At the diagnostic level there is still no simple objective measure to quantify the risk to our patients as are available for other accident risk factors (e.g., using a breathalyzer for alcohol testing). Ideally, we need a “somnotest” to quantify the driving risk, but up to now driving simulators or EEG measures have provided only indirect and variable estimation of the driving risk and are obviously not practicable for field use outside the clinic or laboratory. Treatments other than CPAP or uvulopalatopharyngoplasty could provide an interesting alternative to prevent accidents, but there are still no data on the impact of alertness substances on the driving risk of apneic individuals and oral appliances have not yet been studied regarding driving risk. Studying the impact of extensive driving in treated and untreated patients is also a key factor in the research agenda because of the high prevalence of sleep-disordered breathing in professional drivers. More studies are needed to better define the phenotype of apneic individuals involved in traffic accidents. Whereas only 1 patient of 30 with sleep-disordered breathing is a victim of a sleeprelated accident, it is urgent to track these subjects and develop special evaluations plus driving recommendations (e.g., no nocturnal driving) for these drivers. New pharmacologic countermeasures should be tested, and interindividual response rates to these countermeasures need to be developed. Finally, public campaigns on the risks of drowsy driving and the effectiveness of naps and coffee as countermeasures need to be released in every country.



CHAPTER 69  •  Drowsy Driving  773

❖  Clinical Pearl Drowsiness and sleeping at the wheel are now identified as the reasons behind many fatal traffic accidents. Drowsiness from sleep restriction and nocturnal driving have been incriminated in 20% of traffic accidents. Drugs affecting the central nervous system, sleep-disordered breathing, and narcolepsy have also been associated with an increased risk of accidents. Caffeine or naps have shown a great efficacy to decrease driving impairment in sleepy drivers, but medical treatments such as CPAP are also effective to decrease accidental risk in those with sleep apnea. Many countries systematically evaluate medical disorders among professional drivers, but criteria are still very heterogeneous and an effort toward harmonization would be very beneficial. Objective measurements of sleepiness such as the Maintenance of Wakefulness Test can provide important information in addition to questions on subjective sleepiness while driving. Finally, public awareness on the danger of drowsy driving needs to be reinforced and physicians should play a key role in these educational programs.

REFERENCES 1. World Health Organization. World report on road traffic injury prevention. Geneva: WHO; 2004. 2. Jewett ME, Dijk DJ, Kronauer RE, et al. Dose-response relationship between sleep duration and human psychomotor vigilance and subjective alertness. Sleep 1999;22:171-179. 3. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538. 4. Horne JA, Reyner LA. Sleep related vehicle accidents. BMJ 1995; 310:565-567. 5. Philip P, Vervialle F, Le Breton P, et al. Fatigue, alcohol, and serious road crashes in France: factorial study of national data. BMJ 2001;322:829-830. 6. Connor J, Norton R, Ameratunga S, et al. Driver sleepiness and risk of serious injury to car occupants: population based case control study. BMJ 2002;324:1125. 7. Connor J, Whitlock G, Norton R, et al. The role of driver sleepiness in car crashes: a systematic review of epidemiological studies. Accid Anal Prev 2001;33:31-41. 8. Hakkanen H, Summala H. Sleepiness at work among commercial truck drivers. Sleep 2000;23:49-57. 9. Hakkanen H, Summala H. Fatal traffic accidents among trailer truck drivers and accident causes as viewed by other truck drivers. Accid Anal Prev 2001;33:187-196. 10. Mitler MM, Carskadon MA, Czeisler CA, et al. Catastrophes, sleep, and public policy: consensus report. Sleep 1988;11:100-109. 11. Powell NB, Schechtman KB, Riley RW, et al. Sleepy driver nearmisses may predict accident risks. Sleep 2007;30:331-342. 12. Sagberg F. Road accidents caused by drivers falling asleep. Accid Anal Prev 1999;31:639-649. 13. Philip P, Ghorayeb I, Stoohs R, et al. Determinants of sleepiness in automobile drivers. J Psychosom Res 1996;41:279-288. 14. Philip P, Taillard J, Guilleminault C, et al. Long distance driving and self-induced sleep deprivation among automobile drivers. Sleep 1999;22:475-480. 15. Philip P, Sagaspe P, Moore N, et al. Fatigue, sleep restriction and driving performance. Accid Anal Prev 2005;37:473-478. 16. Philip P, Taillard J, Moore N, et al. The effects of coffee and napping on nighttime highway driving: a randomized trial. Ann Intern Med 2006;144:785-791. 17. Mitler MM, Miller JC, Lipsitz JJ, et al. The sleep of long-haul truck drivers. N Engl J Med 1997;337:755-761.

18. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005;352:125-134. 19. Sagaspe P, Taillard J, Åkerstedt T, et al. Extended driving impairs nocturnal driving performances. Plos One 2008;3:e3493. 20. American Thoracic Society. Sleep apnea, sleepiness, and driving risk. Am J Respir Crit Care Med 1994;150:1463-1473. 21. Aldrich MS. Automobile accidents in patients with sleep disorders. Sleep 1989;12:487-494. 22. Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive sleep apnea. Am Rev Respir Dis 1988;1 38:337-340. 23. Cassel W, Ploch T, Peter JH, et al. [Risk of accidents in patients with nocturnal respiration disorders]. Pneumologie 1991;45 (Suppl. 1):271-275. 24. Haraldsson P-O, Carenfelt C, Diderichsen F, et al. Clinical symptoms of sleep apnea syndrome and automobile accidents. ORL J Otorhinolaryngol Relat Spec 1990;52:57-62. 25. Philip P. Sleepiness of occupational drivers. Ind Health 2005;43: 30-33. 26. Powell NB, Schechtman KB, Riley RW, et al. Sleepy driving: accidents and injury. Otolaryngol Head Neck Surg 2002;126: 217-227. 27. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999;340:847-851. 28. George CF, Smiley A. Sleep apnea and automobile crashes. Sleep 1999;22:790-795. 29. Stoohs RA, Bingham LA, Itoi A, et al. Sleep and sleep-disordered breathing in commercial long-haul truck drivers. Chest 1995; 107:1275-1282. 30. George CF. Sleep apnea, alertness, and motor vehicle crashes. Am J Respir Crit Care Med 2007;176:954-956. 31. Lloberes P, Levy G, Descals C, et al. Self-reported sleepiness while driving as a risk factor for traffic accidents in patients with obstructive sleep apnoea syndrome and in non-apnoeic snorers. Respir Med 2000;94:971-976. 32. Masa JF, Rubio M, Findley LJ. Habitually sleepy drivers have a high frequency of automobile crashes associated with respiratory disorders during sleep. Am J Respir Crit Care Med 2000;162:1407-1412. 33. Ellen RL, Marshall SC, Palayew M, et al. Systematic review of motor vehicle crash risk in persons with sleep apnea. J Clin Sleep Med 2006;2:193-200. 34. Bartels EC, Kusakcioglu O. Narcolepsy: a possible cause of automobile accidents. Lahey Clin Found Bull 1965;14:21-26. 35. George CF, Boudreau AC, Smiley A. Comparison of simulated driving performance in narcolepsy and sleep apnea patients. Sleep 1996;19:711-717. 36. Barbone F, McMahon AD, Davey PG, et al. Association of roadtraffic accidents with benzodiazepine use. Lancet 1998;352:13311336. 37. Leveille SG, Buchner DM, Koepsell TD, et al. Psychoactive medications and injurious motor vehicle collisions involving older drivers. Epidemiology 1994;5:591-598. 38. Hemmelgarn B, Suissa S, Huang A, et al. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997; 278:27-31. 39. Hauser RA, Gauger L, Anderson WM, et al. Pramipexole-induced somnolence and episodes of daytime sleep. Mov Disord 2000; 15:658-663. 40. Hu PS, Trumble DA, Foley DJ, et al. Crash risks of older drivers: a panel data analysis. Accid Anal Prev 1998;30:569-581. 41. Young T, Blustein J, Finn L, et al. Sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. Sleep 1997;20:608-613. 42. Banks S, Catcheside P, Lack LC, et al. The Maintenance of Wakefulness Test and driving simulator performance. Sleep 2005;28: 1381-1385. 43. Sagaspe P, Taillard J, Chaumet G, et al. Maintenance of Wakefulness Test as a predictor of driving performance in patients with untreated obstructive sleep apnea. Sleep 2007;30:327-330. 44. Philip P, Sagaspe P, Taillard J, et al. Maintenance of Wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64:410-416. 45. Haraldsson PO, Carenfelt C, Lysdahl M, et al. Does uvulopalatopharyngoplasty inhibit automobile accidents? Laryngoscope 1995; 105:657-661.

774  PART II / Section 9  •  Occupational Sleep Medicine 46. Krieger J, Meslier N, Lebrun T, et al. Accidents in obstructive sleep apnea patients treated with nasal continuous positive airway pressure: a prospective study. The Working Group ANTADIR, Paris and CRESGE, Lille, France. Association Nationale de Traitement a Domicile des Insuffisants Respiratoires. Chest 1997;112: 1561-1566. 47. George CF. Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 2001;56:508-512. 48. Sassani A, Findley LJ, Kryger M, et al. Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep 2004;27:453-458. 49. Reyner LA, Horne JA. Evaluation of “in-car” countermeasures to sleepiness: cold air and radio. Sleep 1998;21:46-50. 50. Garbarino S, Mascialino B, Penco MS, et al. Professional shift-work drivers who adopt prophylactic naps can reduce the risk of car accidents during night work. Sleep 2004;27:1295-1302. 51. Reyner LA, Horne JA. Suppression of sleepiness in drivers: combination of caffeine with a short nap. Psychophysiology 1997;34:721-725. 52. Sagaspe P, Taillard J, Chaumet G, et al. Aging and nocturnal driving: better with coffee or a nap? A randomized study. Sleep 2007; 30:1808-1813.

53. Alonderis A, Barbe F, Bonsignore M, et al. Medico-legal implications of sleep apnoea syndrome: driving license regulations in Europe. Sleep Med 2008;9:362-375. 54. Rodenstein D. Driving in Europe: the need of a common policy for drivers with obstructive sleep apnoea syndrome. J Sleep Res 2008; 17:281-284. 55. Booker HE, Hauser WA, Chrokroverty S, et al. Executive summary: conference on neurological disorders and commercial drivers. Washington, DC: U.S. Department of Transportation; 1988, p 8. 56. Hartenbaum N, Collop N, Rosen IM, et al. Sleep apnea and commercial motor vehicle operators: statement from the joint task force of the American College of Chest Physicians, the American College of Occupational and Environmental Medicine, and the National Sleep Foundation. Chest 2006;130:902-905. 57. Hoffman B, Wingenbach DD, Kagey AN, Schaneman JL, Kasper D. The long-term health plan and disability cost benefit of obstructive sleep apnea treatment in a commercial motor vehicle driver population. J Occup Environ Med 2010;52:473-477.

Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management Jennifer McDonald, Dipali Patel, and Gregory Belenky Abstract Managing fatigue to reduce the risk of error, incident, and accident will depend on the evidence base built upon monitoring sleep and performance in the workplace. Fatigue, defined objectively as degraded operational performance, is a function of sleep, circadian rhythm, and workload. In the operational (field or workplace) environment, sleep can be measured subjectively by self-report or objectively using field- or workplace-friendly technology such as wrist actigraphy. Performance can be measured subjectively by self-report or objectively by performance measures added to the workplace (e.g., the psychomotor vigilance task), or measurement can be derived from the actual work performed using embedded metrics (e.g., lane deviation in commercial trucking). Sleep and performance studies conducted in the workplace reveal that performance is impaired by sleep loss and that performance is restored by sleep (main sleep period and

Imagine a near future in which unobtrusive, continuous, personal biomedical status monitoring is ubiquitous. A personal biomedical status monitor could measure a host of parameters, including metabolic indices (e.g., blood glucose, caloric expenditure), cardiovascular parameters (e.g., blood pressure, electrocardiogram), and inflammatory markers (e.g., C-reactive protein). It could guide medical treatment in the chronically ill, help sustain health and well-being in the healthy, and, combined with objective measures of work performance, sustain productivity and safety in the workplace. Components of such a system are already in use (e.g., continuous glucose monitoring in patients with diabetes, electrocardiographic monitoring to trigger defibrillation in patients with arrhythmias). With respect to occupational sleep medicine, comprehensive biomedical status monitoring could include measurement of sleep–wake history (e.g., by actigraphy) and circadian phase (method to be developed) and could be used as input for biomathematical models predicting, in real time, fatigue-related performance decrements. These predicted individual performance decrements, calibrated and validated against embedded-in-the-workplace measures of performance (e.g., changes in lane deviation in commercial drivers, flight operations quality assurance [FOQA] data in commercial pilots) and integrated into the objective function of existing commercial rostering and scheduling software, could enable the implementation of system-wide fatigue risk management systems to improve safety and productivity. Such fatigue risk management systems could be capable of continuous, real-time optimization and reoptimization of rosters and schedules ensuring the best possible sleep opportunity, monitoring the use made of this opportunity, and monitoring actual performance in the workplace.

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naps). It appears that it is total sleep in 24 hours that determines performance and that an amount of actual sleep split into two or three sleep periods is as performance sustaining as the same amount of actual sleep consolidated into a single sleep period. Sleep and performance studies conducted in the workplace can inform the development of interventions to counteract the effects of fatigue on workplace performance, a primary intervention being to provide adequate opportunity for and proper circadian placement of sleep, including both main sleep period and naps. It is possible to imagine a system of workplace fatigue risk management using real-time measurement of sleep and performance as inputs to biomathe­ matical models predicting performance and using these performance predictions to optimize scheduling in real time. Such fatigue risk management would preserve performance, productivity, and safety, and would likely sustain long-term health and well-being in working people.

Fatigue risk management, as conceptualized here, will depend on the real-time, objective measurement of sleep– wake history, circadian phase, and performance. In anticipation of fatigue risk management through monitoring of personal biomedical status, prediction of performance, and integration of predictions into rostering and scheduling software, this chapter reviews the findings of field studies on the effects of shift timing and duration and subsequent sleep on postsleep performance. Granted that the findings of such studies are very much after the fact compared to the real-time optimization through measurement envisioned here, they nevertheless give an idea of what is to come and suggest the utility of such studies in developing evidence-based fatigue risk management (see Chapter 68).

SLEEP, CIRCADIAN RHYTHM, WORKLOAD, AND OPERATIONAL PERFORMANCE Sleep and Sleep Loss Sleep loss (sleep deprivation and sleep restriction) leads to fatigue, operationally defined subjectively by self-report and objectively by degraded alertness and cognitive performance. Sleep loss related fatigue is largely a function of three interacting factors: sleep–wake history, circadian rhythm, and workload (see Chapter 65). Performance and its inverse, sleep propensity, vary over the 24-hour period of a day, in parallel with the sinusoidal circadian rhythm in core body temperature.1 Working night shifts or travelling across time zones disrupts the normal relationship between sleep and work timing and the circadian rhythm and impairs sleep, alertness, and performance 775

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(see Chapter 71). Workload—roughly task duration, complexity, and intensity—contributes to performance degradation by increasing effects of time on task and decreasing sleep opportunity.2 In addition, there are enduring individual differences in response to sleep loss and in the relationship of circadian phase to the light dark cycle.3 Laboratory studies have demonstrated that both acute total sleep deprivation and chronic partial sleep restriction lead to declines in alertness and cognitive performance, well-being, and health. Acute total sleep deprivation degrades cognitive performance linearly over days, modulated within days by the circadian rhythm, with a loss in the capacity to do useful mental work of 17% to 25% per day.4,5 Mild, moderate, and severe sleep restriction (7, 5, or 3 hours in bed per night for 7 days, respectively) leads to sleep-dose-dependent decreases in performance over time in comparison to baseline or to sleep augmentation (9 hours in bed per night).6 For 7 and 5 hours in bed per night, performance appears to stabilize at lower levels after 3 or 4 days, but for 3 hours in bed per night, performance continues to degrade across the 7-day experimental period. In a parallel study, chronic sleep restriction of 6 and 4 hours in bed per night for 14 days led to cognitive decrements comparable to 1 to 2 days of total sleep deprivation, also in a sleep-dose-dependent manner.7 Even mild sleep restriction (7 hours in bed per night) degraded performance over time.6 In the first study,6 at the end of the 7-day sleep restriction period participants were allowed 8 hours in bed per night recovery sleep for 3 nights. In contrast to acute total sleep deprivation, where recovery is complete in 1 to 2 days, performance in the 7, 5, and 3 hour time in bed groups did not recover over the 3-day recovery period. Sleep loss and fatigue lead to decreased efficiency and productivity in the workplace, increased accidents, and economic losses, in the form of additional costs to employers and employees and to society as a whole.8 Furthermore, sleep loss is associated with significant adverse effects on mental and physical health, including weight gain and obesity,9 hypertension and cardiovascular problems,10 gastrointestinal disease, chronic fatigue, substance and alcohol abuse, family problems, and mood difficulties.11 Thus, the adverse effects of sleep loss and sleep loss–related fatigue are varied and far reaching. Circadian Rhythm The circadian rhythm (the sinusoidal 24-hour rhythm of the endogenous biological clock) modulates alertness, performance, and sleep propensity (see Section 5). The circadian rhythms in performance and sleep propensity parallel the circadian rhythm in core body temperature. The rhythm in performance peaks subsequent to the peak in the circadian temperature rhythm and troughs subsequent to the trough in circadian temperature rhythm. Performance is modulated by circadian rhythm both when persons are well rested and when they are sleep deprived or sleep restricted. With respect to sleep propensity, it is difficult to fall asleep and to stay asleep when core body temperature is rising or high; it is easy to fall asleep and to stay asleep when core body temperature is falling or low. In modulating fatigue risk, the circadian rhythm

modulates the risk of injury, a correlate of decreased performance. Risk of injury increases depending on the shift worked, with the lowest rates of injury risk on morning shifts and highest rates on night shifts.12 Injury rates on the job are highest during the late night and early morning circadian low.12 Mild to moderate sleep loss, common for night shift workers who typically experience restricted sleep during the day,13 leads to declines in performance.6 Thus, both sleep–wake history and the circadian rhythm modulate alertness, sleep propensity, and performance. Workload and Operational Environment Workload is not well defined and not easily measured in either laboratory or field. As an expedient, studies have equated workload with work task duration. Five factors are related to workload that operate to impair performance.14 These include time on task, task sequence, time of day, number of tasks performed, and whether sleep loss is partial or total. Fatigue as a result of time on task has been shown to be relieved by breaks within the shift.9 Thus, fatigue from time on task recovers after a simple break from the task and does not require sleep. In contrast, fatigue and performance decrements related to time awake can only be reversed by sleep.15 Overall, the fatigue resulting from working long hours or overtime shifts increases the risk of accident.16 Workload, time of day, and sleep loss all interact to affect performance. The operational environment is defined as a work setting in which human performance plays a critical role and there is a high risk that if human performance degrades the system will fail. In the operational environment, the human in the operational loop has limited time to decide and act upon a course of action.2 Operational environments include military operations, maritime operations, medicine, the various modes of land transportation, aviation, security work, energy generation, resource extraction (e.g., mining), financial markets, and industrial production. In these settings, the operational demands described previously (shift timing and duration, work intensity, and difficulty and complexity of the work tasks) degrade performance directly through the effects of workload and indirectly by reducing the amount of time available for sleep, thus reducing total sleep time, a primary determinant of alertness and performance.2 Degraded operational performance leads to a loss in productivity and a decrease in safety through increased risk of error, incident, and accident. Human error, with sleep loss as a contributing factor, has led to major disasters, including Chernobyl, Three Mile Island, and the Exxon Valdez,12 and probably the Challenger launch decision. Risk of accident increases approximately 18% on afternoon shifts and 30% on night shifts compared to risk on morning shifts, with risk increasing across successive nights worked.12 A significant increase in injury rates results from degraded operational performance.17 This risk extends past the end of the shift. The rate of motor vehicle accidents following night shift work is greater than that following day shift work.18 Thus, decreased operational performance resulting from fatigue decreases safety and productivity, increases the risk of error, incident, and accident, and can generate large economic losses.



CHAPTER 70  •  Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management  777

TECHNIQUES FOR MEASURING SLEEP AND PERFORMANCE IN THE OPERATIONAL ENVIRONMENT Historical Perspective In the 1980s, when one of us (G.B.) was directing the U.S. Army’s research program in sleep and performance, measuring sleep in the field environment by actigraphy was a relatively young, developing technology. We proudly presented our early field actigraph studies to U.S. Army Major General Maxwell Thurman, the then U.S. Army Deputy Chief of Staff for Personnel. General “Max” was not impressed. He harrumphed and said, “I don’t care how much they sleep, I want to know how well they perform.” An actigraphically recorded sleep–wake history is a marvel of applied information technology, but in itself an actigraphically derived sleep–wake history does not say much about the wearer’s performance. In response to General Max’s challenge, we developed a mathematical model that used sleep–wake history and estimated circadian phase as its inputs and yielded a minute-by-minute prediction of performance as its output. Our model and other similar models have become commercial products with application in the developing field of fatigue risk management.2,19 General Max would have been pleased: With actigraphy we will know how much people sleep, and applying mathematical models to the actigraphic data we will be able to predict how well they will perform. Measuring Sleep Sleep can be measured objectively using polysomnography (PSG) and actigraphy, and it can be measured subjectively using a sleep diary or other means of self-report. Polysomnography is the standard for sleep measurement in laboratory studies of sleep and performance. Using a network of electrodes, PSG measures the electrical potentials of the brain, eyes, and muscles and can determine sleep–wake status and the stages of sleep (see Chapter 141).20 PSG is not practical for data collection during field studies of sleep and performance, especially field studies attempting to capture running sleep–wake histories in multiple subjects over weeks and months. Actigraphy can accurately measure total sleep time and is validated as a measure of total sleep time against PSG (see Chapter 147).20 Thus, actigraphy can reliably (relative to PSG) assess the duration of main sleep periods and supplemental naps and thus provide a running sleep–wake history. The actigraph is a small, self-contained, wristwatch-size device worn on the nondominant wrist that sums arm movements over consecutive 60-second epochs, generating a minute-by-minute record of activity that can be scored for sleep–wake state by a validated sleep-scoring algorithm. This method can be used to collect continuous sleep–wake history data over consecutive 24-hour periods for weeks at a time and allows collection of an objective record of sleep–wake history (main sleep periods and naps) comparable to that obtained by PSG in a laboratory study.20 Sleep diaries allow a participant to record sleep time for a given time period based upon his or her subjective sense and recollection. Sleep diaries offer the advantages of being easy to implement and inexpensive. Sleep diaries can be useful as adjuncts to actigraphy because they can bridge

periods of data lost through actigraph malfunction or the actigraph being off the wrist. Performance and Total Sleep Time in 24 Hours Studies have demonstrated that performance is a function of total sleep time in 24 hours, regardless of whether the sleep is consolidated or split21 and irrespective of sleep stages (e.g., rapid eye movement [REM] sleep or non-REM [NREM] sleep and its stages). It does not appear to matter whether sleep is obtained in a single consolidated sleep bout or distributed in two or three bouts over 24 hours (split sleep). Given equal total sleep time, split sleep appears to sustain performance as well as sleep consolidated into a single sleep bout.21 Thus, total sleep time measured by actigraphy can be used to predict performance in operational settings.20,22 Performance and Napping Napping is potentially an effective way to augment total sleep time and improve performance in shift workers whose main sleep period occurs during the day and at an adverse circadian phase. Indeed, with any worker experiencing sleep restriction, napping to supplement the main sleep period improves performance.23,24 Napping may be the most effective way to counter fatigue, improving performance by increasing total sleep time.13 Total sleep time per 24 hours, including both main sleep period and napping, is the key to performance. Added, Simulator-Derived, and Embedded Performance Metrics Alertness and, broadly speaking, cognitive performance (attention, vigilance, learning, and memory) can be measured in the field by added, simulator-derived, or embedded performance metrics. Added metrics are those that are not intrinsic to the workplace and include self-report, laboratory tests ported to personal digital assistants (PDAs) and similar devices, and paper-and-pencil testing. Added metrics typically lack ecological validity. Simulator-derived metrics include performance in simulated work environments (e.g., driving simulators in commercial trucking, flight simulators in commercial aviation). Embedded performance metrics are taken from the workplace (e.g., lanedeviation sensors in commercial trucking, FOQA data in commercial aviation, and evaluation of workplace performance by expert raters). Embedded metrics are those intrinsic to the workplace and are almost by definition ecologically valid. An example of a laboratory test ported to a PDA to measure performance in field studies is the psychomotor vigilance task (PVT).25 The PDA-based PVT is a portable, self-contained, simple reaction time test that measures the ability to sustain attention and vigilance over time and is sensitive to time awake (sleep–wake history, sleep loss), time of day (circadian rhythm), and time on task (workload).26 Paper-and-pencil testing can include neuropsychological performance measures. Performance measures added to the work environment have been used in studies with medical residents.27 These added performance measures typically interrupt the normal flow of work and generally lack ecological validity.

778  PART II / Section 9  •  Occupational Sleep Medicine

In contrast to added performance metrics, embedded performance metrics (e.g., lane deviation and FOQA) do not interrupt the flow of work and add ecological validity. Embedded metrics include measures of performance that can be derived from job performance, such as medical errors committed,28 observed attentional failures,29 injuries at work,30 critical incidents,31 performance of military tasks in field training exercises,32,33 driving errors,34,35 and, in commercial aviation, automated flight data recording.36 Finally, performance measures taken from workplace simulations (e.g., driving simulators) may be used in both field and laboratory studies. These add a degree of ecological validity to the investigation because they are designed to recreate in simulation actual job duties. Examples include studies investigating simulated motor vehicle driving,37 simulated train driving,38 simulated medical procedure completion,39 and simulated military operations.32,33

A REVIEW OF FIELD SLEEP AND PERFORMANCE STUDIES The literature on field studies of sleep and performance spans 50 years and involves diverse populations and a variety of methods. Recent studies have supported the development of systems for fatigue risk management within or as an alternative to prescriptive hours-of-service rules. These studies include work with medical professionals, commercial long-haul truck drivers, shift workers, and employees working extended hours (those who work long shifts or more than one shift per job per day). A focus of study has been medical professionals, with an emphasis on obtaining the evidence base to develop public policy with respect to medical residents’ work hours.18,28,29 The majority of these studies focus on the relationship between work hours and performance rather than the relationship between sleep and performance. The performance measures used fall largely into the three categories mentioned earlier: added metrics, embedded metrics, and metrics drawn from simulator performance. In studies showing a link between longer work hours and degraded performance, this link is presumably mediated by a combination of sleep loss, adverse circadian rhythm phase, and time on task. Similar to research with medical professionals, sleep and performance studies with commercial truckers have as their rationale relevance to safety and public policy development. Studies of driving performance have shown that long hours on duty or decreased sleep opportunity result in decreased vigilance as measured by PVT performance and speed limit violations,34 greater attentional lapses as measured by electrooculography (EOG),40 increased selfreported sleepiness,18 increased incidents or accidents,31 and increased lane deviation and speed variability.35 Similar studies have been conducted in the rail industry measuring sleep time, sleep opportunity, attention, and performance relevant to train conducting.34,38 Research on other shift workers has focused on schedule optimization and safety, with measurements concentrated on hours worked and hours slept. Night-shift workers suffer from chronic sleep restriction engendered by attempting daytime sleep at what is, in effect, an adverse circadian phase.23 Studies in shift workers have shown,

using either self-report or objective measures of sleep, a decrease in total sleep time in 24 hours due to hours worked or type of shift.41 Using objective measures of sleep, some studies find that working the night shift impairs sleep and degrades performance,41 and others find no relationship.42 In studies of night shift workers without objective measures of sleep, some have found degraded performance,43 and others have found no change.44 Another population of interest for objective work hours, sleep, and performance studies is workers who work extended work hours, either by virtue of working extended shifts or by working multiple shifts in one 24-hour period (e.g., working a double shift or holding two jobs). The literature on extended work hours is limited.45

METHODOLOGICAL FACTORS IN FIELD STUDIES OF SLEEP AND PERFORMANCE The methodological factors necessary for good field studies of sleep and performance include ecological validity, objective measures of sleep, objective measures of performance that are sensitive to sleep loss, control for circadian factors, and, if possible, an adequately rested control group.46 Studies in Military Field Training Exercises In the mid to late 1970s, researchers in the United Kingdom conducted two studies of sleep and performance in military field training exercises (Exercises Early Call I and Early Call II).32,33 These studies used objective metrics of performance including added, embedded, and simulated measures of performance and objective measures of sleep. In Early Call I, three platoons of airborne infantry, sleep condition randomized by platoon, were allowed a zero, 1.5-hour, or 3-hour sleep opportunity each night over a 10-day period. In Early Call II, soldiers were deprived of all sleep for 90 hours and then allowed a 4-hour sleep opportunity each night for the next 6 days. In both Early Call I and II, ecologically valid complex task performance (e.g., shooting at targets popping up at random) declined more than simple task performance (e.g., shooting a tight cluster of rounds at a fixed stationary target) during sleep loss. From Early Call I and II, it was concluded that soldiers were ineffective after 48 hours without sleep. From Early Call II, it was concluded that 4 hours of sleep opportunity produced recovery in cognitive functioning approximating values obtained during the control condition before sleep deprivation. This latter conclusion from Early Call II needs qualification. On closer examination, the daily 4-hour sleep opportunity in this study only partially restored performance after prolonged total sleep deprivation. Studies of Physicians in Training In medical settings, a substantial body of evidence demonstrates that sleep loss leads to decreased safety for patients, physicians, and the general public. Medical residents’ work schedules combine those of rotating shift workers and employees working extended hours, and have similar degrees of sleep loss and subjective complaints.47 Residents on call demonstrate decreased sleep as measured by



CHAPTER 70  •  Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management  779

Table 70-1  Medical Residents’ Work, Sleep, and Medical Errors Work Schedule PARAMETER

TRADITIONAL*

INTERVENTION†

Work (hours/week)

84.9 (range, 74.2-92.1)

65.4 (range 57.6-76.3)

Maximum shift (hours)

34

16

Sleep (hours/day)

6.6 ± 0.8

7.4 ± 0.9

Serious medical errors per 1000 patient-days

136

100

*Work schedule allowed a maximum of 34 consecutive hours on duty and averaging 85 hours on duty per week. † Work schedule limited to a maximum of 16 consecutive hours on duty and averaging 65 hours on duty per week. Summarized from Landrigan CP, Rothschild JM, Cronin JW, et  al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 2004;351:1838-1848; and Lockley SW, Cronin JW, Evans EE, et  al. Effect of reducing interns’ weekly hours on sleep and attentional failures. N Engl J Med 2004;351: 1829-1836.

actigraphy and decreased performance as measured by the PVT.48 Effect of Sleep on Task Performance Twenty medical interns (physicians in their first year of postgraduate of training) were compared working an “intervention” schedule (limited to a maximum of 16 consecutive hours on duty and averaging 65 hours on duty per week) versus working a “traditional” schedule (allowed a maximum of 34 consecutive hours on duty and averaging 85 hours on duty per week).28,29 Each intern served as his or her own control in this within-subjects design. On the intervention schedule the interns averaged more sleep than on the traditional schedule (7.4 ± 0.9 hours per day of sleep on the intervention schedule versus 6.6 ± 0.8 hours per day of sleep on the traditional schedule). In association with the decrease in maximum consecutive hours worked, reduction in hours worked per week, and increase in hours slept per day, interns made substantially fewer serious medical errors (100 medical errors per 1000 patient-days on the intervention schedule versus 136 medical errors per 1000 patient-days on the traditional schedule)28 (Table 70-1). Further investigations based on survey data from 2737 physicians in postgraduate training supported and extended these findings.28,29 These additional studies found that working extended hours (24 hours or more) compared to working a normal day shift increased automobile crashes, near misses, and falling asleep while driving.18 Working extended hours was also associated with increased medical errors, attentional failures (e.g., falling asleep during lectures, rounds, and patient care, including surgery), and fatigue-related adverse events resulting in fatality.”49 Finally, working extended hours was related to increased incidence rates of percutaneous needle sticks.30 These studies18,28-30,49 indicate a risk to physicians, patients, and

the general public from physicians working extended hours. They demonstrate that performance is impaired with extended work hours and (given the attentional failures) the ability to learn is likely impaired as well. Similarly, medical residents working a heavy call rotation (averaging 90 hours of work per week) showed degraded attention, vigilance, and simulated driving performance similar to those of persons with a blood alcohol concentration of 0.04 to 0.05  g/100  mL.46 These residents were less able to maintain speed and lane position, and they experienced more off-road accidents in the driving simulator after being on this heavy call rotation than residents working light call (averaging 44 hours of work per week). Further, when compared to the effects of alcohol ingestion, residents working heavy call had similar crash rates, attentional lapses, and slowing of reaction time, as well as 30% greater simulated speed variability. Effect of Sleep on Cognitive Performance Medical residents work extended hours providing patient care, and concurrently they are expected to learn new skills and new information. Alertness and attentional performance can be reliably measured using the PVT.25 Measuring learning and memory requires other tests. A meta-analysis of 60 studies investigating cognitive performance in health care professionals indicated that cognitive performance decreases with sleep loss.27 In health care professionals, vigilance and complex task performance appear to be more vulnerable to sleep loss than other functions.50 Consistent findings have come from studies using intelligence tests. Scores on an intelligence test taken after five consecutive day shifts were higher than scores obtained after five consecutive night shifts.51 This is consistent with findings from a study in medical residents in which the effect of one night’s sleep loss on test scores from the American Board of Family Practice In-Training Examination reduced the apparent level of training of these residents from 3 years to 1 year.52 Of the studies cited, only one made objective measures of sleep loss (measured through continuous PSG).29 One of the studies51 did not obtain any measure of sleep, and the remaining studies relied on self-reported sleep hours. Just one of the studies assessed the effects of chronic sleep restriction,53 the type of sleep loss engendered by extended work hours and shift work and typical of the schedules worked by medical residents. A Series of Field Studies in Other Industries Investigations with nonmedical shift workers include a series of studies by researchers investigating the relation of on-the-job sleepiness to total sleep time obtained while being on call or working the night shift.54-56 In railway locomotive engineers (train drivers), subjective and objective sleepiness increased during a night train trip.54 These data provide an indication of operational errors made when train drivers become fatigued, the prime example from this study being two drivers failing to respond to signals despite the presence of an observer.

780  PART II / Section 9  •  Occupational Sleep Medicine

Ship engineers in the merchant marine on or off call for shipboard malfunctions were studied.55 While the time of going to bed and time of rising did not differ between on-call nights and nights free from duty, total sleep time was reduced by 1.5 hours on the on-call nights. This sleep reduction was due to the time spent responding to alarms while on call. A third study56 investigated paper mill workers who worked on a continuously rotating three-shift system (shift start times at 6 am, 2 pm, and 10 pm), working 2 to 4 days on each shift. PSG recordings were taken from these workers during two 24-hour periods, once while working nights and once while working afternoons. Consistent with the increased sleepiness while working the night shift54 and disturbed, truncated sleep while on call,55 it was found that the day sleep associated with night shift work was 2 hours shorter than the night sleep associated with afternoon shift work. Additionally, although no workers napped during the day while working afternoon shifts, 28% of the night-shift workers took an afternoon nap averaging 44 minutes in duration, and 20% of the night shift workers had a sleep period averaging 43 minutes while on duty during the night shift. When nap length was included in the total sleep time length, the total sleep time difference between nappers and nonnappers disappeared. Another study42 focused on how sleep and performance are affected by changing from a rotating three-shift schedule (8 hours per shift) to a rotating two-shift schedule (12 hours per shift), with total hours worked per week held constant. There was no increase in accidents when working the longer shift. Subjectively, workers felt they had improved sleep and more time with friends and family on the longer shift because they worked fewer days per week. There was a reduction in napping frequency when working the 12-hour shift schedule, from about 50% of workers taking an off-duty nap when on the 8-hour shift schedule compared to about 25% of workers on the 12-hour shift schedule. Night shift work was the focus of further studies in this series, including a study57 investigating adjustment to the night shift in oil rig workers in the North Sea working a 2-week schedule of 12-hour shifts, with the first week being a night shift (6:30 pm to 6:30 am) and the second week being a day shift (6:30 am to 6:30 pm). Using actigraphy to measure sleep and a 5-minute reaction-time task to measure performance, the authors found that unlike other field studies, and similar to laboratory studies in which the light–dark cycle is reversed, personnel appeared to adapt to night shift work as indicated by increasing sleep time and improving performance across successive days on the night shift. This successful adaptation was likely due to study participants living and working indoors so that moving to the night shift was accompanied by a reversal of the normal diurnal light– dark cycle. Driving Home after the Night Shift An additional experiment was conducted to investigate the effects of driving home following night-shift work.58 Shift workers participated in daytime simulated driving follow-

ing either a normal night of sleep or a night of night-shift work. The study found an increase in incidents while driving after working the night shift (7.6 ± 2.1) relative to driving following a night of sleep (2.4 ± 1.1). There were more accidents while driving after working the night shift. Blink duration was also longer after working the night shift. Subjective sleepiness was higher following the night shift than it was following a normal night of sleep. A follow-up analysis of these data40 found a relationship between ratings on the Karolinska Sleepiness Scale (KSS) with the objective driving measure of lateral position and duration of eye blink. More Studies in Train Drivers Sleep and performance in train drivers has been studied in simulated59 and actual extended railroad operations.34 Simulated train driving occurred in an 8-hour simulated shift testing period, with a daytime driving period following a night’s sleep and a nighttime driving period after drivers had worked two consecutive night shifts. For this study, the researchers calculated a fatigue score for each subject’s session based on a fatigue performance prediction model, the Fatigue Audit InterDyne (FAID) model.60 Attention and alertness, as measured by the PVT, decreased significantly as model-predicted fatigue increased. Additionally, extreme speed violations and penalty brake applications increased as fatigue increased. Fuel use and braking errors increased at low and moderate fatigue levels but decreased at high levels of fatigue. This improvement in measured driving performance at high fatigue levels may be associated with decreases in driving safety, as the authors postulate that these apparent improvements in driving performance reflect cognitive disengagement, a passive coping mode, in which the train drivers “let the train run itself.” Researchers34 conducted a field study of sleep and performance with 10 train drivers on a 106-hour relay that included an 18-hour layover. Each driver was run through two conditions: early schedule (those who drove immediately) and late schedule (those who rested in the crew van first). The relay operation began at 9:30 am and involved 8-hour shift rotations, with five or six between-shift rest opportunities available depending upon the shift schedule worked. There was an 18-hour layover before the return journey. Drivers had worse performance on the late schedule compared to the early schedule. Drivers obtained 4.86 ± 1.02 hours of sleep per 24 hours during the early rotation and 5.14 ± 0.40 hours total sleep per 24 hours during the late rotation. Drivers in this study favored use of a split-sleep strategy, consistent with other studies.21,61,62 Performance was not adversely affected by split sleep. It may be that the drivers’ splitting their sleep resulted in more optimal placement of sleep opportunity, thus improving subsequent performance. Finally, extended work hours in train drivers have been studied.63 Researchers found that early in the roster (including three 8-hour sleep opportunities) and late in the roster (including two 8-hour sleep opportunities) drivers obtained similar amounts of sleep during the trip (3.9 ± 1.1 hours and 4.2 ± 1.2 hours per sleep opportunity respectively); however, early-roster drivers’ sleep amounts



CHAPTER 70  •  Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management  781

per sleep opportunity decreased as the trip progressed. PVT lapses for the late-roster drivers were more frequent toward the end of the trip, and alertness was lower in the final PVT.

mance prediction models.20,65 Further validation and development of these models through evidence gathered in field studies of sleep and performance will enable fatigue risk management.

USEFULNESS OF FIELD STUDIES OF SLEEP AND PERFORMANCE Field studies, such as those described here, provide us with information regarding sleep and performance in the workplace. In general, they support findings from laboratory studies. In some cases, field studies go beyond simple confirmation of laboratory work and reveal phenomena not found in laboratory studies (e.g., successful adjustment to night shift).57 Extended work hours and work during the night shift lead to decreased sleep and decreased performance, which in turn likely lead to increased risk of errors, incidents, and accidents. When interventions that improve scheduling and create more optimal sleep opportunities are implemented, sleep time increases and errors, incidents, and accidents decrease. These studies suggest the importance of investigating not only acute total sleep deprivation but also chronic partial sleep restriction, the latter being a more common occurrence in operational environments. Field studies of sleep and performance have application to the broader issues of sleep and performance including making public policy, developing standards of fitness for duty, optimizing schedules, and educating shift workers, and are essential to the emerging art and science of fatigue risk management. A notable success in the translation of research into recommendations for practice is the effect of field studies of sleep and performance in medical house staff on the recent Institute of Medicine report on resident duty hours.64

THE FUTURE OF SLEEP AND PERFORMANCE MONITORING IN THE WORKPLACE We anticipate that objective and subjective monitoring of sleep and performance in the workplace will play an increasingly important role in fatigue risk management to manage sleep and duty times to sustain optimal performance given operational constraints. Already studies of fatigue risk management are providing guidance for operational intervention and the construction of public policy around issues of fatigue in the workplace. Integrating such an approach and screening for sleep disorders management into the workplace may reduce health care and disability costs, and absenteeism.66

❖  Clinical Pearls Split sleep (two or three episodes in 24 hours) seems to be as effective as consolidated sleep in sustaining performance; thus, when the main sleep period is restricted or truncated, napping is an effective strategy to sustain performance. Measuring sleep and performance in the operational environment can provide the evidence base for safety and performance-enhancing changes in rostering and scheduling.

REFERENCES

SLEEP AND PERFORMANCE STUDIES AND THE MANAGEMENT OF FATIGUE-ASSOCIATED RISK OF ERROR, INCIDENT, AND ACCIDENT Sleep and performance studies in operational environments are the evidence base for managing fatiguerelated risk. The degraded alertness and cognitive performance resulting from sleep loss is largely a function of three factors: sleep–wake history, circadian rhythm, and workload (see Chapter 65). Certain aspects of the operational environment (e.g., working night shifts, transmeridian travel, shift timing and duration) can negatively affect those factors through disrupting circadian rhythms, increasing time-on-task effects, and decreasing the opportunity for sleep. The incorporation of fatigue risk management systems into an operational framework will translate the findings from the studies cited here into practical application in the 24/7 work environment and provide the evidence base for fatigue risk management and optimization of rostering and scheduling. Sleep–wake histories recorded in field studies can be used to predict performance on a minute-to-minute basis through the use of biomathematical sleep/perfor-

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36. US General Accounting Office. Aviation safety: US efforts to implement flight operations quality assurance programs. Flight Safety Foundation Digest 1998;17:1-36. 37. Akerstedt T, Peters B, Anund A, et al. Impaired alertness and performance driving home from the night shift: a simulator study. J Sleep Res 2005;14:17-20. 38. Thomas GR, Raslear TG, Kuehn GI. The effects of work schedule on train handling performance and sleep of locomotive engineers: a simulator study. (Report No. DOT/FRA/ORD-97-09). Washington, DC: Department of Transportation; 1997. 39. Grantcharov TP, Bardram L, Funch-Jensen P, et al. Laparoscopic performance after one night call in a surgical department: a prospective study. BMJ 2001;323:1222-1223. 40. Ingre M, Akerstedt T, Peters B, et al. Subjective sleepiness, simulated driving performance and blink duration: examining individual differences. J Sleep Res 2006;15:47-53. 41. Signal TL, Gander PH. Rapid counterclockwise shift rotation in air traffic control: effects on sleep and night work. Aviat Space Environ Med 2007;78:878-885. 42. Lowden A, Kecklund G, Axelsson J, et al. Change from an 8-hour shift to a 12-hour shift, attitudes, sleep, sleepiness and performance. Scand J Work Environ Health 1998;24:69-75. 43. Smith L, Totterdell P, Folkard S. Shiftwork effects in nuclear power workers: a field study using portable computers. Work Stress 1995;9:235-244. 44. Peacock B, Glube R, Miller M, et al. Police officers’ response to 8 and 12 hour shift schedules. Ergonomics 1983;26:479-493. 45. Rosa RR. Performance, alertness, and sleep after 3-5 years of 12 h shifts: a follow-up study. Work Stress 1991;5:107-116. 46. Arnedt JT, Owens J, Crouch M, et al. Neurobehavioral performance of residents after heavy night call vs. after alcohol ingestion. JAMA 2005;294:1025-1033. 47. Epstein R, Tzischinsky O, Herer P. Can we consider medical residents as shift workers? J Hum Ergol 2001;30:375-379. 48. Saxena AD, George CFP. Sleep and motor performance in on-call internal medicine residents Sleep 2005;28:1386-1391. 49. Barger LK, Ayas NT, Cade BE, et al. Impact of extended-duration shifts on medical errors, adverse events, and attentional failures. PLoS Med 2006;3:2440-2448. 50. Rollinson DC, Rathlev NK, Moss N, et al. The effects of consecutive night shifts on neuropsychological performance of interns in the emergency department: a pilot study. Ann Emerg Med 2003;41: 400-406. 51. Dula D, Dula N, Hamrick C, et al. The effect of working serial night shifts on the cognitive functioning of emergency physicians. Ann Emerg Med 2001;38:152-155. 52. Jacques CH, Lynch JC, Samkoff JS. The effects of sleep loss on cognitive performance of resident physicians. J Fam Prac 1990;30:223-229. 53. Hawkins MR, Vichick DA, Silsby HD, et al. Sleep and nutritional deprivation and performance of house officers. J Med Educ 1985;60:530-535. 54. Torsvall L, Akerstedt T. Sleepiness on the job: continuously measured EEG changes in train drivers. Electroencephalogr Clin Neurophysiol 1987;66:502-511. 55. Torsvall L, Akerstedt T. Disturbed sleep while being on-call: an EEG study of ships’ engineers. Sleep 1988;11:35-38. 56. Torsvall L, Akerstedt T, Gillander K, et al. Sleep on the night shift: 24 hour EEG monitoring of spontaneous sleep/wake behavior. Psychophysiology 1989;26:352-358. 57. Bjorvatn B, Stangenes K, Oyane N, et al. Subjective and objective measures of adaptation and readaptation to night work on an oil rig in the North Sea. Sleep 2006;29:821-829. 58. Akerstedt T, Peters B, Anund A, et al. Impaired alertness and performance driving home from the night shift: a simulator study. J Sleep Res 2005;14:17-20. 59. Dorrian J, Hussey F, Dawson D. Train driving efficiency and safety: examining the cost of fatigue. J Sleep Res 2007;16:1-14. 60. Dawson D, Fletcher A. A quantitative model of work-related fatigue I: background and definition. Ergonomics 2001;44:144163. 61. Mollicone DJ, Van Dongen HPA, Dinges DF. Optimizing sleep wake schedules in space: sleep during chronic nocturnal sleep restriction with and without diurnal naps. Acta Astronaut 2007;60: 354-361.



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62. Mollicone DJ, Van Dongen HPA, Rogers NL, et al. Response surface mapping of neurobehavioral performance: testing the feasibility of split sleep schedules in space operations. Acta Astronaut 2008;63:833-840. 63. Lamond N, Darwent D, Dawson D. Train drivers’ sleep and alertness during short relay operations. Appl Ergon 2005;36: 313-318. 64. Institute of Medicine: Resident duty hours: enhancing sleep, supervision, and safety. Washington, DC: National Academies Press; 2008.

65. Hursh SR, Raslear TG, Kaye AS, et al. Validation and calibration of a fatigue assessment tool for railroad work schedules, a summary report. (Report No. DOT/FRA/ORD-06/21). Washington, DC: US Department of Transportation; 2006. 66. Hoffman B, Wingenbach DD, Kagey AN, Schaneman JL, Kasper D. The long-term health plan and disability cost benefit of obstructive sleep apnea treatment in a commercial motor vehicle driver population. J Occup Environ Med 2010;52:473-477.

Shift Work, Shift-Work Disorder, and Jet Lag Christopher L. Drake and Kenneth P. Wright Jr. Abstract Shift work and travel across time zones are commonplace in industrialized society. Adjustment to these circadian challenges requires abrupt and often large shifts in physiology to match behavioral changes in the timing of sleep–wake schedules. There are clear individual differences in the ability to adapt to this mismatch between circadian physiology and sleep–wake behavior. These differences can impact several areas of functioning, including the sleep–wake, cardiovascular, and gastrointestinal systems in certain individuals. Among the most common consequences of working at night are insomnia and excessive sleepiness, which contribute to other morbidity (e.g., accidents) and are the defining symptoms of shift-work sleep disorder (SWD). Those older than age 50 years and individuals with an early morning circadian preference appear more vulnerable to these effects of shift work. For the subset of individuals with SWD there remains a need to deconstruct the morbidity of the disorder into its causal components (i.e., insomnia, excessive sleepiness, and circadian desynchrony) and their interaction. Effective treatments for symptoms of SWD are available and include the use of nocturnal bright light and daytime darkness as well as sleep- and wake-

The increased use of technologies such as artificial light and jet aircraft have increased exposure to sleep–wake schedules that oppose internal circadian physiology. The ever-increasing societal pressure in industrialized countries to abandon the customary 9-to-5 workday results in job-driven schedules and sleep times that are at odds with endogenous rhythms, which are tightly regulated by the suprachiasmatic nucleus, the “master” biological clock. The abnormal sleep and wakefulness patterns experienced by shift workers are associated with significant morbidity and mortality. Although other chapters in this volume address the physiologic basis for conditions such as jet lag and shift-work disorder (SWD) in terms of biological regulation of the circadian system, the discussion in this chapter bridges basic science and laboratory studies and explores the implications of the underlying physiology to patient and public health. A summary is provided of available laboratory and field-based occupational health data that can inform the clinician and the patient as to clinical issues central to SWD and travel across time zones (jet lag).

SHIFT WORK Prevalence The current total working population of the United States is approximately 145.9 million.1 The prevalence of shift work (i.e., permanent night, rotating, and evening shifts) is difficult to determine. Estimates vary depending on the definition employed and the region studied, but U.S.based estimates suggest that nearly 20% of employed 784

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71

enhancing medications. The efficacy of such treatments for morbidity outside the sleep–wake system remains to be demonstrated. Jet lag is a common problem and symptoms include gastrointestinal disturbance, daytime fatigue, sleepiness, and insomnia. Cognitive impairments associated with jet lag can have serious consequences, resulting in drowsy driving and impaired decision-making. Because the average period of the circadian clock is longer than 24 hours, jet lag is typically worse after eastward than westward travel. Interventions such as the use of appropriately timed bright light and darkness can improve circadian adaptation to time zone changes. Other interventions including sleep-promoting agents and melatonin and its agonists (during the biological daytime) may promote sleep but may not improve wakefulness in the new time zone. Melatonin agonists are available, but no clinical trials have been reported to date regarding the efficacy of these medications for the treatment of jet lag. Preadaptation of the circadian clock, use of caffeine, and brief naps in the new time zone are useful countermeasures to promote wakefulness after jet travel across time zones and its associated sleep loss.

adults are shift workers. The proportion may be higher if workers with early-morning shifts and infrequent or irregular shifts are included. In the United States today, 17.7% to 25.9% of the total workforce start shifts between 2 pm and 6:30 am.2 These data suggest that between 25.8 and 37.8 million U.S. adults are shift workers on a regular or rotating basis. Data from other countries also indicate that a high prevalence of the population is engaged in shift work: in the United Kingdom, estimated prevalence is 22%; in Australia, 13%; in Greece, 25%; and in Finland, 25%.3,4 Not all individuals exposed to shift work develop SWD. Many factors, including scheduling differences, shift frequency, shift duration, family/social responsibilities, and differences in sleep and circadian physiology can affect an individual’s response to shift work and hence the development of SWD. These same factors are important influences on the development of jet lag and its impact on work performance and health. Types Although the literature is not always precise in defining shift work in terms of start times, the following classifications are based not only on statistics from the U.S. Department of Labor but also with respect to differences in circadian physiology. Night-Shift Workers Night-shift workers with regular start times between 6 pm and 4 am make up an estimated 4.25% of the total U.S. workforce.5 However, this is a conservative estimate because it does not include variable shift schedules.



Although some have speculated that permanent night work may have benefits in terms of circadian adjustment to shift work relative to variable shift schedules and have advised shift workers to stay on a night-shift schedule on days off, there is little support for this contention.6 Indeed, both objective and subjective measurements show that night shifts result in greater loss of total sleep time than eveningand slow rotating-shift schedules.7-9 Sleep loss accumulates and its impact grows over successive night shifts. The result is a buildup of homeostatic sleep debt combined with the effects of circadian misalignment, with both having serious implications for productivity and safety in shift workers. In fact, sleep loss alone has been shown to impair alertness and performance, including driving ability, as much as alcohol intake associated with a breath ethanol concentration up to 0.19%.10 Not surprisingly, the night shift produces the greatest degree of sleepiness relative to daytime work, evening shifts, and even rotating shifts, with the sleepiness greatest during the early morning hours close to commute times.11,12 Early Morning-Shift Workers The International Classification of Sleep Disorders (ICSD) classifies early morning shifts as those starting between 4 am and 7 am.13 This is the most common alternate work shift with at least 18.1 million U.S. workers (12.4% of the workforce) falling into this category.5 Given these start times many early morning-shift workers wake before 5 am. As a consequence, these workers are likely to be on the road at their nadir of circadian alertness and may also be particularly sleep deprived, owing to their early time of rising. This is consistent with the high rate of excessive sleepiness reported in this population.14 Using objective measures of sleep, Kecklund and colleagues showed that early morning-shift workers accrue significantly less sleep than those who work during the day; stage 2 and rapid eye movement (REM) sleep were particularly reduced.14 Indeed, their sleep disturbance is close to that of permanent night workers.15 These factors, coupled with severe sleep inertia at that hour,16 suggest that early morning-shift workers may have the highest risk of all workers for automotive accidents. Further examination of the prevalence of excessive sleepiness and resultant risk of accidents in this specific population is needed. Evening/Afternoon-Shift Workers Evening-shift workers with regular start times between 2 pm and 6 pm make up 4.3% of all U.S. workers5 and can be impaired in terms of social isolation and quality of life.17 Although the literature clearly documents the presence of significant morbidity in shift workers, not all shifts are associated with these effects. In fact, the average eveningshift worker actually sleeps 7.6 hours/night,8 which is longer than most day workers (6.8-7.0 hours/night).12 As noted, the human circadian pacemaker has an intrinsic period that is on average slightly longer than 24 hours.18 The resulting tendency to delay internal rhythms combined with schedules that allow later morning wakeup times may account for the increased total sleep time of evening-shift workers. However, some evening-shift workers have shortened sleep times due to family obliga-

CHAPTER 71  •  Shift Work, Shift-Work Disorder, and Jet Lag  785

tions that require earlier wakeup times on days off that could result in significant impairment over time. Rotating-Shift Workers The U.S. population is estimated to include 4 million rotating-shift workers (approximately 2.7% of the total workforce),2 but nearly all shift workers could be considered to have rotating schedules because most (particularly married workers) revert to a normal pattern of nocturnal sleep during days off. Nonetheless, even on their days off, rotating-shift workers remain sleepier than daytime workers.19 In a meta-analysis of sleep patterns, workers on rotating shifts had nearly as much sleep reduction as permanent night workers relative to day workers.8 Workers with regular rotating shift schedules face additional challenges related to the speed and direction of shift rotations. Rapid shift rotations (e.g., multiple rotation within a week) are associated with reduced total sleep duration compared with slower rotations (e.g., at least 3 weeks per shift schedule).8 In terms of direction, both rapid clockwise and counterclockwise rotations negatively impact total sleep duration and increase circadian misalignment.20 These effects are thought to be less severe for workers experiencing a clockwise rotation because of the natural tendency of the circadian clock to delay to a later time18 and increased time between shifts. However, shift direction and duration may interact, with findings from at least one controlled study showing that clockwise and counterclockwise rotations in rapidly rotating shift systems are not significantly different in terms of either total sleep duration or degree of excessive sleepiness.21 Some individuals have circadian clock periods that are shorter than 24 hours, and they would be expected to adapt more easily to counterclockwise shift rotations. Prior to a counterclockwise rotation, 80% to 90% of workers nap before the midnight shift, as opposed to only 40% to 60% before a clockwise rotation, which may help to ameliorate some of the expected impairments in sleep and sleepiness during a counterclockwise rotation. This interpretation is also consistent with numerous studies demonstrating the beneficial effects of napping among shift workers.22,23 Circadian Misalignment and Effects of Light Exposure Human physiology is organized by the internal circadian clock such that sleep and its associated functions are promoted during the biological night, when levels of the hormone melatonin are high, and wakefulness and its associated functions are promoted during the biological day, when endogenous melatonin levels are low.24 The internal circadian clock in humans has a period that is on average slightly longer than 24 hours,18 and thus the average adult requires the phase and period of his or her internal clock to be reset on a daily basis to remain entrained to the 24-hour day.25 Light is the dominant environmental time cue that entrains the human circadian clock to the 24-hour day, and the timing of light exposure will determine whether the internal clock is phase delayed or advanced (Fig. 71-1).26 Circadian misalignment can be caused by schedules induced by shift work and jet travel that rapidly alter exposure to environmental time cues and require wakefulness during the biological night and

Maximum phase advance with melatonin

Maximum phase advance with light

Phase shift

Delay westward

Advance eastward

786  PART II / Section 9  •  Occupational Sleep Medicine

Maximum phase delay with light

14 17 20 23 2

Maximum phase delay with melatonin 5

8 11 14 17 20 23

Approximate clock hour for someone with a bedtime at 24:00 hr Figure 71-1  Schematic representation of the phase response curves to 1 day of light exposure (6.7 hrs) (blue line) and 3 days of 3 to 5 mg of exogenous melatonin administration (red line) when the circadian system is entrained to local environmental time. The circadian phase resetting response to light and melatonin depends on the internal biological time of exposure. Generally, bright light exposure before habitual bedtime and several hours thereafter will induce the largest westward phase delays, whereas bright light exposure just before the habitual time of awakening and several hours thereafter will induce the largest eastward phase advances. The time at which phase delays cross over to phase advances is on average about 2.5 hours before the habitual time of awakening in young adults and about 2 hours in older adults.153 Therefore, bright light exposure too close to the crossover point may shift the circadian phase in a direction opposite to what is desired. Opposite to the effects of light, ingestion of exogenous melatonin in the late afternoon will induce the largest eastward phase advances, whereas melatonin ingestion shortly after the habitual time of awakening and several hours thereafter will induce the largest westward phase delays. The time at which melatonin-induced phase delays change to phase advances is, on average, in the early afternoon.103,104

sleep during the biological day. The resulting circadian misalignment associated with shift work and jet lag can produce sig­nificant morbidity associated with disturbed sleep, impaired alertness, as well as a direct effect of circadian misalignment. Morbidity Associated with Shift Work Sleepiness and Insomnia Among the most common problems experienced by shift workers are excessive sleepiness and insomnia, resulting from imposition of a sleep–wake schedule that opposes the body’s internal circadian clock.27,28 For example, measures of sleepiness in anesthesia residents demonstrate impaired alertness after a single night shift similar to levels observed in sleep disorders.29 Chronic shift work tends to increase the sleepiness, because shift workers may further deprive themselves of sleep by reducing the amount of time spent in bed during the day.30 This is understandable, because everyday domestic activities are likely to conflict with the opportunity for sleep. In addition, it is difficult to maintain sleep when the circadian clock is promoting wakefulness.27,28 Shift workers may also remain awake longer when changing from one shift schedule to another, producing a

further accumulation of sleep debt. Difficulty rapidly shifting the circadian clock combined with erratic exposure to light in shift workers31 also places significant restrictions on adapting biological rhythms to shift-work schedules. Thus, in some workers, both sleep disturbance and sleepiness continue even after months or years of shift work. Reduced Alertness and Accidents Converging evidence from controlled laboratory settings, large epidemiologic studies, and clinical samples has established an incontrovertible link between shift work and accidents.32,33 In a classic study, Smith and colleagues demonstrated that working a night shift increased on-road accidents by 50%.34 In a recent study of a large sample of nurses, 79.5% of those working the night shift reported at least one drowsy driving incident, equal to an increased odds ratio (OR) of 3.96 (95% confidence limit [CI] = 3.244.84) relative to nurses working a day shift.35 Residents who have frequent on-call schedules have 6.7 times the risk of motor vehicle accidents compared with those working less-demanding call schedules.36 Others have shown that risk increases nearly 10% for every extended shift worked in a month.37 Sleepiness-related impairment is not confined to motor vehicle accidents; for example, findings from studies of medical personnel have also demonstrated an increased number of accidents associated with the use of sharp instruments and items (percutaneous injuries),38 medication and diagnostic errors,39 and increased patient death rates associated with extended and unconventional shift schedules.40 These findings are not surprising in light of a study by Arnedt and colleagues showing that residents on heavy call rotations have driving impairments similar to residents on light call rotations with a blood alcohol concentration of 0.05%.41 In industrial settings, the risk of both accidents and injuries increases by more than 30% on the night shift; moreover, it increases over successive night shifts and rises exponentially with successive hours on a shift.32 Major catastrophes such as those at Three Mile Island, at Chernobyl, and from the Exxon Valdez oil spill have all occurred during the night shift, drawing increased attention to both the risks and costs associated with shift work schedules.42,43 The cost of sleepiness-related accidents in the United States is estimated at up to $40 billion per year, representing 24% of the total cost of traffic accidents in the United States.44 These data suggest that the economic savings associated with shift work for specific industries should be carefully weighed against the overall cost to society. Work Productivity and Quality of Life The negative impact of shift work is not limited to adverse events. It also affects productivity. An association of shift work with reduced dexterity and efficiency,45 impaired threat detection,46 and lower productivity47 has been demonstrated. Thus, overall worker productivity is significantly reduced during the night shift in a broad range of occupational settings.42 There is also evidence for increased absenteeism in night workers compared with day workers, particularly for those experiencing insomnia and/or excessive sleepiness.12



The negative effects of shift work affect the family system as well as the individual’s quality of life.48 Studies show a 57% higher divorce rate,49 reduced job satisfaction,50 and reduced family and social interaction.12 Findings from a 5-year longitudinal study demonstrated a relationship between parental shift work and poor school performance and behavioral problems in children 5 to 12 years old after controlling for a number of demographic variables.51 The reader is also referred to more extensive reviews on work-related and quality-of-life variables in shift workers.48 Health Effects of Shift Work A wealth of information documents the negative health effects associated with shift work. Notable are a 36% to 60% increased risk of breast cancer in large prospective studies,52,53 a fourfold increased risk of duodenal ulcers verified by endoscopy,54 and increased cardiovascular morbidity and mortality,55-57 including atherosclerosis and myocardial infarction.55 Poor eating habits58 and other adverse health behaviors among shift workers may account for some of the increased morbidity. Moreover, findings from one study demonstrated that a weekly 12-hour shift in the light–dark cycle relative to endogenous circadian rhythms decreased survival by 11% in hamsters with cardiomyopathic heart disease.59 This finding suggests that these morbidities are not simply related to health habits but may be inherently related to misalignment of circadian rhythms and the sleep–wake cycle. With respect to the risk of breast cancer, investigators have suggested that reduced free radical scavenging due to suppression of the hormone melatonin by nocturnal light exposure, thereby reducing its potential tumor-inhibiting effects, could be a mediating factor.60 Findings of reduced breast cancer risk by 20% to 50% in blind women61 and an inverse relationship between level of blindness and cancer risk62 provide some support for this hypothesis. Finally, data suggest that the risk of cancer increases with the number of years on shift work.52

SHIFT-WORK DISORDER Individuals on the same shift schedule differ dramatically in response to shift work with regard to two of the most common consequences, excessive sleepiness and insomnia.12,63 The inability of a subset of individuals to tolerate shift work may be related, in part, to findings from several laboratory studies indicating that most night workers do not fully adapt their internal circadian rhythms to their adjusted sleep–wake schedule.64 The subgroup of nonadapted workers have reduced daytime sleep relative to those whose melatonin profiles showed rapid shifts in response to night work.65 Individual differences in vulnerability to insomnia, vulnerability to excessive sleepiness, and/or differences within the circadian system itself (i.e., period, amplitude, response to light) may account for the adverse response to shift work. Data suggest approximately 50% genetic heritability estimates for vulnerability to insomnia.66 Because this vulnerability can be elicited by a circadian challenge such as a major shift in the sleep–wake cycle,67 individual vulnerability to sleep disturbance remains a plausible determi-

CHAPTER 71  •  Shift Work, Shift-Work Disorder, and Jet Lag  787

nant of shift-work tolerance. However, studies of trait vulnerability to sleep disturbance68,69 have yet to be performed in shift workers. Individuals also differ in the degree to which sleep loss impairs alertness and performance.70 Vulnerability to sleep loss is related to at least one genetic variant in the coding region of the circadian clock gene PER3.71 Furthermore, in one study of shift workers, increased perceived need for sleep was associated with intolerance for shift work.63 In terms of the circadian system, findings from one study suggested that individuals unable to tolerate shift work had an observed oral temperature and grip strength rhythm that appeared to be different from 24 hours, pointing toward a proclivity to circadian desynchrony in nontolerant workers.72 One predictor of shift tolerance is circadian preference (i.e., morningness/eveningness),73 a heritable trait linked to a length polymorphism in the PER3 gene74 and the intrinsic period of the circadian clock.75 Morningtype individuals tend to have a reduced tolerance for shift work compared with evening type individuals.76 Moreover, the fact that older individuals tend to be more morning types77 may partly explain the age-related reduced ability to cope with shift work and jet lag.78 A reduced capacity for older individuals to shift their endogenous circadian rhythms in response to moderate light levels is also a possible contributing factor for shift work intolerance in that population (>50 years old).79 Finally, in tightly controlled laboratory settings, clock gene expression shows considerable intersubject variability after a night-shift schedule in comparison to a daytime work schedule.80 The presence of these individual differences in the circadian and sleep–wake system response to shift work81 led to the development of diagnostic criteria for SWD (Table 71-1).13 Individuals diagnosed with SWD are unable to tolerate the effects of a shift-work schedule13 and may present with excessive sleepiness or insomnia despite adequate time in bed (∼7 to 8 hours), stable sleep schedules, and the absence of other sleep disorders. Although few studies specifically address SWD, the sleep of these individuals likely includes sleep fragmentation, early final awakenings, and an inability to remain awake during the early morning work/commute hours.82 These deficits can impact job performance, driving safety, quality of life, work satisfaction, and health.12,63 In addition to further research on the sleep and alertness of individuals with SWD, a major challenge for future studies will be to determine which specific morbidities are associated with insomnia versus excessive sleepiness versus both symptoms of the condition, versus a direct effect of circadian misalignment. Prevalence Because few shift workers have been reported to fully adjust their internal circadian rhythms to that of the imposed shift-work schedule, the prevalence of SWD would be expected to be high.6 Clinical evaluation of insomnia and excessive sleepiness in shift workers is necessary to determine the actual prevalence of SWD, but few population-based data are available. In one representative sample, the prevalence of the disorder has been conservatively estimated at 14% to 32% of night-shift workers and 8% to 26% of rotating-shift workers.12

788  PART II / Section 9  •  Occupational Sleep Medicine Table 71-1  Diagnostic Criteria for Shift-Work Disorder International Classification of Sleep Disorders Criteria (ICSD-2): General Criteria for Any Circadian Rhythm Sleep Disorder A.  There is a persistent or recurrent pattern of sleep disturbance due primarily to one of the following: i. Alterations of the circadian time-keeping system. ii.  Misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. B. The circadian-related sleep disruption leads to insomnia, excessive sleepiness, or both. C. The sleep disturbance is associated with impairment of social, occupational, or other areas of functioning. Specific Criteria for Circadian Rhythm Sleep Disorder, Shift-Work Type (327.36)* A. There is a complaint of insomnia or excessive sleepiness that is temporally associated with a recurring work schedule that overlaps the usual time for sleep. B. The symptoms are associated with the shift work schedule over the course of at least 1 month. C. Sleep log or actigraphy monitoring (with sleep diaries) for at least 7 days demonstrates disturbed circadian and sleep-time misalignment. D. The sleep disturbance is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR): Diagnostic Criteria for Circadian Rhythm Sleep Disorder (307.45) A. A persistent or recurrent pattern of sleep disruption leading to excessive sleepiness or insomnia that is due to a mismatch between the sleep-wake schedule required by a person’s environment and his or her circadian sleep-wake pattern. B. The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The disturbance does not occur exclusively during the course of another sleep disorder or other mental disorder. D. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Specify Type: Shift-Work Type: insomnia during the major sleep period or excessive sleepiness during the major awake period associated with night shift work or frequently changing shift work. *ICD-9 code: 327.36 Circadian rhythm sleep disorder, shift-work type

Morbidity In addition to sleep–wake disturbances, Gumenyuk and colleagues have shown that persons with SWD have significant alterations in neurophysiologic measures of attention and memory relative to night-shift controls without SWD.82a In a comparison of shift workers with and without SWD, those with SWD had a higher prevalence of ulcers.12 In addition, affected individuals exhibited higher rates of absenteeism and significant difficulties with family and social activities compared with shift workers without SWD. Higher rates of major depression were also found

in individuals with SWD. A relationship has also been found between reduced satisfaction with the work schedule and excessive sleepiness on the night shift.63 Not surprisingly, individuals with SWD report higher rates of sleepiness-related accidents than non-SWD controls or day workers. While increased rates of heart disease have been found in shift workers, this morbidity may not be directly related to the excessive sleepiness or sleep disturbance characteristic of SWD.12 However, additional studies with patients meeting diagnostic criteria are needed before definitive conclusions regarding unique morbidity in SWD (as opposed to shift work per se) can be determined. Clinical Evaluation SWD can be diagnosed by a thorough sleep history, although polysomnography may be indicated if there is a high suspicion of another sleep disorder (e.g., obstructive sleep apnea).83 The clinical evaluation of SWD is similar to that of other sleep disorders, particularly the other circadian rhythm sleep disorders covered in Chapter 41. However, the evaluation of the shift worker requires careful attention to additional details related to the effects of the work–sleep schedule on cognitive, social, and healthrelated functioning. Insomnia and the ability to maintain wakefulness, particularly during sedentary activities (e.g., commute home from work), should be carefully assessed, because SWD patients have a twofold increase in sleepiness-related accidents compared with shift workers who do not meet diagnostic criteria.12 The use of a sleep diary with a focus on regularity, duration, and timing of bed times and actigraphy over 1 to 2 weeks are helpful to confirm the degree and pattern of sleep disturbance and circadian disruption.84 The timing of obtaining this information should include periods of being on the work schedule that produces the symptom-complex. Fatigue is often confused with sleepiness and is a common presenting complaint by patients.85 If fatigue is present, an important differential diagnosis in the shift worker is major depressive disorder.12 As opposed to excessive sleepiness, patients with mental or muscle fatigue (as opposed to sleepiness) may find that sedentary activities or rest without sleeping may improve their symptoms. On the other hand, patients with excessive sleepiness often state that sedentary activities or “rest” periods exacerbate their complaint. This is an important distinction to make, because patients frequently do not recognize that dozing off in such situations is abnormal. The judicious use of brief, well-validated, and standardized tools for the assessment of sleepiness cannot be overemphasized.84 The Epworth Sleepiness Scale (ESS) is particularly helpful in this regard and can be performed easily in most clinical settings. A score of greater than 10 on the ESS is generally considered clinically important. Using ESS cutoffs, prevalence rates of excessive sleepiness of up to 44% have been reported,12 compared with a consistently lower prevalence (24% to 33%) in representative samples of daytime workers.12,86,87 Assessment tools such as the Insomnia Severity Index and the Pittsburgh Sleep Quality Index are patient-administered tools helpful for determining the extent and relative impact of sleep disturbance.88 Practical issues regarding their implementation are discussed in detail in Chapter 77.



Extensive clinical guidelines for the general evaluation of insomnia, including its relation to functioning, have been published and should be considered when evaluating a shift worker.89 Patient difficulty initiating or maintaining sleep is important when considering appropriate treatment strategies. In contrast to medium-acting compounds (halflife of 5 to 12 hours), short-acting hypnotics (i.e., half-life of 1.5 hours) may have little benefit in shift workers with isolated sleep maintenance problems (i.e., difficulty staying asleep with no problems falling asleep). However, residual sedation should be considered when using longer-acting hypnotic medications because shift workers frequently have shorter sleep periods compared with day workers. Behavioral treatment of insomnia in shift workers may be helpful, but specific approaches (e.g., relaxation therapy, stimulus control techniques), have not been systematically evaluated. A thorough history of the patient’s recent work schedule is also essential to diagnosis, because many types of shift schedules, particularly rapidly backward rotating schedules, can cause significant sleep disturbance and excessive sleepiness.90 If an evening-shift worker presents with excessive sleepiness or insomnia, causes other than the effects of circadian misalignment due to shift work should be considered because evening shifts are not as likely to cause SWD as other types of shift schedules. However, additional research is needed to determine whether SWD is common in evening workers with a strong morning circadian phase preference or high social/domestic demands. The clinician also needs to be aware of potential psychological (i.e., depression), gastrointestinal, cardiovascular, and cancer risks of shift work; and workers should have regular physical examinations that include attention to these conditions.91 The health risk related to substance use for insomnia (e.g., illicit drugs and alcohol), poor diet, and nicotine use common in shift workers should also be addressed during the clinical evaluation. Finally, educating the shift worker with regard to appropriate sleep hygiene practices with an emphasis on adequate sleep opportunity is highly beneficial. Treatment Because the specific pathophysiology of SWD is unknown, treatment is necessarily targeted at either of the two symptoms or directly at the trigger itself (i.e., circadian misalignment). A cardinal feature of the disorder is that symptoms are directly linked to the shift-work schedule and thus likely to remit after returning to daytime work.13 Short of going off the night shift, occupational adjustments such as slower rotations with weeks spent on a particular shift, moving to an evening shift, changing from backward to forward shift rotation, and incorporating increased worker control by allowing “self-scheduling” of shifts may be of some benefit.92 However, in most cases clinical intervention is needed because occupational constraints generally prevent scheduling adjustments or a return to a diurnal schedule. Even before the diagnosis of SWD is made, the clinician must address all potential safety concerns. Indeed, the threshold for immediate treatment intervention should be lower in a shift worker presenting with excessive sleepiness while driving and for occupations in which performance is

CHAPTER 71  •  Shift Work, Shift-Work Disorder, and Jet Lag  789

critical for individual or public safety.13 Shift workers typically have a chaotic sleep–wake schedule and may drastically curtail their time in bed in an attempt to meet their social, occupational, and daily obligations. This may be due to a short shift transition, long overtime hours to keep up with work demands, a second job, or staying awake to engage in normal social activities during the day. All of these factors can make it difficult for the shift worker to get enough sleep. Clearly, even shift workers need 7 to 8 hours of time in bed (i.e., sleep opportunity) per day. The clinician needs to address this issue with each patient. Circadian Interventions Interventions, particularly appropriately timed bright light aimed at shifting endogenous rhythms, have been extensively studied in shift workers. Exposure to bright light in the evening near habitual bedtime and for several hours thereafter will induce a phase delay of internal biological time, whereas exposure to bright light in the morning from approximately 2 hours before habitual wake time and thereafter will induce a phase advance (see Fig. 71-1). In general, for every hour of properly timed exposure to bright light, there is a 0.5-hour shift in internal biological time. Using these principles, bright light interventions aimed at producing phase delays of the circadian pacemaker (e.g., light during the first half of the night shift and daytime darkness) have been shown to improve daytime sleep and nocturnal functioning.93,94 In an early landmark study, Czeisler and colleagues treated circadian misalignment due to shift work with exposure to 7.5 hours of bright light (7,000-12,000 lux) on 4 consecutive nights in the laboratory and scheduled sleep in darkness between 9 am and 5 pm at home.93 In comparison to a control group exposed to room light (∼150 lux) and unscheduled sleep, those treated had a 9.6-hour delay (i.e., to a later hour) of their circadian rhythms (i.e., temperature, cortisol, alertness). They also averaged 2 hours more sleep during the day and showed improved nocturnal alertness and cognitive performance. Additional studies supporting this observation are thoroughly reviewed elsewhere.95 Despite the ability to achieve large phase shifts in controlled laboratory environments, producing complete circadian adaptation in most shift workers in the field is difficult.96-100 Phase shifting requires extensive control over environmental light and darkness (i.e., dark goggles and bright light), which may not be practical in all real-world settings. Furthermore, complete circadian phase reversals are likely to be “maladaptive” because family and social obligations may force patients to revert to a diurnal schedule on their days off. Recognition of practical limitations regarding continuous bright light exposure (e.g., 6 to 8 hours at ∼10,000 lux) and the limitations of complete phase shifts has led some investigators to study the sleep and performance effects of using brief intermittent light exposure to induce a “compromise” circadian phase (i.e., moderate but stable delays) compatible with permanent night work and common day schedules on days off. In a study by Smith and Eastman,101 subjects engaged in three simulated night shifts (11 pm to 7 am) followed by 2 “weekend” days off with a final episode of four additional night shifts, closely

790  PART II / Section 9  •  Occupational Sleep Medicine

simulating the variable sleep–wake schedule of shift workers that often occurs in the real world. Subjects were exposed to brief light pulses during the night (15 minutes each hour; total light exposure duration of 1.25 hours per shift) and wore sunglasses while outside, with the goal of achieving a moderately delayed or “compromise” circadian phase position in which the lowest point of alertness would occur just a few hours after their shift work ended (∼10 am). The intervention produced a larger delay in onset of melatonin secretion from 9 pm to 4:30 am (∼7.5-hour delay) compared with the control group (∼3.5-hour delay). Sleep duration as determined by actigraphy and sleep logs improved in the delayed group relative to the controls. Treatment also resulted in better and more consistent psychomotor performance. Importantly, delayed circadian phase was positively correlated with improved sleep even in the control group (r = 0.65), suggesting that some individuals benefit from even small delays in circadian phase and emphasizing potentially important individual differences in the response to large and abrupt circadian shifts of the sleep–wake cycle. Although the effectiveness of this intervention for SWD needs to be studied, maintaining stable circadian delays of about 4 hours improves sleep and cognitive performance during a shift-work schedule. Compounds with phase-shifting properties (e.g., chronobiotics) may also be beneficial for shift workers. Exogenous melatonin is perhaps the strongest nonphotic time cue in humans. Normally, endogenous melatonin levels rise about 2 hours before habitual bed time,102 remain high across the night, and decline again near the habitual time of awakening. Use of exogenous melatonin to shift circadian rhythms generally follows the reciprocal of the phaseresponse curve for light (see Fig. 71-1). Thus, melatonin ingested during the biological day can be used to phase advance or phase delay the circadian phase.103,104 Properly timed exogenous melatonin administration for 3 days can lead to an approximate 1.5-hour shift in internal biological time.103 However, for melatonin to be an effective phase resetting agent, control over light exposure appears necessary because bright light can counter the phase shift produced by melatonin. In a recent controlled study, 4 days of treatment with 1, 2, or 4 mg of the melatonin agonist ramelteon had significant phase-advancing effects of 80 to 90 minutes when normal sleep–wake schedules were abruptly shifted by 5 hours.105 Although these effects may have more practical applications for circadian rhythm disorders such as delayed sleep phase syndrome and jet lag,106 in which modest shifts in the circadian pacemaker may improve symptoms, melatonin or melatonin agonists may still provide benefits in patients with SWD via the sleep-promoting and phaseshifting properties of these compounds.107,107a,107b In studies of shift work, melatonin (0.5 to 3 mg) was able to improve circadian adaptation through phase delays or advances depending on the time of administration.94,107 However, it must be emphasized that although chronobiotic compounds may have some benefits in shift workers, these will generally be easily counteracted by inappropriate exposure to the more powerful zeitgeber, daylight during the early morning hours. Melatonin does exert some performance impairment at doses as low as 5 mg, suggesting caution if wakefulness is intended to be maintained for more than 30

minutes after administration.107 Finally, no large-scale clinical trials have evaluated the effectiveness or safety of melatonin use, which should be discussed with the patient’s physician. In the United States, melatonin is available as a dietary supplement. There are available melatonin preparations that are certified for purity and dosage level, and such a preparation should be used. Use of melatonin to induce and maintain sleep as opposed to phase-shifting properties is reviewed later. Findings from studies have also demonstrated the ability of exercise interventions to delay circadian rhythms.108 However, without adequate control over light exposure, the usefulness of such interventions alone may be limited, owing to the extensive time required for significant phaseshifting effects and the potential counteractive effects of daytime light exposure on circadian adjustment in shift workers. Improving Diurnal (and Nocturnal) Sleep Shift workers should be encouraged to attempt sleep immediately after the night shift and to maintain a sleepconducive environment during their sleep time, using light-blocking shades, ear plugs, and a comfortable eye mask. If near-complete circadian alignment is achieved in a shift worker, improvements in daytime sleep do occur.93,109 However, the practical limitations of circadian interventions often prevent complete alignment (e.g., diurnal light exposure), thus necessitating interventions directly targeting sleep improvement. Owing to a lack of circadian adjustment in shift workers, sleep disturbance typically occurs during the latter half of daytime sleep.109 Use of two sleep periods: (1) an “anchor” sleep period of about 4 hours that represents a time of day (e.g., 8 am to 12 pm) when the shift worker is instructed to “always sleep” regardless of it being a workday or day off and (2) another 3- to 4-hour sleep period taken at irregular times depending on the work schedule may help to stabilize circadian rhythms and increase sleep duration for a given 24-hour period.110 Although the ability of melatonin to produce circadian phase shifts is limited when control over light exposure is difficult or when endogenous melatonin is present,107 exogenous melatonin doses between 1 and 10  mg and melatonin agonists, administered during the biological day when endogenous melatonin levels are low, can increase total sleep time even at doses as low as 0.3 mg.107a,107b,111,112 In terms of shift workers, some improvements in sleep have been shown with melatonin at doses between 5 and 10  mg,113,114 whereas others using subjective measures of sleep115,116 or lower doses (∼2 mg) have not found soporific effects.117 Studies in diagnosed SWD patients are needed because some of the subjects in previous studies may not have had significant sleep disturbance. Use of the benzodiazepine triazolam in individuals on a simulated shift-work schedule was shown to be beneficial for improving sleep during the daytime hours (30 to 60 minutes/day) but showed minimal to no effects on alertness during the night.118,119 The use of newer benzodiazepine receptor agonists have produced essentially similar results on subjective reports of daytime sleep120 and slight improvements in nocturnal performance but evidence for worsened mood.121 Individuals diagnosed with SWD may show greater benefits, but this has yet to be demonstrated.



Despite its sedative properties, the use of alcohol as a hypnotic in SWD should be strongly discouraged, particularly owing to the resultant fragmentation of sleep in the second half of the night after alcohol administration, a time when sleep is uniquely vulnerable to disruption in this population.122 Napping during the day before the night shift and for brief episodes during the night have been effective as countermeasures to improve alertness and performance in a number of studies.22,23,123 In two recent studies, the combination of an evening nap and caffeine (∼250 to 350 mg) 30 minutes before the night shift was particularly beneficial for improving alertness and performance for up to 3 nights.124 Findings from one recent study in shift workers who were professional drivers demonstrated that a clinically feasible combination of brief naps (2 at 20 minutes each) and a short light exposure period (10 minutes, 5000 lux) can reduce polysomnographically measured falling asleep at the wheel.23 Pharmacologically Enhancing Alertness Many individuals who experience sleepiness take stimulants such as caffeine or amphetamines. Caffeine can be used to improve wakefulness and performance during the biological night.124,125 Although prenap caffeine may be beneficial in reducing the performance-impairing effects of sleep inertia after brief naps,126 this approach has yet to be tested in patients with SWD. In a study by Wyatt and colleagues, low-dose caffeine (0.3 mg/kg/hr) administered over several periods of extended wakefulness (∼29 hours) helped subjects remain awake and improved memory and psychomotor performance.127 Overall, stimulant drugs have several disadvantages that offset their ability to enhance alertness, including the development of tolerance and withdrawal in the case of caffeine128 and the high potential for abuse of Schedule II medications such as amphetamines and methylphenidate.129,130 Benzodiazepine receptor agonists have been shown to improve daytime sleep in simulated shift-work environments,118,119 yet these medications do not normalize nocturnal alertness.118,121,131 Consequently, medications indicated for enhancing alertness in SWD have been used to promote nocturnal wakefulness in patients.83 A study on the use of modafinil for treatment of SWD provides evidence for its therapeutic benefit in occupationally related outcomes, including sleepiness while driving. In that study, 204 patients who met the criteria for SWD were given either 200  mg of modafinil or a placebo for 3 months during the clinical field trial.132 The group taking modafinil showed significant improvement over those taking the placebo in psychomotor vigilance and drowsy driving on the commute home, among other endpoints. Patients also had significant reductions in objectively defined sleepiness on the Multiple Sleep Latency Test during the night shift, although alertness levels did not normalize to those seen during typical daytime assessments. Importantly, modafinil did not have detrimental effects on subsequent daytime sleep when taken at the beginning of the night.132 Armodafinil, the longer lasting isomer of modafinil, has also been shown to be effective for the treatment of excessive sleepiness in SWD and has reduced the level of sleepiness during the commute home.132a It has been FDA

CHAPTER 71  •  Shift Work, Shift-Work Disorder, and Jet Lag  791

approved for use in SWD and shown to significantly improve excessive sleepiness, overall clinical condition, and performance in this patient population.132a Additional studies regarding pharmacologic treatment of circadian desynchrony are reviewed in Chapter 73. Enhancing Alertness with Combined Treatments Several investigations have examined the efficacy of combined treatments for promoting wakefulness during the biological night. Combined treatments studied include caffeine and bright light,125 caffeine and naps,124 and naps and modafinil.133 Such wakefulness promoting treatment combinations have been reported to be better than the use of either treatment alone (Video 71-1). Management Guidelines for Shift-Work Sleep Disorder In light of the paucity of clinical tools for assessing and treating SWD, we have proposed a brief set of clinical guidelines (Table 71-2). These are based on established circadian principles, the rich literature on morbidity associated with shift work, and data from the few currently available studies on the assessment and treatment of SWD and tolerance to shift work. Several highly useful clinical case reviews from initial evaluation through treatment follow-up are presented in Chapter 72, with specific reference to high-risk occupations.

JET LAG Many millions of people travel via jet plane each year. Jet lag results from a mismatch between internal biological time and environmental time caused by rapid eastward or westward travel across multiple time zones. Disturbed and/ or shortened sleep duration before and during travel also contribute to jet lag symptoms. Symptoms include daytime fatigue and sleepiness and insomnia in the new time zone. Gastrointestinal disturbance is common and may be related to individuals eating at a biological time when the body is not prepared to intake nutrition.134,135 Daytime sleepiness can lead to difficulties concentrating and can impair tasks such as driving and decision-making. Although the circadian principles used in the management of jet lag are similar to those of shift work, environmental cues often support adaptation after travel to a different time zone. Thus, jet lag symptoms typically subside in a few days but in some cases can last for weeks. Circadian misalignment and the symptoms of jet lag occur because immediately after eastward jet travel attempts at sleep in the new time zone are made at the new environmental bedtime before the beginning of the biological night of the traveler. Sleep in the new time zone is thus disturbed, and such sleep disruption contributes to subsequent daytime sleepiness and reports of fatigue. Daytime sleepiness and fatigue also occur because wakefulness occurs during the biological night. Individual differences in the ability to sleep during the biological day (vulnerability to insomnia) and to maintain alert wakefulness during the biological night (vulnerability to sleep deprivation) may also contribute to jet lag symptoms. The cognitive impairments associated with jet lag can have serious consequences, resulting in drowsy driving or flying

792  PART II / Section 9  •  Occupational Sleep Medicine Table 71-2  Clinical Guidelines for Assessment and Management of SWD Assessment I. Determine circadian misalignment (sleep diaries and or actigraphy) II. Assess sleep disturbance A. Determine difficulty falling asleep, staying asleep, or having nonrestorative sleep (both during daytime and nighttime sleeps) B. Measure degree of alertness C. Assess falling asleep during inappropriate circumstances or times (ESS), with special attention to drowsy driving D.  Determine important job-related factors: duration of commute after shift, number of consecutive shifts, type of shift, time between shifts III.  Determine impact on social and domestic responsibilities.150 Management91 I. Shift workers should have regular physicals with attention to psychological (i.e., depression), gastrointestinal, cardiovascular, and potential cancer risks of shift work91 A.  Sleep-related comorbidity: determine risk of sleep disordered breathing, restless legs syndrome, or other potential sleep disorder B. Other comorbidity: identify medical or psychiatric disorders which may contribute to the symptoms of insomnia or excessive sleepiness II. Determine if removal from shift work is appropriate or practically feasible If patient meets criteria for a diagnosis of shift work disorder, cessation of the shift work schedule should be the first option discussed with the patient III.  Determine patient-specific therapeutic approach A.  Circadian adaptation 1. Consider individual difference factors (e.g., age, phase preference) 2. Consider compromise phase position (e.g., partial phase delay using bright light during first half of night and increased darkness during daytime) 3.  Night workers—on days off adopt a late sleep schedule (i.e., bedtime 3-4 AM) B.  Symptom management 1. Insomnia a.  Sleep hygiene i.  Target inappropriate sleep hygiene and encourage use of eye mask, ear plugs, and light blocking shades during daytime sleep b.  Sleep maintenance a primary concern i. Consider intermediate half-life (5-8 hours) acting hypnotic ii.  Consider melatonin treatment for daytime sleep (∼3 mg) c.  Sleep initiation problems i.  Consider short-acting hypnotic d. Sleep problems on days off i.  Consider fixed sleep–wake schedule and consider anchor sleep 2. Excessive sleepiness (i.e., Epworth Sleepiness Scale Score 43 cm58

Sleep-disordered breathing

Waist circumference >88 cm, >102 cm

Metabolic disregulation

Figure 72-4  Conceptual model of relationship of sleep restriction and disruption to metabolic disregulation, obesity, and sleep-disordered breathing.55

improve an officer’s ability to cope with the inherent rigors of shift work include screening for primary sleep disorders, managing sleep restriction, and minimizing circadian disturbance. Recovery, which is a function of sleep and rest, is critical for maintaining general health. Shift work often interferes with sleep, which forms the platform on which nutrition and physical activity interact with domestic life factors. Based on the current evidence, primary care, occupational medicine, and sleep physicians can help minimize and mitigate the negative effects of shift work and erratic work hours in police by: • Screening clinically for primary sleep disorders • Screening specifically for sleep-disordered breathing • Educating officers about the importance of managing chronic cumulative sleep debt • Educating officers about the connection between weight control, obesity, metabolic syndrome, cardiovascular disease, and sleep/circadian factors • Motivating officers to do their best with regard to behaviors over which they have at least partial control (i.e., physical activity, nutrition, rest and sleep) Police agencies also can contribute to this effort by conducting educational programs that reinforce the importance of getting adequate sleep. This combination of physician and agency interventions can help officers focus on critical factors that will improve their ability to withstand the rigors of shift work in a challenging work environment. Shift Work: The Organization Sleep physicians should be aware that both management and labor share responsibility for mitigating the impact

24

3-7 times/wk

50 24

 5-HT > DA) Anticholinergic effects Clomipramine Tricyclic antidepressant MAO uptake blocker (5-HT > NE >> DA) Anticholinergic effects Desmethylclomipramine (NE >> 5-HT > DA) is an active metabolite No specificity in vivo Other Medications Sodium Oxybate Might act via GABAB or hydroxybutyrate receptors Reduces dopamine release

via

specific

gamma-

Atomoxetine Specific adrenergic reuptake blocker (NE) Normally indicated for attention-deficit/hyperactivity disorder Also effective on daytime sleepiness DA, dopamine; GABA, gamma-aminobutyric acid; 5-HT, serotonin; MAO, monoamine oxidase; NE, norepinephrine. For details, see references 15, 40, 41, and 45-48.

Increased Dopaminergic Transmission Mediates the Wake-Promoting Effects of Currently Prescribed Stimulant Compounds Commonly prescribed stimulant compounds include amphetamine-like drugs, such as dextroamphetamine, methamphetamine, methylphenidate, pemoline, and modafinil (see Box 84-1). Like tricyclic antidepressants, amphetamine-like drugs are nonspecific pharmacologically. Their main effect is to globally increase monoaminergic transmission by stimulating monoamine release and blocking monoamine reuptake. Abuse and dose escalation can occur with amphetamine, especially in patients without cataplexy. Less abuse is reported with methylphenidate, and modafinil is not believed to be addictive.

Studies have shown that the wake-promoting effect of these compounds is secondary to stimulation of dopamine release and inhibition of reuptake.46,47 The mode of action of modafinil is debated, but this compound also selectively inhibits dopamine uptake.48 All these compounds are ineffective in dopamine transporter knockout mice, suggesting a primary mediation of wake promotion via dopaminergic systems.47 Interestingly, compounds selective for dopaminergic transmission have no effect on cataplexy, whereas amphetamine-like compounds with combined dopaminergic and adrenergic effects have some anticataplectic properties at high doses.41,49 Adrenergic effects of amphetamine-like stimulants also correlate with the respective effects of these compounds on normal REM sleep.15,49 Dopaminergic-specific uptake blockers have

942  PART II / Section 11  •  Neurologic Disorders

little effect on REM sleep when compared to adrenergic or serotoninergic compounds.15 The most important effects of dopaminergic uptake blockers are to reduce total sleep time and slow-wave sleep.50 This preferential effect of dopaminergic uptake blockers on non-REM (NREM) sleep correlates with electrophysiologic data. As opposed to adrenergic or serotoninergic neurons, the firing rate of dopaminergic neurons is known to remain relatively constant during REM sleep.51,52 Interestingly, studies in humans and narcoleptic canines have shown that large doses of stimulants are needed to polygraphically normalize narcoleptic subjects. In our narcoleptic Doberman population, doses equivalent to 60 mg/day were needed to reduce daytime sleep to control levels.22 In both control and narcoleptic animals, however, the dose-response curves for modafinil or amphetamine were parallel. This result suggests that there is no difference in sensitivity to stimulants in narcoleptic animals but rather that higher doses are needed in narcoleptic animals because of their extreme baseline sleepiness.22 However, one study has suggested increased wake-promoting effects of modafinil in rodents with hypocretin deficiency.53 Sodium Oxybate (Gamma-Hydroxybutyrate) Sodium oxybate, also called gamma-hydroxybutyrate (GHB), is a sedative anesthetic compound known to increase slow-wave sleep and, to a lesser extent, REM sleep.15 Abuse in the context of rave parties has been reported, and prescription of the compound is highly regulated, with centralized distribution. Because slow-wave sleep is associated with growth hormone (GH) release, GHB also induces GH release and has been abused by athletes. When administered at night, it consolidates sleep and improves daytime functioning. Because of its short half-life (~30  min), it must be administered twice a night. Interestingly, cataplexy and daytime alertness also improve over time, sometimes producing a full therapeutic effect only after several months of treatment and dose adjustments.16 The mode of action of GHB on sleep and narcolepsy is unclear. GHB has a major effect on dopamine transmission, reducing firing rate and raising brain content of dopamine.15,54 Other effects on opioid, glutamatergic, and cholinergic transmission have been reported.54 Specific GHB receptors have been identified, but the compound is also a GABAB agonist.54 Most studies to date suggest that the sedative-hypnotic effect is mediated via GABAB agonist activity.54,55 Whether this effect also mediates the anticataplectic effects after long-term administration is unknown. Other Known Modulators of Narcolepsy Symptoms The effects of more than 200 compounds with various modes of action have been examined in human patients and narcoleptic canines.15 In almost all cases except a few, similar effects were found in humans and canines.15 Almost all the effects have been reported for monoaminergic and cholinergic compounds. With cataplexy being easier to study than sleep in canines, most studies have also focused on cataplexy rather than sleepiness. For cataplexy, the findings were generally consistent with pharmacologic studies

of REM sleep. As is the case for REM sleep, the regulation of cataplexy is modulated positively by cholinergic systems and negatively by monoaminergic tone.15 Muscarinic M2 or M3 receptors mediate the cholinergic effects, and monoaminergic effects are mostly modulated by postsynaptic adrenergic alpha1 receptors and presynaptic D2 or D3 autoreceptors.15 A number of studies have shown abnormal cholinergic and monoaminergic receptor density and neurotransmitter levels in brain and CSF samples human or canine narcolepsy.15,56-68 Local injection studies in selected brain areas of narcoleptic canines have also shown functional relevance for some of these abnormalities.69-71 As a result, cholinergic hypersensitivity, dopaminergic abnormalities, and decreased histaminergic tone are likely to be critical downstream mediators of the expression of the narcolepsy symptomatology.68-71 The cholinergic and monoaminergic imbalances observed in narcolepsy are best illustrated by the finding that in asymptomatic animals heterozygous for the hcrtr2 mutation, a combination of cholinergic agonists with an alpha1 blocker or a D2 or D3 agonist can trigger cataplexy.21 A possible application of these findings is illustrated by the recent development of histaminergic H3 antagonists, drugs that are known to stimulate histamine release via the H3 receptor, as novel wake-promoting stimulants for the treatment of narcolepsy.72

HYPOCRETIN AND INVOLVEMENT IN NARCOLEPSY Anatomy and Physiology of the Hypocretin Neuropeptide System The hypocretin/orexin system was discovered almost simultaneously by two groups of scientists, hence the two conflicting names. De Lecea and colleagues first isolated the prepro-hypocretin transcript (clone 35) and suggested the existence of two resulting processed neuropeptides sharing extensive homology with each other and weak homology with secretin.73 These neuropeptides were called Hypocretin 1 and Hypocretin 2, to indicate hypothalamic peptides of the incretin family. Using cell lines expressing various orphan G protein–coupled receptors (GPCR), Sakurai and coworkers screened tissue extracts for GPCR agonist activity.74 Two mature peptides stimulating the orphan HFGAN72 GPCR cell line were isolated and called Orexin-A and B.74 The name was chosen from Greek orexis (“appetite”) based on associated studies suggesting stimulation of appetite after central administration. A second receptor with high homology with HFGAN72 was also identified by homology. The two G protein– coupled receptors were initially called orexin receptor 1 and 274 but their official names are HCRTR1 and HCRTR2 in genetic databases. HCRTR1 (OxR1) binds hypocretin-1 (OxA) selectively, whereas HCRTR2 (OxR2) binds both hypocretin-1 (OxA) and hypocretin-2 (OxB) with similar affinity.74 The two receptors mostly couple with Gq and stimulate cellular activity in most cell types.75-77 Only a few thousand cell bodies containing these two peptides are found in the entire brain, all within the perifornical area of the posterior hypothalamus. Contrasting with this discrete perikaria localization, the neurons project widely in the central nervous system.75-77 Limbic system



CHAPTER 84  •  Narcolepsy: Pathophysiology and Genetic Predisposition  943

areas (including amygdala and nucleus accumbens), monoaminergic cell groups (adrenergic locus coeruleus, serotoninergic raphe nuclei, dopaminergic ventral tegmental area and substantia nigra, histaminergic tuberomammillary nuclei), intrahypothalmic nuclei, and various periventricular organs are densely innervated.75-77 Hypocretin immunoreactive varicose terminals are also seen in the cerebral cortex, spinal cord, and thalamus. The strongest extrahypothalamic prepro-hypocretin immunoreactive projection is found in the locus coeruleus. Hypocretin has also been suggested to be present in selected peripheral tissue (testis, gut) at very low levels of expression. Hypocretin Deficiency and Human Narcolepsy and Cataplexy As expected from the observation that most cases of human narcolepsy are sporadic and not fully genetic, as in dogs or mice, an extensive genetic screening study did not identify numerous prepro-hypocretin, hcrtr1, or hcrtr2 mutations in human narcolepsy.8,78,79 Surprisingly, even familial cases of narcolepsy (some of which were HLA-DQB1*0602 negative) did not have any hypocretin mutations, suggesting further heterogeneity in genetic cases.8 Rather, only a single case with a signal peptide mutation of the preprohypocretin gene was identified. This case has an extremely early onset (6 months), severe narcolepsy and cataplexy, DQB1*0602 negativity, and undetectable levels of hypocretin-1 in cerebrospinal fluid (CSF).8 This observation indicates that hypocretin system gene mutations can cause narcolepsy, as in animal models. Following on the cloning of the canine narcolepsy gene, we have also found that most patients who have sporadic HLA-DQB1*0602–positive narcolepsy with cataplexy have undetectable hypocretin-1 levels in the CSF.7-12,80 Follow-up neuropathologic studies in 10 narcoleptic patients also indicated dramatic loss of hypocretin-1, hypocretin-2, and prepro-hypocretin mRNA in the brain and hypothalamus of narcoleptic patients (Fig. 84-2).8,9 These subjects have no hypocretin gene mutations and a peripubertal or postpubertal disease onset81 as opposed to a 6-month onset in patients with a prepro-hypocretin mutation.8 Together with the tight HLA association,13,14 a likely pathophysiologic mechanism in most narcolepsy patients could thus involve an autoimmune alteration of hypocretin-containing cells in the CNS. Hypocretin Transmission in Sleep Regulation The potential role of hypocretin in the regulation of normal sleep is only beginning to emerge. Central (intracerebroventricular or local injections) but not peripheral administration of hypocretin-1 stimulates wakefulness and reduces REM sleep. Hypocretin antagonists promote NREM and REM sleep, including in humans. In rats and monkeys, cisternal CSF hypocretin-1 fluctuates, with maximal levels at the end of the active period (night in rodents) and minimum levels at the end of the inactive period (amplitude is 40%).82 Using in vivo dialysis, a similar profile is observed in rat brain tissue extracellular fluid.83 In diurnal, wake-consolidated squirrel monkeys, cisternal hypocretin-1 levels also peak in the late evening, around bedtime (amplitude ≥40%).84 These results suggest

NARCOLEPTIC CONTROL

f

1 cm

f

1 cm

Figure 84-2  Hypocretin (hcrt) and melanin-concentrating hormone (MCH) expression studies in the hypothalamus of control and narcoleptic subjects. Hypocretin and MCH neurons are intermingled in this region of the hypothalamus. Staining of adjacent brain sections for MCH is shown for comparison as a control. Prepro-hypocretin mRNA molecules are detected in the hypothalamus of control (right) but not narcoleptic subjects. MCH mRNA molecules are detected in the same region in both control and narcoleptic sections. f, fornix. Scale bar represents 10 mm. (Derived from Peyron C, Faraco J, Rogers W, et  al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6[9]:991-997, with modifications.)

that hypocretin may be important to promote wakefulness in the evening in humans. In this model, hypocretin would oppose the sleep debt that has accumulated since early morning, allowing a constant level of wakefulness through the day.84 Additional studies suggest that diurnal fluctuations in hypocretin release are driven both directly by the circadian clock and indirectly by the increased sleep debt.32 It is also still uncertain at this stage how hypocretin release and activity fluctuates across the various sleep stages (REM versus NREM). In lumbar CSF, hypocretin-1 only has limited diurnal fluctuation (10%), suggesting a dampening and delay of changes when reaching the lumbar sack (minimal levels in morning).85,86 This finding is important practically because time of CSF collection has no significant effect for purposes of diagnosing narcolepsy.10,87 The most dense reported hypocretin projections are to the monoaminergic cell groups of the locus coeruleus (norepinephrine), substantia nigra and ventral tegmental area (dopamine), raphe magnus (serotonin), and tuberomammillary (histamine) neurons. Dopamine and histamine cell groups have one of the highest densities of hypocretin-2 receptors88 and may be especially important.75-77,89 Increased dopamine level in the amygdala is one of the most consistent neurochemical abnormalities reported in canine narcolepsy.56,58 Decreased histamine levels are also observed in the brain of narcoleptic canines.68 In vivo dialysis studies have indicated a critical role for the dopamine mesolimbic and mesocortical system in regulating alertness and triggering cataplexy by emotions. Histaminergic transmission has long been recognized as a critical wake-promoting neurotransmitter.90 Dopamine and histaminergic projections may thus be centrally involved in controlling both cataplexy and alertness.

944  PART II / Section 11  •  Neurologic Disorders

Similar to REM sleep, cataplexy is controlled by pontine cholinergic REM-on cells and aminergic locus REM-off cells.15 Removing hypocretin-excitatory projections to monoamine cell groups could decrease monoaminergic tone and produce a cholinergic-aminergic imbalance consistent with sleepiness and abnormal REM sleep in narcolepsy. Hypocretin projections to the basal forebrain area, an area with cholinergic hypersensitivity in narcoleptic animals, are also likely to be involved.69,70 It is also likely that hypocretin is critical to the integration of sleep regulation with metabolic status, although the importance of this effect could depend on the species.

GENETIC ASPECTS OF HUMAN NARCOLEPSY Familial Aspects of Human Narcolepsy The familial occurrence of narcolepsy and cataplexy was first reported in 1877 by Westphal.91 Since then, numerous case reports have appeared in the literature. Until recently, narcolepsy was considered a familial disorder. More recent studies have shown that earlier reports were often confounded by unrecognized obstructive sleep apneas. One frequently cited publication by Krabbe and Magnussen92 reports that “narcoleptic” (obese) relatives of a narcoleptic proband would frequently fall asleep while playing cards, falling forward on the table, snoring loudly and becoming cyanotic during the episodes. In more recent studies, the risk of a first-degree relative to develop narcolepsy and cataplexy has been shown to be only 1% to 2% (see reference 93 for review). A larger portion of relatives (4% to 5%) may have isolated daytime sleepiness, when other causes of daytime sleepiness have been excluded.93 These figures are important to keep in mind because they are helpful in reassuring patients regarding the risk to their children and relatives. A 1% to 2% risk is 10- to 40-fold higher than in the general population but remains manageable. A 4% to 5% risk for daytime sleepiness is not negligible, but similar values have been reported for excessive daytime sleepiness in the general population independent of narcolepsy.94-96 Twin Studies and Environmental Factors in Narcolepsy The only systematic twin study available was performed by Hublin and colleagues in white Finns.96 All three twins identified were from dizygotic pairs, so the protocol was not informative to establish concordance in monozygotic twins. Twenty monozygotic twin reports are available in literature (see reference 93 for review). Five to seven are discordant for narcolepsy, depending on how strictly concordance is determined clinically.93,97-99 Most cases of human narcolepsy therefore require the influence of environmental factors for the pathology to develop. This is also substantiated by the fact that onset is not at birth but rather in adolescence,6,81 suggesting the existence of triggering factors. The nature of the environmental factor involved is still unknown. Factors often cited are head trauma,100-102 sudden change in sleep–wake habits98,103 or various infections.104,105 These factors may be involved, but studies all use a retrospective design, limiting the value of any reported differ-

ence. Some studies have suggested increased incidence of narcolepsy in persons born in March and decreased incidence in persons born in September, suggesting the influence of perinatal factors,81,106,107 as reported in other autoimmune diseases. Human Narcolepsy, Human Leukocyte Antigen, and the Immune System The observation that narcolepsy is associated with HLA DR2 and DQ1 was first reported in Japan in 1983.108,109 It was quickly confirmed in Europe and North America; 90% to 100% of all patients with cataplexy carry the HLA DR2 subtype.13,14,110-116 Because many diseases associated with HLA (also called major histocompatibility complex [MHC]) are known to be autoimmune diseases, this discovery led to the hypothesis that narcolepsy might result from an autoimmune insult within the CNS. The finding of hypocretin cell loss in human narcolepsy8,9 suggests that the autoimmune process could target this small population of hypothalamic neurons. Attempts at verifying an autoimmune mediation have generally been disappointing.116-120 Human narcolepsy is not associated with any striking pathologic changes in the CNS or with increased incidence in the occurrence of oligoclonal bands in the CSF.116-119 Gliosis in brains of human narcoleptics has been reported8,9,121 but remains controversial, as are imaging findings suggesting macroscopic hypothalamic changes.122-124 Similarly, peripheral immunity does not seem to be altered even around disease onset.116,117 Lymphocyte CD4/CD8 populations, various autoantibody levels, erythrocyte sedimentation rate, and C-reactive protein are within the normal range and were found not to change up to a year after disease onset. Since this discovery, HLA DR and DQ typing has changed from serologic to molecularly based, and the broad DR2 and DQ1 subtypes have been further divided into DR15, DQ6, and then DRB1*1501, DQA1*0102, and DQB1*0602 (Fig. 84-3). The key gene involved was next found to be DQB1*0602, a subtype of DQ1. This is especially important in African-American patients, many of whom are DQB1*0602 positive but DR2 negative.13,14,125,126 Subjects were also found to be DQA1*0102 positive,13,14,125,126 a less-specific marker than DQB1*0602. Novel DNA markers developed in the HLA DQ region have been tested to further map the narcolepsy susceptibility region within the DQA1-DQB1 interval.127,128 This segment was entirely sequenced and shown to contain no new genes.128 It is also worth noting that in all narcolepsy susceptibility DR-DQ haplotypes identified, both DQA1*0102 and DQB1*0602 are present,125 thus suggesting that the active DQA1*0102/DQB1*0602 heterodimer is necessary for disease predisposition. A number of other DR-DQ haplotypes in the population carry DQA1*0102 without DQB1*0602, and those do not predispose to narcolepsy.126 Conversely, although DQB1*0602 subjects are almost always DQA1*0102 positive, rare haplotypes with DQB1*0602 but without DQA1*0102 are observed in the control population but not in narcoleptic patients.126 Both the DQA1*0102 and the DQB1*0602 alleles might thus be needed for predisposition.126 Findings in families and in unrelated patients also suggest that most if not all the DQB1*0602/DQA1*0102



CHAPTER 84  •  Narcolepsy: Pathophysiology and Genetic Predisposition  945

DQA1

DQB1 12 Kb Serologic typing

DRB1 85 Kb

DQ6 DNAbased typing DQB1*0602 and DQA1*0102

DR5

DR2

DQ1

DQ5

DR15

DR16

DR11

DR12

Other DQB1*06 DRB1*1502 and DQA1*01 (Asians) subtypes DRB1*1101 DRB1*1501 African Americans (Whites and Asians) DRB1*1503 (African Americans)

Figure 84-3  Human leukocyte antigens (HLAs) DR and HLA DQ alleles typically observed in narcolepsy. The genes for the DR and DQ alleles are located very close to each other on chromosome 6p21. These genes encode heterodimeric HLA proteins composed of an α and a β chain. In the DQ locus, both the DQα and DQβ chains have numerous polymorphic residues and are encoded by two polymorphic genes, DQA1 and DQB1, respectively. Polymorphism at the DR(αβ) level is mostly encoded by the DRB1 gene, so only this locus is depicted in this figure. DQB1*0602, a molecular subtype of the serologically defined DQ1 antigen, is the most specific marker for narcolepsy across all ethnic groups. It is always associated with the DQA1 subtype, DQA1*0102. In whites and Asians, the associated DR2 subtype DRB1*1501 is typically observed with DQB1*0602 (and DQA1*0102) in narcoleptic patients. In African Americans, either DRB1*1503, a DNA-based subtype of DR2, or DRB1*1101, a DNA-based subtype of DR5, are most often observed together with DQB1*0602. Other DRB1 alleles (DRB1*0301, DRB1*0806, DRB1*08del, DRB1*12022 and DRB1*1602) have been observed together with DQB1*0602 in much rarer cases.

alleles present in the population predispose equally to narcolepsy. One such finding comes from multiplex families, in which several patients are DQB1*0602 positive. In many cases, DQB1*0602 has been inherited from different branches of the family (for example in one case from the father and the other case from the mother) and are thus not identical by descent (IBD).93 It has been shown that subjects homozygous for DQB1*0602 have a twofold to fourfold increased risk for developing narcolepsy when compared to DQB1*0602 heterozygotic subjects.14,128 Finally, risk in DQB1*0602 heterozygotic persons is modulated by the other DQB1 allele. Most notably, risk is increased in DQB1*0602/DQB1*0301 heterozygotes and reduced in DQB1*0602/DQB1*0601 and DQB1*0602/ DQB1*0501 heterozygotes.14,129 Overall, the data accumulated to date strongly suggest that the HLA-DQ alleles themselves (most notably DQB1*0602 and DQA1*0102) rather than a yet-unknown genetic factor in the region predispose to narcolepsy. Human Leukocyte Antigen and Narcolepsy in Clinical Practice The usefulness of HLA typing in clinical practice is limited by several factors. First, the HLA association is very high (greater than 90%) only in narcoleptic patients with clearcut cataplexy.13 Clear-cut cataplexy is defined as episodes of muscle weakness triggered by laughter, joking, or anger. Muscle weakness episodes triggered by anger, stress, other negative emotions or physical or sexual activity might not

be cataplexy if joking or laughing is not also mentioned as a triggering factor.4 In patients without cataplexy or with doubtful cataplexy, HLA DQB1*0602 frequency is also increased (40% to 60%) but many patients are DQB1*0602 negative.13 Secondly, a large number of controls (approximately 12% in Japanese, 25% in whites and Chinese, 38% in African Americans) have the HLA DQB1*0602 marker without having narcolepsy. Finally, a few rare patients with clear-cut cataplexy do not have the HLA DQB1*0602 marker.130 Despite these limitations, HLA typing is probably most useful in atypical cases or in narcolepsy without definite cataplexy. A negative result should lead the clinician to be more cautious in excluding other possible causes of daytime sleepiness such as abnormal breathing during sleep. In practical terms, it is always more useful to request HLA DQB1*0602 high-resolution typing rather than DR typing to confirm the diagnosis of narcolepsy. If a patient is homozygous for DQB1*0602, the narcolepsy diagnosis is even more probable. A study has shown that 18% to 30% of narcoleptic subjects are DQB1*0602 homozygous versus 0% to 4% in African-Americans and white controls.14,128 In whites, DR2 and DQB1*0602 typing is almost equivalent, and it is probably unnecessary to retype patients who have been shown to be DR2 (or DR15, or DRB1*1501) positive using serologic typing techniques. Most white subjects with DR2 are also DQB1*0602 positive, but the situation is somewhat different in Asians and African Americans. It is not necessary to test for DQA1*0102, because almost all subjects with DQB1*0602 are also DQA1*0102 positive. Most HLA typing laboratories also do not routinely type for DQA1. HLA DQB1*0602 Negativity HLA DQB1*0602-negative subjects with typical and severe cataplexy have been reported, but these subjects are exceptionally rare.130 An increase in DQB1*0301 has been suggested in these cases but needs further substantiation.14 Most of these patients have normal CSF hypocretin-1, suggesting a different pathophysiology (Fig. 84-4).10 Interestingly, two partially concordant monozygotic twins reported in the literature were DQB1*0602 negative.93 A number of DQB1*0602 negative families (with normal CSF hypocretin-1) have been reported in which narcolepsy with cataplexy seems to be transmitted as a highly penetrant autosomal dominant trait, and many patients experience narcolepsy and cataplexy whereas other family members have sleepiness and documented REM abnormalities during the MSLT.10,93 These results emphasize the fact that HLA typing and CSF hypocretin-1 results should be interpreted in conjunction with a careful family history. HLA DQB1*0602-negative subjects with cataplexy have also been reported in the context of posttraumatic narcolepsy in the United States.99 This finding would need confirmation in other cultures because the issue could easily be confounded by medicolegal factors in North America. Genetic Factors other Than Human Leukocyte Antigen Genetic factors other than HLA-DQ and DR are likely to be involved in predisposition to narcolepsy. The increased

946  PART II / Section 11  •  Neurologic Disorders 700

Lumbar CSF hypocretin-1 (pg/mL)

600 500

59% (41)

92% (37)

31% (22) 10% (7)

8% (3)

100% (9)

91% (84) 7% (6) 2% (2)

nt ro

Co

Co

nt ro

ls (5 6 HL A– ls ( ) Na 18 rc H o LA w/ +) C Na at rc (H o LA w/ Na –) C at rc o ( H w/ L A+ o Na Ca ) rc t o w/ (HL A– o Ca ) t( HL A+ ) IH (H LA –) IH (H LA +) KL S OS (8) AS (3 6) RL S ( In so 20) m ni a( 9)

0

6% (13)

100

93% (192) 1% (1)

200

81% (22)

300

7% (2) 11% (3)

400

Figure 84-4  Lumbar cerebrospinal fluid (CSF) hypocretin-1 concentrations in controls versus subjects with narcolepsy and other sleep disorders (from an update of the Stanford Center for Narcolepsy Research database). Each point represents the concentration of hypocretin-1 as measured in unextracted lumbar CSF of a single subject. Subjects are differentiated according to HLA DQB1*0602 status and include controls; samples were taken during both night and day. Patients are classified according to the International Classification of Sleep Disorders,1 but cases without cataplexy are subdivided into cases with atypical (triangle) and no cataplexy (squares). Clinical subgroups include narcoleptic subjects (Narco) with (w) and without (w/o) cataplexy, idiopathic hypersomnia (IH), periodic hypersomnia (KLS; Kleine-Levin syndrome), obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), and insomnia. Secondary narcolepsy/hypersomnia cases are not included. In the text, levels are described as low (200  pg/mL). Note that these values are largely artificial and are meant to represent approximately 30% of mean control value as tested in a given center using direct radioimmunoassay and a set of healthy controls. Mean CSF hypocretin-1 concentration was not significantly different between HLA DQB1*0602-positive and HLA DQB1*0602-negative controls. The percentage and number of subjects is specified for each group of subjects according to the two CSF hypocretin thresholds. (Data derived from Mignot E, Lammers GJ, Ripley B, et  al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59[10]:1553-62; Bassetti C, Gugger M, Bischof M, et al. The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A). Sleep Med 2003;4[1)]7-12; Hong SC, Lin L, Jeong JH, et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep 2006;29[11]:1429-38; and Lin L, Mignot E. Human leukocyte antigen and narcolepsy: Present status and relationship with familial history and hypocretin deficiency. In: Bassetti C, Billiard M, Mignot E, editors. Narcolepsy and hypersomnia. New York: Informa Health Care; 2007. p 411-426.)

familial risk in first-degree relatives (10-fold in Japanese, 20-fold to 40-fold in whites) cannot be explained solely by the sharing of HLA subtypes, estimated to explain a twofold to threefold increased risk.93 Additionally, the existence of HLA-negative families suggests disease heterogeneity and the possible involvement of other genes. Linkage

analysis in HLA-DQB1*0602-positive Japanese families has suggested the existence of a susceptibility gene on 4q13-23.131 A possible association with tumor necrosis factor α (TNF-α) gene polymorphism (independent of HLA) has also been suggested.132-134 Other results indicate that a polymorphism in the catechol-O-methyltransferase (COMT) gene, a key enzyme in the degradation of catecholamines, might also modulate disease severity.135,136 More recently, studies have moved toward systematic genome coverage using genome-wide association (GWA) designs.137,138 In the study of 222 patients and 389 controls and replication in 159 patients versus 190 controls, Miyagawa’s group139 found involvement of rs5770917, a polymorphism located between CPT1B and CHKB, two genes that regulate cholinergic metabolism or beta-chain fatty acid oxidation, respectively. A similar effect of rs5770917 (and a significant HLA association) was also observed in cases with essential hypersomnia syndrome, a milder form of narcolepsy without cataplexy defined in Japan by sleepiness, refreshing naps, and no cataplexy,138 suggesting a disease continuum. Although the effect occurs weakly in Koreans,139 the same polymorphism had no effect in a large sample of whites.140 In a second, larger GWA study in whites, Hallmayer140 found a solid association with polymorphisms in the T-cell receptor α (TCRA) locus, with highest significance at rs1154155 (average allelic odds ratio [OR], 1.69; genotype OR 1.94 and 2.55, P < 10-21, 1830 subjects, 2164 controls). In contrast to the Miyagawa study,139 the finding replicated extremely strongly in all ethnic groups, most notably Asians. Surprisingly, it is the first documented genetic involvement of the TCRA locus, the major receptor for HLA-peptide presentation, in any disease. In contrast to HLA (which can be expressed in many cells), the T-cell receptor protein is only expressed in T lymphocytes, thus this finding demonstrates that narcolepsy must be autoimmune or immune related. Because it is still unclear how specific HLA alleles confer susceptibility to more than 100 HLA-associated disorders,141 narcolepsy will provide new insights on how interactions between HLA and T-cell receptors contribute to organ-specific autoimmune targeting.

CLINICAL OVERLAPS OF THE HYPOCRETIN DEFICIENCY SYNDROME CSF Hypocretin-1 Testing in Narcolepsy The observation that cerebrospinal fluid (CSF) hypocretin-1 levels are decreased in patients with narcolepsy provides a new test to diagnose this disorder (Table 84-2, Fig. 84-4). Using a large sample of patients and controls, we have conducted a quality receiver operating curve (QROC) analysis to determine the CSF hypocretin-1 values most specific and sensitive to diagnose narcolepsy.10 A cutoff value of 110  pg/mL was the most predictive overall (30% of mean control values). A majority of samples had undetectable levels (less than 40 pg/mL in most assays), and a few samples had detectable but very diminished levels. None of the patients with idiopathic hypersomnia, sleep apnea, restless legs syndrome, or insomnia had



CHAPTER 84  •  Narcolepsy: Pathophysiology and Genetic Predisposition  947

Table 84-2  Sensitivity and Specificity of Diagnostic Tests NARCOLEPSY WITH CATAPLEXY TEST

SENSITIVITY‡

SPECIFICITY§

NARCOLEPSY WITHOUT CATAPLEXY* SENSITIVITY‡

SPECIFICITY§

IDIOPATHIC HYPERSOMNIA† SENSITIVITY‡

SPECIFICITY§

HLA

89.3% (822/1291)

76.0% (1291)

45.4% (306/1291)

76.0% (1291)

17.7% (62/1291)

76.0% (1291)

MSLT

87.9% (964/1095)

96.9% (1095)

N/A

96.9% (1095)

N/A

96.9% (1995)

Hcrt ≤ 110 pg/mL

83.3% (233/182)

100%

14.8% (162/182)

100%

0.0% (49/182)

100%

Hcrt ≤ 200 pg/mL

85.0% (233/182)

98.9%

22.8% (162/182)

98.9%

6.1% (49/182)

98.9%

CSF, cerebrospinal fluid; Hcrt, CSF hypocretin-1; HLA, human leukocyte antigen; MSLT, multiple sleep latency test; N/A, not applicable as part of the clinical definition; SOREMP, sleep-onset REM period; CSF hypocretin-1 data from the Stanford Center for Narcolepsy Research database and CSF from healthy control subjects (volunteers or subjects undergoing spinal surgery). HLA data from the Stanford Center for Narcolepsy Research database and ethnically matched controls: Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001;68:686-699. MSLT data from the Stanford Center for Narcolepsy Research database, and 1095 random controls from Mignot E, Lin L, Finn L, et  al. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 2006;129(Pt. 6):1609-1623; and Singh M, Drake CL, Roth T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 2006;29:890-895. *Narcolepsy with atypical and no cataplexy are grouped as narcolepsy without cataplexy per American Academy of Sleep Medicine. International Classification of Sleep Disorders, 2nd ed, Diagnostic and Coding Manual. Westchester, Ill: American Academy of Sleep Medicine; 2005. † Idiopathic hypersomnia includes both patients as defined by a positive MSLT or with prolonged sleep time independent of MSLT results. A positive MSLT is a mean sleep latency ≤8 min and ≥2 SOREMPs for narcolepsy without cataplexy, and mean sleep latency ≤8 min and 10) than females (65% compared to 48%, P = 0.001). Patients with recurrent

strokes had a higher percentage of SDB (AHI > 10) than initial strokes (74% compared to 57%, P = 0.013). Patients with unknown etiology of stroke had a higher and cardioembolic etiology a lower percentage of SDB than patients with other etiologies.51c From the acute to the subacute phase of stroke, SDB improves.31,35-37,43 Nevertheless, a significant percentage of patients (up to 50%) exhibit an AHI of at least 10/hr months to years after the acute event (see Table 88-1). Central events improve more than obstructive events. One study suggested a better improvement of SDB in hemorrhagic strokes as compared to ischemic strokes.37 Clinical Features Symptoms Sleep-disordered breathing can manifest with a variety of symptoms and signs that are sometimes attributed to the underlying brain damage. Nighttime symptoms of SDB include difficulties falling asleep (sleep-onset insomnia, see later); respiratory noises (snoring, stridor); irregular or periodic respiration, apneas; disrupted sleep with increased motor activity and frequent awakenings; sudden awakenings with or without choking sensations, shortness of breath, palpitations, and panic attacks; orthopnea; and increased sweating. In patients with severe hypoventilation, arousal responses can be suppressed by increasing sleep debt and can lead to death during sleep. Daytime symptoms of SDB include headaches, fatigue and excessive daytime sleepiness, concentration and memory difficulties, irritability, and depression. Some patients also exhibit breathing irregularities during wakefulness including dyspnea, apneas, inspiratory breath holding (apneustic breathing), irregular breathing, rapid shallow breathing (hyperpnea and central hyperventilation), hiccup, and other breathing abnormalities. Breathing Disturbances during Sleep The most common form of SDB in stroke patients is OSA (Fig. 88-1). Severe OSA (with AHI 20 to 30) is found in 20% to 30% of patients. Occasionally, patients present with both OSA and Cheyne-Stokes breathing, with predominance of the first in rapid eye movement (REM) sleep and of the latter in light non-REM (NREM) sleep.26 Cheyne-Stokes breathing is a type of periodic breathing in which central apneas and hypopneas are separated by a crescendo–decrescendo respiratory pattern (Fig. 88-2). Central periodic breathing can be defined as three or more cycles of regular crescendo–decrescendo breathing associated with a reduction of at least 50% in nasal airflow and effort lasting at least 10 seconds. In the first few days after stroke, Cheyne-Stokes breathing and central periodic breathing during at least 10% of recording time is present in 10% to 40% of patients31,33,48,52,53 Central hypoventilation, failure of automatic breathing (Ondine’s curse) and other neurogenic breathing disturbances are less common and usually associated with brainstem strokes. Breathing Disturbances while Awake Breathing abnormalities occurring during wakefulness following hemispheric strokes have not been well studied. Such abnormalities can include selective impairment of

PATIENTS

128 patients (71 men) with acute stroke (80 patients) or TIA

24 patients (13 men) with acute ischemic or hemorrhagic stroke

47 patients with subacute stroke admitted to a rehabilitation unit

147 patients with subacute first-ever stroke (95 men) admitted to a rehabilitation unit

161 patients with acute first-ever (ischemic or hemorrhagic) stroke or TIA (82 men) 86 subjects reexamined subacutely

50 patients with acute ischemic stroke (30 men)

120 patients with acute ischemic stroke (50 men)

51 patients with acute ischemic stroke (28 men) 20 patients not receiving CPAP reexamined subacutely

68 patients with acute stroke 50 reexamined subacutely

106 patients with acute ischemic and hemorrhagic stroke (70 men) 51 reexamined subacutely

39 patients with subacute stroke (16 with hemorrhage) admitted to a rehabilitation unit

86 patients with TIA (49 men)

STUDY

Bassetti et al. (1996, 1999)

Dyken et al. (1996)

Good et al. (1996)

Wessendorf et al. (2000)

Parra et al. (2000)

Iranzo et al. (2002)

Turkington et al. (2002)

Hui et al. (2002)

Harbison et al. (2002)

Szücs et al. (2002)

Disler et al. (2002)

McArdle et al. (2003)

Table 88-1  Sleep-Disordered Breathing after Stroke

SDB: 29 No SDB: 27 27 ± 4

SDB: 26 ± 3 No SDB: 26 ± 4

24 ± 4

24 ± 4

25 ± 5

NA

NA

27 ± 5

72 ± 9

67 ± 9

79 ± 10

64 ± 13

73 ± 11

67 ± 14

65 ± 15 65 ± 11

Men: 28 ± 1 Women: 33 ± 2

65 ± 10

61 ± 10

29 ± 2

59 ± 15

Continued

AHI ≥ 15/hr in 50% of patients Mean AHI (21 ± 17/hr) similar to age- and sex-matched controls Oxygen desaturations more frequent in patients (12/hr vs. 6/hr)

AHI > 15/hr in 50% of patients studied by respirography 2 mo after stroke

ODI ≥ 10/hr in 70% of patients with ischemic stroke and in 64% of patients with hemorrhagic stroke studied by respirography. After 3 mo significant improvement only in patients with hemorrhagic stroke.

AHI ≥ 10/hr in 94% (≥30/hr in 46%) of patients studied by respirography within the first 2 wk after stroke (mean interval, 10 day) AHI higher in patients with lacunar stroke AHI reduction from the acute to the subacute phase: 31 ± 17 vs 24 ± 16, 6-9 wk after stroke (mean interval, 45 d)

AHI ≥ 10/hr in 67% (≥20/hr in 49%) of patients studied within the first 4 days after stroke, compared with 24% in controls AHI reduction from the acute to the subacute phase: 32 ± 17 vs 23 ± 19, 1 mo after stroke

RDI ≥ 10/hr in 61% (≥15/hr in 45%) of patients studied by respirography within 24 hr after stroke RDI higher in supine sleeping position RDI predicted by BMI, neck circumference, and limb weakness

AHI ≥ 10/hr in 62% studied by PSG 12 ± 5 hr after stroke Increased probability of sleep-related stroke onset in SDB subjects SDB associated with early neurologic worsening, not with functional outcome at 6 mo

AHI ≥ 10/hr in 71% (≥30/hr in 28%) of patients studied by respirography 48-72 hr after stroke AHI ≥ 10 in 62% (≥30/hr in 20%) of patients 3 mo after stroke AHI and central apnea index lower in subacute phase: 17 ± 14 vs. 22 ± 17/hr and 3 ± 8 vs. 6 ± 10/hr, respectively CSB in 26% of patients (7% in the subacute phase)

AHI ≥ 10/hr in 44% (≥20/hr in 22%) of patients studied by PSG 46 ± 20 day after stroke.

ODI > 10 in 32% of patients studied by oximetry

AHI ≥ 10/hr in 77% of men and 64% of women studied by PSG 2-5 wk after stroke, as compared with 23% and 14% of age-matched controls.

AHI ≥ 10/hr in 62% of patients studied by PSG 1-71 day after stroke or TIA (mean interval of 9 day), as compared with 12% in 19 age- and sex-matched controls AHI predicted by age, BMI, snoring history, diabetes mellitus, severity of stroke

BODY MASS INDEX (KG/M2) FREQUENCY AND CHARACTERISTICS OF SDB

AGE (YR)

CHAPTER 88  •  Sleep and Stroke  995

214 patients with acute ischemic stroke (142 men)

93 patients with subacute (ischemic and hemorrhagic) stroke

90 patients (70 men) with chronic (ischemic and hemorrhagic) stroke

152 patients (103 men) with acute ischemic stroke 33 reexamined after 6 mo

70 patients (60 men) with acute ischemic stroke and TIA

55 patients (32 male) with acute stroke

30 patients (20 men) with ischemic stroke

60 patients (41 men) with acute ischemic stroke

74 patients (49 men) with first-ever acute ischemic stroke

166 patients (98 men) with subacute ischemic stroke

61 patients with acute ischemic stroke and 13 patients with TIA

Dziewas et al. (2005, 2007)

Nopmaneejumruslers et al. (2005)

Cadhilac et al. (2005)

Bassetti et al. (2006)

Wierzbicka et al. (2006), Rola et al. (2007)

Broadley et al. (2007)

Brown et al. (2008)

Yan-Fang et al. (2007)

Siccoli et al. (2008)

Martinez-Garcia et al. (2009)

Byung-Euk et al. (2010)

25 ± 3

28 ± 4

NA 24 ± 3

58 ± 9

63 ± 13

73 ± 11 63 ± 10

67

NA

AHI ≥ 10/hr in 53% of patients studied by respirography 2 day after stroke

27 ± 4

71

AHI ≥ 5/hr in 65% of stroke patients and 67% of TIA patients studied by respirography within 7 day after stroke AHI predicted by NIH Stroke Scale score on admission and at discharge

Stroke: 29 ± 4 TIA: 29 ± 5

66 ± 11

AHI ≥ 10 in 69% of TIA patients and 51% of stroke patients studied within 48 hr of cerebrovascular event

AHI ≥ 10 in 81% (≥20 in 58%) of patients studied by respirography 58 ± 2 days after stroke

Central AHI ≥ 10 in 41% of patients studied by respirography 45 ± 26 hr after stroke. CSB predicted by age, stroke severity and topography, cardiac function (ECG, ejection fraction).

AHI ≥ 15 in 50% of patients studied by PSG 6 ± 3 day (1-13 day) after stroke Barthel index at 3 mo predicted by Scandinavian Stroke Scale score and AHI

AHI ≥ 5/hr in 73% of patients studied within 7 day after stroke Patients with higher NIH Stroke Scale score spent more time in a supine sleeping position, suggesting that supine sleeping might contribute to elevated AHI in the acute stroke phase

AHI ≥ 10/hr in 58% (≥20 in 31%, ≥30 in 17%) of patients studied by respirography 3 ± 2 day after stroke AHI predicted by age, diabetes mellitus, and nighttime onset of stroke Reduction of AHI from the acute to the subacute phase (32 ± 11 vs. 16 ± 11)

28 ± 3

56 ± 13

AHI ≥ 10/hr in 81% of patients studied by respirography 3 yr after stroke AHI predicted by type and severity (at 1 mo) of stroke

Central AHI ≥ 10/hr (CSB) in 19% of patients studied by PSG 44 ± 3 day after stroke CSB predicted by reduced nocturnal transcutaneous PCO2 and left ventricular ejection fraction

—

No CSB: 28 ± 1 CSB: 27 ± 1

66 ± 1 (no CSB) 71 ± 3 (CSB)

AHI ≥ 10/hr in 51% of patients studied by respirography within 72 hr after admission Higher AHI (27 ± 21 vs. 15 ± 15/hr) in patients with recurrent strokes Atherosclerotic internal carotid artery plaques more frequent in patients with AHI ≥ 10/hr (51%) vs. patients with AHI < 10/hr (33%)

64 ± 15

No SDB: 25 ± 3 SDB: 27 ± 4

BODY MASS INDEX (KG/M2) FREQUENCY AND CHARACTERISTICS OF SDB

65 ± 13

AGE (YR)

Note: With the exception of Dyken’s paper, only studies with more than 30 patients are presented. AHI, apnea–hypopnea index; BMI, body-mass index; CPAP, continuous positive airway pressure; CSB, Cheyne-Stokes breathing; ECG, electrocardiogram; NA, not available; NIH, National Institutes of Health; ODI, oxygen desaturation index; PSG, polysomnography; RDI, respiratory distress index; SDB, sleep-disordered breathing; TIA, transient ischemic attack.

PATIENTS

STUDY

Table 88-1  Sleep-Disordered Breathing after Stroke—cont’d

996  PART II / Section 11  •  Neurologic Disorders



CHAPTER 88  •  Sleep and Stroke  997

Figure 88-1  Obstructive sleep apnea in acute ischemic stroke. This 70-year-old man (HRS) has left middle cerebral artery stroke, carotid artery occlusion, and atrial fibrillation. He has habitual snoring but no excessive daytime sleepiness on history. Aphasia and severe hemiparesis are clinically apparent. National Institutes of Health (NIH) stroke score is16, and there are no signs of heart failure. Polysomnography 2 days after stroke onset shows an apnea–hypopnea index (AHI) of 79 (33 obstructive, 42 mixed) and minimal oxygen desaturation of 85%. The AHI is normalized ( 10 found within 24 hours of stroke onset) and functional outcome (as assessed by the Barthel index) and mortality at 6 months in a series of 120 patients.110 In a study of 60 patients, Yan-Fang and Yu-Fing reported a poorer functional outcome (as estimated by the Barthel Index) at 6 months in patients with an AHI greater than 15.47 Diagnosis Based on its impact on stroke outcome and treatability, SDB should be assessed by history and nocturnal recordings (respirography) in all patients with TIA and stroke.

1000  PART II / Section 11  •  Neurologic Disorders

The suspicion should be particularly high in obese men with history of habitual snoring, witnessed apneas, hypertension, diabetes mellitus, and sleep-onset stroke.27,32,43 Stroke topography and etiology and history of excessive daytime sleepiness are, conversely, poor predictors of SDB in stroke victims. Respirography is sufficiently accurate to diagnose SDB and estimate its severity even in the acute setting.43 Full polysomnography is needed only in a minority of patients. The optimal timing of sleep studies after stroke or TIA is unknown. Although studies within days of a stroke might be less representative of the baseline condition attained several weeks to months after the ischemic event, treatment of SDB soon after stroke could potentially minimize further damage to injured neural tissue and improve outcome.105 Brown and coworkers estimated that screening and treatment of SDB in stroke patients are cost-effective.111 Treatment As a consequence of brain vulnerability to hypoxia and cardiovascular instability, SDB might impede recovery of ischemic but not yet irreversibly damaged brain tissue. Furthermore, SDB can predispose to serious complications, such as aspiration or respiratory arrest, and contribute to short-term and long-term morbidity and mortality of stroke patients (see earlier). Treatment of SDB in stroke patients represents a clinical, technical, and logistical challenge. Treatment strategies should always include prevention and early treatment of secondary complications (e.g., aspiration, respiratory infections, pain) and a cautious use or avoidance of alcohol and sedative-hypnotic drugs, which can all negatively affect breathing control during sleep. Patient positioning in the acute phase can influence oxygen saturation as well.45,98 Continuous positive airway pressure is the treatment of choice for OSA. Automatic CPAP systems can be used for simultaneous detection of upper airway obstructions and treatment, which is made possible by automatic titration of CPAP pressure.34 The compliance for autotitrating continuous positive airway pressure in the first 3 months after TIA was found to be acceptable (≥4 hours per night for ≥75% of nights) in 12 of 30 patients with SDB.51b Compliance is influenced by the spontaneous improvement of SDB after the acute phase (see earlier) and by the absence of excessive daytime sleepiness in most patients with stroke and SDB. In addition, compliance can be expected to be a problem also in stroke patients with dementia, delirium, aphasia, anosognosia, and pseudobulbar or bulbar palsy. Treatment of SDB in stroke patients was assessed in 10 studies and almost 600 patients (Table 88-2). Wessendorf and colleagues reported a 70% CPAP compliance in 105 stroke patients admitted in a rehabilitation unit. Poor compliance was associated with aphasia and severe stroke. CPAP use led to an improvement of subjective well-being and nighttime blood pressure values in a group of 41 and 16 patients, respectively.30 Sandberg’s group reported a reduction in depressive symptoms after one month of CPAP and poor compliance in patients with delirium and cognitive deficits. No improvement was conversely found

on neurologic recovery, as assessed by the Barthel index.112 Disler and colleagues reported good compliance in five consecutive patients with stroke and SDB treated in a rehabilitation unit.34 Later studies found a generally lower CPAP compliance (about 50% in the acute phase and 30% in the chronic phase; range, 12% to 82%) in stroke patients with SDB. Hui and coworkers found that only 4 (12%) out of 34 patients continued CPAP over more than 3 months.35 Martinez-Garcia and colleagues reported in a series of 51 patients a compliance of 29% over the first month.50 In that study, CPAP use led to a significant, fivefold decrease in vascular events. Bassetti’s group reported that only 8 (22%) out of 36 patients discharged from acute hospital with CPAP continued this treatment on a long-term base (60 months).43 No predictors of long-term compliance could be found. Palombini and colleagues found a compliance of only 22% over the first 2 months after stroke.113 Hsu and coworkers randomized 30 patients with stroke and AHI of 30 to CPAP or no treatment.114 Only 7 (47%) of 15 patients kept CPAP for more than 4 weeks and the average use of CPAP was only 1.4 hours per night. Martinez and colleagues reported a reduction of 5-year mortality in 28 stroke patients with mild to moderate SDB (AHI = 20) who were treated with CPAP as compared to 68 patients with SDB who did not tolerate treatment.49 In this study, the long-term CPAP compliance was 30%. The choice of the headgear may have had an influence on the acceptance of CPAP.115 In patients with central apneas and Cheyne-Stokes breathing improvements of breathing disturbances may be achieved with oxygen.102 A method of ventilatory support called adaptive servo-ventilation may also be considered. Wessendorf’s group found that adaptive servoventilation prevented central apneas in stroke patients with heart failure more efficiently than CPAP or oxygen.116 Tracheostomy and mechanical ventilation might become necessary in patients with central hypoventilation. Control of central apneas and ataxic breathing usually requires assisted ventilation. Hiccup can be treated with neuroleptics or with baclofen.117

SLEEP–WAKE DISTURBANCES Epidemiology Sleep–wake disturbances are found in 20% to 50% of stroke patients. Presentations include increased sleep needs (hypersomnia), excessive daytime sleepiness, fatigue, and insomnia. Not uncommonly, after a stroke, patients report a combination of these symptoms. In a series of 285 consecutive patients we found that 21 months after stroke 27% of patients slept at least 10 hours per day (hypersomnia), 28% had an Epworth Sleepiness Scale score of at least 10 (excessive daytime sleepiness), and 46% had a fatigue severity scale score of at least 3 (fatigue) (unpublished observation). Other studies have similarly suggested a high frequency (30% to 70% of patients) of poststroke fatigue.118,119 In a series of 277 consecutive patients evaluated 3 months after stroke, insomnia was reported by 57% of patients. In 18% of the 277 patients, insomnia appeared de novo after stroke.120



CHAPTER 88  •  Sleep and Stroke  1001

Table 88-2  Effect of Continuous Positive Airway Pressure after Stroke STUDY

PATIENTS

AGE (YR)

BMI

FINDINGS

Wessendorf et al. (2001)

105 stroke patients (ischemic and hemorrhagic), RDI ≥15/hr (80 men, 25 women) Patients recruited in a rehabilitation unit 60 day after stroke and followed up over 10 day

61 ± 19

27 ± 4

70% of patients tolerated CPAP (mean CPAP pressure: 9 ± 2 cm H2O) CPAP reduced respiratory events by 82% and increased minimal SaO2 from 76 ± 10 to 89 ± 45% Poor CPAP compliance associated with low Barthel index and aphasia Subjective well-being significantly improved in compliant patients In 16 patients on CPAP, mean nocturnal blood pressure decreased by 8 ± 7 mm Hg

Sandberg et al. 2002

63 patients with ischemic stroke with RDI ≥ 15/hr Patients recruited in a rehabilitation unit 2-4 wk after stroke and followed up over 28 day

No CPAP: 77 ± 8 CPAP: 78 ± 6

No CPAP: 25 ± 5 CPAP: 24 ± 4

Randomized trial, CPAP used by 27/30 patients for 4 wk Compared to control group, depressive symptoms (MADRS total score) improved in patients randomized to nCPAP treatment (P =.004) No significant treatment effect was found with regard to delirium, MMSE or Barthel ADL index Delirium and low cognitive level (MMSE score) explained poor compliance with nCPAP

Hui et al. (2002)

34 patients with ischemic stroke with an AHI ≥ 10/hr Patients recruited 4 day after stroke Follow-up over 3 mo

64 ± 13

24 ± 4

CPAP titration successfully performed in 47% of patients (mean CPAP pressure, 11 ± 1 cm H2O) Only 12% of patients had long-term compliance (average CPAP use, 2.5 ± 0.6 hr/night) 100% were snorers and 75% suffered from daytime sleepiness

Martinez-Garcia et al. (2005)

51 patients with ischemic stroke with an AHI ≥ 20/hr, recruited 2 mo after stroke and followed up over 18 mo

73 ± 9

27 ± 4

15/51 patients (29%) tolerated CPAP and continued therapy over at least 1 mo (mean CPAP pressure, 8 ± 4 cm H2O; mean CPAP use, 6.4 ± 2.2 hr/night) CPAP reduced AHI from 41 ± 14 to 4 ± 3/hr Incidence of new vascular events (stroke, angina, MI) significantly lower in compliant patients (7% vs. 36%)

Hsu et al. (2006)

30 patients with stroke with AHI ≥ 30/hr, for which 658 patients had to be screened Randomization to CPAP over 8 weeks or no treatment Treatment initiated 21-25 day after stroke Patients followed up over up to 6 mo Patients balanced for NIHSS and ESS

No CPAP: mean 73 CPAP: mean 74

No CPAP: mean 25 CPAP: mean 27

Randomized trial Poor objective CPAP, averaging 1.4 hr/night Study ended early because of poor recruitment CPAP treatment resulted in no significant improvements in neurologic outcome, anxiety, depression, or quality of life No significant difference in 24-hr daytime and nighttime systolic BP, diastolic BP, and MAP between groups Only 7/15 patients (47%) used CPAP >4 wk Treatment discontinued in 8 patients because of problems with mask or machine, strokerelated confusional states, or upper airway symptoms CPAP use positively correlated with higher Barthel index and better language capabilities Continued

1002  PART II / Section 11  •  Neurologic Disorders Table 88-2  Effect of Continuous Positive Airway Pressure after Stroke—cont’d STUDY

PATIENTS

AGE (YR)

BMI

FINDINGS

Bassetti et al. (2006)

70 acute ischemic stroke patients with AHI > 15/hr or AHI > 10/hr plus EDS Patients recruited within 1 wk after stroke and followed up over up to 5 yr

56 ± 13

26 ± 4

CPAP treatment successfully initiated in 69% of patients, with compliance until patient discharge in 51% and long-term compliance in 15% CPAP users did not differ from nonusers with respect to age, gender, BMI, history of hypertension, diabetes, or coronary disease No difference in EDS, initial NIHSS and initial AHI

Palombini and Guilleminault (2006)

32 patients with stroke evaluated for CPAP study. 11 patients refused to participate, 21 patients assessed by respirography. 14 patients with AHI ≥ 10/hr enrolled during acute hospital stay Patients followed up over 8 wk

62 ± 13

23 ± 3

12/14 patients agreed to initiate CPAP at home (mean pressure 8 ± 4 cm H2O); 7 (50%) continued CPAP over the whole observation period Treatment stopped because of problems with cognition and orientation, inability to apply headgear, mask, and hose, and to readjust equipment

Broadley et al. (2007)

16 stroke patients with AHI ≥ 15/hr enrolled during first week after stroke and followed up over 6 wk

71

27 ± 4

13/16 patients agreed to initiate CPAP therapy, which was tolerated by 8 patients

Scala et al. (2009)

12 patients (4 men, 8 women) recruited within 48 hr after stroke and studied over a single night

75 ± 5

27 ± 5

CPAP acceptance was 84%: 42% using CPAP > 6 hr, 42% 1-3 hr per night (mean 5.2 ± 4.0 hr)

Martinez-Garcia et al. (2009)

166 patients with ischemic stroke, 96 of them with AHI ≥ 20/hr were offered CPAP Patients recruited 2 mo after stroke and followed up over 5 yr

No CPAP: mean 76 CPAP: mean71

No CPAP: mean 28 CPAP: mean 27

Prospective observations study 28/96 patients with AHI ≥ 20 and long-term CPAP treatment had lower mortality (50%) vs. patients with AHI ≥ 20 and no CPAP (68%)

Bravata et al. (2010)

30 patients with acute TIA

Auto-CPAP use over 90 days after acute event was acceptable (≥4 hours per night for ≥75% of nights) in 40% of patients

ADL, activities of daily living; AHI, apnea–hypopnea index; BMI, body-mass index; BP, blood pressure; CPAP, continuous positive airway pressure; EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; MAP, mean arterial blood pressure; MI, myocardial infarction; MMSE, Mini Mental State Exam; nCPAP, nasal continuous positive airway pressure; NIHSS, National Institutes of Health Sleepiness Scale; RDI, respiratory distress index.

Sleep-related movement disorders and parasomnias are less often observed after stroke. In a series of 137 patients assessed 1 month after stroke, restless legs symptom (RLS) symptoms were found de novo in 12% of patients.121 Other sleep–wake disturbances following stroke include an abnormal transition from wake to sleep and vice versa, with confusion between dream and reality (oneiric state), dream changes, and an altered perception of time (Zeitgefühl).122,123

Clinical Features Hypersomnia and Excessive Daytime Sleepiness Hypersomnia is defined clinically as a reduced latency to sleep, increased sleep, or excessive daytime sleepiness. In patients with strokes that affect activating arousal pathways or the paramedian thalamus, hypersomnia can alternate with insomnia (see earlier). Façon and coworkers described, for example, a 78-year-old patient with a tegmental mesencephalic infarct in whom severe, persistent hypersomnia



CHAPTER 88  •  Sleep and Stroke  1003

was accompanied by an inversion of the sleep–wake cycle with nocturnal agitation.124 Poststroke hypersomnia, with or without excessive daytime sleepiness, is usually observed in association with thalamic (Fig. 88-4), mesencephalic, or upper pontine strokes. Less commonly, strokes in the caudate, striatum, lower pons (Fig. 88-5), medial medulla, and cerebral hemispheres (with or without mass effect) (Fig. 88-6) may be complicated by hypersomnia.125 In deep (subcortical) hemispheric and thalamic stroke, hypersomnia may correspond to presleep behavior, during which patients yawn, stretch, close their eyes, curl up, and assume a normal sleeping posture, while complaining of a constant sleep urge.126 Some of these patients are able to control this behavior when stimulated or given explicit, active tasks to perform. This presleep behavior may be compulsive in that removing the patient from bed can result in repeated attempts to lie down and adopt a sleeping posture. However, during what appear to be daytime sleep periods, relatively quick responses to questions or requests suggest wakefulness. For this peculiar dissociation between lack of autoactivation in the presence of preserved

A

heteroactivation, Laplane suggested the term athymormia, or “pure psychic akinesia.”127 In some patients, hypersomnia evolves to extreme apathy, with lack of spontaneity and initiative, slowness, poverty of movement, and catalepsy, a condition for which the term akinetic mutism was coined.128 Akinetic mutism, and a less severe form, usually referred to as abulia, can persist despite normalization of vigilance or even after appearance of insomnia. In some of these patients, the eventual diagnosis is poststroke fatigue (see later) or poststroke depression. Narcolepsy-like phenotypes have rarely been seen following stroke, even in the absence of human leukocyte antigen (HLA) positivity and cerebrospinal fluid (CSF) hypocretin-1 deficiency.129-131 Hypersomnia with hyperphagia (Kleine-Levin–like syndrome) was reported after multiple cerebral strokes.132 Fatigue A continuum exists of hypersomnia, depression, and fatigue, which is defined as a feeling of physical tiredness, exhaustion with lack of energy accompanied by a strong

C

B 18:00

22:00

02:00

06:00

10:00

14:00

Arousal MT Wake REM S1 S2 S3 S4

D

E

Figure 88-4  Hypersomnia after bilateral paramedian thalamic stroke. This 65-year-old male patient (KM) had initial coma, followed by severe hypersomnia (A), vertical gaze palsy (B), amnesia, and disturbed time perception (Zeitgefühl). Brain MRI shows a bilateral paramedian thalamic stroke (C, D). Polysomnography performed 12 days after stroke onset demonstrates (E) a drastic reduction of sleep spindles and (F) loss of spindle peak (12-14 Hz activity) on spectral analysis (as compared to normal control [G]). A severe central apnea (apnea–hypopnea index, 54/hr) was observed in the acute phase (in the absence of any signs of cardiac dysfunction) but not on follow-up few months later. Actigraphy performed within the first month after stroke shows time “asleep” (rest or sleep) during 61% of the recording time (2 weeks) (H). One year after stroke, the patient still reports increased sleep needs (15 hours per day), apathy (athymormia) and attentional and memory deficits. Modafinil at a dose of 200 mg per day improved his hypersomnia. (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.) (From Bassetti CL, Hermann DM. Sleep and stroke. In: Vinken PJ, Bruyn GW. Handbook of clinical neurology. Sleep disorders. New York: Elsevier; 2010. In press.) Continued

102

102

101

101 Power (µV2)

Power (µV2)

1004  PART II / Section 11  •  Neurologic Disorders

100

10−1

10−1

10−2

10−2 5

F

100

10

15

20

25

5

30

G

Frequency (Hz)

10

15

20

25

30

Frequency (Hz)

H Figure 88-4, cont’d

desire for sleep, with usually normal or (paradoxically decreased) sleep propensity. Fatigue may be more common in brainstem strokes.133 The Epworth Sleepiness Scale is a useful tool to differentiate fatigue from excessive daytime sleepiness.134 Insomnia Insomnia is defined by a difficulty in initiating or maintaining sleep, early awakenings, and insufficient sleep quality. Particularly in patients with subcortical (Fig. 88-7), thalamic, thalamomesencephalic, and large tegmental pontine stroke, insomnia may be accompanied by an inversion of the sleep–wake cycle, with insomnia and agitation during the night and hypersomnia during the day.135-138 In the literature, reports of stroke patients with welldocumented (primary) neurogenic insomnia are rare. Van Bogaert and colleagues reported, for example, a patient with pontomesencephalic stroke who presented an almost complete insomnia over more than two months.135 Freemon and coworkers reported a patient with locked-in syndrome due to pontomesencephalic stroke who presented with polysomnographically confirmed insomnia, which was almost complete for more than 1 month.139 Another patient reported by Girard and colleagues with locked-in syndrome due to bilateral basal pontine stroke with extension

to the pontine tegmentum experienced nearly complete, polysomnographically proved insomnia over as long as 6 months.136 Sleep-Related Movement Disorders and Parasomnias REM sleep behavior disorder (RBD) has been reported to occur after strokes in the tegmentum of the pons.140,141 Restless legs syndrome has been observed de novo after stroke.142-145 In a recent series of 137 patients with stroke, RLS was found mainly after pontine, thalamic, basal ganglia, and corona radiata strokes.121 Most commonly RLS was bilateral, appeared within 1 week after stroke, and was accompanied by periodic limb movements (PLMs) in sleep. After stroke, PLMs can increase (and even appear de novo) and lead to insomnia (Fig. 88-8). PLMs can also decrease after unilateral hemispheric stroke and can persist after spinal stroke.146,147 A reduction in physiologic NREM sleep myoclonus has been described in the hemiplegic limbs of a few stroke patients.148 Hallucinations and Altered Dreaming Only few papers have reported on poststroke dream characteristics.149 Patients with strokes in the pontomesencephalic or mesencephalic tegmentum and in the paramedian



CHAPTER 88  •  Sleep and Stroke  1005

0.6

F3C3-P3O1

Coherence

0.5

Left

F4C4-P4O2

Right

0.4 0.3 0.2 0.1 0

5

10

15

20

25

0

5

10

15

20

25

Frequency (Hz)

2 days after CVI 8 days after CVI 70 days after CVI

Figure 88-5  Hypersomnia or excessive daytime sleepiness after pontomedullary stroke. This 39-year old male patient (UM) had pontomedullary ischemia following subarachnoid hemorrhage and embolization of a giant aneurysm of the basilar artery. This resulted in clinical brainstem syndrome with singultus, left IX, X, XII palsy, dysarthria, gait ataxia, and mild left hemiparesis. Sleep symptoms were postintervention severe excessive daytime sleepiness (EDS; Epworth Sleepiness Score: 23/24) and increased sleep needs (12-14 hours/day). Polysomnography showed sleep efficiency 97%, slow-wave sleep 8% of total sleep time, no sleep apnea, and no periodic limb movements in sleep. The multiple sleep latency test showed mean sleep latency 1 minute and no sleep-onset REM periods. Actigraphy showed time “asleep” (rest or sleep) during 43% of the recording time (2 weeks). Cerebrospinal fluid levels of hypocretin-1 were normal. The patient does not wish any treatment for his EDS and hypersomnia. (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.)

thalamus can experience peduncular hallucinosis of Lhermitte, characterized by complex, often colorful, dreamlike visual hallucinations, particularly in the evening and at sleep onset (Fig. 88-9).14,150-152 Peduncular hallucinosis might represent a release of REM sleep mentation. It can be associated with insomnia and resolves spontaneously in most cases.

Figure 88-6  Hypersomnia and sleep architecture changes after middle cerebral artery stroke. This 39-year old female patient (FF) had aphasia, right hemiparesis, depressed mood, and crying spells. National Institutes of Health (NIH) Stroke Score was 16. The patient’s sleep needs increased in the first 1 to 2 weeks after the stroke (12 hours/day as compared to 7 hours/ day before stroke), followed by mild excessive daytime sleepiness (Epworth Sleepiness Score, 12). At 12 months, the patient reported a decrease in sleep needs to 10 hours per 24 hours. Repeated polysomnographic recordings (day 2, day 8, and 70 days after stroke) demonstrate a progressive recovery of spindling activity (coherent activity around 12  Hz) over both the affected (left) and the nonaffected (right) hemisphere. (MRI pictures courtesy of Prof. G. Schroth, Institute of Neuroradiology, University Hospital, Bern, Switzerland.)

The Charles Bonnet syndrome generally involves lesscomplex visual hallucinations that also occur in the setting of diminished arousal.153 These hallucinations, “release phenomena” after stroke that involves vision or visual field abnormalities, may be limited to a hemianopic field.154,155 Cessation or reduction of dreaming occurs in the Charcot-Wilbrand syndrome and is occasionally limited to alteration of the visual component of the dream (as in the original patient described by Charcot).13,156 This syndrome can occur in patients with parietooccipital, occipital, or deep frontal strokes, and the lesions are often bilateral.149,157-161 Patients often, but not invariably, show deficient revisualization (referred to as visual irreminiscence), topographical amnesia, and prosopagnosia. Conversely, REM sleep characteristics may be normal.162 Severe insomnia and loss of dreaming has been reported following lateral medullary stroke.138 Focal (temporal) seizures secondary to stroke can lead to the syndrome of dream–reality confusion or to recurrent

1006  PART II / Section 11  •  Neurologic Disorders

Figure 88-7  Insomnia after subcortical stroke. This 68-year-old female patient (MZ) had left subcortical hemispheric stroke (corona radiata), with clinically mild right hemisyndrome, National Institutes of Health (NIH) Stroke Score of 6. In the first poststroke week, she had almost complete insomnia and excessive daytime sleepiness (EDS). Two weeks later, she showed recovery from EDS and improvement in insomnia, with 2 to 3 hours of sleep per night. Sleep–wake functions normalized after 4 weeks. (MRI pictures courtesy of Prof. G. Schroth, Institute of Neuroradiology, University Hospital, Bern, Switzerland.)

nightmares, which may be more common with right-sided lesions and can be controlled with antiepileptics.163 An increased frequency or vividness of dreaming can occur following stroke, particularly after thalamic, parietal, and occipital stroke.157 A few patients with severe motor deficits report the persistence of normal motor functions during dreams for up to several years after stroke. Waking up in the morning is a source of great distress in these patients. In other patients, motor handicap may, conversely, be apparent in incorporated in dreams within a few days from stroke onset. Pathophysiology In patients with stroke, sleep–wake disturbances are often of multifactorial origin. In addition to brain damage per se, environmental factors including noise, light, and intensive medical monitoring can contribute to the development of sleep–wake disturbances. Furthermore, SDB, cardiorespiratory disorders, seizures, infections, fever, and drugs can aggravate sleep fragmentation and result in sleep disturbances. Anxiety, depression, and psychological stress (difficulties in coping with stroke in general) often accompany and complicate stroke and can further contribute to sleep–wake disturbances. The importance of these factors is well illustrated by the high occurrence rate of sleep– wake disturbances among intensive care unit (ICU) patients who do not have brain damage.164,165 Hypersomnia and Excessive Daytime Sleepiness A decreased arousal due to lesions involving the ascending arousal pathways is most commonly responsible for poststroke hypersomnia.125 The most severe and persisting forms of dearousal are seen in patients with bilateral lesions of the thalamus, subthalamic or hypothalamic area, tegmental midbrain, and upper pons, where fibers of the ascending arousal pathways are bundled and can be severely

injured even by single small lesions. Such strokes can cause initial coma or, conversely, manic delirium, hyperalertness, and insomnia before hypersomnia evolves. At the thalamomesencephalic level, the dorsomedial nucleus, intralaminar nuclei, centromedian nucleus, and cephalic portions of the ascending reticular activating system are usually involved. Mental arousal seems to be affected more severely by medial lesions, and motor arousal is impaired more strongly by lateral lesions.166,167 Other areas in which stroke can occasionally produce hypersomnia include the caudate, striatum, tegmental pons, median regions of the medulla, and cerebral hemispheres. Hypersomnia after hemispheric stroke usually implicates large lesions, on the left more than on the right and anteriorly more than posteriorly.129,168-170 In large hemispheric strokes, dearousal results from disruption of the upper brainstem secondary to vertical (transtentorial) or horizontal displacement of the brain due to brain edema.171 The occurrence of sleep–wake disturbances following cortical and striatal strokes without mass effect supports the assumption that the role of these structures is in maintenance of arousal and more generally in sleep– wake regulation.172-174 Hypersomnia with increased sleep per 24 hours (active hypersomnia) has occasionally been documented polysomnographically in patients with thalamic, mesencephalic, and pontine stroke.175-177 In a 23-year-old patient with bilateral diencephalic stroke following surgical removal of a craniopharyngeoma. CSF hypocretin-1 levels were low, suggesting a link between poststroke hypersomnia and a deficient hypocretin neurotransmission.178 In two patients with hypersomnia following thalamic and pontine stroke, respectively, we found normal CSF hypocretin-1 levels (see Fig. 88-5).125 Fatigue Fatigue may develop following stroke in association with sleep–wake disturbances (hypersomnia, excessive daytime sleepiness and insomnia), mood and emotional changes, neurologic deficits, and neuropsychological sequelae. Poststroke fatigue is often multifactorial in origin. An overlap exists between poststroke fatigue and poststroke depression. Psychological stress with inadequate coping with stroke consequences in general probably plays an important role, as suggested by the absence of a correlation between poststroke fatigue and stroke size and site and by a high incidence of fatigue following myocardial infarction (without brain damage).179 A dysfunction of arousal and attentional circuits, as suggested also for some forms of poststroke hypersomnia (see earlier), has been postulated also for poststroke fatigue.133 Insomnia Mild to moderate insomnia is a common, usually nonspecific, and multifactorial complication of acute stroke. Recurrent arousals, sleep discontinuity, and sleep deprivation can result from preexisting disorders (e.g., heart failure, pulmonary disease), SDB, medications, infections and fever, inactivity, environmental disturbances (e.g., on ICU), stress, and depression. Psychotropic agents, anxiety, dementia, preexisting insomnia, and stroke severity were found to be risk factors for poststroke insomnia.120



CHAPTER 88  •  Sleep and Stroke  1007

A

B

C Figure 88-8  Insomnia and left-sided periodic limb movements after right paramedian pontine stroke. This 60-year-old patient (WE) had unilateral lacunar stroke in the right paramedian pons (A and B). He developed acutely severe insomnia, with involuntary, jerky, and tremor-like movements of the left leg and arm appearing periodically at sleep onset and during sleep (periodic limb movements, LM, C). The patient denied restless legs symptoms. (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.)

Insomnia may also be related to brain damage per se, a situation for which the term agrypnia has been suggested.180,181 Lesions in the dorsal or tegmental brainstem areas, in the paramedian or lateral thalamus, and subcortically (see Fig. 88-7) have been found to cause poststroke insomnia.14,135,136,138,139,181 The observation in some of these patients of rapid transitions from insomnia to hypersomnia emphasizes the dual role of such brain areas as thalamus, basal forebrain and pontomesencephalic and pontomedullary junction in sleep–wake regulation.182,183 Sleep-Related Movement Disorders and Parasomnias The appearance of RBD after pontine tegmental stroke is consistent with the central role of this brain region in the regulation of REM atonia.184 The de novo onset of restless

legs syndrome after subcortical and brainstem strokes emphasizes the contribution of a dysfunction of the corticospinal system in the pathophysiology of this disorder.121 Clinical Significance The presence of sleep–wake disturbances after stroke are associated with cognitive and psychiatric (depression, anxiety) disturbances.119,120,177,185,186 More recently it was shown that in patients with stroke, sleep between rehabilitation sessions can positively influence motor recovery and learning.187,188 Sleep deprivation and sleep disturbance have been shown experimentally to aggravate the outcome in a rat model of stroke.189 Sleep-enhancing drugs (sodium oxybate) were, on the other hand, shown to accelerate motor recovery in a mouse model of stroke.189a

1008  PART II / Section 11  •  Neurologic Disorders

changes in sleep–wake rhythms and sleep or rest needs following stroke (see Figs. 88-4 and 88-5).125,177

Figure 88-9  Dreamlike hallucinations after unilateral paramedian thalamic stroke. This 62-year-old patient (PV) had left paramedian thalamic stroke and presented clinically with confusional state, abulia, anomia, and moderate to severe amnesia in the absence of major sleep–wake disturbances. In the first few days after hospital admission, the patient had recurrent episodes of visual and acoustic hallucinations in form of human figures (mostly relatives, partial insight) seen on the right side of the visual field, which the patient describes as dreamlike. At 7 months after stroke, the patient had persistent memory problems and reported almost daily episodes of psychic hallucinations (“sensed presence”) and a disturbed time perception (Zeitgefühl). (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland)

In the general population, both hypersomnia and insomnia have been linked with increased mortality.190 One study has shown that insomnia with objective short sleep duration is associated with an increased risk for hypertension.191 Fatigue at 2 years after stroke has been found to predict institutionalization and mortality.192 Whether sleep–wake disturbances directly influence stroke recovery and mortality remains unknown. The presence of restless legs syndrome after stroke has also been linked with a poorer outcome.192a Diagnosis The recognition and diagnosis of poststroke sleep–wake disturbances occurs primarily on clinical grounds. Validated questionnaires such as the Epworth Sleepiness Scale and the Fatigue Severity Scale can help in recognizing poststroke sleepiness and fatigue.193 In stroke patients, the correlation between sleep–wake disturbances and sleep EEG is complex.172,194 In patients with poststroke hypersomnia, sleep EEG can reveal both a reduction and, less commonly, an increase of NREM or REM sleep. In hypersomnia following thalamic infarcts, sleeplike behavior may be accompanied by a variety of EEG patterns, including diffuse low-voltage alpha-beta activity, NREM stage 1 sleep, slow-wave activity, and REM sleep.166,176,177,194,195 Multiple sleep latency tests and other vigilance tests can be used to document excessive daytime sleepiness (see Fig. 88-5). They may become inadequate in patients with thalamocortical lesions.177 Actigraphy is helpful to estimate

Treatment Hypersomnia and Excessive Daytime Sleepiness Treatment of poststroke hypersomnia is often ineffective. In individual patients, some improvement is seen in thalamic and mesencephalic stroke with amphetamines, modafinil, methylphenidate, and dopaminergic agents.125 In patients with paramedian thalamic stroke, treatment with 20 to 40 mg of bromocriptine can improve apathy and presleep behavior.126 Improvement of alertness with 20 mg of methylphenidate and 200  mg of modafinil has been reported in patients with bilateral mesodiencephalic paramedian infarct.125,176 Treatment of an associated depression with stimulating antidepressants can also improve poststroke hypersomnia. It is noteworthy that a favorable influence on early poststroke rehabilitation was reported for both methylphenidate (5 to 30  mg/day in a 3-week trial) and levodopa (100 mg/day in a 3-week trial), an effect that may at least in part be related to improved arousal in these patients.196,197 Fatigue Activating antidepressants and amantidine can be tried for poststroke fatigue.198 A study reported no effect of fluoxetine.199 Modafinil was shown to improve fatigue after brainstem/diencephalic but not cortical stroke.199a Insomnia Treatment of poststroke insomnia should include placement of patients in private rooms at night, protection from nocturnal noise and light, increased mobilization with exposure to light during the day, and, if necessary, temporary use of hypnotics that are relatively free of cognitive side effects, such as benzodiazepine-like substances (zolpidem, zopiclone) and benzodiazepines. These substances can enhance not only sedation and neuropsychological deficits in stroke patients, and they can also lead to the reemergence of other neurologic symptoms and should therefore be used with caution.200 In a small randomized, double-blind trial of 12 patients with poststroke insomnia, zopiclone (3.75 to 7.5  mg) was as effective as lorazepam (0.5 to 1.0 mg).201 In a study of 51 stroke patients, 60 mg/ day of mianserin led to a better improvement of insomnia complaints than placebo, even in patients without associated depression.202 Sleep-Related Movement Disorders and Parasomnias Clonazepam 0.5 to 2.0  mg taken 1 to 2 hours before bedtime is the treatment of first choice in REM sleep behavior disorder. Ropirinol (0.125 to 1  mg/day) and pramipexol (0.125 to 0.5 mg/day) usually improve restless legs syndrome in stroke patients.121 Sleep Architecture Changes Abnormalities in sleep macro- and microstructure are common after acute stroke but result only in part from acute brain damage. Changes in sleep architecture depend upon patient and health characteristics present before the stroke (e.g., age, respiratory disturbances), topography and



CHAPTER 88  •  Sleep and Stroke  1009

In animal models as well as in patients with stroke, changes in sleep behavior and sleep EEG depend upon stroke topography, and the correlation between the two is sometimes poor.203,204 In patients with diffuse cortical, thalamic, or pontine stroke, for example, sleep–wake physiologic cyclicity in eyelid tone, respiration, temperature, and motor activity can occur despite prominent EEG abnormalities.177

L EOG-A2 R EOG-A1 Chin EMG F4-C4 C4-A2 P4-02 T4-T6

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F3-C3 C3-A1 P3-01 T3-T5

A L EOG-A2 R EOG-A1 Chin EMG F4-C4 C4-A2 P4-02 T4-T6 F3-C3

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C3-A1 P3-01 T3-T5

B Figure 88-10  Sleep spindles and sawtooth waves after severe middle cerebral artery stroke. This 58-year-old man had a moderately severe left middle cerebral artery stroke (Scandinavian Stroke Score, 33/58). Polysomnography 9 days after stroke showed mild obstructive sleep apnea (apnea–hypopnea index,16). A, In NREM sleep, spindling decreased ipsilaterally, with three spindles per hour recorded at C3 and 172 per hour at C4. B, In REM sleep, sawtooth waves were symmetrical. EMG, electromyogram; EOG, electrooculogram.

extent of the lesion, associated complications of stroke (e.g., SDB, fever, infections, cardiovascular disturbances, depression, anxiety), drug treatment, and time after stroke onset. Even patients without brain damage who are admitted to an intensive care unit after acute myocardial infarction can have a decreased total sleep time, sleep efficiency, REM sleep, and slow-wave sleep.164 Some changes in sleep architecture are more specifically related to brain damage (see later). Examples are persistent alteration of spindling and slow-wave sleep in supratentorial stroke and persistent REM sleep abnormalities in infratentorial stroke.

Supratentorial Strokes Reductions in NREM sleep, total sleep time, and sleep efficiency can follow acute supratentorial stroke.172,205-210 Reduction of spindling can be observed in thalamic and cortical or subcortical stroke (Fig. 88-10, see Fig. 88-4).186,211-214 In unilateral thalamic strokes, sleep spindles may be preserved.177,186,208,215 Rarely, spindling and slowwave sleep increase in the acute stage of large middle cerebral artery stroke.207,213,216 In some such cases, the increase in scored slow-wave sleep can reflect a generalized increase in delta activity during both sleep and wakefulness.209,217 Changes in sleep spindle and slow-wave activity do not always coincide. Transient reductions in REM sleep can occur in the first days after supratentorial stroke.208,213 Changes in REM sleep can persist after large hemispheric strokes with poor outcome.207,210 Sawtooth waves can be decreased bilaterally in large hemispheric strokes, especially those that involve the right side.208,218 Changes in sleep architecture after hemispheric stroke often do not have high localizing value.208 Some reports have suggested, however, that right-sided strokes can preferentially decrease REM sleep and REM density and that left-sided strokes can selectively reduce NREM stage 4 sleep.206,219 Cortical blindness has been associated with a reduction of rapid eye movements.220 Spindling and, to a lesser degree, slow-wave activity and K complexes appear to be often (but not invariably) reduced in paramedian thalamic stroke.177,186,215 In severe hypersomnia following paramedian thalamic strokes, prolonged polygraphic recordings can demonstrate an almost continuous state of light NREM stage 1 sleep, perhaps reflecting inability to make the transition from wake to sleep or to produce full wakefulness.177 In these patients, REM sleep can occur at night and during the day despite the absence of slow-wave sleep.177 Like the EEG of wakefulness, the sleep EEG undergoes a reorganization after acute damage, but data on this subject are scarce.221 Hachinski’s group reported that during clinical recovery from a large left hemispheric stroke, one patient had progressive deterioration of the sleep EEG on the right side.213 In patients with paramedian thalamic stroke, recovery from hypersomnia can occur despite the persistence of significant NREM sleep changes.177,186,195 In hemispheric stroke, conversely, sleep EEG changes (over the healthy hemisphere) usually recover over time, even in patients with severe strokes (more than 50 mL in volume).172 Infratentorial Strokes Bilateral paramedian infarcts in the pontine tegmentum or large bilateral infarcts in the ventrotegmental pons can lead to reduction in NREM and, especially, REM

1010  PART II / Section 11  •  Neurologic Disorders

sleep.175,222-227 Normal sleep EEG features such as sleep spindles, K complexes, and vertex waves may be completely lost.223,228 Patients usually present clinically with crossed or bilateral sensorimotor deficits, oculomotor disturbances, and, at least initially, disturbances of consciousness. In rare instances, the only focal finding in a patient with severe sleep EEG changes may be a horizontal gaze palsy.229 Patients with abnormal sleep architecture might complain of insomnia, but isolated REM sleep loss can persist for years without cognitive or behavioral consequences.225,230 Bilateral infarction near, but not in, the pontine tegmentum, or infarction of this area only on one side, usually does not alter sleep architecture. Reported examples have included patients with bilateral pontomedullary junction infarcts, bilateral ventral pontine infarcts with locked-in syndrome, and unilateral pontine tegmental infarcts.228 However, exceptions have also been described: A patient with a hematoma in the left pontine tegmentum had an ipsilateral abnormal EEG during REM sleep (despite normal rapid eye movements and muscle atonia),231 and a patient with a hematoma in the right pontine tegmentum had increased NREM stages 1 and 2 sleep and increased total sleep time accompanying clinical hypersomnia.175 Occasionally, NREM or REM sleep may be altered selectively. Strokes that affect the pontomesencephalic junction tegmentum and the raphe nucleus can lead to a moderate to marked decrease in total sleep time with reduction in NREM sleep but no major changes in REM sleep.139,177 Infarctions of the paramedian thalamus and of the lower pons have been associated with absence of slowwave sleep but preservation of REM sleep and appearance of REM at sleep onset.177,224 In contrast, infarction in the lower pons can cause an almost completely selective decrease in REM sleep.228 Increased REM sleep has been noted in one patient who had an infarct in the mesencephalic tegmentum and in another with an infarct in the pontomedullary junction.232 Increased NREM and (to a lesser extent) REM sleep have been reported in patients with mesencephalic stroke.226 Clinical Significance Based in theoretical considerations, it is reasonable to postulate a correlation (if not even some overlap) between the neuronal synchrony necessary to generate normal EEG activity and underlying normal cognitive functions. The existence of a such a direct relationship has never been proved in stroke patients. Nevertheless, wake and sleep EEG changes after stroke have been linked with stroke severity and with clinical and cognitive outcome.172,177,186,208,210,212,213,218,233,234 Low sleep efficiency, decreased spindles, K complexes, slow-wave sleep, and REM sleep predict poor outcome when found after hemispheric strokes.

CIRCADIAN ASPECTS AND DISTURBANCES Ischemic stroke, like myocardial infarction and sudden death, occurs most often in the morning hours, particularly after awakening, between 6 am and noon. A meta-analysis of 31 publications reporting the circadian timing of 11,816

strokes found a 49% increase in stroke of all types (ischemic stroke, hemorrhagic stroke, TIA) between 6 am and noon.235 Lago and colleagues found a higher incidence of strokes on awakening in thrombotic (29%) and lacunar (28%) stroke than in embolic stroke (19%).236 There was no difference in circadian rhythm between first and recurrent stroke. Possible explanations for this pattern have focused on circadian or postural changes in platelet aggregation, thrombolysis, blood pressure, heart rate, and catecholamine levels that occur after awakening and resumption of physical and mental activities.237 In addition, the most prolonged REM sleep period, during which autonomic system instability are known to occur,83,238,239 occurs close to awakening. The highest incidence in the early hours of the morning can be overestimated because of patients who awaken with stroke. Treatment with aspirin does not modify the circadian pattern of stroke onset.240,241 Whereas intracerebral and subarachnoid hemorrhages rarely occur at night, 20% to 40% of ischemic strokes occur at night.242 This suggests that sleep represents a vulnerable phase for a subset of patients with cerebrovascular disease. Sleep-onset stroke should prompt the association with sleep-disordered breathing (see earlier). Acute brain infarction—particularly when the right hemisphere and the insula are affected—can disturb normal circadian variation in autonomic functions (e.g., heart rate, blood pressure, temperature control) and breathing and contribute to increased poststroke cardiovascular morbidity.48,243-247,249 Acute stroke also can alter other circadian functions such as sleep-related secretion of growth hormone and melatonin.216,248 Actigraphy in a few patients with acute stroke and multiinfarct dementia has demonstrated disruption, shortening, lengthening, or shifting of sleep–wake cycles.125 In patients who awaken from coma caused by large hemispheric or brainstem strokes, a polyphasic sleep–wake rhythm often precedes the reappearance of a monophasic rhythm.166 Alteration of circadian variation in core temperature was documented in a patient with a focal (neoplastic) lesion of the ventral hypothalamus, but never following acute stroke.250 However, hyperthermia—which, in some cases, implies diencephalic dysfunction—correlates with stroke severity and represents a bad prognostic sign after acute stroke.251 REFERENCES 1. Diaz J, Sempere AP. Cerebral ischemia: new risk factors. Cerebrovasc Dis 2004;17:43-50. 2. Adams HP, Bendixen BH, Kappelle LJ. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 1993;24:35-41. 3. The European Stroke Organisation (ESO) Executive Committee and the ESO writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507. 4. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2009;359: 1317-1329. 5. Sacco RL, Adamas R, Albers GW, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Stroke 2006;37:577-617. 6. Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin Hop Rep 1818;2:216-218.



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192. Glader EL, Stegmayr B, Asplund K. Poststroke fatigue: a 2-year follow-up study of stroke patients in Sweden. Stroke 2002;33: 1327-1333. 192a.  Medeiros CA, de Bruin PF, Paiva TR, et al. Clinical outcome after acute ischaemic stroke: the influence of restless legs syndrome. Eur J Neurol 2010 (Epub ahead of print). 193. Valko PP, Bassetti CL, Bloch K, et al. Validation of the Fatigue Severity Scale in a Swiss cohort. Sleep 2008;31:1601-1607. 194. Bassetti C, Aldrich M. Idiopathic hypersomnia. A study of 42 patients. Brain 1997;120:1423-1435. 195. Guilleminault C, Quera-Salva MA, Goldberg MP. Pseudo-hypersomnia and pre-sleep behaviour with bilateral paramedian thalamic lesions. Brain 1993;116:1549-1563. 196. Grade C, Redford B, Chrostowski J, et al. Methylphenidate in early poststroke recovery. A double-blind, placebo controlled study. Arch Phys Med Rehab 1998;79:1047-1050. 197. Scheidtmann K, Fries W, Muller F, Koenig E. Effect of levodopa in combination with physiotherapy on functional recovery after stroke: a prospective, randomized, double-blind study. Lancet 2001;358:787-790. 198. De Groot MH, Philipps SJ, Eskes GA. Fatigue associated with stroke and other neurologic conditions: implications for stroke rehabilitation. Arch Phys Med Rehab 2003;84:1714-1720. 199. Choi-Kwon S, Choi J, Kwon SU, et al. Fluoxetine is not effective in the treatment of post-stroke fatigue: a double-blind, placebocontrolled study. Cerebrovasc Dis 2007;23:103-108. 199a.  Brioschi A, Gramigna S, Werth E, et al. Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients. Eur Neurol 2009;62:243-249. 200. Goldstein LB. Common drugs may influence motor recovery. The Sygen in Acute Stroke Study Investigators. Neurology 1995; 45:865-871. 201. Li Pi Shan RS, Ashworth NL. Comparison of lorazepam and zopiclone for insomnia in patients with stroke and brain injury: a randomized, cross-over, double blind trial. Am J Phys Med Rehab 2004;83:421-427. 202. Palomäki H, Berg AT, Meririnne E, et al. Complaints of poststroke insomnia and its treatment with mianserin. Cerebrovasc Dis 2003;15:56-62. 203. Feldman SM, Waller HJ. Dissociation of electrocortical activation and behavioural arousal. Nature 1962;4861:1320-1322. 204. Baumann CR, Kilic E, Petit B, et al. Sleep EEG changes after middle cerebral artery infarcts in mice: different effects of striatal and cortical lesions. Sleep 2006;29:1339-1344. 205. Sumra RS, Pathak SN, Singh N, Singh B. Polygraphic sleep studies in cerebrovascular accidents. Neurol India 1972;20:1-7. 206. Körner E, Flooh E, Reinhart B, et al. Sleep alterations in ischemic stroke. Eur Neurol 1986;25:104-110. 207. Giubilei F, Iannilli M, Vitale A, et al. Sleep patterns in acute ischemic stroke. Acta Neurol Scand 1992;86:567-571. 208. Bassetti C, Aldrich MS. Sleep electroencephalogram changes in acute hemispheric stroke. Sleep Med 2001;2:185-194. 209. Müller C, Achermann P, Bischof M, et al. Visual and spectral analysis of sleep EEG in acute hemispheric stroke. Eur Neurol 2002; 48:164-171. 210. Terzoudi A, Vorvolakos T, Heliopoulos I, et al. Sleep architecture in stroke and relation to outcome. Eur Neurol 2009;61: 16-22. 211. Greenberg R. Cerebral cortex lesions: the dream process and sleep spindles. Cortex 1966;2:357-366. 212. Hachinski V, Mamelak M, Norris JW. Prognostic value of sleep morphology in cerebral infarction. Amsterdam: Excerpta Medica; 1979. 213. Hachinski V, Mamelak M, Norris JW. Clinical recovery and sleep architecture degradation. Can J Neurol Sci 1990;17: 332-335. 214. Gottselig J, Bassetti C, Achermann P. Power and coherence of sleep spindle activity following hemispheric stroke. Brain 2002;125: 373-385. 215. Santamaria J, Pujol M, Orteu N, et al. Unilateral thalamic stroke does not decrease ipsilateral sleep spindles. Sleep 2000;23: 333-339. 216. Culebras A, Miller M. Absence of sleep-related elevation of growth hormone level in patients with stroke. Arch Neurol 1983;40: 283-286.

217. Yokohama E, Nagata K, Hirata Y, et al. Correlation of EEG activities between slow-wave sleep and wakefulness in patients with supratentorial stroke. Brain Topogr 1996;8:269-273. 218. Ron S, Algom D, Hary D, Cohen M. Time-related changes in the distribution of sleep stages in brain injured patients. Electroencephalogr Clin Neurophysiol 1980;48:432-441. 219. Ribeiro Pinto L, Baptistas Silva A, Tufik S. Rapid eye movements density in patients with stroke (abstract). Sleep Res 1994;076. 220. Appenzeller O, Fischer AP. Disturbances of rapid eye movements during sleep in patients with lesions of the nervous system. Electroencephalogr Clin Neurophysiol 1968;25:29-35. 221. Hirose G, Saeki M, Kosoegawa H, et al. Delta waves in the EEGs of patients with intracerebral hemorrhage. Arch Neurol 1981;38: 170-175. 222. Cummings JL, Greenberg R. Sleep patterns in the “locked-in” syndrome. Electroencephalogr Clin Neurophysiol 1977;43: 270-271. 223. Autret A, Laffont F, De Toffol B, Cathala HP. A syndrome of REM and non-REM sleep reduction and lateral gaze paresis after medial tegmental pontine stroke. Arch Neurol 1988;45:1236-1242. 224. Tamura K, Karacan I, Williams RL, Meyer JS. Disturbances of the sleep–waking cycle in patients with vascular brain stem lesions. Clin Electroencephalogr 1983;14:35-46. 225. Gironell A, de la Calzada MD, Sagales T, Barraquer-Bordas L. Absence of REM sleep and altered non-REM sleep caused by a hematoma in the pontine tegmentum. J Neurol Neurosurg Psychaitry 1995;59:195-196. 226. Beck U, Kendel K. Polygraphische Nachtsschlafuntersuchugnen bei Patienten mit Hirnstammläsionen. Arch Psychiat Nervenkr 1971;214:331-346. 227. Landau ME, Maldonado JY, Jabbari B. The effects of isolated brainstem lesions on human REM sleep. Sleep Med 2005;6:37-40. 228. Markand ON, Dyken ML. Sleep abnormalities in patients with brainstem lesions. Neurology 1976;26:769-776. 229. Vallderiola F, Santamaria J, Graus F, Tolosa E. Absence of REM sleep, altered NREM sleep and supranuclear horizontal gaze palsy caused by a lesion of the pontine tegmentum. Sleep 1993;16: 184-188. 230. Lavie P, Pratt H, Scharf B, et al. Localized pontine lesion: nearly total absence of REM sleep. Neurology 1984;34:118-120. 231. Kushida CA, Rye DB, Nummy D. Cortical asymmetry of REM sleep EEG following unilateral pontine hemorrhage. Neurology 1991;41:598-601. 232. Popoviciu L, Asgian B, Corfarici D, et al. Anatomoclinical and polygraphic features in cerebrovascular diseases with disturbances of vigilance. In: Tirgu-Mures L, Popoviciu L, Asgia B, et al, editors. Sleep 1978: Fourth European Congress on Sleep Research. New York: Karger; 1980. p. 165-169. 233. Hachinski V, Mamelak M, Norris JW. Sleep morphology and prognosis in acute cerebrovascular lesions. Amsterdam: Excerpta Medica; 1977.

CHAPTER 88  •  Sleep and Stroke  1015 234. Siccoli MM, Rölli-Baumeler N, Achermann P, Bassetti CL. Correlations between sleep and cognitive functions after hemispheric ischaemic stroke. Eur J Neurol 2008;15(6):565-572. 235. Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 1998;29:992-996. 236. Lago A, Geffner D, Tembl J, et al. Circadian variation in acute ischemic stroke. A hospital-based study. Stroke 1998;29:1873-1875. 237. Krantz DS, Kop WJ, Gabbay FH, et al. Circadian variation of ambulatory myocardial infarction. Triggering by daily activities and evidence for an endogenous circadian component. Circulation 1996;93:1364-1371. 238. Verrier RL, Muller JE, Hobson JA. Sleep, dreams, and sudden death: the case for sleep as an autonomic stress test for the heart. Cardiovasc Res 1996;31:181-211. 239. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904. 240. Marsh EE, Biller J, Adams HP, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol 1990;47:1178-1180. 241. Bassetti C, Aldrich M. Night time versus daytime transient ischemic attack and ischemic stroke: a prospective study of 110 patients. J Neurol Neurosurg Psychiatry 1999;67:463-467. 242. Wroe SJ, Sandercock P, Bamford J, et al. Diurnal variation in incidence of stroke: Oxfordshire community stroke project. BMJ 1992;304:155-157. 243. Sander D, Klingelhöfer J. Stroke-associated pathological sympathetic activation related to size of infarction and extent of insular damage. Cerebrovasc Dis 1995;5:381-385. 244. Yoon BW, Morillo CA, Cechetto DF, Hachinski V. Cerebral hemispheric lateralization in cardiac autonomic control. Arch Neurol 1997;54:741-744. 245. Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllylä VV. Circadian rhythm of heart rate variability is reversibly abolished in ischemic stroke. Stroke 1997;28:2150-2154. 246. Dawson SL, Evans SN, Manktelow BN, et al. Diurnal blood pressure change varies with stroke subtype in the acute phase. Stroke 1998;29:1519-1524. 247. Dawson SL, Mantelow BN, Robinson TG, et al. Which parameters of beat-to-beat blood pressure and variability best predict early outcome after acute ischemic stroke? Stroke 2000;31:463-468. 248. Beloosesky Y, Grinblat J, Laudon M, et al. Melatonin rhythms in stroke patients. Neurosci Lett 2002;319:103-106. 249. Jain S, Namboodri KKN, Kumari S, Prabhakar S. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurol 2004;4:1-6. 250. Schwartz WJ, Busis NA, Hedley-Whyte ET. A discrete lesion of ventral hypothalamus and optic chiasm that disturbed the daily temperature rhythm. J Neurol 1986;233:1-4. 251. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relations to stroke severity, infarct size, mortality, and outcome. Lancet 1996;347:422-425.

Sleep and Neuromuscular Diseases Michelle T. Cao, Charles F.P. George, and Christian Guilleminault Abstract Neuromuscular disorders consist of central and peripheral neurologic disorders with impairment of the motor system. The disability of patients with a neuromuscular disorder worsens during sleep, and the abnormal sleep and secondary impairment of daytime function further degrade quality of life. Nocturnal sleep disruptions may be the result of pain and discomfort related to weakness, rigidity, or spasticity that limit movement and posture. Sleep disruptions may also be related to autonomic dysfunction (often seen in these patients), poor sphincter control, problems with clearance of secretions, and

Neuromuscular disorders are diseases caused by impairment of the motor unit comprising the lower motor neuron, nerve root, peripheral nerve, myoneural junction, and muscle. Any classification of neuromuscular disease may be somewhat arbitrary, and the astute clinician must keep in mind that the pathologic process can involve several segments of the nervous system and muscle. For example, myopathies lead to progressive peripheral motor and sensory impairment along with autonomic dysfunction. Disorders such as amyotrophic lateral sclerosis (ALS) or Creutzfeldt-Jacob disease can progress rapidly toward death, whereas certain chronic polyneuropathies such as Charcot-Marie-Tooth or autonomic syndromes such as familial dysautonomia can have a slower evolution. Patients with neuromuscular syndromes are at risk for sleep-related problems. (Video 89-1) Weakness, rigidity, and spasticity limit movements and posture changes during sleep, leading to discomfort, pain, and disrupted sleep. Difficulty with maintaining positions of comfort can lead to cramping, abnormal uncontrolled movements, and weakness, which also contribute to poor sleep. Abnormal sphincter control can induce urinary and fecal disturbances in the form of nocturia, incomplete emptying or incontinence, constipation, or painful defecation. The sleeprelated changes in respiration put the patient with a neuromuscular disorder at a specific ventilatory risk by impairing ventilation. Chronic respiratory muscle failure usually develops slowly over years. It can initially manifest with disordered breathing during sleep, followed by progression to nocturnal hypoventilation then to diurnal hypoventilation, cor pulmonale, and eventual respiratory failure and end-stage disease. Because of its slow progression, ventilatory failure in some disorders can go undetected for some time and contribute to increased mortality. Limited attention is often paid to the impact of sleeprelated issues in this population, particularly because most clinics see a limited number of patients with neuromuscular disorders. Even in a specialized neuromuscular clinic, less than 2% of patients are asked about their sleep-related problems or have been given a prior sleep evaluation.1 1016

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abnormal movements and actions during sleep. Most importantly, sleep-related hypoventilation can occur in all patients, and overlooking this can lead to death. Daytime evaluation can determine the severity of the disability but might not identify the presence and severity of an associated sleeprelated disorder. Nonspecific symptoms of daytime fatigue and sleepiness indicate poor sleep in these patients. Polysomnography is the only test that can objectively identify and evaluate the severity of sleep-related disorders. By recognizing and treating sleep-related problems, improved survival and better quality of life can be achieved in this group of patients.

Moreover, the common problems (i.e., spasticity, sphincter dysfunction, pain, abnormal movement, confusional arousal) leading to sleep fragmentation, insomnia, parasomnias, daytime tiredness, and sleepiness are rarely dealt with by the sleep specialist. Thus, a multidisciplinary approach to treatment is mandatory in neuromuscular disorders.

EPIDEMIOLOGY AND GENETICS Each neuromuscular syndrome has its own epidemiology and etiology. For example, ALS affects 0.005% of the U.S. population, and multiple sclerosis (MS), a neurodegenerative disorder, affects 0.11%. However, there are no cumulative prevalence data that include all neuromuscular disorders. Many neurologic disorders such as maltase deficiency myopathy, myotonic dystrophy, Rett syndrome, or familial dysautonomia have a clear genetic origin. Other disorders are secondary to infectious, vascular, malignant, or degenerative diseases, and the presence or absence of a genetic component has not been demonstrated. Despite the number of reports of abnormal sleep and breathing in patients with neuromuscular diseases, and the number of studies dealing with the treatment of the concomitant respiratory insufficiency,2-5 there are few large studies that examine the prevalence of sleep-disordered breathing in these patients. One study from New Mexico1 attempted to gather information from its entire clinic population of more than 300 patients. (The clinic provided free care including neurologic, orthopedic, and physical therapy services, and such access ensured that virtually all patients with neuromuscular disease from the state would be referred.) Although complete data were available for only 60 patients (20% of the clinic population), the researchers demonstrated that sleep and breathing abnormalities are or may be present in more than 40% of patients who are routinely followed at the neuromuscular disorders clinic.1 Such a high prevalence should not be surprising given the vulnerability of such patients to sleep-related reductions in muscle tone and overall ventilation.



PATHOPHYSIOLOGY The diaphragm is the major muscle of respiration during wake and sleep. During non–rapid eye movement (NREM) sleep, there is an overall reduction in ventilation that is related to sleep state changes in the chemical control of breathing and in response to an increased impedance of the respiratory system. However, rib cage activity is maintained, albeit reduced, as is diaphragmatic activity. The importance of the diaphragm is particularly evident during rapid eye movement (REM) sleep. During REM sleep, there is postsynaptic inhibition of somatic motor neurons, which causes further reduction or even complete loss of tone in rib cage and other accessory muscles of respiration but leaves the diaphragm relatively unaffected. Thus, the diaphragm is the main muscle of respiration during REM sleep, and any process affecting the diaphragm, whether a myopathy or a process involving its innervation, can be expected to cause significant changes in breathing and oxygenation during this stage of sleep. In patients with bilateral diaphragmatic paralysis, marked oxygen desaturation can occur during REM sleep.6-8 The REM sleep–related inhibition of intercostal and accessory muscles leads to profound hypoventilation during this sleep stage, because patients with diaphragmatic paralysis are completely dependent on intercostal and accessory muscles for breathing. This suppression of accessory respiratory muscle tone is a normal process of REM sleep and is seen in normal subjects and in patients with lung disease.9-11 Depending on the type of neuromuscular disorder, breathing abnormalities during sleep may be present as central apneas, obstructive apneas, or periods of prolonged hypoventilation. Sleep disruption with frequent arousals may be seen in patients with neuromuscular disorders as a result of discomfort in the recumbent position, secretion clearance, sphincter control problems, or increase in upper airway resistance from muscle weakness and craniofacial changes due to the long-standing muscle weakness. Periods of hypoventilation can contribute to frequent arousals, reduced sleep time, and sleep deprivation through both ventilatory and arousal responses to changes in oxygen saturation and carbon dioxide levels. Although these changes may be protective to overall ventilation in the short term, over time ventilatory responses to changes in oxygen and carbon dioxide levels become blunted. This blunting process leads to further worsening of hypoventilation, eventually occurring during both wakefulness and sleep. CLINICAL FEATURES Features Common to Most Neuromuscular Disorders Nonspecific complaints such as increased tiredness, daytime fatigue, or disrupted nocturnal sleep can be the initial manifestations of a slowly evolving neuromuscular disease of adult onset.1 Such nonspecific complaints may also be the sole indication of a slow progression of a neuromuscular disorder during sleep. The presence of a neuromuscular condition may bias the clinician toward believing that complaints of tiredness or daytime fatigue are simply part of the neurologic problem itself, and the

CHAPTER 89  •  Sleep and Neuromuscular Diseases  1017

impaired sleep mechanisms and sleep-related disturbances may be ignored. Problems with clearance, such as managing saliva or gastric contents, can lead to significant drooling, esophageal reflux, or pulmonary congestion from aspiration or retained secretions. Impairment of cough mechanisms can further impair the ability of the lungs to clear secretions. Autonomic dysfunction may be present in the form of abnormal sensitivity to temperature or to pressure, with discomfort related to the use of sheets and blankets. Cerebral lesions can lead to complex regional pain syndrome, with a prominence in the evening and early part of the night. The disease can affect patients psychologically, and their disability can lead to anxiety, depression, and secondary sleep-onset insomnia, as can be seen with many other chronic illnesses. Pharmacologic agents that are prescribed in the evening might have alerting effects, whereas others used in the morning might lead to daytime sleepiness. In all, patients with chronic evolving neuromuscular disorders have many factors that can disrupt sleep and worsen daytime functioning and quality of life. The addition of sleeprelated problems complicates the already existing neurologic issues. Specific Neuromuscular Disorders Neurodegenerative Diseases Neurodegenerative diseases are a group of heterogeneous diseases of the central nervous system for which no causal agent has been identified. These include both somatic and autonomic disorders, both of which have direct and indirect effects on sleep. Somatic diseases involve the cortex, such as Alzheimer’s disease and MS; the basal ganglia (including basal ganglia plus syndromes) such as Parkinson’s disease, progressive supranuclear palsy, Huntington’s chorea, torsion dystonia, or Tourette’s syndrome; the cerebellum (including cerebellum plus syndromes) such as spinocerebellar ataxias; or motor neurons, such as ALS or motor neuron disease. Autonomic degenerative processes can cause multiple-system atrophy or the Shy-Drager syndrome (see Video 87-5). Sleep disturbances such as insomnia, hypersomnia, circadian rhythm disturbances, parasomnias, and sleep-disordered breathing may be seen in neurodegenerative disorders. Because these illnesses are more common in older adults, the sleep changes occurring with normal aging should also be considered. Still, some of the changes in sleep can be related to environmental factors (e.g., living in nursing home) or mood disorders. (The behavior changes associated with the disappearance of physiologic active muscle atonia normally seen during REM sleep secondary to neurodegenerative disorders leading to REM behavior disorder are not reviewed in this chapter.) Although ALS has not been shown to directly affect the sleep-regulating areas of the brain, it is likely that the indirect effects of the disease cause sleep disruption. Periodic limb movements associated with arousals and sleepdisordered breathing contribute to the sleep disruption in some patients with ALS. Sleep-disordered breathing is reported to be present in 17% to 76% of patients with ALS.12 ALS patients with normal respiratory function, normal phrenic motor responses, and preserved motor

1018  PART II / Section 11  •  Neurologic Disorders

units on needle electromyography of the diaphragm can have sleep-disordered breathing with periodic mild oxygen desaturation independent of sleep stage (REM and NREM).13 However, respiratory-related sleep disruption is generally not significant until phrenic nerves are involved and the diaphragm becomes paralyzed. Once there is involvement of phrenic nerves, severe hypoventilation and oxygen desaturation occur during REM sleep. Almost invariably, these patients ultimately need some form of ventilatory support. Some ALS patients without any respiratory disturbance or periodic limb movements still have sleep fragmentation, independent of age. This suggests that other factors contribute to disturbed sleep, such as anxiety, depression, pain, choking, excessive secretions, fasciculations and cramps, and the inability to find a comfortable position or turn oneself freely in bed. Orthopnea, a common complaint in ALS, can also contribute to sleep disruption.14,15 Spinal Cord Disease Poliovirus infection targets the nervous system in several ways, producing meningitis and affecting cranial motor nuclei and spinal cord anterior horn cells, causing acute paresis. As a result, there are many possible effects on respiration. Abnormalities in central regulation of breathing in patients with acute and convalescent poliomyelitis were described in 1958 by Plum and Swanson.16 Subsequently, central, mixed, and obstructive events have been noted.17 Sleep and breathing abnormalities are seen not only in patients who are on respiratory assistance (rocking beds) during sleep but also before ventilatory assistance is initiated.18 Sleep abnormalities include decreased sleep efficiency, increased arousal frequency, and varying degrees of apnea and hypopnea. After treatment of sleep and breathing abnormalities, many symptoms often attributed to the postpolio syndrome improve. Although not all symptoms can be explained, daytime symptoms may be explained by poor sleep quality and abnormal respiration during sleep. Poliomyelitis can alter central and peripheral respiratory functions decades after the acute infection, a condition known as postpolio syndrome.19 Muscle atrophy and immobility lead to kyphoscoliosis and potentially morerestricted ventilation. The anatomic deformities resulting from poliomyelitis can cause chronic pain and consequent sleep abnormalities. Also, bulbar involvement can affect upper-airway muscles. Sleep-disordered breathing is reported to be present in 31% of patients with postpolio syndrome.12 Prolongation of REM latency can result from prolonged recruitment time for damaged neurons in the pontine tegmentum.20 Whether postpolio syndrome has caused fatigue and weakness or these are results of disturbed sleep and thus are potentially treatable can be investigated by sleep studies. Inherited metabolic diseases such as subacute necrotizing encephalomyelopathy (Leigh’s disease) typically appear in childhood and may be associated with respiratory disturbance. Rarely, this disease first appears in adulthood, with automatic respiratory failure during sleep.21 Syringomyelia can be associated with central, mixed, and obstructive apneic events. The involvement of the bulbar and high cervical neurons is responsible for the development of

hypoventilation and central sleep apnea.22-24 The syndrome can be associated with other malformations of the base of skull or high cervical junction (platybasia, Chiari malformations25) that may also give a variable type of sleepdisordered breathing. Polyneuropathies The most common polyneuropathy associated with sleepdisordered breathing is Charcot-Marie-Tooth syndrome, also called hereditary motor and sensory neuropathy.26 This is characterized by chronic degeneration of peripheral nerves and roots, resulting in distal muscle atrophy that begins at the feet and legs and later involves the hands. Sleep-disordered breathing can occur in these patients as result of a pharyngeal neuropathy leading to upper airway obstruction (obstructive apnea, upper airway resistance syndrome)27 or with diaphragmatic dysfunction.28 Autonomic neuropathy, particularly when secondary to type 1 diabetes, may be associated with impaired chemosensitivity to carbon dioxide, although the effects on sleep and breathing are not consistent.29 Neuromuscular Junction Impairments Myasthenia gravis is a disorder of the neuromuscular junction characterized by weakness and fatigability of skeletal muscles. Sleep breathing abnormalities can occur as a result of diaphragmatic weakness. Risk factors for the development of sleep-related ventilatory problems in myasthenia gravis patients include age, restrictive pulmonary syndrome, diaphragmatic weakness, and daytime alveolar hypoventilation.30 Younger patients with a shorter duration of illness are least likely to experience any sleeprelated hypoventilation or oxygen desaturation,31 whereas older patients with moderately increased body mass index, abnormal total lung capacity, and abnormal daytime blood gases are most likely to develop hypopneas or apneas, particularly during REM sleep.32 Sleep apnea is diagnosed in 60% of patients with myasthenia gravis even when the disease is in a clinically stable stage.12,33 A prospective study by Nicolle and colleagues found that obstructive sleep apnea was the predominant abnormality occurring in 36% of myasthenia gravis patients and had significant associations with older age, male gender, elevated body mass index, and corticosteroid use.34 Other neuromuscular disorders that can disturb normal sleep include congenital myasthenic syndromes,35 botulism, hypermagnesemia, and tick paralysis. A careful history is extremely helpful in making the diagnosis in these circumstances. Dyspnea that worsens with activity, morning headache, paroxysmal nocturnal dyspnea, fragmented sleep, and daytime somnolence are among the symptoms that suggest the presence of sleep-disordered breathing in these syndromes. Muscular Diseases M YOTONIC D YSTROPHY Myotonic dystrophy is an autosomal dominant inherited illness; patients present with myotonia and nonmuscular dystrophy. In this illness, there is consistent involvement of facial, masseter, levator palpebrae, sternocleidomastoid, forearm, hand, and pretibial muscles; myotonic dystrophy is, in a sense, a distal myopathy. However, pharyngeal and



laryngeal muscles can also be involved, as well as respiratory muscles, particularly the diaphragm. Central abnormalities also occur in myotonic dystrophy, causing excessive sleepiness via different mechanisms.36-39 For example, damage in dorsomedial nuclei of the thalamus can lead to a medial thalamic syndrome characterized by apathy, memory loss, and mental deterioration. Loss of 5-hydroxytryptamine (serotonin) neuronal cell bodies of the dorsal raphe nucleus and the superior central nucleus,39 as well as dysfunction of the hypothalamic hypocretin system,40 can result in hypersomnia and abnormal results on a multiple sleep latency test (reflecting sleep-onset REM periods) in these patients.37,40 Excessive daytime sleepiness has been found to be common in myotonic dystrophy, being reported in 33.1% to 77% of patients in several studies.41 Involvement of the respiratory muscles can predispose to breathing and oxygenation changes during sleep. There has been ample evidence for the occurrence of periods of alveolar hypoventilation, predominantly in REM sleep,42-44 obstructive apneas,45 and central apneas.46 However, the development of sleep breathing abnormalities in myotonic dystrophy is not simply caused by muscle weakness. When sleep and breathing in patients with myotonic dystrophy are compared with those in patients with nonmyotonic respiratory muscle weakness and in control subjects, periods of hypoventilation and apneas (central and obstructive) occurred in those with myotonic dystrophy and at higher incidences than in nonmyotonic patients who had the same degree of muscle weakness (measured by maximal inspiratory and expiratory pressures).47 This finding adds further evidence that respiratory muscle weakness alone does not account for abnormal breathing in patients with myotonic dystrophy. As a result of muscle weakness, development of craniofacial structures in patients with myotonic dystrophy is impaired. They experience more vertical facial growth than normal subjects, and they have more narrowed maxillary arches and deeper palatal depths. These craniofacial changes can contribute to the development of obstructive sleep apnea. Observations of decreased ventilatory response to hypoxic and hypercapnic stimuli43,48-51 and extreme sensitivity to sedative drugs have suggested a central origin of the breathing impairments in myotonic dystrophy. Whereas increase in ventilation as a result of increased arterial carbon dioxide is a standard technique for assessing control of respiration, in patients with myotonic dystrophy the respiratory muscles must transduce the chemical stimulus. When these muscles are abnormal, as in myotonic dystrophy, it may be difficult to interpret a reduced ventilatory response. That is, chemoreceptor activity and efferent signaling to muscles may be intact, but weak or inefficient respiratory muscles might not permit a normal ventilatory response to a hypoxic stimulus. Measurement of the mouth pressure developed at the beginning of a transiently occluded breath (occlusion pressure, P0.1) can also be used as a measure of respiratory center output.52 In patients with myotonic dystrophy, P0.1 may be as high as or higher than that of control subjects at rest and during stimulated breathing, although overall ventilation is lower.49,53 The finding of a high transdiaphragmatic pressure (Pdi), despite overall lower ventilation,

CHAPTER 89  •  Sleep and Neuromuscular Diseases  1019

suggests that increased impedance of the respiratory system accounts for incomplete transformation into ventilation of normal or increased respiratory center output. Magnetic stimulation of the cortex, in conjunction with phrenic nerve recordings, can be used to test the corticospinal tract to phrenic motor neuron pathways and is a reliable method for diagnosing and monitoring patients with impaired central respiratory drive.54 The use of transcortical and cervical magnetic stimulation demonstrates that more than 20% of patients with myotonic dystrophy have impaired central respiratory drive.55 The finding of neuronal loss in the dorsal central, ventral central, and subtrigeminal medullary nuclei in patients with myotonic dystrophy who exhibit alveolar hypoventilation56 and the severe neuronal loss and gliosis in the tegmentum of the brainstem57 also support a central abnormality. O THER M YOPATHIES Abnormalities in sleep and breathing have been reported in isolated series of patients with various neuromuscular disorders, such as congenital myopathies (nemaline or congenital fiber–type disproportion myopathy58-60) or metabolic myopathies (mitochondrial myopathy [KearnsSayre syndrome]61-63 and acid maltase deficiency).64-66 In all of these cases, there are various alterations in control of breathing and breathing pattern changes, including hypoventilation, obstruction, and central apnea. Severe central sleep apnea and marked oxygen desaturation, particularly during REM sleep, resulting in hypoxia-induced nocturnal seizures, pulmonary hypertension, excessive daytime sleepiness, heart failure, and morning headaches, may be seen in patients with congenital muscular dystrophy,67 and obstructive sleep apnea has also been described in Thomsen’s disease (myotonia congenita).68 Myopathies such as Duchenne’s muscular dystrophy (DMD) can cause restrictive lung disease and chest wall deformities.69 These changes also contribute to ventilatory impairment, fragmented sleep, frequent arousals and sleep stage changes, hypercapnia and hypoxemia (more profound during REM sleep),70,71 development of deformities, chronic pain, and discomfort. There is a bimodal presentation of sleep-disordered breathing in children with DMD, where obstructive sleep apnea is more common in younger children in the first decade of life.72 In younger children with DMD, obstructive sleep apnea was amenable to adenotonsillectomy, whereas in older children who had already developed hypoventilation, obstructive sleep apnea was managed with noninvasive ventilation. A special case is maltase deficiency myopathy, in which the rapid and significant diaphragmatic impairment that occurs long before the wasting of other skeletal muscles explains the severity of the sleep-disordered breathing.73 In fact, the breathing problem during sleep and the secondary daytime tiredness may be presenting symptoms of the myopathy.74 Although the disease progresses rapidly, the diaphragmatic impairment, with clear evidence of sleep-disordered breathing, remains as a major component of the syndrome. Facioscapulohumeral muscular dystrophy is an autosomal dominant disease and the third most common form of muscular dystrophy, after DMD and myotonic dystrophy. Marca and colleagues evaluated 46 patients with facioscapu-

1020  PART II / Section 11  •  Neurologic Disorders

lohumeral muscular dystrophy and found that impaired sleep quality was directly correlated to the severity of the disease. Twenty-seven patients also presented with snoring and 12 reported respiratory pauses during sleep.75

DIAGNOSTIC EVALUATION The clinician who evaluates a patient with a neuromuscular disorder has to consider the type of neurologic disorder and the degree of disability seen during wakefulness. During neurologic assessment, the degree of sensory and motor impairment and the resulting disability, the associated autonomic defects, the intensity of pain and discomfort, and the impact of the illness on the patient’s mood must be assessed. Understanding the patient’s interaction with society and family is an important factor for subsequent treatment decisions. A detailed sleep history is required to outline the severity and type of sleep-related problem(s). For instance, the degree and type of nocturnal disruption, sleep-onset insomnia, awakening difficulties, presence or absence of abnormal behavior during sleep (including confusional arousal), nonrestorative sleep, fatigue, and daytime sleepiness are helpful in the assessment of a sleep-related disorder. General assessment should also determine the degree of pain and discomfort (particularly in the supine position and during sleep), the presence or absence of sphincter problems and urinary or digestive dysfunction during wake and sleep, and any evidence of autonomic dysfunction already present during wakefulness and suspected during sleep (e.g., orthostatic hypotension, dizziness, lightheadedness when standing up just after awakening, cold hands and feet that worsen during the nocturnal period, appearance of skin mottling when supine). The degree of mood impairment caused by illness or sleep disruption should also be characterized. A number of additional diagnostic tests can supplement the evaluation of sleep in the patient with neuromuscular disease. These include a disability index scale,1 a sleep disorder questionnaire, and a sleep log or actigraphy (helpful for investigating daily rhythms and sleep–wake disturbances during a 24-hour period). The severe respiratory insufficiency questionnaire, a multidimensional health-related quality-of-life instrument, may be used for patients who have neuromuscular disorders who are on assisted ventilation.76 Routine measures of pulmonary function (spirometry, lung volumes, diffusing capacity) and gas exchange (Pao2 and Paco2) should be performed in all patients at initial presentation. Static lung volume measurements, both upright and after 15 minutes supine, often demonstrate significant changes caused by respiratory muscle weakness, particularly diaphragmatic weakness. A forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) less than 40% of the predicted value, a Paco2 greater than 45  mm  Hg, and a base excess of 4  mmol/L or greater can indicate that there is a risk for sleep-related hypoventilation; it has been suggested that when these abnormalities are present, polysomnography should be performed.77-79 Supine inspiratory vital capacity less than 40%, 25%, and 12% will likely result in hypoventilation during REM sleep, full night, and daytime, respectively.77

Overnight polysomnography is the key to a definitive evaluation of sleep and breathing in this patient population. Although it can be done in many settings, including at home, in-laboratory evaluation allows additional measures such as video monitoring to document any behavioral changes (e.g., the presence of confusional arousal), parasomnias including REM sleep behavior disorder, or anoxic seizures. More importantly, measurement of transcutaneous or end-tidal CO2 allows continuous tracking of overall ventilation during sleep and can provide a guide for nocturnal ventilatory assistance.

TREATMENT The greatest advances in the medical treatment of neuromuscular disorders have been for sleep-related abnormalities.80 The goal is restoration of normal sleep architecture, with subsequent improvement of sleep, daytime function, and quality of life. Simple measures such as bedding are often overlooked. Many types of beds and mattresses are available with specifications allowing ease of positional changes, avoidance of skin lesions at pressure points, and segmental inflation or deflation (e.g., air mattresses), thus decreasing the consequences of autonomic dysfunction, cramps, spastic contraction, and rigidity. Great efforts should be made to decrease pain and discomfort of any type. Treatment of abnormal behavior and confusional arousals may require sedatives such as benzodiazepines, but such therapy should be considered after careful evaluation of ventilatory function and risk during sleep so as not to worsen the sleep disorder. Judicious use of pharmacologic agents in the morning, such as modafinil, a wake-promoting drug, 100 to 200 mg, can provide daytime alertness without nocturnal sleep disruption. Prior reports on patients with myotonic muscular dystrophy and ALS have shown beneficial effects of modafinil in improving daytime fatigue.81-84 Modafinil has also been shown to be effective in relieving daytime sleepiness and fatigue in neurodegenerative disorders such as MS and Parkinson’s disease.85-90 Modafinil significantly improves daytime wakefulness and fatigue in narcoleptic patients as assessed by the SF-36 and the profile of mood states (POMS) questionnaire.91 This has led to studies evaluating the clinical efficacy of modafinil for daytime fatigue and sleepiness in MS patients, showing conflicting results. Two pilot studies showed that modafinil (200 mg/ day) significantly improved fatigue and sleepiness based on Fatigue Severity Scale (FSS) and Epworth Sleepiness Scale (ESS) scores, and it is well tolerated in patients with MS.89,90 Another study comparing modafinil (400 mg/day) to placebo showed that there was no significant improvement in fatigue based on the Modified Fatigue Impact Scale (MFIS) in MS patients.92 This discrepancy may be related to the dosing schedule (taken in morning versus twice a day) and dose-related effect (400 mg versus 200 mg). There have been two case reports of modafinil improving nocturnal enuresis in two patients with MS who were on the medication for daytime fatigue.93 Treatment of abnormal breathing during sleep should be based on polysomnographic findings and should be adjusted with regular follow-up polysomnographic studies. Various therapies can improve nocturnal hypoventilation



or offset the attendant oxygen desaturation. Supplemental oxygen has been used to alleviate the REM sleep–related oxygen desaturation in patients with DMD; however, little improvement in sleep ensues.94 Because most of the hypoventilation occurs during REM sleep, pharmacologic manipulation of REM sleep by the use of tricyclic antidepressants is a theoretical option and has been attempted with protriptyline. In a small study of patients with DMD, marked improvement in the nocturnal oxygen saturation profile was seen.95 Similar results with protriptyline were seen in patients with restrictive lung disease96; however, anticholinergic side effects limit the widespread use of such therapy. Inspiratory muscle training has demonstrated improved waking respiratory failure in one patient with acid maltase deficiency.65 This patient had abnormal sleep architecture that was unchanged by the muscle training, but there was major improvement in the nocturnal oxygen saturation. Muscle weakness can lead to nocturnal hypoventilation and worsening of oxygenation. Repeated nocturnal asphyxia can lead to increased muscle weakness, which begets further oxygen desaturation, and reversal of the hypoxemia can arrest the muscle weakness. Such a case has been reported where nocturnal ventilation ablated nocturnal hypoxemia in a patient with acid maltase deficiency, and muscle weakness did not progress over an 8-year period.97 Mechanical ventilation has been a mainstay in supporting ventilation since the days of the poliomyelitis epidemics. Rocking beds, negative-pressure tank ventilators, positive-pressure ventilation via tracheostomy, and cuirass ventilation were long-term options in the past, and some patients are still successfully managed with these forms of therapy.2-4 All of these options are cumbersome, severely limit the mobility of patients, and in the case of tracheostomy can have unwanted complications. Therefore, other forms of assisted ventilation have been developed including phrenic nerve pacing, nasal continuous positive airway pressure (CPAP), and noninvasive positive pressure ventilation (NPPV), including bilevel positive airway pressure (BiPAP). In contrast to CPAP (in which delivered airway pressure is constant), the BiPAP system allows delivery of different positive pressures on inspiration and expiration. By adjusting the inspiratory pressure to be higher than the expiratory pressure, the BiPAP system emulates a conventional positive-pressure ventilatory device and may be used as a means of enhancing ventilation. The new-generation NPPV (derived from the BiPAP concept) is equipped with variable-flow pressure-cycled devices and attempt to self-adjust pressures during the night based on specific algorithms. These devices have not been tested enough to show superiority over the ordinary BiPAP systems. However, they are equipped with a function known as rise time and an expanded range of pressures. The rise time (the speed at which airflow is delivered from expiration to inspiration in tenths of a second) is an important component in patient’s comfort and compliance. The rise time is adjusted based on the severity of thoracic muscle weakness, lung inflation capabilities, amount of secretion accumulated in the airway, and other parameters. This adjustment may be critical because the patient might

CHAPTER 89  •  Sleep and Neuromuscular Diseases  1021

not tolerate bilevel equipment if the rise time is inadequate for the situation.98,99 In endotracheally intubated patients or those with a tracheostomy, the differential between expiratory and inspiratory positive airway pressure can be wide. However, unlike an endotracheal or tracheostomy tube, the upper airway is not rigid, and as a result there is variability in airway dilator contraction during inspiration due to several factors, including the degree of local muscle impairment, sleep stage, sleep state, neck position, and narrowing due to anatomic factors (e.g., deviated septum, enlargement of nasal turbinates, presence of adenoids and tonsils). Any of these factors creates turbulence, a phenomenon seen in a circular tube as defined by laws of physics. If the pressure differential becomes wide in the presence of nonlinear flow (turbulence), there will be a greater tendency for upper airway obstruction that translates into flow limitation (visible when studying nasal flow during polysomnography).99 In our practice we keep a maximum differential of 6 cm H2O to avoid iatrogenic induction of variable abnormal upper airway resistance as described earlier. Besides determining appropriate inspiratory and expiratory pressures during overnight polysomnography, the need for a backup respiratory rate may also be assessed. If a backup rate is determined to be helpful, it is commonly set around 10 to 12 breaths per minute, but it will need to be adjusted with time based on the severity and evolution of the syndrome. Bilevel therapy is an effective treatment for a number of neuromuscular diseases,5 and in early stages of the disease it may be as effective as an invasive conventional ventilator. Low-flow oxygen can be bled into the nasal mask during nocturnal sleep to maintain adequate oxygenation. Because the bilevel system acts as a noninvasive ventilator and supports ventilation, it also treats CO2 retention, which is commonly seen in this group of patients in later stages of the disease. In the last 2 decades, NPPV has proved to have a significant positive impact on the natural course of the disease. In neuromuscular diseases, NPPV has been shown to improve quality of life and increase survival.100-107 In postpolio syndrome, the median improvement in life expectancy is more than 20 years. In spinal muscular dystrophy types 2 and 3, DMD, and acid maltase deficiency, the median improvement in life expectancy is 10 years. In myotonic dystrophy, the median improvement in life expectancy is 4 years, and in ALS it is 1 year. Compared to ventilation via tracheostomy, NPPV via nasal interfaces and portable ventilators is becoming the preferred means of assisting ventilation because it simplifies administration of care, is more comfortable for patients, and reduces costs.108,109 Nasal ventilation has been used predominantly nocturnally for patients with postpolio syndrome and other neuromuscular disorders,5,110-117 and it has even been used almost continuously in patients with severe postpolio respiratory insufficiency.114 As the postpolio syndrome and the late sequelae of tuberculosis are disappearing in many parts of the world, ALS has become the most common neuromuscular disorder for which NPPV is used.118 Bourke and colleagues performed a randomized study of 41 ALS patients with orthopnea, maximum inspiratory pressure

1022  PART II / Section 11  •  Neurologic Disorders

less than 60% of predicted, or symptomatic daytime hypercapnia compared to controls and found significant improvements in quality of life, sleep-related symptoms, and survival in those without severe bulbar dysfunction with the use of NPPV.101 These improvements were greater than those achievable with any currently available pharmacotherapy. Therefore, a trial of NPPV in ALS patients is warranted even in those with severe bulbar dysfunction for palliative reasons. Regarding the use of NPPV, the choice of setting can influence sleep architecture and quality in patients with various neuromuscular diseases. Tailoring the setting (an option available depending on which portable ventilator is used) to the individual patient’s respiratory effort rather than the usual clinical parameters is associated with even better nighttime gas exchange, percentage of REM sleep, and sleep quality.119 Various modalities of noninvasive nocturnal ventilation have been developed particularly for use in patients with obesity hypoventilation and cardiac failure (i.e., average volume-assured pressure support and adaptive servo ventilation, respectively).120,121 Average volumeassured pressure support (AVAPS) is a modality that automatically adjusts the pressure support level of a patient to provide a consistent tidal volume with each breath. In this setting, it potentially can be an ideal mode for patients who have neuromuscular disease and who are unable to maintain adequate tidal volume during sleep. In almost every case, not only are the nocturnal ventilation and gas exchange abnormalities normalized, but daytime respiratory failure and excessive daytime sleepiness are improved as well. The use of noninvasive positivepressure ventilation allows patients to return to work and even travel, something previously not possible when they were constrained by reliance on a rocking bed or the complications of tracheostomy for nocturnal ventilatory support.16

DECISION TO ASSIST NOCTURNAL VENTILATION When patients present with disrupted sleep, snoring, excessive daytime sleepiness, and unexplained development of peripheral edema or polycythemia, sleep studies will characterize the breathing disorder, and the decision to assist ventilation is an easy one. For patients with obstructive sleep apnea, nasal CPAP or BiPAP is the preferred treatment; patients with predominantly hypoventilation or central apnea and severe oxygen desaturation should be managed with BiPAP (with or without backup respiratory rate and with or without addition of low-flow oxygen bled into the mask), or noninvasive ventilatory support with portable volume ventilators via nasal or oral interfaces. Nocturnal NPPV should be started when nocturnal hypoventilation is present. Clinical symptoms and physiologic markers of hypoventilation are helpful in assessing disease severity and will assist in the decision to initiate nocturnal NPPV. The course of neuromuscular disease follows a two-step process, with the initial onset of nocturnal hypoventilation that is reversible during wakefulness, followed eventually by development of diurnal hypoventilation with associated clinical symptoms. The

development of daytime hypoventilation is a serious progression that can lead to acute respiratory failure in certain clinical settings. Continuous monitoring of arterial carbon dioxide by end-tidal CO2 or transcutaneous CO2 during an overnight sleep study is necessary for documenting nocturnal hypoventilation. This process may be more severe during REM sleep or might occur exclusively during REM sleep. Arterial blood gas and serum chemistry can document daytime hypoventilation with elevated arterial CO2 (Paco2), associated low arterial oxygen (Pao2), relatively normal pH, and high serum bicarbonate. There are no consensus data; however, in neuromuscular patients many clinicians consider starting NPPV with an arterial Pco2 greater than 45 mm Hg and an arterial Po2 less than 70 mm Hg.122 An isolated change in nocturnal oxygen saturation (Sao2) alone is insufficient for deciding whether the patient needs ventilatory assistance. However, sustained nocturnal oxygen desaturation can suggest the presence of nocturnal hypoventilation. In summary, there is long-standing consensus123 on the management of severe progressive neuromuscular disorders in which respiratory failure plays a significant part of the natural history of the disease. The positive impact of noninvasive ventilatory support in patients with neuromuscular disease has become more clear in the last 2 decades.124,125 The most effective time to introduce noninvasive ventilation is when sleep-disordered breathing develops. The clinician must remember that other systems are severely affected as well (e.g., in ALS). Issues such as quality of life must be taken into account. Without specific guidance from the literature, each patient must be assessed in detail, and the clinician must bear in mind that nocturnal (and later, 24-hour) ventilation will treat only one (albeit important) aspect of the disorder. ❖  Clinical Pearl Sleep is a state of vulnerability for patients with neuromuscular disorders, as normal REM sleep-related changes in ventilation are magnified as a result of muscle weakness. Sleep disturbances, in addition to sleep-disordered breathing, may also be related to spasticity, poor secretion clearance, sphincter dysfunction, inability to turn, pain, and any associated or secondary autonomic dysfunction. All of these factors impair sleep and worsen daytime disability. Noninvasive ventilation is a significant contribution to neuromuscular disease patients by allowing them to live near-normal life expectancy, decreases morbidity and improves mortality. The most effective time to introduce noninvasive ventilation is when sleep-disordered breathing develops.

REFERENCES 1. Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleep and neuromuscular disease: frequency of sleep-disordered breathing in a neuromuscular disease clinic population. Neurology 1996;47: 1173-1180. 2. Howard RS, Wiles CM, Hirsch NP, et al. Respiratory involvement in primary muscle disorders: assessment and management. Q J Med 1993;86:175-189.



CHAPTER 89  •  Sleep and Neuromuscular Diseases  1023 3. Arens R, Muzumdar H. Sleep, sleep disordered breathing, and nocturnalhypoventilation in children with neuromuscular diseases. Paediatr Respir Rev 2010 Mar;11(1):24-30. 4. Iber C, Davies SF, Mahowald MW. Nocturnal rocking bed therapy: improvement in sleep fragmentation in patients with respiratory muscle weakness. Sleep 1989;12:405-412. 5. Guilleminault C, Philip P, Robinson A. Sleep and neuromuscular disease: bilevel positive airway pressure by nasal mask as a treatment for sleep disordered breathing in patients with neuromuscular disease. J Neurol Neurosurg Psychiatry 1998;65:225-232. 6. Newsom-Davis J, Goldman M, Loh L, et al. Diaphragm function and alveolar hypoventilation. Q J Med 1975;45:87-100. 7. Kreitzer SM, Feldman NT, Saunders NA, et al. Bilateral diaphragmatic paralysis with hypercapnic respiratory failure. Am J Med 1978;65:89-95. 8. Skatrud J, Iber C, McHugh W, et al. Determinants of hypoventilation during wakefulness and sleep in diaphragmatic paralysis. Am Rev Respir Dis 1980;121:587-593. 9. Muller NL, Francis DW, Gurwitz D, et al. Mechanisms of hemoglobin desaturation during REM sleep in normal subjects and in patients with cystic fibrosis. Am Rev Respir Dis 1980;121:463469. 10. Johnson MW, Remmers JE. Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984; 57:1011-1017. 11. Millman BP, Knight H, Kline LR, et al. Changes in compartmental ventilation in association with eye movements during REM sleep. J Appl Physiol 1988;65:1196-1202. 12. Atalaia A, Carvalho MD, Evangelista T, et al. Sleep characteristics of amyotrophic lateral sclerosis in patients with preserved diaphragmatic function. Amyotroph Lateral Scler 2007;8:101105. 13. Ferguson KA, Strong MJ, Ahmad D, et al. Sleep-disordered breathing in amyotrophic lateral sclerosis. Chest 1996;110:664-669. 14. David WS, Bundlie SR, Mahdavi Z. Polysomnographic studies in amyotrophic lateral sclerosis. J Neurol Sci 1997;152(Suppl. 1):S29S35. 15. Plum F, Swanson AG. Abnormalities in central regulation of respiration in acute and convalescent poliomyelitis. Arch Neurol Psychiatry 1958;80:267-285. 16. Guilleminault C, Motta J. Sleep apnea syndrome as a long-term sequelae of poliomyelitis. In: Guilleminault C, Dement WC, editors. Sleep apnea syndrome. New York: Alan R Liss; 1978. p. 309-315. 17. Steljes DG, Kryger MH, Kirk BW, et al. Sleep in postpolio syndrome. Chest 1990;98:133-140. 18. Burk JB, James AC. Characteristics and management of postpolio syndrome. JAMA 2000;284:412-414. 19. Siegel H, McCutchen C, Dalakas MC, et al. Physiologic events initiating REM sleep in patients with the postpolio syndrome. Neurology 1999;52:516-522. 20. Cummiskey J, Guilleminault C, Davis R, et al. Automatic respiratory failure: sleep studies and Leigh’s disease. Neurology 1987; 37:1876-1878. 21. Chokroverty S. Sleep-disordered breathing in neuromuscular disorders: a condition in search of recognition. Muscle Nerve 2001;24:451-455. 22. Kimura K, Tachibana N, Kimura J, et al. Sleep-disordered breathing at an early stage of amyotrophic lateral sclerosis. J Neurol Sci 1999;164:37-43. 23. Daube JR. Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. Muscle Nerve 2000;23: 1488-1502. 24. Lam B, Ryan CF. Arnold-Chiari malformation presenting as sleep apnea syndrome. Sleep Med 2000;1:139-144. 25. Stojkovic T, de Seze J, Dubourg O, et al. Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene. Clin Neurophysiol 2003;114:1609-1614. 26. Dematteis M, Pepin JL, Jeanmart M, et al. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet 2001; 357:267-272. 27. Chan CK, Mohsenin V, Loke J, et al. Diaphragmatic dysfunction in siblings with hereditary motor and sensory neuropathy (CharcotMarie-Tooth disease). Chest 1987;91:567-570.

28. Tantucci C, Bottini P, Fiorani C, et al. Cerebrovascular reactivity and hypercapnic respiratory drive in diabetic autonomic neuropathy. J Appl Physiol 2001;90:889-896. 29. Gajdos P, Quera Salva MA. Respiratory disorders during sleep and myasthenia. Rev Neurol (Paris) 2001;157:S145-147. 30. Manni R, Piccolo G, Sartori I, et al. Breathing during sleep in myasthenia gravis. Ital J Neurol Sci 1995;16:589-594. 31. Quera-Salva MA, Guilleminault C, Chevret S, et al. Breathing disorders during sleep in myasthenia gravis. Ann Neurol 1992; 31:86-92. 32. Oztura I, Guilleminault C. Neuromuscular disorders and sleep. Curr Neurol Neurosci Rep 2005;5:147-152. 33. Amino A, Shiozawa Z, Nagasaka T, et al. Sleep apnoea in well controlled myasthenia gravis and the effect of thymectomy. J Neurol 1998;245:77-80. 34. Nicolle MW, Rask S, Koopman WJ, et al. Sleep apnea in patients with myasthenia gravis. Neurology 2006;67:140-142. 35. Iannaccone ST, Mills JK, Harris KM, et al. Congenital myasthenic syndrome with sleep hypoventilation. Muscle Nerve 2000;23: 1129-1132. 36. Phillips MF, Steer HM, Soldan JR, et al. Daytime somnolence in myotonic dystrophy. J Neurol 1999;246:275-282. 37. Gibbs JW 3rd, Ciafaloni E, Radtke RA. Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy. Sleep 2002;25:672-675. 38. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002;19:1194-1201. 39. Ono S, Takahashi K, Jinnai K, et al. Loss of serotonin- containing neurons in the raphe of patients with myotonic dystrophy: a quantitative immunohistochemical study and relation to hypersomnia. Neurology 1998;50:535-538. 40. Martinez-Rodriguez JE, Lin L, Iranzo A, et al. Decreased hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Sleep 2003; 26:287-290. 41. Laberge L, Begin P, Montplaisir J, et al. Sleep complaints in patients with myotonic dystrophy. J Sleep Res 2004;13:95-100. 42. Kilburn KH, Eagan JT, Sieker HO, et al. Cardiopulmonary insufficiency in myotonic and progressive muscular dystrophy. N Engl J Med 1954;261:1089-1096. 43. Coccagna G, Mantovani M, Parchi C, et al. Alveolar hypoventilation and hypersomnia in myotonic dystrophy. J Neurol Neurosurg Psychiatry 1975;38:977-984. 44. Coccagna G, Martinelli P, Lugaresi E. Sleep and alveolar hypoventilation in myotonic dystrophy. Acta Neurol Belg 1982;82: 185-194. 45. Guilleminault C, Cummiskey J, Motta J, et al. Respiratory and hypodynamics study during wakefulness and sleep in myotonic dystrophy. Sleep 1978;1:19-31. 46. Cirignotta F, Mondini S, Zucconi M, et al. Sleep related breathing impairments in myotonic dystrophy. J Neurol 1987;235: 80-85. 47. Gilmartin JJ, Cooper BG, Griffiths CJ, et al. Breathing during sleep in patients with myotonic dystrophy and non-myotonic respiratory muscle weakness. Q J Med 1991;78:21-31. 48. Serisier DE, Mastaglia FL, Gibson GJ. Respiratory muscle function and ventilatory control. I, in patients with motor neurone disease. II, in patients with myotonic dystrophy. Q J Med 1982;51: 205-226. 49. Begin R, Bureau MA, Lupien L, et al. Pathogenesis of respiratory insufficiency in myotonic dystrophy. Am Rev Respir Dis 1982;125:312-318. 50. Carroll JE, Zwillich LW, Weil JV. Ventilatory response in myotonic dystrophy. Neurology 1977;27:1125-1128. 51. Gillam PMS, Heaf PJD, Kaufman L, et al. Respiration in dystrophic myotonia. Thorax 1964;19:112-120. 52. Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure as a measure of the respiratory centre output in conscious man. Respir Physiol 1975;23:181-199. 53. Begin P, Mathieu J, Almirall J, et al. Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy. Am J Respir Crit Care Med 1997;156:133-139. 54. Zifko UA, Hahn AF, Remtulla H, et al. Central and peripheral respiratory electrophysiological studies in myotonic dystrophy. Brain 1996;119:1911-1922.

1024  PART II / Section 11  •  Neurologic Disorders 55. Zifko U, Remtulla H, Power K, et al. Transcortical and cervical magnetic stimulation with recording of the diaphragm. Muscle Nerve 1996;19:614-620. 56. Ono SF, Kanda F, Takahashi K, et al. Neuronal loss in the medullary reticular formation in myotonic dystrophy: a clinicopathological study. Neurology 1996;46:A171. 57. Ono S, Kurisaki H, Sakuma A, et al. Myotonic dystrophy with alveolar hypoventilation and hypersomnia: a clinicopathological study. J Neurol Sci 1995;128:225-231. 58. Riley DJ, Santiago RV, Daniele RP, et al. Blunted respiratory drive in congenital myopathy. Am J Med 1977;63:459-466. 59. Maayan C, Springer C, Armen Y, et al. Nemaline myopathy as a cause of sleep hypoventilation. Pediatrics 1986;77:390-395. 60. Wilson DO, Sanders MH, Dauber JH. Abnormal ventilatory chemosensitivity and congenital myopathy. Arch Intern Med 1987; 147:1773-1777. 61. Carroll JE, Zwillich C, Weil JV, et al. Depressed ventilatory response in oculocraniosomatic neuromuscular disease. Neurology 1976;26:140-146. 62. Weng TR, Schultz GE, Chang HC, et al. Pulmonary function and ventilatory response to chemical stimuli in familial myopathy. Chest 1985;88:488-495. 63. Kotagal S, Archer CR, Walsh JK, et al. Hypersomnia, bithalamic lesions, and altered sleep architecture in Kearns-Sayre syndrome. Neurology 1985;35:574-577. 64. Bellamy D, Newsom-Davis JM, Mickey BP, et al. A case of primary alveolar hypoventilation associated with mild proximal myopathy. Am Rev Respir Dis 1975;112:867-873. 65. Martin RJ, Sufit RI, Ringel SP, et al. Respiratory improvement by muscle training in adult-onset acid maltase deficiency. Muscle Nerve 1983;6:201-203. 66. Margolis ML, Howlett P, Goldberg R, et al. Obstructive sleep apnea syndrome in acid maltase deficiency. Chest 1994;105: 947-949. 67. Kryger MH, Steljes DG, Yee WC, et al. Central sleep apnea in congenital muscular dystrophy. J Neurol Neurosurg Psychiatry 1991;54:710-712. 68. Striano S, Meo R, Bilo L, et al. Sleep apnea syndrome in Thomsen’s disease: a case report. Electroencephalogr Clin Neurophysiol 1983;56:323-325. 69. Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to Duchenne muscular dystrophy and spinal muscular atrophy. Pediatr Pulmonol 2000;29:141-150. 70. American Thoracic Society/European Respiratory Society. ATS/ ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518-624. 71. Phillips MF, Smith PE, Carroll N, et al. Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy. Am J Respir Crit Care Med 1999;160:198-202. 72. Suresh S, Wales P, Dakin C, et al. Sleep-related breathing disorder in Duchenne muscular dystrophy: disease spectrum in the paediatric population. J Paediatr Child Health 2005;41: 500-503. 73. Mellies U, Ragette R, Schwake C, et al. Sleep-disordered breathing and respiratory failure in acid maltase deficiency. Neurology 2001;57:1290-1295. 74. Guilleminault C, Stoohs RA, Querra-Salva MA. Sleep related obstructive and nonobstructive apneas in neurologic disorders. Neurology 1992;42:S53-S60. 75. Marca GD, Frusciante R, Vollono C, et al. Sleep quality in facioscapulohumereral muscular dystrophy. J Neurol Sci 2007; 263:49-53. 76. Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology 2003;61:1652-1661. 77. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000;161:166-170. 78. Ragette R, Mellies U, Schwake C, et al. Patterns and predictors of sleep disordered breathing in primary myopathies. Thorax 2002;57:724-728. 79. Mellies U, Ragette R, Schwake C, et al. Daytime predictors of sleep disordered breathing in children and adolescents with neuromuscular disorders. Neuromuscul Disord 2003;13:123-128. 80. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002;19:1194-1201.

81. MacDonald JR, Hill JD, Tarnopolsky MA. Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy. Neurology 2002;59:1876-1880. 82. Damian MS, Gerlach A, Schmidt F, et al. Modafinil for excessive daytime sleepiness in myotonic dystrophy. Neurology 2001;56: 794-796. 83. Talbot K, Stradling J, Crosby J, et al. Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord 2003;13:357-364. 84. Carter GT, Weiss MD, Lou JS, et al. Modafinil in amyotrophic lateral sclerosis: an open label pilot study. Am J Hosp Palliat Med 2005;22:55-59. 85. Adler CH, Caviness JN, Hentz JG, et al. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 2003;18:287-293. 86. Nieves AV, Lang AE. Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil. Clin Neuropharmacol 2002;25:111-114. 87. Happe S, Pirker W, Sauter C, et al. Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol 2001;248:632-634. 88. Hogl B, Saletu M, Brandauer E, et al. Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, cross-over, placebo-controlled polygraphic trial. Sleep 2002;25:905-909. 89. Zifko UA, Rupp M, Schwarz S, et al. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002;249:983-987. 90. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-183. 91. Feldman NT, Schwartz JRL, Harsh J. Effect of Provigil (modafinil) on the quality of life and mood of patients who previously received unsatisfactory treatment with dextroamphetamine, methylphenidate, or pemoline for excessive daytime sleepiness associated with narcolepsy [abstract]. Sleep 2000;23(Suppl. 2):A307. 92. Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005;64:1139-1143. 93. Carrieri PB, de Leva MF, Carrieri M, et al. Modafinil improves primary nocturnal enuresis in multiple sclerosis. Eur J Neurol 2007;14:e1. 94. Smith PE, Edwards RH, Calverley PM. Oxygen treatment of sleep hypoxemia in Duchenne muscular dystrophy. Thorax 1989;44: 997-1001. 95. Smith PE, Edwards RH, Calverley PM. Protriptyline treatment of sleep hypoxemia in Duchenne muscular dystrophy. Thorax 1989;44:1002-1005. 96. Simons AK, Parker RA, Branthwaite MA. Effects of protriptyline on sleep related disturbance of breathing in restrictive chest wall disease. Thorax 1986;41:586-590. 97. Olsen LG, Hensley MJ, Saunders NA, et al. Sleep breathing and lung disease. In: Saunders NA, Sullivan CE, editors. Sleep and breathing. New York: Marcel Dekker; 1984. p. 517-558. 98. Cao M, Guilleminault C. Pediatric sleep disorders: how can sleep medicine make a difference. Sleep Med Rev 2009;13(2):107-110. 99. Alves R, Resende M, Skomro R, et al. Sleep and neuromuscular disorders in children. Sleep Med Rev 2009;13(2):133-148. 100. Pinto AC, Avangelista T, Carvalho M, et al. Respiratory assistance with a non-invasive ventilator (BiPAP) in MND/ALS patients: survival rates in a controlled trial. J Neurol Sci 1995;129(Suppl.): 19-26. 101. Bourke SC, Tomlinson M, Williams TL, et al. Effects of noninvasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5:140-147. 102. Abboussouan LS, Khan SU, Meeker DP, et al. Effect of noninvasive positive-pressure ventilation on survival in amyotrophic lateral sclerosis. Ann Intern Med 1997;127:450-453. 103. Kleopa KA, Sherman M, Neal B, et al. BiPAP improves survival and rate of pulmonary function decline in patients with ALS. J Neurol Sci 1999;164:82-88. 104. Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest 2002;121:459-464.

105. Gonzalez C, Ferris G, Diaz J, et al. Kyphoscoliotic ventilatory insufficiency: effects of long-term intermittent positive-pressure ventilation. Chest 2003;124:857-862. 106. Farrero E, Prats E, Povedano M, et al. Survival in amyotrophic lateral sclerosis with home mechanical ventilation: the impact of systematic respiratory assessment and bulbar involvement. Chest 2005;127:2132-2138. 107. Young HK, Lowe A, Fitzgerald DA, et al. Outcome of noninvasive ventilation in children with neuromuscular disease. Neurology 2007;68:198-201. 108. Bach JR. A comparison of long-term ventilatory support alternatives from the perspective of the patient and care giver. Chest 1993;104:1702-1706. 109. Bach JR, Intintola P, Alba AS, et al. The ventilator-assisted individual: cost analysis of institutionalization vs rehabilitation and in-home management. Chest 1992;101:26-30. 110. Kerby GR, Mayer LS, Pingleton SK. Nocturnal positive pressure ventilation via nasal mask. Am Rev Respir Dis 1987;135:738-740. 111. Segall D. Noninvasive nasal mask-assisted ventilation in respiratory failure of Duchenne muscular dystrophy. Chest 1988;93:1298-1300. 112. Ellis ER, Grunstein RR, Chan S, et al. Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 1988;94:811-815. 113. Rodenstein DO, Stanescu DC, Delguste P, et al. Adaptation to intermittent positive pressure ventilation applied through the nose during day and night. Eur Respir J 1989;2:473-478. 114. Bach JR, Alba AS, Shin D. Management alternatives for post-polio respiratory insufficiency: assisted ventilation by nasal or oral-nasal interface. Am J Phys Med Rehabil 1989;68:264-271. 115. Heckmatt JZ, Loh L, Dubowitz V. Night-time nasal ventilation in neuromuscular disease. Lancet 1990;335:579-581.

CHAPTER 89  •  Sleep and Neuromuscular Diseases  1025 116. Barbe F, Quera-Salva MA, de Lattre J, et al. Long-term effects of nasal intermittent positive pressure ventilation on pulmonary function and sleep architecture in patients with neuromuscular diseases. Chest 1996;110:1179-1183. 117. Bonekat HW. Noninvasive ventilation in neuromuscular disease. Crit Care Clin 1998;14:775-797. 118. Laub M, Midgren B. Survival of patients on home mechanical ventilation: a nationwide prospective study. Respir Med 2007;101: 1074-1078. 119. Fanfulla F, Delmastro M, Berardinelli A, et al. Effects of different ventilator settings on sleep and inspiratory effort in patients with neuromuscular disease. Am J Respir Crit Care Med 2005;172: 619-624. 120. Ambrogio C, Lowman X, Kuo M, et al. Sleep and non-invasive ventilation in patients with chronic respiratory insufficiency. Intensive Care Med 2008;35:306-313. 121. Storre JH, Seuthe B, Fiechter R, et al. Average volume-assured pressure support in obesity hypoventilation: a randomized crossover trial. Chest 2006;130(3):815-821. 122. Shneerson JM, Simonds AK. Noninvasive ventilation for chest wall and neuromuscular disorders. Eur Respir J 2002;20:480-487. 123. Goldberg A (conference facilitator). Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation: a consensus conference report. Chest 1999;116:521-534. 124. Simonds AK. Recent advances in respiratory care for neuromuscular disorders. Chest 2006;130:1879-1886. 125. Arens R, Muzumdar H. Sleep, sleep disordered breathing, and nocturnal hypoventilation in children with neuromuscular diseases. Paediatr Respir Rev 2010;11:24-30.

Restless Legs Syndrome and Periodic Limb Movements during Sleep

Jacques Montplaisir, Richard P. Allen, Arthur Walters, Luigi Ferini-Strambi Abstract The restless legs syndrome (RLS) is a neurologic condition characterized by an urge to move, usually associated with paresthesia, that occurs or worsens at rest and is relieved by activity. One of the central characteristics of RLS is the worsening of symptoms in the evening and during the night. Several studies have shown that the severity of leg discomfort follow a circadian rhythm, with the maximum occurring after midnight. The symptoms of RLS have a major impact on nocturnal sleep and daytime functioning. A majority of patients report difficulty falling asleep or waking up shortly after sleep onset with unpleasant leg sensations. They also often experience excessive daytime fatigue and somnolence, probably as a consequence of disrupted nocturnal sleep. Although RLS is usually thought to be a condition of adulthood, it is often reported in children, in whom it could be misdiagnosed as growing pains or attention-deficit/hyperactivity disorder. RLS

DESCRIPTION AND EPIDEMIOLOGY Sensory and Motor Manifestations The restless legs syndrome (RLS) has been described for centuries but only in 1945 was it singled out as a distinct clinical entity and named by the Swedish neurologist Carl Ekbom.1 Patients with RLS report an urge to move associated with dysesthesia when they are at rest.2 Patients use different terms to describe the dysesthesia. Some only say that the sensations are uncomfortable and unpleasant, and others use specific terms such as creepy-crawly, jittery, internal itch, or shocklike feelings; up to 50% of RLS patients describe their sensations as painful. Some people, however, describe only an urge to move, and they are unaware of a sensory component. Symptoms are usually felt over large areas of the thighs or calves (or both) and are usually experienced as coming from deep within the legs rather than as superficial. Although it is called restless legs syndrome, the disorder can also involve the arms and other body parts. Michaud and colleagues3 showed that almost 50% of RLS patients have symptoms in the arms. Symptoms in the legs usually precede involvement of the arms by several years. Arm paresthesias have been associated with a higher severity of the disorder. The involvement of the arms without any involvement in the legs rarely occurs. The second clinical characteristic of RLS is that the urge to move or the unpleasant leg sensation begins or worsens during periods of rest or inactivity such as lying down or sitting (Videos 90-1 to 90-3).2 Typically, patients describe exacerbation of symptoms in situations such as watching television, driving or flying long distances, or attending meetings. Symptoms also worsen in association with a decrease in central nervous system (CNS) activity that leads to a decrease in alertness. 1026

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90

has been related to several other medical conditions, especially uremia, anemia, and neuropathies. Several epidemiologic studies have shown that the prevalence of RLS symptoms in the white population is probably around 10% and that approximately 3% can be considered RLS sufferers with moderate to severe symptoms associated with significant impact on daytime functioning. There is substantial evidence for a genetic contribution to RLS. There are major controversies regarding the localization of the neural substrate involved in the pathophysiology of RLS. There is increasing evidence for the presence of brain iron deficiency in patients with RLS. As far as treatment is concerned, four categories of medication are commonly prescribed to treat RLS: dopaminergic agents, opioids, anticonvulsants, and benzodiazepines. Because they are more effective and produce fewer adverse effects, dopaminergic agonists are now considered the firstline treatment.

The urge to move and the unpleasant leg sensations are relieved by activity.2 Patients use different motor strategies to relieve the discomfort. When symptoms occur, they move their legs vigorously, flexing, stretching, or crossing them one over the other. In severe cases, they might walk around for hours in the evening or during the night to relieve the discomfort. The relief is generally described as beginning immediately or soon after the activity begins and this relief usually persists as long as the activity continues. In a majority of patients the relief is complete but patients with severe RLS report that movements do not completely suppress the sensations. When the RLS is so severe that relief with movement does not occur, patients recall that earlier in the course of their disease they were able to obtain relief with movements. In severe cases, symptoms can recur rapidly after the cessation of walking or activity, whereas patients with less-severe symptoms can remain symptom-free for 30 to 60 minutes. One of the central characteristics of RLS is the worsening of symptoms in the evening or during the night.2 Several factors can contribute to the worsening of RLS symptoms at that time. One factor is the increase of sleepiness in the evening compared to the daytime. Another contributing factor is the decrease of motor activity in the evening compared to the daytime.3 A third factor could be that the worsening of symptoms is the manifestation of an intrinsic circadian rhythm in RLS symptoms. Three studies used modified constant routine protocols to investigate the circadian pattern in the occurrence of RLS symptoms.4-6 These studies showed that the severity of leg discomfort followed a circadian rhythm, with a maximum occurring after midnight. The circadian rhythm of RLS symptoms was significantly correlated with that of subjective vigilance, core body temperature, and salivary melatonin secretion. Among these variables, the changes in melatonin



CHAPTER 90  •  Restless Legs Syndrome and Periodic Limb Movements during Sleep  1027

secretion were the only ones that preceded the increase in sensory or motor symptoms of RLS and might therefore have a causal relationship with the expression of RLS symptoms.

starts during pregnancy it eventually becomes persistent later in life. Positive family history is common in women who develop RLS during pregnancy, which suggests that pregnancy facilitates the expression of RLS rather than causes it.

Nocturnal Sleep and Daytime Vigilance A majority of RLS patients complain of poor sleep. In a study of 133 patients, a large majority of RLS patients (84.7%) often experienced difficulty falling asleep at night because of RLS, and 86% reported that symptoms woke them up frequently during the night.7 Ninety-four percent reported at least one of these two manifestations. Sleep laboratory investigations showed that as a group, RLS patients have severe nocturnal sleep disruption compared to normal controls, including longer sleep latency, reduced sleep efficiency, and total sleep time. A great majority of patients with RLS also experience stereotyped repetitive movements once asleep, a condition known as periodic limb movements during sleep (PLMS). Some patients (46.2% of men and 22.2% of women) also report excessive daytime fatigue or somnolence,7 probably as a consequence of disrupted nocturnal sleep. On the other hand, it is surprising to find a large number of patients who do not experience fatigue and are fully alert during the day in spite of severe and chronic sleep deprivation. One study has suggested that RLS patients have an increased level of hypocretin in the CNS, which would counteract the effects of poor sleep and sleep deprivation.8

Epidemiology Lavigne and Montplaisir14 reported, in a population-based survey of 2019 Canadians, that 15% of subjects reported delayed sleep onset with “restlessness in legs” and 10% reported “unpleasant leg sensations” on awakening from sleep. The percentages were substantially greater for the Francophone than the Anglophone Canadians, suggesting a genetic effect. More recently, several large epidemiologic surveys estimated that the true prevalence of RLS is approximately 5% to 10%, making it the most common movement disorder and among the most common sleeprelated disorders.15 RLS increases in prevalence with age. Most studies also showed9,16 notable gender differences, the prevalence for women being approximately twice that for men. An RLS screening questionnaire was completed by 23,052 patients from the United States, France, Germany, Spain and the United Kingdom,17 and 2223 (9.6%) reported weekly RLS symptoms. An RLS sufferer subgroup (3.4%) likely requiring treatment was defined as subjects reporting symptoms that occurred at least twice weekly and that had appreciable negative impact on their quality of life.

Burden of the Illness The effect of RLS on quality of life depends on its severity. One population-based study showed that for subjects with moderate to severe RLS, the SF-36 dimensions of vitality, role physical, pain, physical functioning, and general health were markedly reduced compared to population norms. Also reduced but to a smaller degree were the remaining dimensions of social functioning, role emotional, and mental health.9 The moderate to severe RLS symptoms are associated with disruption in quality of life that is at least as great as the disruption caused by other chronic medical conditions such as diabetes mellitus, depression, osteoarthritis, or hypertension.9 RLS patients also show disruption of cognitive function involving mostly prefrontal cognitive tasks that are known to be sensitive to sleep loss.10

DIAGNOSIS Clinical Diagnosis The diagnosis of RLS is based on the clinical evaluation of the patient. In 1995, a consensus emerged from a large international RLS study group (IRLSSG) about the four essential criteria for the diagnosis of RLS. These criteria were revised at a National Institutes of Health RLS workshop. The final formulation of the new RLS diagnostic criteria is published in Sleep Medicine.2 These criteria are listed in Box 90-1. In addition to these essential criteria, there are supportive clinical features that are not essential but can help resolve diagnostic uncertainty. The features include a positive family history of RLS and a positive therapeutic response to dopaminergic medications.

Clinical Course RLS is thought to be a condition of middle-aged persons, but there is increasing evidence that RLS might start at an earlier age. Familial cases of RLS have an earlier age of onset, typically before the age of 30 years.11,12 Earlyonset RLS was also associated with increased severity of RLS.13 The intensity of sensory and motor symptoms varies greatly from one case to another; it also fluctuates throughout a patient’s lifetime. Sudden remissions, lasting for months or even years, are as difficult to explain as are relapses, which appear without any apparent reason. In severe cases, symptoms are present every night, and in most patients, symptom severity increases with advancing age. In women, RLS often appears for the first time during pregnancy.13 In some cases, RLS is present only during pregnancy, but in some cases where RLS originally

Sleep Laboratory Diagnosis Originally called “nocturnal myoclonus,” periodic limb movements (PLMs) are best described as rhythmic extensions of the big toe and dorsiflexions of the ankle, with occasional flexions of the knee and hip. Methods for recording and scoring PLMS were summarized by Coleman18 and recently revised by a joint task force of the World Association of Sleep Medicine and the International RLS Study Group (IRLSSG).19 According to standard criteria, PLMs are scored only if they are part of a series of four or more consecutive movements lasting 0.5 to 10 seconds with an intermovement interval of 5 to 90 seconds and amplitude greater than 8  mV above the baseline electromyograph (EMG) signal. A PLMS index (number of PLMs per hour of sleep) greater than 5 for the entire night of sleep was considered pathologic18 and can

1028  PART II / Section 11  •  Neurologic Disorders Box 90-1  Diagnostic Criteria Established by the International Restless Legs Syndrome Study Group Essential Features • An urge to move the legs, usually accompanied by or caused by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without the uncomfortable sensation, and sometimes the arms or other body parts are involved in addition to the legs. • The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting. • The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. • The urge to move or unpleasant sensations are worse in evening or night than during the day, or they only occur in the evening or night. When symptoms are very severe, the worsening at night might not be noticeable but must have been previously present. Nonessential but Common Features • Family history: The prevalence of RLS among firstdegree relatives of people with RLS is three to five times greater than in people without RLS. • Response to dopaminergic therapy • Periodic leg movements during sleep (PLMS) or during wakefulness (PLMW). • Natural clinical course: may begin at any age, but most severely affected patients are middle-aged or older. The course is usually progressive, but a static course or remission can occur. • Sleep disturbance • Medical evaluation and physical examination: No abnormalities in the primary form, but in the secondary form, signs of a peripheral neuropathy or radiculopathy may be present. Iron status should be evaluated because decreased iron stores are a significant potential risk factor that can be treated. RLS, restless legs syndrome.

still be used for younger persons, but an index greater than 15 is now often used as a cutoff for older subjects. The number of PLMs varies from night to night, especially in persons with less-severe sleep complaints. PLMs cluster into episodes, each of which lasts several minutes or even hours. In general, these episodes are more numerous in the first half of the night, but they can also recur throughout the entire sleep period. Diagnostic polysomnography always includes central electroencephalography (EEG), electrooculography (EOG), submental EMG, and bilateral EMG of the anterior tibialis muscles. The electrographic picture of a single movement can vary from one sustained contraction to a polyclonic burst with a frequency of approximately 5 Hz. In RLS patients, approximately one third of all PLMS are associated with EEG signs of arousal.20 Movements can be seen on video (Videos 90-4 to 90-10). Regardless of the presence of EEG arousals, almost every PLM is associated with a tachycardia (decreased of R-R intervals for 5 to 10 beats) followed by a bradycardia.20

In addition, continuous monitoring of systolic and diastolic blood pressure reveals significant increases in association with PLMS (on average, 22 mm Hg and 11 mm Hg) (Fig. 90-1).21 These changes were greater in older patients and when PLMs were associated with microarousals. Because RLS patients can have several hundred PLMs every night, PLMS-related blood pressure fluctuations could contribute to the increased risk of cardiovascular diseases in RLS, as reported in two large epidemiologic studies, the Wisconsin Sleep Cohort22 and the Sleep Heart Health Study.23 PLMs were first polygraphically documented in RLS.24 However, PLMs also occur in a wide range of sleep disorders, including narcolepsy, REM sleep behavior disorder, obstructive sleep apnea syndrome (OSAS), insomnia, and hypersomnia. PLMs were also reported in subjects without any sleep complaint, and although they are rare in young persons, they are relatively common in the elderly.25 PLMS in patients who complain of primary sleep-onset or sleep-maintenance insomnia or of primary hypersomnia are called periodic limb movement disorder (PLMD). The basic assumption is that PLMs are responsible for nonrestorative sleep and daytime somnolence reported by these patients. Although some studies have suggested that PLMs may be associated with sleep–wake complaints, most authors have concluded that PLMs have little impact on nocturnal sleep or daytime vigilance.26-29 The same conclusion arises when one considers not only PLMs alone but also PLMs associated with arousals. Although there are major controversies with regard to the functional significance of PLMs, their quantification is a commonly used sleep laboratory diagnostic procedure for RLS. In a recent study of 100 RLS patients and 50 normal controls,30 84% of patients showed a PLMS index greater than 5 and 70% showed an index greater than 10 compared to 36% and 18%, respectively, for the controls. Suggested Immobilization Test A test called the suggested immobilization test (SIT) was designed to quantify both sensory and motor manifestations of RLS in wakefulness.30 During the test, patients remain in bed, reclined at 45-degree angle with their legs outstretched and eyes open. They are instructed to avoid moving voluntarily for the entire duration of the test, which is designed to last an hour and takes place in the evening before bedtime at night (Video 90-12). Surface EMGs from the right and left anterior tibialis are used to quantify leg movements. In addition, every 5 minutes during the test, the patient has to estimate the level of leg discomfort on a scale of 100. Twelve values are obtained (every 5 min for 60 min). The mean leg discomfort score (MDS) represents the average value of these 12 measures. An MDS of 11 has been found to discriminate RLS patients from controls with a sensitivity of 82% and a specificity of 84%. The SIT-PLM index was found less sensitive than the MDS and showed test-to-test variability when the SIT was repeated.31 Severity Assessments The IRLSSG has developed a 10-point scale to measure RLS severity (Box 90-2). This scale has been validated32 by comparing it with independent clinician ratings in a large



CHAPTER 90  •  Restless Legs Syndrome and Periodic Limb Movements during Sleep  1029

EEG

ECG

LAT

RAT

BP

Figure 90-1  Polysomnogram of a patient with restless legs syndrome and periodic limb movements in sleep. The figure shows the periodicity of leg movements and reveals significant increases in blood pressure associated with every periodic limb movement. BP, blood pressure; ECG, electrocardiogram; EEG, left central electroencephalogram; LAT, left anterior tibialis electromyogram; RAT, right anterior tibialis electromyogram.

multicenter study. This scale is now largely used in clinical trials to assess the outcome of pharmacologic treatments. Other clinical scales have been used such as the Johns Hopkins RLS Severity scale, which focuses on the usual time at which the symptoms start to occur. It is assumed that the time of onset of symptoms indicates the length of time in a day for which the patient is likely to have RLS symptoms.15 This scale was found to correlate with both PLMS and sleep efficiency. PLMS and PLMW have also been shown to be correlated with subjective RLS severity.15

RESTLESS LEGS SYNDROME IN CHILDHOOD Diagnostic Criteria Although RLS and PLMS are generally thought to be conditions of adulthood, they have been reported in children (Video 90-11).33-35 Special criteria for the diagnosis of RLS were established for children at a National Institutes of Health consensus conference on RLS.2 For a diagnosis of definite RLS, children must meet all four of the diagnostic criteria established for adults and either the child must be able to describe the leg discomfort in his or her own words, or the child must have two of the three following features: sleep disturbance for age, a PLMS index greater than 5/hour of sleep, or a biological parent or sibling with definite RLS. As in adults with RLS, children with RLS respond to dopaminergic therapy, but controlled studies are lacking.35 Prevalence In one of the early studies of the prevalence of RLS in childhood, consistent leg restlessness was found in 6.1% of 1353 children aged 11 to 13 years over a 3-year period.36 Retrospective studies of RLS symptoms in two separate

series of adults found that 12% to 20% recalled symptom onset before the age of 10 years and 38.3% to 45% before the age of 20 years.7,37 In the vast majority of childhood cases, symptoms are mild and medical attention is not usually sought. A recent large epidemiological study of 10,523 families in the United States. and Great Britain (the Peds REST study) found 1.9% of 8- to 11-year-olds and 2% of 12- to 17-year-olds met criteria for RLS. Moderately or severely distressing RLS symptoms occurred at least twice per week in 0.5% and 1% of these age groups, respectively.38 A close connection was found between growing pains and RLS. The prevalence of children who had growing pains of any frequency was 80.6% in RLS subjects versus 63.2% in non-RLS subjects in the Peds REST study (P < .001).38 Relationship to Attention-Deficit/ Hyperactivity Disorder Much recent literature has focused upon the possible relationship among RLS, PLMS, and ADHD. A large metaanalysis of several studies has confirmed the intimate relationship between PLMS and ADHD.39 In two different series, 26% to 64% of children with ADHD had a PLMS index greater than 5 per hour of sleep.40,41 In these series, children with both ADHD and a PLMS index greater than 5 per hour of sleep had increased incidence of both personal and family history of RLS.40,41 Not only do children with ADHD have more PLMS and RLS,42 but children with PLMS have more ADHD. Approximately 44% of children with PLMS have been found to have symptoms of ADHD.43 These data suggest a possible genetic link between RLS or PLMS and ADHD. A link between ADHD and RLS or PLMS is further suggested by data implying that dopaminergic agents improve not only the RLS or PLMS symptoms but also the ADHD symptoms in children with both RLS and

1030  PART II / Section 11  •  Neurologic Disorders Box 90-2  International Restless Legs Syndrome Study Group Rating Scale 1. Overall, how would you rate the RLS discomfort in your legs or arms? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 2. Overall, how would you rate the need to move around because of your RLS symptoms? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 3. Overall, how much relief of your RLS arm or leg discomfort do you get from moving around? No relief, 4; Slight relief, 3; Moderate relief, 2; Complete or almost complete relief, 1; No RLS symptoms, 0 4. Overall, how severe is your sleep disturbance from your RLS symptoms? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 5. How severe is your tiredness or sleepiness from your RLS symptoms Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 6. Overall, how severe is your RLS as a whole? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 7. How often do you get RLS symptoms? Very often, 4; Often, 3; Sometimes, 2; Occasionally, 1; Never, 0 8. When you have RLS symptoms, how severe are they on an average day? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 9. Overall, how severe is the impact of your RLS symptoms on your ability to carry out your daily affairs, for example carrying out a satisfactory family, home, social, school or work life? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 10.  How severe is your mood disturbance from your RLS symptoms—for example angry, depressed, sad, anxious or irritable? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 In the full version of the scale, each of the choices for question 7 has an operational definition.

PLMS.44 ADHD itself has now been independently linked to iron deficiency because patients with ADHD have statistically significantly lower serum ferritin levels than controls.45 ADHD is also responsive to iron therapy.46 These data further tighten the link between RLS and ADHD.

SECONDARY RESTLESS LEGS SYNDROME RLS and PLMS have been related to several other medical conditions but in only a few cases was the association with RLS well documented. Uremia RLS is often associated with uremia, and 15% to 40% of patients under hemodialysis do actually complain of RLS symptoms. Several factors can predispose uremic patients

to develop RLS, including anemia and peripheral neuropathy. The presence of RLS relates to increased mortality rate in patients with end-stage renal disease.47 Symptoms of RLS were found to resolve after successful kidney transplantation.48 Neuropathies There is some evidence suggesting an association between RLS and peripheral neuropathy, but the extent of this association remains a controversial issue. In 1996, Ondo and Jankovic49 performed EMG and nerve conduction velocities in 41 RLS patients, 15 of which were abnormal. Of the 15 neuropathic RLS patients, only seven showed clinical signs of neuropathy. One argument in favor of a causal relationship is the lower prevalence of family history of RLS among those with neuropathic RLS compared to nonneuropathic RLS. Another study,50 in which a thorough neurologic examination was performed, found polyneuropathy in 8 out of 22 (36%) RLS patients. The neuropathic patients in this study had an older age of onset and reported sensory symptoms usually involving pain. In a third study, axonal atrophy was found by sural nerve biopsy performed in eight RLS patients.51 All these studies suggest that in a significant number of RLS patients, neuropathy may be involved. On the other hand, RLS was found in only 5.2% of 144 patients with a clinical diagnosis of polyneuropathy,52 a prevalence not higher than the prevalence found in the general population. Anemia RLS has been reported in association with iron deficiency anemia and folic acid deficiency anemia. Iron status has been extensively studied and evidence has been found that iron deficiency in the CNS may be involved in primary RLS, even in patients without anemia. Others RLS is common in Crohn’s disease and celiac disease.52a,52b RLS was found in 31% of 135 consecutive patients with fibromyalgia53 and in 30% of 70 patients with rheumatoid arthritis.54 RLS has also been reported anecdotally in association with a wide variety of other medical conditions including diabetes, hypothyroidism and hyperthyroidism, chronic lung disease, leukemia, Isaac’s syndrome, stiff-man syndrome, Huntington’s chorea, and amyotrophic lateral sclerosis. Considering the high prevalence of RLS and PLMS in the general population, these associations found in a limited number of patients should be interpreted with caution. Several substances or medications can induce or worsen RLS or PLMS. These include tricyclic or other antidepressants, lithium carbonate, dopamine D2 receptorblocking agents, such as classic neuroleptics, and centrally active antihistamines and alcohol.

MEDICAL INVESTIGATION RLS and PLMS should be differentiated from other state-dependent sensorimotor disorders, such as positional discomfort, hypnic myoclonus, painful legs and moving toes syndrome, nocturnal leg cramps, neurolepticinduced akathisia, and vascular or neurogenic intermittent



CHAPTER 90  •  Restless Legs Syndrome and Periodic Limb Movements during Sleep  1031

claudication. Whenever the diagnosis is doubtful, a PSG recording should be performed. Two consecutive nights of PSG are recommended. Because the PLMS index shows night-to-night variability, caution should be taken in drawing conclusions from single-night studies. Because a significant number of RLS patients have peripheral neuropathy,49,50 a careful clinical examination of sensory and motor functions should be performed. EMG and nerveconduction studies should be done if the examination suggests a peripheral neuropathy or radiculopathy. Given the aforementioned associations between anemia or iron deficiency, iron status should be studied in every patient. Iron deficiency cannot be determined by history and can occur with normal hemoglobin. Because iron deficiency is usually treatable and because when present it exacerbates or even causes RLS, standard serum tests for ferritin, total iron-binding capacity, and percent saturation should be considered essential to the medical evaluation of RLS. When these levels are abnormal, further medical evaluation is recommended to determine any possible cause, usually involving blood loss. For example, RLS was found much more commonly in blood donors than in the general population, especially for women donors55 and repeat blood donors.56,56a The diet can also be accountable and should be inquired about. In a study on strict vegetarians and vegans, 40% of women younger than 50 years were found to be iron deficient.57

ETIOLOGY AND PHYSIOPATHOLOGY Genetics There is substantial evidence for a genetic contribution to RLS. Familial aggregation has been well documented with more than 50% of idiopathic cases reporting a positive family history of RLS.1,2,7,11,37,57a In most pedigrees, it segregates in an autosomal dominant fashion, with a high penetrance rate (90% to 100%).11 Seven loci for RLS on chromosomes 12q, 14q, 9p, 2q, 20p, 19p, and 16p (RLS1-RLS7) have been mapped in RLS families (for review, see references 58 and 59) supporting the view that RLS is a genetically heterogeneous complex trait. Genetic heterogeneity was somewhat predictable given the high prevalence of the disease and the reported variability in clinical presentation. Association studies have also looked at candidate genes for RLS. Genes related to dopaminergic transmission (D1 to D5 receptors, tyrosine hydroxylase, dopamine-b-hydroxylase) were first investigated, but no association was found.60 However, there was some evidence for a genetic association between the high-activity allele of monoamine oxidase A and a greater risk of being affected with RLS in women.61 A genome-wide association study of RLS identified common variants in three genomic regions: MEIS1, BTBD9, and MAP2K5 on chromosomes 2p, 6p, and 15q, respectively. Each genetic variant was associated with more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk.62 MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. A genome-wide significant association with a common variant in an intron of BTBD9 on chromosome

6p was found independently in the Icelandic population.63 An association between this variant and PLMS without RLS (and the absence of such an association for RLS without PLMS) suggests that it is a genetic determinant of PLMS. These authors found an inverse correlation of the variant with iron stores, which is consistent with the suspected involvement of iron depletion in RLS and PLMS. Neural Substrates There are major controversies with regard to the localization of the neural structures involved in the physiopathology of RLS. There is some evidence of a peripheral origin of RLS. Nerve-conduction abnormalities and small neuropathy were found in a subset of RLS patients, but these abnormal findings were noted in a small subset of patients with secondary RLS, more often in sporadic RLS than in familial RLS and more often in late-onset rather than early-onset RLS. There is most likely a major contribution of the spinal cord to RLS. PLM during sleep and wakefulness were also found in several persons with a spinal cord lesion and even in cases of complete spinal cord transection.64,65 A facilitation of the late component of the flexion reflex indicating a hyperexcitability of motor neurons was found in this condition.66 The late components shared several features with PLMS. This spinal cord generator may be facilitated by the suppression or the decrease of supraspinal inhibitory inputs. On the other hand, an additional long latency component of the blink reflex has been reported in some patients with PLMS.67 This symptom, although not found in every patient, could indicate that PLMS is operative at the pontine level or more rostrally. A study using magnetic resonance imaging (MRI) found no anatomic lesion in patients with RLS.68 However, functional MRI showed that leg-related sensory complaints in RLS were associated with thalamic and cerebellar activation, and periodic leg movements in wakefulness were more closely associated with pontine and red nucleus activation. In neither case was any cortical activation found. The study of 18 patients by transcranial magnetic stimulation also supports a subcortical origin of RLS.69 Neurotransmitter Dysfunctions The therapeutic effects of l-dopa and dopamine agonists on RLS and PLMS support the hypothesis that central dopamine may be involved in the pathophysiology of these conditions. Dopamine antagonists generally make RLS symptoms worse, and in one study they precipitated an increase in PLMW in all but one of the patients evaluated.70 Brain-imaging studies have been inconsistent. Two positron emission tomography (PET) studies with adequate sample sizes showed different results: small but significant decreased striatal binding for raclopride71 and small but statistically significant increased striatal binding for raclopride.72 No differences were found between daytime and nighttime binding, suggesting that variations in D2-receptor availability do not account for the pronounced diurnal nature of the RLS symptoms. Two of three single-photon emission computed tomography (SPECT) studies comparing patients with RLS with age-matched control

1032  PART II / Section 11  •  Neurologic Disorders

subjects failed to find a significant difference,73,74 whereas one study (the only one performed in early evening) reported less binding to D2 receptors for the patients with RLS.75 These studies also looked at binding for the dopamine transporter and failed to find any significant difference between patients with RLS and control subjects. In contrast, two 6-[18F] fluoro-l-dopa PET studies reported small decreases in binding for patients with RLS.71,76 There have been two cerebrospinal fluid (CSF) studies on series of patients with RLS compared with control subjects; both failed to find any significant difference for either homovanillic acid or biopterin that was unrelated to age.77,78 A more-recent report, however, notes that in two different studies with CSF obtained at different times of the day (10 pm and 10 am), there were significant increases in 3-ortho-methyldopa that in one of the samples correlated with increased CSF homovanillic acid.79 This suggests a possible increase in dopaminergic activity. Overall, aside from the remarkable pharmacologic response to dopaminergic medications and the one CSF finding regarding 3-ortho-methyldopa increases, there is scant consistent evidence supporting any significant dopaminergic abnormality in RLS. The positive pharmacologic response to opioid treatment in RLS and the reversal of that treatment with the opiate receptor blocker naloxone has also been used as an argument in favor of the hypothesis of an endogenous opiate system dysfunction in RLS and PLMS.80 However, pharmacologic data suggest that the effect of l-dopa is not secondary to the action of dopamine on the opioid system, but rather the reverse. An opiate receptor PET scan study showed no difference in postsynaptic opiate receptor binding between RLS patients and controls, but there was an inverse correlation between the degree of opiate receptor binding and the severity of RLS.81 A preliminary autopsy study showed decreased levels of the endogenous opioids beta endorphin and met-enkephalin in RLS patients compared to controls.82 Hypocretin (orexin) has been reported to be increased in the CSF of early-onset RLS patients.83 Hypocretin arousal is largely mediated by histamine, and it was found that RLS symptoms can be severely exacerbated by antihistamines,84 suggesting a histaminergic abnormality that might be related to increased hypocretin. Iron Ekbom was among the first to note that RLS commonly occurs with iron-deficiency anemia.85 In addition to irondeficiency anemia, end-stage renal disease, pregnancy, low-density lipoprotein apheresis, and gastric surgery have been clearly established as causes of secondary RLS. All of these conditions involve iron deficiency. Treatment of iron-deficiency anemia can completely resolve all RLS symptoms for some patients.86-88 One study showed no significant differences in serum ferritin or iron, but the CSF ferritin was reduced and transferrin was increased, consistent with a CNS iron deficiency occurring despite apparently normal peripheral iron status.89 MRI and ultrasound studies of regional brain iron content have consistently shown reduced brain iron, particularly in the substantia nigra for subjects with RLS

compared with age-matched control subjects.90-92 Autopsy analyses of substantia nigra tissue from patients with RLS compared with age-matched control subjects have revealed a complex pattern of iron-related abnormalities.93 These data suggest that RLS involves an iron deficiency in the substantia nigra that may be associated with an abnormality in the regulation of the transferrin receptor. These findings, combined with the success of intravenous iron treatments, support the putative concept that a brain iron deficiency causes RLS in many patients. Of interest is the role of iron in dopaminergic transmission in the CNS. Iron deficiency is associated with increased extracellular dopamine, decreased dopamine transporter, and decreased D2 and D1 receptors in the striatum of rats. Thus abnormalities in iron metabolism or environmental factors producing brain iron deficiency may be a primary cause of RLS symptoms or they may be factors contributing to the development of RLS.

TREATMENT Nonpharmacologic It is important to inform patients to maintain good sleep hygiene to prevent the development of psychophysiologic insomnia, which is frequently encountered in RLS. Patients should also refrain from drinking alcohol in the evening because it aggravates symptoms in most patients. Some patients report that they alter their sleep patterns to accommodate their RLS.94 Pharmacologic Four categories of medications are commonly prescribed to treat RLS: dopaminergic agents, opioids, anticonvulsants, and benzodiazepines. Dopaminergic Medications L EVODOPA Several open-label and placebo-controlled studies documented the short-term efficacy and long-term benefit of levodopa, given with a dopa-decarboxylase inhibitor, either benserazide or carbidopa, in idiopathic RLS and RLS associated with uremia. Several adverse effects were reported in patients treated with levodopa, including nausea, vomiting, tachycardia, orthostatic hypotension, hallucinations, insomnia, daytime fatigue, and daytime sleepiness. Two adverse effects were more specifically studied in RLS patients treated with levodopa: morning rebound and RLS augmentation. Morning rebound is characterized by the presence of RLS symptoms occurring de novo as a consequence of evening or nighttime treatment. Augmentation95 is characterized by an earlier onset of symptoms by at least 4 hours or by an earlier onset between 2 and 4 hours plus at least one of the following compared to symptom status before treatment: shorter latency to symptoms when at rest, extension of symptoms to other body parts, greater intensity of symptoms, and shorter duration of relief from treatment. One group96 found augmentation in 29 of 36 (81%) patients treated with levodopa. Increased severity of RLS and higher dosage of levodopa were associated with higher risk of developing augmentation. Another recent study97 showed augmentation in 36 of 60 (60%)



CHAPTER 90  •  Restless Legs Syndrome and Periodic Limb Movements during Sleep  1033

patients treated for 6 months with levodopa (median daily dose of 300 mg; range, 50 to 500 mg). Mild augmentation may be treated by earlier administration of the drug, but in severe cases the medication should be discontinued. D OPAMINE A GONISTS Because they are more effective and produce fewer adverse effects (especially augmentation), dopamine agonists are now considered the first-line treatment for RLS. Several agonists have been studied in RLS. Pergolide, a D2 receptor agonist, was found effective in short-term and longterm follow-up studies.98,99 In 28 patients treated for 416 days with pergolide, persistent efficacy was noted in 79% of patients, but adverse effects were noted in 71%, including augmentation in 27% of patients.99 Cabergoline, a long-acting D2 receptor agonist, was also used successfully to treat RLS.100 Like pergolide, cabergoline is an ergolinederivative drug; agonists of this class are associated with common adverse effects, especially nausea and orthostatic hypotension. Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment with ergolinic dopamine agonists. Some authors have shown that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets.101 Two non–ergoline-derivative agonists, pramipexole and ropinirole, were extensively studied for the treatment of RLS. Pramipexole, a full agonist with high affinity for the D3-receptor subtype, was found very effective in treating RLS and in suppressing PLMS in two double-blind, placebo-controlled studies.102,103 Several long-term follow-up studies of patients treated with pramipexole have shown sustained efficacy of pramipexole in more than 80% of patients.104-106 Augmentation was found in up to 32% of patients on long-term treatment with pramipexole.105 Ropinirole, a dopaminergic agonist with a pharmacologic profile similar to that of pramipexole, was also found effective to treat RLS in placebo-controlled studies.107,108 A long-term open-label study showed that ropinirole maintained the therapeutic efficacy in 82% of RLS patients.109 Like pramipexole, ropinirole is well tolerated and rarely requires the adjunctive use of domperidone. In RLS patients, sleepiness might be seen during treatment with dopamine agonists, but it is much less problematic than in Parkinson’s disease, and no cases of sudden onset of sleep have been reported.110 An exploratory survey study revealed that a small percentage of RLS patients treated with dopaminergic medications noted increased urges and time spent gambling and increased sexual desire,111 a side-effect of dopaminergic medications previously reported in Parkinson’s disease. A new dopamine agonist, rotigotine, has been studied in RLS.112 Transdermal 24-hour delivery of low-dose rotigotine may be used to relieve the nighttime and daytime symptoms of RLS. Skin reactions, mostly mild or moderate, are seen at the application site of the patch in about one third of patients. Opioids The therapeutic effects of opioids have been noted by Ekbom1 and were confirmed in several open-label and controlled clinical trials.94,113-115 A persistent effect of opioids was found in a long-term follow-up studies.114,115

Opioids are often prescribed for severe cases, especially in patients unresponsive to other treatments. Opioids are also very useful during withdrawal from dopaminergic agents in patients who have developed severe augmentation. Although there is little evidence of tolerance or addiction to opioids in the RLS literature, the data are sparse, and therefore prescription of opioids should be restricted to patients without a previous history of substance abuse. Opioids should also be used cautiously in patients who snore and are at risk for having sleep apnea syndrome. Anticonvulsants Studies of anticonvulsants have focused on gabapentin. Several open-label trials and one placebo-controlled study116 showed subjective improvements with gabapentin at doses of 300 to 2400 mg a day. Gabapentin is considered more potent and produces fewer adverse effects than dopaminergic agonists, except for mild daytime somnolence. In mild cases or in patients who have developed adverse effects with dopaminergic medications, gabapentin is a valuable alternative. Because gabapentin is a common treatment for peripheral neuropathy and pain, it has been also recommended for the treatment of neuropathic RLS and in general for patients who use pain as a descriptor for their leg sensations. Benzodiazepines Several studies showed that benzodiazepines, including clonazepam, nitrazepam, lorazepam, and temazepam improve the quality of sleep and reduce PLMS or PLMS associated with arousals in patients with RLS and in patients with both insomnia and PLMS. However, the therapeutic effects of benzodiazepines on subjective ratings of RLS symptoms were either modest or not significant. Therefore benzodiazepines are mostly used to improve sleep continuity in patients with RLS. Because dopaminergic agents often have a stimulating effect and worsen insomnia, benzodiazepines are often used as an adjunctive treatment. Other Treatments When the patient’s ferritin level is less than 45 to 50 µg/L, then oral iron treatment is indicated usually as supplemental treatment. Oral iron treatment can be ferrous sulfate 325 mg, or its equivalent, with vitamin C 100 to 200 mg taken twice a day, preferably on an empty stomach, depending on how well the iron is tolerated. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose (1000  mg/day) failed to demonstrate significant improvement in RLS reported in prior open-label studies with intravenous iron dextran.117 However, the dextran maintains high peripheral iron availability much longer than does the sucrose. Optimal parental iron therapy is unclear.56a,118,119 Clinical Management In summary, dopamine agonists are now considered the treatment of choice for RLS. Because of their side-effect profile, nonergoline derivatives—pramipexole and ropinirole—are preferred. One advantage of pramipexole is its longer duration of action. In several patients, RLS occurs sporadically, with spontaneous remission lasting weeks or even months. Therefore, the physician should use

1034  PART II / Section 11  •  Neurologic Disorders Table 90-1  Management of Restless Legs Syndrome AGENT AND DOSAGE

SIDE EFFECTS

COUNTERMEASURES

Nausea and orthostatic hypotension

Slowly increase dosage or use domperidone if available (10-30 mg)

Insomnia

Use a small dose of benzodiazepines in association with DA agonists

Daytime fatigue and somnolence

Reduce dosage or discontinue DA agonists and use levodopa (if severe and persistent)

Step 1: Dopamine Agonists Pramipexole, 0.125-1.0 mg* Ropinirole, 0.5-4.0 mg*

Compulsive or impulsive behavior

Decreased dose or discontinue DA agonists

Tolerance

Drug holiday for 2 wk, then return to lower dosage

Augmentation

Use small extra dose during daytime or discontinue DA agonists (if severe and persistent)

Same as for DA agonists

See countermeasures for DA agonists

Morning rebound or augmentation of RLS in early evening

Use small extra dose of levodopa during daytime or reduce dosage or combine levodopa with DA agonists or benzodiazepines or discontinue levodopa (if severe and persistent)

Step 2: Dopamine Precursors Levodopa/benserazide or levodopa/carbidopa (regular or slow release), 100/25 or 200/50 mg

Step 3: Benzodiazepines Clonazepam, 0.5-2.0 mg* Temazepam, 15-30 mg* Nitrazepam, 5-10 mg*

Daytime somnolence

Reduce dosage

Tolerance

Drug holiday for 2 wk then return to lower dosage

Constipation

Symptomatic treatment

Dependency

Drug holiday or withdrawal

Daytime fatigue and somnolence

Reduce dosage

Step 4: Opiates Oxycodone, 5 mg† Propoxyphene, 200 mg* Codeine, 15-60 mg* STEP 5: Antiepileptic drugs Gabapentin, 100-400 mg

*One hour before onset of symptoms in the evening or at bedtime if symptoms are not present in the evening † At bedtime and repeated once during the night. DA, dopamine; RLS, restless legs syndrome.

pharmacologic treatments on an irregular basis or consider a drug holiday when appropriate. Continuous pharmacologic treatment should be considered if patients complain of RLS occurring at least three nights per week. All medications treat RLS symptoms and do not influence the course of the illness. Therefore, the clinician should carefully assess the therapeutic benefit versus the severity of adverse effects. A therapeutic flowchart appears in Table 90-1. Each drug is presented with its commonly used therapeutic dosage, its most common side effects, and the appropriate countermeasures to adopt. Higher doses may be administered in severe cases, but when a higher dosage is required, the clinician should carefully assess for the presence of augmentation. If augmentation develops, a different medication should be used. If augmentation occurs with levodopa, patients should be treated with dopaminergic agonists. If it occurs in the course of treatment with agonists, opioids are generally the best alternative treatment. Because of its particular 24-hour transdermal delivery, rotigotine may also be considered in patients who develop augmentation.

❖  Clinical Pearl The clinician should keep in mind that RLS is a common and underdiagnosed condition with a strong genetic component. RLS is showing a good therapeutic response to dopaminergic agonists.

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110. Stiasny K, Möller JC, Oertel WH. Safety of pramipexole in patients with restless legs syndrome. Neurology 2000;55(10): 1589-1590. 111. Driver-Dunckley ED, Noble BN, Hentz JG, et al. Gambling and increased sexual desire with dopaminergic medications in restless lets syndrome. Clin Neuropharmacol 2007;30(5):249-255. 112. Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate to severe restless legs syndrome: a randomized, double-blind, placebo-controlled study. Lancet Neurol 2008;7:595-604. 113. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized doubleblind trial of oxycodone versus placebo. Sleep 1993;16:327-332. 114. Walters AS, Winkelmann J, Trenkwalder C, et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Dis 2001;6:1105-1109. 115. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord 2005;20:345-348. 116. Garcia-Barreguero D, Larrosa de la Liave Y, Verger K, et al. Treatment of restless legs syndrome with gabapentin. Neurology 2002;59:1573-1579. 117. Earley CJ, Horská A, Mohamed MA, et al. A randomized, doubleblind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 2009;10(2):206-211. 118. Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, doubleblind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:1445-1452. 119. Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010;11(5):494-496.

Alzheimer’s Disease and Other Dementias

Dominique Petit, Jacques Montplaisir, and Bradley F. Boeve Abstract Sleep anomalies are found in a variety of conditions causing dementia. Specific features of the sleep and electroencephalographic impairments vary in some respects, but a common pattern emerges. Sleep is usually more fragmented, both from more awakenings and from a longer duration of time awake; slow-wave sleep is decreased; spindles and K-complexes are less well formed or less numerous, so sleep stages are more difficult to distinguish; and rapid eye movement (REM) sleep may be reduced. Quantitative analyses show a slowing of the electroencephalogram (EEG) during wakefulness and, in

ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive decline in memory and other cognitive domains. It is considered the primary cause of irreversible dementia in old age. Diagnostic criteria, first established by the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer’s Disease and Related Disorders Association Work Group, were revised1 in light of the discovery of new markers, brain imaging findings, and cerebrospinal fluid analyses of amyloid B and tau proteins. Accumulation of abnormal tau proteins brings dysfunction and neuronal death. Highly affected structures include: entorhinal cortex, hippocampus, amygdala, nucleus basalis of Meynert, suprachiasmatic nucleus (SCN), intralaminar nuclei of the thalamus, locus coeruleus, raphe nuclei, central autonomic regulators, and the cortex (sparing the primary cortical areas for a long time). Pathologically, findings include neurofibrillary tangles, neuritic plaques, and neuronal loss. Sleep Problems The prevalence of sleep disturbance in AD has been estimated to be around 25% in mild to moderate cases and around 50% in moderate to severe cases. These sleep problems can take many forms: napping excessively during the daytime and having difficulty falling asleep at night, frequent nocturnal awakenings, and waking up to start the day too early. These sleep problems are of consequence because daytime sleepiness, for instance, was found to be associated with greater functional impairments in AD independently of level of cognitive impairment.2 Perhaps the most noticeable sleep problem of patients with AD is the sundowning phenomenon, a delirium-like state characterized by nocturnal agitation or wandering. This phenomenon can be explained, at least in part, by an alteration in the biological clock: the SCN of the hypothalamus. The secretion rhythm of many hormones is affected in the elderly but it is even more apparent in AD patients.3 In addition, there is an earlier timing of the biological clock as evidenced by two common markers, core body temperature and plasma melatonin.3 1038

Chapter

91

Alzheimer’s disease, during REM sleep. These impairments typically worsen with the progression of the disease. Demented patients are also more likely to present with periodic limb movements in sleep and respiratory disturbances. This chapter gives an overview of sleep disturbances, characteristics of sleep architecture and microstructure, and quantitative analyses of wakefulness and sleep EEG in a variety of conditions associated with dementia: Alzheimer’s disease, progressive supranuclear palsy, Parkinson’s disease, dementia with Lewy bodies, vascular dementia, Huntington’s disease, CreutzfeldtJakob disease, and frontotemporal dementia.

Since the turn of the century, a series of pathophysiology findings has shed some light on the circadian rhythm disorder of AD patients. A disrupted melatonin production and rhythm was found,4 even in the early preclinical stages of AD.5 This might be caused by a dysfunction in the sympathetic regulation by the SCN of the pineal melatonin synthesis.4 The SCN itself would be under the modulatory influence of the nucleus basalis of Meynert, which degenerates early in AD. It was proposed that sundowning would be the result of the neocortex being slowly turned off to sleep (due to the defective nucleus basalis) when an arousal signal is still being processed.6 Circadian rhythm disturbances are known to be associated with a variety of medical conditions: cardiovascular problems, the metabolic syndrome, physical disabilities, respiratory symptoms, decreased immune system functioning, and mood and cognitive impairment. Obstructive sleep apnea syndrome (OSAS) has been reported to occur with a greater prevalence in AD patients than in the general population.7 A relationship between AD and apolipoprotein ε (APOE), a lipoprotein made in the liver and brain and involved in cholesterol transport and deposition, were first noted in the early 1990s.8 It was shown that the risk of developing AD was associated with the APOE4 allele. An association has been found between the APOE4 allele and OSAS.9 Finally, the presence of rapid eye movement (REM) sleep behavior disorder (RBD) has been shown in one case of AD with mixed Alzheimer’s and Lewy body dementia (DLB) pathology confirmed on autopsy10 and in one out of 15 consecutive patients with AD.11 The latter study also showed that three more patients with AD presented with REM sleep without atonia. Polysomnography Findings In addition to the presence of sleep problems, sleep architecture is modified in patients with AD. Certain sleep changes seem to be an exaggeration of changes that normally appear with aging. Specifically, patients with AD show an increased number and duration of awakenings and, as a result, an increased percentage of stage 1 sleep. Compared to elderly controls, they also show a reduced



percentage of slow-wave sleep (SWS).12 This is the most consistently reported change in patients with mild to moderate AD. All the prior sleep disturbances worsen with increasing severity of AD.12 Another change in sleep architecture that suggests accelerated aging in AD is a loss of the specific electroencephalographic (EEG) features of stage 2 sleep. Sleep spindles and K-complexes become poorly formed, of lower amplitude, of different frequency, of shorter duration, and much less numerous.13,14 With advancing severity of the disease, due to the absence of these characteristic EEG features, it becomes progressively more difficult to separate stage 2 from stage 1 sleep. The proportion of indeterminate non-REM (NREM) sleep increases even further with the disappearance of the true delta waves of SWS. Conversely, other sleep changes observed in AD do not suggest accelerated aging. Of particular interest is the percentage of REM sleep that remains stable in normal aging but that was reduced in AD patients compared to controls, and this as a result of a decrease in mean REM sleep episode duration.13 Other REM sleep variables, such as REM density, number of REM sleep episodes, and REM sleep latency, are usually unchanged,13,15 as are muscle atonia and phasic electromyographic activity in REM sleep.13 In other words, variables pertaining to the initiation of REM sleep and to its characteristic features were unaffected in mild AD. This is probably because these variables are under the control of the mesopontine cholinergic populations, structures that are relatively spared in mild AD. The lower REM sleep percentage, however, could be due to degeneration of the cholinergic nucleus basalis of Meynert. This nucleus normally exerts an inhibitory influence on the nucleus reticularis of the thalamus,16 the rhythm generator responsible for NREM sleep. Quantitative Electroencephalography in Alzheimer’s Disease Wakefulness Electroencephalogram In AD, waking EEG activity is characterized by more slowing of the dominant occipital rhythm than is found in nondemented old people. There is also an increase in theta and delta activity compared to age-matched controls. Several studies attempted to correlate quantitative waking EEG with clinical severity of AD with variable results. Some demonstrated that relative theta power separated all 4 stages of dementia: none, mild, moderate, and severe dementia. Some reported that decreases of relative power in alpha and beta bands and increases of power in the delta band were correlated with severity of AD. REM Sleep Electroencephalogram EEG slowing was found to be more marked during REM sleep than during wakefulness in AD patients.17,18 Moreover, there was a distinctive topographical pattern of REM sleep EEG slowing in AD patients that parallels findings from neuroradiologic19 and neuropathologic20 studies—a pattern not observed for the waking EEG.21 Indeed, REM sleep EEG slowing was greater in the temporoparietal and frontal regions.18 The quantitative EEG derived from REM sleep (but not from wakefulness) was also correlated with a screening assessment of cognitive functioning in AD (the Mini-Mental State Examination)22 and with a measure

CHAPTER 91  •  Alzheimer’s Disease and Other Dementias  1039

of interhemispheric asymmetry of regional cerebral blood flow.23 REM sleep EEG is superior to wakefulness EEG probably because the cholinergic basal forebrain, which degenerates early in AD, is likely more crucial for EEG activation during REM sleep than during wakefulness. EEG activation during wakefulness is the result of many convergent neuronal and neurotransmitter systems, many of which are not active during REM sleep. The importance of the cholinergic system to cortical activation in REM sleep may also be due to an enhanced activity in the cholinergic system during that state.24 NREM Sleep Electroencephalogram The presence of increased EEG delta activity over the entire sleep–wake spectrum makes it difficult to distinguish, especially in NREM sleep, the pathologic from the normal physiologic delta waves. Despite the increases observed in delta activity, patients with AD had elicited K-complexes less often in response to auditory stimulation than age-matched controls and produced K-complexes of lower amplitude.25 Therefore, patients with AD have an impaired ability to generate normal physiologic delta activity during NREM sleep. In these patients, the probability of eliciting a K-complex was also correlated negatively with dementia.25

PROGRESSIVE SUPRANUCLEAR PALSY Progressive supranuclear palsy (PSP), also called SteeleRichardson-Olszewski syndrome, is characterized by progressive axial rigidity, postural instability, and supranuclear gaze palsy. The dementia that often evolves in PSP primarily reflects dysfunction in the frontosubcortical neural networks.26 Because the sleep characteristics of PSP are discussed in Chapter 87, only the aspects related to the dementia are reviewed here. Excessive daytime somnolence is a common occurrence in PSP. Hypocretin 1 (orexin A) levels were found to be low in PSP, and these levels were inversely correlated with the duration of PSP morbidity.27 Perhaps even more striking is the absence or drastic reduction in REM sleep in PSP patients, especially with the progression of the disease.28,29 A reduction in REM sleep has been generally correlated with a decline in cognitive functioning. Despite this reduction in REM sleep, studies have reported some cases of RBD and REM sleep without atonia in patients with PSP.30,31 RBD is, however, much more prevalent (78%) in a Guadeloupean form of PSP probably due to ingestion of sour sop, a tropical fruit containing mitochondrial poisons.32 Cognitive decline is, in turn, reflected by a slowing of the EEG. One study has quantitatively assessed the EEG from both REM sleep and wakefulness in patients with PSP.28 For the REM sleep EEG, there were no significant between-group differences for any of the 16 regions studied. During wakefulness, a slowing of the EEG was found mainly for the frontal regions, compared to control subjects. The frontal EEG slowing during wakefulness is consistent with the results of numerous neuropsychological studies that show deficits to be related to frontal lobe

1040  PART II / Section 11  •  Neurologic Disorders

functions. The fact that no EEG slowing was found in REM sleep suggests that the slowing observed for wakefulness was not likely due to a cholinergic deficit. This is consistent with findings that normal neocortical and hippocampal choline acetyltransferase activity was found in some patients with PSP.33 Dopamine levels are, however, severely reduced in the caudate, putamen, and substantia nigra in PSP patients.33 A frontal deafferentation from the striatopallidal complex is thought to be responsible for the impairment because there are extensive fiber connections between these nuclei and the prefrontal region. Indeed, the positive correlations between degree of impairment on frontal tasks and EEG slowing observed in our PSP patients suggest that both impairments could be at least partially the result of a dopaminergic deficiency.28

PARKINSON’S DISEASE PD is a progressive neurologic disorder characterized by rigidity, resting tremor, bradykinesia, and an impairment of postural reflexes and gait and caused in part by the degeneration of the dopaminergic cells in the substantia nigra. The sleep modifications experienced by patients with PD are discussed in Chapter 87; therefore, only information relevant to dementia associated with PD is reviewed here. The incidence of overt dementia in PD is relatively high; in a population-based study of dementia in Parkinson’s disease, approximately 80% of nondemented PD patients developed dementia within 8 years.34 Risk factors include advanced age at onset of symptoms, severe motor symptoms (particularly bradykinesia), levodopa-related confusion or hallucinations, presence of speech and axial involvement, presence of depression, and atypical neurologic features, such as modest response to dopaminergic agents or early autonomic dysfunction.35 Demented patients with PD often experience hallucinations. One study found that patients with REM sleep anomalies have more hallucinations than patients without such anomalies.36 It was proposed that sleep reduction, particularly REM sleep reduction, would trigger hallucinations by enabling the emergence of REM sleep during wakefulness. Hallucinations have been significantly correlated with the presence of RBD independently of age, gender, disease duration, or Unified Parkinson’s Disease Rating Scale score but related to the amount of dopaminergic medication.37 There is growing evidence that RBD is an early manifestation of a neurodegenerative disorder, particularly one of the synucleinopathies (e.g., DLB, PD, and multiple system atrophy).38,39 The occurrence of RBD in PD was estimated at 15% with a structured questionnaire40 but at 33% using polysomnographic recordings41; only half of these had been detected at the clinical interview. The phenomenon of REM sleep without atonia would explain the reduction in REM sleep reported in patients with PD when the sleep staging has been performed according to the standard criteria.42 Previous studies had shown that approximately a third of patients with PD presented with EEG slowing regardless of the presence of dementia.37 Even when only nondemented patients with PD were studied, a slowing of the EEG in the temporo-occipital and the frontal regions has been found in some patients.43 It was demonstrated that

only patients with PD who also had RBD had a slowing of the EEG and of the dominant occipital frequency.44 A higher theta power was found during wakefulness in frontal, temporal, parietal, and occipital regions in patients with PD and RBD compared with patients who had PD without RBD and control subjects. The EEG slowing found only in patients with PD and RBD might not be related to an evolutional stage of PD but rather to the presence of RBD itself. In support of this hypothesis, a higher theta power in the frontal, temporal, and occipital region during wakefulness has also been observed in patients who have idiopathic RBD without PD.45 Similarly, patients with PD and concomitant RBD showed a significantly poorer performance on standardized tests measuring episodic verbal memory, executive functions, and visuospatial and visuoperceptual processing compared to both patients with PD without RBD and control subjects.46 Interestingly, patients with idiopathic RBD had a lower performance (compared to control subjects) on the same neuropsychological tests (executive functions and verbal memory)47 than did the patients with PD and RBD. The association of RBD with dementia in PD was more directly demonstrated by one study.48 Of the 65 patients with PD who completed the study, 24 met the clinical diagnosis of RBD. The incidence of RBD was significantly higher in the demented PD group compared to the nondemented PD group (77% versus 27%). Patients who had PD but not RBD had a lower incidence of dementia (7.3%) compared to patients with PD and RBD (42%). The topography of EEG slowing observed in PD with RBD is similar to that of the hypoperfusion and hypometabolism seen in DLB,49,50 the profile of cognitive impairments noted in PD with RBD resembles that of DLB,51 and many RBD patients later develop DLB.52,53 Thus there is reason to believe that the presence of RBD in patients with PD may be an early sign of an evolution toward dementia. Some evidence suggests that cortical Lewy body–type degeneration is the main source of dementia in PD. One study reported diffuse cortical Lewy bodies only in demented patients with PD, whereas nondemented patients had only brainstem Lewy bodies.54 Two other studies have suggested that α-synuclein–positive cortical (especially frontal) Lewy bodies were associated with cognitive impairment, independent of or more specifically than an AD-type pathologic process.55,56 More studies are necessary to determine the pathologic and neurochemical underpinnings of dementia in PD.

DEMENTIA WITH LEWY BODIES Dementia with Lewy bodies represents the second most common neurodegenerative cause of dementia in old age. Until recently, it was a much underdiagnosed form of dementia. The core clinical features of DLB are progressive cognitive decline, spontaneous parkinsonism, recurrent visual hallucinations, and fluctuating cognition and vigilance.57 Autonomic dysfunction is often present.57 It is pathologically characterized by the presence of Lewy bodies in limbic or neocortical structures, or both. Three subtypes of DLB have been put forward: a brainstem subtype, a limbic subtype, and a diffuse neortical subtype.57



A questionnaire study showed that patients with DLB had more overall sleep disturbances, more movement disorders while asleep, and more daytime sleepiness than patients with AD.58 Based on results from the Epworth Sleepiness Scale, 50% of patients with DLB experience excessive daytime sleepiness.59 However, normal hypocretin-1 levels were found in the cerebrospinal fluid of patients with DLB and daytime sleepiness, suggesting that sleepiness in DLB is not related primarily to a dysfunction of hypocretin neurotransmission.27,60 A polysomnographic study61 found that 73% of patients with DLB had a sleep efficiency less than 80%. High proportions of these patients also had pathologic indexes of respiratory disturbances (88%) or periodic leg movements during sleep (PLMS) with arousal (74%).61 A number of studies or review papers have reported that RBD is a common finding in patients with DLB.52,53 Twelve of 15 patients with RBD and a neurodegenerative disease had limbic or neocortical Lewy body disease at autopsy (the other three had multiple system atrophy), which indicates a synucleinopathy.62 It had even been suggested that the inclusion of RBD in the list of core criteria for DLB would improve the sensitivity and specificity of the diagnosis.51,53,62 RBD now figures as a suggestive feature for the diagnosis of DLB in the third report of the DLB consortium57; these criteria have just been validated.63 As in PD, restless legs syndrome (RLS) and PLMS are also common in DLB and can play a part in sleep-onset insomnia and nocturnal arousals or awakenings, respectively.64 A few quantitative EEG studies have reported a slowing of the awake EEG in DLB, expressed as a loss of the alpha rhythm during wakefulness combined with a slowing of both dominant and nondominant rhythms,65 or expressed as an increase in theta activity,66,67 which correlates with the degree of dementia.66 Frontal intermittent rhythmic delta activity has also been reported.67 Fluctuating cognition, one of the core features of DLB, was shown to be reflected in cortical activation by the variability of the mean EEG power in DLB patients compared to both AD patients and elderly control subjects.68

VASCULAR DEMENTIA The term vascular dementia covers a range of problems of various etiologies and includes the entities known as multiinfarct dementia (MID) and Binswanger’s disease. The most studied form of vascular dementia in sleep medicine is probably MID. An actigraphy study found that patients with MID had a significantly greater disruption of sleep– wake cycles associated with poor sleep quality than AD patients.69 There was no correlation, however, between the degree of sleep disruption and the severity of intellectual deterioration. It was reported that sleep apnea syndrome was more strongly associated with MID than with AD.70 Spectral analysis of the waking EEG of patients with MID revealed a lower dominant occipital frequency,71,72 a higher theta and slow alpha power, a lower high alpha power, and more numerous delta waves than that in control subjects.71 In addition, in patients with MID, the alpha waves had migrated to more-anterior regions. There was

CHAPTER 91  •  Alzheimer’s Disease and Other Dementias  1041

no gender difference in the quantitative EEG of patients with MID.71,72 Larger EEG source fluctuations were found in vascular dementia compared to AD patients and controls; the authors reported that this might reflect the patients’ decreased vigilance control and therefore account for their increased fluctuations in cognition.73

HUNTINGTON’S DISEASE Huntington’s disease (HD) is an autosomal dominant hereditary condition associated with atrophy of basal ganglia structures, especially the caudate nucleus, and characterized by choreic movements and progressive dementia associated with psychotic features. A CAG trinucleotide repeat in the IT15 gene located on the short arm of chromosome 4 is the cause of this condition.74 Patients with HD have a disrupted night–day activity pattern. Transgenic mice carrying the HD mutation showed a disruption of night–day activity, which worsened as the degeneration progressed but also showed a marked reduction in the expression of mPer2 and disrupted expression of mBmal1 in the SCN, the motor cortex, and the striatum.75 Ubiquitin-proteasome dysfunction has been suggested to be part of the pathogenesis of HD,76 and such inclusions have been also found in the SCN of the transgenic mice.77 Daily treatment with alprazolam in these mice reversed the dysregulated expression of Per2 and also Prok2, an output factor of the SCN that controls behavioral rhythms, and also markedly improved cognitive performance in a visual discrimination task.78 Restoring circadian rhythms might thus slow cognitive decline that is such a devastating feature of HD. A disturbed sleep architecture has also been reported in patients with Huntington’s disease. Specifically, they showed a longer sleep latency, a lower sleep efficiency, frequent nocturnal awakenings, and less SWS than agematched control subjects.79,80 A PSG study on a large number of patients with HD and control subjects replicated most of these findings except for sleep latency, which was unchanged, and REM sleep latency, which was found to be longer instead of shorter.81 REM sleep duration decreased with disease severity, and it was already significantly reduced in presymptomatic carriers of the defective gene. Three out of 25 patients with HD had RBD. Finally, patients with HD did not have more daytime sleepiness but had more PLMS than controls. Contrary to patients with other neurodegenerative diseases, patients with Huntington’s disease showed a higher density of sleep spindles compared to healthy control subjects.80,82 The sleep disturbances (less SWS and more time spent awake) correlated with the degree of atrophy of the caudate nucleus and the severity of clinical symptoms.80 In fact, a study found sleep disturbances only in moderate to severe cases of Huntington’s disease and none in mild cases.79 However, no correlation was found between the length of the CAG repeat and sleep disturbances.81 Finally, no difference was found on sleep respiratory variables between patients with HD and healthy control subjects.81 On visual inspection, the waking EEG exhibits a gradual slowing and a diminution of amplitude as the disease progresses. A quantitative analysis of the waking EEG in

1042  PART II / Section 11  •  Neurologic Disorders

Huntington’s disease revealed increased theta and de­ creased alpha activity in HD compared to controls; patients with HD were similar to patients with AD.83

CREUTZFELDT-JAKOB DISEASE CJD is a prion-related transmissible spongiform encephalopathy causing extensive neuronal degeneration and pathologic changes, especially in the cortex, and resulting in myoclonic jerks, rapidly evolving dementia, and other signs of central nervous system dysfunctions and leading to death. It develops between the 5th and the 7th decades of life. The mean survival duration is 4 to 8 months84 although 5% to 10% of patients have a clinical course that spans 2 years or more. Two large-sample studies85,86 reported that half of the patients were experiencing sleep disturbances, mostly insomnia. In 15% of these patients, sleep disturbances were a prodromal or presenting symptom. Polysomnographic studies of CJD reveal disorganized sleep patterns with sudden jumps from one sleep stage to the next, very few sleep spindles and K-complexes in stage 2 sleep (which is otherwise normal but difficult to distinguish from stage 3), an absence of stage 4, and a lower percentage of REM sleep, with lower REM density.87,88 Episodes of nocturnal oneiric, sometimes aggressive behavior with dream–reality confusion have been reported in some patients.85,87 Sleep apneas, central or obstructive, also seem prevalent in this condition. The hallmark awake EEG observation in patients with CJD is the presence of periodic sharp wave complexes within a background of generalized slow but low-voltage EEG, suggesting diffuse cerebral pathology.84 Periodic sharp-wave complexes are either simple sharp waves (biphasic or triphasic waves) or complexes with mixed spikes or slow waves. Periodic sharp-wave complexes have been added to the diagnostic criteria for probable CJD89 because they are present in about two thirds of patients and show a high specificity (occurring in only 9% of patients with another neurodegenerative disorder).90 Sleep EEG studies also report the presence of periodic sharp wave complexes as early as 1 to 3 months after the onset of symptoms.91,92 Cyclic changes with periodic complex phases alternating with semirhythmic theta-delta activities have been described.91,92 FRONTOTEMPORAL DEMENTIA Frontotemporal dementia (FTD) is a category of disorders that includes Pick’s disease and corticobasal degeneration. It is a progressive, degenerative condition characterized by a loss of executive and language abilities and a number of noncognitive symptoms, such as loss of insight, overactivity, lack of social awareness, disinhibition, and lack of personal hygiene. Approximately 5% to 15% of patients with dementia have a disorder within the FTD spectrum. It is thought to be underdiagnosed because, in part, of its similarities with AD, especially later in the progression of the disease. However, unlike AD, FTD initially manifests with progressive aphasia and personality changes whereas memory remains relatively intact. Structural and functional brain imaging shows atrophy, reduced cerebral

blood flow, or diminished glucose metabolism in frontal and anterior temporal areas. As in AD, FTD is generally accompanied by a disturbance of the activity rhythm and of the sleep–wake rhythm. However, these disturbances manifest differently in the two conditions, supporting the notion that central changes, rather than environmental factors only (such as institutionalization), cause the rhythm disturbances. In FTD, the activity rhythm is highly fragmented and phase-advanced despite a normal core temperature phase.93 Electroencephalographic slowing during wakefulness is observed in patients with FTD. One study94 found an increased theta power, and another95 reported an increase in both delta and theta power more prominently in anterior regions in a majority of patients. However, 31% had normal EEGs and most patients had a preserved dominant occipital frequency.95 It was found that EEG measures of functional connectivity were normal in patients with mild to moderate FTD.96

TREATMENT OF SLEEP DISORDERS IN PATIENTS WITH DEMENTIA One useful approach to address sleep disorders in the demented patient involves considering symptoms within four major categories: insomnia or fragmented sleep, excessive daytime sleepiness, alteration in the sleep–wake circadian rhythm, and excessive motor activity during the night, including RBD, PLMS, and nocturnal agitation or wandering.97 In addition, one should keep in mind that some of these disturbances could be due to RLS, OSAS, malnutrition, infections, medication effects (and often polypharmacy), depression, bladder catheterization, fecal impactions, or disturbing environmental factors. Management requires the identification and treatment of the underlying medical or psychiatric disorder. For each of these four categories of sleep disorders, we review the appropriate pharmacologic and nonpharmacologic treatment strategies. A summary of selected medication with suggested dosage and titration schedule also appears in Table 91-1. Insomnia Insomnia that is comorbid with other sleep disturbances is a common occurrence in patients with dementia (for review, also see reference 98). These patients are often unable to explain why they are not able to sleep through the night, so caregivers and physicians should carefully investigate the possible sources of the insomnia. Evaluating pain, concomitant medical conditions, and medication effects is essential in order to treat the patient successfully. For example, both untreated depression and some antidepressant medications (fluoxetine and bupropion) can lead to insomnia. The cholinesterase inhibitors, which have been shown to improve cognitive and noncognitive symptoms in patients with AD, can also cause insomnia. This problem usually can be avoided if the medication is administered no later than the evening meal, although in some patients the medication must be given no later than lunchtime. Melatonin was not found effective in treating insomnia in patients with AD in a multicenter, placebo-controlled trial.99



CHAPTER 91  •  Alzheimer’s Disease and Other Dementias  1043

Table 91-1  Sleep Disorders and Disturbances in Dementia: Selected Medications with Suggested Dosing Schedules* INITIAL MEDICATION

DOSE

SUGGESTED TITRATING SCHEDULE

TYPICAL THERAPEUTIC RANGE

Insomnia Trazodone

25 mg qhs

Increase in 25-mg increments q 3-5 d

50-200 mg/night

Chloral hydrate

500 mg qhs

Increase in 500-mg increments q5-7d

500-1500 mg/night

Melatonin

3 mg qhs

3-6 mg nightly

3-12 mg/night

Quetiapine

25 mg qhs

Increase in 25-mg increments q3d

25-100 mg night

Zolpidem

5 mg qhs

Increase to 10 mg qhs if necessary

5-10 mg/night

Restless Legs Syndrome, Periodic Limb Movements in Sleep Carbidopa/levodopa

25/100 or1 tab qhs

Increase to 2 tabs 1 week later if necessary

1-2 tabs qhs

Pramipexole

0.125 mg qhs

Increase in 0.125-mg increments q2-3d

0.25-0.75 mg/night

Gabapentin

100 mg qhs

Increase in 100-mg increments q2-3d

300-1800 mg/night

Excessive Daytime Somnolence Methylphenidate

2.5 mg qAM

Increase in 2.5-5 mg increments q3-5d in bid dosing (AM and noon)

5 mg qAM to 30 mg bid

Modafinil

100 mg qAM

Increase in 100-mg increments q5-7d in bid dosing (AM and noon)

100 mg qam to 400 mg/day (400 mg qAM or 200 mg bid)

Amphetamine/ dextroamphetamine

5 mg qAM

Increase in 5-mg increments q7d in qd-bid dosing (AM and noon)

5 mg qAM to 20 mg bid

REM Sleep Behavior Disorder Clonazepam

0.25 mg qhs

Increase in 0.25-mg increments q7d

0.25-0.75 mg/night

Melatonin

3 mg

3-6 mg/night

3-12 mg/night

Psychotic Features, Behavior Dyscontrol, Nocturnal Agitation, Nocturnal Wandering Donepezil

5 mg qAM

Increase to 10 mg qAM 4 wk later

5-10 mg qAM

Rivastigmine†

1.5 mg bid

Increase in 1.5-mg increments q4w in bid dosing (AM and hs)

3-6 mg bid

Galantamine†

4 mg bid

Increase in 4-mg increments q4wk in bid dosing (AM and hs)

4-12 mg bid

Risperidone

0.5 mg qhs

Increase in 0.5-mg increments q7d in bid dosing (AM and hs)

0.5 mg qhs to 1.5 mg bid

Olanzapine

5 mg qhs

Increase in 5-mg increments q7d in bid dosing (AM and hs)

5 mg qhs to 10 mg bid

Clozapine‡

12.5 mg qhs

Increase in 12.5-mg increments q2-3d

12.5-50 mg qhs

Quetiapine

25 mg qhs

Increase in 25-mg increments q3d

25-100 mg qhs

Valproic acid‡

125 mg qhs

Increase in 125mg increments q 3-7d in bid to tid dosing

250 mg qhs to 500 mg tid

Carbamazepine‡

100 mg qhs

Increase in 100-mg increments q3-7d in bid to tid dosing

200 mg qhs to 200 mg tid

*Disclaimer: The choice of which agents to use and which dosing schedules to recommend must be individualized. It is the responsibility of the clinician to consider potential side effects, drug interactions, allergic response, life-threatening reactions (e.g., leukopenia with clozapine), dosing changes due to renal or hepatic dysfunction, etc., before administering any drug to any patient, including those listed above. Drs. Petit, Montplaisir, Boeve, their respective institutions, and Elsevier, will not be held responsible for any adverse reactions of any kind to any patient regarding the content of this information. † If insomnia is problematic, the second dose should be given no later than the evening meal. ‡ Requires periodic laboratory monitoring; refer to the manufacturer’s instructions for laboratory monitoring. Adapted from Boeve B, Silber M, Ferman T. Current management of sleep disturbances in dementia. Curr Neurol Neurosci Rep 2002;2:169-177.

Simple but effective interventions should probably be tried first, such as instituting proper sleep hygiene (e.g., regular schedule, bedtime routine, white noise), limiting caffeine and alcohol intake, and increasing exercise during the day. Before prescribing medication to treat insomnia, the clinician should keep in mind that many such agents

(especially benzodiazepines) can exacerbate cognitive deficits and OSAS and can induce daytime sleepiness. It has been shown that use of sedative-hypnotics (and also antipsychotics) is associated with longer hospital stays in the acute-care setting.100 If no cause is found for the insomnia, trazodone or chloral hydrate may be considered.

1044  PART II / Section 11  •  Neurologic Disorders

Restless Legs Syndrome In some cases, insomnia can result from untreated RLS. The exact prevalence of RLS in dementias is not known, but it is a common condition in patients with AD, PD, DLB, FTD, and vascular dementia. Several medications, especially dopamine agonists, have been proved efficacious and well tolerated in nondemented persons with RLS (for review, see Chapter 90). However, to our knowledge, no study has assessed the efficacy and safety of these agents in demented patients. In some patients, dopaminergic agents can cause insomnia due to their stimulating effects or can trigger or exacerbate psychosis. Excessive Daytime Sleepiness Excessive sleepiness during the day has been reported mainly in PD. Daytime sleepiness would not result from poor sleep or from dopaminergic therapy but would be part of PD itself.101 Personal experience has taught us that somnolence, not resulting from another primary sleep problem, can also affect patients with AD, DLB, and FTD. In such cases, methylphenidate (at a low dose) or modafinil can be effective in improving alertness without producing undesirable effects. Obstructive Sleep Apnea Syndrome Hypersomnolence can also result from OSAS, a condition often associated with degenerative disorders, especially AD. The relationship between sleep apnea syndrome and dementia is complex. On one hand, it is known that sleep apneas, if left untreated for many years, will induce cognitive deficits, some of which are reversible with continuous positive airway pressure (CPAP) therapy. There have been severe cases of patients with OSAS in whom dementia had been diagnosed and whose dementia subsided with CPAP therapy. One study showed that long-term CPAP treatment succeeded in slowing the cognitive deterioration, and improving sleep and mood in patients with AD and OSAS.101a However, our clinical experience indicates that a small percentage of patients with a dementing illness significantly improve functionally and on psychometric testing with CPAP therapy, that a significant proportion of patients tolerate CPAP and use it nightly, and that even spouses enjoy a more consolidated sleep when their bed partners with dementia are on CPAP therapy. Disorder of the Sleep–Wake Circadian Rhythm Several studies have demonstrated a disorder of the sleep– wake rhythm in patients with dementia, especially in AD and FTD. In fact, insomnia and excessive daytime somnolence can be the manifestation of a primary disorder of the circadian rhythm. It has been proposed that degenerative changes in the biological clock, the SCN of the hypothalamus and in the pineal gland, resulting in reduced melatonin production, are responsible for the disorganization and flattening of the circadian rhythms.3,5 Melatonin can be helpful for sleep–wake cycle disturbances in patients with dementia; it improves sleep, reduces sundowning, and slows down the progression of dementia in AD.102,103 Bright-light therapy administered in the evening was also found effective to alleviate sleep-wake cycle disturbances

in patients with dementia and to consolidate their nighttime sleep.104-106 In some patients, regular daylight exposure is also effective for day–night reversal problems. Excessive Motor Activity during the Night REM Sleep Behavior Disorder REM sleep behavior disorder is prevalent in various degenerative conditions, especially in the synucleinopathies compared to AD, FTD, and PSP. There is a high interpatient variability in the severity of RBD, but the symptoms generally tend to decrease with the progression of the degenerative disease. It is important to differentiate RDB from nocturnal wandering by taking a careful history. When diagnosis is uncertain and the potential for injury is present, a polysomnographic and video recording is justified. The first step in the management of RBD is to ensure the safety of the patient, which means removing potentially dangerous objects from the bedroom, perhaps placing a soft mattress on the floor next to the bed, and so forth. Clonazepam, which is the treatment of choice for RBD in nondemented persons, can potentially worsen some aspects of dementia and can aggravate OSAS. Before prescribing this agent, it is essential to ensure that the patient does not experience OSAS or that CPAP therapy is effective in the apneic patient. Clinical experience shows us that clonazepam is well tolerated and produces few or no cognitive side effects in the vast majority of patients with dementia and concomitant RBD. Melatonin has also been shown to be effective in alleviating RBD symptoms.107,108 If depression is also present, treatments other than nefazodone should be considered because this drug increases REM sleep, contrary to most other antidepressants, and can therefore potentiate RBD. Periodic Limb Movements during Sleep The prevalence of PLMS in dementia has not been estimated exactly. However, it is known to be elevated, especially in the synucleinopathies. Without a polysomnographic recording, the severity and clinical significance of PLMS for a given patient are difficult to assess. If they are bothersome to the patient or cause daytime sleepiness as a result of sleep fragmentation, treatment with dopaminergic agonists can be considered. Dopaminergic agents should be used cautiously, if at all, in patients with psychotic features. Nocturnal Agitation and Wandering One of the heavier burdens on families of elderly demented patients and the primary cause of institutionalization is the lack of sleep due to nocturnal agitation or nocturnal wandering. Nocturnal agitation could be the result of discomfort (constipation, full bladder, clothing, heat, cold), pain (pressure sores, infection), or environmental interruptions (staff noise, light); hence, verifying the potential sources of discomfort and pain is crucial. As for insomnia management, eliminating alcohol and restricting caffeine intake to the morning can help in alleviating nocturnal agitation. Also, behavioral techniques should be tried before resorting to medication. However, if necessary, medication is atypical neuroleptics (respiridone, olanzapine, clozapine, quetiapine), antiepileptics (carbamazepine,



CHAPTER 91  •  Alzheimer’s Disease and Other Dementias  1045

valproic acid), benzodiazepines (clonazepam, lorazepam), or trazodone or chloral hydrate can be effective in treating nocturnal agitation (see Table 91-1 for dosages and titration schedules). Cholinesterase inhibitors can significantly ameliorate hallucinations for patients who are frightened or really bothered by them. In these cases, medications with hallucinatory side effects (levodopa, dopamine agonists, anticholinergics, amantadine, selegiline) should be decreased or eliminated.

CONCLUSIONS Sleep and EEG are customarily impaired in diseases associated with dementia. Although a common general pattern of sleep impairment can be observed in dementia, the study of sleep variables and that of the spectral composition of the EEG in different states can provide valuable tools in establishing a diagnosis and in the evaluation of pharmacologic treatment. ❖  Clinical Pearls The clinician should keep in mind that when managing sleep disturbances in patients with dementia, careful assessment of the underlying causes is essential. Nonpharmacologic treatments, along with ensuring that the basic sleep hygiene rules are followed, should be undertaken before considering medication. One should also keep in mind, before prescribing medication to demented patients, that many agents can exacerbate cognitive deficits and OSAS.

Acknowledgments Dr. Montplaisir is supported by grants from the Canadian Institutes of Health Research. Dr. Boeve is supported by the Alzheimer’s Association and by grants AG06786, AG15866, AG16574, and AG17216 from the National Institute on Aging. REFERENCES 1. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734-746. 2. Lee JH, Bliwise DL, Ansari FP, et al. Daytime sleepiness and functional impairment in Alzheimer disease. Am J Geriatr Psychiatry 2007;15:620-626. 3. Ferrari E, Arcaini A, Gornati R, et al. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Exp Gerontol 2000;35:1239-1250. 4. Wu YH, Swaab DF. The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 2005;38:145-152. 5. Wu YH, Fischer DF, Kalsbeek A, et al. Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the “master clock.” FASEB J 2006;20:1874-1876. 6. Klaffke S, Staedt J. Sundowning and circadian rhythm disorders in dementia. Acta Neurol Belg 2006;106:168-175. 7. Bliwise DL. Sleep apnea, APOE4 and Alzheimer’s disease: 20 years and counting? J Psychosom Res 2002;53:539-546. 8. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:1977-1981.

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1046  PART II / Section 11  •  Neurologic Disorders 32. Cochen De Cock VC, Lannuzel A, Verhaeghe S, et al. REM sleep behavior disorder in patients with guadeloupean parkinsonism, a tauopathy. Sleep 2007;30:1026-1032. 33. Kish SJ, Chang LJ, Mirchandani L, et al. Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol 1985;18: 530-536. 34. Aarsland D, Andersen K, Larsen JP, et al. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 2003;60:387-392. 35. Emre M. Dementia associated with Parkinson’s disease. Lancet 2003;2:229-237. 36. Comella CL, Ristanovic R, Goetz CG. Parkinson’s disease patients with and without REM behavior disorder (RBD): a polysomnographic and clinical comparison. Neurology 1993;43(Suppl. 2): A301. 37. Onofrj M, Thomas A, D’Andreamatteo G, et al. Incidence of RBD and hallucination in patients affected by Parkinson’s disease: 8-year follow-up. Neurol Sci 2002;23:S91-S94. 38. Boeve B, Silber M, Ferman T, et al. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16:622-630. 39. Boeve B, Silber M, Ferman T, et al. REM sleep behavior disorder in Parkinson’s disease, dementia with lewy bodies, and multiple system atrophy. In: Bedard M, Agid Y, Chouinard S, et al, editors. Mental and behavioral dysfunction in movement disorders. Totowa, NJ: Humana Press; 2003. p. 383-397. 40. Comella CL, Nardine TM, Diederich NJ, et al. Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology 1998;51:526-529. 41. Gagnon JF, Bédard MA, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 2002;59:585-589. 42. Rechtschaffen A, Kales A, editors. A manual of standardized terminology, techniques, and scoring system for sleep states of human subjects. Washington, DC: US Government Printing Office; 1968. US Public Health Service Publications No. 204. 43. Soikkeli R, Partanen J, Soininen H, et al. Slowing of EEG in Parkinson’s disease. Electroencephalogr Clin Neurophysiol 1991;79: 159-165. 44. Gagnon JF, Fantini ML, Bédard A, et al. Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia. Neurology 2004;62:401-406. 45. Fantini ML, Gagnon J-F, Petit D, et al. Slowing of EEG in idiopathic REM sleep behavior disorder. Ann Neurol 2003;53: 774-780. 46. Vendette M, Gagnon JF, Décary A, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007;69:1843-1849. 47. Massicotte-Marquez J, Décary A, Gagnon JF, et al. Executive dysfunction and memory impairment in idiopathic REM sleep behaviour disorder. Neurology. 2008;70:1250-1257. 48. Marion MH, Qurashi M, Marshall G, Foster O. Is REM sleep Behaviour disorder (RBD) a risk factor of dementia in idiopathic Parkinson’s disease? J Neurol 2008;255:192-196. 49. Lobotesis K, Fenwick JD, Phipps A, et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001;56:643-649. 50. Minoshima S, Foster NL, Sima AA, et al. Alzheimer’s disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann Neurol 2001;50:358-365. 51. Ferman TJ, Boeve BF, Smith GE, et al. Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc 2002;8: 907-914. 52. Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 1998;51:363-370. 53. Turner RS. Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia with Lewy bodies. J Geriatr Psychiatr Neurol 2002;15:195-199. 54. Kosaka K, Tsuchiya K, Yoshimura M. Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 1988;7:299-305. 55. Mattila PM, Rinne JO, Helenius H, et al. Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive

impairment in Parkinson’s disease. Acta Neuropathol 2000; 100:285-290. 56. Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;54:1916-1921. 57. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 2005;65:1863-1872. 58. Grace JB, Walker MP, McKeith IG. A comparison of sleep profiles in patients with dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatr 2000;15:1028-1033. 59. Boddy F, Rowan EN, Lett D, et al. Subjectively reported sleep quality and excessive daytime somnolence in Parkinson’s disease with and without dementia, dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatry 2007;22:529-535. 60. Baumann CR, Dauvilliers Y, Mignot E, Bassetti CL. Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness. Eur Neurol 2004;52:73-76. 61. Boeve BF, Ferman TJ, Silber MH, et al. Sleep disturbances in dementia with Lewy bodies involve more than REM sleep behavior disorder. Neurology 2003;60:A79. 62. Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003;61:40-45. 63. Fujishiro H, Ferman TJ, Boeve BF, et al. Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases. J Neuropathol Exp Neurol 2008;67:649-656. 64. Boeve BF, Silber MH, Ferman TJ. Current management of sleep disturbances in dementia. Curr Neurol Neurosci Rep 2002;2: 169-177. 65. Briel RC, McKeith IG, Barker WA, et al. EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatr 1999;66:401-403. 66. Barber PA, Varma AR, Lloyd JJ, et al. The electroencephalogram in dementia with Lewy bodies. Acta Neurol Scand 2000;101: 53-56. 67. Calzetti S, Bortone E, Negrotti A, et al. Frontal intermittent rhythmic delta activity (FIRDA) in patients with dementia with Lewy bodies: a diagnostic tool? Neurol Sci 2002;23:S65-S66. 68. Walker MP, Ayre GA, Cummings JL, et al. Quantifying fluctuation in dementia with Lewy bodies, Alzheimer’s disease, and vascular dementia. Neurology 2000;54:1616-1624. 69. Aharon-Peretz J, Masiah A, Pillar T, et al. Sleep–wake cycles in multi-infarct dementia and dementia of the Alzheimer type. Neurology 1991;41:1616-1619. 70. Erkinjuntti T, Partinen M, Sulkava R, et al. Sleep apnea in multiinfarct dementia and Alzheimer’s disease. Sleep 1987;10:419-425. 71. Sato K, Kamiya S, Okawa M, et al. On the EEG component waves of multi-infarct dementia seniles. Int J Neurosci 1996;86:95-109. 72. Signorino M, Pucci E, Belardinelli N, et al. EEG spectral analysis in vascular and Alzheimer dementia. Electroencephalogr Clin Neurophysiol 1995;94:313-332. 73. Tsuno N, Shigeta M, Hyoki K, et al. Fluctuations of source locations of EEG activity during transition from alertness to sleep in Alzheimer’s disease and vascular dementia. Neuropsychobiology 2004;50:267-272. 74. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971-983. 75. Morton AJ, Wood NI, Hastings MH, et al. Disintegration of the sleep–wake cycle and circadian timing in Huntington’s disease. J Neurosci 2005;25:157-163. 76. Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000;23:217-247. 77. Obrietan K, Hoyt KR. CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J Neurosci 2004;24: 791-796. 78. Pallier PN, Maywood ES, Zheng Z, et al. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington’s disease. J Neurosci 2007;27:7869-7878. 79. Hansotia P, Wall R, Berendes J. Sleep disturbances and severity of Huntington’s disease. Neurology 1985;35:1672-1674. 80. Wiegand M, Moller AA, Lauer CJ, et al. Nocturnal sleep in Huntington’s disease. J Neurol 1991;238:203-208.



CHAPTER 91  •  Alzheimer’s Disease and Other Dementias  1047 81. Arnulf I, Nielsen J, Lohmann E, et al. Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol 2008;65: 482-488. 82. Emser W, Brenner M, Stober T, et al. Changes in nocturnal sleep in Huntington’s and Parkinson’s disease. J Neurol 1988;235: 177-179. 83. Streletz LJ, Reyes PF, Zalewska M, et al. Computer analysis of EEG activity in dementia of the Alzheimer’s type and Huntington’s disease. Neurobiol Aging 1990;11:15-20. 84. Wieser HG, Schindler K, Zumsteg D. EEG in Creutzfeldt-Jakob disease. Clin Neurophysiol. 2006;117:935-951. 85. Wall CA, Rummans TA, Aksamit AJ, et al. Psychiatric manifestations of Creutzfeldt-Jakob disease: a 25-year analysis. J Neuropsychiatry Clin Neurosci 2005;17:489-495. 86. Meissner B, Körtner K, Bartl M, et al. Sporadic Creutzfeldt-Jakob disease: magnetic resonance imaging and clinical findings. Neurology 2004;63:450-456. 87. Landolt HP, Glatzel M, Blättler T, et al. Sleep–wake disturbances in sporadic Creutzfeldt-Jakob disease. Neurology 2006;66: 1418-1424. 88. Donnet A, Famarier G, Gambarelli D, et al. Sleep electroencephalogram at the early stage of Creutzfeldt-Jakob disease. Clin Electroencephalogr 1992;23:118-125. 89. World Health Organisation. Consensus on criteria for diagnosis of sporadic CJD. Wkly Epidemiol Rec 1998;73:361-365. 90. Steinhoff BJ, Zerr I, Glatting M, et al. Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease. Ann Neurol 2004;56: 702-708. 91. Calleja J, Carpizo R, Berciano J, et al. Serial waking–sleep EEGs and evolution of somatosensory potentials in CreutzfeldtJakob disease. Electroencephalogr Clin Neurophysiol 1985;60: 504-508. 92. Terzano MG, Parrino L, Pietrini V, et al. Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study. Sleep 1995;18:849-858. 93. Harper DG, Stopa EG, McKee AC, et al. Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration. Arch Gen Psychiatry 2001;58:353-360. 94. Besthorn C, Sattel H, Hentschel F, et al. Quantitative EEG in frontal lobe dementia. J Neural Transm 1996;47:169-181. 95. Yener GG, Leuchter AF, Jenden D, et al. Quantitative EEG in frontotemporal dementia. Clin Electroencephalogr 1996;27:61-68.

96. Pijnenburg YA, Strijers RL, Made YV, et al. Investigation of restingstate EEG functional connectivity in frontotemporal lobar degeneration. Clin Neurophysiol. 2008;119:1732-1738. 97. Boeve BF. Update on the diagnosis and management of sleep disturbances in dementia. Sleep Med Clin 2008;3:347-360. 98. Dauvilliers Y. Insomnia in patients with neurodegenerative conditions. Sleep Med 2007;8:S27-S34. 99. Singer C, Tractenberg RE, Kaye J, et al. A multicenter, placebocontrolled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 2003;26:893-901. 100. Ray WA, Federspeil CF, Schaffner W. A study of antipsychotic drug use in nursing homes: epidemiologic evidence suggesting misuse. Am J Public Health 1980;70:485-491. 101. Arnulf I, Konofal E, Merino-Andreu M, et al. Parkinson’s disease and sleepiness: an integral part of PD. Neurology 2002;58: 1019-1024. 101a.  Cooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med 2009;5:305-309. 102. Srinivasan V, Pandi-Perumal SR, Cardinali DP, et al. Melatonin in Alzheimer’s disease and other neurodegenerative disorders. Behav Brain Functions 2006;2:15-37. 103. Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin 2006;27:41-49. 104. Lyketsos CG, Lindell Veiel L, Baker A, et al. A randomized controlled trial of bright light therapy for agitated behaviors in dementia patients residing in long-term care. Intl J Geriatr Psychiatry 1999;14:520-525. 105. Van Someren E, Kessler A, Mirmiran M, et al. Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients. Biol Psychiatry 1997;41:955-963. 106. Ancoli-Israel S, Gehrman P, Martin JL, et al. Increased light exposure consolidates sleep and strengthens circadian rhythms in severe Alzheimer’s disease patients. Behav Sleep Med 2003;1:22-36. 107. Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. J Sleep Res 2010. In press. 108. Aurora RN, Zak RS, Maganti RK, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6:85-95.

Epilepsy, Sleep, and Sleep Disorders Margaret Shouse and Mark W. Mahowald Abstract Epilepsy is the third most common neurologic disorder after stroke and Alzheimer’s disease in the United States. Sleep, sleep disorders, and epilepsy are commonly associated. It is well known that sleep and sleep deprivation increase the inci­ dence of parasomnias and seizure activity. Conversely, seizure disorders can affect the wake–sleep cycle. Sleep disorders— including parasomnias—can mimic, cause, or even be trig­ gered by epileptic phenomena, and vice versa. A high index of suspicion and a full awareness of the broad spectrum of sleep and epileptic phenomena is instrumental to an accurate diagnosis.1 Epilepsy refers to a host of seizure disorders characterized by uncontrolled abnormal brain electrical discharges associ­ ated with undesirable motor, verbal, or experiential phe­ nomena.2,3 These phenomena often occur during sleep.4 Electroclinical events include interictal discharges (IIDs), which are electrographically but not clinically evident, and ictal events, which are usually electrographically and clinically evident. There are many ways of classifying seizure disorders.2 In spite of considerable diversity in etiologies and in specific ictal or IID characteristics, epileptic seizure manifestations tend to be highly state dependent. Non–rapid eye movement (NREM) sleep is associated with increased incidence and spread of IIDs; clinical accompaniment is most often associated with localization-related epilepsies originating in temporal and frontal lobes.4-6 Rapid eye movement (REM) sleep is a relatively antiepileptic state in that spread of IID is anatomically local­ ized, and clinically evident seizures are usually suppressed.5,7,8

HISTORICAL ASPECTS In 1965, Gastaut and Broughton14 reported the clinical and polygraphic characteristics of sleep-related episodic phenomena in human patients. They outlined major symptoms of two major parasomnias, sleepwalking and sleep terrors. Both occur during NREM sleep, usually when the patient emerges from stage 4 NREM sleep. Prior to this study,14 these parasomnias were associated with seizure disorders. In 1968, Broughton15 questioned the pathophysiologic mechanisms underlying these paroxysmal (sudden) nocturnal events. Although parasomnias and seizure disorders exhibit common features such as abrupt onset, confusion, disorientation, and retrograde amnesia, Broughton proposed that most if not all of these episodes could be related to a disorder of arousal rather than to epilepsy. After Broughton’s pioneering work, the concept of an arousal disorder generating parasomnias was accepted, but subsequent studies also suggest that arousal disorders can provoke, represent, or be caused by seizure disorders. Certain predisposing factors in NREM sleep seem to increase IID and ictal epileptic events.4,5 The incidence of arousal-related paroxysms, such as sleep spindles, K-complexes, bursts of slow waves, and ponto-geniculo-occipital (PGO) spikes, is closely associated with the occurrence of 1048

Chapter

92

Arousal from NREM or REM sleep can also provoke or mimic seizures or parasomnias.9 The facilitation of sleep upon partial seizures depends in part on the location of the epileptic focus.10 The likelihood that the same basic brain circuitry generates both NREM sleep oscillations and electrical seizures with spike–wave complexes explains the close relationship between seizures and sleep.11 With the advent of neurophysiologic monitoring techniques, it has become obvious that state determination is a very complex and dynamic phenomenon involving multiple neural networks, neurotransmitters, neuropeptides, and neurohor­ mones, as well as a myriad of sleep-promoting substances. Given these complexities, it has become clear that determining state may be inexact, with components of two or all three states occurring simultaneously or oscillating rapidly. This concept of state dissociation in animals and humans has been extensively reviewed.12 These mixed or rapidly oscillating states result in fascinat­ ing and perplexing clinical phenomena that can easily be confused with epileptic events; conversely, these sleep disor­ ders may be perfectly imitated by epileptic events. Further­ more, other primary sleep disorders can trigger seizures, and conversely, seizures can trigger abnormal sleep phenomena. Clinically there is substantial overlap among epileptic, sleep, and psychiatric phenomena (Box 92-1). There are five primary determinants of the quality of night­ time sleep and of daytime alertness: homeostatic (duration of prior wakefulness), circadian (biological clock influence), age, drugs, and central nervous system (CNS) pathology.13 These factors determine the overall sleep–wake pattern and also play an integral role in epileptic events.

generalized or focal spikes, epileptiform spike-and-wave, and polyspike-and-wave in human and animal epilepsy.16,17 There is also a statistical relationship between the cyclic alternating pattern (CAP) of fluctuating cortical excitability with both epilepsy and sleep disorders.18,19

EPIDEMIOLOGY There are no definitive epidemiologic studies on the coincidence of parasomnias and seizure disorders, although available studies suggest that nocturnal seizures rarely represent parasomnias.14,15,20 Symptoms of parasomnias—such as nightmares, sleep terrors, violent behavior during sleep, sleepwalking, and REM sleep behavior disorder (RBD)— resemble seizure disorders (notably partial complex seizures), thus warranting comments on reports of incidence, etiology, and clinical course. The incidence of epilepsy has been studied most often in industrialized countries where overall population percentages are similar; available studies conducted in developing countries indicate a higher prevalence than in industrialized countries. The following statistics reflect well-conducted epidemiologic studies in the United States.21 The number of patients in the United States with



CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1049

Box 92-1  Overlap between Sleep and Epileptic Phenomena Sleep Disorder Normal Sleep Phenomena Sleep starts (hypnic jerks) Nightmares Hypersomnia Sleep deprivation Idiopathic central nervous system hypersomnia Narcolepsy • Cataplexy • Sleep paralysis • Hypnagogic hallucinations • Automatic behavior Recurrent hypersomnia • Kleine-Levin • Menstruation-related Sleep apnea that triggers seizures Insomnia Medical Psychiatric Psychological Constitutional Parasomnias Disorders of arousal • Confusional arousals • Sleepwalking • Sleep terrors • Sleepeating REM sleep behavior disorder Dreams, nightmares Enuresis Rhythmic movement disorder Periodic limb movement disorder

Posttraumatic stress disorder Cardiopulmonary disorders • Cardiac arrhythmias • Respiratory dyskinesias Gastrointestinal: paroxysmal choking Panic disorder Psychogenic dissociative disorders Seizures Normal Sleep Phenomena Seizures manifesting as sleep-onset sensorimotor phenomena or nightmares Hypersomnia Hypersomnia as a manifestation of having frequent nocturnal seizures resulting in recurrent arousals or hypersomnia as an accompaniment of epilepsy • Akinetic • Fugue states • Partial complex seizures • Subclinical status • Poriomania Recurrent seizures resulting in prolonged periods of “sleepiness” Seizures resulting in apnea Insomnia Seizures whose arousals

sole

manifestation

is

recurrent

Parasomnias Mesial, frontal, temporal lobe seizures manifesting with complex, bizarre behavior, hypnogenic (nocturnal) paroxysmal dystonia, or autonomic (diencephalic) seizures

Modified from Mahowald MW, Schenck CH: Sleep disorders. In: Engel J Jr, Pedley TA, editors: Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 2705-2715 (with permission).

a diagnosis of epilepsy is about 2.5 million, and the cumulative lifetime incidence ranges from 1.3% to 3.1% of the population by the age of 80 years. Epilepsy is the third most common neurologic disorder after stroke and Alzheimer’s disease in the United States. Epilepsies may be categorized as generalized (40%), localization related (57%), or unclassified (3%). Localization-related epilepsies may be further subclassified as partial complex (36%), simple partial (14%), and partial unknown (7%). Localization-related epilepsies, particularly partial complex seizure disorders with tonic-clonic convulsions, are the prototypical pure sleep epilepsies; nearly 60% of these patients exhibit convulsions only during sleep.22,23 Most of these nocturnal seizure disorders are attributed to temporal or frontal lobe foci.6 Onset can occur at any time, although the average peak age at onset is in adolescence.22 Electroclinical symptoms tend to persist, and over time ictal events or IID events, or both, are likely to disperse across the sleep–wake cycle.21-23 Age at onset of parasomnias such as sleepwalking and sleep terrors is believed to be in childhood. The earlier age at onset of some parasomnias can provide one criterion for differential diagnosis from some nocturnal seizure disorders; however, many epilepsies—such as partial

complex seizure disorders—do not remit spontaneously.21-24 Hereditary factors can be more prevalent in some parasomnias than in partial complex seizure disorders. Still, the most definitive criterion for differential diagnosis is polygraphic evidence of epileptic seizure discharge, and this may be difficult to obtain from surface recordings of patients with deep temporal or frontal lobe foci.25 It is likely that the rarity of nocturnal seizures manifesting as other parasomnias is more apparent than real, the correct diagnosis having been overlooked for lack of consideration.

PATHOGENESIS The hypothalamic and brainstem generators of sleep and arousal have diffuse ascending and descending projections26 that give rise to a number of distinguishing physiologic characteristics called components. Components can be tonic or phasic. Tonic components are sustained background activity, such as degree of electroencephalographic (EEG) synchronization and muscle tone. Phasic components include periodic transients, such as sleep spindles, K-complexes, and muscle twitches. The association of these tonic and phasic events is important to the integrity

1050  PART II / Section 11  •  Neurologic Disorders

of sleep states. Dissociation or abnormality of these components likely contributes to a variety of sleep, arousal, and seizure disorders as well as their interaction. Direct experimental evidence using dissociative manipulations is best documented with respect to spread of EEG and clinically evident seizures that can coexist with or masquerade as parasomnias.27 Two state-specific components affecting epilepsy are the degree to which cellular discharge patterns are synchronized and alterations in antigravity muscle tone.5 NREM sleep and drowsiness differ from alert waking and REM sleep in that EEG activity is synchronized and postural muscle tone is diminished. REM sleep differs from NREM sleep in that EEG activity is desynchronized, and it differs from waking and NREM sleep in that postural muscle tone is absent. REM sleep has sometimes been called “paradoxical sleep”28 because it is characterized by a “highly active brain in a paralyzed body.”29 During NREM sleep, virtually every cell in the brain discharges synchronously, and the discharge can even reach paroxysmal levels similar to those in epileptic states.30 This occurs to a lesser extent in drowsiness. Lasting oscillations of rhythmic burst–pause firing patterns result in concerted synaptic actions. Synchronous synaptic effects, whether excitatory or inhibitory, are likely to augment the magnitude and propagation of postsynaptic responses, including epileptic discharges. During REM sleep and alert waking, cells discharge asynchronously.31 The divergent synaptic signals associated with asynchronous discharge patterns are less likely to augment the magnitude or propagation of epileptic EEG discharges. Skeletal muscle tone also varies by sleep or waking state. Antigravity muscle tone is preserved in NREM sleep and waking,29,32 thus permitting seizure-associated and conceivably parasomnia-associated movement. Profound lower motor neuron inhibition occurs in REM sleep,29,33 creating virtual paralysis (but sparing the diaphragm to permit continued respiration). Disruption of this important component of REM sleep might underlie RBD and can influence clinically evident motor seizures. These different EEG and skeletal motor components can be experimentally dissociated, as depicted in Figure 92-1.7 Figure 92-1A shows normal feline REM sleep. Figure 92-1B shows that NREM sleeplike EEG synchrony during REM sleep can be induced by systemic administration of atropine. Although it is not shown in the figure, atropine also synchronizes the waking EEG. EEG-synchronizing effects are presumably achieved by blocking acetylcholine (ACh) release from cells in the nucleus basalis of the forebrain and pedunculopontine-peribrachial nuclei of the brainstem, because these are the critical generators of the asynchronous EEG discharges that occur in waking and to a greater extent in REM sleep.26,34 Figure 92-1C shows selective loss of postural muscle tone induced by a lesion in the pontine generators of REM sleep atonia.31 Neural generators are thought to be cholinoceptive and glutaminergic cells in the brainstem atonia regions,31,35 which hyperpolarize lower motor neurons.33 Dissociating these EEG and motor components significantly and differentially influences electrographic and clinical seizure manifestations, as illustrated in Figure 92-2. Figure 92-2A shows the distribution of penicillin-

induced spike–wave complexes during intact NREM and REM sleep states. Figure 92-2B shows the effects of atropine administration. The REM sleep EEG is synchronized, and the spike–wave discharge rate is comparable with that in NREM sleep. Although it is not shown in the figure, atropine similarly synchronizes the waking EEG in conjunction with an increase in spike–wave discharge rate. Unlike waking and NREM sleep, there is no clinical manifestation during REM sleep, presumably because of the skeletal motor paralysis unique to that state. Figure 92-2C shows that a pontine lesion eliminates REM sleep atonia so that a clinically evident myoclonic seizure occurs in REM sleep. These results are supported by other experimental and clinical findings indicating that substrates of state-specific components rather than integrity of the state per se can be salient determinants of seizure propagation. Agents that synchronize the EEG, such as cholinergic or noradrenergic antagonists, have proconvulsant effects.36-38 Conversely, agents that desynchronize the EEG discourage epileptic EEG discharge propagation. Examples are cholinergic and noradrenergic agonists39-42 as well as beta-carbolines such as abecarnil,43 which act on central benzodiazepine receptors. Finally, pharmacologic manipulations that induce atonia, such as carbachol infusion into the brainstem, also block clinical motor accompaniment.41 Consistent observations have been reported in experimental models of primary generalized epilepsy, such as electroconvulsive shock, penicillin epilepsy, and photosensitive epilepsy7,37,39; in animal models of localization-related epilepsies, such as limbic system kindling and the cortical alumina cream preparation41,44; and in the clinical literature on symptomatic generalized epilepsies such as West’s syndrome.40 Collectively, the findings confirm that cellular discharge patterns and alterations in tone affect electrographic and clinically evident seizure manifestations in diverse epileptic syndromes, including those that mimic parasomnias. There is growing evidence that glial cells play a role in epilepsy.45,46

CLINICAL FEATURES This section discusses various areas of overlap and confusion between sleep disorders and seizures. These areas include normal events, hypersomnia, insomnia, and parasomnias (see Box 92-1). Normal Sleep Phenomena Sleep Starts Many healthy people experience sleep starts (hypnic jerks) during the transition from waking to sleep. The most common is the motor sleep start, a sudden jerk of all or part of the body, occasionally awakening the victim or bed partner.47,48 Variations include the visual (flashes of light, fragmentary visual hallucinations), auditory (loud bangs, snapping noises), and somesthetic (pain, floating, something flowing through the body) sleep starts, which occur without the body jerk.49-51 Sleep starts represent a normal (although not understood) physiologic event, and they should not be confused with seizures or other neurologic conditions. It is likely that the exploding head syndrome, characterized by a sensation of a loud sound like an explo-



CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1051

Normal REM Sleep Motor cortex VL Thalamus EOG LGN

A

EMG

REM Sleep without EEG Desynchrony: Systemic Atropine Motor cortex

VL Thalamus EOG LGN

B

EMG

REM Sleep without Atonia Motor cortex VL Thalamus EOG LGN

C

EMG 2 sec

100µV

Figure 92-1  A, The top tracing shows normal REM sleep, evidenced by EEG desynchronization and atonia with periodic bursts of phasic events, including REMs and ponto-geniculo-occipital (PGO) spikes. B, The middle tracing shows that systemic atropine selectively abolishes EEG desynchronization. Instead, there is a NREM sleeplike EEG with synchronized background and sleep spindles. However, atonia is intact, as are eye movements and PGO spikes. Clustering of PGOs is diminished as customarily reported. C, The bottom tracing shows that a pontine lesion selectively eliminates atonia. Note presence of tonic electromyographic (EMG) activity in the bottom channel of this tracing. (From Shouse MN, Siegel JM, Wu FM, et al: Mechanisms of seizure suppression during rapid-eye-movement (REM) sleep in cats. Brain Res 1989;505:271-282.)

1052  PART II / Section 11  •  Neurologic Disorders

Penicillin Trial During Normal Sleep SWS

REM Sleep

EEG EOG

A

LGN EMG SWS

Penicillin Trial after Atropine REM Sleep without EEG Desynchrony

EEG EOG

B

LGN EMG SWS

Penicillin Trial after Pontine Lesion REM Sleep without Atonia

EEG EOG LGN

C

EMG 2 sec

100 µV

Figure 92-2  Systemic penicillin epilepsy during slow wave sleep (SWS), the equivalent of NREM sleep in humans (left), and REM sleep (right) before (A) and after (B and C) dissociation of REM-sleep components. Spike–wave paroxysms are visible in the EEG tracing, and myoclonic seizures were associated with electromyographic (EMG) discharges in this cat, as long as lower motor neuron activity is present. (From Shouse MN, Siegel JM, Wu FM, et al: Mechanisms of seizure suppression during rapid-eye-movement [REM] sleep in cats. Brain Res 1989;505:271-282.)

sion or a sensation of bursting of the head,52 is a variant of a sensory sleep start. Similar phenomena might represent the sole manifestation of a seizure.53 There is a single case report of a brainstem lesion associated with auditory sleep starts.54 Nightmares Nightmares are frightening dreams that usually awaken the sleeper from REM sleep (see Chapter 97). Unlike disorders of arousal such as sleep terrors (see later), nightmares are not usually associated with prominent motor or vocal behavior or autonomic excitation, and the arousal results in immediate full wakefulness, with memory for the dream sequence of events that caused the awakening.55 Seizures can manifest as recurrent dreams, nightmares, or disorders of arousal such as sleepwalking and sleep terrors. The diagnosis of seizure-related dreams and nightmares may be overlooked, because the symptom is misinterpreted as a primary sleep phenomenon.56-59 Autosomal dominant frontal epilepsy can also manifest as recurrent nightmares.60 Hypersomnia Epilepsy The sole manifestation of nocturnal seizures may be simple arousals that may or may not be perceived by the patient. If enough arousals occur, the resulting sleep fragmentation will be apparent, with symptoms of severe excessive daytime sleepiness (Fig. 92-3). These seizure-induced arousals may be associated with very minor motor phenomena.61

Some patients with seizures are hypersomnolent during the day, even after discontinuing antiepileptic medication. Seizure-free preadolescent children with epilepsy are sleepier than healthy controls. In one study, there was no difference in objective sleepiness in children with epilepsy on or off medication, suggesting that antiepileptic drugs do not necessarily cause the daytime sleepiness.62 Excessive daytime sleepiness in a patient on antiepileptic medications must not summarily be attributed to antiepileptic medication.63-65 Narcolepsy Narcolepsy is a genetically determined disorder characterized by excessive daytime sleepiness, cataplexy (the sudden loss of muscle tone triggered by emotionally laden events), sleep paralysis, hypnagogic hallucinations, and automatic behavior during which prolonged, complex activities may be performed without conscious awareness or recall.66,67 The spell-like nature of some sleep attacks, cataplexy, and sleep paralysis may be mistaken for seizures. Conversely, atonic (epileptic negative myoclonus) or inhibitory seizures may mimic cataplexy,68-74 and the periods of automatic behavior are often misdiagnosed as partial complex seizures, postictal confusion, or priomania.75,76 The incomplete and waxing and waning nature of cataplexy can imitate tonic–clonic seizure activity. Periodic Hypersomnia (Kleine-Levin Syndrome) The Kleine-Levin syndrome is a poorly understood condition characterized by recurrent periods of hypersomnia. The often-cited association with adolescent males and unusual behavior such as hypersexuality and megaphagia



CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1053

959

F7-T3

P.B. 2-8-88

T3-T5 T5-O1 F8-T4 T4-T6 T6-O2 F3-P3 F4-P4 ECG

Airflow

off off off LOC-A1 ROC-A1 C3-A2 O2-A1 Chin EMG L Anterior Tibialis R Anterior Tibialis 50 µV

1 sec

Figure 92-3  Polysomnographic tracing of a child with a history of a “well-controlled” seizure disorder who complained of severe excessive daytime sleepiness. Notice the EEG evidence of arousals, which were the sole manifestation of seizure activity. The seizure-induced arousal index was nearly 100 per hour of sleep, clearly explaining the daytime complaint.

have been overrated.77,78 Menstruation-related periodic hypersomnia might represent a variant of the Kleine-Levin syndrome.79 Similar recurrent episodes of hypersomnia may be caused by “ictal sleep” lasting 13 days at 10- to 60-day intervals.80,81 Sleep-Disordered Breathing There is an interesting and important relationship between sleep-disordered breathing and seizures (Video 92-1). Nocturnal seizures, probably triggered by periods of hypoxemia, may be the presenting symptom in some persons with obstructive sleep apnea or sleep-related hypoventilation.82,83 Furthermore, sleep apnea can exacerbate seizures in patients who have epilepsy that is caused by sleep disruption, sleep deprivation, hypoxemia, or decreased cerebral blood flow.84 Obstructive sleep apnea may be associated with seizure occurrence in older adults with epilepsy.85 Identification and treatment of sleep-disordered breathing in persons with seizures can improve seizure control.86,87 Some seizure-like spells associated with sleep apnea are actually caused by episodes of cerebral anoxia.88

Seizures can also cause periods of apnea, often repetitive, and can closely mimic the conditions of obstructive or central sleep apnea.89-92 Figure 92-4 shows repetitive apneas as the sole manifestation of seizures, and Figure 92-5 shows obstructive sleep apnea inducing electrical seizure activity. Insomnia Paroxysmal, otherwise unexplained awakenings may be the sole manifestation of nocturnal seizures and result in the complaint of insomnia.93-98 Some patients with occasional paroxysmal periodic motor attacks during sleep have very frequent (every 20 to 60 seconds) subclinical arousals causing severe sleep fragmentation.99 These paroxysmal arousals may be due to deep epileptic foci.100 The arousal preceding nocturnal seizures may be the initial manifestation of the seizure.101 Animal studies support the concept of frequent arousals as the manifestation of seizures.102 This might explain why many patients with epilepsy report frequent, otherwise unexplained nocturnal awakenings.103

1054  PART II / Section 11  •  Neurologic Disorders 901

LOC-A1

902

S.G. 1-18-84

ROC-A1 C3-A2 C4-A1 O1-A2 Chin EMG L Anterior Tibialis EEG

Respitrace

Airflow (mask) SUM

Chest

1 sec

Abdomen SO2 Figure 92-4  Polysomnographic tracing of a 56-year-old man with a long-standing history of well-controlled generalized seizures who developed severe progressive excessive daytime sleepiness. The polysomnogram (PSG) revealed 22 central apneas per hour as the sole manifestation of seizures. Aggressive medical management was unsuccessful. There was marked improvement in his excessive daytime sleepiness following a right frontal lobectomy. (From Mahowald MW, Schenck CH. Sleep disorders. In: Engel J Jr, Pedley TA editors: Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997, pp. 2705-2715.)

Parasomnias Disorders of Arousal Disorders of arousal are the most common and impressive of the NREM sleep parasomnias, and they may readily be confused with epileptic phenomena (see Chapter 94). These occur on a continuum ranging from confusional arousals to sleepwalking to sleep terrors. Disorders of arousal may be difficult to differentiate from nocturnal seizures, and vice versa.104,105 Preservation of consciousness during seizures can lead to their being confused with disorders of arousal or psychogenic conditions.106 Crying (dacrystic) or laughing (gelastic) seizures may be misinterpreted as confusional arousals or sleep terrors.107,108 Both disorders of arousal and seizures may be related to the menstrual cycle.109-111 Arousals of any sort may serve to trigger a disorder of arousal. Therefore, any underlying condition resulting in arousal can cause a disorder of arousal, including sleep apnea, gastroesophageal reflux, or seizures. Thus the clinical event of a sleepwalking or sleep terror episode may, in fact, represent an epiphenomenon of a completely different underlying sleep disorder.20 It is common clinical experience to see an improvement in disorders of arousal following effective treatment of obstructive sleep apnea. Conversely, effective treatment of obstructive sleep apnea with nasal continuous positive airway pressure (CPAP) can result in disorders of arousal, presumably associated with deep NREM-sleep rebound.112,113 It must be remembered that sleep terrors and seizures can coexist in the same person.27

REM Sleep Behavior Disorder REM sleep behavior disorder is a condition in which the usual atonia of REM sleep is absent, hypothetically allowing patients to act out their dreams, often with violent or injurious results (see Chapter 95). RBD is typically a disorder of older men and is often misdiagnosed as a nocturnal seizure or psychogenic event. RBD is readily diagnosable by formal sleep studies, which reveal the absence of somatic muscle atonia of REM sleep. RBD responds very well to clonazepam.114,115 Just as RBD can masquerade as nocturnal seizures, the converse is also true.116 Dream and Nightmare Disturbances Dreams (particularly recurrent dreams) or nightmares as the primary manifestation of nocturnal seizures have been well documented. Recurrent dreams as the manifestation of seizures have been well described.57 Enuresis Enuresis was formerly classified as a disorder of arousal, implying a relationship with NREM or slow-wave sleep.15 However, enuresis can occur during either NREM or REM sleep.117,118 Enuresis may be the sole manifestation of nocturnal seizures.20 Rhythmic Movement Disorder Rhythmic movement disorder refers to a number of actions characterized by stereotyped movements (rhythmic oscillation of the head or limbs, head banging, or body rocking during sleep) seen most often in childhood and rarely in



CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1055

964

965

LOC-A1 ROC-A1 C3-A2 Chin EMG L-R Anterior Tibialis EEG F7-T3 T3-T5 T5-O1 F8-T4 T4-T6 T6-O2 F3-P3 F4-P4

Respitrace

Airflow

1 sec

Chest Abdomen

Tachygraph SO2 Figure 92-5  Polysomnographic tracing showing electrical seizure activity beginning during an episode of obstructive sleep apnea.

adults. Rhythmic movement disorder can occur during any stage of sleep, may be familial, and is not usually associated with underlying psychiatric or psychological conditions.119-121 Rarely, rhythmic movement disorder is the sole manifestation of a seizure.20 Periodic Limb Movement Disorder Periodic limb movement disorder (PLMD) is a diagnosis determined by polysomnography. It is characterized by periodic (every 20 to 30 seconds) dorsiflexion of the great toe or foot or flexion of the entire leg. These movements are not perceived by the patient, and they may be asymptomatic or associated with the complaint of either excessive daytime sleepiness or insomnia.122,123 When prominent, these movements may be confused with myoclonic seizure activity or can actually represent epileptic phenomena.124 Propriospinal myoclonus (Video 92-2). May also be confused with periodic limb movement disorder, and the patient can present with the complaint of insomnia or sleep-related movements that are bothersome to the bed partner.125,126 Periodic limb movement disorder may be particularly dramatic in patients with underlying renal failure.127,128

Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) is often associated with subjective sleep complaints including nightmares and sleep terror–like experiences.129 It may be confused with nocturnal panic or seizures manifesting solely as arousals with fearful affect. Seizures The behavior associated with nocturnal seizures is often bizarre (Videos 92-3 and 92-4). The seizures thus can masquerade as primary sleep parasomnias, secondary sleep parasomnias, or psychiatric conditions.130 The following seizure types are particularly likely to result in diagnostic dilemmas. Classified Seizures Classified seizures often occur during sleep.2 In many people with epilepsy, seizures occur exclusively during sleep, increasing the likelihood of a misdiagnosis of a primary sleep disorder. A conservative estimate is that 10% of patients with epilepsy display seizures exclusively during sleep.131 One type of seizure that typically occurs predominantly in the sleep period is benign childhood epilepsy with centrotemporal spikes (BECT), also known as benign

1056  PART II / Section 11  •  Neurologic Disorders

LOC-A1

ROC-A1 C3-A2 O2-A1

439

1 2 3 4 5

Submental EMG L-R Anterior Tibialis FP1-F7 F7-T3

6 7 8 9 10

T3-T5 11 T5-O1 12 FP2-F8 13 F8-T4

14

T4-T6 T6-O1 9 Figure 92-6  Polysomnographic study showing the prominent state-dependent nature of left-sided centromidtemporal spikes, present almost exclusively during NREM sleep.

Rolandic epilepsy. This form of epilepsy is characterized by unilateral somatosensory onset of paresthesias of the tongue, lips, gums, and cheek, with tonic or tonic–clonic movement of the face, lips, tongue, and pharyngeal muscles, and is associated with drooling. The electrical EEG spike discharges are typically activated by sleep (Fig. 92-6).132 Unusual Behavioral Seizures Seizures of frontal lobe origin can manifest as bizarre behavior such as running, loud vocalization, or cursing (Videos 92-5 to 92-7). The extraordinary behavior and the tendency for the behavior to occur during sleep and to cluster in time promote misdiagnosis (often as a disorder of arousal, RBD, or psychogenic spells).130,133-138 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFE) can manifest with predominantly or exclusively sleep-related motor behavior,137,139 as can supplementary sensorimotor seizures.140 In retrospect, it is probable that many reported unusual nocturnal seizures were due to ADNFE. This condition is characterized by a wide variety of seizure manifestations, previously termed “episodic nocturnal wanderings,” and “hypnogenic (nocturnal) paroxysmal dystonia.” The seizures often involve hyperkinetic

thrashing activity with dystonic posturing, often with vocalization. In addition to the behavioral events, patients with ADNFE can experience innumerable brief arousals from sleep, the sole manifestation of the seizure. The attacks are usually brief and without aura or postictal confusion. The EEG is often obliterated by movement artifact, which makes video-EEG monitoring mandatory.141,142 ADNFE often responds to carbamazepine.60 There is evidence that ADNFE represents a channelopathy.143-145 Similar clinical events can also arise in the temporal region.146,147 Nocturnal frontal lobe epilepsy may be particularly difficult to differentiate from disorders of arousal.105,148,149 Episodic nocturnal wanderings are a manifestation of ADNFE. These wanderings, which respond to anticonvulsants, may be indistinguishable by history from sleepwalking and sleep terrors. The patients ambulate, vocalize, and display violent behavior during sleep. Not all exhibit waking EEG abnormalities. There is growing evidence that many of these cases represent epileptic phenomena and are actually ambulatory automatisms.150 Nocturnal paroxysmal dystonia (NPD) is another manifestation of ADNFE. It is characterized by predominantly



or exclusively nocturnal episodes of coarse, occasionally violent, movements of the limbs associated with tonic spasms, often occurring multiple times nightly. Vocalization or laughter can occur. EEGs between events are normal; during events, EEGs display movement artifact, often without clear evidence of electrical seizure activity.151,152 The cyclic alternating pattern of cortical excitability may play a modulatory role in this condition.19 It is clear that NPD is a seizure disorder.153 NPD may be unilateral,154 and there can be a family history.155 Nocturnal and diurnal paroxysmal dystonia may exist in the same patient, as can reflex and hypnogenic paroxysmal dystonia. There is considerable overlap among the different clinical categories of paroxysmal dyskinesias.156 NPD may be posttraumatic157 and can coexist with panic disorder.158 Carbamazepine is often very effective in eliminating these spells. Vigilance level–dependent tonic seizures159 and familial paroxysmal hypnogenic dystonia155 likely represent variants of this condition. Pure tonic seizures also likely represent a manifestation of ADNFE with arousal (or paroxysmal polyspike activity with arousal). They appear as insomnia or hypersomnia due to seizure-induced arousals or sleep fragmentation. An interesting subtype of hypnic tonic postural seizures has been described in 10 children, many with a positive family history.160 This may be a benign epilepsy syndrome similar to benign childhood epilepsy with centrotemporal spikes,161 childhood epilepsy with occipital paroxysms,162,163 and primary reading epilepsy.160 Autonomic or diencephalic seizures are thought to be rare and could occur with such manifestations as intermittent or paroxysmal apnea,91,164 stridor,165 vomiting,166 coughing,167 laryngospasm,168,169 chest pain and arrhythmias,170-173 paroxysmal flushing, and localized hyperhidrosis.174,175 Isolated autonomic symptoms are a well-documented manifestation of seizures and are probably much more common than generally suspected. These simple autonomic seizures are easily confused with other primary or secondary sleep parasomnias or are misattributed to disorders of other organ systems.176 Electrical Status Epilepticus of Sleep Electrical status epilepticus of sleep (ESES) may be detected during a polysomnogram (PSG) performed for other reasons and is characterized by continuous spike and wave activity during NREM sleep.177 ESES is seen in children who may have a history of seizures or neurologic dysfunction. The prognosis is variable, because ESES can be asymptomatic.178 ESES may share some features with the Landau-Kleffner syndrome.179 Cardiopulmonary Manifestations Cardiac Arrhythmias Cardiac arrhythmias, including asystole, may be a manifestation of seizures masquerading as nocturnal cardiac abnormalities.180,181 Conversely, primary cardiac events (e.g., prolonged QT interval) can manifest as seizures.182 Seizures can manifest as syncope,183 or vice versa.184 Respiratory Dyskinesias Peculiar respiratory irregularities can occur or persist during the sleep period. Examples include segmental

CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1057

myoclonus (such as palatal myoclonus185 or diaphragmatic flutter186) and paroxysmal dystonia.187 Respiratory dyskinesias may also be the manifestation of neuroleptic-induced dyskinesias, which do not always persist during sleep.188 These dyskinesias should be differentiated from unusual nocturnal seizures that manifest with primarily or exclusively respiratory symptoms.89 Gastrointestinal Manifestations The sole manifestation of nocturnal seizures may be paroxysmal choking.189

Case Study A girl who was 3 years and 9 months old and who had tuberous sclerosis was referred for evaluation of progressively severe nocturnal choking and gagging episodes that began at 11 2 years of age. There was a remote history of diurnal spells, felt to be seizures, that resolved spontaneously. Aggressive treatment for gastroesophageal reflux had been ineffective. Her father, a nurse anesthetist, was so concerned that she might die during one of these spells that he slept in the same bed with her and kept an intubation tray at her bedside. A sleep study was requested to evaluate for sleepdisordered breathing, because a tonsillectomy and adenoidectomy were being considered as treatment for these nocturnal choking spells. Because of the possibility of nocturnal seizures, a full-seizure montage was employed. Numerous paroxysmal gen­ eralized bursts of electrical seizure activity, occasion­ ally associated with coughing or gagging sounds, were present (Fig. 92-7). Carbamazepine adminis­ tered at bedtime resulted in immediate cessation of the nocturnal gagging episodes.

Nocturnal Panic Attacks Nocturnal panic attacks can occur in patients with diurnal panic or, rarely, can precede the appearance of diurnal panic. In some cases, panic attacks are exclusively nocturnal.190 The striking similarity of the symptoms of dream anxiety attack, sleep terrors, nocturnal seizures, and nighttime panic urges extreme caution in diagnosis. Obstructive sleep apnea can also cause symptoms of nocturnal panic attacks.191 The common association of the affect of fear as an accompaniment of nocturnal seizures intensifies their confusion with nocturnal panic attack. It must be remembered that seizures and panic can coexist.192 Psychogenic Dissociative States Complex and potentially injurious behavior, occasionally confined to the sleep period, may be the manifestation of a psychogenic dissociative state (Video 92-8). A history of childhood physical or sexual abuse, or both, is virtually always present but may be difficult to elicit. In this condition, unlike other parasomnias or nocturnal seizures, during EEG monitoring the complex behavior is seen to arise from clear EEG-determined wakefulness.193 Pseudoseizures can also arise from apparent sleep.193

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Figure 92-7  Polysomnographic study with a full-seizure montage showing generalized paroxysmal rhythmic activity representing electrical seizure activity. This activity was occasionally associated with coughing or gagging and was followed by an arousal.

DIAGNOSTIC EVALUATION Clinical differentiation between sleep disorders and epileptic events can be difficult, if not impossible, because primary or secondary sleep phenomena can perfectly mimic epileptic phenomena and vice versa. Both epileptic and sleep phenomena should be considered in any case of recurrent, stereotyped, and inappropriate unusual sleeprelated events. The decision to investigate unusual nocturnal events depends upon the clinical situation. The most common condition is the disorder of arousal, which is very common (and normal) in the general population. Simple sleepwalking or sleep terrors can readily be diagnosed clinically. Indications for formal evaluation include behavior that is potentially injurious or violent, that causes disruption for other household members, that results in excessive daytime sleepiness, or that displays unusual clinical features.194 Clinical differentiation between sleep disorders and epileptic phenomena may be most difficult, and misdiagnosis in both directions is common, particularly in the absence of a history of diurnal spells. Waking and sleep-deprived EEGs might not reveal the diagnosis,195,196 necessitating all-night polysomnographic study using a full seizure montage and continuous video recording.197 Even with video recording, interobserver reliability may be poor.198 A number of clinical criteria have been developed to differentiate among the various conditions resulting in complex behaviors arising from the sleep period, but none

is failsafe.149,199-202 Abbreviated EEG montages are inadequate in the differentiation of seizures and nonepileptic events arising from sleep during polysomnography.203 Exclusively nocturnal seizures may be uncommon, but they are routinely misdiagnosed and should never be overlooked as the possible etiology in any sleep-related behavior that is recurrent, stereotyped, or inappropriate, regardless of the specific nature of that behavior. Ambulatory EEG monitoring has led to the misdiagnosis of functional psychiatric disease in a number of our patients who were subsequently demonstrated to have bona fide nocturnal seizures. Erroneous psychogenic branding is reinforced by the bizarre nature of the spells and by the fact that environmental clues may play a role in the context of psychomotor seizures.204 Tassinari has proposed that one explanation for the similarity of motor activities associated with nocturnal seizures and disorders of arousal is that both are due to release of activities generated by central pattern generators triggered by different phenomena.205 Misdiagnosis is common even following formal and appropriate PSG evaluation. Reasons for misdiagnosis include:206 • Obscuration of the scalp EEG by movement artifact. • Absence of scalp-EEG manifestation of the seizure activity. • EEG seizure manifestation appearing to be an arousal pattern. • Absence of EEG or clinical postictal period.



Extensive polysomnographic monitoring employing a full-scalp EEG montage is mandatory. Because the clinical events may be infrequent, multiple studies may be necessary to capture an event. Continuous audiovisual monitoring and recording are indicated, and detailed technician observations are invaluable. The difficulties in evaluating unusual sleep-related events emphasize the necessity of extensive, in-person laboratory monitoring with interpretation of all data (clinical, EEG, sleep, video, and technologist-provided information) by personnel experienced in both sleep medicine and epileptology.

TREATMENT Effective treatment is available for almost all parasomnias, regardless of cause, and is predicated upon an accurate diagnosis. If seizures are responsible for the sleep–wake complaint, treatment is similar to that for other seizure disorders.207 Surgical treatment may be effective in drugresistant nocturnal frontal lobe epilepsy.208 If a primary sleep disorder (such as narcolepsy, sleep apnea, or other parasomnia) is identified, therapy is dictated by the specific diagnosis. Vagal nerve stimulation for treatment of seizures has been reported to improve daytime alertness209; however, vagal nerve stimulation can induce sleep apnea, worsening daytime sleepiness.210 CLINICAL COURSE Few longitudinal studies of nocturnal seizures are available. In some patients the seizures remit spontaneously, and in some patients the seizures become diurnal.211 PITFALLS AND CONTROVERSIES Nocturnal seizures are undoubtedly much more common than generally believed. Underdiagnosis is due to the lack of clinical suspicion. The etiologies of many nocturnal paroxysmal events are not clearly defined. Differential diagnosis of epileptic versus nonepileptic manifestations depends primarily on the use of extracranial recordings, although intracranial EEG recordings are sometimes necessary. Specifically, epileptic seizures originating from mesioorbitofrontal sites often cannot be recorded extracranially, and attacks of uncertain etiology such as sleepwalking, screaming, and complex automatisms may be inaccurately diagnosed as parasomnias. Some evidence also suggests that short-lasting paroxysmal dystonia attacks represent sleep-related frontal lobe seizures.212 In other cases, parasomnias coexist with limbic epilepsy without an apparent common etiology. The interface between sleep disorders and epileptic phenomena is vast and compelling, because sleep affects seizures and seizures affect sleep. The myriad of sleep and epileptic phenomena may perfectly counterfeit one another. A high index of suspicion and a full awareness of the broad spectrum of both sleep and epileptic phenomena is instrumental to an accurate diagnosis. A thorough clinical and laboratory evaluation of unusual phenomena that could be either sleep-related or seizure-related usually leads to a specific diagnosis, with important and effective therapeutic implications. Continued close collaboration

CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1059

between clinicians and basic science sleep and epilepsy researchers will undoubtedly lead to important advances in the understanding of both sleep and epilepsy, with vital clinical diagnostic and therapeutic implications. Acknowledgments We thank our technical and nursing staff, and we thank Paul R. Farber for computer processing and expertise. This work was supported by the Minnesota Regional Sleep Disorders Center and the Hennepin County Medical Center.

❖  Clinical Pearl Nocturnal seizures are routinely misdiagnosed, usually as psychiatric problems or disorders of arousal. Any behavior or experience that is recurrent, stereotyped, and inappropriate may be due to seizures regardless of the nature of the behavior or experience.

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1062  PART II / Section 11  •  Neurologic Disorders 127. Kimmel PL. Sleep disorders in chronic renal disease. J Nephrol 1989;1:59-65. 128. Pressman MR, Benz RL, Peterson DD. High incidence of sleep disorders in end stage renal disease. Sleep Res 1995;24:417. 129. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994. 130. Stores G, Zaiwalla Z. Misdiagnosis of frontal lobe complex partial seizures in children. Adv Epileptol 1989;17:288-290. 131. Young GB, Blume WT, Wells GA, et al. Differential aspects of sleep epilepsy. Can J Neurol Sci 1985;12:317-320. 132. Lerman P. Benign childhood epilepsy with centrotemporal spikes (BECT). In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook, vol 2. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 2307-2314. 133. Fusco L, Iani C, Faedda MT, et al. Mesial frontal lobe epilepsy: a clinical entity not sufficiently described. J Epilepsy 1990;3: 123-135. 134. Marsh GG. Neuropsychological syndrome in a patient with episodic howling and violent motor behavior. J Neurol Neurosurg Psychiatry 1978;41:366-369. 135. Stores G, Zaiwalla Z, Bergel N. Frontal lobe complex partial seizures in children: a form of epilepsy at particular risk of misdiagnosis. Dev Med Child Neurol 1991;33:998-1009. 136. Sussman NM, Jackel RA, Kaplan LR, et al. Bicycling movements as a manifestation of complex partial seizures of temporal lobe origin. Epilepsia 1989;30:527-531. 137. Waterman K, Purves SJ, Kosaka B, et al. An epileptic syndrome caused by mesial frontal lobe seizure foci. Neurology 1987;37: 577-582. 138. Tinuper P, Provini F, Bisulli F, Lugaresi E. Hyperkinetic manifestations in nocturnal frontal lobe epilepsy. Semiological features and physiopathological hypothesis. Neurol Sci 2005;26:S210S214. 139. Hayman M, Scheffer IE, Chinvarun Y, et al. Autosomal dominant nocturnal frontal lobe epilepsy: demonstration of focal frontal onset and intrafamilial variation. Neurology 1997;49:969-975. 140. King DW, Smith JR. Supplementary sensorimotor area epilepsy in adults. Adv Neurol 1996;70:285-291. 141. Oldani A, Zucconi M, Asselta R, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 1998;121:205-223. 142. Oldani A, Zucconi M, Smirne S, Ferini-Strambi L. The neurophysiological evaluation of nocturnal frontal lobe epilepsy. Seizure 1998;7:317-320. 143. Motamedi GK, Lesser RP. Autosomal dominant nocturnal frontal lobe epilepsy. Adv Neurol 2002;89:463-473. 144. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349: 1257-1266. 145. Aridon P, Marini C, Di Resta C, et al. Increased sensitivity of the neuronal nicotinic receptor α2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet 2006;79: 342-350. 146. Mai R, Sartori I, Francione S, et al. Sleep-related hyperkinetic seizures: always a frontal onset? Neurol Sci 2005;26:S220-S224. 147. Nobili L, Cossu M, Mai R, et al. Sleep-related hyperkinetic seizures of temporal lobe origin. Neurology 2004;62:482-485. 148. Nobili L, Sartori I, Terzaghi M, et al. Intracerebral recordings of minor motor events, paroxysmal arousals and major seizures in nocturnal frontal lobe epilepsy. Neurol Sci 2005;26:S215-S219. 149. Nobili L. Nocturnal frontal lobe epilepsy and non-rapid eye movement sleep parasomnias: differences and similarities. Sleep Med Rev 2007;11:251-254. 150. Plazzi G, Tinuper P, Montagna P, et al. Epileptic nocturnal wanderings. Neurology 1995;45(Suppl 4):A332. 151. Lugaresi E, Cirignotta F. Hypnogenic paroxysmal dystonia: epileptic seizure or a new syndrome? Sleep 1981;4:129-138. 152. Hirsch E. Abnormal paroxysmal postures and movements during sleep: partial epilepsy or paroxysmal hypnogenic dystonia. In: Horne J, editor. Sleep ‘90, Tenth European Congress on Sleep Research, Strasbourg (France). Bochum, Germany: Pontenagle Press; 1990. p. 471-473. 153. Hirsch E, Sellal F, Maton B, Fukuyama Y. Nocturnal paroxysmal dystonia: a clinical form of focal epilepsy. Neurophysiol Clin 1994;24:207-217.

154. Oguni M, Oguni H, Kozasa M, et al. A case with nocturnal paroxysmal unilateral dystonia and interictal right frontal epileptic EEG focus: a lateralized variant of nocturnal paroxysmal dystonia? Brain Dev 1992;14:412-416. 155. Lee BI, Lesser RP, Pippenger CE, et al. Familial paroxysmal hypnogenic dystonia. Neurology 1985;35:1357-1360. 156. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995;38:571-579. 157. Biary N, Singh B, Bahou Y, et al. Posttraumatic paroxysmal nocturnal hemidystonia. Mov Disord 1994;9:98-99. 158. Stoudemire A, Ninan PT, Wooten V. Hypnogenic paroxysmal dystonia with panic attacks responsive to drug therapy. Psychosomatics 1987;28:280-281. 159. Rajna P, Kundra O, Halasz P. Vigilance level–dependent tonic seizures—epilepsy or sleep disorder? A case report. Epilepsia 1983; 24:725-733. 160. Vigevano F, Fusco L. Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia 1993;39:110-119. 161. Holmes GL. Rolandic epilepsy: clinical and electroencephalographic features. In: Degen R, Dreifuss FE, editors. Benign localized and generalized epilepsies of early childhood. Amsterdam: Elsevier Science; 1992. p. 29-43. 162. Panayiotopoulos CP. Benign nocturnal childhood occipital epilepsy: a new syndrome with nocturnal seizures, tonic deviation of the eyes, and vomiting. J Child Neurol 1989;4:43-48. 163. Panayiotopoulos CP. Benign childhood epilepsy with occipital paroxysms. In: Andermann F, Beaumanoir A, Mira L, et al, editors. Occipital seizures and epilepsy in children. London: John Libbey; 1993, p. 151-164. 164. Sanmarti FX, Estivill E, Campistol J, et al. [Episodes of apnea in an infant: unusual forms of epileptic seizures]. Rev Electroencephalogr Neurophysiol Clin 1985;14:269-275. 165. Maytal J, Resnick TH. Stridor presenting as the sole manifestation of seizures. Ann Neurol 1985;18:414-415. 166. Panayiotopoulos CP, Panayiotopoulos CP. Autonomic seizures and autonomic status epilepticus peculiar to childhood: diagnosis and management. Epilepsy Behav 2004;5:286-295. 167. Winans HM. Epileptic equivalents, a cause for somatic symptoms. Am J Med 1949;7:150-152. 168. Ravindran M. Temporal lobe seizure presenting as “laryngospasm.” Clin Electroencephalogr 1981;12:139-140. 169. Amir J, Ashkenazi S, Schonfeld T, et al. Laryngospasm as a single manifestation of epilepsy. Arch Dis Child 1983;58:151-153. 170. Devinsky O, Eherenberg B, Barthlen GM, et al. Epilepsy and sleep apnea syndrome. Neurology 1994;44:2060-2064. 171. Kiok MC, Terrence CF, Fromm GH, Lavine S. Sinus arrest in epilepsy. Neurology 1986;36:115-116. 172. Gilchrist JM. Arrhythmogenic seizures: diagnosis by simultaneous EEG/ECG recording. Neurology 1985;35:1503-1506. 173. Hockman CH, Mauch HP, Hoff EC. ECG changes resulting from cerebral stimulation. II. A spectrum of ventricular arrhythmias of sympathetic origin. Am Heart J 1966;71:695-700. 174. Metz SA, Halter JB, Porte DJ, Robertson RP. Autonomic epilepsy: clonidine blockade of paroxysmal catecholamine release and flushing. Ann Intern Med 1978;88:189-193. 175. Kuritzky A, Hering R, Goldhammer G, Bechar M. Clonidine treatment in paroxysmal localized hyperhidrosis. Arch Neurol 1984;41:1210-1211. 176. Liporace JD, Sperling MR. Simple autonomic seizures. In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook, vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 549-555. 177. Kobayashi K, Nishibayashi N, Ohtsuka Y, et al. Epilepsy with electrical status epilepticus during slow sleep and secondary bilateral synchrony. Epilepsia 1994;35:1097-1103. 178. Veggiotti P, Termine C, Granocchio E, et al. Long-term neuropsychological follow-up and nosological considerations in five patients with continuous spikes and waves during slow sleep. Epileptic Disord 2002;4:243-249. 179. Maquet P, Hirsch E, Metz-Lutz MN, et al. Regional cerebral glucose metabolism in children with deterioration of one or more cognitive functions and continuous spike-and-wave discharges during sleep. Brain 1995;118:1497-1520. 180. Weinstein MD, Albertario C. Cardiac asystole and bradycardia as a manifestation of left temporal lobe complex partial seizure. Ann Intern Med 2000;132:165-166.

181. Schuele SU, Bermeo AC, Alexopoulos AV, et al. Videoelectrographic and clinical features in patients with ictal asystole. Neurology 2007;69:434-441. 182. Pacia SV, Devinsky O, Luciano DJ, Vazquez B. The prolonged QT syndrome presenting as epilepsy: a report of two cases and literature review. Neurology 1994;44:1408-1410. 183. Reeves AL, Nollet KE, Klass DW, et al. The ictal bradycardia syndrome. Epilepsia 1996;37:983-987. 184. Bergey GK, Krumholz A, Fleming CP. Complex partial seizure provocation by vasovagal syncope: video-EEG and intracranial electrode documentation. Epilepsia 1997;38:118-121. 185. Lapresle J. Palatal myoclonus. Adv Neurol 1986;43:265-273. 186. Iliceto G, Thompson BL, Day JC, et al. Diaphragmatic flutter, the moving umbilicus syndrome, and “belly dancer’s” dyskinesia. Mov Disord 1990;1:15-22. 187. Sethi KD, Hess DC, Huffnagle VH, Adams RJ. Acetazolamide treatment of paroxysmal dystonia in central demyelinating disease. Neurology 1992;42:919-921. 188. Wilcox PG, Bassett A, Jones B, Fleetham JA. Respiratory dysrhythmias in a patient with tardive dyskinesias. Chest 1994; 105:203-207. 189. Brown LW, Fry JM. Paroxysmal nocturnal choking: a newly described manifestation of sleep-related epilepsy. Sleep Res 1988;17:153. 190. Rosenfeld DS, Furman Y. Pure sleep panic: two case reports and a review of the literature. Sleep 1994;17:462-465. 191. Edlund MJ, McNamara ME, Millman RP. Sleep apnea and panic attacks. Compr Psychiatry 1991;32:130-132. 192. McNamara ME. Absence seizures associated with panic attacks initially misdiagnosed as temporal lobe epilepsy: the importance of prolonged EEG monitoring in diagnosis. J Psychiatry Neurosci 1993;18:46-48. 193. Schenck CS, Milner DM, Hurwitz TD, et al. Dissociative disorders presenting as somnambulism: polysomnographic, video, and clinical documentation (8 cases). Dissociation 1989;4:194-204. 194. Mahowald MW, Rosen GM. Parasomnias in children. Pediatrician 1990;17:21-31. 195. Passouant P. Historical views on sleep and epilepsy. In: Sterman MB, Shouse MN, Passouant P, editors. Sleep and epilepsy. New York: Academic Press; 1982. p. 1-6. 196. Billiard M, Echenne B, Besset A, et al. All-night polygraphic recordings in the child with suspected epileptic seizures, in spite of normal routine and post-sleep deprivation EEGs. Electroencephalogr Clin Neurophysiol 1981;11:450-460. 197. Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066.

CHAPTER 92  •  Epilepsy, Sleep, and Sleep Disorders  1063 198. Vignatelli L, Bisulli F, Provini F, et al. Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures. Epilepsia 2007;48:1506-1511. 199. Derry CP, Davey M, Johns M, et al. Distinguishing sleep disorders from seizures. Diagnosing bumps in the night. Arch Neurol 2006; 63:705-709. 200. Tinuper P, Provini F, Bisulli F, et al. Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep. Sleep Med Rev 2007;11:255-267. 201. Manni R, Terzaghi M, Repetto A. The FLEP scale in diagnosing nocturnal frontal lobe epilepsy, NREM and REM parasomnias: data from a tertiary sleep and epilepsy unit. Epilepsia (Series 4) 2008;1581-1585. 202. Montagna P, Provini F, Bisulli F, Tinuper P. Nocturnal epileptic seizures versus the arousal parasomnias. Somnologie 2008;12: 25-37. 203. Foldvary-Schaefer N, De Ocampo J, Mascha E, et al. Accuracy of seizure detection using abbreviated EEG during polysomnography. J Clin Neurophysiol 2006;23:68-71. 204. Forster FM, Liske E. Role of environmental clues in temporal lobe epilepsy. Neurology 1963;13:301-305. 205. Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26: S225-S232. 206. Mahowald MW, Schenck CH. Parasomnia purgatory—the epileptic/non-epileptic interface. In: Rowan AJ, Gates JR, editors. Nonepileptic seizures, 2nd ed. Boston: Butterworth-Heinemann; 2000. p. 71-94. 207. Dreifuss FE, Porter RJ. Choice of antiepileptic drugs. In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 1233-1236. 208. Nobili L, Francione S, Mai R, et al. Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy. Brain 2007;130:561573. 209. Rizzo P, Beelke M, De Carli F, et al. Chronic vagus nerve stimulation improves alertness and reduced rapid eye movement sleep in patients affected by refractory epilepsy. Sleep 2003;26:607-611. 210. Holmes MD, Chang M, Kapur V. Sleep apnea and excessive daytime somnolence induced by vagal nerve stimulation. Neurology 2003;61:1126-1129. 211. Park SA, Lee BI, Park SC, et al. Clinical courses of pure sleep epilepsies. Seizure 1998;7:369-377. 212. Montagna P. Nocturnal paroxysmal dystonia and nocturnal wandering. Neurology 1992;42(Suppl 6):61-67.

Other Neurologic Disorders Antonio Culebras Abstract Sleep is a function of the brain, and brain alterations affect sleep either by defect or excess. Most neurologic conditions that extensively injure brain function, as well as some lesions in strategic locations such as the brainstem, diencephalon, or thalamus, cause sleep abnormalities. There are numerous examples of acute brain injuries causing abrupt changes in sleep patterns or pathologic alterations in sleep. Stroke, head trauma, diffuse encephalopathies, and the encephalitides are just a few examples of such alterations. Chronic diseases with structural alterations of the brain, such as multiple sclerosis or the neurodegenerative disorders, alter sleep; other chronic neurologic disorders not associated with structural brain alterations, such as headache syndromes, show a peculiar but well-established association with sleep anomalies. The clinical study of neurologic disorders and resulting sleep alterations opens up an opportunity to better comprehend sleep and to participate in the alleviation and management of the primary neurologic disorder and of its associated sleep problems.

HEADACHE There is an intimate relationship between some headache syndromes and sleep.1 Practitioners and patients have been aware of the peculiar effect of sleep on terminating attacks of headache,2 and patients have many times complained of being awakened at night or of waking up in the morning with a headache. The discovery of stage-specific headaches and the intriguing linkage between rapid eye movement (REM) sleep and acute headache attacks3 pointed to the influence that circadian sleep rhythms can have on the advent of headaches. In addition, several well-defined sleep disorders are commonly associated with headaches. These include sleep apnea syndrome and headache on awakening, sleep phase–related headache, and parasomnias and headache. Epidemiologic studies conducted in headache clinics have noted that 17% of the total headache group reports headaches at night or in the early morning before the final awakening period.4 Up to 55% of patients in the headache subgroup had a specific sleep disorder identified by polysomnographic monitoring in a sleep center. The International Classification of Sleep Disorders, 2nd edition,5 recognizes the following headache disorders in association with sleep: classic migraine, migraine with aura, common migraine, migraine without aura, hemiplegic migraine, cluster headache, chronic paroxysmal hemicrania, and hypnic headache. The diagnostic criteria require that the patient complain of headache during sleep or upon awakening from sleep. 1064

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Sleep can terminate attacks of headache and sleep can trigger or promote headaches. Stage-specific headaches include migraine, cluster headache, chronic paroxysmal hemicrania, and hypnic headache. Stage-specific headaches and the linkage between rapid eye movement (REM) sleep and acute headache attacks point to the influence of circadian sleep rhythms on headaches. Some well-defined sleep disorders are commonly associated with headaches, including sleep apnea, sleep phase–related disorders, and parasomnias. Neurologic conditions with extensive brain damage such as multiple sclerosis, traumatic brain injury, infectious or demyelinating encephalitides, and hereditary neurodegenerative disorders can extensively alter sleep–wake schedules and sleep stages. In some instances, specific sleep disorders, such as narcolepsy in patients with plaques of multiple sclerosis in the hypothalamus or REM sleep behavior disorder in neuro­ degenerative disorders, afford the opportunity to confirm hypotheses of sleep dysfunction. Clinicians should also keep in mind that upper cervical cord lesions may be associated with obstructive sleep apnea syndrome, and brain tumors may be associated with a variety of sleep disorders.

Stage-Specific Headaches Migraine Headaches Migraine headaches can occur during the night in association with stages 3 and 4 sleep or REM sleep. Fiftyfour percent (64% women, 35% men) of patients with narcolepsy report migraine with the full complement of the International Headache Society criteria.6 Sleeprelated migraine attacks are characterized by unilateral throbbing head pain in association with nausea, vomiting, scotomata, visual field defects, photophobia, paresthesias, and even hemiparesis and aphasia. Not all symptoms may be present given the idiosyncratic nature of migraine headaches. Attacks can last for hours to several days. Migraine attacks in children younger than 8 years often resolve after an interval of sleep.7 Children with migraine can have an increased incidence of disturbed sleep and parasomnias8 such as somnambulism, night terrors, and enuresis.9 Prolonged deep sleep is a risk factor for the provocation of sleep terrors and somnambulism, as well as for triggering migraine attacks in susceptible patients at any age.10 Although migraine headaches may be provoked by sleep, the most common association is the onset of sleep following a migraine attack. The therapeutic effect of sleep11 in some attacks of migraine may be related to serotonin metabolism, but proof is lacking. The trigeminovascular system, which promotes vasodilation and release of calcitonin gene–related peptide and substance P,12 has been implicated in the mechanism of migraines because calcitonin



gene-related peptide is elevated in the jugular venous blood of migraineurs during the attack.13 Serotonin (5-HT) is released from platelets during migraine headaches, and 5-hydroxyindoleacetic acid, the main metabolite of serotonin, is excreted in excess in the urine following a migraine attack.14 Sumatriptan (an agonist of the 5-HT1 receptor found in cerebral arteries, where it has an inhibitory effect) aborts the migraine headache. Methysergide (antagonist of the 5-HT2 receptor found mainly in temporal arteries, where it has an excitatory effect) also terminates migraines. Abnormal patterns of hypothalamic hormone secretion such as decreased nocturnal prolactin peak, increased cortisol concentrations, a delayed nocturnal melatonin peak, and lower melatonin concentrations have been reported in patients with chronic migraine.15 Proper sleep hygiene is paramount to help prevent sleep-related migraine headaches. Bruni and coworkers16 evaluated the effect of modifying bad sleep habits in 70 migraineurs with poor sleep hygiene. Mean duration and frequency of migraine attacks were significantly reduced when proper sleep hygiene was maintained. Daily administration of preventive therapy should be considered when migraine attacks occur more than twice a month or when they are prolonged and refractory to acute therapy. In women, attacks might cease after menopause. Cluster Headaches Cluster headaches occur in 0.4% of men and 0.8% of women.17 They are characterized by severe unilateral, periorbital, malar, and temporal pain with lacrimation, rhinorrhea, nasal engorgement, forehead perspiration, and flushing of the malar area. Attacks are of abrupt onset and termination, generally last 2 hours or less, and recur several times during the 24-hour period, sometimes at the same time each day. Seventy-five percent of cluster headaches occur predominantly at night between 9 pm and 10 am.18 Cluster headaches have been linked with REM stage and with sleeping late in the morning, a situation that promotes REM sleep, a possible triggering factor. Spontaneous remissions lasting several months are the norm. Chronic Paroxysmal Hemicrania Chronic paroxysmal hemicrania is characterized by attacks of severe pain associated with conjunctival hyperemia, rhinorrhea, and, more rarely, Horner’s syndrome. Attacks may appear predominantly at night, usually waking the patient at the same hour, sometimes in close linkage with REM sleep, leading to the term REM-sleep locked headache. Chronic paroxysmal hemicrania is considered a variant of cluster headache that features more frequent attacks of pain of shorter duration. It responds quasi-specifically to the therapeutic administration of indomethacin. Hypnic Headache Hypnic headache is an idiopathic headache disorder of rare occurrence, observed in older age groups. The mean age of onset is 63 years, with a range of 36 to 83 years.19 The alternative names—clockwise headache and alarm headache—also attest to its regularity and exclusive occurrence at night. Although it is relatively well known among specialists, this headache syndrome has not yet

CHAPTER 93  •  Other Neurologic Disorders  1065

been included in the classification of the International Headache Society. Unlike cluster headache and chronic paroxysmal hemicrania, hypnic headache occurs in a diffuse localization in two thirds of patients. Its intensity varies widely, and only one third of patients complain of severe pain. The pain usually lasts longer than 1 hour, and generally there is only one attack per night, although more than one attack in a night has also been described. The majority of patients experience the attack during the middle third of the night and report regularity in its occurrence. Less than 10% of patients have associated autonomic symptoms such as lacrimation, nasal congestion, or rhinorrhea, and these are usually mild when they occur. Results of laboratory tests including magnetic resonance imaging (MRI) of the head, EEG, and Doppler ultrasound have been invariably normal. Polysomnography has shown occurrence of headache attacks during REM and non-REM sleep.20 The appearance of attacks at the same time during the night has led others to suggest a chronobiological disorder. The differential diagnosis of hypnic headache, cluster headache, chronic paroxysmal hemicrania, and even nocturnal migraine may be difficult at times. The following characteristics should help to make a diagnosis of hypnic headache: older age group, punctuality of attack occurrence, mild or no autonomic symptoms, diffuse location, duration of 1 hour to a maximum of 2 hours, tendency to appear in relation to dreams, and no symptoms characteristic of migraine such as photophobia, phonophobia, or nausea. Prophylaxis of hypnic headache has been successful with lithium carbonate, flunarizine, indomethacin, and caffeine. The attack itself responds best to the administration of aspirin. Hemicrania Horologica Hemicrania horologica, or clocklike hemicrania,21 is a very rare disorder, with headaches lasting 15 minutes, They occur with clocklike precision every 60 minutes, day and night. Hemicrania horologica differs from chronic paroxysmal hemicrania in the lack of autonomic signs, the clocklike regularity over 24 hours, and the response to nonsteroidal antiinflammatory drugs or indomethacin. Unlike with hypnic headache, attacks also occur during the day. Exploding Head Syndrome The exploding head syndrome, originally called “snapping of the brain,”22 is characterized by abrupt flashing lights and noises perceived inside the head during the night.23 The attacks last only seconds and terrify patients despite the absence of pain. The episodes have been shown by polysomnography to appear during any stage of sleep.24 Generally the exploding head syndrome occurs in persons older than 50 years. Headache on Awakening Headache on awakening occurs in half of the patients with sleep apnea syndrome. In at least one study the frequency of headaches was not related to the severity of the syndrome.25 The headache is generally diffuse and of mild to moderate intensity, with a tendency to disappear as the patient becomes increasingly active. Successful

1066  PART II / Section 11  •  Neurologic Disorders

treatment of sleep apnea syndrome is associated with significant improvement of the headache in 30% of patients.26 Prolonged afternoon naps may also be followed by headache. Headaches on awakening in patients with sleep apnea syndrome have been associated with a variety of mechanisms including hypoxemia, hypercapnia, altered cerebral blood flow, and depression. Headaches on awakening may occur with other disorders. These are common in children with brain tumors, but they appear in only 5% of adults with brain tumors. They may also appear in relation to bruxism, systemic hypertension, depression, muscle contraction, alcohol intoxication, and sinus inflammation. Bruxism, or clenching and grinding of teeth, is a parasomnia that occurs predominantly in stages 1 and 2 NREM sleep and sometimes in REM sleep, occasionally leading to headache on awakening. The prevalence is 8% in the adult population27 and somewhat higher in children.28 It has been related to psychophysiologic stress and iatrogenic interventions, but it may be idiopathic. Both phasic and tonic oromandibular muscle contraction have been observed in bruxism. Frequent grinding causes abnormal wear of the teeth and occasional fractures of teeth or of tooth restorations; temporomandibular joint disorder and jaw pain are not uncommon when the disorder is chronic and severe. Headaches are presumably caused by temporomandibular joint stress and muscle contraction. Patients with many nocturnal events and associated arousals may complain of fatigue and sleepiness during the ensuing day. Masseter muscle hypertrophy may be observed in patients with chronic sleep bruxism, although daytime bruxism may cause hypertrophy too. Insomnia and Headache Insomnia and headache are not uncommonly comorbid conditions. In the postconcussion syndrome, insomnia and headache are prominent symptoms. On the other hand, insomnia and daytime fatigue are commonly reported by patients with chronic headache. Chronic headache sufferers feel more tired (especially the women) and do not sleep as well at night (especially the men).29 Fibromyal­ gia occurs in 35.6% of patients with chronic migraine, also known as transformed migraine; this group of patients has a higher incidence of insomnia.30 Headaches in Children Chronic headaches in children are often associated with sleep alterations. Common sleep disorders are decreased duration of sleep at night, poor sleep hygiene, increased number of nocturnal awakenings, somnambulism, somniloquy, enuresis, and snoring.31 In a study of the prevalence of sleep disorders in children with headaches, the authors32 found that children with headaches have a significantly higher prevalence of excessive daytime sleepiness, narcolepsy, and insomnia compared with children without headaches (P < 0.005). The study contradicts previous work stating that children with headaches have a higher prevalence of sleep apnea, restlessness, and parasomnias, an association that may be more specific for genuine migraines and not for headaches in general. The authors conclude that pediatricians should inquire about

daytime sleepiness, narcolepsy, and insomnia in children with headaches. Drugs and Headache A variety of drugs used for treatment of sleep disorders can cause headache as a prominent adverse event. Modafinil improves wakefulness in patients with excessive sleepiness associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from six randomized, double-blind, placebo-controlled studies using modafinil evaluated 1529 outpatients receiving modafinil 200, 300, or 400  mg or placebo once daily for up to 12 weeks. Overall modafinil was well tolerated versus placebo, but headache occurred in 34% vs. 23%, respectively.33 Headache has also been cited as a common adverse effect in patients taking ramelteon for treatment of insomnia.34 Headache is the most common side effect reported by patients taking melatonin.35 Common side effects of amphetamines during long-term treatment in patients with narcolepsy include headache along with irritability, bad temper, and profuse sweating.36 Differential Diagnosis and Diagnostic Workup Nocturnal migraine, cluster headache, nocturnal paroxysmal hemicrania, and hypnic headache need to be differentiated from other acute severe headaches, such as those associated with intracranial brain tumors, ruptured aneurysm, and meningitis. Patients with intracranial tumors who are awakened at night by headache report improvement on getting out of bed. Headaches on awakening, as observed in sleep apnea patients, are also seen in patients with severe hypertension, depression, intracranial tumor, muscle-contraction headache, alcohol intoxication, and craniofacial sinus disease. Hypnic headache differs from migraine headache, cluster headache, and chronic paroxysmal hemicrania because the pain is commonly diffuse or bilateral and patients are older. Autonomic symptoms are more prominent in cluster headache and chronic paroxysmal hemicrania. Causes for concern are first or worst-ever headache, associated neurologic symptoms or signs, progressive worsening of headache over days or weeks, intractable nausea or vomiting, fever, lethargy, confusion, and stiff neck. Patients who exhibit causes for concern should have neurologic consultation, neuroimaging studies, and lumbar puncture. Nocturnal polysomnography is indicated for the study of patients suspected of having sleep apnea syndrome or recurrent parasomnias. Videotaping should always be included in the polysomnographic study of parasomnias. Patients with migraine, cluster headache, and hypnic headache can wake up with an acute attack more often during REM sleep than during other stages of sleep, and those with cluster headache and chronic paroxysmal hemicrania can suffer the attack at the same time of the night every night. Attacks of chronic paroxysmal hemicrania may be so closely linked to REM sleep that they have been termed REM-sleep locked. Polysomnography has been recommended in patients complaining of early morning and nocturnal headaches.37 In a study of 25 patients with headache, Paiva and coworkers found 21



patients with disturbed sleep, and in 13 patients the clinical diagnosis had to be reassessed after polysomnography due to the finding of obstructive sleep apnea, periodic limb movements in sleep (PLMS), alpha-delta sleep, and insomnia.

MANAGEMENT Preventive treatment of migraine, cluster headaches, and chronic paroxysmal hemicrania includes good sleep hygiene, with avoidance of precipitating factors such as sleep deprivation, excessive sleep, stress, trauma, and ingestion of certain idiosyncratic foods including alcohol. Pharmacologic prevention of migraine includes administration of beta-blockers, flunarizine, valproic acid, topiramate, calcium channel blockers, serotonin receptor antagonists (methysergide, only for use in periods not to exceed 4 weeks), and 5-HT2 antagonists (cyproheptadine and methylergonovine). Prevention may also be achieved with antidepressants that interact with serotoninergic receptors such as tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and selective serotonin reuptake inhibitors (fluoxetine and sertraline); anticonvulsants, particularly in children with abnormal EEG; and nonsteroidal antiinflammatory agents.38 Migraine attacks may be aborted with administration of sumatriptan, a 5-HT1 selective agonist, given via subcutaneous injection (6 mg, may repeat after 1 hour; limit is two injections in 24 hours). Other abortive medications include ergotamine derivatives, acetaminophen, corticosteroids, and nonsteroidal antiinflammatory derivatives. Symptomatic treatment for migraine attacks includes nonsteroidal antiinflammatory derivatives, mixed barbiturate and analgesics, antiemetics (promethazine, 50 mg), and, if pain is severe, meperidine (50 mg) or codeine sulfate (30 mg). Cluster headaches may be prevented with ergotamine derivatives at bedtime (1 to 3  mg sublingual), amitriptyline (150 mg daily), methysergide (6 to 8 mg daily), prednisone (40  mg daily), and lithium carbonate (initial dose 250  mg). Acute attacks are terminated with inhalation of oxygen. Chronic paroxysmal hemicrania responds specifically to indomethacin (50 mg at bedtime or 25 mg 3 times a day). Morning headaches related to sleep apnea syndrome generally disappear with successful management of the sleep apnea. Hypnic headaches have responded to any of the following regimens at bedtime: coffee; ergotamine tartrate, 0.6  mg; phenobarbital, 40  mg, with belladonna, 0.2  mg; atenolol, 25  mg; aspirin, 325  mg, with caffeine, 40 mg; indomethacin, 25 mg; and flunarizine, 5 mg. Successful prophylaxis with lithium carbonate has also been reported. Reassurance and administration of clomipramine are curative in most instances of exploding head syndrome. Bruxism is treated with stress management, a mouth guard, or an intraoral occlusal splint.39 For shortterm management, diazepam (5 mg) given at bedtime will reduce teeth-grinding. The manifestations of postconcussion syndrome respond in many instances to the administration of tricyclic antidepressants. Drug-related headaches tend to be benign and respond to conventional analgesics or disappear gradually with continued use of the drug. These headaches generally disappear with discontinuation of the drug.

CHAPTER 93  •  Other Neurologic Disorders  1067

HEAD TRAUMA Severe head trauma, whether open or closed, is characterized by loss of consciousness. Structural lesions ensue following traumatic brain injury (TBI); some lesions appear weeks or even months after the event. It is estimated that 500,000 people are hospitalized annually in the United States as a result of head trauma, and 90,000 become permanently disabled, with major medical and social consequences.40 Severe head trauma disrupts brain functions, including the sleep–wake schedule. Mild head trauma is even more prevalent, affecting close to 1.5 million persons annually,41 but its sequelae are less predictable and not so well known. When evaluating a patient with a disturbance of the sleep–wake schedule following TBI, it is important to determine whether the sleep alteration preceded the injury or appeared following the event. Sleep Disruption and Recovery TBI can cause diffuse or localized brain lesions as well as increased intracranial pressure during the acute stage. Sleep studies of patients with TBI have not used uniform measures, and the results have been diverse. The emerging pattern is of major disruption of sleep stages in cases of severe brain injury. Sleep spindles tend to disappear when the lesions are acute and severe,42 showing a high correlation with the Glasgow outcome scores; recovery of sleep spindles suggests improvement of brain function. In patients with traumatic coma, the occurrence of EEG patterns resembling sleep carries a favorable prognosis. Individual sleep stages are generally less distinct during the acute phase. In the initial phase of recovery while the patient emerges from the coma, hypersomnia is common, with poor recollection of dreams. As the rehabilitation progresses, the organization of sleep stages tends to become normalized. Weeks to months following recovery of consciousness, sleep stages 3 and 4 and REM sleep are decreased along with total sleep time.43 The early appearance of sleep–wake cycling indicates a better prognosis. Sleep fragmentation and decreased sleep quality have been reported44 following minor head injury without loss of consciousness. Surveys performed after mild head injury indicate that insomnia predominates over hypersomnia.45 The prevalence of sleep–wake cycle disturbance in patients with closed head injury has been estimated at 68% in a survey conducted in an inpatient specialized brain injury rehabilitation unit.46 Clinical Manifestations Sleep–wake disturbances, particularly excessive daytime sleepiness, fatigue, and hypersomnia, are common after TBI and significantly impair quality of life. In almost one out of two patients, posttraumatic sleep–wake disorders appear to be directly related to the TBI. An involvement of the hypocretin system in the pathophysiology of posttraumatic sleep–wake disorders appears possible. In one study,47 low levels of hypocretin-1 in cerebrospinal fluid (CSF) were found in 4 of 21 patients 6 months after TBI, as compared to 25 of 27 patients in the first days after TBI.

1068  PART II / Section 11  •  Neurologic Disorders

Sleep-Disordered Breathing Sleep-disordered breathing (SDB) may be caused by injuries of the brain or cervical cord, and they may be worsened by accompanying injuries in other organs, most prominently the upper airway. In a study of 22 patients with stable spinal cord injury, Short and colleagues found 10 patients with sleep-disordered breathing.48 The con­ dition has also been observed in studies of patients with posttraumatic quadriplegia.49,50 Aggravation of sleepdisordered breathing can occur with the administration of sedatives or hypnotics commonly administered to these patients. Posttraumatic Hypersomnia Posttraumatic hypersomnia is a common occurrence following significant brain injury. It may appear in patients recovering from posttraumatic coma or in patients whose head trauma was deemed relatively benign and not associated with loss of consciousness. The medicolegal implications are important because patients might lose their jobs or at the very least complain of deterioration in the quality of life. In Guilleminault’s study of 184 patients with posttraumatic hypersomnia, 103 were involved in litigation.51 The author divided patients into two groups: group A with premorbid sleep disorder and group B without preceding sleep alteration. Group B was further subdivided into three categories: (1) normal polysomnography with abnormal results on the multiple sleep latency test (MSLT) and an average sleep latency between 6 and 10 minutes; (2) coma, with TBI and hydrocephalus; and (3) coma with or without neurologic sequelae followed by a syndrome of subwakefulness independent of depression. In Guilleminault’s experience, response to treatment is poor in subgroups 1 and 2, whereas patients in subgroup 3 might respond to treatment with amphetamines. Common complaints of patients with posttraumatic hypersomnolence are, in addition to daytime sleepiness, difficulty performing, inability to work, memory difficulties, speech difficulties, poor concentration, and depressive affect. These patients might complain also of headaches, restless sleep, heavy snoring, leg and body jerks during sleep, night terrors, night sweats, nightmares, and seizures during sleep. Posttraumatic Narcolepsy Posttraumatic narcolepsy has been reported in a few cases. Narcolepsy may have preceded the head trauma,52 or the head injury may have served as a triggering factor to unmask premorbid narcolepsy.53 In light of new knowledge about the etiology of narcolepsy, it is conceivable that severe head trauma can affect the hypothalamic system significantly enough to alter the neurotransmitter hypocretin, either transiently or permanently. It is known that following significant TBI there is a decrease in CSF hypocretin levels, perhaps nonspecifically, as a result of hemodynamic changes.54 Narcolepsy with cataplexy developed in a man with acromegaly 2 weeks following irradiation of the pituitary gland. Because the patient had normal CSF concentrations of hypocretin, the authors suggested that the damage was inflicted to hypocretin receptors rather than to secretors

of the neurotransmitter.55 These observations suggest that symptomatic narcolepsy may be caused by physical damage to the hypocretin system, and it is only a matter of time before posttraumatic hypocretin insufficiency with hypersomnia is reported.56 Posttraumatic Kleine-Levin syndrome responsive to lithium administration has been reported in two cases.57 Circadian Rhythm Disorders Circadian rhythm disorders have been described following TBI. Reversal of the circadian rhythm58 and resetting of the biological clock in comatose patients following TBI have also been reported.59 Posttraumatic psychiatric and behavioral disorders can lead to sleep–wake alterations, although the premorbid condition needs to be factored in. Insomnia Insomnia is a common complaint following TBI, with a reported prevalence of 30% to 70%.60,61 Most studies of insomnia in patients with TBI are based upon subjective questionnaires. Comorbid factors that can promote insomnia such as pain, anxiety, depression, medications, or adverse sleep environment are present in many TBI patients during the period of rehabilitation.62 Because persistent insomnia affects 30% of the adult population, it is unclear in many cases of TBI if insomnia represents a preexisting condition aggravated by the traumatic occurrence and comorbidities. Once the factors contributing to insomnia are identified in a given case, specific effective behavioral or pharmacologic therapies, or both, may be undertaken.63 Dreaming Disorders Dreaming can disappear following TBI, perhaps related to impairment of visual memory.64 Paradoxically, studies performed in patients following TBI have found no correlation between amount of REM sleep and loss of dreaming.65 Hallucinations in the recovery phase of TBI might reflect the recovery of REM sleep and breakthrough of REM sleep into wakefulness, as a dissociated state.66

MULTIPLE SCLEROSIS Epidemiology The association between multiple sclerosis and sleep disorders is more common than expected by chance. Reports published in the first half of the 20th century cite cases of multiple sclerosis associated with sleep attacks termed narcolepsy.67-69 Subsequently, cases of narcolepsy with cataplexy in multiple sclerosis, familial or not, were reported.70,71 Later reports pointed out that sleep disturbance is relatively common in multiple sclerosis and that a multifactorial etiology that ranges from depression to lesion site72,73 should be considered. There is coincidence of genetic susceptibility between multiple sclerosis and narcolepsy. The susceptibility to multiple sclerosis is coded by genes within or close to the human leukocyte antigen (HLA) DR-DQ subregion.74 On the other hand, patients with narcolepsy exhibit the highest known association between the HLA DR2 and DQw1 antigens and a disease entity. This has led some



CHAPTER 93  •  Other Neurologic Disorders  1069

authors to postulate a common immunogenetic etiology.75 Others have postulated that the HLA Dw2 haplotype in patients with multiple sclerosis and narcolepsy extends to the DRB5 locus.76 Some studies report hypersomnia in certain multiple sclerosis patients. These patients have lesions seen on MRI that suggest plaques in the hypothalamus, as well as undetectable levels of hypocretin in spinal fluid.77 Restless legs syndrome (RLS) is significantly associated with multiple sclerosis, especially in patients with severe pyramidal and sensory disability. The results of a multicenter study involving 861 patients with multiple sclerosis78 strengthen the idea that the inflammatory damage correlated with multiple sclerosis can induce a secondary form of RLS. In this study, the prevalence of RLS was 19% in multiple sclerosis compared to 4.2% in control subjects. RLS in patients with multiple sclerosis has a significant impact on sleep quality; therefore, it should be searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.

methasone85 or prednisolone therapy.86 Dopaminergic agonists may be useful for control of RLS and PLMS. Sleep paralysis in a 40-year-old woman with remitting progressive multiple sclerosis disappeared with weak electromagnetic field treatments delivered extracerebrally once or twice a week over a period of 3 weeks.87 Using this treatment in patients with multiple sclerosis, the same author88 reported restoration of dream recall in four patients, attenuation of suicidal behavior in three additional patients (attributed to improved mental depression),89 and resolution of partial cataplexy in another patient with chronic progressive multiple sclerosis.90

Clinical Manifestations Chronic fatigue is common in multiple sclerosis and can confound the interpretation of sleep disturbances. Patients report difficulty falling asleep, restless sleep, nonrestorative sleep, and early morning awakenings more often than control subjects.79 A variety of underlying physical and emotional factors (bladder problems, spasticity, muscle spasms, periodic leg movements, depression, and anxiety) that converge to disturb nocturnal sleep should be considered. Excessive daytime somnolence may be secondary to nocturnal disruption, which is likely amenable to proper management (see Video 89-1). In a study of 28 consecutive patients with multiple sclerosis, 54% reported sleep-related problems,80 including difficulty initiating or maintaining sleep, frequent awakenings due to leg spasms, habitual snoring, and nocturia. Sleep apnea syndrome occurred in two patients, and three showed episodes of nocturnal desaturation. MRI of the brain was abnormal in 20 of 22 cases studied. Polysomnographic studies of patients with definite multiple sclerosis have shown significantly reduced sleep efficiency and more awakenings during sleep, suggesting a multifactorial etiology of the sleep disorder. In a polysomnographic study of 25 patients with definite multiple sclerosis, sleep efficiency was significantly reduced and awakenings were increased.81 Periodic leg movements were found in 36% of patients compared with 8% of controls. Central sleep apneas were found in two patients. MRI of the brain showed a greater load of lesions in the cerebellum and brainstem in patients with periodic leg movements.

Clinical Manifestations Neurodegenerative disorders may have predominantly cerebellar dysfunction, as in some forms of olivopontocerebellar degeneration, extrapyramidal manifestations as in the synucleinopathies, or a combination of cerebellar and sensorimotor signs as in the spinocerebellar atrophies. Patients with neurodegenerative disorders have many sleep-related complaints including insomnia, hypersomnia, circadian dysrhythmia, abnormal movements, and abnormal behavior in sleep. They are also at risk for the development of sleep apnea syndrome and PLMS. Excessive daytime somnolence secondary to fragmentation of nocturnal sleep caused by sleep apnea, PLMS, or other factors is a common complaint.

Management Fatigue is the most pervasive symptom in multiple sclerosis. Amantadine and modafinil have been suggested for alleviating chronic fatigue in these patients.82,83 Modafinil was assessed in a single-blind study involving 72 patients with multiple sclerosis.84 The results suggested that 200  mg/day of modafinil significantly improved fatigue and was well tolerated.84 Some authors have reported a regression of symptoms of sleep disturbance with dexa-

HEREDITARY NEURODEGENERATIVE AND METABOLIC DISORDERS The occurrence of sleep disorders in this large group of neurologic conditions is limited to case reports and very short series of patients. The list continues to expand with the addition of new reports from the literature.

Diagnosis The sleep evaluation of patients with a neurodegenerative disorder should include overnight polysomnography followed by MSLT. The objectives are to assess the presence of sleep apnea syndrome, PLMS, and REM sleep without atonia and to measure excessive daytime somnolence. In some cases, the MSLT shows REM sleep in daytime naps with short-onset REM sleep latencies suggestive of narcolepsy. In special circumstances of suspected abnormal motor activity, video recording of nocturnal sleep is desirable. Actigraphy has been used in some laboratories to document motor activity during sleep and waking that may unveil a circadian dysrhythmia. Treatment Management of sleep disorders in patients with neurodegenerative disorders follows the general guidelines. Sedatives and hypnotics should be administered with caution to this group of patients to avoid aggravation of muscle weakness or gait ataxia, not only during daytime hours but also during nocturnal awakenings with ambulation in the dark. Illustrative Neurodegenerative Disorders Machado-Joseph Disease Machado-Joseph disease91 is a type 3 spinocerebellar ataxia. Increased prevalence of RLS and PLMS has also

1070  PART II / Section 11  •  Neurologic Disorders

been reported in this condition. The clinical evaluation of patients with spinocerebellar ataxia type 3 should pursue possible presence of sleep apnea syndrome and PLMS. REM sleep behavior disorder (RBD), a condition also prevalent in the synucleinopathies has been reported in association with Machado-Joseph disease and may be related to striatal monoaminergic deficit.92,93 Vocal cord abductor paralysis and stridor have also been described in Machado-Joseph disease.94 Charcot-Marie-Tooth Disease Charcot-Marie-Tooth (CMT) disease is a hereditary motor and sensory polyneuropathy characterized by degeneration of peripheral nerves and roots. Patients exhibit distal muscle weakness, atrophy, and sensory impairment. Phrenic neuropathy can cause dysfunction of the diaphragm, leading to chronic hypoventilation, particularly in REM sleep.95 Vocal cord dysfunction, possibly due to laryngeal nerve involvement, is found in association with several CMT types and can often mimic asthma. Patients with CMT disease have a high incidence of significant sleep apnea events whose severity is highly correlated with the severity of peripheral neuropathy. In patients with CMT type 1, a significant correlation between the apnea–hypopnea index and neurologic disability was found in one study of 14 unrelated patients, and body mass index and age were not correlated to apnea–hypopnea index. Researchers have hypothesized that sleep apnea events in CMT disease are the consequence of pharyngeal neuropathy affecting the function of pharyngeal dilator muscles, a phenomenon that increases the collapsibility of the upper airway, leading to recurring obstructive respiratory events.96,97 Bilevel positive airway pressure may be more appropriate than continuous positive airway pressure for treating sleep apnea in the patient with concomitant restrictive pulmonary impairment.98 Niemann-Pick Disease Niemann-Pick disease type C is a rare autosomal-recessive condition characterized by the accumulation of unesterified cholesterol in many tissues and storage of sphingolipids in liver and brain. Adult patients exhibit ataxia, dystonia, dementia, and vertical supranuclear palsy along with hepatosplenomegaly. Some patients report hypersomnia and cataplexy. Recent investigations have shown reduced CSF levels of hypocretin in this condition, which are likely responsible for sleep abnormalities and cataplexy.99 Vancova and coworkers suggest that lipid storage abnormalities in Niemann-Pick disease might affect hypocretin-containing cells. Cataplexy attacks respond to the administration of tricyclic antidepressants.

ACUTE ENCEPHALITIDES Sleeping Sickness Sleeping sickness is a meningoencephalitis caused by the protozoan Trypanosoma brucei. The parasite is transmitted to humans by the sting of the tsetse fly in Africa, where 20,000 new cases are reported each year. Sleeping sickness begins with a phase of systemic disease, after which the parasite invades the CNS with manifestations of insomnia

and daytime hypersomnia, followed by psychomotor retardation. The disease then progresses to extrapyramidal manifestations, ataxia, gait disorder, seizures, coma, and death. Polysomnography reveals sleep-onset REM periods shortly after CNS invasion by trypanosomes, then highamplitude slow waves suggesting a diffuse encephalopathy, with preservation of REM-sleep parameters until the final phases of the disease.100,101 CSF analysis has shown increases in cell count, high protein content, and increased immunoglobulin M (IgM) levels.102 Neuropathologic studies have shown demyelinating lesions in cerebral hemispheres and brainstem.103 Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis is an acute inflammatory demyelinating disease of the CNS following viral illness or vaccination. The disorder is probably mediated by immunologic mechanisms. There is a report of hypersomnia in a 5-year-old girl with acute disseminated encephalomyelitis.104 The CT of her head showed hypodensity lesions involving basal ganglia as well as posterior hypothalamus and brainstem. Following treatment with intravenous dexamethasone, hypersomnia improved and the lesions disappeared. Total sleep time and slow-wave sleep were increased, and REM stage was within the normal range in the polysomnographic study during the hypersomnic state. Hypocretin levels in CSF were not assayed. There are published case reports of severe sleep alterations including REM sleep behavior disorder, hypersomnia, and insomnia associated with limbic encephalitis that were in some instances reversed with immunotherapy and steroid administration.105,106 Transient obstructive sleep apnea has been described in association with presumed viral encephalopathy.107 Paradoxical respiratory efforts during sleep along with frequent episodes of tachybradycardia and asystole led to suspicion of obstructive sleep apnea syndrome, which was documented with portable polysomnography. All apnea events and cardiovascular concomitants resolved with continuous positive airway pressure (CPAP) applications. This case illustrates the occurrence of sleep-related transient respiratory obstructions in diffuse acute encephalopathy that, if undetected, can lead to serious cardiovascular consequences. Similar alterations can occur in acute encephalopathies of different etiologies. Sedating medications commonly administered to patients in the critical care setting can aggravate the sleep apnea syndrome. Encephalitis Lethargica Encephalitis lethargica of von Economo has virtually disappeared. Its peak incidence spanned several decades in the early part of the 20th century.108 The clinical and neuropathologic study of this form of encephalitis brought to light the correlation between hypothalamic lesions and sleep disorders and contributed to understanding of the links between basal ganglia lesions and extrapyramidal movement disorders.109 The most common forms in the context of an acute febrile encephalitis were lethargic and ophthalmoplegic followed by hyperkinetic.110 The postencephalitic syndrome with prominent parkinsonian features was diagnosed on average 2 years after the episode of acute



Figure 93-1  CT scan of the head of a 55-year-old man complaining of headaches and excessive daytime somnolence that was initially diagnosed as sleep apnea syndrome. The large cystic mass compressing the diencephalon and floor of the third ventricle was found at operation to be a craniopharyngioma. (Reprinted with permission from Culebras A. Clinical handbook of sleep disorders. Boston: Butterworth-Heinemann; 1996.)

encephalitis lethargica, although it often appeared immediately afterward.108

BRAIN TUMORS Brain tumors can disrupt sleep–wake cycles by virtue of their location or indirectly by causing intracranial hypertension or hydrocephalus, or both. Symptomatic narcolepsy has been reported in association with craniopharyngioma compressing the floor of the third ventricle (Fig. 93-1).111 Symptomatic narcolepsy has also been reported in gliomas and colloid cysts of the third ventricle, as well as in pituitary adenomas and midbrain gliomas.112 Lower brainstem tumors have been associated with severe hypoventilation and respiratory failure during sleep (Ondine’s curse) requiring tracheotomy. Increased intracranial hypertension and obstructive hydrocephalus have been associated with subalertness and lethargy. Sleepiness following hypothalamic injury in the course of resection of an astrocytoma has been reported in association with a low concentration of hypocretin in CSF.113 Fatigue and drowsiness are prominent symptoms in patients with systemic cancer and brain metastases.114 SPINAL CORD DISEASE Pathophysiology Sleep-related ventilatory function depends on the integrity of the spinal cord. In patients with spinal cord lesions, sleep disturbances related to respiratory dysfunction are common. The phrenic nerve controls diaphragmatic motor function. It originates in the phrenic nucleus, which forms

CHAPTER 93  •  Other Neurologic Disorders  1071

the ventral medial cell column of the cervical ventral gray horn, extending from C3 to the caudal part of C5. The descending respiratory pathway is formed by crossed fibers situated deep in the anterior white column in the vicinity of the anterior horn projecting mainly from the ventral respiratory group in the medulla. High cervical lesions and phrenic nerve damage cause unilateral or bilateral paralysis of the diaphragm, depending on the extent of the cervical cord lesion or on whether one or both phrenic nerves are involved. The intercostal muscles receive their innervation via descending pathways located dorsal to diaphragmatic pathways in the vicinity of the lateral spinothalamic tract. Voluntary respiration is mediated by fibers in the lateral pyramidal tract, whereas involuntary automatic respiration is mediated by reticulospinal fibers emerging from the brainstem respiratory centers. Spinal motor nuclei situated in segments T1 to T11 give origin to intercostal nerves that innervate intercostal muscles. Accessory respiratory muscles receive innervation from cranial nerve XI and nerves C1 to C8. Upper airway muscles involved in nasal, pharyngeal, and laryngeal dilation are innervated by cranial nerves V (tensor veli palatini muscles), VII (levator alae nasi muscles), X (cricothyroid and thyroarytenoid muscles), XII (genioglossus, genihyoid, sternohyoid, and sternothyroid muscles), and C1 to C4 (geniohyoid, sternothyroid, and sternohyoid muscles). These are unaffected by spinal cord lesions below C5, a lesion compatible with a respirator-free life. Lesions of the phrenic and intercostal motor neurons in the spinal cord can occur with spinal cord tumors, spinal trauma, spinal surgery (e.g., cervical cordotomy or anterior spinal surgery), and in demyelinating myelitis. Patients with syringomyelia and syringobulbia (fluid-filled cavities in the spinal cord or brainstem, respectively) with dysphonia and dysphagia are particularly prone to severe respiratory disturbances during sleep (Video 93-1).115 In one study of 22 patients with stable spinal cord lesion above T10,48 45% had some evidence of obstructive sleep apnea syndrome. Cognitive changes in patients with tetraplegia may be related to sleep apnea syndrome.116 Although excessive daytime somnolence secondary to sleep-related respiratory dysfunction is the most common symptom, patients with spinal cord diseases can complain of insomnia as a result of immobility, neck pain, and central pain syndrome. Phrenic nerve damage leads to diaphragmatic paralysis. Unilateral paralysis is asymptomatic, but bilateral paralysis is invariably symptomatic and may be life-threatening. Paresis or weakness with partial diaphragmatic dysfunction can cause sleep-related ventilatory insufficiency. In the supine position, patients complain of profound difficulty breathing because of decreased lung volume and increased respiratory effort as the abdominal contents rise into the thorax. In bilateral severe or acute cases, patients present with nocturnal orthopnea, cyanosis, and fragmented sleep followed by morning headaches, vomiting, and daytime lethargy. Phrenic nerve weakness or paralysis is most prominent in REM sleep when the diaphragm is the only functional respiratory muscle. Upper airway resistance is also higher in REM sleep, contributing to decreased ventilatory efficiency. Patients with weak pharyngeal dilator

1072  PART II / Section 11  •  Neurologic Disorders

muscles and a weak diaphragm as a result of a diffuse neuromuscular disorder or bilateral phrenic nerve paralysis exhibit the most serious compromise in REM sleep.117 Craniovertebral junction malformation or Chiari malformation in adults, with or without syringomyelia and basilar invagination, produces neuronal dysfunction of the brainstem, cerebellum, cranial nerves, and upper spinal cord (Video 93-2). The incidence of sleep apnea syndrome is significantly higher in patients with craniovertebral junction malformation, especially if basilar invagination is present.118 Obstructive sleep apnea syndrome can appear following anterior cervical spine fusion. Guilleminault and coworkers119 found that placement of anterior cervical plates at the C2 to C4 level reduced the size of the upper airway, causing obstructive sleep apnea syndrome. The condition was controlled with positive airway pressure applications. Restless legs syndrome and PLMS can appear in patients after acute transverse myelitis.120 PLMS has been reported in patients with syringomyelia.121 Treatment Treatment for sleep-related respiratory dysrhythmias in spinal cord diseases should follow the same general principles as those suggested for neuromuscular disorders. Noninvasive ventilation has improved the quality of life and increased survival in many forms of neuromuscular disorder. Patients with significant neuromuscular disorders or high spinal cord disease should be considered candidates for evaluation with polysomnography. In most patients with neuromuscular conditions the most effective time to introduce noninvasive ventilation is when symptomatic sleep-disordered breathing develops.122 A word of caution comes from a study123 showing that obese patients who have spinal cord injury and are taking antispasticity medications might have a higher risk for developing snoring and obstructive sleep apnea. The greatest risk appeared in patients taking diazepam or diazepam and baclofen in combination.

❖  Clinical Pearls Headaches on awakening, as observed in sleep apnea patients, are also seen in patients with severe hypertension, depression, intracranial tumor, muscle-contraction headache, alcohol intoxication, and craniofacial sinus disease. In headache patients, causes for concern are first or worst-ever headache, associated neurologic symptoms or signs, progressive worsening of headache over days or weeks, intractable nausea or vomiting, fever, lethargy, confusion, and stiff neck. Following significant TBI, the early appearance of sleep–wake cycling indicates a better prognosis. The association between multiple sclerosis and sleep disorders is more common than expected by chance. Sleep apnea in patients with Charcot-Marie-Tooth disease may be the consequence of pharyngeal neuropathy affecting the function of pharyngeal dilator muscles.

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CHAPTER 93  •  Other Neurologic Disorders  1073 30. Pérez MF, Young WB, Kaup AO, et al. Fibromyalgia is common in patients with transformed migraine. Neurology 2001;57: 1326-1328. 31. Smeyers P. Headaches in childhood: association with sleep disorders and psychological implications. Rev Neurol 1999;28(Suppl. 2):S150-S155. 32. Luc ME, Gupta A, Birnberg JM, Reddick D, Kohrman MH. Characterization of symptoms of sleep disorders in children with headache. Pediatr Neurol 2006;34:7-12. 33. Roth T, Schwartz JR, Hirshkowitz M, et al. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007;3(6):595-602. 34. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and doseresponse study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17-24. 35. Buysse DB, Schweitzer PK, Moul DE. Clinical pharmacology of other drugs used as hypnotics. In: Kryger MH, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th ed. Philadelphia: Saunders; 2005. p. 452-467. 36. Nishino S, Mignot E. Wake-promoting medications: basic mechanisms and pharmacology. In: Kryger MH, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th ed. Philadelphia: Saunders; 2005. p. 468-483. 37. Paiva T, Batista A, Martins P, Martins A. The relationship between headaches and sleep disturbances. Headache 1995;35:590-596. 38. Baumel B. Migraine: a pharmacologic review with newer options and delivery modalities. Neurology 1994;44:S13-S17. 39. Holmgren K, Sheikholeslam A, Riise C. Effect of full arch maxillary occlusal splint on parafunctional activity during sleep in patients with nocturnal bruxism and signs and symptoms of craniomandibular disorders. J Prosthet Dent 1993;69:293-297. 40. Goldstein M. Traumatic brain injury. Ann Neurol 1990;27:237. 41. Sosin DM, Sniezek JE, Thurman DJ. Incidence of mild and moderate brain injury in the United States. Brain Injury 1996;10: 47-54. 42. Rae-Grant AD, Barbour PJ, Reed J. Development of a novel EEG rating scale for head injury using dichotomous variables. EEG Clin Neurophysiol 1991;79:349-357. 43. Ron S, Algom D, Hary D, Cohen M. Time-related changes in the distribution of sleep stages in brain-injured patients. Electroencephalogr Clin Neurophysiol 1980;48:432-441. 44. Levin HS, Mattis S, Ruff RM, et al. Neurobehavioral outcome following minor head injury: a three center study. J Neurosurg 1987;66:234-243. 45. Segalowitz SJ, Lawson S. Subtle symptoms associated with selfreported mild head injury. J Learn Disabil 1995;28:309-319. 46. Makley MJ, English JB, Drubach DA, et al. Prevalence of sleep disturbance in closed head injury patients in a rehabilitation unit. Neurorehabil Neural Repair 2008;22:341-347. 47. Baumann CR, Werth E, Stocker R, et al. Sleep–wake disturbances 6 months after traumatic brain injury: a prospective study. Brain 2007;130:1873-1883. 48. Short DJ, Stradling JR, Williams SJ. Prevalence of sleep apnea in patients over 40 years of age with spinal cord lesions. J Neurol Neurosurg Psychiatry 1992;55:1032-1036. 49. Cahan C, Gothe B, Decker MJ, et al. Arterial oxygen saturation over time and sleep studies in quadriplegic patients. Paraplegia 1993;31:172-179. 50. Bach JR, Wang TG. Pulmonary function and sleep disordered breathing in patients with traumatic tetraplegia: a longitudinal study. Arch Physical Med Rehabil 1994;75:279-284. 51. Guilleminault C. Post-traumatic hypersomnia. Course 3AS.007. 52nd Annual Meeting of the American Academy of Neurology, San Diego, Calif, 2000. 52. Good JL, Barry E, Fishman PS. Posttraumatic narcolepsy: the complete syndrome with tissue typing. J Neurosurg 1989;71: 765-767. 53. Maccario M, Ruggles KM, Meriwether MW. Post-traumatic narcolepsy. Military Med 1987;152:370-371. 54. Ripley B, Overeem S, Fujiki N, et al. CSF hypocretin/orexin levels in narcolepsy and other neurologic conditions. Neurology 2001; 57:2253-2258. 55. Dempsey OJ, McGeoch P, de Silva RN, et al. Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation. Neurology 2003;61:537-540.

56. Mignot E, Chen W, Black J. On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy. Sleep 2003;26:646-649. 57. Gill RG, Young JPR, Thomas DJ. Kleine-Levin syndrome: report of two cases with onset of symptoms precipitated by head trauma. Br J Psychiatry 1988;152:410-412. 58. Billiard M, Negri C, Baldy-Moulinier M, et al. Organisations du sommeil chez les sujets attaint d’inconscience post-traumatique chronique. Rev EEG Neurophysiol 1979;9:149-152. 59. Alster J, Pratt H, Feinsod M. Density spectral array, evoked potentials, and temperature rhythms in the evaluation and prognosis of the comatose patient. Brain Injury 1993;7:191-208. 60. Ouellet MC, Beaulieu-Bonneau S, Morin CM. Insomnia in patients with traumatic brain injury: frequency, characteristics, and risk factors. J Head Trauma Rehabil 2006;21:199-212. 61. Fichtenberg NL, Zafontes RD, Putnam S, et al. Insomnia in a post– acute brain injury sample. Brain Injury 2002;16:197-206. 62. Fichtenberg NL, Millis SR, Mann NR, et al. Factors associated with insomnia among post–acute traumatic brain injury survivors. Brain Injury 2000;14:659-667. 63. Thaxton L, Myers MA. Sleep disturbances and their management in patients with brain injury. J Head Trauma Rehabil 2002;17: 335-348. 64. Humphrey ME, Zangwill OL. Cessation of dreaming after brain injury. J Neurol Neurosurg Psychiatry 1951;14:322-325. 65. Prigatano GP, Orr WC, Zeiner HK. Sleep and dreaming disturbances in closed head injury patients. J Neurol Neurosurg Psychiatry 1982;45:78-80. 66. Mahowald MW, Woods SR, Schenck CH. Sleeping dreams, waking hallucinations, and the central nervous system. Dreaming 1998;8: 89-102. 67. Jacobsohn E. Fall von Narcolepsie. Klin Wochenschr 1926;2:2188. 68. Guillain G, Alajouanine T. La somnolence dans la sclérose en plaques. Les episodes aigus ou subaigus de la sclérose en plaques pouvant simuler l’encéphalite léthargique. Ann Med 1928;24: 111-118. 69. Grigioresco D. Contribution a l’étude des troubles du sommeil aux lésions des noyeaux gris centraux dans la sclérose en plaques. Rev Neurol II 1932;27-45. 70. Berg O, Hanley J. Narcolepsy in two cases of multiple sclerosis. Acta Neurol Scand 1963;39:252-257. 71. Ekbom K. Familial multiple sclerosis associated with narcolepsy. Arch Neurol 1966;15:337-344. 72. Leo GJ, Rao M, Bernardin L. Sleep disturbances in multiple sclerosis. Neurology 1991;41:320. 73. Clark CM, Fleming JA, Li D, et al. Sleep disturbance, depression, and lesion site in patients with multiple sclerosis. Arch Neurol 1992;49:641-643. 74. Hillert J, Olerup O. Multiple sclerosis is associated with genes within or close to the HLA-DR-DQ subregion on a normal DR15, DQ6, Dw2 haplotype. Neurology 1993;43:163-168. 75. Younger DS, Pedley TA, Thorpy MJ. Multiple sclerosis and narcolepsy: possible similar genetic susceptibility. Neurology 1991;41: 447-448. 76. Fogdell A, Hillert J, Sachs C, Olerup O. The multiple sclerosis and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens 1995;46:333-336. 77. Iseki K, Mezaki T, Oka Y, et al. Hypersomnia in MS. Neurology 2002;59:2006-2007. 78. Italian REMS Study Group, Manconi M, Ferini-Strambi L, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep 2008;31:944-952. 79. Saunders J, Whitham R, Schaumann B. Sleep disturbance, fatigue, and depression in multiple sclerosis. Neurology 1991;41:320. 80. Tachibana N, Howard RS, Hirsch NP, et al. Sleep problems in multiple sclerosis. Eur Neurol 1994;34:320-323. 81. Ferini-Strambi L, Filippi M, Martinelli V, et al. Nocturnal sleep study in multiple sclerosis: correlations with clinical and brain magnetic resonance imaging findings. J Neurol Sci 1994;125(2): 194-197. 82. Zifko UA. Management of fatigue in patients with multiple sclerosis. Drugs 2004;64:1295-1304. 83. Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45:19561961.

1074  PART II / Section 11  •  Neurologic Disorders 84. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis: a two centre phase study. J Neurol Neurosurg Psychiatry 2002;72: 179-183. 85. Schluter B, Aguigah G, Andler W. Hypersomnia in multiple sclerosis. Klin Padiatr 1996;208:103-105. 86. Wang CY, Kawashima H, Takami T, et al. A case of multiple sclerosis with initial symptoms of narcolepsy. Brain Dev 1998;30: 300-306. 87. Sandyk R. Resolution of sleep paralysis by weak electromagnetic fields in a patient with multiple sclerosis. Int J Neurosci 1997;90: 145-157. 88. Sandyk R. Weak electromagnetic fields restore dream recall in patients with multiple sclerosis. Int J Neurosci 1995;82:113-125. 89. Sandyk R. Suicidal behavior is attenuated in patients with multiple sclerosis by treatment with electromagnetic fields. Int J Neurosci 1996;87:5-15. 90. Sandyk R. Resolution of partial cataplexy in multiple sclerosis by treatment with weak electromagnetic fields. Int J Neurosci 1996; 84:157-164. 91. Syed BH, Rye DB, Singh G. REM sleep behavior disorder and SCA-3 (Machado-Joseph disease). Neurology 2003;60:148. 92. Gilman S, Koeppe RD, Chervin FB, et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003;61:29-34. 93. Friedman JH, Fernandez HH, Sudarsky LR. REM behavior disorder and excessive daytime somnolence in Machado-Joseph disease (SCA-3). Mov Disord 2003;18:1520-1522. 94. Iranzo A, Muñoz E, Santamaría J, et al. REM sleep behavior disorder and vocal cord paralysis in Machado-Joseph disease. Mov Disord 2003;18:1179-1183. 95. Culebras A. Sleep disorders and neuromuscular disorders. In: Culebras A, editor. Sleep disorders and neurologic diseases. New York: Informa Healthcare USA; 2007. 96. Dematteis M, Pépin JL, Jeanmart M, et al. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet 2001; 357:267-272. 97. Dziewas R, Waldmann N, Böntert M, et al. Increased prevalence of obstructive sleep apnoea in patients with Charcot-Marie-Tooth disease: a case control study. J Neurol Neurosurg Psychiatry 2008 Jul;79(7):829-831. 98. Aboussouan LS, Lewis RA, Shy ME. Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease. Lung 2007;185:1-7. 99. Vankova J, Stepanova I, Jech R, et al. Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C. Sleep 2003;26: 427-430. 100. Schwartz BA, Escande C. Sleeping sickness: sleep study of a case. Electroencephalogr Clin Neurophysiol 1970;29:83. 101. Buguet A, Bisser S, Josenando T, et al. Sleep structure: a new diagnostic tool for stage determination in sleeping sickness. Acta Trop 2005;93:107-117. 102. Whittle HC, Greenwood BM, Bidwell DE, et al. IgM and antibody measurements in the diagnosis and management of Gambian trypanosomiasis. Am J Trop Med Hyg 1977;26:1129-1134. 103. Kristensson K, Bentivoglio M. Pathology of trypanosomiasis. In: Dumas M, Bouteille B, Bughet A, editors. Progress in human African trypanosomiasis, sleeping sickness. Paris: Springer; 1999. p. 157-181

104. Kanbayashi T, Goto A, Hishikawa Y, et al. Hypersomnia due to acute disseminated encephalomyelitis in a 5-year old girl. Sleep Med 2001;2:347-350. 105. Montiel P, Sellal F, Clerc C, et al. Limbic encephalitis with severe sleep disorder associated with voltage-gated potassium channels (VGKCs) antibodies. Rev Neurol (Paris) 2008;164:181-184. 106. Compta Y, Iranzo A, Santamaría J, et al. REM sleep behavior disorder and narcoleptic features in anti-Ma2–associated encephalitis. Sleep 2007;30(6):767-769. 107. Dyken ME, Yamada T, Berger HA. Transient obstructive sleep apnea and asystole in association with presumed viral encephalopathy. Neurology 2003;60:1692-1694. 108. Corral-Corral I, Quereda Rodríguez-Navarro C. Post-encephalitic syndromes in the Spanish medical literature. Rev Neurol 2007; 44:499-506. 109. Ransmayr G. Constantin von Economo’s contribution to the understanding of movement disorders. Mov Disord 2007;22: 469-475. 110. Corral-Corral I, Quereda Rodríguez-Navarro C. How did encephalitis lethargica affect Spain? An analysis of the cases reported between 1918 and 1936. Rev Neurol 2007;44:245-253 111. Culebras A. Sleep disorders associated with psychiatric, medical and neurologic disorders. In: Culebras A, editor. Clinical handbook of sleep disorders. Boston: Butterworth-Heinemann; 1996. p. 233-281. 112. Aldrich MS, Naylor MW. Narcolepsy associated with lesions of the diencephalons. Neurology 1989;39:1505-1508. 113. Arii J, Kanbayashi T, Tanabe Y, et al. A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology 2001;56:1775-1776. 114. Chow E, Fan G, Hadi S, et al. Symptom clusters in cancer patients with brain metastases. Clin Oncol (R Coll Radiol) 2008;20:76-82. 115. Nogués M, Gene R, Benarroch E, et al. Respiratory disturbances during sleep in syringomyelia and syringobulbia. Neurology 1999;52:1777-1783. 116. Sajkov D, Marshall R, Walker P, et al. Sleep apnea related hypoxia is associated with cognitive disturbances in patients with tetraplegia. Spinal Cord 1998;36:231-239. 117. Culebras A. Sleep and neuromuscular disorders. Neurol Clin 1996;14:791-805. 118. Botelho RV, Bittencourt LR, Rotta JM, Tufik S. A prospective controlled study of sleep respiratory events in patients with craniovertebral junction malformation. J Neurosurg 2003;99: 1004-1009. 119. Guilleminault C, Li KK, Philip P, et al. Anterior cervical spine fusion and sleep disordered breathing. Neurology 2003;61:9799. 120. Brown LK, Heffner JE, Obbens EA. Transverse myelitis associated with restless legs syndrome and periodic movements of sleep responsive to an oral dopaminergic agent but not to intrathecal baclofen. Sleep 2000;23:591-594. 121. Nogués M, Cammarota A, Leiguarda R, et al. Periodic limb movements in syringomyelia and syringobulbia. Mov Disord 2000;15: 113-119. 122. Simonds AK. Recent advances in respiratory care for neuromuscular disease. Chest 2006;130(6):1879-1886. 123. Ayas NT, Epstein LJ, Lieberman SL, et al. Predictors of loud snoring in persons with spinal cord injury. J Spinal Cord Med 2001;24:30-34.

Parasomnias

Section

Mark W. Mahowald and Michel A. Cramer Bornemann 94  Non-REM Arousal

Parasomnias 95  REM Sleep Parasomnias 96  Other Parasomnias

97  Idiopathic Nightmares and

Dream Disturbances Associated with Sleep–Wake Transitions

Non-REM Arousal Parasomnias Mark W. Mahowald and Michel A. Cramer Bornemann Abstract Parasomnias are defined as unpleasant or undesirable behavioral or experiential phenomena that occur predominantly or exclusively during the sleep period. These were initially thought to represent a unitary phenomenon, often attributed to psychiatric disease. As more parasomnias are being carefully studied both polygraphically and clinically, it is becoming apparent that parasomnias are not a unitary phenomenon, but rather are due to a large number of completely different conditions, most of which are diagnosable and treatable. Moreover, most, in fact, are not the manifestation of psychiatric disorders and are far more prevalent than previously suspected. The parasomnias may be conveniently categorized as primary parasomnias (disorders of the sleep states per se), and secondary parasomnias (disorders of other organ systems manifest themselves during sleep). The primary sleep parasomnias can be classified according to the sleep state of

There is compelling evidence that extensive reorganization of central nervous system activity occurs as the brain cycles through the three primary states of being: wakefulness, non–rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. The concept that certain parts of the nervous system are active in one state but not in the other two is erroneous. Almost all portions of the nervous system are active across all three states of being, but active in a different mode. The reticular response reversal phenomenon, in which excitation of the same anatomic site can have opposite effects on motor activity, depending upon the state (wake or REM) during stimulation is testimony to that fact.2,3 Relevant to many of the parasomnias occurring in humans is the demonstration that the effects of cholinergic drug injection into the pontine reticular formation of cats may have dramatically different effects, depending upon the state of the animal at the time of injection: If the drug is administered during NREM sleep, a state identical to naturally occurring REM sleep is induced; if it is administered during wakefulness, a waking-dissociated state occurs, characterized by EEG desynchronization and muscle atonia in a cat that appeared to be awake and able to track objects in its visual field.4 The concept that

12

98  Disturbed Dreaming as a

Factor in Medical Conditions 99  Sleep Bruxism

Chapter

94

origin: rapid eye movement (REM) sleep, non-REM (NREM) sleep, or miscellaneous (i.e., those not respecting sleep state). The secondary sleep parasomnias can be further classified by the organ system involved1 (see Box 96-1). The focus of this chapter is on the NREM sleep arousal parasomnias, which occur on a broad spectrum and include confusional arousals, sleepwalking, and sleep terrors. The underlying pathophysiology is state dissociation—the brain is partially awake and partially in NREM sleep. The result of this mixed state of being is that the brain is awake enough to perform very complex, and often protracted motor or verbal functions, but it is asleep enough not to have conscious awareness of or responsibility for these actions. These NREM parasomnias are not usually due to underlying serious psychological or psychiatric conditions, and more importantly, they are diagnosable and usually readily treatable.

wake and sleep are all-or-none and therefore mutually exclusive states is erroneous. Sleep is not a global or whole-brain phenomenon.5 Such a waking-dissociated state is likely the basis for many human parasomnias, both REM and NREM parasomnias. A intracerebral neurophysiologic study in a patient with a NREM parasomnia supports this concept.6 Parasomnias are clinical phenomena that appear as the brain becomes reorganized across states; therefore, they are particularly apt to occur during the transition periods from one state to another. In view of the large number of neural networks, neurotransmitters, and other statedetermining substances that must be recruited synchronously for full state declaration and the frequent transitions among states during the wake–sleep cycle, it is surprising that errors in state declaration do not occur more often than they do.7-9 The concept that sleep and wakefulness are not invariably mutually exclusive states and that the various statedetermining variables of wakefulness, NREM sleep, and REM sleep can occur simultaneously or oscillate rapidly is key to the understanding the primary sleep parasomnias. The mixture of wakefulness and NREM sleep would explain confusional arousals (sleep drunkenness), automatic 1075

1076  PART II / Section 12  •  Parasomnias

behavior, or microsleeps.9 The tonic and phasic components of REM sleep can become dissociated, intruding or persisting into wakefulness, explaining cataplexy, wakeful dreaming, lucid dreaming, and the persistence of motor activity during REM sleep (REM sleep behavior disorder [RBD]).10

EPIDEMIOLOGY AND RISK FACTORS The disorders of arousal are the most impressive and most common of the NREM sleep parasomnias. These share common features: They tend to arise from slowwave sleep (stages 3 and 4 of NREM sleep), therefore usually occurring in the first third of the sleep cycle (and rarely during naps), and they are common in childhood, usually decreasing in frequency with increasing age.11,12 There is often a family history of disorders of arousal; however, this association has recently been questioned.13 A specific HLA gene (DQB1) appears to confer susceptibility to sleepwalking.14 Importantly, although they most commonly occur during stage N3 sleep (stages 3 and 4 of NREM sleep or slow-wave sleep), disorders of arousal can occur during any stage of NREM sleep, and they can occur late in the sleep period.15 Disorders of arousal may be associated with febrile illness, prior sleep deprivation, physical activity, or emotional stress.16-18 Contrary to popular opinion, alcohol appears not to play a role in triggering disorders of arousal.19 Medication-induced cases have been reported with sedative-hypnotics, neuroleptics, minor tranquilizers, stimulants, and antihistamines, often in combination with each other.17,20-24 There have been numerous reports of extremely complex activities attributed to sedative-hypnotic agents, often resulting in forensic issues. This issue is thoroughly discussed in Chapter 63. In some women, disorders of arousal be exacerbated by pregnancy or menstruation, whereas in others, disorders of arousal may be alleviated by pregnancy, suggesting hormonal influences.25-27 Such precipitants should be thought of as triggering events in susceptible persons, and not causing them. Underlying predisposing, priming, and precipitating factors have been thoroughly reviewed elsewhere.18 Numerous other sleep disorders that result in arousals (obstructive sleep apnea,28 nocturnal seizures, or periodic limb movements) can provoke these disorders. Sleepdisordered breathing has been found to be more prevalent in children and adults with disorders of arousal. One study found that sleep fragmentation induced by sleepdisordered breathing is more common in adults with disorders of arousal than in normal subjects.29,30 The combination of frequent arousals and sleep deprivation seen in these other sleep disorders provide fertile ground for the appearance of disorders of arousal. These represent a sleep disorder within a sleep disorder—the clinical event is a disorder of arousal, but the true culprit is a different, unrelated sleep disorder. This would explain the common clinical experience of improvement of disorders of arousal following identification and treatment of obstructive sleep apnea.31 Conversely, effective treatment of obstructive sleep apnea with nasal CPAP can result in disorders of arousal, presumably associated with deep NREM sleep rebound.32,33

Persistence of these activities beyond childhood or their development in adulthood is often taken as an indication of significant psychopathology.34,35 Numerous studies have dispelled this myth, indicating that significant psychopathology is usually not present in adults with disorders of arousal.36-38 In one study in children, there was an association between disorders of arousal and anxiety.39 These arousals might not be the culmination of ongoing psychologically significant mentation, in that somnambulism can be induced in normal children by standing them up during slow-wave sleep,40,41 and sleep terrors can be precipitously triggered in susceptible persons by sounding a buzzer during slow-wave sleep.11,42 The mechanism of these disorders is not clear, but clearly both genetic43 and environmental factors are operant. It has been suggested that sleep terrors may be the manifestation of anomalous REM sleep mixed with NREM sleep.44

PATHOGENESIS In addition to the phenomenon of state dissociation, in which two states of being overlap or occur simultaneously, there are likely additional underlying physiologic phenomena that contribute to the appearance of complex motor actions during sleep. These include locomotor centers, sleep inertia, and sleep state instability. Locomotor Centers Locomotor centers, present in multiple sites in the central nervous system, may play a role in the disorders of arousal, which represent motor activity that is dissociated from waking consciousness.45 These areas project to the central pattern generator of the spinal cord, which itself is able to produce complex stepping movements in the absence of supraspinal influence.46 This accounts for the fact that decorticate experimental and barnyard animals are capable of performing very complex, integrated motor acts.47 A biological substrate is further supported by the similarity between spontaneously occurring sleep terrors in humans and sham rage induced in animals.48-50 Indeed, human neuropathology can result in similar activities.51-55 Dissociation of the locomotor centers from the parent state of NREM sleep would explain the presence of complex motor behavior seen in disorders of arousal. Spontaneous locomotion following decerebration in cats clearly indicates that such centers, if dysfunctional, release motor activity into the sleeping state.56,57 Single proton emission computed tomography (SPECT) study of a sleepwalker suggested activation of thalamocingulate pathways and persisting deactivation of other thalamocortical arousal systems, resulting in a dissociation between body sleep and mind sleep.58 The concept that the cortex itself can actually be a central pattern generator could explain the expression of previously learned behavior occurring during disorders of arousal.59 Sleep Inertia Sleep inertia (also termed sleep drunkenness) refers to a period of impaired performance and reduced vigilance following awakening from the regular sleep episode or from a nap. This impairment may be severe, last minutes



to hours, and be accompanied by polygraphically recorded microsleep episodes.60-63 Support of a gradual disengagement from sleep to wakefulness comes from neurophysiologic studies in animals64 and cerebral blood flow studies in humans.65-67 The persistent reduction, lasting minutes, of the photomyoclonic response upon awakening from NREM sleep is further confirmation of a less-thanimmediate transition from sleep to wakefulness.68 There appears to be great interindividual variability in the extent and duration of sleep inertia, both following spontaneous awakening after the major sleep period and following naps. Sleep inertia likely plays a role in the susceptibility to disorders of arousal.64 Sleep State Instability The cyclic alternating pattern (CAP) may also play a role in the etiology of disorders of arousal.69 CAP is a physiologic component of NREM sleep and is functionally correlated with long-lasting arousal oscillations. CAP is a measure of NREM instability, with high level of arousal oscillation.70 More sophisticated monitoring techniques, such as topographical EEG mapping, suggest that there may be more delta EEG activity before the onset of sleep terrors.71 There is no difference in the macrostructural sleep parameters between patients with disorders of arousal and controls. However, patients with disorders of arousal have been found to have increases in CAP rate, in number of CAP cycles, and in arousals with EEG synchronization. An increase in sleep instability and in arousal oscillation is a typical microstructural feature of slowwave sleep–related parasomnias and may play a role in triggering abnormal motor episodes during sleep in these patients.72,73 Microarousals preceded by EEG slow-wave synchronization during NREM sleep are more common in patients with sleepwalking and sleep terrors than in controls. This supports the existence of an arousal disorder in these persons.72 Although some have reported hypersynchronous delta activity on polysomnograms (PSGs) of young adults with sleepwalking.74 this has not been the experience of others.75 EEG spectral analysis studies indicate that patients with sleepwalking demonstrate an instability of slow-wave sleep, particularly in the early portion of the sleep period.76 Impairment of efficiency of inhibitory cortical circuits during wakefulness has been reported.77

CLINICAL FEATURES Disorders of arousal occur on a broad spectrum ranging from confusional arousals, through somnambulism (sleep walking), to sleep terrors (also termed pavor nocturnus and erroneously, incubus or succubus) (Videos 94-1 and 94-2). Some take the form of specialized behavior (discussed later) such as sleep-related eating and sleep-related sexual activity without conscious awareness. Confusional Arousals Confusional arousals are often seen in children and are characterized by movements in bed, occasionally thrashing about, or inconsolable crying.78 Sleep drunkenness is probably a variation on this theme.17 The prevalence of confusional arousals in adults is approximately 4%.79

CHAPTER 94  •  Non-REM Arousal Parasomnias  1077

Sleepwalking Sleepwalking is prevalent in childhood (1% to 17%), peaking at 11 to 12 years of age, and is far more common in adults (nearly 4%) than generally acknowledged.79-82 Sleepwalking may be either calm or agitated, with varying degrees of complexity and duration. Sleep Terrors Sleep terrors are the most dramatic disorder of arousal. It is commonly initiated by a loud, blood-curdling scream associated with extreme panic, followed by prominent motor activity such as hitting the wall, running around or out of the bedroom, even out of the house—resulting in bodily injury or property damage. A universal feature is inconsolability. Although the victim appears to be awake, he or she usually misperceives the environment, and attempts at consolation are fruitless and might serve only to prolong or even intensify the confusional state. Some degree of perception may be evident, such as running for and opening a door or window. Complete amnesia for the activity is typical, but amnesia may be incomplete.11,12,83 The intense endogenous arousal and exogenous unarousability constitute a curious paradox. As with sleepwalking, sleep terrors are much more prevalent in adults than generally acknowledged (4% to 5%).84 Although usually benign, sleep terrors may be violent, resulting in considerable injury to the victim or others or damage to the environment, occasionally with forensic implications.85,86 Specialized Forms of Disorders of Arousal Sleep-Related Eating Disorder The sleep-related eating disorder, characterized by frequent episodes of nocturnal eating, generally without full conscious awareness, usually not associated with waking eating disorders, likely represents a specialized form of disorder of arousal. This condition often responds to treatment with a combination of dopaminergic and opiate agents or topiramate.87 d-Fenfluramine, which is no longer available, has also been reported to be effective.88 Formal sleep studies are indicated, because sleep-related eating may be the manifestation of other sleep disorders such as restless legs syndrome, periodic limb movements of sleep, or obstructive sleep apnea, all of which predispose to arousal.89-94 Nocturnal binging may be induced by benzodiazepine medication.95 and sleep-related eating has been associated with zolpidem administration and olanzapine.96-98 The sleep-related eating disorder is distinct from the night-eating syndrome characterized by morning anorexia, evening hyperphagia (while awake), and insomnia and associated with hypothalamic-pituitary axis abnormalities.99-101 Sleepsex Inappropriate sexual behavior occurring during the sleep state without conscious awareness, presumably the result of and mixture of wakefulness and sleep, have been reported.102 Such activities can result in feelings of guilt, shame, or depression and can have medicolegal implications.103 (See also Chapter 63.)

1078  PART II / Section 12  •  Parasomnias Case Study An 18-year-old white man who resides in a rural Midwestern farming community is academically doing well as a senior in high school. The patient reluctantly presented to the Sleep Center based more upon the persistence of his mother, who has had increasing concerns over her only child’s safety, particularly at night. According to his parents, since childhood their son has had nocturnal activities arising within a few hours after sleep onset. Believing that these activities would resolve as their son grew out of adolescence and into adulthood, the parents were at first not overly concerned and were initially able to easily maintain the safety of their son by remaining vigilant and subtly intervening when necessary. With time these activities have maintained their almost nightly regularity but have developed at times into something more complex, sustained, and violent. Given that their son has grown to be 77 inches tall with a weight of 235 pounds, parental interventions to quell their son’s suddenly eruptive nocturnal activities have become problematic for both parties. The patient states that he has always been completely unaware of these episodes and has no recollection of the events the following morning. Additionally, the parents raise further concern over safety because their son intends to enroll in a college away from home and is looking forward to living in either a dormitory or a high-rise apartment. Without responsible vigilance in college, the parents fear the worst for their son. Of course, the patient, wanting to finally exert his independence, lacked proper insight into understanding the gravity of his situation and clearly had become antagonistic over his parents’ concerns. Given the patient’s continued lack of awareness in these matters, coupled with his sincere denial of any difficulties with either sleep initiation or maintenance, the direct involvement of the patient’s parents was crucial in attaining a comprehensive history as well as a thorough clinical characterization of their son’s activities from sleep. According to his mother, since childhood the patient has had sleep disturbances almost every night. Typically, these episodes occur within the first 2 hours after he has gone to bed, and only rarely do they occur in the latter third of the night. The episodes are characterized by somniloquy, somnambulism, and a general “thrashing around in his bed,” leaving his bedding in complete disarray. Less commonly, the patient abruptly wakes up his household with fits of “screaming and yelling at the top of his lungs.” Despite his parents’ efforts at reassurance and solace, the patient remained unreceptive and inconsolable. In the same way these “night terrors,” as the mother called them, came on, so too would they spontaneously abate. Though the patient’s nocturnal activities were unremitting over recent years, his parents began to discern a trend toward more worrisome physical actions. These particularly “severe” episodes were punctuated by

violent outbursts of punching, hitting, and kicking inflicted upon a foe unseen to the parents in the room. Never at any time were these combative actions directed toward the parents. Many times over recent years the patient was caught attempting to get out through the front door, even though he was visibly asleep. On one occasion the mother caught her son just as he was attempting to leave through an upstairs window, having “already completely kicked out the storm window.” In the last 2 years, it has not been uncommon for the patient to have sustained bruises and superficial cuts to his extremities as a result of these activities arising from sleep. Lastly, the parents note that these “severe” episodes increase in frequency when the patient is staying away from home, such as in a hotel or at summer camp. Aside from a mild form of delayed sleep phase syndrome and consequent volitional sleep deprivation supported by 3 weeks of sleep diaries, the patient has otherwise been absolutely healthy and has not suffered from any medical, neurologic, or mental conditions. The patient does not drink alcohol or partake in illicit drugs. The patient is not taking any prescription medications, including selective serotonin reuptake inhibitors (SSRIs). The patient does not have a history that suggests sleep-disordered breathing or any other primary sleep disorder. Family history is devoid of any nocturnal behavior suggestive of parasomnias. A formal nocturnal polysomnograph (PSG) was undertaken using a full seizure montage. The baseline PSG did not reveal any sleep-disordered breathing, nocturnal myoclonus, or periodic limb movements. Sleep architecture was within normal limits, and the patient attained a sleep efficiency of 96%. Stage REM was attained and observed to have normal atonia. A full seizure montage was employed. There was no electrical or clinical seizure activity. Four discrete episodes of spontaneous NREM-related confusional arousals were observed and were associated with complex motor activity (Fig. 94-1) with overt vocalizations. These confusional arousals were not associated with consequent EEG slowing. As suspected by the clinical history and further supported by the findings on the PSG, a NREM parasomnia was diagnosed. The patient developed a better understanding of his problem after replaying his findings on the PSG video monitor. Management strategies included teaching proper sleep hygiene and minimizing volitional sleep deprivation; refraining from or minimizing alcohol use; discussing techniques to ensure a supportive environment with appropriate responsible vigilance provided by a team of family or friends; lengthy instructional measures to ensure safety, including a strong recommendation for the patient to attain housing on the ground level or basement of his chosen residence; and nightly use of a long-acting sedative hypnotic of the benzodiazepine class.



CHAPTER 94  •  Non-REM Arousal Parasomnias  1079

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Figure 94-1  Polysomnographic example of disorder of arousal. This is a 1-minute epoch of a full seizure montage of the patient in the case study. Note the precipitous arousal from slow-wave sleep without anticipatory tachycardia. Although the patient appears to be awake and talking, the EEG shows persistent slowing.

DIAGNOSIS Isolated, often bizarre, sleep-related events may be experienced by perfectly normal people, and most do not warrant further extensive or expensive evaluation. The initial approach to the complaint of unusual sleep-related behavior is to determine whether further evaluation is necessary. The patient should be queried regarding the exact nature of the events. Because many of these episodes may be associated with partial or complete amnesia, additional descriptive information from a bed partner or other observer can prove invaluable. Home videotapes of the clinical event may be quite helpful. In general, indications for formal evaluation of parasomnias include activities that are potentially violent or injurious, are extremely disruptive to other household members, result in the complaint of excessive daytime sleepiness, and are associated with medical, psychiatric, or neurologic symptoms or findings.1 Serious attention should be paid to such parasomnia complaints under these circumstances. Formal PSG studies, appropriately performed, provide direct or indirect diagnostic information in the majority of cases. This is of more than academic interest, because most of these conditions are readily treatable. Emphasis must be placed on the types of studies required; routine PSGs performed for conventional sleep disorders are inadequate. In addition to the physiologic parameters monitored in the standard PSG, there must be an expanded EEG montage and there must be continuous audiovisual monitoring.74,104

Observation by an experienced technologist is invaluable. Multiple night studies may be required to capture an event. Interpretation should be made by a polysomnographer experienced in these disorders. Sleep deprivation prior to formal PSG study can increase the likelihood of capturing an event in the sleep laboratory.105 Unattended studies have no role in the evaluation of parasomnias.106

DIFFERENTIAL DIAGNOSIS Numerous other conditions can perfectly mimic the disorders of arousal. These include obstructive sleep apnea, REM sleep behavior disorder, nocturnal seizures, psychogenic dissociative disorders, and malingering.107-109 NREM parasomnias may be particularly difficult to differentiate from nocturnal epileptic phenomena.110 There may be an association between disorders of arou­ sal, migraine headache,111 neurofibromatosis type 1,112 or Tourette’s syndrome.113,114 In preverbal children, nocturnal cluster headaches can mimic sleep terrors.115 Obstructive sleep apnea may be associated with and even manifest as disorders of arousal.29,109,116 TREATMENT Given the high prevalence of these disorders in normal persons, formal sleep center evaluation should be confined to cases in which the sleep-related activities are

1080  PART II / Section 12  •  Parasomnias

potentially injurious or violent, are extremely bothersome to other household members, result in symptoms of excessive daytime sleepiness, or have unusual clinical characteristics. Treatment is often not necessary. Reassurance of their typically benign nature, lack of psychological significance, and the tendency to diminish over time, is often sufficient. Objective studies documenting efficacy of medication efficacy. Tricyclic antidepressants and benzodiazepines may be effective, and they should be administered if the activity is dangerous to person or property or extremely disruptive to family members.17 Paroxetine and trazodone have been reported effective in isolated cases of disorders of arousal.117,118 Nonpharmacologic treatment such as psychotherapy,42 progressive relaxation,119 or hypnosis120 is recommended for long-term management. Anticipatory awakening has been reported to be effective in treating sleepwalking in children.121 The avoidance of precipitants such as drugs and sleep deprivation is also important. Administration of dopaminergic agents, opiates, or topiramide has been reportedly effective in the sleep-related eating disorder.87,122-124

CLINICAL COURSE AND PREVENTION The natural history of the disorders of arousal is to diminish with increasing age. However, this pattern is hardly universal, and these conditions can persist into, or even begin in, adulthood. Identifiable risk factors in a given patient, such as sleep deprivation or alcohol or medication administration, should be avoided. PITFALLS AND CONTROVERSIES Inasmuch as the disorders of arousal are extremely prevalent in the normal population, the decision to treat with pharmacologic or behavioral therapy may be difficult. Certainly if there is a history of potentially violent or injurious behavior, treatment is warranted. However, our center has seen patients with a history of very benign and infrequent sleepwalking episodes in childhood present with severely injurious sleep-related behavior as adults.86 ❖  Clinical Pearl Disorders of arousal are very common in children and adults, and they are not related to significant underlying psychiatric or psychological problems. The activities may be very complex and protracted. Evaluation and treatment is advised for patients whose activities are potentially violent or are very disturbing to other family members. Because other parasomnias, particularly the REM sleep behavior disorder and nocturnal seizures, can perfectly mimic disorders of arousal, extensive PSG evaluation by clinicians experienced in these disorders is recommended.

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2. Chase MH, Wills N. Brain stem control of maseteric reflex activity during sleep and wakefulness. Exp Neurol 1979;64:118-131. 3. Chase MH. The motor functions of the reticular formation are multifaceted and state-determined. In: Hobson JA, Brazier MAB, editors. The reticular formation revisited. New York: Raven Press; 1980. p. 449-472. 4. Lopez-Rodriguez F, Kohlmeier K, Morales FR, et al. State dependency of the effects of microinjection of cholinergic drugs into the nucleus pontalis oralis. Brain Research 1994;649:271-281. 5. Krueger JM, Rector DM, Roy S, et al. Sleep as a fundamental property of neuronal assemblies. Nat Rev Neurosci 2008;9(12): 910-919. 6. Terzaghi M, Tassi L, Didato G, et al. Evidence of dissociated arousal states during NREM parasomnia from an intracerebral neurophysiological study. Sleep 2009;32:409-412. 7. Mahowald MW, Schenck CH. Status dissociatus—a perspective on states of being. Sleep 1991;14:69-79. 8. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology 1992;42:44-52. 9. Mahowald MW, Schenck CH. Evolving concepts of human state dissociation. Arch Ital Biol 2001;139:269-300. 10. Mahowald MW, Schenck CH. REM sleep behavior disorder. In: Kryger MH, Dement W, Roth T, editors. Principles and practice of sleep medicine. 2nd ed. Philadelphia: Saunders; 1994. p. 574-588. 11. Fisher C, Kahn E, Edwards A, et al. A psychophysiological study of nightmares and night terrors. I. Physiological aspects of the stage 4 night terror. J Nerv Ment Dis 1973;157:75-98. 12. Fisher C, Kahn E, Edwards A, et al. A psychophysiological study of nightmares and night terrors. III. Mental content and recall of stage 4 night terrors. J Nerv Ment Dis 1974;158:174-188. 13. Mahowald MW, Schenck CH. NREM sleep parasomnias. Neurol Clin 2005;23:1077-1106. 14. Lecendreux M, Bassetti C, Dauvilliers Y, et al. HLA and genetic susceptibility to sleepwalking. Molec Psychiatry 2003;8:114-117. 15. Naylor MW, Aldrich MS. The distribution of confusional arousals across sleep stages and time of night in children and adolescents with sleep terrors. Sleep Res 1991;20:308. 16. Vela Bueno A, Blanco BD, Cajal FV. Episodic sleep disorder triggered by fever—a case presentation. Waking Sleeping 1980; 4:243-251. 17. Nino-Murcia G, Dement WC. Psychophysiological and pharmacological aspects of somnambulism and night terrors in children. In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York: Raven Press; 1987. p. 873-879. 18. Pressman MR. Factors that predispose, prime, and precipitate NREM parasomnias in adults: clinical and forensic implications. Sleep Med Rev 2007;11:5-30. 19. Pressman MR, Mahowald MW, Schenck CH, et al. Alcohol-induced sleepwalking or confusional arousal as a defense to criminal behavior: review of scientific evidence, methods and forensic considerations. J Sleep Res 2007;16:198-212. 20. Warnes H, Osivka S, Montplaisir J. Somnambulistic-like behavior induced by lithium-neuroleptic treatment. Sleep Res 1993; 22:287. 21. Mendelson WB. Sleepwalking associated with zolpidem. J Clin Psychopharmacol 1994;14:150. 22. Harazin J, Berigan TR. Zolpidem tartrate and somnambulism. Mil Med 1999;164:669-670. 23. Chiu YH, Chen CH, Shen WW, et al. Somnambulism secondary to olanzapine treatment in one patient with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. [case reports letter] 2008;32:581-582. 24. Kolivakis TT, Margolese HC, Beauclair L, et al. Olanzapineinduced somnambulism. Am J Psychiatry [case reports letter]. 2001;158:1158. 25. Schenck CH, Mahowald MW. Two cases of premenstrual sleep terrors and injurious sleep-walking. J Psychosom Obstet Gynecol 1995;16:79-84. 26. Snyder S. Unusual case of sleep terror in a pregnant patient. Am J Psychiatry 1986;143:391. 27. Berlin RM. Sleepwalking disorder during pregnancy: a case report. Sleep 1988;11:298-300. 28. Guilleminault C, Silvestri R. Disorders of arousal and epilepsy during sleep. In: Sterman MB, Shouse MN, Passouant PP, editors. Sleep and epilepsy. New York: Academic Press; 1982. p. 513-531.



CHAPTER 94  •  Non-REM Arousal Parasomnias  1081 29. Espa F, Dauvilliers Y, Ondze B, et al. Arousal reactions in sleepwalking and night terrors in adults: the role of respiratory events. Sleep 2002;25:871-875. 30. Guilleminault C, Palombini L, Pelayo R, et al. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 2003;111:e17-e25. 31. Lateef O, Wyatt J, Cartwright R. A case of violent non-REM parasomnias that resolved with treatment of obstructive sleep apnea (abstract). Chest 2005;128:461S. 32. Millman RP, Kipp GR, Carskadon MA. Sleepwalking precipitated by treatment of sleep apnea with nasal CPAP. Chest 1991;99: 750-751. 33. Fietze I, Warmuth R, Witt C, et al. Sleep-related breathing disorder and pavor nocturnus. Sleep Res 1995;24A:301. 34. Kales JD, Kales A, Soldatos CR. Night terrors. Clinical characteristics and personality factors. Arch Gen Psychiatry 1980;47: 1413-1417. 35. Soldatos CR, Kales A. Sleep disorders: research in psychopathology and its practical implications. Acta Psychiatr Scand 1982;65: 381-387. 36. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related injury in 100 adult patients: a polysomnographic and clinical report. Am J Psychiatry 1989;146:1166-1173. 37. Guilleminault C, Moscovitch A, Leger D. Forensic sleep medicine: nocturnal wandering and violence. Sleep 1995;18:740-748. 38. Llorente MD, Currier MB, Norman S, et al. Night terrors in adults: phenomenology and relationship to psychopathology. J Clin Psychiatry 1992;53:392-394. 39. Laberge L, Tremblay RE, Vitaro F, et al. Development of parasomnias from childhood to early adolescence. Pediatrics 2000; 106:67-74. 40. Broughton RJ. Sleep disorders: disorders of arousal? Science 1968;159:1070-1078. 41. Kales A, Jacobson A, Paulson MJ, et al. Somnambulism: psychophysiological correlates. I. All-night EEG studies. Arch Gen Psychiatry 1966;14:586-594. 42. Kales JD, Cadieux RJ, Soldatos CR, et al. Psychotherapy with night-terror patients. Am J Psychother 1982;36:399-407. 43. Hori A, Hirose G. Twin studies on parasomnias. Sleep Res 1995;24A:324. 44. Arkin AM. Night-terrors as anomalous REM sleep component manifestation in slow-wave sleep. Waking Sleeping 1978;2: 143-147. 45. Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26:S225S232. 46. Mori S, Nishimura H, Aoki M. Brain stem activation of the spinal stepping generator. In: Hobson JA, Brazier MAB, editors. The reticular formation revisited. New York: Raven Press; 1980. p. 241-259. 47. Rossignol S, Dubuc R. Spinal pattern generation. Curr Opin Neurobiol 1994;4:894-902. 48. Elliott FA. Neuroanatomy and neurology of aggression. Psychiatr Ann 1987;17:385-388. 49. Siegel A, Pott CB. Neural substrates of aggression and flight in the cat. Prog Neurobiol 1988;31:261-283. 50. Bandler R. Brain mechanisms of aggression as revealed by electrical and chemical stimulation: suggestion of a central role for the midbrain periaqueductal region. Prog Psychobiol Physiol Psychol 1988;13:67-154. 51. Kelts KA, Hoehn MM. Hypothalamic atrophy. J Clin Psychiatry 1978;39:357-358. 52. Kelleffer FA, Stern WE. Chronic effects of hypothalamic injury. Arch Neurol 1970;22:419-429. 53. Reeves AG. Hyperphagia, rage, and dementia accompanying a ventromedial hypothalamic neoplasm. Arch Neurol 1969;20: 616-624. 54. Haugh RM, Markesbery WR. Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of behavior and endocrine and autonomic function. Arch Neurol 1983;40: 560-563. 55. Sano K, Mayanagi Y. Posteromedial hypothalamotomy in the treatment of violent, aggressive behavior. Acta Neurochir 1988;44(Suppl.):145-151.

56. Lai YY, Siegel JM. Brainstem-mediated locomotion and myoclonic jerks. I. Neural substrates. Brain Res 1997;745:257-264. 57. Lai YY, Siegel JM. Brainstem-mediated locomotion and myoclonic jerks. II. Pharmacological effects. Brain Res 1997;745:265-270. 58. Bassetti C, Vella S, Donati F, et al. SPECT during sleepwalking. Lancet 2000;356:484-485. 59. Yuste R, MacLean JN, Smith J, et al. The cortex as a central pattern generator. Nat Rev Neurosci 2005;6:477-483. 60. Achermann P, Werth E, Dijk D-J, et al. Time course of sleep inertia after nighttime and daytime sleep episodes. Arch Ital Biol 1995;134:109-119. 61. Dinges DF. Napping patterns and effects in human adults. In: Dinges DF, Broughton RJ, editors. Sleeping and alertness: chronobiological, behavioral, and medical aspects of napping. New York: Raven Press; 1989. p. 171-204. 62. Dinges DF. Are you awake? Cognitive performance and reverie during the hypnopompic state. In: Bootzin RR, Kihlstrom JF, Schacter DL, editors. Sleep and cognition. Washington, DC: American Psychological Association; 1990. p. 159-175. 63. Tassi P, Muzet A. Sleep inertia. Sleep Med Rev 2000;4:341-353. 64. Horner RL, Sanford LD, Pack AI, et al. Activation of a distinct arousal state immediately after spontaneous awakening from sleep. Brain Res 1997;778:127-134. 65. Koboyama T, Hori A, Sato T, et al. Changes in cerebral blood flow velocity in healthy young men during overnight sleep and while awake. EEG Clin Neurophysiol 1997;102:125-131. 66. Balkin TJ, Wesensten NJ, Braun AR, et al. Shaking out the cobwebs: changes in regional cerebral blood flow (rCBF) across the first 20 minutes of wakefulness. Journal of Sleep Res 1998;21:411.A. 67. Balkin TJ, Braun AR, Wesensten NJ, et al. The process of awakening: a PET study of regional brain activity patterns mediating the re-establishment of alertness and consciousness. Brain Res Bull 2002;12:2308-2319. 68. Meier-Ewert K, Broughton RJ. Photomyoclonic response of epileptic and non-epileptic subjects during wakefulness, sleep and arousal. EEG Clin Neurophysiol 1967;23:142-151. 69. Parrino L, Halasz P, Tassinari CA, et al. CAP, epilepsy and motor events during sleep: the unifying role of arousal. Sleep Med Rev 2006;10:267-285. 70. Terzano MG, Parrino L, Spaggiari MC. The cyclic alternating pattern sequences in the dynamic organization of sleep. EEG Clin Neurophysiol 1988;69:437-447. 71. Zadra AL, Nielsen TA. Topographical EEG mapping in a case of recurrent sleep terrors. Dreaming 1998;8:67-74. 72. Halasz P, Ujszaszi J, Gadoros J. Are microarousals preceded by electroencephalographic slow wave synchronization precursors of confusional awakenings? Sleep 1985;8:231-238. 73. Zuccone M, Oldani A, Ferini-Strambi L, et al. Arousal fluctuations in non–rapid eye movement parasomnias: the role of cyclic alternating pattern as a measure of sleep instability. J Clin Neurophysiol 1995;12:147-154. 74. Blatt I, Peled R, Gadoth N, et al. The value of sleep recording in evaluating somnambulism in young adults. EEG Clin Neurophysiol 1991;78:407-412. 75. Schenck CH, Pareja JA, Patterson AL, et al. An analysis of polysomnographic events surrounding 252 slow-wave sleep arousals in 38 adults with injurious sleepwalking and sleep terrors. J Clin Neurophysiol 1998;15:159-166. 76. Bruni O, Ferri R, Novelli L, et al. NREM sleep instability in children with sleep terrors: the role of slow wave activity interruptions. Clin Neurophysiol 2008;119:985-992. 77. Oliviero A, Della Marca G, Tonali PA, et al. Functional involvement of cerebral cortex in adult sleepwalking. J Neurol 2007;254:1066-1072. 78. Rosen G, Mahowald MW, Ferber R. Sleepwalking, confusional arousals, and sleep terrors in the child. In: Ferber R, Kryger M, editors. Principles and practice of sleep medicine in the child. Philadelphia: Saunders; 1995. p. 99-106. 79. Ohayon M, Guilleminault C, Priest RG. Night terrors, sleepwalking, and confusional arousal in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry 1999;60:268-276. 80. Hublin C, Kaprio J, Partinen M, et al. Prevalence and genetics of sleepwalking; a population-based twin study. Neurology 1997;48:177-181.

1082  PART II / Section 12  •  Parasomnias 81. Klackenberg G. Somnambulism in childhood—prevalence, course and behavior correlates. A prospective longitudinal study (6-16 years). Acta Paediatr Scand 1982;71:495-499. 82. Bixler EO, Kales A, Soldatos CR, et al. Prevalence of sleep disorders in the Los Angeles metropolitan area. Am J Psychiatry 1979;136: 1257-1262. 83. Kahn E, Fisher C, Edwards A. Night terrors and anxiety dreams. In: Ellman SD, Antrobus JS, editors. The mind in sleep psychology and psychophysiology. 2nd ed. New York: John Wiley & Sons; 1991. p. 437-447. 84. Crisp AH. The sleepwalking/night terrors syndrome in adults. Postgrad Med J 1996;72:599-604. 85. Mahowald MW, Bundlie SR, Hurwitz TD, et al. Sleep violence— forensic science implications: polygraphic and video documentation. J Forensic Sci 1990;35:413-432. 86. Mahowald MW, Schenck CH, Goldner M, et al. Parasomnia pseudo-suicide. J Forensic Sci 2003;48:1158-1162. 87. Howell MJ, Schenck CH, Crow SJ. A review of nighttime eating disorders. Sleep Med Rev 2009;13:23-34. 88. Mancini MC, Aloe F. Nocturnal eating syndrome: a case report with therapeutic response to dexfenfluramine. Sao Paulo Med J 1994;112:569-571. 89. Schenck CH, Mahowald MW. Review of nocturnal sleep-related eating disorders. Int J Eat Disord 1994;15:343-356. 90. Schenck CH, Hurwitz TD, O’Connor KA, et al. Additional categories of sleep-related eating disorders and the current status of treatment. Sleep 1993;16:457-466. 91. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep 1991;14: 419-431. 92. Manni R, Ratti MT, Tartara A. Nocturnal eating: prevalence and features in 120 insomniac referrals. Sleep 1997;20:734-738. 93. Winkelman JW. Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry 1998;59:14-19. 94. Vetrugno R, Manconi M, Ferini-Strambi L, et al. Nocturnal eating: sleep-related eating disorder or night eating syndrome? A videopolysomnographic study. Sleep 2006;29:949-954. 95. Menkes DB. Triazolam-induced nocturnal bingeing with amnesia. Austr N Z J Psychiatry 1992;26:320-321. 96. Paquet V, Strul J, Servais L, et al. Sleep-related eating disorder induced by olanzapine. [case reports letter]. J Clin Psychiatry 2002;63:597. 97. Hwang TJ, Ni HC, Chen HC, et al. Risk predictors for hypnosedative-related complex sleep behaviors: a retrospective, crosssectional pilot study. J Clin Psychiatry 2010 Apr 20. [Epub ahead of print] 98. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med 2007;3:637-638. 99. Birketvedt GS, Florholmen J, Sundsfjord J, et al. Behavioral and neuroendocrine characteristics of the night-eating syndrome. J Am Med Assoc 1999;282:657-663. 100. Birketvedt GS, Sundsfjord J, Florholmen JR. Hypothalamicpituitary-adrenal axis in the night eating syndrome. Am J Physiol— Endocrinol Metab 2001;282:657-663. 101. Stunkard A, Allison KC. Two forms of disordered eating in obesity: binge eating and night eating. Int J Obes Relat Metab Disord 2003;27:1-12. 102. Schenck CH, Arnulf I, Mahowald MW. Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences. Sleep 2007;2007: 683-702.

103. Guilleminault C, Moscovitch A, Yuen K, et al. Atypical sexual behavior during sleep. Psychosom Med 2002;64:328-336. 104. Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066. 105. Zadra A, Pilon M, Montplaisir J. Polysomnographic diagnosis of sleepwalking: effects of sleep deprivation. Ann Neurol 2008;63: 513-519. 106. Mahowald MW, Schenck CH. Parasomnia purgatory—the epileptic/non-epileptic interface. In: Rowan AJ, Gates JR, editors. Non-epileptic seizures. Boston: Butterworth-Heinemann; 1993. p. 123-139. 107. Schenck CH, Mahowald MW. REM parasomnias. Neurol Clin 1996;14:697-720. 108. Mahowald MW, Schenck CH. NREM parasomnias. Neurol Clin 1996;14:675-696. 109. Goodwin JL, Kaemingk KL, Fregosi RF, et al. Parasomnias and sleep disordered breathing in Caucasian and Hispanic children—the Tucson children’s assessment of sleep apnea study. BMC Medicine 2004;2:14. 110. Tinuper P, Provini F, Bisulli F, et al. Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep. Sleep Med Rev 2007;11:255-267. 111. Casez O, Dananchet Y, Besson G. Migraine and somnambulism. Neurology 2005;65:1334-1335. 112. Johnson H, Wiggs L, Stores G, et al. Psychological disturbance and sleep disorders in children with neurofibromatosis type 1. Dev Med Child Neurol 2005;47:237-242. 113. Barabas G, Matthews WS, Ferrari M. Disorders of arousal in Gilles de la Tourette’s syndrome. Neurology 1984;34:814-817. 114. Wand RR, Matazow GS, Shady GA, et al. Tourette syndrome: associated symptoms and most disabling features. Neurosci Biobehav Rev 1993;17:271-275. 115. Isik U, D’Cruz OF. Cluster headaches simulating parasomnias. Pediatr Neurol 2002;27:227-229. 116. Guillemiault C, Kirisoglu C, Bao G, et al. Adult chronic sleepwalking and its treatment based on polysomnography. Brain 2005;128: 1062-1069. 117. Lillywhite AR, Wilson SJ, Nutt DJ. Successful treatment of night terrors and somnambulism with paroxetine. Br J Psychiatry 1994;164:551-554. 118. Balon R. Sleep terror disorder and insomnia treated with trazodone: a case report. Ann Clin Psychiatry 1994;6:161-163. 119. Kellerman J. Behavioral treatment of night terrors in a child with acute leukemia. J Nerv Ment Dis 1979;167:182-185. 120. Hauri P, Silber MH, Boeve BF. The treatment of parasomnias with hypnosis: a 5-year follow-up study. J Clin Sleep Med 2007;3: 369-373. 121. Tobin JD Jr. Treatment of somnambulism with anticipatory awakening. J Pediatr 1993;122:426-427. 122. Schenck CH, Mahowald MW. Combined bupropion-levodopa therapy of nocturnal sleep-related eating and sleep disruption in two adults with chemical dependency (letter). Sleep 2000;23:587-588. 123. Schenck CH, Mahowald MW. Dopaminergic and opiate therapy of nocturnal sleep-related eating disorder associated with sleepwalking or unassociated with another nocturnal disorder (abstract). Sleep 2002;45:A249. 124. Winkelman JW. Treatment of nocturnal eating syndrome and sleep-related eating disorder with topiramate. Sleep Med 2003;4: 243-246.

REM Sleep Parasomnias Mark W. Mahowald and Carlos H. Schenck Abstract Rapid eye movement (REM) sleep is characterized by numerous physiologic variables that usually occur in concert to produce the fully declared REM sleep. The majority of the REM sleep parasomnias reflect state dissociation, a condition seen when not all of the elements usually comprising REM sleep are present, resulting in fascinating clinical phenomena. The most common and best-studied REM sleep parasomnia is the REM sleep behavior disorder (RBD). In patients with RBD, somatic muscle atonia—one of the defining features of REM sleep—is

REM SLEEP BEHAVIOR DISORDER The discovery of rapid eye movement (REM) sleep in 1953 by Aserinsky and Kleitman expanded the states of mammalian being to three: wakefulness, non-REM (NREM) sleep, and REM sleep. Each of these conditions has its own neuroanatomic, neurophysiologic, neuropharmacologic, and behavioral correlates. Intrusion of components of one state into another can cause severe symptoms in patients. In experiments reported in 1965, bilateral lesions of pontine regions adjacent to the locus coeruleus in cats caused absence of the expected atonia associated with REM sleep, allowing the cats to demonstrate prominent motor activities during REM sleep (oneiric activities).3 This animal model has been important in further studies demonstrating the similarity between the states of wakefulness and REM sleep4 and in studies evaluating the statedependent vulnerability to epileptic activity.5 In the 1970s, scattered reports of dream-enacting behavior involving humans appeared; the polygraphic and behavioral condition was sometimes referred to as “stage 1 REM with tonic electromyogram.”6-9 Recognition of REM sleep behavior disorder (RBD) as a distinct clinical disorder followed the report in 1986 of a series of adults with RBD.10 The cat model has been extended to the rat.11,12 Numerous physiologic phenomena occur during REM sleep13-26 and fall into two categories: tonic (appearing throughout a REM period) and phasic (occurring intermittently during a REM period). Tonic elements include electromyographic (EMG) suppression, low-voltage desynchronized electroencephalogram (EEG), high arousal threshold, hippocampal theta rhythm, elevated brain temperature, poikilothermia, olfactory bulb activity, and penile tumescence. Phasic elements include rapid eye movements (REMs), middle ear muscle activity, tongue movements, somatic muscle twitches of the limbs, variability of autonomic activity (cardiac and respiratory), and pontogeniculo-occipital (PGO) spikes. It is not known whether dreaming occurs tonically or phasically during REM sleep. The synchronizer (pacemaker) for the sleep–wake cycle appears to reside in the suprachiasmatic nucleus of the hypothalamus,27,28 but the generators or executors of the

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absent, permitting the acting out of dream mentation, often with violent or injurious results. RBD is overwhelmingly a disorder affecting older men, many of whom eventually develop neurodegenerative disorders. Increasingly, medications prescribed for psychiatric symptoms (predominantly selective serotonin reuptake inhibitors), are the cause of RBD. The vast majority of patients with RBD respond to clonazepam. Further study of the REM parasomnias will serve to teach us much about sleep and the function of the central nervous system.1,2

various REM phenomena, both tonic and phasic, are located in the pons.17,29,30 The tonic and phasic neurophysiologic processes underlying each state can be variously dissociated and recombined across states.31 For REM sleep, the processes that generally occur in concert may also be seen in dissociated form, both experimentally (e.g., REM sleep–deprived animals with PGO spikes occurring in NREM sleep and wakefulness)32 and in human and animal disease (narcolepsy). In narcolepsy, the best-understood dissociated state, the sleep attacks, hypnagogic hallucinations, sleep paralysis, cataplexy, and automatic behavior each represent the intrusion or persistence of one state of being into another (i.e., cataplexy may be the inappropriate isolated intrusion of REM sleep atonia into wakefulness, usually induced by an emotionally laden event).33,34 RBD likewise represents a dissociated state: REM sleep containing one element of wakefulness—muscle tone. Epidemiology and Risk Factors A recent phone survey of more than 4900 persons between the ages of 15 and 100 years of age indicated an overall prevalence of violent behavior in general during sleep of 2%, one quarter of which were likely due to RBD, giving an overall prevalence of RBD at 0.5%.35 Another survey estimated the prevalence of REM sleep behavior to be 0.38% in elderly persons.36 Increasingly, RBD is becoming associated with underlying neurologic conditions. RBD and Extrapyramidal Disease As more patients with “idiopathic” RBD are carefully followed over time, it is becoming clear that the majority eventually develop neurodegenerative disorders, most notably the synucleinopathies: Parkinson’s disease, multiple system atrophy (MSA; including olivopontocerebellar degeneration and the Shy-Drager syndrome), dementia with Lewy body disease, or pure autonomic failure. RBD may be the first manifestation of these conditions, and it can precede any other manifestation of the underlying neurodegenerative process by more than 10 years.37-47 Combined animal and human studies have identified physiologic and anatomic links between RBD and 1083

1084  PART II / Section 12  •  Parasomnias

neurodegenerative disorders, leading to the proposal that neurodegeneration can begin in either the rostroventral midbrain or the ventral mesopontine junction and progressively extend to the rostral or caudal part of the brainstem. When the lesion starts in the ventral mesopontine region, RBD develops first, but when the lesion initially involves the rostroventral midbrain, Parkinson’s disease is the initial manifestation.48 Systematic longitudinal study of patients with such neurologic syndromes indicates that RBD and REM sleep without atonia may be far more prevalent than previously suspected. Although the prevalence of RBD in Parkinson’s disease is unknown, subjective reports indicate that 25% of patients with Parkinson’s disease have sleep-related behavior suggesting RBD or they have sleep-related injurious behavior, and polysomnographic studies found RBD in up to 47% of patients with Parkinson’s disease who had sleep complaints.49-52 In one large series of patients with MSA, 90% were found to have REM sleep without atonia and 69% had clinical RBD.53 In another, nearly half had RBD.54 The presence of RBD might differentiate pure autonomic failure from MSA with autonomic failure.55 The finding of incidental Lewy body disease in one patient asymptomatic for Parkinson’s disease suggests that this condition might explain idiopathic RBD in some older patients.56 The presentation of RBD and dementia is suggestive enough of dementia with Lewy body disease that RBD has been proposed as one of the core diagnostic features of dementia with Lewy body disease.57 The link between Parkinson’s disease and RBD (Video 95-1) is supported by the fact that impaired olfactory and color discrimination is common to both.58–59a Also, the possible presence of cognitive deficits and slowing in the waking electroencephalogram in idiopathic RBD share common features with dementia with Lewy body disease.60-62 RBD is also seen in non–synucleinopathy-related Parkinson’s disease, in Guadeloupian parkinsonism, and progressive supranuclear palsy (tauopathies).63-65 The clinical features of RBD are identical in the idiopathic cases and in those with Parkinson’s disease or MSA.66 Interestingly, there is a striking (77%) male predominance in patients with Parkinson’s disease who display RBD.67 To date, no reliable tests have been shown to identify which subgroup of patients with idiopathic RBD is prone to develop Parkinson’s disease.68 The waking motor impairments of Parkinson’s disease can improve or even normalize during REM sleep–related movements in Parkinson’s disease patients with RBD. In a study of 53 patients with Parkinson’s disease and RBD who slept with bed partners, 100% reported improvement of at least one of the following during RBD episodes: faster, stronger, or smoother movements; more intelligible, louder, or better articulated speech; or normalization of facial expression. Furthermore, 38% of bed partners reported that movements were “much better” even in the most disabled Parkinson’s disease patients. The responsible mechanisms for these fascinating observations remain obscure.69 RBD and Narcolepsy RBD might also be yet another manifestation of narcolepsy. It is present in more than half of patients with narcolepsy, it may be an early symptom in childhood

narcolepsy, and it might even be the presenting symptom in narcolepsy.70-74 These patients usually have hypocretin-1 deficiency.72 Tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs), prescribed to treat cataplexy, can trigger or exacerbate RBD in this population. The demographics (age and sex) of RBD in narcolepsy conform to those of narcolepsy, indicating that RBD in these patients is yet another manifestation of state boundary dyscontrol seen in narcolepsy.75 RBD and Other Conditions Other conditions reported to be associated with RBD include mitochondrial encephalomyopathy, normal pressure hydrocephalus, Tourette’s syndrome, Machado-Joseph disease (spinocerebellar ataxia type 3), cerebellopontine angle tumors, group A xeroderma, multiple sclerosis, ischemic or hemorrhagic cerebrovascular disease, focal brain lesions, autism, Möbius syndrome, voltage-gated potassium channel autoimmunity, and Guillain-Barré syndrome.76-91 Pathogenesis The generalized atonia of REM sleep results from active inhibition of motor activity by pontine centers of the peri– locus coeruleus region, which exert an excitatory influence upon the reticularis magnocellularis nucleus of the medulla via the lateral tegmentoreticular tract. The reticularis magnocellularis nucleus, in turn, hyperpolarizes spinal motor neuron postsynaptic membranes via the ventrolateral reticulospinal tract.92,93 Loss of muscle tone during REM sleep is very complex and has been shown to result from a combination of inactivation of brainstem motor inhibitory systems and inactivation of brainstem facilitative systems.94,95 Normally the atonia of REM sleep is briefly interrupted by excitatory inputs that produce the rapid eye movements and the muscle jerks and twitches characteristic of REM sleep.96-98 REM atonia is thought to be mediated by glycine99 and may be influenced by medullary enkephalinergic neurons.100 The prevailing hypothesis that REM atonia is caused by glycinergic inhibition has been questioned.101 Bilateral pontine tegmental lesions in cats result in persistent absence of REM atonia associated with prominent motor activity during REM sleep.3,15,24,93,102-104 That this represents REM sleep rather than waking activity is supported by the presence of other features typical of REM: loss of thermoregulation, the closed nictitating membrane, miotic pupils (despite signs of autonomic activity), and blunted response to stimuli.22 Cats receiving pontine tegmental lesions exhibit a range of REM sleep activities that can appear as soon as the second day after the lesion has been produced. Loss of REM atonia has been shown to be necessary, but not sufficient, to allow the expression of REM activities. The specific site of a pontine lesion determines whether loss of atonia occurs with simple movements or more complex activities suggesting that the pontine tegmentum is responsible for two separate mechanisms of skeletal motor inhibition during REM sleep: the atonia system and a system that suppresses phasic brainstem motor pattern generators.15 A lesion damaging the atonia mechanism would produce only REM sleep with augmented tone (REM without atonia [RWA]), whereas a lesion affecting both



mechanisms (tonic and phasic), would also release complex activities, with the stereotypical repertoire depending on the precise location of the lesion. Although the classic experimental animal model of RWA involves bilateral perilocus coeruleus lesions,3 it is clear that other regions of the central nervous system can affect muscle tone during REM sleep, including the medulla105 and possibly even the hypothalamus.30 Relevant animal studies have indicated a co-localization of the locomotor and atonia systems operating during REM sleep.106 Given the clear neuroanatomic substrate of a REM behavioral syndrome in cats, experiments of nature could be expected, resulting in an analogous disorder in humans. The pathophysiology of RBD in humans may be presumed to be similar to that postulated for experimental cats,15 namely the loss of REM atonia coupled with enhancement of phasic motor drive. Neuroimaging studies indicate dopaminergic abnormalities in RBD. Single photon emission computed tomography (SPECT) studies have found reduced striatal dopamine transporters,107,108 and decreased striatal dopaminergic innervation has been reported.109 Decreased blood flow in the upper portion of the frontal lobe and pons has been reported,110 as has functional impairment of brainstem neurons.111 Positron-emission tomography (PET) and SPECT studies have revealed decreased nigrostriatal dopaminergic projections in patients with MSA and RBD.112 Decreased blood flow in the upper portion of the frontal lobe and pons has been found in one magnetic resonance imaging (MRI) and SPECT study.110 Impaired cortical activation as determined by electroencephalographic spectral analysis in patients with idiopathic RBD supports the relationship between RBD and neurodegenerative disorders.113 RBD in humans occurs in an acute and a chronic form. Until recently, most reported cases of acute transient RBD fell in the toxic or metabolic category, and the best-studied conditions were the withdrawal states, most commonly involving ethanol.6 Comparable patterns have been described with nitrazepam withdrawal and biperiden intoxication.7,8 Currently, the most common cause of acute RWA and RBD may be iatrogenic. Acute RBD is almost always induced by medications (most commonly tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs)) or associated with withdrawal (alcohol, barbiturate, or meprobamate).114,115 Excessive caffeine ingestion has also been implicated,116 as has chocolate ingestion.117 The chronic form is most often either idiopathic or associated with neurologic disorders. Each basic category of neurologic disease (vascular, neoplastic, toxic or metabolic, infectious, degenerative, traumatic, congenital, and idiopathic) could be expected to manifest this disorder. Although RBD has not been reported following infection or trauma, a recent study of persistent hypersomnolence following Epstein-Barr viral infection (infectious mononucleosis and Guillain-Barré syndrome)118 and a case with absent REM sleep as a sequela to a strategically located pontine shrapnel fragment119 indicate that these categories will eventually be implicated. A familial association has been documented120 (Fig. 95-1) and is occasionally sug-

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Figure 95-1  Abnormal REM sleep polysomnograms of a 10-year-old girl (A) and her 8-year-old brother (B), in which gross body movements accompany bursts of aperiodic chin and limb electromyographic (EMG) twitching (7-11). REM sleep is identified by the presence of rapid eye movements (1-2), an activated EEG (3-6), and a predominantly atonic chin EMG. These two siblings and their father had demonstrated excessive limb jerking during sleep throughout their lives. For the girl, removal of a brainstem astrocytoma was followed by the onset of nightmares and complex, disruptive sleep behavior, which persisted for 1 year, when treatment with clonazepam induced prompt control of both dream and motor problems. A, ear; C, central; E, eye; ECG, electrocardiogram; O, occipital; subscripts 1 and 3, left; subscripts 2 and 4, right.

gested historically during clinical evaluations. Spontaneously occurring idiopathic RBD has been reported in dogs and cats.121,122 The overwhelming male predominance of RBD (not seen in the associated neurodegenerative disorders) raises the intriguing question of hormonal influences, as suggested in male-aggression studies in animals and humans.123125 Another possible explanation for the male predominance is sex differences in brain development and aging.126-128 There is evidence for a sex difference in the effects of sex steroids on the development of the locus coeruleus in rats.129 However, serum sex hormone levels are normal in idiopathic RBD or RBD associated with Parkinson’s disease.130,131 The typically late-age onset of RBD suggests an organic brain factor and may be a manifestation of the reversal or disintegration of ontogeny of state appearance.132 One highly speculative but tantalizing etiologic possibility is that RBD represents a delayed manifestation of REM sleep abnormalities occurring early in development. This explanation invokes the well-documented prolonged effect of

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pharmacologic manipulation upon developing neural tissues.133 In rats, Corner has described an RBD-like polysomnographic (PSG) pattern persisting into adulthood following clomipramine-induced neonatal REM sleep suppression.134 Another is the possible presence of neuronal-specific antibodies as described in neurologic paraneoplastic syndromes and the stiff-man syndrome.135 One study failed to identify anti–locus coeruleus–specific antibodies in patients with RBD.136 As autopsy material becomes available, direct neuropathologic examination could provide important correlative information. The chronic idiopathic category represents patients whose RBD is not associated with psychopathology or detectable neuropathology. Clinical Features The cases reported to date have strikingly similar clinical features.114 The presenting complaint is that of vigorous sleep activities usually accompanying vivid striking dreams (Videos 95-2 and 95-3). These activities can result in repeated injury, including ecchymoses, lacerations, and fractures. Some of the self-protection measures taken by the patients (tethering themselves to the bed, using sleeping bags or pillow barricades, or sleeping on a mattress in an empty room) reveal the recurrent and serious nature of these episodes.137,138 The potential for injury to the patient or the bed partner raises interesting and difficult forensic medicine issues.139 RBD may have serious psychological ramifications for the bed partner: One woman committed suicide because her husband with RBD could not share their bed.140 Chronic RBD is more common in older men and may be preceded by a lengthy prodrome. In some cases there is a familial predisposition. Because effective and safe treatment is available, precise diagnosis is critical. Case Studies The following cases illustrate the idiopathic subtype of RBD and describe the main reason for seeking medical attention. Past history and current neurologic and psychiatric evaluations were unremarkable, apart from the findings reported. All four men were known by day to be calm and friendly people whose nocturnal behavior was completely out of (waking) character. Clonazepam controlled problematic activities and abnormal dreams in each. Figure 95-2 illustrates attempted dream enactments during the REM sleep of the patient described in Case 3.

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Figure 95-2  Polygraphic correlates of nocturnal dream-enacting behavior. REM sleep contains dense, high-voltage REM activity (1-2) and an activated electroencephalogram (3-5, 12-17). The electrocardiogram (11) has a constant rate of 64 per minute, despite vigorous limb movements, a finding that is consistent with REM sleep and inconsistent with a conventional arousal. Chin electromyographic (EMG) tone is augmented with phasic accentuations (6). Arms (7-8) and legs (9-10) show aperiodic bursts of intense EMG twitching, which accompany gross behavior noted by the technician. This sequence culminates in a spontaneous awakening, when the man reports a dream of running down a hill in Duluth, Minnesota, and taking shortcuts through backyards, when he suddenly finds himself on a barge that is rocking back and forth. He feels haunted and desperately holds onto anything to prevent falling into the cargo hold, where there are skeletons. He then awakens. A, ear; C, central; E, eye; F, frontal; O, occipital; T, temporal; subscripts 7, 3, 5, and 1, left; subscripts 8, 4, 6, and 2, right.

Case 1 A 77-year-old minister presented with a 20-year history of frequent somniloquy and aggressive behavior that occurred during “fighting dreams” of defending himself against assaultive children and adults. Although his wife had sustained repeated blows, she remained in bed to protect him from harming himself. Referral was prompted by an injury to his chest from jumping into a table while dreaming. Despite vigorous sleep movements, he generally awakened feeling refreshed. However, fatigue had recently started to interfere with his busy preaching schedule. His wife recalled a memorable night when “he said he was flying above some trees and there was a phone sitting out there on the table and it was ringing, so he

swooped down to answer the phone and, just as he landed, somebody hit him and when he jumped away, he actually bolted out of the bed and was in the hall, just like that.” Medical history was remarkable for coronary artery bypass surgery 3 years previously, which was followed by a pronounced depression of consciousness lasting 4 days and a right-sided hemiplegia that gradually resolved. A mild memory deficit ensued, and his preexisting sleep disturbance intensified. Current neurological examination revealed a memory deficit, mild horizontal nystagmus, modest right-sided cogwheel rigidity, and peripheral neuropathy.



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A 57-year-old retired school principal presented with concern over the possibility of injuring his wife. For 2 years he had inadvertently punched and kicked her during vivid nightmares of protecting himself and family from aggressive people and snakes. Nocturnal arousals were uncommon and he felt refreshed most mornings. He developed an adjustment disorder with depressed mood141 subsequent to a myocardial infarction 1 year previously, but treatment with desipramine and trazodone did not control his problematic sleep movements. The Minnesota Multiphasic Personality Inventory (MMPI) revealed a chronic tendency for somatization. Two brothers reported identical sleep and dream disturbances that had persisted since adolescence. One of them tore the headboard off a bed while dreaming of fighting a bear.

the transition from stage 3-4 to stage 2 sleep with REMs, a vivid dream, and behavioral enactment. This case most likely represents a parasomnia overlap state (discussed later in the section “Variations of REM Sleep Behavior Disorders”). Idiopathic RBD is a chronic progressive disorder, with increasing complexity, intensity, and frequency of expressed behavior. Although irregular jerking of the limbs can occur nightly, the major movement episodes appear intermittently, with a frequency minimum of once in 2 weeks to a maximum of four times nightly on 10 consecutive nights. Observed somniloquy runs the spectrum from short and garbled to long-winded and clearly articulated. Angry speech with shouting, but also laughter, can emerge. One patient appeared to have a dissociated RBD lucid dream state in that he could carry on lengthy and coherent conversations with his wife and family while dreaming and incorporate the conversational material into his dreams. The extended prodrome of prominent limb and body movements during sleep in some patients might reflect a developmental failure to fully establish REM sleep atonia, predisposing them to RBD. Most patients complained of sleep injury but rarely of sleep disruption. They usually did not awaken from their own violent activity but rather from the yelling, often persistent, of their wives. Two conclusions can be drawn. First, chronic RBD is principally a motor disorder and uncommonly also an arousal disorder. Second, the very high arousal threshold constitutes another physiologic marker of REM sleep, which is known to have the highest threshold for arousal compared to wakefulness or NREM sleep.18-20 In addition, the autonomic nervous system was generally not activated during episodes of vigorous REM sleep activities, as indicated by Figure 95-2. However, a few patients described episodes of vivid dreaming with behavioral enactment from which they awakened in a terrified state with full subjective autonomic activation. In RBD patients, arousal from sleep to alertness and orientation is usually rapid and accompanied by complete dream recall (very unlike the confusional arousals observed in the disorders of arousal such as sleepwalking or sleep terrors). After awakening, behavior and social interactions are appropriate, mitigating against a NREM sleep relationship, delirious states, or ictal phenomena, and further supporting a REM sleep phenomenon. The activities, although complex and violent, are of briefer duration than those seen in the disorders of arousal. In some patients, the clinical features contain elements of both RBD and disorders of arousal (see later). Furthermore, appetitive behavior (feeding or sexual) has not been seen as a manifestation of RBD in humans or in the animal model.15

Behavioral Features and their Bases The history of dream-enacting behavior occurring at least 90 minutes after sleep onset and as late as the terminal morning awakening strongly suggests a REM sleep disorder, and in our laboratory nearly all such episodes take place within REM sleep. One rare example of a NREM dream enactment (see Fig. 1 in reference 10) was actually a dissociated state in which an RBD process intruded into

Dream Disorder and Behavior Disorder The Hobson and McCarley activation-synthesis model of dream formation states that during REM sleep, brainstem generators phasically activate motor, perceptual, affective, cognitive, and amnestic circuits whose information flow is synthesized into dreams by the forebrain.142,143 This model would theoretically predict the dream changes observed in patients with RBD. Intensified activity of these generators or biased activation of particular circuits should induce corresponding changes in dream process and content. We

Case 2 A 60-year-old surgeon began to punch and kick his wife and jump out of bed during nightmares of being attacked “by criminals, terrorists, and monsters who always tried to kill me.” Work-related stress was the presumed cause of his sleep disturbance, but the violent behavior intensified despite retirement 3 years later. He sustained several head lacerations and his wife once had a severe headache for 2 days after receiving an accidental blow to the ear. The proper diagnosis was established after 11 years. A prodrome of excessive limb and body jerking during sleep had been present for at least 33 years.

Case 3 A 62-year-old industrial plant manager experienced a progressive disorder of “military nightmares” and combative sleep behavior, which had begun 10 years previously after visiting locations where he had fought in World War II. A psychiatrist diagnosed a posttraumatic stress disorder, but treatment was ineffective, and he continued to scream profanities, throw punches, kick, sit up, and jump out of bed while dreaming of being attacked by enemy soldiers. He broke lamps and once kicked a hole in the wall. One dream-incurred head laceration required 10 sutures. He considered his sleep to be sound and had consistent diurnal alertness. He saw four physicians, including two psychiatrists, for this sleep problem before referral to our center. He had a childhood history of sleepwalking.

Case 4

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theorize that both these conditions occur to produce RBD. As already proposed for cats with pontine lesions, disinhibition of selective brainstem motor pattern generators accounts for the differential release of stereotypical REM behavior.15 This same process might produce both the behavior and dream disorder of RBD. For example, the generator for violent behavior might become disinhibited and coactivate both a descending output to the spinal motor neurons and an ascending output to forebrain dream-synthesizing centers, thus producing the simultaneous movement and dreaming. These two outputs from the same generator may be isomorphic, so that command for dream action (fictive movements) is equivalent to command for actual movements,144 resulting in acting out of dreams. In our series of patients with RBD, all who acted violently during REM sleep also had violent dreams. In fact, dream recall was most complete following behavioral enactment. The REM sleep activities we observed in our patients corresponded to the reported dream mentation. Most patients repeatedly experienced a typical RBD nightmare, which consisted of being attacked by animals or unfamiliar people, few of whom were bizarre in appearance. Characteristically, the dreamer would either fight back in self-defense or else attempt to flee. Fear, rather than anger, was the usual accompanying emotion reported. An ironic situation was produced by RBD when a dreaming husband would fight to defend his wife from an aggressor while actually striking her in bed. Her yells would then awaken him to the unfortunate reality of his violent oneiric activity. In these patients, medication suppressed both the vigorous sleep activities and the abnormal dreaming, which adds further support to the activation-synthesis model. A singular feature of the dream-enacted episodes in this group of patients is that customary dreams are generally not being played out; rather, distinctly altered, stereotypical, repetitive, and action-packed dreams are put on display. The violence of the sleep-related behavior is often discordant with the waking personality. The increased aggressive dream content experienced by patients with RBD is not associated with increased daytime aggressiveness.145 Diagnosis Routine medical history-taking should include questions that screen for abnormal sleep movements and altered dreams, especially in older adults, in patients of any age who have acute or chronic central nervous system disorders—particularly those who have neurologic conditions that predispose to RBD such as Parkinson’s disease or MSA—or in patients receiving psychoactive medications known to trigger RBD. The diagnosis of RBD may be suspected on clinical grounds; however, our experience has shown that PSG confirmation is mandatory. The complaint of sleep-related injurious or violent activities should be taken very seriously. Reported injuries in our series include lacerations and fractures to the patient and bed partner. RBD has also resulted in subdural hematomas and other serious injuries.146-148 Detailed polysomnographic data in these patients have been reported elsewhere.10,137,149 The overall sleep architecture is usually normal, with the expected cycling of NREM and REM sleep. Most of our subjects had excessive slow-wave sleep for age. Although some of these patients

were initially thought to have a seizure disorder explaining the movements during sleep, neither EEG electrical nor clinical seizure activity has been detected. The conventional scoring parameters of Rechtschaffen and Kales150 must be modified to allow for the persistence of EMG tone during epochs that are otherwise clearly REM sleep. These periods are similar to the “stage 1 REM with tonic EMG” described by the Japanese,9 the “stage 1 REM” seen in delirium tremens,151 and those recorded in the chronic pontine-lesioned cats.3,15,24,93,102-104 There is persistence of muscle tone during REM sleep, and it may be strikingly augmented for prolonged periods, occasionally lasting much of the REM sleep cycle. The onset of a REM sleep period is often marked by a sudden increase in chin EMG activity or prominent twitching in conjunction with REMs. In addition to the intermittent absence of atonia, there are varying amounts of limb twitching (usually far in excess of that observed in normal REM sleep), gross body movements, and complex—often violent—activities that correlate with reported dream mentation. Tachycardia might not accompany these impressive movements. A similar lack of autonomic arousal during REM sleep was observed in a study of delirium tremens.151 This likely represents paresis of the sympathetic nervous system (inactivation of the locus coeruleus) characteristic of REM sleep.152,153 A curious feature of the chin EMG and extremity movements seen during the REM period is the variability of involvement and distribution. The chin EMG may be augmented without body movements, or it may be atonic despite flailing extremities, as shown in Figure 95-3. The arms and legs often move independently, necessitating monitoring of all limbs. Some patients demonstrated persistent (over the span of several years) lateralization of limb EMG activity or also predominant upper or lower extremity movements. Most all patients displayed prominent aperiodic movements of all extremities in every conceivable combination during all stages of NREM sleep. These aperiodic movements are similar but more intense than the fragmentary myoclonus described by Broughton and colleagues in patients with a wide variety of sleep disorders and occasionally as an incidental observation.154,155 Most RBD patients also showed conventional periodic movements of sleep, usually involving the legs, infrequently associated with arousals. Prolonged episodes of aperiodic and periodic movements restricted to the arms were noted occasionally. Figures 95-4 and 95-5 exemplify some of these dissociated wake-REM states. Prominent changes in sleep patterns likely representing variations of RBD have been described in the drug-induced variety of RWA,156,157 narcolepsy,75 and Parkinson’s disease.158,159 Figure 95-6 is a dramatic example of venlafaxine-induced RBD in a 9-year-old boy. Diagnostic Criteria The minimum diagnostic criteria for RBD we have formulated can be satisfied in either of two ways. The diagnosis can be made in patients with a history of problematic sleep behavior that is harmful or potentially harmful, or that disrupts sleep continuity, or that is annoying to the patient or bed partner and that includes excessive augmentation of chin EMG tone or excessive chin or limb EMG twitching,



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Figure 95-3  REM sleep polysomnogram illustrating extensive preservation of submental electromyographic (EMG) atonia (7), despite the emergence of gross arm movements that are noted by the technician and reflected by the prominent twitching in the upper extremity EMGs (8-11). A rapid eye movement (1-2) immediately precedes the onset of complex behavior. A, ear; C, central; ECG, electrocardiogram; LOC, left outer canthus; O, occipital; ROC, right outer canthus; subscripts 1 and 3, left; subscripts 2 and 4, right.

irrespective of chin EMG tone, on polysomnography during REM sleep. In patients with no history of problematic sleep behavior, diagnosis can be made based on excessive augmentation of chin EMG tone or excessive chin or limb EMG twitching irrespective of chin EMG tone on polysomnography during REM sleep and video recording of excessive limb or body jerking, complex movements, or vigorous or violent movements during REM sleep (Video 95-4). A report of dream changes accompanying the sleep activities can buttress the history. The determination of what constitutes excessive EMG augmentation, EMG twitching, or limb jerking requires meticulous execution of standard recording techniques and an experienced polysomnographer. We recommend that any patient with suspected RBD undergo a systematic evaluation consisting of: • Review of sleep and wake complaints (from patient or bed partner) • Neurologic and psychiatric examinations • A sleep laboratory study that includes continuous videotaping of behavior during standard polygraphic monitoring150 of the electrooculogram (EOG), EEG, EMG (chin, bilateral extensor digitorum, and anterior tibialis muscles), electrocardiogram (ECG), and nasal air flow. A certified technician makes written observations of

ongoing activities. The REM density score (REM activity units on a scale of 0 to 8 per minute) is determined by a standard technique160 • Because of the association between RBD and narcolepsy, a multiple sleep latency test161 is routinely administered the day following the overnight sleep study. More extensive neurologic evaluation including multimodal evoked potentials, brain imaging by MRI or computed tomography (CT), or comprehensive neuropsychological testing by methods previously reported149 are indicated only if there is a suggestion of neurologic dysfunction by history or neurologic examination. Differential Diagnosis RBD can masquerade as many other conditions (Box 95-1). Most conditions in this differential diagnosis represented an initial clinical misdiagnosis in our series, leading to inappropriate and ineffective treatment. The differential diagnosis of these disorders has been extensively reviewed elsewhere.162 The disorders of arousal, nocturnal seizures, and rhythmic movement disorder are discussed elsewhere in this volume. It should be remembered that the clinical event (arousal) might not be primary but rather triggered by another, underlying sleep disorder, such as apnea leading to arousal triggering sleep terror. Nocturnal behavior induced by obstructive sleep apnea or

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Figure 95-5  Nocturnal polysomnogram of a dissociated state in a 58-year-old man with multiple sclerosis. A pathologic process usually confined to NREM sleep—periodic leg movements (12)—has intruded into REM sleep, which has typical rapid eye movements (1-2) and a desynchronized electroencephalogram (3-6). Chin electromyographic (EMG) atonia alternates every 3 sec with augmented tone (7). A, ear; C, central; E, eye; ECG, electrocardiogram; O, occipital; subscripts 1 and 3, left; subscripts 2 and 4, right. 150 mV 2 sec

B Figure 95-4  Nocturnal polysomnograms that depict contrasting forms of skeletal muscle activity in a 70-year-old man. Eye tracings, 1-2; electroencephalogram, 3-5; electromyogram (EMG) of chin, arms, and legs, 6-10. A, Lateralized periodic leg movements appear every 20 to 30 seconds throughout a period of stage 2 NREM sleep. B, A different pattern emerges 3 minutes later at the onset of REM sleep, in which both arms have frequent aperiodic movements. REM alpha is present. Chin atonia does not occur in REM sleep but does appear suddenly in NREM sleep just before a leg movement. This man developed a chronic REM sleep behavior disorder at the time of subarachnoid hemorrhage 6 years previously. A, ear; C, central; E, eye; O, occipital; subscripts 1 and 3, left; subscripts 2 and 4, right.

sleep-related seizures can mimic activities of RBD.163-165 Overlap parasomnias are characterized by the clinical history suggestive of sleepwalking or sleep terrors, with PSG features of motor disinhibition during both REM and NREM sleep.166 It is likely that a recent series of somnambulistic-like behavior in elderly subjects found to have PSG features of RBD represents this phenomenon.167 Nocturnal panic disorder is poorly understood and requires more study. It is well established that psychogenic dissociative disorders can arise predominantly or exclusively from the sleep period.168 Finally, our group has seen extremely violent sleep-period behavior that we suspect represents malingering.169 Variations of REM Sleep Behavior Disorders P ARASOMNIA O VERLAP S YNDROME There is a subgroup of parasomnia patients with both clinical and PSG features of both RBD and disorders of

Box 95-1  Differential Diagnosis of REM Sleep Behavior Disorder Disorders of arousal • Primary •  Confusional arousals •  Sleepwalking •  Sleep terrors • Secondary •  Obstructive sleep apnea •  Periodic limb movement disorder •  Gastroesophageal reflux •  Nocturnal seizures Parasomnia overlap syndrome Nocturnal seizures Rhythmic movement disorder Posttraumatic stress disorder Nocturnal panic disorder Psychogenic dissociative disorder or conversion hysteria Malingering

arousal (sleepwalking and sleep terrors). These cases demonstrate motor and behavioral dyscontrol extending across NREM and REM sleep and suggest the possibility of a unifying hypothesis for disorders of arousal and RBD: The primary underlying feature is motor disinhibition during sleep. When it is predominantly during NREM sleep, it manifests as disorders of arousal, and when it is predominantly during REM sleep, it manifests as RBD. The parasomnia overlap syndrome occupies an intermediate position, with features of both.166 One AIDS-related case with prominent brainstem involvement has been identified. The abnormal motor and verbal nocturnal activities



CHAPTER 95  •  REM Sleep Parasomnias  1091

LOC-A1 ROC-A1 C3-A2 Submental EMG L. Ext. Digitorum EMG R. Ext. Digitorum EMG L. Ant. Tibialis EMG R. Ant. Tibialis EMG

Venlafaxine-induced RBD in 9-y.o. boy Figure 95-6  Polysomnogram of a 9-year-old boy who developed RBD coincident with his being placed on venlafaxine 550  mg daily. Note the prominent tonic and phasic muscle activity of the extremities during REM sleep. A, ear; C, central; ECG, electrocardiogram; LOC, left outer canthus; O, occipital; ROC, right outer canthus; subscripts 1 and 3, left; subscripts 2 and 4, right.

of status dissociatus might respond to treatment with clonazepam.170,171 A GRYPNIA E XCITATA Agrypnia excitata is characterized by generalized overactivity associated with loss of slow-wave sleep, mental oneiricism (inability to initiate and maintain sleep with wakeful dreaming), and marked motor and autonomic sympathetic activation seen in such diverse conditions as delirium tremens, Morvan’s fibrillary chorea, and fatal familial insomnia.172-174 Oneiric dementia is likely a related condition.175 Agrypnia excitata is similar to status dissociatus, which may be the most extreme form of RBD, appearing to represent the complete breakdown of state-determining boundaries. Clinically, patients with status dissociatus, by observation of behavior, appear to be either awake or asleep; however, clinically, their behavioral sleep is very atypical, characterized by frequent muscle twitching, vocalization, and reports of dreamlike mentation upon spontaneous or forced awakening. Polygraphically, there are no features of either conventional REM or NREM sleep; rather, there is the simultaneous mixture of elements of wakefulness, REM sleep, and NREM sleep. “Sleep” may be perceived as normal and restorative by the patient, despite the nearly continuous motor and verbal activities and absence of polysomnographically defined REM or NREM sleep. Conditions associated with status dissociatus include protracted withdrawal from alcohol abuse, narcolepsy, olivopontocerebellar degeneration, and prior openheart surgery. The clinical history alone is insufficient to make the diagnosis, which can be established only with extensive PSG evaluation, including employment of a full seizure montage, respiratory recording, monitoring of all extremities, continuous audiovisual documentation, and detailed observations made by experienced technicians. The physi-

cal and psychological consequences of an erroneous diagnosis are obvious. The impressive response to treatment emphasizes the importance of a definitive diagnosis.137,176 Treatment The acute form is self-limited following discontinuation of the offending medication or completion of withdrawal. About 90% of patients with chronic RBD respond well to clonazepam administered half an hour before sleep time. The dose ranges from 0.5 to 2.0 mg, and there has been little, if any, tendency to develop tolerance, dependence, abuse, or adverse sleep effects despite years of continuous administration and efficacy.137,177 Melatonin at doses up to 12  mg at bedtime or pramipexole may also be effective.178-181 Although tricyclic antidepressants sometimes induce or potentiate RBD, imipramine has been reported effective in three clonazepam-resistant patients.182 Likewise, there are reports of response to an SSRI (paroxetine).183,184 Carbamazepine has been effective in one case.185 Levodopa may be effective, particularly in cases where RBD is the harbinger of Parkinson’s disease.186 There have been anecdotal reports of response to gabapentin, MAOIs, donepezil, and clonidine.187,188 In RBD associated with narcolepsy, the tricyclic antidepressants or MAOIs administered for cataplexy may be continued and clonazepam may be added.75 The treatment of medication-induced or Parkinson’s disease–associated RBD is the same as for idiopathic RBD.38 Pallidotomy has been effective in one case of RBD associated with Parkinson’s disease, whereas chronic bilateral subthalamic stimulation was not.189-191 An isolated episode of RBD has been reported immediately following left subthalamic electrode implantation for the treatment of Parkinson’s disease.192 Underlying obstructive sleep apnea should be ruled out before prescribing clonazepam.193,194 The fact that clonazepam results in striking clinical improvement without discernable effect upon PSG-

1092  PART II / Section 12  •  Parasomnias

recorded RWA raises the possibility that it acts preferentially upon the locomotor systems, rather than those affecting REM atonia.195 The other essential therapeutic intervention concerns environmental safety. Clonazepam is not failsafe: One patient injured himself during a violent dream 1 year after initiating very satisfactory pharmacotherapy. There was no recurrence during the ensuing 5 months, even though the dose was not increased. Therefore, potentially dangerous objects should be removed from the bedroom, cushions put around the bed, and perhaps the mattress placed on the floor and windows protected. We anticipate some cases in which drug intolerance or ineffectiveness will lead to discontinuation, requiring maximal environmental safety. Clinical Course and Prevention The clinical course depends upon the etiology. Idiopathic RBD is often slowly progressive, as is RBD associated with the synucleinopathies. RDB symptoms may precede other features of synucleinopathies by decades.195a Interestingly, RBD associated with neurodegenerative disorders might remit spontaneously, as the underlying neurodenerative process progresses. Drug-induced RBD will usually improve upon withdrawal of the offending medication. The only known preventable cause of RBD is medicationinduced RBD. Pitfalls and Controversies Numerous parasomnias can perfectly mimic RBD, mandating formal sleep studies to rule out NREM parasomnias, nocturnal seizures, obstructive sleep apnea, psychogenic dissociative disorders, or malingering. Perspectives and Implications A common thread linking RBD and the disorders of arousal is the appearance of motor activity that is dissociated from waking consciousness. In RBD, the motor behavior closely correlates with dream imagery, and in disorders of arousal, it often occurs in the absence of (remembered) mentation. One intriguing explanation for the dissociation of behavior from consciousness has been proposed by Tassinari, who suggests that the activities are generated by locomotor centers released during REM sleep.196 This dissociation of the locomotor centers from the parent state of REM or NREM sleep would explain the presence of complex motor behavior seen in RBD and in disorders of arousal. RBD is an exciting experiment of nature, extending our understanding of state declaration. Its association with narcolepsy and its clinical similarity to status dissociatus and the parasomnia overlap syndrome expand the concept of state boundary dyscontrol. The identification of yet other state declaration errors, and their induction by, or response to, specific pharmacologic agents, promise to unveil much about the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of waking and sleep. Such experiments of nature underscore the symbiotic relationship between clinical and basic science medicine.

OTHER REM SLEEP PARASOMNIAS Nightmares and impaired sleep-related penile erections are discussed elsewhere in this volume.

REM Sleep–Related Sinus Arrest REM sleep–related sinus arrest,197 first described by Guilleminault and colleagues in 1984,198 is a cardiac rhythm disorder that affects otherwise healthy young adults of either sex and is characterized by sinus arrest during REM sleep, usually in clusters, with asystoles lasting up to 9 seconds. In one case, vocalizations occurred during periods of REM sleep asystole, with a loud scream and a sensation of being “shocked” (but without chest pain or related symptoms) associated with the longest asystole.199 Periods of asystole do not occur during NREM sleep and are not associated with sleep apnea. Some patients experience faintness, light-headedness, and blurred vision during abrupt awakenings, and syncope can occur during ambulation after an awakening. Also, there may be complaints of vague chest pain or tightness or intermittent palpitations during the daytime. However, daytime ECG (including Holter monitoring) is usually completely normal, and angiography, when performed, is unremarkable. The underlying pathophysiology, therefore, appears to be autonomic dysfunction. The clinical course is unknown. Complications include loss of consciousness and even cardiac arrest from prolonged asystole. This condition must be considered in cases of sudden, unexplained death during sleep. Treatment is usually not indicated, although prophylactic intervention would include a ventricular-inhibited pacemaker with a low rate limit. Sleep-Related Painful Erections Sleep-related painful erection is characterized by penile pain with erections that typically occur during REM sleep.200 Middle-aged or older men are typically affected; they complain of recurrent awakenings with partial or full erections and pain. The cumulative effects of nightly sleep disruption and sleep loss can result in the additional complaints of insomnia, irritability, anxiety, and daytime somnolence. There is usually a history of normal erections during wakefulness. There is little evidence of underlying psychiatric disease, and pathology of the penis is usually not found. Spinal cord pathology has been implicated in one case.201 Although the course is not well known, it appears that this condition can become more severe over time. No systematic studies of treatment efficacy have been performed, but clozapine, propranolol, baclofen, clozapine, or paroxetine may be effective.202-204 ❖  Clinical Pearl REM sleep behavior disorder is the most common of the REM parasomnias and is seen primarily in older men. The presence of RBD in younger persons, particularly younger women, should lead to the suspicion of medication-induced RBD or RBD associated with narcolepsy or a structural central nervous system lesion.

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100. Fort P, Rampon C, Gervasoni D, et al. Anatomical demonstration of a medullary enkephalinergic pathway potentially implicated in the oro-facial muscle atonia of paradoxical sleep in the cat. Sleep Res Online 1998;1:102-108. 101. Brooks PL, Peever JH. Glycinergic and GABAA-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J Neurosci 2008;28:35353545. 102. Henly K, Morrison AR. A re-evaluation of the effects of lesions of the pontine tegmentum and locus coeruleus on phenomena of paradoxical sleep in the cat. Acta Neurobiol Exp 1974;34:215232. 103. Trulson ME, Jacobs BL, Morrison AR. Raphe unit activity during REM sleep in normal cats and in pontine lesioned cats displaying REM sleep without atonia. Brain Res 1981;226:75-91. 104. Friedman L, Jones BE. Study of sleep–wakefulness states by computer graphics and cluster analysis before and after lesions of the pontine tegmentum in the cat. EEG Clin Neurophysiol 1984; 57:43-56. 105. Lai YY, Siegel JM. Medullary regions mediating atonia. J Neurosci 1988;8:4790-4796. 106. Lai YY, Siegel JM. Muscle tone suppression and stepping produced by stimulation of midbrain and rostral pontine reticular formation. J Neurosci 1990;10:2727-2734. 107. Eisensehr I, Linke R, Noachtar S, et al. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behavior disorder. Comparison with Parkinson’s disease and controls. Brain 2000;123:1155-1160. 108. Eisensehr I, Linke R, Tatsch K, et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003;26:507-512. 109. Albin RL, Koeppe RA, Chervin RD, et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 2000;55:1410-1412. 110. Shirakawa S-I, Takeuchi N, Uchimura N, et al. Study of image findings in rapid eye movement sleep behavioral disorder. Psychiatry Clin Neurosci 2002;56:291-292. 111. Miyamoto M, Miyamoto T, Kubo J, et al. Brainstem function in rapid eye movement sleep behavior disorder: the evaluation of brainstem function by proton MR spectroscopy (1H-MRS). Psychiatry Clin Neurosci 2000;54:350-351. 112. Gilman S, Koeppe RA, Chervin R, et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003;61:29-34. 113. Fantini ML, Gagnon JF, Petit D, et al. Slowing of electroencephalogram in rapid eye movement sleep behavior disorder. Ann Neurol 2003;53:774-780. 114. Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in Sleep. Sleep 2002;25:120-130. 115. Parish JM. Violent dreaming and antidepressant drugs: or how paroxetine made me dream that I was fighting Saddam Hussein. J Clin Sleep Med 2007;3:529-531. 116. Stolz SE, Aldrich MS. REM sleep behavior disorder associated with caffeine abuse. Sleep Res 1991;20:341. 117. Vorona RD, Ware JC. Exacerbation of REM sleep behavior disorder by chocolate ingestion: a case report. Sleep Med 2002;3: 365-367. 118. Guilleminault C, Monini S. Mononucleosis and chronic daytime sleepiness. A long-term follow-up study. Arch Int Med 1986;146: 1333-1335. 119. Lavie P, Pratt H, Sharf B, et al. Localized pontine lesion: nearly total absence of REM sleep. Neurology 1984;34:118-120. 120. Schenck CH, Bundlie SR, Smith SA, et al. REM behavior disorder in a 10 year old girl and aperiodic REM and NREM sleep movements in an 8 year old brother. Sleep Res 1986;15:162. 121. Hendricks JC, Lager A, O’Brien D, et al. Movement disorders during sleep in cats and dogs. J Am Vet Med Assoc 1989;194: 686-689. 122. Hendricks JC, Morrison AR, Farnbach GL, et al. Disorder of rapid eye movement sleep in a cat. J Am Vet Med Assoc 1980; 178:55-57.

CHAPTER 95  •  REM Sleep Parasomnias  1095 123. Goldstein M. Brain research and violent behavior. Arch Neurol 1974;30:1-34. 124. Moyer KE. Kinds of aggression and their physiological basis. Commun Behav Biol 1968;2(Part A):65-87. 125. Ramirez JM. Hormones and aggression in childhood and adolescence. Aggress Violent Behav 2003;8:621-644. 126. Coffey CE, Licke JF, Saxton JA, et al. Sex differences in brain aging. A quantitative magnetic resonance imaging study. Arch Neurol 1998;55:169-179. 127. Patwardhan AJ, Eliez S, Bender B, et al. Brain morphology in Klinefelter syndrome. Neurology 2000;54:2218-2223. 128. Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 2007;62:847-855. 129. Guillamon A, de Blas MR, Segovia S. Effects of sex steroids on the development of the locus coeruleus in rats. Dev Brain Res 1988;40:306-310. 130. Iranzo A, Santamaria J, Vilaseca I, et al. Absence of alterations in serum sex hormone levels in idiopathic REM sleep behavior disorder. Sleep 2007;30:803-806. 131. Chou KL, Moro-de-Casillas ML, Amick MM, et al. Testosterone not associated with violent dreams or REM sleep behavior disorder in men with Parkinson’s. Mov Disord 2007;22:411-414. 132. Corner MA. Ontogeny of brain sleep mechanisms. In: McGinty DJ, Drucker-Colin R, Morrison AR, Parmeggiani PL, editors. Brain Mech Sleep. New York: Raven Press; 1985. p. 175-197. 133. Corner MA, Ramakers GJA. Spontaneous firing as an epigenetic factor in brain development—physiological consequences of chronic tetrodotoxin and picrotoxin exposure on cultured rat neocortex neurons. Dev Brain Res 1992;65:57-64. 134. Corner MA, Mirmiran M, Bour HLMG, et al. Does rapid eye movement sleep play a role in brain development? Prog Brain Res 1980;53:347-356. 135. Brashear HR, Phillips II LH. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991;41:1588-1592. 136. Schenck CH, Ullevig CM, Mahowald MW, et al. A controlled study of serum anti–locus ceruleus antibodies in REM sleep behavior disorder. Sleep 1997;20:349-351. 137. Schenck CH, Mahowald MW. Polysomnographic, neurologic, psychiatric, and clinical outcome report on 70 consecutive cases with REM sleep behavior disorder (RBD): sustained clonazepam efficacy in 89.5% of 57 treated patients. Cleveland Clin J Med 1990; 57(Suppl.):S9-S23. 138. Mahowald MW, Schenck CH. REM sleep behavior disorder. In: Thorpy MJ, editor. Handbook of sleep disorders. New York: Marcel Dekker; 1990. p. 567-593. 139. Cramer Bornemann MA, Mahowald MW, Schenck CH. Parasomnias. Clinical features and forensic implications. Chest 2006; 130:605-610. 140. Yeh S-B, Schenck CH. A case of marital discord and secondary depression with attempted suicide resulting from REM sleep behavior disorder in a 35-year-old woman. Sleep Med 2004;5:151154. 141. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1987. 142. Hobson JA, McCarley RW. The brain as a dream state generator: an activation-synthesis hypothesis of the dream process. Am J Psychiatry 1977;134:1335-1348. 143. McCarley RW, Hobson JA. The form of dreams and the biology of sleep. In: Wolman BB, editor. The handbook of dreams. New York: Van Nostrand Reinhold; 1979. p. 76-130. 144. McCarley RW. REM dreams, REM sleep and their isomorphisms. In: Chase M, Weitzman ED, editors. Sleep disorders, basic and clinical research. New York: SP Medical and Scientific Books; 1983. p. 363-393. 145. Fantini ML, Corona A, Clerici S, et al. Increased aggressive dream content without increased daytime aggressiveness in REM sleep behavior disorder. Neurology 2005;65:1010-1015. 146. Dyken ME, Lin-Dyken DC, Seaba P, et al. Violent sleep-related behavior leading to subdural hemorrhage. Arch Neurol 1995; 52:318-321. 147. Gross PT. REM sleep behavior disorder causing bilateral subdural hematomas. Sleep Res 1992;21:204.

1096  PART II / Section 12  •  Parasomnias 148. Morfis L, Schwartz RS, Cistulli PA. REM sleep behavior disorder; a treatable cause of falls in elderly people. Age Ageing 1997; 26:43-44. 149. Schenck CH, Bundlie SR, Patterson AL, et al. Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. J Am Med Ass 1987;257:1786-1789. 150. Rechtschaffen A, Kales A. A manual of standardized terminology: techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute; 1968. 151. Gross MM, Godenough D, Tobin M, et al. Sleep disturbances and hallucinations in the acute alcoholic psychoses. J Nerv Ment Dis 1966;142:493-514. 152. Morrison AR, Reiner PB. A dissection of paradoxical sleep. In: McGinty DJ, Drucker-Colin R, Morrison A, et al. editors. Brain mechanisms of sleep. New York: Raven Press; 1985. 153. Siegel JM. Mechanisms of sleep control. J Clin Neurophysiol 1990;7:49-65. 154. Broughton R, Tolentino MA. Fragmentary pathological myoclonus in NREM sleep. EEG Clin Neurophysiol 1984;57:303-309. 155. Broughton R, Tolentino MA, Krelina M. Excessive fragmentary myoclonus in NREM sleep: a report of 38 cases. EEG Clin Neurophysiol 1985;61:123-133. 156. Guilleminault C, Raynal D, Takahashi S, et al. Evaluation of short-term and long-term treatment of the narcolepsy syndrome with clomipramine hydrochloride. Acta Neurol Scand 1976;54: 71-87. 157. Besset A. Effect of antidepressants on human sleep. Adv Biosci 1978;21:141-148. 158. Mouret J. Differences in sleep in patients with Parkinson’s disease. EEG Clin Neurophysiol 1975;38:653-657. 159. Askenasy JJM. Sleep patterns in extrapyramidal disorders. Int J Neurol 1981;15:62-76. 160. Taska L, Kupfer D. A system for the quantification of phasic ocular activity during REM sleep. Sleep Watchers 1983;6:15-17. 161. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519-524. 162. Mahowald MW, Schenck CH. Parasomnia purgatory—the epileptic/non-epileptic interface. In: Rowan AJ, Gates JR, editors. Non-epileptic seizures. Boston: Butterworth-Heinemann; 1993. p. 123-139. 163. Nalamalapu U, Goldberg R, DePhillipo M, et al. Behaviors simulating REM behavior disorder in patients with severe obstructive sleep apnea. Sleep Res 1996;25:311. 164. D’ Cruz OF, Vaughn BV. Nocturnal seizures mimic REM behavior disorder. Am J END Technol 1997;37:258-264. 165. Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior disorder. Sleep 2005;28:203206. 166. Schenck CH, Boyd JL, Mahowald MW. A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997;20:972-981. 167. Tachibana N, Sugita Y, Terashima K, et al. Polysomnographic characteristics of healthy elderly subjects with somnambulism-like behaviors. Biolo Psychiatry 1991;30:4-14. 168. Schenck CS, Milner DM, Hurwitz TD, et al. Dissociative disorders presenting as somnambulism: polysomnographic, video, and clinical documentation (8 cases). Dissociation 1989;4:194-204. 169. Mahowald MW, Schenck CH, Rosen GR, et al. The role of a sleep disorders center in evaluating sleep violence. Arch Neurol 1992;49:604-607. 170. Mahowald MW, Schenck CH. Status dissociatus—a perspective on states of being. Sleep 1991;14:69-79. 171. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology 1992;42:44-52. 172. Lugaresi E, Provini F. Agrypnia excitata: clinical features and pathophysiological implications. Sleep Med Rev 2001;5:313-322. 173. Montagna P, Lugaresi E. Agrypnia excitata: a generalized overactivity syndrome and a useful concept in the neurophysiology of sleep. Clin Neurophysiol 2002;113:552-560. 174. Plazzi G, Montagna P, Meletti S, et al. Polysomnographic study of sleeplessness and onericisms in the alcohol withdrawal syndrome. Sleep Med 2002;3:279-282.

175. Cibula JE, Eisenschenk S, Gold M, et al. Progressive dementia and hypersomnolence with dream-enacting behavior. Oneiric dementia. Arch Neurol 2002;59:630-634. 176. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related injury in 100 adult patients: a polysomnographic and clinical report. Am J Psychiatry 1989;146:1166-1173. 177. Aurora RN, Zak RS, Maganti RK, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6:85-95. 178. Anderson KN, Jamieson S, Graham AJ, et al. REM sleep behaviour disorder treated with melatonin in a patient with Alzheimer’s disease. Clin Neurol Neurosurg 2008;110:492-495. 179. Boeve BF, Silber MH, Ferman JT. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003;4:281-284. 180. Fantini ML, Gagno J-F, Filipini D, et al. The effects of pramipexole in REM sleep behavior disorder. Neurology 2003;61:1418-1420. 181. Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behavior disorder. Sleep Med 2006;7:418-423. 182. Matsumoto M, Mutoh F, Naoe H, et al. The effects of imipramine on REM sleep behavior disorder in 3 cases. Sleep Res 1991;20A: 351. 183. Takahashi T, Mitsuya H, Murata T, et al. Opposite effect of SSRIs and tandospirone in the treatment of REM sleep behavior disorder. Sleep Med 2008;9:317-319. 184. Yamamoto K, Uchimura N, Habukawa M, et al. Evaluation of the effects of paroxetine in the treatment of REM sleep behavior disorder. Sleep Biol Rhythms 2006;4:190-192. 185. Bamford C. Carbamazepine in REM sleep behavior disorder. Sleep 1993;16:33. 186. Tan A, Salgado M, Fahn S. Rapid eye movement sleep behavior disorder preceding Parkinson’s disease with therapeutic response to levodopa. Mov Disord 1996;11:214-216. 187. Mike ME, Kranz AJ. MAOI suppression of RBD refractory to clonazepam and other agents. Sleep Res 1996;25:63. 188. Ringman JM, Simmons JH. Treatment of REM sleep behavior disorder with donepezil: a report of three cases. Neurology 2000;55:870-871. 189. Rye DB, Dempsay J, Dihenia B, et al. REM-sleep dyscontrol in Parkinson’s disease: case report of effects of elective pallidotomy. Sleep Res 1997;26:591. 190. Iranzo A, Valldeoriola F, Santamaria J, et al. Sleep symptoms and polysomnographic architecture in advanced Parkinson’s disease after chronic bilateral subthalamic stimulation. J Neurol Neurosurg Psychiatry 2002;72:661-664. 191. Arnulf I, Bejjani BP, Garma L, et al. Improvement of sleep architecture in PD with subthalamic stimulation. Neurology 2000; 55:1732-1734. 192. Piette T, Mescola P, Uytdenhoef P, et al. A unique episode of REM sleep behavior disorder triggered during surgery for Parkinson’s disease. J Neurol Sci 2007;253:73-76. 193. Schuld A, Kraus T, Haack M, et al. Obstructive sleep apnea syndrome induced by clonazepam in a narcoleptic patient with REM-sleep-behavior disorder. J Sleep Res 1999;8:321-322. 194. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. [erratum appears in Neurology 1996;46(6):1787]. Neurology 1996;46:388-393. 195. Watanabe T, Sugita Y. REM sleep behavior disorder (RBD) and dissociated REM sleep. Nippon RTNSHO (Jpn J Clin Med) 1998;56:433-438. 195a.  Claassen DO, Josephs KA, Ahlskog JE, et al. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010;75:494-499. 196. Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005; 26:s225-s232. 197. Diagnostic Classification Steering Committee. International classification of sleep disorders: diagnostic and coding manual. Rochester, Minn: American Academy of Sleep Medicine; 1990. 198. Guilleminault C, Pool P, Motta J, et al. Sinus arrest during REM sleep in young adults. N Engl J Med 1984;311:1106-1110.

199. Rattenborg NC, Lindblom S, Best J, et al. REM sleep-related asystole associated with unusual polysomnographic features: a case history. Sleep Res 1995;24:324. 200. American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual. 2 ed. Westchester, Ill: American Academy of Sleep Medicine; 2005. 201. Karsenty G, Werth E, Knapp PA, et al. Sleep-related painful erections. Nat Clin Pract Urol 2005;2:256-260.

CHAPTER 95  •  REM Sleep Parasomnias  1097 202. Steiger A, Benkert O. Examination and treatment of sleep-related painful erections—a case report. Arch Sex Behav 1989;18:263267. 203. Ferini-Strambi L, Zucconi M, Castronovo V, et al. Sleep-related painful erections: clinical and polysomnographic findings. Sleep Res 1996;25:241. 204. van Driel MF, Beck JJ, Elzevier HW, et al. The treatment of sleeprelated painful erections. J Sex Med 2008;5:909-918.

Other Parasomnias Mark W. Mahowald Abstract As mentioned in the preceding two chapters, parasomnias may conveniently be divided into two major categories: Primary parasomnias are those due to disorders of sleep per se, and the secondary parasomnias are those that result from dysfunction of other organ systems and that take advantage of the sleeping state to declare themselves. By far, the primary sleep parasomnias are the most common; they are usually the

NORMAL SLEEP PHENOMENA It should be remembered that some normal phenomena arising from REM or NREM sleep may be bothersome enough to a patient to seek medical attention. Sleep Paralysis Sleep paralysis likely represents the persistence of REM sleep atonia into wakefulness and is extremely common in patients who are not narcoleptic, occurring in more than 33% of the general population. It may be familial, and it is more common in the setting of sleep deprivation and being in the supine position. When occurring in isolation, it can lead to erroneous diagnoses such as cardiac disease or seizures or to unwarranted psychiatric diagnoses. Rarely, episodes of periodic paralysis arising from the sleep period may be confused with true sleep paralysis. Management is reassurance that this is a normal phenomenon. Hypnagogic and Hypnopompic Hallucinations Prominent vivid dreamlike mentation can occur at sleep onset, during light NREM sleep, and even during relaxed wakefulness.1 As with sleep paralysis, such sleep onset and sleep offset hallucinatory phenomena are quite common in the nonnarcoleptic population, and they may be combined with sleep paralysis (often referred to as the “old hag” phenomenon).2 As a matter of fact, the original meaning of the word nightmare referred not to the current use of the term (a dream anxiety attack arising from the sleep period) but rather to a combination of sleep paralysis and hypnagogic hallucinations occurring at sleep onset.3 Patients can be reassured that these hallucinations are normal sleep phenomena and not symptoms of psychiatric disease. Sleep Starts (Hypnic Jerks) Sleep starts are experienced by many normal persons during the transition between wake and sleep. The most common is the motor sleep start, a sudden jerk of all or part of the body, occasionally awakening the victim or bed partner. These are so prevalent as to rarely result in neurologic consultation.4 However, variations on this theme can result in neurologic consultation. These include visual (flashes of light, fragmentary visual hallucinations), audi1098

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rapid eye movement (REM) sleep behavior disorder if from REM sleep or disorders of arousal if from non-REM sleep. There remains a large group of other parasomnias, many of which are poorly understood, that can cause impressive and distressing activities arising from the sleep period but that are unrelated to disorders of arousal or REM sleep behavior disorder. This last chapter on parasomnias discusses these lesscommon but fascinating phenomena.

tory (loud bangs, snapping noises) or somesthetic (pain, tingling, floating, something flowing through the body) sleep starts. These sensory phenomena can occur without the body jerk.5 Sleep starts represent a normal (although not understood) physiologic event, and they should not be confused with seizures or other neurologic conditions. Explosive tinnitus, characterized by a loud crashing or banging noise occurring during sleep most likely represents an auditory sleep start.6 It is also likely that the exploding head syndrome (see later discussion) is a variant of a sensory sleep start. Sleep starts may be repetitive, and they should not be confused with epileptic phenomena. Familiarity with nonmotor sleep starts should eliminate unnecessary testing and pharmacologic treatment. There is a single case report of an auditory sleep start associated with insomnia due to a brainstem lesion.7 Management is simply reassurance.

MISCELLANEOUS PRIMARY SLEEP PARASOMNIAS There remain a number of primary sleep phenomena that are poorly understood and appear not to respect sleep stages. (Bruxism is discussed in Chapter 99.) Box 96-1 outlines the various parasomnias. Sleep-Related Expiratory Groaning (Catathrenia) Groaning during sleep has been termed catathrenia (Video 96-1).8 The groans occur intermittently during either REM or NREM sleep and are characterized by prolonged, often very loud, often socially disruptive groaning sounds during expiration. Catathrenia often begins in childhood, but generally it does not come to medical attention until the person plans to sleep in a dormitory environment, such as in college or the military, or when he or she begins to share a bed with another. It is poorly understood, and there is no known effective treatment. Although there have been some reports of a possible relationship with obstructive sleep apnea and response to treatment with nasal continuous positive airway pressure (CPAP), and there have clearly been a number of cases that did not respond to nasal CPAP.9 There is absolutely no evidence that catathrenia is



CHAPTER 96  •  Other Parasomnias  1099

Box 96-1  Primary Sleep Parasomnias NREM Sleep Normal: sleep starts • Motor • Sensory (visual, auditory, somesthetic) • Exploding head syndrome • Explosive tinnitus Abnormal: disorders of arousal • Confusional arousals • Sleepwalking • Sleep terrors REM Sleep Normal • Sleep paralysis • Hypnagogic and hypnopompic hallucinations Abnormal • REM sleep behavior disorder • REM-related painful erections • Dream anxiety attacks (nightmares)

• Exploding head syndrome • Hypnic headache Tinnitus Seizures Cardiopulmonary Cardiac arrhythmias Nocturnal angina pectoris Nocturnal asthma Respiratory dyskinesias Sleep hiccup Miscellaneous • Choking • Defibrillator shocks • Coughing Gastrointestinal Gastroesophageal reflux Diffuse esophageal spasm Abnormal swallowing

Miscellaneous Nocturnal groaning (catathrenia) Bruxism Enuresis Rhythmic movement disorder Propriospinal myoclonus Somniloquy (sleeptalking)

Miscellaneous Nocturnal muscle cramps Nocturnal pruritus Trichotillomania Night sweats Nocturnal tongue biting Benign nocturnal alternating hemiplegia of childhood

Secondary Sleep Parasomnias Central Nervous System Headaches • Vascular • Nonvascular

Functional Disorders Nocturnal panic attacks Posttraumatic stress disorder Psychogenic dissociative disorder Malingering, conversion hysteria, Munchausen syndrome, Munchausen syndrome by proxy

related to any underlying psychological or psychiatric problems. Enuresis Enuresis was formerly classified as a disorder of arousal, implying a relationship with slow-wave sleep.10 However, enuresis can occur during either NREM or REM sleep, and the sleep of enuretic children is normal.11 Enuresis is very common in childhood, and it much more prevalent in adolescence and adulthood than generally appreciated (1% to 2% of 18 year-olds and 0.5% of adults).12,13 Many etiologies have been suggested, including genetic,14 behavioral and psychological, bladder size or reactivity abnormalities, lack of vasopressin release during sleep, and delayed development.15 Despite considerable literature, the causes of enuresis remain enigmatic. Local urologic abnormalities account for only 2% to 4% of pediatric cases.16 No specific psychopathology has been identified, and there is overwhelming evidence that enuretic children have no more behavioral or psychological problems than nonenuretic children and that genetic factors are important.17 Formal urologic evaluation is usually not indicated, and simple reassurance and understanding on the part of both

the child and the parents are often sufficient. Conditioning with a bell-and-pad device is effective but may be transient.18 Psychotherapy is generally ineffective and indicated only if obvious psychopathology is present.12 Tricyclic antidepressants (imipramine or desipramine) are effective and may be employed for short-term treatment, but long-term pharmacologic treatment is to be discouraged. Their mechanism of action is not known, but it appears not to involve peripheral anticholinergic effects.19 Desmopressin, an intranasally administered vasopressin analogue, has been reported to be of benefit.20 Enuresis may be the sole manifestation of nocturnal seizures and can accompany obstructive sleep apnea or other primary sleep disorders.21 Formal polysomnographic study with a full seizure montage and enuresis detector is indicated in patients with atypical histories or failure to respond to conventional therapy. Rhythmic Movement Disorder Rhythmic movement disorder (RMD), formerly termed jactatio capitis nocturna, refers to a group of actions characterized by stereotyped movements (rhythmic oscillation of the head or limbs, head-banging or body-rocking during sleep) seen most commonly in childhood (Videos 96-2 and

1100  PART II / Section 12  •  Parasomnias

96-3). Its persistence into adulthood is not uncommon. It is familial in some cases. RMD can arise from all stages of sleep, including REM sleep, and it can occur during the transition from wake to sleep.22 Significant injury from repetitive pounding can result.23 The etiology of RMD is unknown, and no systematic studies of pharmacologic or behavioral treatment have been reported, although tricyclic antidepressants and benzodiazepines, particularly clonazepam, may be effective.24 Preliminary data suggest that the use of a waterbed can improve the rhythmic actions,25 as can controlled sleep restriction.26 Hypnosis was effective in a single case.27 Posttraumatic cases involving only the foot have been reported.28 Rarely, RMD is the sole manifestation of a seizure29 or is associated with REM sleep behavior disorder.30 Propriospinal Myoclonus Propriospinal myoclonus is a spinal cord–mediated movement disorder, occasionally associated with acquired spinal cord lesions. It is characterized by repetitive jerks occurring during the transition from wake to sleep.31 Propriospinal myoclonus may be confused with restless legs syndrome or periodic limb movements in sleep, and it can serve to shed light on the pathophysiology of these two disorders.32 It has been described in various neurologic conditions such as restless legs syndrome, paraneoplastic syndromes, and cervical disk herniation, and in extreme cases it can result in life-threatening respiratory compromise.33-36 The movements can appear during relaxation and can result in severe insomnia, particularly at sleep onset.37 Clonazepam or anticonvulsant medications may be effective in alleviating these movements.31 Propriospinal myoclonus may be related to segmental myoclonus, both spinal and palatal.38 Somniloquy (Sleeptalking) Sleeptalking is very common in the general population, might have a genetic component,39 and can occur in either REM or NREM sleep.40 Most cases are not associated with serious psychopathology.41

SECONDARY SLEEP PARASOMNIAS The secondary phenomena are parasomnias representing abnormal or excessive autonomic or physiologic events arising from specific organ systems and occurring preferentially during the sleep period. These can be approached by the offending organ system. Central Nervous System Parasomnias Seizures Nocturnal seizures are an important cause of complex motor actions arising from the sleep period and are discussed in Chapter 92. Headaches V ASCULAR H EADACHES Although some headaches have historically been referred to as “vascular headaches,” there is now overwhelming evidence that the etiology of this headache type is not vascular,

but rather a primary neurologic phenomenon.42 Many headache syndromes are sleep related.43 The headache symptoms of cluster headache, chronic paroxysmal hemicrania, and possibly migraines, in some cases, tend to be related to REM sleep, explaining the common report of sleep-related headaches in these conditions.44 This fact explains the worsening of these symptoms following the discontinuation of REM sleep–suppressing agents (which results in a rebound of REM sleep) such as tricyclic antidepressants, monoamine oxidase inhibitors, clonidine, alcohol, and amphetamines. Circadian rhythm abnormalities can play a role in cluster headache and chronic paroxysmal hemicrania.45,46 Episodic paroxysmal hemicrania might respond to calcium channel blockers or topiramate.47,48 Sleep-disordered breathing can serve as a risk factor for headaches in some persons with cluster headaches.49 N ONVASCULAR H EADACHES Although morning headaches may be more prevalent in persons with sleep complaints in general, headaches are not a reliable marker for sleep-disordered breathing.50 However, in some susceptible persons, obstructive sleep apnea can trigger cluster headaches, which respond to bilevel positive airway pressure (BiPAP).51 Headaches associated with sleep-disordered breathing are more commonly seen in patients with neuromuscular disease who experience REM sleep–related hypoventilation, with hypercapnia-induced migraines arising from the sleep period. Carbon monoxide poisoning must never be overlooked as a cause of morning headaches. E XPLODING H EAD S YNDROME This syndrome is characterized by abrupt arousal, usually occurring in the transition from wake to sleep, with the sensation of a loud sound like an explosion or a sensation of bursting of the head.52 Most reported cases occur in the twilight state of sleep onset, but polysomnographic recording has documented their occurrence during both wakefulness and well-declared REM sleep.53,54 These events might represent a variant of sleep starts55 and are usually benign; however, similar phenomena can represent the sole manifestation of a seizure.56 Clomipramine or nifedipine may be effective, but they are not indicated in most cases due to the benign nature of the condition.57 There is a single case report of exploding head syndrome followed by sleep paralysis as a migraine aura.58 H YPNIC H EADACHE The hypnic headache syndrome has been described in a number of older patients with regular awakenings from sleep at a consistent time of night (usually 4 to 6 hours after sleep onset), occasionally during a dream, with a diffuse headache that generally lasts 30 to 60 minutes and is associated with nausea but no autonomic symptoms. Although only approximately 50 patients with this syndrome have been reported, it is likely more common than previously thought. The headaches are usually generalized, but they may be unilateral59 and may be protracted.60 This condition is felt to be a benign sleep-related headache syndrome affecting the elderly. The few cases studied during sleep suggest it most commonly arises from REM



sleep. It might also represent a circadian rhythm phenomenon and might respond to lithium, indomethacin, prednisone, flunarizine, gabapentin, acetazolamide, or caffeine administered before bedtime.61-63 A detailed neurological history and examination should be performed to rule out focal neurologic conditions such as a posterior fossa meningioma masquerading as hypnic headaches.64 Tinnitus Tinnitus can persist during sleep, resulting in sleep complaints in up to 50% of patients.65 The sleep complaints are not associated with mood or emotional distress.66 Subjective improvement in sleep followed use of an electrical tinnitus suppressor or bedside sound generators.67,68 In another study, nortriptyline decreased depression, functional disability, and loudness of tinnitus, but sleep was not mentioned.69 This condition is poorly understood and requires more systematic study before any conclusions may be reached. Evidence exists that tinnitus may be centrally mediated.70 The term explosive tinnitus most likely refers to an auditory sleep start.6 There is no known predictably effective treatment. Cardiopulmonary Parasomnias Cardiac arrhythmias, nocturnal angina pectoris, and nocturnal asthma are covered elsewhere. (See Chapters 111, 116, 118, and 121.) Respiratory Dyskinesias There are numerous respiratory dyskinesias that occur or persist during the sleep period. These include segmental myoclonus such as palatal myoclonus71,72 or diaphragmatic flutter73 as well as paroxysmal dystonia.74 Respiratory dyskinesias may also be the manifestation of neurolepticinduced dyskinesias, and they might or might not persist during sleep.75 These should be differentiated from unusual nocturnal seizures that manifest with primarily or exclusively respiratory symptoms.76 Effective treatments remain to be identified. Sleep Hiccup Persistent hiccup can continue during all stages of sleep, but its appearance during sleep in persons with chronic hiccup is variable.77 The frequency diminishes during sleep, more so in REM than NREM sleep. Interestingly, sleep hiccups are rarely associated with arousals.78 No treatment studies are available. Miscellaneous Cardiorespiratory Parasomnias Isolated cases of sleep-related dyspnea and choking have been reported. The etiology and treatment are unclear.79 Paroxysmal choking may be the sole manifestation of nocturnal seizures.80 Phantom shocks from implantable cardioverter-defibrillators have been reported. Patients are awakened from a sound sleep with the sensation of having received a defibrillator discharge. These were not associated with dream recall. By observation, there was a motor jolt associated with crying out, as though an actual shock had been administered. Review of the counters indicated that no shock had been delivered. These phantom shocks

CHAPTER 96  •  Other Parasomnias  1101

should be verified before medical treatment or device reprogramming is prescribed.81 Intractable cough associated with the supine position, presumably due to position-related collapse of the upper airway, responsive to nasal CPAP has been reported.82,83 Gastrointestinal Parasomnias Numerous gastrointestinal events may result in paroxysmal arousals during sleep, often mimicking disorders of other organ systems. Gastroesophageal reflux disease (GERD) is covered elsewhere in Chapter 127. Diffuse Esophageal Spasm Nocturnal diffuse esophageal spasm simulates nocturnal cardiac disease, occasionally even resulting in arrhythmias.84,85 Diagnosis may be made with esophageal manometric monitoring. Treatment includes administration of anticholinergics, nitrates, or calcium antagonists.86 Abnormal Swallowing Abnormal swallowing during sleep can cause arousals induced by coughing, aspiration, or choking. Polysomnographic studies show brief episodes of coughing and gagging.87 Etiology and treatment are unknown. Miscellaneous Secondary Parasomnias Nocturnal Muscle Cramps The complaint of muscle cramping, often nocturnal, is extremely common but poorly understood. The true incidence and etiology are unknown, and there has been no systematic study of nocturnal muscle cramps. A subjective response to quinine sulfate, magnesium, vitamin E, gabapentin, or verapamil has been reported, as has an isolated case responding to transcutaneous nerve stimulation.88-93 Nocturnal Pruritus Patients with a wide variety of dermatologic disorders associated with pruritus may demonstrate recurrent episodes of scratching during sleep, resulting in sleep disruption.94 These scratching episodes occur during all stages of sleep, being most often in light NREM, intermediate in REM, and least often in slow-wave sleep.95,96 Circadian factors have been suggested.97 The duration of scratching episodes is the same among the sleep stages.98 Anecdotal response to lidocaine patches or mirtazapine have been reported.99,100 Such scratching can interfere with treatment and can play a role in factitious dermatoses.101 Trichotillomania In some persons, trichotillomania (the compulsion to pull out one’s hair) may be confined to sleep.102 Imipramine has been effective in one case.103 Night Sweats Night sweats are very common, but they tend not to be reported to physicians.104 Night sweats (unrelated to infectious, endocrine, or malignant conditions) may be associated with a number of unrelated conditions includ-

1102  PART II / Section 12  •  Parasomnias

ing obstructive sleep apnea,105 spinal syringomyelia,106 medications,104 gastroesophageal reflux,107 and autonomic seizures.108 Although night sweats may be associated with other subjective sleep complaints, there is no association with objective evidence of specific sleep disorders.97 Night sweats can also appear around the time of menopause.109 The degree of sweating during sleep may be impressive, necessitating several nightly changes of pajamas and bedding. Benztropine has been reportedly effective in venlafaxine-induced night sweats.110 There is no known effective treatment for idiopathic recurring night sweats. Nocturnal Tongue Biting Tongue biting during sleep has been reported as a manifestation of a number of unrelated conditions, including myoclonic activity, nocturnal seizures, disorders of arousal, and rhythmic movement disorder.111-116 Benign Nocturnal Alternating Hemiplegia of Childhood Benign nocturnal alternating hemiplegia of childhood, a presumably rare condition, is associated with brief periods of hemiplegia arising from the sleep period, rarely occurring during wakefulness. This condition might resolve spontaneously. There is no known treatment. The mechanism is unknown, but there is a high frequency of migraine in relatives. It may be a channelopathy such as hemiplegic migraine or episodic ataxia type 2.117

malingering), unlike other parasomnias, the complex behavior during polysomnographic monitoring is seen to arise from well-developed EEG-determined wakefulness.125 The term pseudoparasomnia has been proposed for this condition.126 Malingering, Conversion Hysteria, or Munchausen’s Syndrome Malingering, conversion hysteria, or Munchausen syndrome can appear to a sleep specialist as sleep-related stridor, asthma, upper airway obstruction, or sleep-related violent behavior in adults,127-132 or as sleep apnea (Munchausen by proxy) in children.133 Cyclic hypersomnia has also been reported as a manifestation of a factitious disorder.134

❖  Clinical Pearl The vast majority of parasomnias are due to either disorders of arousal or the REM sleep behavior disorder. There remain a large number of other parasomnias that may be confused with the more common ones. Careful evaluation by history and polysomnographic study will usually identify the true underlying problem. Undoubtedly, as more patients experiencing unusual phenomena arising from the sleep period are evaluated and studied thoroughly, more fascinating parasomnias will be identified, with important therapeutic implications.

FUNCTIONAL DISORDERS Posttraumatic Stress Disorder Posttraumatic stress disorder is covered in Chapter 53. Nocturnal Panic Attacks Sleep-related panic attacks occur in many (30% to 50%) patients with diurnal panic, and they can precede the appearance of diurnal panic or may be exclusively nocturnal.118 Panic disorder can begin in childhood and adolescence and can masquerade as a wide variety of neurologic syndromes.119 Subjective sleep complaints are common in patients with panic disorder (up to 70%) and include insomnia, nocturnal panic attacks, or fear of going to bed or falling asleep.120 Formal sleep studies may be unremarkable, with no abnormalities of sleep macrostructure or excessive arousability, but suggest that nocturnal panic is a NREM phenomenon.121 It is easy to understand how nocturnal panic and other sleep disorders characterized by precipitous arousals (particularly sleep apnea or gastroesophageal reflux) may be confused.122 The striking similarity of the symptoms of dream anxiety attacks, sleep terrors, nocturnal seizures, sleep apnea, and nighttime panic urges caution in diagnosis. Psychogenic Dissociative States Complex, potentially injurious behavior, occasionally confined to the sleep period, may be the manifestation of a psychogenic dissociative state.123 A history of childhood physical or sexual abuse is virtually always present but may be difficult to elicit.124 In this condition (and

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CHAPTER 96  •  Other Parasomnias  1103 14. Bakwin H. The genetics of enuresis. In: Kolvin I, MacKeith S, Meadow R, editors. Bladder control and enuresis. London: Lavenham Press; 1973. 15. Butler RJ, Holland P. The three systems: a conceptual way of understanding nocturnal enuresis. Scand J Urol Nephrol 2000;34: 270-277. 16. Fritz GK, Anders TF. Enuresis: the clinical application of an etiologically based classification system. Child Psychiatry Hum Dev 1979;10:103-113. 17. Hublin C, Kaprio J, Partinen M, et al. Nocturnal enuresis in a nationwide twin cohort. Sleep 1998;21:579-585. 18. Alon US. Nocturnal enuresis. Pediatr Nephrol 1995;9:94-103. 19. Rapoport JL, Mikkelsen EJ, Zavadi LA, et al. Childhood enuresis. II. Psychopathology, tricyclic concentration in plasma, and antidiuretic effect. Arch Gen Psychiatry 1980;37:1146-1152. 20. Neveus T, Bader G, Sullen U. Enuresis, sleep and desmopressin treatment. Acta Paediatr 2002;91:1121-1125. 21. Umlauf MG, Chasens ER. Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis. Sleep Med Rev 2003;7: 403-411. 22. Mayer G, Wilde-Frenz J, Kurella B, et al. Sleep related rhythmic movement disorder revisited. J Sleep Res 2007;16:110-116. 23. Whyte J, Kavey NB, Gidro-Frank S. A self-destructive variant of jactatio capitis nocturna. J Nerv Ment Disord 1991;179:49. 24. Merlino G, Serafini A, Dolso P, et al. Association of body rolling, leg rolling, and rhythmic feet movements in a young adult: a videopolysomnographic study performed before and after one night of clonazepam. Mov Disord 2008;23:602-607. 25. Garcia J, Rosen G, Mahowald M. Waterbeds in treatment of rhythmic movement disorders: experience with two cases. Sleep Res 1996;25:243. 26. Etzioni T, Katz N, Hering E, et al. Controlled sleep restriction for rhythmic movement disorder. J Pediatr 2005;147:393-395. 27. Rosenberg C. Elimination of a rhythmic movement disorder with hypnosis—a case report. Sleep 1995;18:608-609. 28. Broughton R. Pathological fragmentary myoclonus, intensified hypnic jerks and hypnagogic foot tremor: three unusual sleeprelated movement disorders. In: Koella WP, Obal F, Schulz H, Visser P, editors. Sleep ’86. Stuttgart: Gustav Fischer Verlag; 1988. p. 240-243. 29. Guilleminault C, Silvestri R. Disorders of arousal and epilepsy during sleep. In: Sterman MB, Shouse MN, Passouant PP, editors. Sleep and epilepsy. New York: Academic Press; 1982. p. 513-531. 30. Manni R, Terzaghi M, Manni R, et al. Rhythmic movements in idiopathic REM sleep behavior disorder. Mov Disord 2007; 22:1797-1800. 31. Montagna P, Provini F, Plazzi G, et al. Propriospinal myoclonus upon relaxation and drowsiness: a cause of severe insomnia. Mov Disord 1997;12:66-72. 32. Plazzi G, Provini F, Ligouri R, et al. Propriospinal myoclonus at the transition from wake to sleep. Sleep Res 1996;26:438. 33. Capelle HH, Wohrle JC, Weigel R, et al. Propriospinal myoclonus due to cervical disc herniation. Case report. J Neurosurg Spine 2005;2:608-611. 34. Manconi M, Sferrazza B, Iannaccone S, et al. Case of symptomatic propriospinal myoclonus evolving toward acute “myoclonic status.” Mov Disord 2005;20:1646-1650. 35. Salsano E, Ciano C, Romano S, et al. Propriospinal myoclonus with life threatening tonic spasms as paraneoplastic presentation of breast cancer. J Neurol Neurosurg Psychiatry 2006;77:422-424. 36. Vetrugno R, Provini F, Plazzi G, et al. Propriospinal myoclonus: a motor phenomenon found in restless legs syndrome different from periodic limb movements during sleep. Mov Disord 2005;20: 1323-1329. 37. Vetrugno R, Provini F, Meletti S, et al. Propriospinal myoclonus at the sleep–wake transition: a new type of parasomnia. Sleep 2001;24:835-843. 38. Bauleo S, De Mitri P, Coccagna G. Evolution of segmental myoclonus during sleep: polygraphic study of two cases. Ital J Neurol Sci 1996;17:227-232. 39. Reimao RN, Lefevre AB. Prevalence of sleeptalking in childhood. Brain Dev 1980;2:353-357. 40. Arkin AM, Toth MF, Baker J, et al. The frequency of sleep talking in the laboratory among chronic sleep talkers and good dream recallers. J Nerv Ment Dis 1970;151:369-374.

41. Hublin C, Kaprio J, Partinen M, et al. Sleeptalking in twins: epidemiology and psychiatric comorbidity. Behav Genet 1998;28: 289-298. 42. Welch KM, Cutrer FM, Goadsby PJ. Migraine pathogenesis. Neurology 2003;60(Suppl. 2):S9-S14. 43. Alberti A. Headache and sleep. Sleep Med Rev 2006;10:431-437. 44. Sahota PK, Dexter JD. Sleep and headache syndromes: a clinical review. Headache 1990;30:80-84. 45. Micieli G, Cavallini A, Facchinetti F, et al. chronic paroxysmal hemicrania: a chronobiological study (case report). Cephalgia 1989;9:281-286. 46. Della Marca G, Vollono C, Rubino M, et al. A sleep study in cluster headache. Cephalalgia 2005;26:290-294. 47. Cohen AS, Goadsby PJ. Paroxysmal hemicrania responding to topiramate. J Neurol Neurosurg Psychiatry 2007;78:96-97. 48. Coria F, Claveria LE, Jimenez-Jimenez FJ, et al. Episodic paroxysmal hemicrania responsive to calcium channel blockers. J Neurol Neurosurg Psychiatry 1992;55:166. 49. Chervin R, Zallek SN, Lin X, et al. Sleep disordered breathing in patients with cluster headache. Neurology 2000;54:23022306. 50. Goder R, Friege L, Fritzer G, et al. Morning headaches in patients with sleep disorders: a systematic polysomnographic study. Sleep Med 2003;4:385-391. 51. Chervin RD, Zallek SN, Lin X, et al. Timing patterns of cluster headaches and association with symptoms of obstructive sleep apnea. Sleep Res Online 2000;3:107-112. 52. Chakravarty A. Exploding head syndrome: report of two new cases. Cephalalgia 2008;28:399-400. 53. Sachs C, Svanborg E. The exploding head syndrome: polysomnographic recordings and therapeutic suggestions. Sleep 1991;14: 263-266. 54. Walsleben JA, O’Malley EB, Freeman J, et al. Polysomnographic and topographic mapping of EEG in the exploding head syndrome. Sleep Res 1993;22:284. 55. Pearce JMS. Exploding head syndrome. Headache 2001;41: 602-603. 56. Fornazzari L, Farcnik K, Smith I, et al. Violent visual hallucinations and aggression in frontal lobe dysfunction: clinical manifestations of deep orbitofrontal foci. J Neuropsychiatry Clin Neurosci 1992;4:42-44. 57. Jacome DE. Exploding head syndrome and idiopathic stabbing headache relieved by nifedipine. Cephalalgia 2001;21:617618. 58. Evans RW, Evans RW. Exploding head syndrome followed by sleep paralysis: a rare migraine aura. Headache 2006;46:682-683. 59. De Simone R, Marano E, Ranieri A, et al. Hypnic headache: an update. Neurol Sci 2006;27:S144-S148. 60. Ghlotto N, Sances G, Di Lorenzo G, et al. Report of eight new cases of hypnic headache and mini-review of the literature. Funct Neurol 2002;17:211-219. 61. Evers S, Goadsby PJ. Hypnic headache. Clinical features, pathophysiology, and treatment. Neurology 2002;60:905-909. 62. Sibon I, Ghorayeb I, Henry P. Successful treatment of hypnic headache syndrome with acetazolamide. Neurology 2003;61: 1157-1158. 63. Liang JF, Fuh JL, Yu HY, et al. Clinical features, polysomnography and outcome in patients with hypnic headache. Cephalalgia 2008;28:209-215. 64. Peatfield RC, Mendoza ND. Posterior fossa meningioma presenting as hypnic headache. Headache 2003;43:1007-1008. 65. Hebert S, Carrier J, Hebert S, et al. Sleep complaints in elderly tinnitus patients: a controlled study. Ear Hear 2007;28:649655. 66. Hallum RS. Correlates of sleep disturbance in chronic distressing tinnitus. Scand Audiol 1996;25:263-266. 67. Handscomb L. Use of bedside sound generators by patients with tinnitus-related sleeping difficulty: which sounds are preferred and why? Acta Otolaryngol Suppl 2006;556:59-63. 68. Matsushima J, Sakai N, Sakajiri M, et al. An experience of the usage of electrical tinnitus suppressor. Artificial Organs 1996; 20:955-958. 69. Sullivan M, Katon W, Russo J, et al. A randomized trial of nortriptyline for severe chronic tinnitus. Arch Intern Med 1993;153: 2251-2259.

1104  PART II / Section 12  •  Parasomnias 70. Plewnia C, Bartels M, Gerloff C. Transient suppression of tinnitus by transcranial magnetic stimulation. Ann Neurol 2002;53: 263-266. 71. Jankovic J, Pardo R. Segmental myoclonus: clinical and pharmacologic study. Arch Neurol 1986;43:1025-1031. 72. Lapresle J. Palatal myoclonus. Adv Neurol 1986;43:265273. 73. Iliceto G, Thompson BL, Day JC, et al. Diaphragmatic flutter, the moving umbilicus syndrome, and “belly dancer’s” dyskinesia. Mov Disord 1990;1:15-22. 74. Sethi KD, Hess DC, Huffnagle VH, et al. Acetazolamide treatment of paroxysmal dystonia in central demyelinating disease. Neurology 1992;42:919-921. 75. Rich MW, Radwany SM. Respiratory dyskinesia. An underrecognized phenomenon. Chest 1994;105:1826-1832. 76. Walls TJ, Newman PK, Cumming WJK. Recurrent apnoeic attacks as a manifestation of epilepsy. Postgrad Med J 1981; 57:575-576. 77. Launois S, Bizec JL, Whitelaw WA, et al. Hiccup in adults: an overview. Eur Respir J 1993;6:563-575. 78. Arnulf I, Boisteanu D, Whitelaw WA, et al. Chronic hiccups and sleep. Sleep 1995;19:227-231. 79. DeRoeck J, Van Hoof E, Cluydts R. Sleep-related expiratory groaning: a case report. Sleep Res 1983;12:237. 80. Brown LW, Fry JM. Paroxysmal nocturnal choking: a newly described manifestation of sleep-related epilepsy. Sleep Res 1988; 17:153. 81. Kowey PR, Mainchak RA, Rials SJ. Things that go bang in the night. N Engl J Med 1992;327:1884. 82. Bonnet R, Jorres R, Downey R, et al. Intractable cough associated with the supine body position. Effective therapy with nasal CPAP. Chest 1995;108:581-585. 83. Teng AY, Sullivan CE. Nasal mask continuous positive airway pressure in the treatment of chronic nocturnal cough in a young child. Respirology 1997;2:131-134. 84. Fontan JP, Heldt GP, Heyman MB, et al. Esophageal spasm associated with apnea and bradycardia in an infant. Pediatrics 1984; 73:52-55. 85. Bortolotti M, Cirignotta F, Labo G. Atrioventricular block induced by swallowing in a patient with diffuse esophageal spasm. JAMA 1982;248:2297-2299. 86. Traube M, McCallum RW. Primary oesophageal motility disorders. Current therapeutic concepts. Drugs 1985;30:66-77. 87. Guilleminault C, Eldridge FL, Phillips JR, et al. Two occult causes of insomnia and their therapeutic problems. Arch Gen Psychiatry 1976;33:1241-1245. 88. Weiner IH, Weiner HL. Nocturnal leg muscle cramps. JAMA 1980;244:2332-2333. 89. Baltodano N, Gallo BV, Weidler DJ. Verapamil vs quinine in recumbent nocturnal leg cramps in the elderly. Arch Intern Med 1988;148:1969-1970. 90. Mills KR, Newham DJ, Edwards RHT. Severe muscle cramps relieved by transcutaneous nerve stimulation: a case report. J Neurol Neurosurg Psychiatry 1982;45:539-542. 91. Connolly PS, Shirley EA, Wasson JH, et al. Treatment of nocturnal leg cramps. A crossover trial of quinine vs vitamin E. Arch Intern Med 1992;152:1877-1880. 92. Serrao M, Rossi P, Cardinali P, et al. Gabapentin treatment for muscle cramps: an open-label trial. Clin Neuropharmacol 2000; 23:45-49. 93. Kannan N, Sawaya R. Nocturnal leg cramps: clinically mysterious and painful—but manageable. Geriatrics 2001;56. 94. Bender BG, Ballard R, Canono B, et al. Disease severity, scratching, and sleep quality in patients with atopic dermatitis. J Am Acad Dermatol 2008;58:415-420. 95. Aoki T, Kushimoto H, Hishikawa Y, et al. Nocturnal scratching and its relationship to the disturbed sleep of itchy subjects. Clin Exp Dermatol 1991;16:268-272. 96. Monti JM, Vignale R, Monti D. Sleep and nighttime pruritus in children with atopic dermatitis. Sleep 1989;12:309-314. 97. Mold JW, Goodrich S, Orr W. Associations between subjective night sweats and sleep study findings. J Am Board Fam Med 2008;21:96-100. 98. Savin JA, Paterson WD, Oswald I, et al. Further studies of scratching during sleep. Br J Dermatol 1975;93:297-302.

99. Gabriel GM, Crone CC. Nocturnal pruritus in a cardiac pretransplant patient. Psychosomatics 2001;42:344-346. 100. Sandroni P. Central neuropathic itch: a new treatment option? Neurology 2002;59:778-779. 101. Brodland DG, Staats BA, Peters MS. Factitial leg ulcers associated with an unusual sleep disorder. Arch Dermatol 1989;125: 1115-1118. 102. Murphy C, Redenius R, Zallek S. Sleep-isolated trichotillomania: a survey of dermatologists. J Clin Sleep Med 2007;3:719-721. 103. Murphy C, Valerio T, Zallek SN. Trichotillomania: an NREM sleep parasomnia? Neurology 2006;66:1276. 104. Mold JW, Mathew MK, Shuaib B, et al. Prevalence of night sweats in primary care patients: an OKPRN and TAFP-Net collaborative study. J Fam Pract 2002;51:452-456. 105. Duhon DR. Night sweats: two other causes (letter). J Am Medical Assn 1994;271:1577. 106. Gordon D. Night sweats: two other causes (letter). J Am Medical Assn 1994;271:1577. 107. Reynolds WA. Are night sweats a sign of esophageal reflux? J Clin Gastroenterol 1989;11. 108. Solomon GE. Diencephalic autonomic epilepsy caused by a neoplasm. J Pediatr 1973;83:277-280. 109. Woodward S, Freedman RR. The thermoregulatory effects of menopausal hot flashes on sleep. Sleep 1994;17:497-501. 110. Pierre JM, Guze BH. Benztropine for venlafaxine-induced night sweats (letter). J Clin Psychopharmacol 2000;20:269. 111. Johnson LF, Kinsbourne M, Renuart AW. Hereditary chin-trembling with nocturnal myoclonus and tongue-biting in dizygous twins. Dev Med Child Neurol 1971;13:726-729. 112. Vasiknanonte P, Kuasirikul S, Vasiknanonte S. Two faces of nocturnal tongue biting. J Med Assoc Thailand 1997;80:500506. 113. Tuxhorn I, Hoppe M. Parasomnia with rhythmic movements manifesting as nocturnal tongue biting. Neuropediatrics 1993;24: 167-168. 114. Edwards JC, Dinner DS, Gordon PH. Violent tongue biting as a parasomnia. Sleep Res 1997;26:358. 115. Aguglia U, Gambardella A, Quattrone A. Sleep-induced masticatory myoclonus: a rare parasomnia associated with insomnia. Sleep 1991;14:80-82. 116. Vetrugno R, Provini F, Plazzi G, et al. Familial nocturnal faciomandibular myoclonus mimicking sleep bruxism. Neurology 2002;58:644-647. 117. Chaves-Vischer V, Picard F, Andermann E, et al. Benign nocturnal alternating hemiplegia of childhood: six patients and long-term follow-up. In: Brazil CW, Malow BA, Sammaritano M, editors. Sleep and epilepsy: the clinical spectrum. Amsterdam: Eslevier; 2002. p. 283-289. 118. Craske MG, Rowe MK. Nocturnal panic. Clin Psychol Sci Prac 1997;4:153-174. 119. Black B, Robbins DR. Panic disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 1990;29:36-44. 120. Lepola U, Koponen H, Leinonen E. Sleep in panic disorders. J Psychosomatic Res 1994;38(Suppl. 1):105-111. 121. Landry P, Marchand L, Mainguy N, et al. Electroencephalography during sleep of patients with nocturnal panic disorder. J Nerv Ment Dis 2002;190:559-562. 122. Edlund MJ, McNamara ME, Millman RP. Sleep apnea and panic attacks. Compr Psychiatry 1991;32:130-132. 123. Agargun MY, Kara H, Ozer OA, et al. Characteristics of patients with nocturnal dissociative disorders. Sleep Hypnosis 2001;3: 131-134. 124. Chu JA, Dill DL. Dissociative symptoms in relation to childhood physical and sexual abuse. Am J Psychiatry 1990;147:887892. 125. Schenck CS, Milner DM, Hurwitz TD, et al. Dissociative disorders presenting as somnambulism: polysomnographic, video, and clinical documentation (8 cases). Dissociation 1989;4:194-204. 126. Molaie M, Deutsch GK. Psychogenic events presenting as parasomnia. Sleep 1997;20:402-405. 127. Mahowald MW, Schenck CH, Rosen GR, et al. The role of a sleep disorders center in evaluating sleep violence. Arch Neurol 1992;49:604-607. 128. Baker CE, Major E. Munchausen’s syndrome. A case presenting as asthma requiring ventilation. Anaesthesia 1994;49:1050-1051.

129. Elshami AA, Tino G. Coexistent asthma and functional upper airway obstruction. Case reports and review of the literature. Chest 1996;110:1358-1361. 130. Walker FO, Alessi AG, Digre KB, et al. Psychogenic respiratory distress. Arch Neurol 1989;46:196-200. 131. Butani L, O’Connell EJ. Functional respiratory disorders. Ann Allergy Asthma Immunol 1997;79:91-101.

CHAPTER 96  •  Other Parasomnias  1105 132. Goldman J, Muers M. Vocal cord dysfunction and wheezing. Thorax 1991;46:401-404. 133. Skau K, Mouridsen SE. Munchausen syndrome by proxy: a review. Acta Paediatr 1995;84:977-982. 134. Feldman MD, Russell JL. Factitious cyclic hypersomnia: a new variant of factitious disorder. South Med J 1991;84: 1991.

Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions Tore Nielsen and Antonio Zadra Abstract Nightmares and other common disturbances of dreaming involve a perturbation of emotional expression during sleep. Nightmares, the most prevalent dream disturbance, are now recognized as comprising several dysphoric emotions, including especially fear, although some argue that existential (or grief) dreams should be considered a separate entity. A genetic basis for nightmares has been demonstrated and their pathophysiology involves a surprising underactivation of the sympathetic nervous system in many instances. Personality factors, such as nightmare chronicity and distress and coping styles, are mediating determinants of their clinical severity,

Because most common dreaming disturbances (Table 97-1) involve a perturbation of emotional expression during sleep, their study may help clarify the role of emotion in dream formation, dream function, and sleep mechanisms more generally. Physiologic evidence for emotional activity during rapid eye movement (REM) sleep is substantial. Autonomic system variability increases markedly in conjunction with central phasic activation,1 as seen especially in measures of cardiac function,2,3 respiration,4 and skin and muscle sympathetic nerve activity.5 Brain imaging, too, demonstrates increased metabolic activity in limbic and paralimbic regions during REM sleep,6 activity similar to that seen during strong emotion in the waking state.7 These dramatic autonomic fluctuations globally parallel dreamed emotional activity, which is detectable throughout most dreaming when appropriate probes are employed.8 Some studies indicate that most dreamed emotion is negative,9 primarily fearful,8 and may conform to a surgelike structure within REM episodes.10 Many theorists interpret the various forms of phasic activity occurring during sleep as indicating dream-related affective activity.11,12 Waking state emotional and cognitive reactions are also implicated in dream disturbances. For the most common disturbances, such as nightmares, dreamed emotions become unbearably intense, provoking an awakening that can lead to further distress, depressed mood, avoidance and coping behavior, and often even impairment of subsequent sleep. Perturbation of dream-related emotion can thus lead to a cycle of sleep disruption and avoidance, insomnia,13 and psychological distress that often leads the person to seek out professional help.14 However, causal relationships among emotion, dreaming, and other associated symptoms are not well understood. The emotional disruption inherent in nightmare disorder may be limited to sleep-related processes, in which case the dreaming process itself might be considered 1106

Chapter

97

as are drug and alcohol use. Many treatments have been described, with much support for the effectiveness of shortterm cognitive and behavior interventions such as systematic desensitization and imagery rehearsal. Several related dream disturbances occur at the transitions into or out of sleep and involve dysphoric emotions ranging from malaise to fear to frank terror. These disturbances include sleep starts, terrifying hypnagogic hallucinations, sleep paralysis, somniloquy with dream content, false awakenings, and disturbed lucid dreaming. The distinctive nature of these disturbances may be mediated by immediately preceding waking state processes (e.g., consciousness, sensory vividness) that intrude upon or carry over into dreaming.

pathologic in some sense.15 However, the widespread belief that dreaming can serve an emotionally adaptive function (see Chapter 54) also suggests that some dream disturbances are adaptive reactions to more basic pathophysiologic factors rather than pathological per se.16

IDIOPATHIC NIGHTMARES Historical Aspects The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)17 criteria for nightmare disorder (Table 97-2) have not changed substantially since the disorder was previously described as “dream anxiety disorder” in the DSM-III-R and “dream anxiety attack” in the DSMIII. The International Classification of Sleep Disorders, 2nd edition (ICSD-II) criteria for nightmares (see Table 97-2) have changed only slightly since the first edition (ICSD). Some new research on the phenomenology of nightmares has prompted a redefinition of the term nightmare in the more recent ICSD-II. The widely accepted definition of a nightmare has long been “a frightening dream that awakens the sleeper,” but researchers have come to reevaluate these defining features. Some18 argue that the “awakening” criterion should indeed designate nightmares but that disturbing dreams that do not awaken (“bad dreams”) should nevertheless be considered clinically significant. Whether or not the person awakens presumably reflects a dream’s emotional severity, but it is not the only index of severity. First, among patients with various psychosomatic disorders, even the most macabre and threatening dreams do not necessarily produce awakenings.19 Second, less than one fourth of patients with chronic nightmares report “always” awakening from their nightmares, and these awakenings do not correlate with either nightmare intensity or psychological distress.13 Third, among subjects with both nightmares and bad dreams, approximately 45% of bad dreams are rated



CHAPTER 97  •  Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions  1107

Table 97-1  Sleep Disorders in Which Disturbed Dreaming is Common SLEEP DISORDER

CODE*

STAGE

PREVALENCE

ESSENTIAL FEATURES

Nightmare disorder

307.47-0

REM, 2

Preschoolers: 5%-30% Young adults: 2%-5%

Frightening dreams; awakening

Terrifying hypnagogic hallucinations

307.47-4

Sleep onset

Rare Narcolepsy: 4%-8%

Terrifying dreams similar to those from sleep

Sleep starts

307.47-2

Sleep onset

Lifetime: 60%-70% Extreme form: rare

Sudden brief jerks associated with sensory flash, hypnagogic dream, or feeling of falling

Sleep paralysis

780.56-2

Sleep onset or offset

Isolated, normal persons: 1/lifetime in 40%-50% Familial: rare

Paralysis of voluntary muscles; acute anxiety (with or without dreams) is common

*American Sleep Disorders Association: International classification of sleep disorders, revised: diagnostic and coding manual. Westchester, Ill: American Sleep Disorders Association; 1997.

Table 97-2  Clinical Criteria for Nightmare Disorder DSM-IV DIAGNOSTIC CRITERIA FOR NIGHTMARE DISORDER (307.47)

ICSD-II DIAGNOSTIC CRITERIA FOR NIGHTMARES (307.47-0)

Nature of recalled dream

Repeated awakenings from the major sleep period or naps with detailed recall of extended and extremely frightening dreams, usually involving threats to survival, security, or self-esteem.

Recurrent episodes of awakenings from sleep with recall of intensely disturbing dream mentation, usually involving fear or anxiety but also anger, sadness, disgust, and other dysphoric emotions. Recall of sleep mentation is immediate and clear.

Nature of awakening

On awakening from the frightening dreams, the person rapidly becomes oriented and alert (in contrast to the confusion and disorientation seen in sleep terror disorder and some forms of epilepsy).

Alertness is full immediately on awakening, with little confusion or disorientation.

Nature of distress

The dream experience, or the sleep disturbance resulting from the awakening, causes clinically significant distress or impairment in social, occupational, or other important areas of function.

Associated features include at least one of the following: • Return to sleep after the episodes is typically delayed and not rapid.

Timing

The awakenings generally occur during the second half of the sleep period.

The episodes typically occur in the latter half of the habitual sleep period.

Differential diagnosis

The nightmares do not occur exclusively during the course of another mental disorder (e.g., a delirium, posttraumatic stress disorder) and are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

Nightmares are distinguished from several other disorders in a Differential Diagnosis section: seizure disorder, arousal disorders (sleep terrors, confusional arousal), REM sleep behavior disorder, isolated sleep paralysis, nocturnal panic, posttraumatic stress disorder, acute stress disorder.

CRITERIA

on a level of emotional intensity that is equal to or exceeds that of the average nightmare.20 In short, whereas disturbing dreams often can awaken a sleeper, awakenings are not the sole or even the best index of the severity of the disorder. Similarly, researchers have come to define nightmares more inclusively with respect to their emotional tone. This is reflected in the modified ICSD-II definition of nightmares as “disturbing mental experiences” rather than as “frightening dreams” as in the ICSD. Although fear remains the most commonly reported nightmare emotion,20

some argue18 that nightmares can involve any unpleasant emotion. However, distressing dreams related to bereavement are considered by some as constituting a distinct nosologic entity known as existential dreams.21 Prevalence and Frequency Lifetime prevalence for a nightmare experience in the general population is unknown but may well approach 100%. If we consider only dreams of attack and the pursuit theme, which are the most common nightmare themes, the lifetime prevalence varies from 67%22 to 90%.23 Pursuit

Age

0

Boys Girls

yr

10 11 12 13 14 15 16 17 18

*

B

Age

C

*

*

*

.40

*

.30

* *

Males Females

.20

-2 30 9 -3 4 35 -3 9 40 -4 45 4 -4 9 50 -5 4 55 -5 9

5

6

yr 5

o m yr 2

4

yr 5 3

A

2

yr 5

m

m

o

o

0.0

10

.50

-2 4

1.0

*** *** *** ***

25

2.0

15

-1 9

3.0

.60

15

4.0

20

20

Boys Girls

Log (nightmares/mo + 1)

% Often + always

5.0

% Much + very much

1108  PART II / Section 12  •  Parasomnias

Age

Figure 97-1  Nightmare prevalence over the lifespan. A, Proportion of preschool children having bad dreams “often” or “always” as reported by parents in a longitudinal study (girls: n = 490-493; boys: n = 468-477).24 No sex difference is apparent at any age. B, Proportion of children and adolescents having nightmares “much” or “very much” in the last month (girls: n = 3372, mean age = 14.1 ± 2.05 years; boys: n = 3355; mean age = 14.0 ± 2.12) (***P < .0001)25; C, log(number of nightmares in a typical month + 1) reported by respondents to an Internet questionnaire (female: n = 19,367, mean age = 24.9 ± 10.14 years; male: n = 4,623; mean age = 25.5 ± 10.81) (*P < .05). (From Nielsen TA, Petit D. Description of parasomnias. In Kushida CA, editor. Handbook of sleep disorders. Oxford: Taylor and Francis; 2008. p. 459-479.)

alone has a lifetime prevalence of 92% among women and 85% among men.23 An ensemble of population studies indicates that the prevalence and frequency of nightmares increases through childhood into adolescence, when a marked gender difference takes hold (Fig. 97-1). Preschoolers report bad dreams surprisingly seldom. From 1.3% to 3.9% of parents report that their children have them “often” or “always” and there is no gender difference at this age (see Fig. 97-1A).24 Subsequently, as shown in a study of 6727 Kuwaiti 10- to 18-year-old children,25 nightmare prevalence increases from ages 10 to 13 years for both boys and girls and thereafter continues to increase for girls but decreases progressively for boys (see Fig. 97-1B). This finding replicates with more precision our finding that boys and girls aged 13 years report bad dreams often with about equal prevalence (boys, 2.5%; girls, 2.7%), whereas at age 16 years prevalence for the same children diverges markedly (boys, 0.4%; girls, 4.9%).26 The gender difference is then maintained into adulthood and old age, even though the prevalence of nightmares decreases steadily over time for both men and women (see Fig. 97-1C).27 This general profile of age and gender differences is consistent with a large corpus of research for young children,28 adolescents,26 young adults,29 middle-aged adults,30 and the general population.31 Slightly different patterns have been reported for some pediatric32 and elementary school33 samples, however. Nightmare prevalence may be elevated in clinical populations. For example, 25% of chronic alcoholics and drug users report nightmares “every few nights” on the Minnesota Multiphasic Inventory (MMPI),34 and 66% of suicide attempters report moderate or severe nightmares.35 However, other findings of elevated prevalence are difficult to assess because a frequency criterion is not specified; for example, approximately 24% of nonpsychotic patients seen in psychiatric emergency services report nightmares, but with an unknown frequency.36 When compared to results from daily home logs, however, retrospective self-reports underestimate current nightmare frequency by a factor of 2.5 in young adults18 to a factor of more than 10 in the healthy elderly.37 In general, a 1-month retrospective estimate is closer to the

estimate provided by daily logs than is a 12-month retrospective estimate and is thus the preferred standard for retrospective assessment. Because nightmare prevalence and frequency are seriously underestimated by retrospective instruments, daily logs are the method of choice. Familial Pattern Twin-based studies have identified persistent genetic effects on the disposition to nightmares in childhood, as reported retrospectively by adults, and in adulthood,30a as well as genetic influences on the co-occurrence of nightmares and some other parasomnias, such as sleeptalking, but not others, such as bruxism.38 In the Finnish twin cohort study, a genetic basis for nightmares was shown in the proportion of phenotypic variance in trait liability for nightmare prevalence attributable to genetic influences at about 45%.30 A second study reports a 51% genetic influence.30a Pathophysiology One laboratory study of nightmares39 indicates moderate arousal—increased heart and respiration rates—during some nightmare episodes, but unexpectedly low arousal in most others. These early findings constitute the principal empirical basis for diagnostic guidelines such as the ICSD and DSM-IV, but there are serious problems with the work, such as the inclusion of psychiatric patients and patients with posttraumatic stress disorder (PTSD) in the study sample. Recordings of heart rate and respiration rate during nightmare and non nightmare REM sleep episodes confirmed a moderate level of sympathetic arousal during nightmares.40 Mean heart rate for nightmare sleep was elevated (by about 6 bpm) for the 3 minutes before awakening. Mean respiration rate was only marginally higher at this time. We have recorded higher absolute and relative alpha power over primarily right posterior sites in the last 2 minutes of nightmare sleep. However, these changes might reflect processes of awakening. The typical sleep of nightmare subjects does not differ dramatically from that of paired controls41; although elevated levels of periodic limb movements in sleep (PLMS) have been observed for both idiopathic and PTSD nightmare sufferers.42 REM sleep measures suggest that night-



Percent skipped REM periods

CHAPTER 97  •  Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions  1109

A

70 60 50

*

40 27.3

30 20 9.1

10

0

0 REM1

Mean (SD) %REM

%REM-1st Third

B

19 17 15 13 11 9 7 5 3 1

Nightmare Control

50.0

REM2

%REM-2nd Third

%REM-3rd Third

Nightmare (N = 14) Control (N = 11)

Night 1 Night 3 Night 1 Night 3 Night 1 Night 3

Figure 97-2  Reduced REM propensity among nightmare subjects. A, Elevated number of skipped early REM periods for nightmare subjects on baseline night suggests low REM propensity. Nightmare subjects skipped 7 of 14 expected REM1 periods and 3 of 14 expected REM2 periods; control subjects skipped 1 (*P = .042, Fisher exact test) and 0 (not significant), respectively. B, REM sleep as a percentage of total time asleep (REM%) separated by thirds of the night. Relative to night 1, nightmare subjects showed REM rebound in the first third of night 3 (P = .003) but not the second (P = .128) or third (P = .776) thirds. Control subjects showed REM rebound in the second (P = .018) and third (P = .050) thirds but not the first (P = .275). REM propensity for nightmare subjects is thus low precisely at the time of night when REM sleep is normally most prevalent and most intense (from Nielsen, et al., Sleep Medicine 2010;11:172-179).

mare subjects have abnormally low REM sleep propensity, even during recovery sleep following partial REM sleep deprivation in a 3-night protocol (Fig. 97-2).41 Personality Although many studies report relationships between nightmare frequency and measures of psychopathology,18,26 some do not.43 Several detailed reviews are available.14,44,45 Inconsistent relationships between nightmares and psychopathology likely reflect mediating factors, among which three—nightmare chronicity, nightmare distress, and coping style—are reviewed below. Nightmare Chronicity Adults with a lifelong history of frequent nightmares compose an idiopathic nightmare subgroup with more psychopathologic symptoms than matched controls, such as higher neuroticism and MMPI scores.46 However, Hartmann47 found that no one measure of psychopathology

adequately describes these persons. He proposed48 a general “boundary permeability” personality dimension, correlated with nightmare prevalence,49 which, at one extreme (thin boundaries) characterizes lifelong sufferers who are more open, sensitive, and vulnerable to intrusions than thick-boundary subjects, including a greater sensitivity to events not usually viewed as traumatic.47 Nightmare Distress Nightmare frequency and waking distress over one’s nightmares are only moderately correlated measures in adults50 and largely unrelated in adolescents.51 Subjects might have only few nightmares (e.g., one per month) yet report high levels of associated distress and vice versa. It is nightmare distress, not necessarily nightmare frequency, that is significantly related to psychopathology, especially to measures of anxiety and depression.52 Thus, nightmareinduced distress might simply be an expression of a more general distress style.14 However, even though both state (stress) and trait personality measures correlate with nightmare frequency, trait measures do not account for any variance beyond that accounted for by state measures.53 Nightmare distress should be evaluated during clinical intake because, although it is not among the diagnostic criteria of the DSM-IV or ICSD-II, it is central to defining nightmares as a clinical problem. Coping Style Given the central role of nightmare distress, a person’s ability to cope with stress may be pivotal in whether a clinical problem with nightmares develops. Dysfunctional coping strategies such as dissociation might exacerbate both nightmare distress and chronicity. College students with nightmares report both higher rates of childhood trauma and higher scores on dissociative coping (Dissociative Experiences Scale, DES) than do students without nightmares.54 Adaptive and maladaptive coping strategies may come into play at a very young age because dissociation scores on the Child Dissociative Checklist are associated with nightmares among children as young as 3 to 4 years.55 Effects of Drugs and Alcohol Numerous classes of drugs trigger nightmares and bizarre dreams, including catecholaminergic agents, beta-blockers, some antidepressants, barbiturates, and alcohol. One review56 suggests that the therapies most often associated with nightmares are sedative/hypnotics, beta-blockers, and amphetamines and that REM suppression is a frequent mechanism of action. Among catecholaminergic agents, reserpine, thioridazine, and levodopa are all occasionally associated with vivid dreams and nightmares,57-59 as are beta-blockers such as betaxolol, metropolol, bisoprolol, and propranolol.60-62 Among the antidepressants, bupropion leads to more vivid dreams and nightmares than do other antidepressants.63 The selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluvoxamine suppress dream recall frequency while simultaneously increasing subjective dream intensity and bizarreness, possibly due to serotoninergic REM suppression.64 Bedtime administration of tricyclic and neuroleptic agents leads to a higher recall of frightening dreams than when these are taken in

1110  PART II / Section 12  •  Parasomnias Table 97-3  Drugs Reported in Case Studies to Increase Frequency of Nightmares DRUG

FUNCTION

REFERENCE

Betaxolol

Beta-blocker

Mort, 1992126

Carbachol

Cholinergic agent

Mort, 1992126

Donepizil

Cholinesterase inhibitor

Ross and Shua-Haim, 1998127

Erythromycin

Antibiotic

Black and Dawson, 1988133

Fluoxetine

Antidepressant

Lepkifker, Dannon, Iancu, et al, 1995128

Naproxen

Nonsteroidal antiinflammatory

Bakth and Miller, 1991129

Nitrazepam

Benzodiazepine hypnotic

Girwood, 1973132

Thiothixene

Neuroleptic

Solomon, 1983125

Triazolam

Benzodiazepine hypnotic

Forman and Souney, 1989131

Verapamil

Antimigraine agent

Kumar and Hodges, 1988130

two daily doses,65 even though normal dream recall frequency remains the same. Neuroleptics and tricyclics appear to render dream affect more dysphoric rather than to increase dream recall per se. Withdrawal from barbiturates is associated with REM rebound, vivid dreaming, and nightmares.66 A hypothesis has been advanced that barbiturate suppression of REM sleep, much like with alcohol, causes REM sleep rebound after discontinuation of the drug and consequently longer and more vivid dreams.67 In addition, several case studies have alerted physicians to the nightmare-causing effects of specific substances (Table 97-3). Evening, but not morning, doses of the acetylcholinesterase inhibitor donepezil induces nightmares.68 The antimalarial drug mefloquine produces vivid dreams and nightmares.69 Sleep and dream disturbances follow alcohol withdrawal. Alcoholic patients report more vivid dreams and nightmares following withdrawal than they do during ingestion; although these are more frequent in the week following withdrawal, they are still present in subsequent weeks. The nightmares and insomnia of withdrawal can lead to resumed drinking in an attempt to normalize sleep. In fact, 29% of a group of 100 alcoholics reported further drinking to alleviate nightmares.70 This relationship is also of critical importance because of the danger of alcohol self-medication for PTSD71 and other nightmare-producing disorders. Vivid and macabre dreaming may be central to the delirium tremens (DTs) of acute alcohol withdrawal.72 Because alcohol suppresses REM sleep, and because REM percentage (particularly at sleep onset) is extremely elevated in patients with DTs,73 a theory of DT hallucinations emphasizing REM rebound and intrusion of dreaming into wakefulness has been proposed.74 Case studies strongly suggest that hallucinations may seem to continue uninterrupted from an ongoing nightmare.75 DT sleep appears to be a mixture of REM sleep with “stage 1 REM sleep with tonic EMG,” which distinguishes it from the sleep of alcoholics without DTs.76 Some have failed to observe this pattern, however.77 The similarity of sleep patients with DTs to those with REM sleep behavior disorder (RBD) has also been noted.78 Acute withdrawal from cocaine often induces unpleasant dreams.79 Strange dreams, including nightmares, are one of the most consistently reported effects of withdrawal from cannabis; they are persistent, lasting for longer than

45 days after withdrawal.80 In two studies, strange dreams are rated to be “severe” and “moderate” by 20% and 37% of adults and by 8% and 15% of adolescents seeking treatment.81,82 The neuropharmacologic bases of drug-induced or withdrawal-associated disturbed dreaming remain unclear. There may be a balance among various neurotransmitter systems such that nightmares are produced by reduced brain norepinephrine and serotonin or increased dopamine and acetylcholine.47 REM suppression is implicated as a mechanism in the action of many agents (e.g., betablockers), as is dopamine receptor stimulation.56 Dissociation of dream initiation and intensification processes by separate neuromodulatory systems may also be implicated64 (see Chapter 48). Recurrent Dreaming and Nightmares Repetitive dreams, such as posttraumatic nightmares, depict—over numerous, highly similar versions—an unresolved experience, such as a motor vehicle accident or war trauma. These are also referred to as replicative nightmares (see Chapter 53). Recurrent dreams depict conflicts or stressors metaphorically over repeated instances and are also primarily unpleasant in nature.83 The most frequent recurrent dreams of adults are pseudonightmarish: being endangered (e.g., chased, threatened with injury), being alone and trapped (e.g., in an elevator), facing natural forces (e.g., volcanic eruptions), or losing one’s teeth. Dreams with less recurrence—recurrent themes and recurrent contents—extend over long dreams series and are associated with more mild psychopathology, possibly even with attempts at emotional adaption.84 Subjects with recurrent dreams show less successful adaptation on measures of anxiety, depression, personal adjustment, and life-events stress than those without recurrent dreams.85 However, the maintained cessation of recurrent dreaming may reflect an upturn in well-being.86 Case studies have been described in which progressive changes in repetitive dream elements occur as a function of successful psychotherapy.87 Treatment A wide variety of treatments for nightmares has been reported.88,89 Although psychotherapy aimed at resolving conflict has traditionally been the treatment of choice,90 it lacks empirical support. On the other hand, there is much



CHAPTER 97  •  Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions  1111

Table 97-4  Treatment Recommendations for Nightmares Level A: Supported by a substantial amount of high-grade evidence and/or based on a consensus of clinical judgment

Image Rehearsal Therapy (IRT)

Level B: Supported by a sparse amount of high-grade evidence or a substantial amount of low-grade data and/or clinical consensus by task force

Systematic Desensitization Progressive Deep Muscle Relaxation training

Level C: Supported by low-grade data without volume to recommend more highly; likely subject to revision with further studies

Lucid Dreaming Therapy Self-Exposure Therapy

Recommendations adapted from Aurora RN, Zak RS, Auerbach SH, et al. AASM Standards of Practice Committee. Best practice guide­ lines for the treatment of nightmare disorders in adults. J Clin Sleep Med 2010;6:389-401.

support for diverse cognitive behavior interventions that require six or fewer sessions. Systematic desensitization and relaxation techniques, used to countercondition a relaxation response to anxiety-provoking nightmare contents, have been effective in several case studies and in two controlled studies.91 Imagery rehearsal, which teaches patients to change their remembered nightmares and to rehearse new scenarios, has reduced both nightmare distress and frequency.92 The rationale for this approach as well as the major steps covered in therapy have been summarized for clinicians.93 Other treatments with some empirical support are lucid dreaming,94,95 eye movement desensitization and reprocessing,96 and hypnosis.97 Treatment guidelines for nightmares associated with PTSD are reviewed in Box 129-9. Treatment guidelines for nightmare disorder are summarized in Table 97-4.97a

DREAM DISTURBANCES OF THE SLEEP–WAKE TRANSITION Several interrelated dream disturbances occur at the transitions into or out of sleep. These share the attributes of vivid, often intensely real, sensory imagery and disturbing affects such as fear. The distinctive reality quality might stem from an interleaving or boundary dissociation of sleep–wake processes at this time, such as intrusions of real perceptions into sleep or of dreamed objects or characters into wakefulness.98 The nature of the intruding components can determine the distinctiveness of the transition disturbance, including typical or odd combinations such as a frightening hypnagogic image terminating in a sleep start or incomprehensible sleeptalking accompanying sleep paralysis. Sleep Starts Sleep starts, also known as predormital or hypnic myoclonus and hypnagogic or hypnic jerks, are brief phasic contractions of the muscles of the legs, arms, face, or neck that occur at sleep onset. They are often associated with brief,

albeit vivid and forceful, dream events. Perhaps the most common of these events is the illusion of suddenly falling that incites a vigorous, startling jerk. Brief sensory flashes also occur; sometimes they are somatic and somewhat difficult to describe. Complex hypnagogic images can also occur. Mild starts are a normal—even universal—feature of falling asleep, with a prevalence as high as 60% to 70%.99 More-extreme starts can engender difficulties in initiating sleep.100 Sleep starts can bear a striking resemblance to exploding head syndrome101 in that the latter also occurs at sleep onset and produces sudden loud auditory sensations or bright light flashes, or both. Sounds are described variously as thunderclaps, clashes of cymbals, doors slamming, electric shocks, loud snaps, bomblike explosions, and so forth.101 In a sample of 50 patients, 10% reported a concurrent flash of light, 6% reported the curious sensation of stopped breathing and having to make an “uncomfortable gasp” to start again, and 94% reported fear, terror, palpitations, or forceful heartbeats as an aftereffect.101 It is not known whether chronic sleep starts are primarily a disturbance of motor systems, perhaps akin to PLMS, with epiphenomenal imagery, or a disturbance of imagery systems per se, such that gripping images provoke the disruptive reflex activity. EEG events have been noted to accompany sleep starts102; however, more systematic studies of the variety of EEG burst patterns accompanying drowsiness103 are needed. Terrifying Hypnagogic Hallucinations Terrifying hypnagogic hallucinations (THHs) are terrifying dreams similar to those from REM sleep; after a sudden awakening at sleep onset there is prompt recall of frightening content.99 Because they arise from sleep-onset REM (SOREM) episodes, they may be aggravated by factors that predispose to this type of sleep, for example, withdrawal from REM-suppressant medication, chronic sleep deprivation, sleep fragmentation, or narcolepsy. Other sleep and medical disorders can accompany the condition. Content analyses of THHs are lacking, but clinical and anecdotal reports suggest that the themes of attack and aggression also found in REM sleep nightmares are common. THHs are perhaps more anxiety provoking than most nightmares because of a vivid sense of reality related to their close proximity to wakefulness and because of frequently accompanying feelings of paralysis. These features are illustrated in the case example.

Case Study A 36-year-old woman with PTSD had severe THHs. At age 19 years, she was abducted and sexually and physically abused for more than 3 days by motorcycle gang members. She regularly re-experienced these horrors through flashbacks and nightmares, but even worse were the THHs with paralysis occurring as she returned to sleep after a nightmare. She felt as if she were awake, aroused and terrified, yet unable to move; time seemed to pass in slow motion during these “replays.”104

1112  PART II / Section 12  •  Parasomnias

The suffering during such episodes is exacerbated by the patient’s simultaneous sense of wakefulness and inability to move or call for help. Further, the intense anxiety associated with recurrent THHs can disrupt sleep onset sufficiently to produce sleep-onset insomnia.99 Prevalence figures for THHs are not available, but an estimate for patients with narcolepsy is 4% to 8%.105 Isolated Sleep Paralysis Isolated sleep paralysis (ISP) consists of episodes of muscle paralysis with clear consciousness that occurs at sleep onset or upon transitions into wakefulness. Physiologic mechanisms of ISP have been studied in some detail,106 but the relationship of ISP to nightmares requires further study. For example, nightmare subjects rate their own home dreams to contain significantly more feelings of inhibition or ineffectuality than do control subjects.41 Patients seldom present for symptoms of ISP alone, but they might when the frequency of their episodes increases, for example, to one per day. Frightening sleep paralysis episodes have also been referred to as sleep paralysis nightmares, and their role in the misdiagnosis of hysteria and allegations of abuse have been described.107 Etiology Although psychopathology does not seem to be a direct cause of ISP,108 associations have been reported between ISP and psychopathologies such as social anxiety,109 panic disorder110 and depression.111 Psychopathologic factors might influence ISP indirectly by their influence on stress and overwork and subsequent disruptive effects on sleep108 or by modulating vigilance levels during sleep disruption.112 Sleep-related life habits are also associated with ISP occurrence in nonnarcoleptic populations,113 for example, poor sleep quality, insufficient sleep, and a proclivity to daytime sleep—all factors that can favor the occurrence of SOREM episodes.113 In fact, ISP episodes have been elicited experimentally by a schedule of sleep interruptions producing SOREM.112 Other mediating factors may be phase advance or rapid resetting of the circadian clock, as is the case with jet lag,114 or sleeping in the supine position.108 However, daytime imaginativeness, as indexed by standardized questionnaires, and vividness of nighttime imagery, as measured by selfreported frequencies of nightmares and sleep terrors and dream vividness, are personality factors most predictive of ISPs in a large college student cohort.108 ISP is typically accompanied by vivid hypnagogic hallucinations. In fact, it is rare to find ISP in the absence of other hallucinatory activity. Only 1.6% (of 387) subjects experienced ISP without other attributes.108 Of six experimentally elicited ISP episodes, all but one included auditory or visual hallucinations and unpleasant emotions.115 Conversely, it is not true that most hypnagogic hallucinations are accompanied by sleep paralysis. Given this association of sleep paralysis with hypnagogic hallucinations, it is unclear whether sleep paralysis is, as some have suggested,116 a type of perception, that is, of ongoing REM sleep muscle atonia. Rather, paralysis sensations may be dreamed, which could account for why the episodes are often reported to be accompanied by odd feelings of oppression, pressure on the chest, or being beaten or choked violently. It could also

explain how paralysis and felt ineffectuality appear routinely and in such variety in normal dreams and nightmares.12 Prevalence Multiple ISP episodes have a low prevalence, occurring “often or always” in 0% to 1% of young adults and “at least sometimes” in 7% to 8% of young adults.105 On the other hand, the ICSD-R99 cites the lifetime prevalence at 40% to 50%, which is somewhat higher than other estimates. We found rates of 25% to 36% among three university student cohorts, which is similar to the 26% reported for 208 Japanese undergraduates,117 the 21% for 1798 Canadian undergraduates,108 and the 34% for 200 sleep-disorder patients. Use on questionnaires of a culturally identifiable term for sleep paralysis, such as kanashibari in Japan, can increase the prevalence estimate by an additional 8%117; the adjusted estimate of 39% corresponds well with estimates from other cultures, such as 37% of 603 Hong Kong undergraduates reporting at least one episode of ghost oppression, the Chinese equivalent of kanashibari.118 One survey of Newfoundland villagers found as many as 62% admitting to old hag attacks.119 Somniloquy with Dream Content Sleeptalking has been observed in all stages of sleep, but especially in non-REM (NREM) stages 2, 3, and 4.120 Arkin120 identified various orders of concordance between sleep-speech and later dream reports. For first-order concordances, sleep-speech exactly matches content in the dream; for example, a subject shouting “No! No!” who dreamed of shouting these words when seeing her baby fall from the bed. For second-order concordances, a conceptual or emotional link between sleep-speech and the dream is preserved; for example, a nightmare patient dreamed repeatedly of trying to yell “Burglars!” but in reality called out “Mama!” Absence of concordance is also seen: One study of 28 chronic sleeptalkers found it in 16.7% of REM, 32.9% of stage 2, and 38.5% of stage 3-4 sleep somniloquy episodes.120 As with sleep paralysis, it remains unknown why imagery and behavior are dissociated in this manner. False Awakening False awakenings are nowhere classified as pathologic, but they can nonetheless produce anxious reactions. Two types of false awakening have been distinguished primarily on the basis of the degree of anxious affect associated.121 Both types usually consist of dream imagery in which the person is (falsely) waking up from sleep or, in variations, from a dream and can engender some confusion while dreaming as to whether one is actually awake or asleep. Both are also often associated with experienced separation from the sleeping body, or out-of-body experience, and of becoming aware of dreaming while dreaming, or lucid dreaming.121 Type 1 awakenings are the more common type and usually depict realistic instances of the person waking up in his or her habitual bed followed by, in many cases, depictions of activities such as dressing, eating breakfast, and setting off for work. Some discrepancy in the imagery might fully awaken the person with the surprising realization that it was just a dream. The dreams are often repetitive, depicting a succession of awakenings or of setting off for work.



CHAPTER 97  •  Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions  1113

Type 2 false awakenings are less pleasant than type 1 in that the apparent awakenings in bed are accompanied by a “stressed, electrified, or tense” atmosphere and feelings of “foreboding or expectancy” that may be “apprehensive or oppressively ominous.”121 There may be hallucinations of ominous or anxiety-provoking sounds or strange apparitions of persons or monsters. False awakenings are clearly not always about a person’s own home and bed because instances have been elicited in laboratory subjects that incorporated the laboratory bed and setting.122 Pathologic and Disturbed Lucid Dreaming Lucid dreaming is occasionally associated with disturbed or pathologic reactions. Typically, lucid dreaming is perceptually vivid—the dreamer often feels awake—with a limited capacity to control the unfolding of some dreamed events. It is often spontaneously triggered within a nightmare and can be used in a therapy context to resolve the distressing contents of recurrent nightmares.94 However, some have reported diverse negative reactions associated with lucid dreaming, including a type of burnout resulting from too frequent intentional use of the mental state, mental confusion, and “quasi-psychotic splits with reality” induced by the overlapping of perceptual and dreamlike mentation, and intense fear associated with the loss of control of the vivid dream contents.123 ❖  Clinical Pearl The diagnosis and treatment plan for a great many sleep problems can be enhanced by querying patients during the clinical interview about the nature of their dreams and nightmares and whether they have changed quantitatively or qualitatively since the onset of symptoms. For example, distressing nightmares are often symptomatic of a more general anxiety problem.

REFERENCES 1. Parmeggiani PL. The autonomic nervous system in sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 194-203. 2. Baharav A, Kotagal S, Gibbons V, et al. Fluctuations in autonomic nervous activity during sleep displayed by power spectrum analysis of heart rate variability. Neurology 1995;45:1183-1187. 3. Verrier RL, Muller JE, Hobson JA. Sleep, dreams, and sudden death: the case for sleep as an autonomic stress test for the heart. Cardiovasc Res 1996;31:181-211. 4. Orem J. Respiratory neurons and sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 177-193. 5. Noll G, Elam M, Kunimoto M, et al. Skin sympathetic nerve activity and effector function during sleep in humans. Acta Physiol Scand 1994;151:319-329. 6. Maquet P. Positron emission tomography studies of sleep and sleep disorders. J Neurol 1997;244(Suppl. 1):S23-S28. 7. Paradiso S, Robinson RG, Andreasen NC, et al. Emotional activation of limbic circuitry in elderly normal subjects in a PET study. Am J Psychiatry 1997;154:384-389. 8. Nielsen TA, Deslauriers D, Baylor GW. Emotions in dream and waking event reports. Dreaming 1991;1:287-300. 9. Hall C, van de Castle RI. The content analysis of dreams. New York: Appleton-Century-Crofts; 1966.

10. Kramer M. The selective mood regulatory function of dreaming: An update and revision. In: Moffitt A, Kramer M, Hoffmann R, editors. The functions of dreaming. Albany: State University of New York Press; 1993. p. 139-196. 11. Rechtschaffen A. The psychophysiology of mental activity during sleep. In: McGuigan FJ, Schoonoer RA, editors. The psychophysiology of thinking: studies of covert processes. New York: Academic Press; 1973. p. 153-205. 12. Kuiken D, Sikora S. The impact of dreams on waking thoughts and feelings. In: Moffitt A, Kramer M, Hoffmann R, editors. The functions of dreaming. Albany: State University of New York Press; 1993. p. 419-476. 13. Krakow B, Kellner R, Pathak D, et al. Imagery rehearsal treatment for chronic nightmares. Behav Res Ther 1995;33:837843. 14. Levin R, Nielsen TA. Disturbed dreaming, posttraumatic stress disorder, and affect distress: a review and neurocognitive model. Psychol Bull 2007;133:482-528. 15. Kramer M. Nightmares (dream disturbances) in posttraumatic stress disorder: implication for a theory of dreaming. In: Bootzin RR, Kihlstrom JF, Schacter DL, editors. Sleep and cognition. Washington, DC: American Psychological Association; 1992. p. 190-203. 16. Lara-Carrasco J, Nielsen T, Solomonova L, et al. Overnight emotional adaptation to negative stimuli is altered by REM sleep deprivation and is correlated with intervening dream emotions. J Sleep Res 2009;18;178-187. 17. American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed (DSM-IV). Washington, DC: American Psychiatric Association; 1994. 18. Zadra A, Donderi DC. Nightmares and bad dreams: their prevalence and relationship to well-being. J Abnorm Psychol 2000; 109:273-281. 19. Levitan HL. The significance of certain catastrophic dreams. Psychother Psychosom 1976;27:1-7. 20. Zadra A, Pilon M, Donderi DC. Variety and intensity of emotions in nightmares and bad dreams. J Nerv Ment Dis 2006;194: 249-254. 21. Busink R, Kuiken D. Identifying types of impactful dreams—a replication. Dreaming 1996;6:97-119. 22. Harris I. Observations concerning typical anxiety dreams. Psychiatry 1948;11:301-309. 23. Hall CS. The significance of the dream of being attacked. J Pers 1955;24:168-180. 24. Simard V, Nielsen TA, Tremblay RE, et al. Longitudinal study of bad dreams in preschool children: prevalence, demographic correlates, risk and protective factors. Sleep 2008;31:62-70. 25. Abdel-Khalek AM. Nightmares: prevalence, age and gender differences among Kuwaiti children and adolescents. Sleep Hypnosis 2006;8:33-40. 26. Nielsen TA, Laberge L, Tremblay R, et al. Development of disturbing dreams during adolescence and their relationship to anxiety symptoms. Sleep 2000;23:727-736. 27. Nielsen TA, Stenstrom P, Levin R. Nightmare frequency as a function of age, gender and September 11, 2001: findings from an Internet questionnaire. Dreaming 2006;16:145-158. 28. Muris P, Merckelbach H, Gadet B, et al. Fears, worries, and scary dreams in 4- to 12-year-old children: their content, developmental pattern, and origins. J Clin Child Psychol 2000;29:43-52. 29. Coren S. The prevalence of self-reported sleep disturbances in young adults. Int J Neurosci 1994;79:67-73. 30. Hublin C, Kaprio J, Partinen M, et al. Nightmares: familial aggregation and association with psychiatric disorders in a nationwide twin cohort. Am J Med Genet 1999;88:329-336. 30a.  Coolidge FL, Segal DL, Coolidge CM, et al. Do nightmares and generalized anxiety disorder in childhood and adolescence have a common genetic origin? Behav Genet 2010;40:349-356. 31. Claridge GK, Clark K, Davis C. Nightmares, dreams, and schizotypy. Br J Clin Psychol 1997;36:377-386. 32. Salzarulo P, Chevalier A. Sleep problems in children and their relationship with early disturbances of the waking-sleeping rhythms. Sleep 1983;6:47-51. 33. Fisher BE, Pauley C, McGuire K. Children’s Sleep Behavior Scale: normative data on 870 children in grades 1 to 6. Percept Mot Skills 1989;68:227-236.

1114  PART II / Section 12  •  Parasomnias 34. Cernovsky ZZ. MMPI and nightmares in male alcoholics. Percept Mot Skills 1985;61:841-842. 35. Sjostrom N, Waern M, Hetta J. Nightmares and sleep disturbances in relation to suicidality in suicide attempters. Sleep 2007;30: 91-95. 36. Brylowski A. Nightmares in crisis: clinical applications of lucid dreaming techniques. Psychiatr J U Ottawa 1990;15:79-84. 37. Salvio MA, Wood JM, Schwartz J, et al. Nightmare prevalence in the healthy elderly. Psychol Aging 1992;7:324-325. 38. Hublin C, Kaprio J, Partinen M, et al. Parasomnias: co-occurrence and genetics. Psychiatr Genet 2001;11:65-70. 39. Fisher C, Byrne J, Edwards A, et al. A psychophysiological study of nightmares. J Am Psychoanal Assoc 1970;18:747-782. 40. Nielsen TA, Zadra A. Laboratory studies of idiopathic nightmares. Abstracts of the Journée Académique du Département de Psychiatrie, Centre Fernand-Séguin, Louis H Lafontaine Hospital, Montréal, May 16, 1997. 41. Nielsen TA, Paquette T, Solomonova E, et al. REM sleep characteristics of nightmare sufferers before and after REM sleep deprivation. Sleep Med 2010;11:172-179. 42. Germain A, Nielsen TA. Sleep pathophysiology in PTSD and idiopathic nightmare sufferers. Biol Psychiatry 2003;54:1092-1098. 43. Wood JM, Bootzin RR. The prevalence of nightmares and their independence from anxiety. J Abnorm Psychol 1990;99:64-68. 44. Spoormaker VI, Schredl M, Bout JV. Nightmares: from anxiety symptom to sleep disorder. Sleep Med Rev 2005;10:19-31. 45. Nielsen T, Levin R. Nightmares: a new neurocognitive model. Sleep Med Rev 2007;11:295-310. 46. Berquier A, Ashton R. Characteristics of the frequent nightmare sufferer. J Abnorm Psychol 1992;101:246-250. 47. Hartmann E. The nightmare: The psychology and the biology of terrifying dreams. New York: Basic Books; 1984. 48. Hartmann E, Elkin R, Garg M. Personality and dreaming: the dreams of people with very thick or very thin boundaries. Dreaming 1991;1:311-324. 49. Hartmann E. Boundaries of dreams, boundaries of dreamers: thin and thick boundaries as a new personality measure. Psychiatr J U Ottawa 1989;14:557-560. 50. Belicki K. Nightmare frequency versus nightmare distress: relations to psychopathology and cognitive style. J Abnorm Psychol 1992; 101:592-597. 51. Roberts J, Lennings CJ. Personality, psychopathology and nightmares in young people. Pers Indiv Dif 2006;41:733-744. 52. Miro E, Martinez MP. Affective and personality characteristics in function of nightmare prevalence, nightmare distress, and interference due to nightmares. Dreaming 2005;15:89-105. 53. Schredl M. Effects of state and trait factors on nightmare frequency. Eur Arch Psychiatry Clin Neurosci 2003;253:241-247. 54. Agargun MY, Kara H, Ozer OA, et al. Nightmares and dissociative experiences: the key role of childhood traumatic events. Psychiatr Clin Neurosci 2003;57:139-145. 55. Carlson SM, Tahiroglu D, Taylor M. Links between dissociation and role play in a nonclinical sample of preschool children. J Trauma Dissociation 2008;9:149-171. 56. Thompson DF, Pierce DR. Drug-induced nightmares. Ann Pharmacother 1999;33:93-98. 57. Kales A, Scharf MB, Bixler EO, et al. Sleep laboratory drug evaluation: thioridazine (Mellaril), a REM enhancing drug. Sleep Res 1974;3:55. 58. Moskovitz C, Moses H, Klawans HL. Levodopa-induced psychosis: a kindling phenomenon. Am J Psychiatr 1978;135:669-675. 59. Sharf B, Moskovitz C, Lupton MD, et al. Dream phenomena induced by chronic levodopa therapy. J Neural Trans 1978;43: 143-151. 60. Cove-Smith JR, Kirk CA. CNS-related side-effects with metropolol and atenolol. Eur J Pharmacol 1985;28:69-72. 61. Davidov ME, Glazer N, Wollam G, et al. Comparison of betaxolol, a new β1-adrenergic antagonist, to propranolol in the treatment of mild to moderate hypertension. Am J Hypertens 1988;1: 206S-210S. 62. Kuriyama S. Bisoprolol-induced nightmares. J Hum Hypertens 1994;8:731-732. 63. Balon R. Bupropion and nightmares. Am J Psychiatr 1996;153: 579-580.

64. Pace-Schott EF, Gersh T, Silvestri R, et al. SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subject. J Sleep Res 2001;10:129-142. 65. Strayhorn JM, Nash JL. Frightening dreams and dosage schedule of tricyclic and neuroleptic drugs. J Nerv Ment Dis 1978;166: 878-880. 66. Firth H. Sleeping pills and dream content. Br J Psychiatry 1974; 124:547-553. 67. Oswald I, Priest RG. Five weeks to escape the sleeping-pill habit. Br Med J 1965;2:1093-1095. 68. Kitabayashi Y, Ueda H, Tsuchida H, et al. Donepezil-induced nightmares in mild cognitive impairment. Psychiatr Clin Neurosci 2006;60:123-124. 69. Burke BM. Mefloquine. Lancet 1993;341:1605-1606. 70. Hershon HI. Alcohol withdrawal symptoms and drinking behavior. J Stud Alcohol 1977;38:953-971. 71. Stewart SH. Alcohol abuse in individuals exposed to trauma—a critical review. Psychol Bull 1996;120:83-112. 72. Hishikawa Y, Sugita Y, Teshima T, et al. Sleep disorders in alcoholic patients with delirium tremens and transient withdrawal hallucinations—reevaluation of the REM rebound and intrusion theory. In: Karacan I, editor. Psychophysiological aspects of sleep. Park Ridge, NJ: Noyes Medical; 1981. p. 109-122. 73. Rowland RH. Sleep onset rapid eye movement periods in neuropsychiatric disorders: implications for the pathophysiology of psychosis. J Nerv Ment Dis 1997;185:730-738. 74. Feinberg I. Hallucinations, dreaming and REM sleep. In: Keup W, editor. Origin and mechanisms of hallucinations. New York: Plenum; 1970. p. 125-132. 75. Gross MM, Goodenough D, Tobin M, et al. Sleep disturbances and hallucinations in the acute alcoholic psychoses. J Nerv Ment Dis 1966;142:493-514. 76. Tachibana M, Tanaka K, Hishikawa Y, et al. A sleep study of acute psychotic states due to alcohol and meprobamate addiction. In: Weitzman ED, editor. Advances in sleep research, vol. 2. New York: Spectrum Publications; 1975. p. 177-205. 77. Wolin SJ, Mello JK. The effects of alcohol on dreams and hallucinations in alcohol addicts. Ann NY Acad Sci 1973;215:266302. 78. Mahowald MW, Schenck CH. REM sleep behavior disorder. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 574-588. 79. Schierenbeck T, Riemann D, Berger M, Hornyak M. Effect of illicit recreational drugs upon sleep: cocaine, ecstasy and marijuana. Sleep Med Rev 2008;12(5):381-389 80. Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004;161:1967-1977. 81. Vandrey R, Budney AJ, Kamon JL, et al. Cannabis withdrawal in adolescent treatment seekers. Drug Alcohol Depend 2005;78: 205-210. 82. Budney AJ, Novy PL, Hughes JR. Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction 1999;94:1311-1322. 83. Cartwright RD. The nature and function of repetitive dreams: a survey and speculation. Psychiatry 1979;42:131-137. 84. Domhoff GW. The repetition of dreams and dream elements: a possible clue to a function of dreams? In: Moffitt A, Kramer M, Hoffmann R, editors. The functions of dreaming. Albany: State University of New York Press; 1993. p. 293-320. 85. Zadra AL, O’Brien S, Donderi DC. Dream content, dream recurrence and well-being: a replication with a younger sample. J Imag Cogn Pers 1998;17:293-311. 86. Brown RJ, Donderi DC. Dream content and self-reported wellbeing among recurrent dreamers, past-recurrent dreamers, and nonrecurrent dreamers. J Pers Soc Psychol 1986;50:612-623. 87. Bonime W. The clinical use of dreams. New York: Basic Books; 1962. 88. Halliday G. Direct psychological therapies for nightmares: a review. Clin Psychol Rev 1987;7:501-523. 89. Coalson B. Nightmare help: treatment of trauma survivors with PTSD. Psychotherapy 1995;32:381-388. 90. Jones E. On the nightmare. New York: Liveright; 1951.



CHAPTER 97  •  Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions  1115

91. Miller WR, DiPilato M. Treatment of nightmares via relaxation and desensitization: a controlled evaluation. J Consult Clin Psychol 1983;51:870-877. 92. Germain A, Nielsen TA. Impact of imagery rehearsal treatment on distressing dreams, psychological distress, and sleep parameters in nightmare patients. Behav Sleep Med 2003;1:140-154. 93. Krakow B, Zadra A. Clinical management of chronic nightmares: imagery rehearsal therapy. Behav Sleep Med 2006;4:45-70. 94. Zadra AL, Pihl RO. Lucid dreaming as a treatment for recurrent nightmares. Psychother Psychosom 1997;66:50-55. 95. Spoormaker VI, van den Bout J, Meijer EJG. Lucid dreaming treatment for nightmares: a series of cases. Dreaming 2003;13: 181-186. 96. Marquis J. A report on seventy-eight cases treated by eye movement desensitization. J Behav Ther Exp Psychiatr 1991;22: 187-192. 97. Kingsbury SJ. Brief hypnotic treatment of repetitive nightmares. Am J Clin Hyp 1993;35:161-169. 97a.  Aurora RN, Zak RS, Auerbach SH, et al. AASM Standards of Practice Committee. Best practice guidelines for the treatment of nightmare disorders in adults. J Clin Sleep Med 2010;6:389-401. 98. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology 1992;42(Suppl. 6):44-52. 99. American Sleep Disorders Association. International classification of sleep disorders, revised: diagnostic and coding manual. Westchester, Ill: American Sleep Disorders Association; 1997. 100. Broughton R. Pathological fragmentary myoclonus, intensified “hypnic jerks” and hypnagogic foot tremor: three unusual sleeprelated movement disorders. Sleep 1988;86:240-243. 101. Pearce JM. Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatr 1989;52:907-910. 102. Oswald I. Sudden bodily jerks on falling asleep. Brain 1959;82:92101. 103. Bartel P, Robinson E, Duim W. Burst patterns occurring during drowsiness in clinical EEGs. Am J EEG Technol 1995;35: 283-295. 104. Hudson JI, Manoach DS, Sabo AN, et al. Recurrent nightmares in posttraumatic stress disorder: association with sleep paralysis, hypnopompic hallucinations, and REM sleep (brief reports). J Nerv Ment Dis 1991;179:572-573. 105. Partinen M. Epidemiology of sleep disorders. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 437-452. 106. Hishikawa Y, Shimizu T. Physiology of REM sleep, cataplexy, and sleep paralysis. In: Fahn S, Hallett M, Luders HO, et al, editors: Negative motor phenomena. Advances in neurology, vol 67. Philadelphia: Lippincott-Raven; 1995. p. 245-271.

107. Powell RA, Nielsen TA. Was Anna O.’s black snake hallucination a sleep paralysis nightmare? Dreams, memories, and trauma. Psychiatry 1998;61:239-241. 108. Spanos NP, DuBreuil C, McNulty SA, et al. The frequency and correlates of sleep paralysis in a university sample. J Res Pers 1995;29:285-305. 109. Simard V, Nielsen TA. Sensed presence as a possible manifestation of social anxiety. Dreaming 2005;15:245-260. 110. Mellman TA, Aigbogun N, Graves RE, et al. Sleep paralysis and trauma, psychiatric symptoms and disorders in an adult African American population attending primary medical care. Depress Anxiety 2008;25:435-440. 111. Szklo-Coxe M, Young T, Finn L, et al. Depression: relationships to sleep paralysis and other sleep disturbances in a community sample. J Sleep Res 2007;16:297-312. 112. Takeuchi T, Fukuda K, Sasaki Y, et al. Factors related to the occurrence of isolated sleep paralysis elicited during a multi-phasic sleep– wake schedule. Sleep 2002;25:89-96. 113. Takeuchi T, Fukuda K, Yamamoto Y, et al. What kind of sleeprelated life style affects the occurrence of sleep paralysis in normal individuals? Sleep Res 1997;26:518. 114. Snyder S. Isolated sleep paralysis after rapid time zone change (“jet lag”) syndrome. Chronobiology 1983;10:377-379. 115. Takeuchi T, Miyasita A, Sasaki Y, et al. Isolated sleep paralysis elicited by sleep interruption. Sleep 1992;15:217-225. 116. Giaquinto S, Pompeiano O, Somogyi I. Supraspinal inhibitory control of spinal reflexes during natural sleep. Experientia 1963;19:652-653. 117. Fukuda K. One explanatory basis for the discrepancy of reported prevalences of sleep paralysis among healthy respondents. Percept Mot Skills 1993;77:803-807. 118. Wing YK, Lee ST, Chen CN. Sleep paralysis in Chinese: ghost oppression phenomenon in Hong Kong. Sleep 1994;17:609613. 119. Ness RC. The Old Hag phenomenon as sleep paralysis: a biocultural interpretation. Cult Med Psychiat 1978;2:15-39. 120. Arkin AM. Sleep-talking: psychology and psychophysiology. Hillsdale, NJ: Lawrence Erlbaum; 1981. 121. Green C, McCreery C. Lucid dreaming. The paradox of consciousness during sleep. London: Routledge; 1994. 122. Nielsen TA, Montplaisir J. REM sleep hallucinatory episodes induced by somatic stimulation: a phenomenological report. Tenth Congress of the European Sleep Research Society. Strasbourg, France, May 1990. 123. Gackenbach J, Bosveld J. Control your dreams. New York: Harper & Row; 1989.

Disturbed Dreaming as a Factor in Medical Conditions Tore Nielsen Abstract Disturbed dreaming has been identified as a primary or secondary symptom in many medical conditions. The quality of such dreaming can be conveniently classified as varying along a continuum of subjective intensity. At one extreme, dream recall ceases entirely (global cessation of dreaming) or is unusually impoverished in quantity or content (dream impoverishment). Impoverishment affects patients with alexithymia, posttraumatic stress disorder (PTSD), and some brain syndromes. At the other extreme, dreaming is profuse and vivid (excessive dreaming), affecting patients with epic dreaming, some brain lesions, and withdrawal from some medications, or it becomes so intense that it is confused with reality (dream– reality confusion) as is the case with bereavement or the

Beyond common nightmares (see Chapter 97), dreaming disturbances appear as defining or comorbid symptoms of many medical conditions (Table 98-1). In this chapter, these disturbances are classified as falling along a continuum of increasing vividness or intensity, particularly of the apparent reality of the dream experience. At the lower extreme of this continuum, dream recall can cease or the realism of dream content can become impoverished in some respect. At the higher extreme, dream recall can become excessive or dream content unusually vivid and emotional, often being confused with reality or rigidly repetitive in structure. The full range of human emotions, be they dysphoric or euphoric, can appear in disturbed dreams (Fig. 98-1). The intensity dimension of disturbance varies globally in how intensely real the dream experience appears. As described in Chapter 51, reality simulation is widely viewed to be a basic function of the dream-production mechanism, approximating both the process and the contents of typical waking experience. One notable feature of this mechanism is the heightening of perception-like imagery or emotion to the point of equaling or exceeding what is normally perceived or felt during wakefulness. A second notable feature is the increased presence of episodic memory material in dream content. Such material is usually restricted to mere fragments of remembered (episodic) experience (see Chapter 55), but it can become more salient in replay nightmares (see Chapter 53), repetitive dreams, and so forth. Both of these features are likely in play during the most extremely intense dreams, such as those occurring in intensive care unit delirium or dream-reality confusion.

GLOBAL CESSATION OF DREAMING About a third of patients with neurologic illnesses report having ceased dreaming altogether.1 Solms1 and Doricchi2 report that parietal lobe involvement differentiates patients 1116

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98

postpartum state, intensive care unit (ICU) delirium, limbic lobe damage, and psychotic states. Intense dreaming may become rigidly repetitive (repetitive dream content). Conditions such as rapid eye movement (REM) sleep behavior disorder with or without parkinsonism, epilepsy, PTSD, migraine, and cardiac illness are affected by dream repetition. The intensity dimension of dream disturbance appears to mirror various aberrations of dreaming’s normal capacity to simulate reality. Accordingly, episodic memories, which are normally absent from dream content, appear more frequently in disturbed dreams. Although effective treatments are available for several common dream disturbances, the development of new treatments might benefit from attention to intensified reality simulation and the role of episodic memory activation.

with and without global cessation of dreaming (GCD); 42% of GCD patients have parietal lesions and an additional 7% have lesions in proximity to parietal lobe.1 Frontal lobe lesions characterize some patients (8%) with GCD,1 which is consistent with the reduced dream recall that follows upon frontal lobotomy3 (but see reference 2). An additional 43% of GCD patients have diffuse and nonlocalizable lesions.1 It is noteworthy, however, that few such patients are subjected to rigorous REM sleep awakenings to determine whether the capacity for dream recall under optimal conditions is, in fact, absent. Such studies might reveal that many patients who appear to have GCD instead have dream impoverishment.

IMPOVERISHED DREAMING Dream impoverishment is an attenuation, but not total cessation, in the recall, length, vividness, emotionality, or narrative complexity of dream imagery. Impoverished dreaming has been documented for some types of brain syndromes, for patients with alexithymia, and for patients with posttraumatic stress disorder (PTSD), who also have a high incidence of comorbid alexithymia.4 Impoverished Dreaming in Brain Syndromes In chronic brain syndrome, dream recall from REM sleep deteriorates as the illness progresses from mild (57% recall) to severe (35%) to aged and severe (8%).5 In patients with Korsakoff’s psychosis caused by chronic alcohol abuse, near-normal REM sleep time (29.4%) but poor dream recall (3%) is observed.6 Patients who have permanent amnesia for recent events due to mild encephalitis also have impoverished dreaming; the frequency of their REM awakening reports (28%) is less than normal (75%), and the reported dream content is simple, nonsymbolic and repetitious, stereotyped, and lacking in emotions and day residues.7 Impoverished dream recall has been noted



CHAPTER 98  •  Disturbed Dreaming as a Factor in Medical Conditions  1117

Table 98-1  Medical Conditions in which Dreaming is Disturbed DISTURBANCE

CONDITIONS COMMONLY AFFECTED

ESSENTIAL FEATURES

Global cessation of dreaming

Neurologic illness Parietal lobe lesions Frontal lobotomy

Complete loss of dream recall; often sudden onset consequent upon illness or medical procedure

Impoverished dreaming

Brain syndromes Alexithymia PTSD

Reduction in recall, vividness, or complexity of dreaming

Excessive dreaming

Epic dreaming Brain damage Drug withdrawal

Dreaming seems to continue throughout the sleep period; can involve dream vivification or banal or repetitive dream content

Repetitive dream content

RBD/parkinsonism Epilepsy PTSD Migraine Cardiac disease

Frequent recurrence of repetitive or episodic memory content, e.g., features of prior trauma, epileptic aura, or cardiac symptoms

Dream–reality confusion

Bereavement Postpartum state ICU delirium Psychotic and near-psychotic states

Dream vivification; banal episodic content may be confused with actual events

ICU, intensive care unit; PTSD, posttraumatic stress disorder; RBD, REM sleep behavior disorder.

Intensification Positive affect

Dream repetition

Dreamreality confusion

Impoverishment

At

te

nu

at

io

n

Excessive dreaming

Global cessation

Negative affect Figure 98-1  Dream disturbances may be conceptualized as falling along a continuum that captures variations in dreaming’s natural capacity to simulate waking-state experiences of reality (see Chapter 51 for discussion). On the x-axis, disruption of reality simulation during dreaming varies from one extreme of attenuation, associated with cessation and impoverishment of dreaming, to the opposite extreme of intensification (vivification), associated with excessive dreaming, content repetition, and complete confusion of dreaming with reality. On the y-axis, the reality simulation capacity is largely independent of the emotions represented in the dream, which can vary from positive to neutral to negative. However, the intensity of dreamed emotions likely does co-vary with the intensification of reality simulation.

following left8 but not right9 hemispherectomy and supports the more general conclusion10 that left hemisphere processes are more critical for dream generation than are right hemisphere processes. Impoverished Dreaming in Alexithymia Alexithymia refers to a difficulty in verbalizing emotions, literally, to a lack of a lexicon for describing feelings. Early investigations of patients who have psychosomatic disor-

ders linked an alexithymic response style with diminished dream recall11 and an absence of affect in dreams.12 Reduced dream recall among alexithymic patients has since been replicated and linked with the difficulty identifying feelings subscale.13,14,14a One study of subjects with nocturnal asthma15—a population in whom comorbid alexithymia is common—revealed that REM sleep awakenings produced an elevated incidence of impoverished dreaming, especially dreams reported with short sentences and the frequent impression of dreaming but without recall of specific contents. Studies have reported evidence that specific sensory and structural features in dreams are impoverished among alexithymic patients. One study found that alexithymic patients reported colorless dreams16 and a second found that subjects with nonclinical alexithymia had less fantastic dream content than did controls but did not differ on other measures of dream recall and emotion.17 Sleep studies have not yet identified a consistent pattern of changes that might explain dream impoverishment. In one study,18 higher alexithymia scores were associated with more frequent REM episodes, shorter REM latencies, and more stage 1 sleep during and immediately after REM sleep. However, alexithymia was also related to increased NREM stage 1 and decreased NREM stages 3 and 4. In a second study,19 alexithymia scores did not correlate with any polysomnographic variable or with REM density; however, an association with shortened REM latencies was observed. Finally, alexithymia is reliably associated with certain sleep disorders, including chronic insomnia and parasomnias.16 In sum, although converging evidence indicates that dream impoverishment is associated with alexithymia, more research is needed to clarify relationships between alexithymic factors and various attributes of dream recall, content, and emotion and sleep polysomnography. It also bears noting that other patterns of disturbed dreaming characterize some alexithymic patients, such as dreams that are extremely macabre, nightmarish, or lacking in ego and

1118  PART II / Section 12  •  Parasomnias

emotional control.20 A similar paradoxical combination of both impoverished and nightmarish dreams is also found among some PTSD patients. Impoverished Dreaming in PTSD In contrast to the high prevalence of nightmares in PTSD (see Chapter 53), one long-term consequence of PTSD appears to be impoverishment of some dreaming attributes (for review see reference 21). Both home and laboratory studies indicate that PTSD patients have lower than normal levels of dream recall and that dreams tend to be brief, to deal with trivial daily events, and to be associated with paradoxically high REM densities.22 One laboratory study of disturbed dreamers found dream recall 42% to 54% of the time compared with 89% to 96% for controls.22 Similarly, a group of 12 “well-adjusted” PTSD patients had a lower dream-recall rate from REM sleep (33.7%) than did 11 less-adjusted (50.5%) and 10 control (80%) subjects.23 Well-adjusted patients reported less complex, less salient dreams; fewer dreams with anxiety, aggression, and conflict; and higher denial of emotions toward their dreams. In contrast, a few studies failed to demonstrate reduced dream recall in PTSD patients24,25 although one has reported that laboratory dream recall is negatively correlated with trauma severity.25 Two, likely interrelated, explanations for these findings have been suggested. First, dream impoverishment in PTSD might reflect an adaptive response or strategy that reduces dream recall and thereby suppresses the occurrence of nightmares.23 Second, mechanisms producing dream impoverishment in alexithymia might also be implicated in PTSD because of its high incidence of comorbidity with alexithymia4; up to 85% of PTSD patients may be alexithymic.26 Hyperarousal and emotional numbing may be common to the etiologies of both conditions. Emotional numbing (considered equivalent to alexithymia in PTSD4) is best predicted by the number of hyperarousal symptoms in PTSD patients.27 PTSD patients might expend so much cognitive, behavioral, and emotional effort on managing hyperarousal and reactivity that they exhaust their emotional resources including, possibly, a depletion of catecholamines.28

EXCESSIVE DREAMING Several conditions are characterized by dreams that are excessively abundant or intense. Epic dreaming refers to complaints of excessive dreaming combined with daytime fatigue.29,30 Patients complain of dreaming all night long about continuous physical activity, often of a banal nature, such as repetitive housework or endless walking through snow or mud. Sensations of acceleration or spinning are also reported. Such dreams occur nightly in 90% of affected patients, and comorbid nightmares are reported by 70%.29 Unlike nightmares, however, epic dreams can lack vivid emotion altogether. The endless dreaming and feelings of fatigue can produce distress, which leads the dreamer to seek medical consultation. No clinical abnormalities have been observed, leaving its etiology and pathophysiology unclear. Cognitive, relaxation, and drug-based treatments and hypnosis have proved ineffective.29 Comparative

studies of epic dreams and nightmares might clarify whether their repetitive motor imagery is a type of nightmare stripped of its emotions. Excessive dreaming characterizes some patients with brain lesions1 and includes increases in both dream frequency and vividness.31 Some patients also report dreaming the same content throughout the night, despite intervening episodes of wakefulness.1,31 Neuropsychological evidence suggests anterior limbic system involvement. Excessive, vivid, and early-onset dreaming can also appear after withdrawal from certain medications such as tricyclic antidepressants32 and short half-life serotonin reuptake inhibitors such as paroxetine or fluvoxamine (see Chapter 48).33

REPETITIVE DREAM CONTENT Dream content repeats itself so often that a repetition dimension of dreaming has been postulated.34 The recurring emotions and themes of nightmares and other typical dreams exemplify this. Here, I consider mainly dreams that occur in conjunction with a medical condition and for which their content, structure, or affective quality has become so highly repetitive that it causes patients distress. Neurobiological and psychological features of the concomitant medical condition are widely thought to shape the repetitive content of such dreams. Assault and Defense Dreams in REM Sleep Behavior Disorder and Parkinsonism REM sleep behavior disorder (RBD) is characterized by sleep-related motor activity that appears to enact the patient’s ongoing dream or nightmare.35,36 Dreamenacting activities were reported by 93%, 87%, 82%, and 64% of patients in four large samples (N = 93, 96, 91, and 52, respectively). Polysomnographic (PSG) evidence suggests that RBD patients do not enact all of their REM dreams, although their partial enactment is suggested by elevated levels of muscle tone (e.g., submentalis37). Patients do not always recall dream content for specific episodes, possibly because most patients are elderly and have reduced dream recall or because some of the dreams lack salience. Nonetheless, a majority of patients report retrospectively that their dreams are more vivid, violent, action-filled, and nightmarish since the onset of their RBD.38 Clonazepam suppresses dream-enacting behavior and the disturbing dreams accompanying them.39 Pramepexole and melatonin have limited effects; melatonin appears to re-establish REM atonia.40 Although a panoply of dream-enacting activities has been reported, associated dream themes are largely repetitive in their structure and emotional content.41,42 This is shown in Table 98-2, which summarizes examples of dreams for which specific enacting activities have been identified by authors. The most common repetitive pattern is that of imminent threat (29/37 or 78.4%), to which patients reacted with vigorous defensive actions (19/29 or 65.5%), attempts to escape (24.1%), or unspecified reactions (10.3%). Most threats (16/29 or 55.2%) were from humans; the rest were from animals (37.9%) or machines (6.9%). Six (6/37 or 16.2%) pleasurable dreams were also

77

Case 1

Mahowald, 2000

N/S

62

—

Husain, 2001103

—

N/S

—

Boeve 2004102

Mahowald, 200041

74

—

M

M

M

N/S

M

—

—

—

—

—

Defend wife from an aggressor

Flying above some trees, he swoops down to answer a ringing phone on a table. As he lands, someone hits him and he jumps away

Pleasurable dream of fishing

Fighting animals in a cave

Being chased by a big black dog

Tried to kick someone high up who had stolen backpacking gear

(same)

“Swimming, floating on my back and then decided … to do … a flip, under the water”

Riding a bicycle, chased by a dog, tried to kick it in the shins

—

“A cat was biting me, and I was squeezing it”

Standing on the wing of an aircraft, hollered and dove off head-first to avoid being struck by the wing of a 2nd aircraft

Wrestling with someone

(same)

M

—

—

Walking down hall of a hospital, thought woman with bottle in hand was about to throw acid at him, went to throw himself through a door

Being chased down a stairway, rounded a corner, tried to pivot around (like around a pole)

70

—

M

M

—

(same)

67

65

—

(same)

—

(same)

M

Trying to hit someone on the other side of a screen door who kept dodging his blows

67

Killing a 6-inch long cockroach

—

—

“Something … was moving and I struck out at it”

Ice skating with his father; his father fell and patient had to jump over him

M

—

“I was arguing and kicking this dog who was growling”

(same)

72

—

M

—

“In a car … started to move backwards … about to go down a ramp. I jumped out of the car to try to stop its movement [by pushing on it]”

Trying to run down the river

75

—

M

—

“I was on a bicycle and turned around; there was a dog. I was angry and scared because I thought he wanted to bite me. I started to chase him away by kicking him”

DREAM CONTENTS

Playing volleyball

65

—

M

—

DIAGNOSIS

(same)

51

—

Schenck, 2005101

M

SEX

(same)

64

AGE (YR)

—

SUBJECT

Fantini, 2009*

STUDY

Table 98-2  Summary of Published Accounts of Dream Enacting in REM Sleep Behavior Disorder

Struck wife in bed Continued

Quickly bolted out of the bed into the hallway

Sat on the edge of his bed as if holding a fishing pole

Passenger on a commercial flight exhibited punching and kicking

Got out of bed and ran into wall, hitting and cutting his eye

Kicked the wall and broke his big toe

Kicking his wife

Grabbed lamp by bed and banged it down on his foot

Fell out of bed and cut head

Squeezed own armpit so tightly it turned black and blue next day

Dove head-first over the end of the bed with blankets and pillows going with him; scraped head and ear against vanity

Had wife in a headlock

Jumped out of bed

Hit his wife with his fist

Jumped out of bed, hitting and cutting cheekbone on nightstand

Kicking legs in the air

Sitting up in bed, pushing out his arms

Stomping feet up and down on the bed

Kicked the poodle off the bed, causing it to yelp

Kicked the wall so hard he put a big hole in it

Jumped out of bed and was pushing against the bed

Kicking his wife, who woke him up

DREAM-ENACTING ACTIVITIES

CHAPTER 98  •  Disturbed Dreaming as a Factor in Medical Conditions  1119

104

62

69

Case 1

Case 5

(same)

70

Patient 5

M

M

M

M

M

M

M

—

Shy-Drager syndrome

Treated for diabetes and hypertension

—

Parkinsonism

—

“I was dreaming of being caught and tied up by people who were going to beat me and I was terrified”

I was being beaten by someone I had never seen before and I wanted to get away

Threw something at a bear to stop it from chasing him

To prevent an alligator from getting into his car, he holds its snout with great force

A man had approached him at a party, yanked off his bowtie, threw it in some mud, stamped on it, irritating the patient, who retaliated by throwing punches with his right arm

Being in military combat, enemy soldiers above him, aiming their weapons and shooting through a circle made by his arms and clasped hands down into the ground, he sprang backward rapidly for safety

Chased by a lion and screams for help

Trying to stop his friends from beating their children

Saw Viet Cong soldiers in the trees outside house, then inside house; chased soldier

Someone wanted to shoot him

*Personal communication, 2009 N/S, not stated; PSG, polysomnography; PTSD, posttraumatic stress disorder.

Sforza, 1988112

Culebras, 1989111

69

73

79

45

Fig. 7

Mahowald, 1990110 MB

(same)

—

Chung, 1994109

PTSD

—

M

—

Coy, 1996108

61

—

Standing in a garden, she leaned forward to pat a child on the head

Sforza, 1997107

—

77

—

Morfis, 1997106

F

Surrounded by snakes, had to roll down a slope to escape

M

Defending herself against an enemy

Running for a touchdown, spikes a football in the end zone

DREAM CONTENTS

74

—

Lewy body disease

DIAGNOSIS

Case 2

F

M

SEX

Had won a mahjong game, stood up and walked away from table

72

70

Patient 1

Case 1

AGE (YR)

SUBJECT

(same)

Chiu, 1997105

Boeve, 1998

STUDY

Table 98-2  Summary of Published Accounts of Dream Enacting in REM Sleep Behavior Disorder—cont’d

Moved arms as if to tear someone away, then moved and raised arms and tried to lift legs; after 2 min made sudden body jerks, raised arms in searching and reaching gestures with vocalizations; episode ended in sudden body jerk

Made protective hand and arm movements, leg movements, lifted head and neck with eyes closed as if to avoid or escape something, vocalized, made fearful, pained grimaces

Threw bed covers

Woke up to wife’s shouting and “strongly grabbing her arm”

PSG revealed right arm twitching, chin activation, activation of four limbs, body lifting and repeated punching of the bed rail with the right arm, banging head on bed rail awakened patient

Patient had “flown over my night table about 4 feet and landed on the floor, cutting my left cheek just below the eye and causing a lengthy nosebleed”

Screamed aloud during REM sleep

Flailed arms, screamed, moved vigorously

Loaded a .22-caliber rifle, checked rooms, tripped over furniture and discharged weapon into his own foot

Talking and smiling, reaching for or picking up something, tried to sit up in bed screaming and sending someone away

Standing on the bed, fell to the floor, with laceration to forehead

Lying on floor with bruises and lacerations on head and limbs

Fell to ground and hit her head

Grabbed neck of screaming granddaughter and tried to strangle her

Held wife’s head in headlock, moved legs as if running, exclaimed “I’m gonna make that touchdown!” and attempted to throw wife’s head down toward foot of the bed

DREAM-ENACTING ACTIVITIES

1120  PART II / Section 12  •  Parasomnias



CHAPTER 98  •  Disturbed Dreaming as a Factor in Medical Conditions  1121

100

.064 .003

RBD Controls

.0001

Percent of dreams

80 .00001 60

40 .002 20

.088

.0001

.088

.077

Sex

Success

0 Animal

Self-neg

Neg-emot

Agg/Fr

Aggressor

Aggress

Friend

Figure 98-2  Dreams reported by 98 patients with REM sleep behavior disorder (RBD) exhibit more aggression and negativity and less prosocial behavior than dreams reported by 69 controls. Of nine content characteristics differentiating groups, RBD patients display more animal characters, self-negativity, negative emotions, aggressive versus friendly interactions, dreamer as aggressor, and dreams with at least one aggression. In contrast, they display fewer dreams with at least one friendly interaction, at least one sexual reference, and at least one success (From Fantini ML, Corona A, Clerici S, et al. Aggressive dream content without daytime aggressiveness in REM sleep behavior disorder. Neurology 2005;65:1010-1015.

Table 98-3  Dream Content Themes in Patients with Parkinson’s Disease RBD (N = 36)

NON-RBD (N = 84)

DREAM CONTENT

N

%

N

%

Chased by person

18

50.0*

7

8.3

22.2

7

8.3

38.9*

0

0.0 1.2

Chased by animal

8

Defense against attack by person

14

Defense against attack by person

4

8.3

1

Aggression by the dreamer

6

16.7*

1

1.2

Adventure or sports

6

16.7

9

10.7

Falling

10

27.8

17

20.2

Lost

8

22.2

15

17.9

Bizarre

3

8.3

5

6.0

Death

5

13.9

7

8.3

Enclosed space

8

22.2

16

19.0

Work related

9

25.0

18

21.4

16

44.4

38

45.2

9

25.0

27

32.1

66.7*

34

40.5

Family or daily activity Past Vivid dreams

24

RBD, REM sleep behavior disorder. *P < .01. From Borek LL, Kohn R, Friedman JH. Phenomenology of dreams in Parkinson’s disease. Mov Dis 2007;22:198-202.

reported. Similar results have been reported for a sample of 37 RBD patients reporting dreams to their physicians43: 89% were aggressive in nature and attacks were by humans for 57% of patients and by animals for 30%. Another study of RBD dream content (Table 98-3) reveals similar fractions (e.g., chase by humans, 50%; chase by animals, 22%).44 Although RBD patients report more dreams with aggressive interactions (especially self as aggressor) than

do controls (Fig. 98-2), they do not have higher scores on a daytime Aggression Questionnaire; in fact, they score lower than controls on physical aggressiveness.45 Dream aggression may be less prevalent for female RBD patients; compared with male RBD patients, their dreams are nonviolent, contain only fear (rather than anger and fear), and do not depict physical confrontation with an assailant.44 Samples of women studied to date are small, however.

1122  PART II / Section 12  •  Parasomnias

The repetitive nature of RBD attack and defense dreams remains a source of speculation. One possibility is that the dreams are intensified instances of the most typical dream type, pursuit or assault dreams.46 Such intensification might result from increased levels of motor neuron activity or autonomic dysfunction. A growing literature links RBD with deficits in autonomic function, specifically, diffuse loss of innervation of cardiac sympathetic terminals47 and reduced REM sleep cardiac variability.48 Autonomic dysfunction might also explain patients’ nonaggressive waking dispositions. Another possibility is that a neurodegenerative process underlying many cases of RBD leads to the release of archaic dream patterns such as aggression and animal characters (see Fig. 98-2). It is also unknown how exactly RBD sleep activities reflect their associated dream contents. Reported dreams match activities in general respects (see Table 98-2), but in some cases dreamed and enacted actions differ subtly. For example, Schenck and Mahowald38 report that male patients often dream about repulsing attackers who are threatening their wives only to find on awakening that they themselves are attacking their wives. Such errors resemble cases of somnambulistic violence; for example, a patient dreamed of removing an attackers hands from his wife’s neck while he was in fact throttling her. Analyses of dream contents with video-verified behavioral episodes are clearly needed to clarify this issue. Parkinson’s Disease RBD is known to herald Parkinson’s disease (PD) and other synucleinopathic disorders such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) by up to several years.38,49 The presence of RBD among patients with PD is a risk factor for subsequent hallucinations,49 and RBD with hallucinations can presage development of further cognitive impairments.50 Accordingly, vivid dreams, nightmares, dream enactment, and other parasomnias are common among synucleinopathy patients. Because altered dreaming is more prevalent if hallucinations are also part of the clinical portrait, it is possible that dreaming is implicated in the etiology of synucleinopathic hallucinations. Estimates of comorbid hallucination and dreaming in patients with PD is relatively high (e.g., 61.3%, 59%, and 48% in three studies). Laterality of brain dysfunction in PD correlates with both dreaming and hallucinations; patients with right hemisphere dysfunction exhibit both nocturnal hallucinations and more vivid dreaming relative to those with left hemisphere dysfunction.51 That RBD may be associated with development of hallucinations independent of PD severity52 supports the notion that REM mechanisms are implicated in the expression of both dreams and hallucinations. So too does the fact that more REM aberrations (e.g., fragmentation,53 reduced REM percentage54) occur among PD patients with hallucinations than among those without hallucinations. In fact, PD hallucinations and delirium episodes often correspond with brief daytime REM sleep episodes.55 Common treatments for Parkinson’s disease and other synucleinopathies (e.g., levodopa) might account for some alterations in dreaming,52 but the prevalence of altered dreaming after long-term levodopa treatment is only

31%,56 and dosage does not differ between patients who hallucinate and those who do not.57 Dream Repetition in Epilepsy Case studies1,58-60 demonstrate at least two ways episodic memories for seizure activity may be reflected during dreaming. First, epileptogenic features such as auras, phosphenes, or ictal imagery can appear in recurrent nocturnal dreams. Second, recurrent dream themes can appear in close proximity to later seizures. One laboratory study illustrates repetition of dream content that had been present as mental content in epileptic seizures,58 and thus might reflect episodic memories of those seizures. One patient reported in two of three recalled REM sleep dreams (out of 32 REM awakenings) and during seizures telling somebody else he was dying. A second patient reported in two of three recalled REM sleep dreams (six awakenings), in one of two end-of-night dreams (stage not specified), and in her seizures that she was “on a board” going over water and afraid of falling. Repetitive dreams unrelated to seizure content but nonetheless related to the disease have also been discussed.61 However, the existence or importance of such dreams is difficult to discern given the high prevalence of nightmares and nightmarish dreams in the general population46 and the predominance of fear as an ictal emotion.62 Dream repetition might derive from the same discharge pathways active during epileptic seizures; activity in these pathways is stereotyped in expression but changes spontaneously over time.63 Although one review of dream anomalies in epilepsy1 suggests that right hemisphere temporal structures might be a source of such patterning (i.e., right hemisphere involvement in 63% of cases, left hemisphere involvement in 11% of cases, bilateral involvement in 26% of cases), a PSG study of right hemisphere and left hemisphere epilepsy cases64 found few differences in dream content measures. REM sleep anomalies, such as rhythmic temporal epileptiform activity, might also be a source of dream repetition.58 Patients with temporal lobe epilepsy also display other types of dream disturbance. Dream impoverishment is suggested by the fact that laboratory recall is “spotty and confused, short in length and poorly detailed” in some patients.65, p. 370 They also have more unpleasant and higherintensity emotions than do controls,66 a pattern reminiscent of PTSD (see next section). Type of epileptic focus might play a role in such disturbances: Patients with complex partial seizures recall dreams on more days (55%) than do those with generalized seizures (25%), independent of side of epileptic focus, presence of brain lesion, or presence or absence of seizures on the day of recall.67 Medication use is also a potential confounder; medicated patients’ dreams are more vivid than nonmedicated patients’ or controls’ dreams.66 Re-experiencing Dreams in Posttraumatic Stress Disorder A high proportion of PTSD patients report re-experiencing their traumatic events through recurrent nightmares (see Chapter 53). PTSD patients with combat trauma are more likely to state that their nightmares exactly or almost exactly replicate an actual event compared with combat



CHAPTER 98  •  Disturbed Dreaming as a Factor in Medical Conditions  1123

veterans who have nightmares but not a diagnosis of PTSD.68 To illustrate, a 45-year-old concentration camp survivor reported the same dream of a traumatic persecution that he had experienced at the age of 6 years (4 decades earlier) regardless of the REM or NREM sleep stage he awoke from.69 This re-experiencing phenomenon is one of the clearest examples of how episodic memories, normally minimized during dreaming, can become hyperactivated. Other aspects of PTSD dreams are treated in more detail in the earlier section “Impoverished Dreaming.” Migraine Dreams Dream repetition is prevalent among headache sufferers, particularly migraineurs. One study70 proposed criteria for defining three highly consistent dream patterns (horrifying nightmares, nostalgic technicolor, waking dreams) that could be useful in diagnosis. Criteria included recurrence, brilliant colors, occurrence at specific times of the patient’s life, particular emotional tones that carry over into waking, and, occasionally, carry-over in the form of hallucinations. Nightmares of terror are by far the most predominant theme (61% of dreams), although other dysphoric themes such as frustration, loss, incest, and outsized creatures also occur. Dreams that precede migraines contain more anger, misfortune, apprehension, and aggressive interactions than do dreams not preceding migraines.71 One source of the repetitive quality of migraine dreams may be similar to the neurophysiological sources suggested earlier for cases of epilepsy, i.e., the neurophysiological activities causing the migraine-related pain and negative emotion may also partially shape the formation of migraine dreams. Prodromal Cardiac Dreams A form of repetition is seen in the recurrent themes of prodromal dreams: dreams that are shaped by ongoing or occult medical conditions. Such dreams can manifest before overt symptoms appear, an occurrence that figured largely in the earliest days of medical science.72 Prodromal dream themes have been proposed for a number of specific illnesses, including gastrointestinal, pulmonary, gynecologic and obstetric, dental, and arthritic.73 In the case of patients with nonacute cardiac conditions, prodromal dreams were identified to accompany heart

function. This appeared as negative relationships between cardiac ejection fraction on the one hand and dreamed death references in men and separation references in women on the other.74 A number of other cardiac-related dream themes have been identified that are direct (e.g., pain or pressure in the arm, heart, chest, or neck), indirect (e.g., clutching or squeezing, references to death, blood, pain), or metaphoric (e.g., explosions) in nature.73 Patients sometimes have “killer dreams” before the occurrence of near-fatal cardiac events, despite the absence of telltale cardiovascular risk factors.75 Some examples appear in Table 98-4. Among men and women who had nightmares very often, the percentages of patients possessing both irregular heart rhythm and spasmodic chest pain were three and seven times higher, respectively, than among those who had nightmares very seldom or never.76

DREAM–REALITY CONFUSIONS As dream imagery grows increasingly vivid and intense, it also appears to more closely approximate real sensorimotor and emotional experience (reality simulation) and confusion between dreaming and reality can result. This intensification is common for nightmares and sleep paralysis attacks. Four other conditions are also characterized by dream–reality confusions. Existential Bereavement Dreams One category of realistic dreams, referred to as existential dreams, often culminate in intensely real endings that can awaken the sleeper.77 The heightened reality quality includes simulation of distressing emotions such as sadness, despair, or guilt; salient bodily feelings such as ineffectuality and paralysis; and failures in attaining goals. Themes often involve separation and loss and the appearance of deceased family figures. These distinguish existential dreams from typical nightmares. Their clinical importance is their appearance during bereavement, which involves a range of distressing emotions other than fear. Existential dreams are common for up to 5 years following a loss, whereas nightmares are more salient immediately after a loss.78 Postpartum Infant Peril Dreams Many new mothers experience vivid dreams of their infants in peril; the realism of these dreams is belied by the fact

Table 98-4  Prodromal Dream Themes in Patients Suffering Serious Cardiac Events CASE

AGE (YR)

SEX

DREAM CONTENT

CARDIAC SYMPTOMS

1

23

M

Dream that he was murdered with his father

Awoke (6 am) with crushing chest pain; cardiac arrest 1 hr later

2

38

M

Dream that he died in a car crash

Awoke (3 am) with severe chest pain and vomiting; presented with acute myocardial infarction 2 hr later

3

42

F

Dreamed that she was running away from the police

Awoke (4 am) with chest pain and shortness of breath; presented with acute myocardial infarction within 1 hr

4

52

M

Nightmare that his son, an illegal immigrant, died walking in the desert

Awoke (3 am) with chest pains; total occlusion of right coronary artery

From Parmar MS, Luque-Coqui AF. Killer dreams. Can J Cardiol 1998;14:1389-1391.

1124  PART II / Section 12  •  Parasomnias

that they are often accompanied by behaviors such as searching, calling out, or crying while the woman is asleep.79 A common, highly realistic, theme that we have dubbed the BIB (baby-in-bed) dream type, is that the infant is lost in the bed and the mother, while still asleep, searches frantically for the child while crying, calling out in alarm, or touching her spouse. Peril dreams and sleep behavior are both prevalent and disturbing. Of women able to recall a dream of their infant, 63% report at least one peril dream associated with sleep behavior,79 41% report continuing anxiety after awakening, and 60% report needing to check on their infant. Sleep behaviors are predicted by self-reported sleep disruption and prior psychopathologic factors such as somnambulism, general psychopathology, and attachment disturbance.

average prevalence of 37% (range, 0% to 74%). Disturbed sleep can contribute to ICU dreams and to ICU psychosis more generally.88 Depending on circumstances, such as mechanical ventilation, ICU patients might sleep only a couple of hours a day.89 Their sleep displays extremely poor efficiency, with fragmentation, frequent arousals, prolonged sleep latencies, and a predominance of stages 1 and 2 over stages 3 and 4 or REM sleep.90 Circadian rhythm of melatonin is typically abolished.91 Because stage 1 sleep can account for as much as 40% of total sleep time (versus 5% in controls89), hypnagogic hallucinations may be more salient and enable vivid and frightening sleeponset dreams.92 Guillain-Barré syndrome patients in the ICU who report dreamlike hallucinations also have disrupted sleep with frequent sleep-onset REM periods.93

Intensive Care Unit Dream Delirium Dream intensification is reported by patients recovering from life-threatening conditions in the intensive care unit (ICU). They often report nightmares containing feelings of extreme horror, dread, or impending death and themes depicting their medical afflictions, agonizing treatments, isolation, dependency, and the real possibility of death. Many studies attest to their high prevalence, their alarming nature, and their potentially traumatizing long-term effects. For example, one 6-month follow-up study of 464 Portuguese ICU patients revealed that 51% recalled ICU dreams and nightmares.80 Of these, 14% claimed that the dreams and nightmares continue to disturb daily life 6 months later and they scored lower than normal on a health-related quality-of-life measure. The phenomenon is illustrated by a nightmare from a patient residing in an ICU for 28 days following a peripheral artery bypass graft surgery: “The staff was trying to kill me first in the hospital and ultimately moved me to a basement. … They were extracting my blood by force to sell it. … I was in fear of dying … I pleaded for my life.”81,p. 268 Clearly, such dreams are potentially traumatic—especially if there is persistent confusion of the dreams with reality. One evaluation of traumatic ICU experiences in 80 patients with acute respiratory distress revealed that nightmares are the most commonly remembered trauma (64% patients).82 They are described as “bizarre and extremely terrifying” and far more common than anxiety (41%), pain (40%), or respiratory distress (38%). On follow-up,83 ICU nightmares remain the most prevalent traumatic memory (75%) and predict the future development of PTSD. Length of stay in the ICU is the strongest predictor of ICU nightmares.84,85 Of 127 patients in the ICU for longer than 1 day, 18.1% reported nightmares and 14.2% reported hallucinations; of the 162 staying less than 1 day, the corresponding figures were 2.5% and 0.6%.85 Two thirds of patients premedicated with benzodiazepines later report postoperative dreams, and half of these are nightmares.86 Other contributing factors include pain, anxiety, noise, the inability to lie comfortably in bed, mechanical ventilation, and female gender.84 Vivid ICU dreams are part of the larger constellation of symptoms (e.g., delusions, hallucinations, disorientation, fluctuating consciousness)87 referred to as ICU delirium (ICU psychosis, ICU syndrome) and whose prevalence varies considerably. A review of 26 studies88 found an

Psychotic Dream-Related Aggression An extreme form of dream–reality confusion appears during psychotic episodes or among borderline psychotic patients. In fact, a hallmark of psychotic dreaming is the intensification of dreaming to the point that it is mistaken for reality and, during psychotic episodes, may be lived as a real event.94 Realistic dreams can precede violent psychotic acts, and they occasionally seem to play a causal role. For example, an authoritative dreamed voice might command a crime, or a person might act aggressively in response to being murdered repeatedly in his or her dreams.95,96 There are several reports of violent psychotic acts that follow from such extremely confusional dreams (see reference 97 for review). In one,98 a 53-yr-old “deranged” man attacked 10 young children in a church cafeteria with knives: “In my dreams, I heard a voice saying that my wish will be fulfilled and I will live only if I kill many people”; he told police that he heard the voice when awake as well. Hempel and colleagues96 report five persons with psychotic dream-related aggression; two were charged with homicide and three with violent assaults. All were relatively young (27 to 43 years old), suffered from paranoid psychosis, and typically awakened from their dreams agitated and hostile. Hempel and colleagues propose psychotic dreamrelated aggression (PDRA) as a nosologic category that distinguishes it from somnambulistic violence and other parasomnias.

TREATMENT The emotional—often bizarre—nature of disturbed dreaming in many conditions inclines patients toward reluctance in disclosing their dreams spontaneously to health professionals. It is also, unfortunately, the case that some medical practitioners do not fully appreciate the value of questioning patients about disturbed dreaming. Thus, opportunities for enhancing diagnosis and offering effective treatment may be lost. Additionally, effective patient–physician communication of dream disturbances may be mitigated by psychological, sociologic, and cultural factors. Some patients might have expressive difficulties, such as alexithymia, that hinder self-disclosure. Others might avoid speaking openly about dreams because they consider them to reflect a pathologic state of mind. Yet others may attribute spiritual significance to dreams,



CHAPTER 98  •  Disturbed Dreaming as a Factor in Medical Conditions  1125

believing them to originate in the workings of malevolent spirits or other sacred figures. Some patients might thus feel guilt, shame, or embarrassment in revealing dreams with taboo or incriminating contents. Sleep specialists, by the simple fact that they are interested in sleep phenomena, are in a privileged position to help such patients reveal their dream problems and achieve some measure of relief from them. Sensitivity to factors that influence patients’ willingness to self-disclosure—especially within multicultural settings—can facilitate this goal. Successful treatment also depends upon proper identification of factors responsible for disturbing sleep and dreaming. Close scrutiny of medication regimens is vital because many agents are known or strongly suspected to alter the quality of sleep and dreams. Discontinuing or replacing these medications or adjusting their dosage could alleviate symptoms effectively. Similarly, state stress and anxiety are amenable to short-term interventions that can diminish symptoms rapidly. Evaluation of a patient’s sleep hygiene might also reveal behavior that produces sleep fragmentation and deprivation, both of which affect the quality of dreaming (see Chapter 52). Finally, personality variables such as alexithymia or depression are easily assessed and might suggest avenues for therapeutic intervention. Such factors are often amenable to cognitive behavior therapies, which are largely successful in treating nightmares and related dream disturbances. However, new therapies are under development. Their efficacy might benefit by addressing anomalies of the reality-simulation function of dreaming (intensification of perception-like and emotional features, emergence of episodic material in dream content) as these appear in several forms of disturbed dreaming.

❖  Clinical Pearl Assessment of changes in dreaming (including impoverishment or intensification) in a variety of medical conditions can reveal serious comorbid symptoms that can facilitate diagnosis and whose treatment can aid long-term prognosis.

REFERENCES 1. Solms M. The neuropsychology of dreams. Mahway, NJ: Lawrence Erlbaum Associates; 1997. 2. Doricchi F, Violani C. Dream recall in brain-damaged patients: a contribution to the neuropsychology of dreaming through a review of the literature. In: Antrobus JS, Bertini M, editors. The neuropsychology of sleep and dreaming. Hillsdale, NJ: Lawrence Erlbaum; 1992. p. 99-129. 3. Jus A, Jus K, Villeneuve A, et al. Studies on dream recall in chronic schizophrenic patients after prefrontal lobotomy. Biol Psychiatry 1973;6:275-293. 4. Badura AS. Theoretical and empirical exploration of the similarities between emotional numbing in posttraumatic stress disorder and alexithymia. J Anxiety Disord 2003;17:349-360. 5. Kramer M, Roth T, Trinder J. Dreams and dementia: a laboratory exploration of dream recall and dream content in chronic brain syndrome patients. Int J Aging Hum Dev 1975;6:169-178. 6. Greenberg R, Pearlman C, Brooks R, et al. Dreaming and Korsakoff’s psychosis. Arch Gen Psychiatry 1968;18:203-209.

7. Torda C. Dreams of subjects with loss of memory for recent events. Psychophysiol 1969;6:358-365. 8. McCormick L, Nielsen T, Ptito M, et al. Case study of REM sleep dream recall after left hemispherectomy. Brain Cogn 1998;37:M15. 9. McCormick L, Nielsen TA, Ptito M, et al. REM sleep dream mentation in right hemispherectomized patients. Neuropsychol 1997;35: 695-701. 10. Antrobus J. Cortical hemisphere asymmetry and sleep mentation. Psychol Rev 1987;94:359-368. 11. Sifneos PE. The prevalence of “alexithymic” characteristics in psychosomatic patients. Psychother Psychosom 1973;22:255-262. 12. Levitan HL. The significance of certain dreams reported by psychosomatic patients. Psychother Psychosom 1978;30:137-149. 13. De Gennaro L, Ferrara M, Cristiani R, et al. Alexithymia and dream recall upon spontaneous morning awakening. Psychosom Med 2003;65:301-306. 14. Nielsen TA, Ouellet L, Warnes H, et al. Alexithymia and impoverished dream recall in asthmatic patients: evidence from self-report measures. J Psychosom Res 1997;42:53-59. 14a.  Nielsen TA, Levrier K, Montplasir J. Dreaming correlates of alexithymia among sleep-disordered patients. Dreaming (in press 2010). 15. Monday J, Montplaisir J, Malo JL. Dream process in asthmatic subjects with nocturnal attacks. Am J Psychiatr 1987;144:638-640. 16. Hyyppä MT, Lindholm T, Kronholm E, et al. Functional insomnia in relation to alexithymic features and cortisol hypersecretion in a community sample. Stress Med 1990;6:277-283. 17. Parker JDA, Bauermann TM, Smith CT. Alexithymia and impoverished dream content: evidence from rapid eye movement sleep awakenings. Psychosom Med 2000;62:486-491. 18. Bazydlo R, Lumley MA, Roehrs T. Alexithymia and polysomnographic measures of sleep in healthy adults. Psychosom Med 2001;63:56-61. 19. De Gennaro L, Ferrara M, Curcio G, et al. Are polysomnographic measures of sleep correlated to alexithymia? A study on laboratoryadapted sleepers. J Psychosom Res 2002;53:1091-1095. 20. Levitan H, Winkler P. Aggressive motifs in the dreams of psychosomatic and psychoneurotic patients. Interfaces 1985;12:11-19. 21. Lavie P. Sleep disturbances in the wake of traumatic events. N Engl J Med 2001;345:1825-1832. 22. Kramer M, Schoen LS, Kinney L. Psychological and behavioral features of disturbed dreamers. Psychiatr J U Ottawa 1984;9: 102-106. 23. Kaminer H, Lavie P. Sleep and dreaming in Holocaust survivors. Dramatic decrease in dream recall in well-adjusted survivors. J Nerv Ment Dis 1991;179:664-669. 24. Dow BM, Kelsoe JR Jr, Gillin JC. Sleep and dreams in Vietnam PTSD and depression. Biol Psychiatry 1996;39:42-50. 25. Lavie P, Katz N, Pillar G, et al. Elevated awaking thresholds during sleep: characteristics of chronic war-related posttraumatic stress disorder patients. Biol Psychiatry 1998;44:1060-1065. 26. Hyer L, Woods MG, Summers MN, et al. Alexithymia among Vietnam veterans with posttraumatic stress disorder. J Clin Psychiatry 1990;51:243-247. 27. Weems CF, Saltzman KM, Reiss AL, et al. A prospective test of the association between hyperarousal and emotional numbing in youth with a history of traumatic stress. J Clin Child Adolesc Psychol 2003;32:166-171. 28. Litz BT, Schlenger WE, Weathers FW, et al. Predictors of emotional numbing in posttraumatic stress disorder. J Trauma Stress 1997;10:607-618. 29. Schenck CH, Mahowald MW. A disorder of epic dreaming with daytime fatigue, usually without polysomnographic abnormalities, that predominantly affects women. Sleep Res 1995;24:137. 30. Zadra AL, Nielsen TA. Epic dreaming: a case report. Sleep Res 1996;25:148. 31. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautomania with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997-1003. 32. Dilsaver SC, Greden JF. Antidepressant withdrawal phenomena. Biol Psychiatry 1984;19:237-256. 33. Belloeuf L, Le Jeunne C, Hugues FC. [Paroxetine withdrawal syndrome] (Syndrome de sevrage à la paroxétine). Ann Med Interne (Paris) 2000;151(Suppl A):A52-A53. 34. Domhoff GW. Finding meaning in dreams. A quantitative approach. New York: Plenum; 1996.

1126  PART II / Section 12  •  Parasomnias 35. Mahowald MW, Schenck CH. REM sleep behavior disorder. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 574-588. 36. Schenck CH, Mahowald MW. REM sleep parasomnias. Neurol Clin 1996;14:697-720. 37. Ferri R, Franceschini C, Zucconi M, et al. Searching for a marker of REM sleep behavior disorder: submentalis muscle EMG amplitude analysis during sleep in patients with narcolepsy/cataplexy. Sleep 2008;31:1409-1417. 38. Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002;25:120-138. 39. Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep in 170 adults. Am J Med 1996;100:333-337. 40. Gugger JJ, Wagner ML. Rapid eye movement sleep behavior disorder. Ann Pharmacother 2007;41:1833-1841. 41. Mahowald MW, Schenck CH. REM sleep parasomnias. In: Kryger M, Roth N, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 724-741. 42. Schenck CH, Bundlie SR, Ettinger MG, et al. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986;9:293-308. 43. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123:331-339. 44. Borek LL, Kohn R, Friedman JH. Phenomenology of dreams in Parkinson’s disease. Mov Dis 2007;22:198-202. 45. Fantini ML, Corona A, Clerici S, et al. Aggressive dream content without daytime aggressiveness in REM sleep behavior disorder. Neurology 2005;65:1010-1015. 46. Nielsen TA, Zadra AL, Simard V, et al. The typical dreams of Canadian university students. Dreaming 2003;13:211-235. 47. Miyamoto T, Miyamoto M, Suzuki K, et al. 123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder. Sleep 2008; 31:717-723. 48. Lanfranchi PA, Gagnon JF, Colombo R, et al. Autonomic regulation during sleep in idiopathic rapid eye movement sleep behavior disorder. Sleep 2007;30:1019-1025. 49. Arnulf I, Leu S, Oudiette D. Abnormal sleep and sleepiness in Parkinson’s disease. Curr Opin Neurol 2008;21:472-477. 50. Sinforiani E, Pacchetti C, Zangaglia R, et al. REM behavior disorder, hallucinations and cognitive impairment in Parkinson’s disease: a two-year follow up. Mov Disord 2008;23:1441-1445. 51. Stavitsky K, McNamara P, Durso R, et al. Hallucinations, dreaming, and frequent dozing in Parkinson disease: impact of right-hemisphere neural networks. Cogn Behav Neurol 2008;21:143-149. 52. Onofrj M, Thomas A, D’Andreamatteo G, et al. Incidence of RBD and hallucination in patients affected by Parkinson’s disease: 8-year follow-up. Neurol Sci 2002;23(Suppl 2):S91-S94. 53. Pappert EJ, Goetz CG, Niederman FG, et al. Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson’s disease. Mov Dis 1999;14:117-121. 54. Comella CL, Tanner CM, Ristanovic RK. Polysomnographic sleep measures in Parkinson’s disease patients with treatment-induced hallucinations. Ann Neurol 1993;34:710-714. 55. Houeto JL, Arnulf I. Psychic disorders and excessive daytime sleepiness. Rev Neurol (Paris) 2002;158:102-107. 56. Sharf B, Moskovitz C, Lupton MD, et al. Dream phenomena induced by chronic levodopa therapy. J Neural Trans 1978;43:143-151. 57. Arnulf I, Bonnet AM, Damier P, et al. Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 2000; 55:281-288. 58. Epstein AW. Effect of certain cerebral hemispheric diseases on dreaming. Biol Psychiatry 1979;14:77-93. 59. Reami DO, Silva DF, Albuquerque M, et al. Dreams and epilepsy. Epilepsia 1991;32:51-53. 60. Vercueil L. Dreaming of seizures. Epilepsy Behav 2005;7:127-128. 61. Epstein AW. Recurrent dreams; their relationship to temporal lobe seizures. Arch Gen Psychiatry 1964;10:25-30. 62. Biraben A, Taussig D, Thomas P, et al. Fear as the main feature of epileptic seizures. J Neurol Neurosurg Psychiatry 2001;70: 186-191.

63. Epstein AW. Dreaming and other involuntary mentation. An essay in neuropsychiatry. Madison, Conn: International Universities Press; 1995. 64. Cipolli C, Bonanni E, Maestri M, et al. Dream experience during REM and NREM sleep of patients with complex partial seizures. Brain Res Bull 2004;63:407-413. 65. Silvestri R, Bromfield E. Recurrent nightmares and disorders of arousal in temporal lobe epilepsy. Brain Res Bull 2004;63: 369-376. 66. Gruen I, Martinez A, Cruzolloa C, et al. Characteristics of the emotional phenomena in the dreams of patients with temporal lobe epilepsy. Salud Mental 1997;20:8-15. 67. Bonanni E, Cipolli C, Iudice A, et al. Dream recall frequency in epilepsy patients with partial and generalized seizures: a dream diary study. Epilepsia 2002;43:889-895. 68. van der Kolk B, Blitz R, Burr W, et al. Nightmares and trauma: a comparison of nightmares after combat with lifelong nightmares in veterans. Am J Psychiatr 1984;141:187-190. 69. Hefez A, Metz L, Lavie P. Long-term effects of extreme situational stress on sleep and dreaming. Am J Psychiatr 1987;144:344-347. 70. Lippman CW. Recurrent dreams in migraine: an aid to diagnosis. J Nerv Ment Dis 1954;120:273-276. 71. Heather-Greener GQ, Comstock D, Joyce R. An investigation of the manifest dream content associated with migraine headaches: a study of the dreams that precede nocturnal migraines. Psychother Psychosom 1996;65:216-221. 72. Gallop D. Aristotle on sleep and dreams: a text and translation with introduction, notes and glossary. Calgary, Alberta, Canada: Broadview Press; 1990. 73. Garfield P. The healing power of dreams. New York: Simon & Schuster; 1991. 74. Smith RC. Do dreams reflect a biological state? J Nerv Ment Dis 1987;175:201-207. 75. Parmar MS, Luque-Coqui AF. Killer dreams. Can J Cardiol 1998;14:1389-1391. 76. Asplund R. Nightmares, sleep and cardiac symptoms in the elderly. Neth J Med 2003;61:257-261. 77. Busink R, Kuiken D. Identifying types of impactful dreams—a replication. Dreaming 1996;6:97-119. 78. Kuiken D. Euro–North American paths through bereavement. 12th Annual International Conference of the Association for the Study of Dreams, New York, June 20-24, 1995. 79. Nielsen T, Paquette T. Dream-associated behaviors affecting pregnant and postpartum women. Sleep 2007;30:1162-1169. 80. Granja C, Lopes A, Moreira S, et al. Patients’ recollections of experiences in the intensive care unit may affect their quality of life. Crit Care 2005;9:R96-109. 81. Roberts BL, Rickard CM, Rajbhandari D, et al. Factual memories of ICU: recall at two years post-discharge and comparison with delirium status during ICU admission—a multicentre cohort study. J Clin Nurs 2007;16:1669-1677. 82. Schelling G, Stoll C, Haller M, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 1998;26:651-659. 83. Stoll C, Kapfhammer HP, Rothenhausler HB, et al. Sensitivity and specificity of a screening test to document traumatic experiences and to diagnose post-traumatic stress disorder in ARDS patients after intensive care treatment. Intensive Care Med 1999;25:697-704. 84. Roberts BL, Rickard CM, Rajbhandari D, et al. Patients’ dreams in ICU: recall at two years post discharge and comparison to delirium status during ICU admission. A multicentre cohort study. Intensive Crit Care Nurs 2006;22:264-273. 85. Rundshagen I, Schnabel K, Wegner C, et al. Incidence of recall, nightmares, and hallucinations during analgosedation in intensive care. Intensive Care Med 2002;28:38-43. 86. Noble DW, Power I, Spence AA, et al. Sleep and dreams in relation to hospitalization, anaesthesia and surgery. A preliminary analysis of the first 100 patients. In: Benno B, Fitch W, Millar K, editors. Memory and awareness in anaesthesia. Amsterdam: Swets & Zeitlinger; 1990. p. 219-225. 87. McGuire BE, Basten CJ, Ryan CJ, et al. Intensive care unit syndrome: a dangerous misnomer. Arch Intern Med 2000;160: 906-909. 88. Dyer I. Preventing the ITU syndrome or how not to torture an ITU patient! Part 2. Intensive Crit Care Nurs 1995;11:223-232.



CHAPTER 98  •  Disturbed Dreaming as a Factor in Medical Conditions  1127

89. Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic recording of sleep in nine patients receiving postoperative care. Br Med J 1985;290:1029-1032. 90. Friese RS. Sleep and recovery from critical illness and injury: a review of theory, current practice, and future directions. Crit Care Med 2008;36:697-705. 91. Olofsson K, Alling C, Lundberg D, et al. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand 2004;48:679-684. 92. Jones C, Griffiths RD, Humphris G. Disturbed memory and amnesia related to intensive care. Memory 2000;8:79-94. 93. Cochen V, Arnulf I, Demeret S, et al. Vivid dreams, hallucinations, psychosis and REM sleep in Guillain-Barré syndrome. Brain 2005;128:2535-2545.

94. Capozzi P, De Masi F. The meaning of dreams in the psychotic state. Theoretical considerations and clinical applications. Int J Psychoanal 2001;82:933-952. 95. Felthous AR. Unusual case report: do violent dreams cause violent acts? Crim Behav Ment Health 1993;3:12-18. 96. Hempel AG, Felthous AR, Meloy JR. Psychotic dream-related aggression: a critical review and proposal. Aggress Violent Behav 2003;8:599-620. 97. Nielsen TA. Disturbed dreaming in medical conditions. In: Kryger M, Roth N, Dement WC, editors. Principles and practice of sleep medicine, 4th ed. Philadelphia: Elsevier Saunders; 2005. p. 936-945. 98. Associated Press. Man slashes 10 children in Seoul church cafeteria. Montreal Gazette, September 5, 2002.

Sleep Bruxism

Chapter

Gilles Lavigne, Christiane Manzini, and Nelly T. Huynh

Abstract Sleep bruxism, characterized by teeth grinding or jaw clenching, causes tooth destruction, headache, orofacial pain, and jaw dysfunction. In the general population, 8% of adults are conscious of teeth grinding sounds during sleep, as are their sleep partners. The causes of sleep bruxism range from psychosocial factors (e.g., life stress, anxiety) to an excessive sleep arousal response. Clinical recognition is based on a current history of teeth grinding or a stiff or painful jaw upon

The most recent International Classification of Sleep Disorders1 categorizes sleep bruxism as a sleep-related movement disorder and defines it as an oral activity characterized by grinding or clenching of the teeth during sleep. Because it is probable that sleep bruxism differs in terms of etiology from daytime parafunctional jaw muscle activity,2 it should be distinguished from teeth clenching, bracing, or gnashing while awake.3 Teeth grinding and sleep bruxism frequency is reportedly variable over time; some patients go several nights or even weeks without bruxism episodes.2 However, in cases of moderate to severe sleep bruxism, teeth grinding is present every week.4 Patients with sleep bruxism typically experience either phasic (rhythmic) or tonic (sustained) motor activity in jaw muscles (e.g., the masseter and temporalis), with the variable presence of teeth grinding sounds.2,5 The element of sound is the major reason people seek consultation. Teeth-grinding sounds disrupt the bed partner’s sleep. Other reasons for seeking help are related to tooth wear, orofacial pain or temporal area headaches, and tooth hypersensitivity to cold air, beverages, and food. An absence of a medical cause is considered to be primary, or idiopathic sleep bruxism, whereas sleep bruxism associated with a medical condition is the secondary form (Boxes 99-1 and 99-2). The latter is noted after drug intake or withdrawal (e.g., neuroleptics that can induce oral tardive dyskinesia and grinding); this secondary form is classified as iatrogenic. Several orofacial activities are often concomitant: grimacing, chewing automatism, or excessive lip and tongue movements such as thrust or protrusion. In this chapter, the term sleep bruxism is used to denote teeth grinding and oromotor-related activities occurring during sleep, as reported by the bed partner or family, regardless of whether it occurs in the primary or secondary (iatrogenic) form.

ETIOLOGY Throughout the 20th century, support for different theories regarding the etiology of bruxism has swung like a pendulum; theories range from the role of peripheral dental occlusion,6 to a global explanation that includes personality style, the person’s capacity to adapt to life pres1128

99

awakening; tooth wear is often observed but is not a key element in diagnosis, because it can be inaccurate. Final confirmation of current sleep bruxism is made by polygraphic recording of jaw muscle activity, together with, when possible, audio and video signals to rule out common, but nonspecific, orofacial motor manifestations (e.g., myoclonus, tics, swallowing, somniloquy). Techniques for managing sleep bruxism include sleep improvements, relaxation techniques, oral devices (e.g., occlusal bite splint), and medications (e.g., muscle relaxants).

sures presented by the psychosocial environment, and neurochemical and homeostatic sleep maintenance versus arousal mechanisms associated with activity of the autonomic and motor nervous systems.2,6-11

EPIDEMIOLOGY AND RISK FACTORS Most studies and surveys reporting the prevalence (the number of positive cases at a given time) of sleep bruxism are based on self-reports of clenching during the daytime or both clenching and grinding during sleep. As yet, no longitudinal study using biological recordings has been conducted to estimate the fluctuation or persistence of sleep bruxism in a given person with respect to age. Moreover, many patients with sleep bruxism are not aware of grinding if they sleep alone or with a bed partner who sleeps deeply. The overall prevalence of awake clenching is approximately 20% of the adult population, with more women reporting their awareness of clenching than men.12 According to parents’ reports, the incidence of sleep grinding in children younger than 11 years is between 14% and 20%. Concomitant oral activity such as nail biting (onycophagia) is also noted in 9% to 28% of those reporting sleep bruxism, thumb sucking is seen in 21% of children, and snoring is heard in 14%.13,14 In adults, the prevalence of grinding drops with age, from 13% in those 18 to 29 years old to 3% in those 60 years and older, with a mean of 8%.15 No further gender differences have been noted. Caution is necessary in interpreting these numbers, however, because reduced incidence with age can result from inaccurate estimates due to the high prevalence of denture users in the older population (e.g., greater than 40% in some geographic areas). Several concomitant risk factors have been linked to sleep bruxism. Psychological factors such as anxiety, competitiveness, stress, and maladaptive or less-positive coping strategies16 have been associated with sleep bruxism, but some findings remain controversial.17,18 Restless legs syndrome is associated with sleep bruxism, but only in 10% of the RLS population. Survey results show sleep apnea to be a risk factor (significant low odds ratio), a finding to further validate.19,19a Regarding smoking as a risk factor, it remains to be determined whether the variance can be



CHAPTER 99  •  Sleep Bruxism  1129

Box 99-1  Types of Bruxism Awake versus Sleep Time Awake Time Tooth clenching or tapping Jaw bracing without tooth contact (grinding is rarely noted during the daytime) Sleep Time Teeth grinding with phasic (rhythmical) or tonic (sustained) or mixed (both types) jaw muscle contractions Primary and Idiopathic versus Secondary and Iatrogenic Forms Primary and Idiopathic No known medical or dental causes Could be associated with exacerbating psychosocial factors in some patients Secondary Associated with a medical or psychiatric condition Could also be iatrogenic; see Box 99-2 Iatrogenic Following drug intake or withdrawal.

explained by the physiologic influences of nicotine or the perception of smoking as an oral habit.20 Another variable is the concomitant finding of orofacial pain or joint sound or lock at the temporomandibular level; patients with sleep bruxism are more at risk for pain and jaw limitation.21,22 For example, we found that half of patients with high incidence of sleep bruxism muscle activity reported mild pain in the morning, which was associated with a lower frequency of sleep bruxism episodes per hour of sleep than in matched controls.22-24 The prevalence of grinding noted in an institutionalized developmentally delayed population is similar to the figure reported in the general population.15,25 A study made of 5- to 18-year-old children with sleep bruxism, as confirmed in sleep laboratory, revealed a higher prevalence of attention behavior and somatic problems.26 Use of several medications or recreational drugs is also a risk factor for sleep bruxism (see Box 99-2).

PATHOPHYSIOLOGY No single mechanism or theory explains the pathophysiology of sleep bruxism.7,23,27 Rather, this motor activity is more likely to be the product of biological and psychosocial influences in a given person (Video 99-1). Bruxism

Box 99-2  Secondary or Iatrogenic Bruxism The following medical conditions and drug chemicals have been associated with or reported in literature with teeth grinding or bruxism-like orofacial motor activities.2,15,19,30,42-44,47,48,56,70-73,86-88,90 Not all associated bruxism is sleep related. Movement Disorders Oral tardive dyskinesia Oromandibular dystonia (Meige’s syndrome) Parkinson’s disease Tics: simple (grunting) and complex (Tourette’syndrome) Huntingdon’s disease Hemifacial spasm Sleep-Related Disorders Sleep fragmentary myoclonus: oromandibular, facial, lingual Sleep-disordered breathing: apnea, snoring Periodic limb movements REM sleep behavior disorder Epilepsy Night terrors Confusional awakening Neurologic or Psychiatric Disorders Cerebellar hemorrhage or infarct Olivopontocerebellar atrophy and Shy-Drager syndrome Coma Neurologic complications related to Whipple’s disease Mental health problems such as dementia, depression, developmental delay Chemical substance and medication related to secondary bruxism Iatrogenic bruxism (e.g., risk of initiation or exac­ erbation)

Chemical Substances with Abuse Potential Alcohol Nicotine (smoking) Caffeine (?) Cocaine (awake clenching) MDMA (3,4-menthylenedioxymethamphetamine [Ecstasy]) Medications Amphetamine Methylphemidate (Ritalin) for attention-deficit/hyperactivity disorder Antidopaminergic Haloperidol (Haldol) Antipsychotics Haloperidol (Haldol) Lithium (Lithane, etc.) Chlorpromazine (Thorazine) Antidepressants (Selective Serotonin Reuptake Inhibitors) Fluoxetine (Prozac) Sertraline (Zoloft) Citalopram (Celexa) Cardioactives Calcium Blocker Flunarizine (Sibelium, Cinnarizine) Antiarrythmic Flecainide (Tambocor)

1130  PART II / Section 12  •  Parasomnias

probably results from a series of influences that do not obey a mechanistic model or the logic of an algorithm. Rhythmical Masticatory Muscle Activity during Sleep in Asymptomatic Sleepers Research involving the recording of masseter electromyographic EMG activity to assess rhythmic masticatory motor activity (RMMA) in the jaw-closer muscles found that about 60% of “normal” sleepers exhibited RMMA (three masseter muscle bursts or contractions within an episode, in the absence of teeth grinding) during sleep.28 In patients with somnambulism and sleep terrors, the term chewing automatism was used to describe the slow rhythmic masticatory activity.29 This term was later used in the identification of the orofacial activities noticed with the rapid eye movement (REM) behavior disorders.30 Phasic oromotor activity is associated with RMMA, and in sleep bruxism it is probably an extreme manifestation of an ongoing or natural activity during sleep. Stress and Psychosocial Influences Bruxism was associated with anxiety and hyperactivity, but strong evidence is absent.27 Rigorous evidence is lacking to support the notion that sleep bruxism is an anxiety-related disorder.17,19 However, patients with sleep bruxism seem to be more task-oriented as a result of their personality and coping style, as opposed to being in a pathologic stress or anxiety-related pattern. Findings in Sleep Studies comparing young, healthy patients who have sleep bruxism and control subjects have shown that the former demonstrate normal sleep organization and macrostructure.5,31-33 Their sleep latency, total sleep time, percentage of time spent in the various sleep stages, and number of awakenings are within normal limits. They also report a normal amount of time spent awake during the sleep period, and they demonstrate sleep efficiency that falls within the usual range of good sleepers (greater than 90%). Thus, they do not complain about sleeping poorly.32 Interestingly, and like episodes of sleep apnea in patients with that disorder, most sleep bruxism episodes (74%) were observed while sleepers were in the supine position.34 Sleep bruxism episodes are most often (greater than 80% of the time) scored in sleep stages 1 and 2,26,32,33,35 although the literature is confusing on this point.36 A high incidence of destructive sleep bruxism, scored from electroencephalographic (EEG) artifacts, was also previously reported in REM sleep36 in patients suffering from depression, and this probably represented secondary sleep bruxism. In sleep bruxism subjects, it was observed that approximately 10% to 25% of sleep bruxism occurred in REM.26,34,35 Most studies support the idea that rather than triggering sleep arousal, sleep bruxism is concomitant or secondary to cyclic alteration in sleep patterns. During sleep, every 20 to 60 seconds, an observable cyclic electroencephalographic-electrocardiographic-electromyographic (EEG-ECG-EMG) activation occurs, called the cyclic alternating pattern (CAP). Interestingly, close to 80% of sleep bruxism episodes have been observed in

association with the CAP, which may act as a resetting mechanism for physiologic functions in relation to sleep environment or endogenous factors.7,9,27,33 The association between sleep bruxism and CAP is supported by findings showing that more than 50% of sleep bruxism episodes occur in clusters (within 100 seconds) and that approximately 15% to 20% occur in the transition from deep sleep (stage 3-4) to REM sleep.33,37 These findings are also consistent with the observation that sleep bruxism is preceded by alpha EEG activity and is associated with a tachycardia.35,38 We have also noticed that RMMA or sleep bruxism episodes occur after physiologic events. In the minutes preceding RMMA or sleep bruxism episodes, there is a slight change in autonomic-cardiac sympathetic (increased) and parasympathetic (decreased) balance; then, at minus 4 seconds, there is a rise in EEG alpha and delta activity, followed by a tachycardia initiated one heartbeat before the onset of jaw-opener muscle activity, associated with a major rise in respiratory amplitude (big breath). About 800  msec later, the jaw-closer muscle contractions start.8,9,27,37,38 These findings support the concept that sleep bruxism is secondary to exaggerated transient motor and autonomic nervous system activation in relation to sleep arousals. Also, young and otherwise healthy patients with sleep bruxism show a normal rate of brief arousals (less than 14 per hour of sleep).35,39 To further explore the mechanism involved in initiating sudden RMMA or sleep bruxism, we developed an experimental model that could trigger arousals during sleep without inducing awakenings. The application of a brief vibrotactile stimulation induced frequent sleep arousals that were followed by RMMA in all patients with sleep bruxism, with teeth-grinding occurring in 86% of trials.40 We therefore suggest that sleep bruxism or teeth grinding is one of the events occurring along the sequence of physiologic activations associated with microarousals (Fig. 99-1).7,9,27,38 The role of cortical EEG activity in the genesis of sleep bruxism has also been studied. There is an increase in alpha and delta activity in the cascade of physiologic activations associated with microarousals.38 EEG K-complexes were not reported to be more frequent in the 60 seconds before sleep bruxism episodes, and, overall, patients with sleep bruxism had 40% fewer K-complex events than matched normals.41 This finding is contrary to previous reports based on studies made in the absence of comparison with normal sleepers. Indirect evidence further suggests that trigeminal motor excitability in patients with self-reported teeth grinding comes mainly under brainstem and not cortical influences.7,9,27 Oromotor Excitability There is little experimental evidence to support a role for the motor system as a primary factor in the genesis of sleep bruxism. At best, some very indirect information from animal physiologic studies may help us understand how the motor system is comodulated during sleep.7 For humans, as for animals, it has been suggested that fluctuations in the activity of the reticular motor area in relation to sleep onset and maintenance could be associated with brief periodic motor excitation.9,27



CHAPTER 99  •  Sleep Bruxism  1131 CASCADE IN SB

Physiological activity (% occurence)

Time sequence

Heart

Brain

≈ –60 sec* ↑ Sympathetic tone ↓ Parasympathetic tone ≈ –4 sec ↑ Cortical EEG ↑ Heart rate (≈ 90%) ≈ –1 sec ↑ Breathing ↑ EMG activity

(≈ 80%)

SB onset (time 0)

?: Change in airway patency ?: If jaw protrusion ↑ EMG/RMMA

(100%)

≈ +3 sec

Management strategies A. Behavioral

Jaw opening muscles

Jaw closing muscles

C. Pharmacological ? Benzodiazepine ? Muscle relaxant ? Dopaminergic drugs ? Serotonin-related ? β-Blocker ? Botulinum toxin

?: Saliva Tooth grinding

(≈ 45%)

(≈ 60%) ≈ +5 to 15 sec Swallowing Laryngeal movements *at least 60 sec

Tooth contact

Oropharyngeal muscles

B. Orodental oral splint

Unknown mechanisms

Figure 99-1  Cascade of physiologic events in genesis of sleep bruxism and rhythmic masticatory muscle activity (left) and courses of action for management (right).

Catecholamines and Neurochemistry An early report on Parkinson’s disease linking the use of levodopa (l-dopa) to teeth grinding provided initial support for the suggestion that grinding may be related to dopaminergic brain-related neurotransmitters.2 Teeth grinding, as a manifestation of oromandibular tardive dyskinesia, was also reported for some schizophrenic patients being treated with neuroleptic drugs.42 From these reports, the association of dopamine with sleep bruxism pathophysiology appeared somewhat weak. These patients already had altered nigrostriatal neurons due to disease or to medication. Some evidence further suggests that catecholamines, such as dopamine and norepinephrine, might have a role in sleep bruxism pathophysiology.11,43,44 A controlled polysomnographic study of patients with sleep bruxism with the catecholamine precursor l-dopa revealed a modest reduction in sleep bruxism frequency in comparison to placebo.43 The use of a dopaminergic modest agonist, bromocriptine, in a double-blind control design (using domperidone, a peripheral dopamine blocker, to prevent side effects such as nausea or vomiting) failed to show either a reduction in sleep bruxism motor episodes or a change in dopamine striatal binding.44 The other catecholamine-related medication reported to reduce sleep bruxism and teeth grinding is propranolol, a beta-blocker.45 This medication was also associated with a reduction in daytime teeth grinding in two neuroleptictreated patients presenting with abnormal orofacial movements.46 However, a controlled study of young patients with sleep bruxism revealed that propranolol was not deleterious to their sleep and neither reduced teeth grinding nor influenced the frequency and duration of jaw muscle contraction.47 Also, when interpreting studies using specific pharmacologic agents in sleep bruxism, it should

be noted that other neurotransmitters (e.g., serotonin, cholecystokinin, gamma-aminobutyric acid) and drugs (e.g., selective serotonin reuptake inhibitors, dopamine antagonists, calcium channel inhibitors) exacerbate teeth grinding and rhythmic movement modulation (see Box 99-2).7,9,27,48 Genetics and Familial Predisposition As yet, no genetic markers have been found for transmitting sleep bruxism. It is, however, interesting that between 21% and 50% of patients with sleep bruxism have a firstdegree relative who ground his or her teeth in childhood.13,49 Furthermore, studies of monozygotic and dizygotic twins showed that sleep bruxism was more often observed in monozygotic twins.49,50 A concomitant finding in a recent Finnish study revealed that childhood sleep bruxism persisted in a large number of adults (greater than 86.9%).50 On the other hand, a twin study did not find any genetic correlation with sleep bruxism.51 Thus, the pattern of inheritance for sleep bruxism is unknown, and the role and influences of familial and environmental factors remain to be assessed.27,50 Possible Role of Local Factors It has been suggested that tooth occlusal or morphologic interferences were responsible for teeth grinding. Although this concept of a peripheral cause for sleep bruxism is still reported in the literature, it remains controversial.6,27,52-54 On the basis of noncontrolled evidence, tooth contact is not a dominant activity in a 24-hour cycle; it has been estimated to occur for approximately 17.5 minutes per 24 hours.55 Moreover, during sleep, oromotor muscle activity related to sleep bruxism is present for approximately 8 minutes (about 2% of sleep time) over a 7- to 8-hour sleep period and does not always occur with tooth contact; grinding sounds are reported in approximately 44% of

1132  PART II / Section 12  •  Parasomnias

sleep bruxism or RMMA episodes.5,34 The debate over the role of dental occlusion in sleep bruxism is beyond the scope of this chapter; reviews have described peripheral sensory influences on sleep bruxism.52,53 Reduced Salivary Flow, Airway Patency, and Jaw Motor Activity during Sleep Another question is whether the lower salivary flow during sleep increases the risk for tooth wear.56 It appears that no sleep data directly support this premise. The low salivary flow observed during sleep may be related to low swallowing frequency: between 2.1 and 9.1 swallowing movements per hour are observed in sleep, compared with 25 per hour during daytime.57 Based on data retrieved from an analysis of laryngeal swallowing movements observed in controls and in sleep-bruxism subjects, it was hypothesized that RMMA could be associated with an increase in salivary flow during sleep to lubricate the oroesophageal tissues.34,56 Lack of saliva, a natural orodental lubricant, may then cause a dramatic breakdown in the tooth structure of patients with sleep bruxism. Consequently, specific clinical management could be planned for oral dryness in sleep.56 However, it remains to be understood why some frequent teeth grinders show little tooth wear; it may be that a better quality and volume of saliva lubrication or stronger tooth enamel (e.g., density) explains such observations. Sleep breathing disorders (e.g., sleep apnea) have been associated with sleep bruxism.19,19a Results from a large population survey have suggested that self-reports of sleep apnea were two or three times higher in subjects also aware of teeth grinding.19 Because sleep is usually associated with a jaw-opening retrusive position, a tongue muscle relaxation (e.g., genioglossus), and a reduction of airway patency, it remains to be investigated whether RMMA-related sleep arousal assists in the recovery of airway patency or whether this is just a concomitant and typical motor response associated with sleep arousal.7-9,27

CLINICAL FEATURES Clinicians can diagnose sleep bruxism in their patients using the following clinical features as a guide1,2,6,54,58,59: • Teeth grinding or tapping sounds noticed by the patient’s sleep partner or a family member is probably most reliable (Videos 99-2 to 99-4). • The presence of tooth wear (Box 99-3) can be an indication, but it is not accurate in the absence of witnessed grinding or tapping. • Complaints of jaw muscle discomfort, fatigue or stiffness, and occasional headaches (e.g., temporalis muscles) are unspecific symptoms. Other signs and symptoms, all unspecific for sleep bruxism, include tooth sensitivity to hot or cold (one tooth or unspecific several teeth), muscle hypertrophy, temporomandibular joint (TMJ) sound (clicking) or jaw lock (e.g., reduction of opening amplitude)and tongue indentations. Teeth grinding or tapping sounds have to be objectively distinguished from confounding oral sounds during sleep such as snoring, throat grunting, tongue clicking, or TMJ sounds with jaw movements.27,60 The presence of muscle or TMJ tenderness or pain is usually confirmed by digital palpation. Use of a visual analogue scale (e.g., 0 to 100 mm

Box 99-3  Clinical Features of Bruxism Reported by Patients During Sleep Teeth-grinding sounds, usually noticed by another person Possible teeth tapping or oromandibular myoclonus On Awakening during the Night or in the Morning Tooth wear or chipping incisal border Muscle hypertrophy affecting aesthetics Jaw muscle discomfort (fatigue or tension) with or without pain Temporal muscle headache or tenderness Stiff jaw, reduced mobility, difficulty biting food at breakfast Exacerbation by life pressure or stress Teeth hypersensitive to cold food (sometimes to heat), liquid, or air Frequent failure of tooth restorations (e.g., filling, bridge) Observed by Clinicians Tooth wear or fracture, shiny spots on fillings Masseter muscle hypertrophy on voluntary jaw clenching (less important at temporalis level) Muscle (masseter, temporalis, pterygoid, sternocleidomastoid) tenderness or pain upon digital palpation Temporomandibular joint tenderness or pain upon digital palpation Tongue indentation Tense personality or hypervigilant patient (subjective appreciation) Polygraphic observation of jaw muscle activity with audible teeth-grinding sounds Others Exacerbation of periodontal disease (a controversial issue) Reduction in salivary flow, xerostonia Lip and cheek biting Burning tongue with concomitant oral habits

with no pain, and worst pain at either extreme) or a numerical scale (0 to 10) can be used to score the patient’s subjective reports. Close to 50% of patients with sleep bruxism complain of pain on awakening and occasionally during sleep.24,61 By contrast, patients with diurnal clenching mainly report pain toward the end of the afternoon and in the evening.22,23 Tooth wear represents a challenge for the clinical recognition of current sleep bruxism.54,58 Attrition caused by bruxism differs from attrition resulting from dental work (e.g., crown, bridge or denture, tooth equilibration with a dental bur), from trauma (e.g., pipe, sports injury, abrasive dust in the working milieu), or from erosion caused by chemicals (e.g., lemon sucking, gastroesophageal reflux, or vomiting). Tooth wear may be exacerbated by craniodental morphology, which changes with aging. Clinicians need to be aware that observations at the time of examination might have no link with current muscle activity, because teeth grinding frequency fluctuates over time.2,4,54 Wear



can also be localized to one tooth, a few teeth, or a full segment (e.g., the lower incisors).59 The wear pattern can be seen within the normal movement range or in an eccentric jaw position. Finally, although 100% of patients with bruxism show tooth wear, so do 40% of those who are asymptomatic.62 Thus, tooth wear alone cannot be relied on for a definite diagnosis of sleep bruxism, and the other factors mentioned must also be taken into consideration. Tooth sensitivity to temperature stimulations (e.g., cold liquid or air) is also reported after sleep periods with teeth clenching, grinding, or tapping. Another type of tooth substance loss, cervical lesion (a groove in the tooth and gum region), was reported to be three times more prevalent in persons with sleep bruxism.63 However, the cause and effect link remains to be proved. A clinical feature used to recognize sleep bruxism is masseter muscle hypertrophy. This is easily seen when the subject is voluntarily clenching the teeth together: a unilateral or bilateral mass protrudes on the side of the face below the zygomatic arch. This condition needs to be differentiated from swelling resulting from periodontal abscess or the trauma of wisdom tooth extraction, from parotid gland tumor, from blockage of the parotid salivary duct by a calculus, or from sustained contraction of the masseter muscle that constricts the salivary flow. This last problem is named the parotid-masseter syndrome.2

DIAGNOSTIC EVALUATION Clinical Clinical diagnosis of sleep bruxism is based on the patient’s history and orofacial examination. Mostly, the presence of tooth wear can be scored from criteria derived from the literature.6,54,59 To assess tooth wear, dry the tooth with air or cotton and use a dental mirror with a light source. Tooth wear can be monitored over time by taking dental arch impressions and visually analyzing wear patterns using casts or models. For research purposes, scanning electron microscopy or computerized laser analysis could be used. Another technique monitors wear intensity using intraoral appliances, such as the Bruxscore Plate.64 The validity of this measure for assessing sleep bruxism frequency is, however, questionable: Bruxscore Plate data do not correlate strongly with ongoing sleep bruxism muscle activity as monitored with ambulatory EMG units.64 Moreover, the presence of an oral appliance can influence ongoing EMG activity (causing either an increase or a decrease).65 Muscle hypertrophy that is not specific for diagnosing sleep bruxism may be recognized by taking into consideration the patient’s age and dentofacial morphology, having ruled out any unusual condition (see earlier) or swelling caused by infection in the salivary gland. The patient clenches the teeth, which induces a protruding mass at the masseter muscle level (rarely, the temporalis). Using the fingers to palpate the area, a positive score is given if the contracted muscle volume increases at least twofold. For research purposes, sliding rules or ultrasonography measures can also be used, although they have not yet been validated for diagnosing sleep bruxism.66 In addition, we suggest that the following be noted in the patient file (see Box 99-3): location and severity of

CHAPTER 99  •  Sleep Bruxism  1133

tooth wear; the presence or absence of masseter muscle hypertrophy; report of sensitive teeth or pain or tenderness in response to digital palpation of muscles and the TMJ; maximum jaw displacement (use the space between both upper and lower central incisors as a reference point); and the presence or absence of joint sounds (e.g., TMJ clicking or grating) using finger palpation. Ambulatory Monitoring and Sleep Laboratory Recording Sleep bruxism motor activity may also be monitored using polygraphy, but this method is recommended only for patients with severe teeth grinding, in the presence of other sleep disorders (e.g., apnea, epilepsy), or for clinical trials.58 First, audio and video home recordings (a home camera with black light in the room) can help to estimate sound frequency and jaw displacement. However, in the absence of polygraphy, it can be very difficult to distinguish the sounds of snoring throat grunting, tooth tapping, TMJ clicking, teeth grinding, and jaw movements such as swallowing, rumination, typical chewing-like movements, smiling, or orofacial myoclonia.60 Second, ambulatory EMG recordings can be used to monitor sleep bruxism at home. Some systems allow only one channel to be used to monitor masseteric EMG (surface) activity during sleep.65,67 Full ambulatory multichannel (EEG, EMG, ECG, respiration, movement, etc.) recorders, with a very good quality EMG signal, are also currently available. Although the use of ambulatory recordings allows patients to be monitored in the home environment, it does have some limitations. In the absence of audio and video recordings, it is difficult to precisely assess the specificity of EMG activity over the large spectrum of orofacial activities that occur during sleep, such as swallowing, coughing, grunting, sighs, yawning, sleep talking, and smiling.27,60,68 Moreover, up to 30% of all orofacial activities scored during sleep (polygraphic and audiovisual recordings) might not be specific to sleep bruxism.32,60 Despite these limitations, ambulatory recordings are a valuable complement to sleep laboratory recordings because they allow low-cost monitoring over several nights in the patient’s natural environment. The suggested sleep bruxism scoring algorithm for ambulatory recordings needs further validation along with laboratory polysomnography (Box 99-4).67,69 Third, in the sleep laboratory (a highly controlled but decidedly less-natural milieu), recording the following biological signals often completes the diagnosis of sleep bruxism (Fig. 99-2)24,32,58: • Two EEG readings (C3A2, O2A1); • Right and left EOG; • EMGs (surface) from both jaw masseter (right and left; in single or jump channel) and temporalis (optional, to improve scoring) muscles for sleep bruxism scoring with chin or suprahyoid muscles for standard sleep hypotonia in REM sleep, and of the anterior tibialis to rule out periodic limb movements in sleep (PLMS); • Nasal air flow, respiratory effort (via chest belt), and microphone recording for sleep apnea and snoring assessments; • Audio and video recordings to identify and quantify jaw and orofacial activities (zoom is on face).

1134  PART II / Section 12  •  Parasomnias Box 99-4  Criteria for Diagnosis of Sleep Bruxism by Masseter or Temporal Electromyography Ambulatory Criteria EMG (RMS) level: >10% of maximum (voluntary clench while awake) EMG periodicity: 3 sec minimum; >0.25 sec to rule out myoclonus Heart rate change: >5% in beats per minute with an EMG event Minimum acquisition: 16.7 Hz or 0.05 sec frequency for EMG or time resolution Sleep Laboratory Criteria Mean SB EMG potentials: >10% or 20% of the maximal clench while awake, masseter muscles SB event episodes types are scored • Phasic (rhythmic): >3 EMG bursts, separated by 2 interburst pauses, in masseter or temporalis muscle, each burst lasting >0.25 sec and 2.0 sec • Mixed: both phasic and tonic types Minimum acquisition: 128 Hz Diagnostic cut-off criteria • Bruxism events per hour: >4 RMMA for moderate to frequent EMG events or • Bruxism bursts per hour: >2 RMMA for mild frequency EMG events plus • At least one episode of grinding per sleep period Data are expressed in index as • Number of SB events per hour of sleep • Number of SB bursts (contractions) per hour of sleep • Number of SB episodes per night • Duration of SB EMG activity per hour of sleep Ambulatory criteria and sleep laboratory criteria from references 5, 24, 28, 32, 33, 35, 36, and 67-69. EMG, electromyogram; RMMA, rhythmic masticator muscle activity; RMS, root mean square of masseter muscle; SB, sleep bruxism.

LOC–A1

130 µV/cm

EMG–

170 µV/cm

C3–A2

120 µV/cm

MAL

130 µV/cm

MAR

130 µV/cm

TEL

130 µV/cm

TER

130 µV/cm

01: 38: 33

01: 38: 40

01: 38: 50

Figure 99-2  Polygraphic traces of one rhythmic sleep bruxism episode (same subject as in Fig. 99-3). The three upper traces are left eye (EOG = LOC − A1), submental EMG and C3A2 EEG; all show the rhythmic pattern with movement artifacts in both EOG and EEG. The left (L) and right (R) masseter (MA) and temporalis (TE) muscle activity is associated with 11 phasic (rhythmic) bursts. In this patient, the level of muscle activity was elevated and a co-contraction between closer (MA and TE) and submental opener muscles (EMG) is noted. LOC, Left outer canthus.

Chin EMG alone is not very accurate for scoring sleep bruxism. These recordings should be made in a temperaturecontrolled room where light (use black lights for video) and sound are minimal. Before sleep, subjects should swallow, cough, open their jaw vertically and laterally, as well as clench and tap the teeth to help score and assess the EMG signal recognition pattern. All-night data are recorded with a computer at a minimum acquisition speed of 128  Hz32 and are analyzed according to the standard Rechtschaffen and Kales criteria described in Chapter 141. Computer screen segments of 20 or 30 seconds can be used. The EMG sleep bruxism episodes of at least 10% to 20% of the maximum voluntary contraction while awake are scored in parallel with audio and video signals. Three types of sleep bruxism events are identified: phasic, tonic, or mixed, according to criteria derived from the literature (see Box 99-4).5,32,36 If bursts of less than 0.25 second are noticed in the temporalis or masseter muscles, they are scored as twitches or myoclonic events and are distinguished from bruxism.52,68,70,71 We have found that 10% of those in whom sleep bruxism was clinically diagnosed had this activity during sleep. Because repetitive myoclonus can be concomitant with epileptic spikes,70 our patients were recorded for a third night using a full EEG montage. No such neurologic events were found in any of our young and otherwise healthy patients who had oromandibular myoclonus. The frequency of sleep bruxism bursts (single EMG events) is quantified in RMMA episodes per night and per hour of sleep, with or without the presence of grinding sounds or leg movement. Through training, technicians can achieve a strong reliability in scoring the frequencies of events and a moderate capacity to discriminate episode types (e.g., phasic, tonic, or mixed).32 It is strongly suggested that the audiovisual signal be used in parallel with a polygraphic recording to differentiate sleep bruxism episodes occurring with snoring, swallowing, major body movement (e.g., PLMS), somniloquy, and so forth.60 Other Diagnostic Features Using the cutoff criteria described in Box 99-4 to establish a sleep diagnosis, bruxism can be correctly predicted in most patients with sleep bruxism, and asymptomatic status can be confirmed in most controls.24,32 The clinical use of these research cutoffs needs further validation in a larger population. Even when the first night is used mostly for habituation, approximately 10% of subjects with sleep bruxism invited to the sleep laboratory did not have a full first night of sleep (i.e., they had several awakenings with no habituation to sleep laboratory conditions, or they refused to appear for the experimental second night). In a retrospective analysis of patients with sleep bruxism lasting 2 months to 7.5 years (3 to 8 night recordings), we estimated that the time-to-time variability of RMMA or sleep bruxism index per hour of sleep was 25.3%, whereas the variability in the number of episodes of teeth grinding was 53%.4 Other sleep architecture variables, such as sleep duration and efficiency, number of awakenings and arousal movements, and sleep stage distribution, do not usually differ between patients with primary sleep bruxism and asymptomatic controls.5,31-33 However, the most significant sleep-



related variables characterizing sleep bruxism are the following: • Up to three times more EMG bruxism/RMMA episodes occur per hour of sleep.31-33 • Most sleep bruxism episodes can usually be scored in light-sleep stages (60% to 85% in stages 1 and 2) rather than in REM sleep.5,31-33,36 • More sleep bruxism episodes can be noted when subjects sleep on their backs.34,72 In young and otherwise healthy subjects, no obvious differences were noted in the frequency of periodic leg movements during sleep.32,35,73 As described earlier, at the EEG level, most sleep bruxism episodes can be observed in relation to the active phase of the cyclic alternating pattern (CAP),33 and the presence of K-complexes is two to three times less frequent than in matched asymptomatic subjects.41 Some EEG alpha-wave intrusions may also be noted before sleep bruxism episodes, but the specificity of this observation needs further validation in a controlled study.35 Finally, an autonomic response is noticeable with sleep bruxism episodes (as is the case for body movements during sleep), and acceleration in heart rate precedes or is concomitant with sleep bruxism.35,37

TREATMENT/MANAGEMENT As yet, there is no specific cure for bruxism. The clinician’s role is to manage sleep bruxism, with the primary goals of preventing damage to the orofacial structures and reducing sensory complaints. Current interventions are oriented toward behavioral, orodental, and pharmacologic strategies, but controlled studies confirming the efficacy of these strategies are still required6,38,47,48,53,74-76 (see Fig. 99-1). Some of the following recommendations directly address the patient’s awareness of the disorder and management of life stress and anxiety (Box 99-5 and Fig. 99-3). Behavioral Strategies Behavioral strategies should begin with a short and comprehensive explanation of bruxism to the patient, including its definition, causes, and consequences. Next, the clinician should give instructions on sleep hygiene. The psychological and behavioral management strategies for sleep bruxism have been of major interest for years.77 No persistent or clear effects have been obtained with strategies aimed at relaxation and tension reduction or exercise,77,78 but several patients have reported a sensation of well being. One study reported a reduction in both EMG activity and grinding frequency after hypnotherapy.79 However, no control therapy was used. The use of biofeedback is also reported to reduce sleep bruxism EMG activity, but this effect might not last over time without the regular use of the device.77,80 Occlusal Appliances Occlusal appliances such as a mouth guard or stabilization bite splint can protect the orofacial structures from damage. The soft mouth guard is usually recommended for use only on a short-term basis because degradation can occur rapidly. The hard occlusal stabilization splint, covering a full dental arch (Fig. 99-3), is particularly useful (e.g., for protecting teeth) for patients who are frequent and severe

CHAPTER 99  •  Sleep Bruxism  1135

Box 99-5  Palliative Management for Sleep Bruxism Behavioral (Modest Evidence)2,6,53, 77-79,80,91 Explanation of causes or exacerbation factors for sleep bruxism Reversing the habit of clenching the teeth or bracing the jaw during daytime in reaction to life pressures (e.g., by abdominal breathing) Lifestyle, sleep hygiene, relaxation, including autohypnosis or winding down before sleep Biofeedback Physical therapy and training (relaxation, breathing) Psychological therapy for managing stress and life pressures Orodental2,6,52,54,74-77,81-83,85,91,92 Mouth guard (soft, short term) for tooth protection (−) Bite splint (hard, need control visits) for tooth protection; risk of aggravating sleep apnea in patients with respiratory disturbance in sleep (+ in short term) Splint with vibration or electrical lip stimulation device; new (+ in short term) Anterior tooth device, e.g., nociceptive trigeminal inhibition (+ in short term) Mandibular advancement appliance (+ in short term) Dental occlusion (controversy exists over tooth equilibration and orthodontic bite corrections) Pharmacologic (Short-Term Use in Clinic for Acute or Severe Condition)2,6,11,27,43-48,74,86-88,93 Sedative and Muscle-Relaxant Properties Diazepam (+/cr) Clonazepam (+) Lorazepam (?) Methocarbamol (+) Cyclobenzaprine (?) Buspirone (+/cr) Serotonin-Related Properties Tryptophan (0) Amitriptyline (0) Venlafaxine (+/cr) Trazodone (?) Dopaminergic-Related Properties Levodopa (+) Bromocriptine (0) Pergolide (+cr) Pramipexole (?) Gamma-hydroxybutyric acid (+/cr) Metoclopramide (+/cr) Cardioactive Propranolol (−) Clonidine (+ but side effects) Other83,87,88,94 Tiagabine (+/cr) Botulinum toxin (?; one controlled study for SB) CPAP (?) Symbols in parentheses following each treatment indicate level of evidence: +, evidence of SB reduction; −, evidence of SB exacerbation; 0, no effect; ?, evidence questionable or unknown; cr, mostly based on case report.

1136  PART II / Section 12  •  Parasomnias

the short- and mid-term benefits and the safety of oral devices for managing sleep bruxism alone or in the presence of sleep breathing disorders (e.g., snoring, apnea– hypopnea syndrome). Tooth Equilibration Tooth equilibration, to reduce occlusal interference, has also been suggested as a treatment for sleep bruxism, but the efficacy of such therapy for bruxism is controversial.6,52,53 A

B Figure 99-3  A, An oral appliance (bite splint) made in hard acrylic to protect the upper teeth from wear associated with grinding. B, A similar appliance in the mouth.

grinders or clenchers.6,53 However, not every patient finds relief with these orthopedic treatments. A few experimental control studies using occlusal splint or control devices revealed that the frequency of RMMA, a marker of sleep bruxism, is initially reduced for a period of 7 to 15 days but that RMMA frequency tends to return to baseline level over time.76,81,82 Patient compliance with these oral devices is low over time, and splints are mainly used to prevent tissue damage (e.g., tooth wear or chipping). The use of an oral appliance that pushes the mandible forward to improve breathing during sleep (mandibular advancement appliance), also reduces the frequency of RMMA and sleep bruxism.83,83a It remains possible that the short-term effect of any device or appliance is associated with muscle fibers and spindle adaptation to changes in jaw position or to tongue position and airway patency. Moreover, the use of a maxillary occlusal splint is not recommended in patients with sleep apnea because it can aggravate respiratory disturbances.84 A comparative analysis using the concept of number needed to treat before a clinical benefit can be perceived revealed that occlusal splints and mandibular advancement appliances provide acceptable short-term therapy for protecting teeth from the consequences of sleep bruxism.74 Two Cochrane critical analyses highlighted the need for well-designed randomized, control trials before drawing conclusions about the benefit of oral devices in the management of sleep bruxism.75,85 Relevant outcomes need to be identified using valid scoring methods that assess both

Pharmacologic Management Pharmacologic management is indicated on a short-term basis only (see Box 99-5).48 Clinicians report that centrally acting drugs in the benzodiazepine group and muscle relaxants reduce bruxismrelated motor activity. To our knowledge, only diazepam and methocarbamol have been tested in open study design.2,71 Clonazepan was reported to reduce sleep bruxism in a wide age range of patients.86 However, addiction risk needs to be considered. These medications are usually prescribed at bedtime, and patients must be informed of possible side effects (e.g., not driving in the morning due to potential drowsiness). Antidepressants such as tricyclics have also been used for managing sleep bruxism, but two controlled studies using ambulatory EMG failed to support the efficacy of a small dose of amitriptyline in management of sleep bruxism.48 The use of selective serotonin reuptake inhibitors such as fluoxetine, sertraline, and citalopram has been reported to induce clenching or grinding.48 The use of l-tryptophan (a serotonin precursor) in sleep bruxism management has been reported to have no effect. The use of a weight-control medication related to serotonin, fenfluramine (Ponderal), has been noted to exacerbate grinding. Therefore, caution is suggested before using serotonin-related medication in patients with sleep bruxism. The literature on the safe use of dopamine-related medications is inconclusive.48 Patients with chronic antidopaminergic drug exposure (e.g., haloperidol, a dopaminergic antagonist) exhibited iatrogenic grinding similar to that associated with oral tardive dyskinesia, and a similar effect was seen with l-dopa (a dopaminergic precursor) in a patient already suffering from Parkinson’s disease.46 A randomized experimental trial demonstrated that acutely administered l-dopa modestly reduced bruxism activity in otherwise healthy patients with sleep bruxism, whereas bromocriptine had no effect.43,44 So far, too few studies have been performed on dopaminergic regimens (e.g., ldopa) to consider these in the long-term management of sleep bruxism. It also remains to be demonstrated whether, as in the case of periodic leg movement syndrome (PLMS) (see Chapter 90), a pharmacologic rebound will induce a resurgence of sleep bruxism activity later in the night or during the next day. Another pharmacologic avenue for sleep bruxism management is the use of a beta-adrenergic antagonist, such as propranolol, or clonidine, an alpha agonist. A controlled experimental trial performed in our laboratory with young patients with sleep bruxism, using placebo or long-action propranolol, resulted in no net reduction of sleep bruxism.47 We found that clonidine reduced sleep bruxism by 60%,



CHAPTER 99  •  Sleep Bruxism  1137

but severe hypotension was experienced in the morning by 20% of subjects, which limits clinical use.47 Botulinum toxin is reported to reduce the occurrence of RMMA and sleep bruxism.87,88 However, at this time, no controlled studies with polygraphic recordings have demonstrated that botulinum toxin has long-term efficacy and safety for sleep bruxism. Moreover, it has been reported that the botulinum toxin is carried to the central nervous system, and it is not known whether this explains its effects or whether it signifies a potential risk for the patient.89 Further advice could be given for the management of sleep bruxism in patients with secondarily hypersensitive teeth who can use fluoride gel (e.g., Gelkam). Children and Teenagers Sleep bruxism in can be managed in these populations by using behavioral and relaxation methods. The contribution of tonsil and adenoids to sleep bruxism should be excluded.

PITFALLS AND CONTROVERSIES The presence of tooth wear alone is not sufficient to diagnose sleep bruxism, because the tooth wear might have occurred years ago. At a clinical examination, a current report of teeth grinding by the patient’s sleep partner is among the reliable clinical variable indicators of ongoing sleep bruxism. Polysomnographic recording, including EMG of the jaw closing muscles, is not mandatory except if the patient has a concomitant sleep disorder (e.g., apnea, sleep epilepsy, or teeth tapping) or if a clinical trial is planned. In this case, the specificity of polygraphy scoring is greatly improved through the use of audio and video recordings to exclude oral sounds associated with sleep talking, teeth tapping, snoring, TMJ sounds, or grunting. Current studies on the pathophysiology of sleep bruxism suggest that RMMA and teeth grinding are linked to sleep arousals. The role of dental occlusion, (i.e., interferences between tooth microcontacts) and of dopaminergic substances are less significant in the genesis of sleep bruxism than was originally thought. We do not know enough about the role of familial and genetically transmitted factors.

❖  Clinical Pearl In the management of sleep bruxism, the sleep medicine clinician should distinguish primary sleep bruxism from secondary sleep bruxism related to sleep or medical disorders, including arousal-related disorders, sleep apnea, tics such as grunting or teeth tapping, sleep-related epilepsy, and medicationrelated tardive dyskinesia. Dental splints reduce tooth damage and teeth grinding sounds but are not recommended for use by patients with sleep apnea. Medications, such as muscle relaxants and anxiolytics, are indicated for short-term use in more severe cases. In children, cognitive behavior approaches and the use of a soft mouth guard for those with severe grinding is an option, but in the absence of further evidence, clinicians should be prudent and closely monitor the evolution of signs and symptoms, plus controlling for respiratory disturbances.

Acknowledgments The sleep bruxism studies were made possible by the support of the Canadian Institutes Health Research (CIHR) and the Fonds de Recherche en Santé du Québec (FRSQ). Gilles Lavigne is a Canada Research Chair. Our thanks to Alice Petersen for editing the text and to Carmen Remo for manuscript preparation. REFERENCES 1. American Association of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual, 2nd ed. Westchester, Ill: American Association of Sleep Medicine; 2005. 2. Rugh JD, Harlan J. Nocturnal bruxism and temporomandibular disorders. Adv Neurol 1988:329-341. 3. de Leeuw R. Orofacial pain guidelines for assessment, diagnosis, and management. Hanover Park, Ill: Quintessence Publishing; 2008. 4. Lavigne GJ, Guitard F, Rompré PH, et al. Variability in sleep bruxism activity over time. J Sleep Res 2001;10:237-244. 5. Reding GR, Zepelin H, Robinson JE Jr, et al. Nocturnal teethgrinding: all-night psychophysiologic studies. J Dent Res 1968;47: 786-797. 6. Okeson JP. Management of temporomandibular disorders and occlusion, 6th ed. St. Louis: Mosby Elsevier; 2008. 7. Lavigne GJ, Kato T, Kolta A, et al. Neurobiological mechanisms involved in sleep bruxism. Crit Rev Oral Biol Med 2003;14:30-46. 8. Khoury S, Rouleau GA, Rompré PH, et al. A significant increase in breathing amplitude precedes sleep bruxism. Chest 2008;134: 332-337. 9. Lavigne GJ, Huynh N, Kato T, et al. Genesis of sleep bruxism: motor and autonomic–cardiac interactions. Arch Oral Biol 2007;52: 381-384. 10. Lobbezoo F, Naeije M. Bruxism is mainly regulated centrally, not peripherally. J Oral Rehabil 2001;28:1085-1091. 11. Chen WH, Lu YC, Lui CC, et al. A proposed mechanism for diurnal/ nocturnal bruxism: hypersensitivity of presynaptic dopamine receptors in the frontal lobe. J Clin Neurosci 2005;12:161-163. 12. Glaros AG. Incidence of diurnal and nocturnal bruxism. J Prosth Dent 1981;45:545-549. 13. Abe K, Shimakawa M. Genetic and developmental aspects of sleeptalking and teeth-grinding. Acta Paedopsychiatr 1966;33: 339-344. 14. Laberge L, Tremblay RE, Vitaro F, et al. Development of parasomnias from childhood to early adolescence. Pediat 2000;106:67-74. 15. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep 1994;17:739-743. 16. Schneider C, Schaefer R, Ommerborn MA, et al. Maladaptive coping strategies in patients with bruxism compared to non-bruxing controls. Int J Behav Med 2007;14:257-261. 17. Pierce CJ, Chrisman K, Bennett ME, et al. Stress, anticipatory stress, and psychologic measures related to sleep bruxism. J Orofacial Pain 1995;9:51-56. 18. Major M, Rompré PH, Guitard F, et al. A controlled daytime challenge of motor performance and vigilance in sleep bruxers. J Dent Res 1999;78:1754-1762. 19. Ohayon MM, Li KK, Guilleminault C. Risk factors for sleep bruxism in the general population. Chest 2001;119:53-61. 19a.  Smith MT, Wickwire EM, Grace EG, et al. Sleep disorders and their association with laboratory pain sensitivity in temporomandibular joint disorder. Sleep 2009;32:779-790. 20. Lavigne GL, Lobbezoo F, Rompré PH, et al. Cigarette smoking as a risk factor or an exacerbating factor for restless legs syndrome and sleep bruxism. Sleep 1997;20:290-293. 21. Svensson P, Jadidi F, Arima T, et al. Relationships between craniofacial pain and bruxism. J Oral Rehab 2008;35:524-547. 22. Dao TT, Lund JP, Lavigne GJ. Comparison of pain and quality of life in bruxers and patients with myofascial pain of the masticatory muscles. J Orofac Pain 1994;8:350-356. 23. Lavigne GJ, Rompré PH, Montplaisir J, et al. Motor activity in sleep bruxism with concomitant jaw muscle pain. Eur J Oral Sci 1997;105:92-95. 24. Rompré PH, Daigle-Landry D, Guitard F, et al. Identification of a sleep bruxism subgroup with a higher risk of pain. J Dent Res 2007;86:837-842.

1138  PART II / Section 12  •  Parasomnias 25. Richmond G, Rugh JD, Dolfi R, et al. Survey of bruxism in an institutionalized mentally retarded population. Am J Ment Defic 1984;88:418-421. 26. Herrera M, Valencia I, Grant M, et al. Bruxism in children: effect on sleep architecture and daytime cognitive performance and behavior. Sleep 2006;29:1143-1148. 27. Lavigne GJ, Khoury S, Abe S, et al. Bruxism physiology and pathology: an overview for clinicians. J Oral Rehabil 2008;35:476-494. 28. Lavigne GJ, Rompré PH, Poirier G, et al. Rhythmic masticatory muscle activity during sleep in humans. J Dent Res 2001;80: 443-448. 29. Halász P, Ujszaszi J. Chewing automatism in sleep connected with micro-arousals: an indicator of propensity to confusional awakenings? In: Koella WP, Schulz OF, Visser P, editors. Sleep 1986. Stuttgart: Gustav Fisher Verlag; 1988. p. 235-239. 30. Sforza E, Zucconi M, Petronelli R, et al. REM sleep behavioral disorders. Eur Neurol 1988;28:295-300. 31. Sjoholm T, Lehtinen II, Helenius H. Masseter muscle activity in diagnosed sleep bruxists compared with non-symptomatic controls. J Sleep Res 1995;4:48-55. 32. Lavigne GJ, Rompré PH, Montplaisir JY. Sleep bruxism: validity of clinical research diagnostic criteria in a controlled polysomnographic study. J Dent Res 1996;75:546-552. 33. Macaluso GM, Guerra P, Di Giovanni G, et al. Sleep bruxism is a disorder related to periodic arousals during sleep. J Dent Res 1998;77:565-573. 34. Miyawaki S, Lavigne GJ, Mayer P, et al. Association between sleep bruxism, swallowing-related laryngeal movement, and sleep positions. Sleep 2003;26:461-465. 35. Bader GG, Kampe T, Tagdae T, et al. Descriptive physiological data on a sleep bruxism population. Sleep 1997;20:982-990. 36. Ware JC, Rugh JD. Destructive bruxism: sleep stage relationship. Sleep 1988;11:172-181. 37. Huynh N, Kato T, Rompré PH, et al. Sleep bruxism is associated to micro-arousals and an increase in cardiac sympathetic activity. J Sleep Res 2006;15:339-346. 38. Kato T, Rompré P, Montplaisir JY, et al. Sleep bruxism: an oromotor activity secondary to micro-arousal. J Dent Res 2001;80:19401944. 39. Boselli M, Parrino L, Smerieri A, et al. Effect of age on EEG arousals in normal sleep. Sleep 1998;21:351-357. 40. Kato T, Montplaisir JY, Guitard F, et al. Evidence that experimentally induced sleep bruxism is a consequence of transient arousal. J Dent Res 2003;82:284-288. 41. Lavigne GJ, Rompré PH, Guitard F, et al. Lower number of K-complexes and K-alphas in sleep bruxism: a controlled quantitative study. Clin Neurophysiol 2002;113:686-693. 42. Micheli F, Pardal MF, Gatto M, et al. Bruxism secondary to chronic antidopaminergic drug exposure. Clin Neuropharmacol 1993;16: 315-323. 43. Lobbezoo F, Lavigne GJ, Tanguay R, et al. The effect of catecholamine precursor l-dopa on sleep bruxism: a controlled clinical trial. Mov Disord 1997;12:73-78. 44. Lavigne GJ, Soucy JP, Lobbezoo F, et al. Double-blind, crossover, placebo-controlled trial of bromocriptine in patients with sleep bruxism. Clin Neuropharmacol 2001;24:145-149. 45. Sjoholm TT, Lehtinen I, Piha SJ. The effect of propranolol on sleep bruxism: hypothetical considerations based on a case study. Clin Auton Res 1996;6:37-40. 46. Amir I, Hermesh H, Gavish A. Bruxism secondary to antipsychotic drug exposure: a positive response to propranolol. Clin Neuropharmacol 1997;20:86-89. 47. Huynh N, Lavigne GJ, Lanfranchi P, et al. The effect of two sympatholytic medications—propranolol and clonidine—on sleep bruxism: experimental randomized controlled studies. Sleep 2006; 29:307-316. 48. Winocur E, Gavish A, Voikovitch M, et al. Drugs and bruxism: A critical review. J Orofac Pain 2003;17:99-111. 49. Lindqvist B. Bruxism in twins. Acta Odontol Scand 1974;32: 177-187. 50. Hublin C, Kaprio J, Partinen M, et al. Sleep bruxism based on selfreport in a nationwide twin cohort. J Sleep Res 1998;7:61-67. 51. Michalowicz BS, Pihlstrom BL, Hodges JS, et al. No heritability of temporomandibular joint signs and symptoms. J Dent Res 2000; 79:1573-1578.

52. Kato T, Thie NM, Huynh N, et al. Topical review: sleep bruxism and the role of peripheral sensory influences. J Orofac Pain 2003;17:191-213. 53. Lobbezoo F, van der Zaag J, van Selms MK, et al. Principles for the management of bruxism. J Oral Rehab 2008;35:509-523. 54. Johansson A, Johansson AK, Omar R, et al. Rehabilitation of the worn dentition. J Oral Rehab 2008;35:548-566. 55. Graf H. Bruxism. Dent Clin North Am 1969;13:659-665. 56. Thie NM, Kato T, Bader G, et al. The significance of saliva during sleep and the relevance of oromotor movements. Sleep Med Rev 2002;6:213-227. 57. Lichter I, Muir RC. The pattern of swallowing during sleep. Electro Clin Neurophysiol 1975;38:427-432. 58. Koyano K, Tsukiyama Y, Ichiri R, et al. Assessment of bruxism in the clinic. J Oral Rehab 2008;35:495-508. 59. Tsiggos N, Tortopidis D, Hatzikyriakos A, et al. Association between self-reported bruxism activity and occurrence of dental attrition, abfraction, and occlusal pits on natural teeth. J Prosthet Dent 2008;100(1):41-46. 60. Dutra KMC, Pereira Jr FJ, Rompré PH, et al. Orofacial activities in sleep bruxism patients and in normal subjects: a controlled polygraphic and audio-video study. J Oral Rehabil 2009;36(2):86-92. 61. Rossetti LMN, Pereira de Araujo CDR, Rossetti PHO, et al. Association between rhythmic masticatory muscle activity during sleep and masticatory myofascial pain: a polysomnographic study. J Orofac Pain 2008;22:190-200. 62. Menapace SE, Rinchuse DJ, Zullo T, et al. The dentofacial morphology of bruxers versus non-bruxers. Angle Orthod 1994;64:43-52. 63. Ommerborn MA, Schneider C, Giraki M, et al. In vivo evaluation of noncarious cervical lesions in sleep bruxism subjects. J Prosthet Dent 2007;98:150-158. 64. Pierce CJ, Gale EN. Methodological considerations concerning the use of bruxcore plates to evaluate nocturnal bruxism. J Dent Res 1989;68:1110-1114. 65. Clark GT, Beemsterboer PL, Solberg WK, et al. Nocturnal electromyographic evaluation of myofascial pain dysfunction in patients undergoing occlusal splint therapy. J Am Dent Assoc 1979;99: 607-611. 66. Bakke M, Thomsen CE, Vilmann A, et al. Ultrasonographic assessment of the swelling of the human masseter muscle after static and dynamic activity. Arch Oral Biol 1996;41:133-140. 67. Gallo LM, Lavigne G, Rompré P, et al. Reliability of scoring EMG orofacial events: polysomnography compared with ambulatory recordings. J Sleep Res 1997;6:259-263. 68. Walters AS, Lavigne G, Hening W, et al. The scoring of movements in sleep. J Clin Sleep Med 2007;3:155-167. 69. Ikeda T, Nishigawa K, Kondo K, et al. Criteria for the detection of sleep-associated bruxism in humans. J Orofacial Pain 1996;10: 270-282. 70. Meletti S, Cantalupo G, Volpi L, et al. Rhythmic teeth grinding induced by temporal lobe seizures. Neurol 2004;62:2306-2309. 71. Kato T, Blanchet PJ, Montplaisir JY, et al. Sleep bruxism and other disorders with orofacial activity during sleep. In: Chokroverty S, Hening WA, Walters AS, editors. Sleep and movement disorders. Philadelphia: Butterworth Heinemann; 2003. p. 273-285. 72. Okeson JP, Phillips BA, Berry DTR, et al. Nocturnal bruxing events in healthy geriatric subjects. J Oral Rehab 1990;17:411-418. 73. Okeson JP, Phillips BA, Berry DTR, et al. Nocturnal bruxing events in subjects with sleep-disordered breathing and control subjects. J Craniomand Dis Fac Oral Pain 1991;5:258-264. 74. Huynh NT, Rompré PH, Montplaisir JY, et al. Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size. Int J Prosthodont 2006;19:435-441. 75. Macedo CR, Silva AB, Machado MA, et al. Occlusal splints for treating sleep bruxism (tooth grinding). Cochrane Database Syst Rev 2007;(4):CD005514. 76. Harada T, Ichiki R, Tsukiyama Y, et al. The effect of oral splint devices on sleep bruxism: a 6-week observation with an ambulatory electromyographic recording device. J Oral Rehabil 2006;33: 482-488. 77. Pierce CJ, Gale EN. A comparison of different treatments for nocturnal bruxism. J Dent Res 1988;67:597-601. 78. Moss RA, Hammer D, Adams HE, et al. A more efficient biofeedback procedure for the treatment of nocturnal bruxism. J Oral Rehab 1982;9:125-131.

79. Clarke JH, Reynolds PJ. Suggestive hypnotherapy for nocturnal bruxism: a pilot study. Am J Clin Hypnosis 1991;33:248-253. 80. Jadidi F, Castrillon E, Svensson P. Effect of conditioning electrical stimuli on temporalis electromyographic activity during sleep. J Oral Rehabil 2008;35:171-183. 81. Dube C, Rompré PH, Manzini C, et al. Quantitative polygraphic controlled study on efficacy and safety of oral splint devices in toothgrinding subjects. J Dent Res 2004;83:398-403. 82. van der Zaag J, Lobbezoo F, Wicks DJ, et al. Controlled assessment of the efficacy of occlusal stabilization splints on sleep bruxism. J Orofac Pain 2005;19:151-158. 83. Landry ML, Rompré PH, Manzini C, et al. Reduction of sleep bruxism using a mandibular advancement device: an experimental controlled study. Int J Prosthodont 2006;19:549-556. 83a.  Landry-Schönbeck A, de Grandmont P, Rompré PH, Lavigne GJ. Effect of an adjustable mandibular advancement appliance on sleep bruxism: a crossover sleep laboratory study. Int J Prosthodont 2009;22:251-259. 84. Gagnon Y, Mayer P, Morisson F, et al. Aggravation of respiratory disturbances by the use of an occlusal splint in apneic patients: a pilot study. Int J Prosto 2004;17(4):447-453. 85. Jagger R. The effectiveness of occlusal splints for sleep bruxism. Evid Based Dent 2008;9:23. 86. Saletu A, Parapatics S, Saletu B, et al. On the pharmacotherapy of sleep bruxism: placebo-controlled polysomnographic and psychometric studies with clonazepam. Neuropsychobiology 2005;51: 214-225.

CHAPTER 99  •  Sleep Bruxism  1139 87. Tan E-K, Jankovic J. Treating severe bruxism with botulinum toxin. J Am Dent Assoc 2000;131:211-216. 88. Lee SJ, McCall WD Jr, Kim YK, et al. Effect of Botulin toxin injection on nocturnal bruxism: a randomized controlled trial. Am J Phys Med Rehabil 2010;89:16-23. 89. Filippi GM, Errico P, Santarelli R, et al. Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol (Stockh) 1993; 113:400-404. 90. Miyamoto K, Ozbek MM, Lowe AA, et al. Mandibular posture during sleep in patients with obstructive sleep apnoea. Arch Oral Biol 1999;44:657-664. 91. Baad-Hansen L, Jadidi F, Castrillon E, et al. Effect of a nociceptive trigeminal inhibitory splint on electromyographic activity in jaw closing muscles during sleep. J Oral Rehabil 2007;34:105-111. 92. Watanabe T, Baba K, Yamagata K, et al. A vibratory stimulationbased inhibition system for nocturnal bruxism: a clinical report. J Prosthet Dent 2001;85:233-235. 93. Van der Zaag J, Lobbezoo F, Van der Avoort PG, et al. Effects of pergolide on severe sleep bruxism in a patient experiencing oral implant failure. J Oral Rehabil 2007;34:317-322. 94. Kast RE. Tiagabine may reduce bruxism and associated temporomandibular joint pain. Anesth Prog 2005;52:102-104.

Sleep Breathing Disorders

Section

13

Mark H. Sanders 100  Central Sleep Apnea

and Periodic Breathing 101  Anatomy and Physiology of Upper Airway Obstruction 102  Snoring 103  Genetics of Obstructive Sleep Apnea 104  Cognition and Performance in Patients with Obstructive Sleep Apnea 105  Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome

106  Medical Therapy for

Obstructive Sleep Apnea 107  Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 108  Surgical Management for Obstructive Sleep-Disordered Breathing 109  Oral Appliances for Sleep-Disordered Breathing

Central Sleep Apnea and Periodic Breathing Andrew Wellman and David P. White Abstract Central sleep apnea is a disorder characterized by recurrent episodes of apnea during sleep, resulting from temporary suspension of ventilatory effort. Such apneas generally result from the strong dependence of ventilation during sleep on the metabolic control system and, in particular, arterial PCO2. Examples include central apneas that occur during the transition from wake to sleep, when waking PCO2 may be below sleeping levels and therefore nonstimulatory to ventilatory effort, when the gain of the ventilatory control system is high (Cheyne-Stokes respiration, high-altitude periodic breathing, and possibly idiopathic central sleep apnea), or when PCO2 control mechanisms are defective (hypercapnic respiratory failure and narcotic-induced central apneas). It is also becoming increasingly recognized that central apneas can occur during titration of continuous positive airway pressure (CPAP) in some persons (complex sleep apnea). Regardless of the cause, central apneas often produce arousals from sleep, which can lead to difficulty sustaining sleep and to daytime somnolence. This reflects the symptoms with which these patients may present. The prevalences of

1140

110  Management of

Obstructive Sleep Apnea–Hypopnea Syndrome 111  Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 112  Restrictive Lung Disorders 113  Noninvasive Ventilation to Treat Chronic Ventilatory Failure 114  Obstructive Sleep Apnea and Metabolic Dysfunction 115  Obstructive Sleep Apnea, Obesity, and Bariatric Surgery

Chapter

100

most disorders that are associated with central sleep apnea have been minimally studied, although most are believed to be relatively uncommon. Cheyne-Stokes respiration may be an exception, because a relatively high prevalence has been observed in patients with congestive heart failure. Diagnosis of central sleep apnea generally requires a fullnight polysomnographic evaluation, ideally including measurement of esophageal pressure. However, use of chest and abdominal wall motion as a marker of respiratory effort would be unlikely to lead to an incorrect diagnosis. Treatment of central sleep apnea must be directed, as much as possible, toward the underlying cause. Sleep-onset central apneas do not require treatment unless they are frequent and result in desaturation or repetitive arousals. Cheyne-Stokes respiration is best managed with CPAP alone or in combination with adaptive servoventilation, whereas idiopathic central sleep apnea and high-altitude periodic breathing often respond to oxygen or acetazolamide. Complex sleep apnea often improves over time with consistent CPAP use. Hypercapnic respiratory failure usually requires noninvasive nocturnal ventilation. Thus, the cause of the disordered breathing must be clarified to optimize management.



CHAPTER 100  •  Central Sleep Apnea and Periodic Breathing  1141 Central apnea

Obstructive apnea

Airflow Respiratory effort

10 sec

Figure 100-1  The relation between airflow and respiratory effort is demonstrated in both central and obstructive apnea. During a central apnea, there is cessation of airflow for at least 10 seconds with no associated ventilatory effort. An obstructive apnea is defined as a similar cessation of airflow but with continued respiratory effort.

Cessation of breathing during sleep can result from obstruction of the upper airway (obstructive apnea), absence of inspiratory effort (central apnea), or a combination of the two. The term central sleep apnea is used to describe both the pattern of an individual event and the clinical disorder characterized by repeated episodes of apnea during sleep resulting from the temporary suspension of ventilatory effort.1 A central apnea is conventionally defined as a period of at least 10 seconds without airflow due to absence of evident inspiratory effort. This condition differs from the obstructive or mixed apnea by the absence of upper airway obstruction and subsequent inspiratory attempts against the occluded airway (Fig. 100-1). Although this chapter is concerned with central sleep apnea, central and obstructive events are rarely seen in isolation. The vast majority of patients with central apneas also have some obstructive events. This observation suggests that the mechanisms responsible for the different types of apnea must overlap, and research indicates this is likely to be the case. The muscles of the upper airway (the genioglossus and others) behave as ventilatory muscles,2 dilating or stiffening the pharynx on inspiration. If a decrease or loss of activity occurs in both upper airway muscles and the diaphragm,3 one of several consequences seems likely: 1. The decrement in motor tone of the pharyngeal dilator muscles could lead to upper airway occlusion, with subsequent obstructed inspiratory efforts when diaphragmatic inspiratory activity resumes (a mixed apnea). 2. This loss of pharyngeal muscle activity could yield upper airway collapse, but pharyngeal and diaphragmatic muscles resume activation simultaneously, giving the appearance of a central apnea when airway obstruction was actually present during the apnea. 3. If loss of upper airway muscle activity does not lead to pharyngeal obstruction, a pure central apnea will very likely be seen, with no activation of the diaphragm. The propensity of the upper airway to collapse in a given patient may therefore be important in determining whether a central or obstructive apnea results when neural ventilatory “drive” or output to ventilatory muscles decreases during sleep. After tracheostomy for obstructive sleep apnea, periodic fluctuations in ventilation with or without central apnea can persist, but they generally resolve over a period of months.4,5 This can also occur when CPAP is initiated to alleviate upper airway obstruction (complex sleep apnea). In addition, it has been observed that the treatment of

central apneas with either a respiratory stimulant (e.g., acetazolamide6) or diaphragmatic pacing7 can result in obstructive events. Finally, studies report objective evidence of pharyngeal airway narrowing during purely central apneas.8 These observations imply some commonality in the pathophysiology of the various types of apnea, so it is not surprising that central and obstructive apneas are often seen in the same person. Patients with predominantly central sleep apnea constitute less than 10% of persons with sleep apnea in most sleep laboratory populations.1,9-11 As a result, only a small number of studies with more than a few such patients have been reported, which makes knowledge of this disorder scant. Most of this chapter provides a discussion of patients with central sleep apnea who breathe normally during the day; however, any patient with hypoventilation during wakefulness almost certainly has hypoventilation with or without central apneas during sleep. It is important to recognize that a pause in generating inspiratory effort can result from a variety of physiologic or pathophysiologic events. The term central sleep apnea reflects several breathing patterns, all of which include pauses in inspiratory effort; it does not represent a single entity or result from a single cause. Examples include Cheyne-Stokes respiration, high-altitude periodic breathing, and idiopathic central sleep apnea observed at sea level. Each has a different pathogenesis but is manifested by central apneas during sleep. To understand central sleep apnea, the normal mechanisms controlling ventilation during wakefulness and sleep, and the pathologic influences on these mechanisms, must be understood. All possible causes of central apnea must be considered in caring for patients with this disorder.

PATHOPHYSIOLOGY Because central apneas are defined as pauses in breathing due to lack of inspiratory effort, a complete loss of electromyographic activity of the ventilatory muscles during such an apnea would be expected, and this has been demonstrated.3 After the apnea, there is a resumption of normal ventilatory muscle activity. This finding implies that the neuronal output to these muscles ceases during central apnea and returns at the end of the ventilatory pause. Central apneas therefore represent a loss of inspiratory drive. Although the cause of central apnea in many patients remains obscure, investigation into the control of breathing has pointed to a number of possible mechanisms. Control of Breathing Ventilation is controlled by a number of processes that have been generally grouped under three headings.12 The first is the automatic or metabolic control system, consisting of the chemoreceptors (carotid body for hypoxia and carotid body plus medullary chemoreceptors for hypercapnia), vagally mediated intrapulmonary receptors, and various brainstem mechanisms (namely the pre-Bötzinger complex13) that process the information from these peripheral receptors to generate rhythmic breathing. This metabolic system keeps ventilation regular and ensures that the quantity of ventilation occurring at any time is well matched to metabolic requirements. The second

1142  PART II / Section 13  •  Sleep Breathing Disorders

system is the behavioral control system. It seems clear that the activities of normal life, such as talking and eating, can influence ventilation and are thought of as behavioral or volitional influences. The origin of this neural input to respiration is probably in the forebrain. The third ventilatory control process in awake humans and animals is the wakefulness stimulus, with increased ventilation being inherent to the waking state.12 Although the mechanisms responsible for this effect of wakefulness on ventilation are poorly defined, it has been proposed that it either results from the influence of the descending arousal systems on respiratory pattern generators in the brainstem or it is a product of tonic input from nonrespiratory sensory mechanisms such as sight or hearing on the respiratory control system.14,15 The important point is that during wakefulness, ventilation is controlled by both the metabolic and the behavioral systems, including this wakefulness stimulus. Ventilation is likely to persist during wakefulness even with the complete absence of metabolic mechanisms. During sleep, particularly non–rapid eye movement (NREM) sleep, breathing is controlled almost solely by the metabolic control system, with ventilation being tightly linked to afferent input from chemoreceptors and vagal intrapulmonary receptors.16 This observation was demonstrated in dogs by blocking the input from each of these receptors and monitoring the change in ventilatory pattern. These interventions produced a marked slowing of ventilatory frequency, with long apneic periods. Apnea can also be produced during sleep (with few to no apneas during wakefulness) by partial destruction of the pre-Bötzinger complex in rats.17 The pre-Bötzinger complex is a major site of respiratory rhythm generation and is modulated by chemoreceptor stimuli. In humans, oxygen administration, which reduces the hypoxic stimulus to breathing, has been shown to decrease ventilation during sleep and to initially prolong apneas in some persons in whom such events were already present. In addition, hypocapnic alkalosis, which reduces the hypercapnic ventilatory drive, has been shown to produce central apneas in otherwise normal men.18,19 This combination of studies indicates the importance of both the hypoxic and the hypercapnic influences on breathing during sleep. The implication is that maintenance of neuronal output to the respiratory muscles during sleep may be critically dependent on incoming stimuli, such as those from chemoreceptors. Considerable investigation has been directed at determining the influence of sleep itself on chemoreceptor activity.20,21 Although this is still controversial, the majority of the available information suggests that ventilatory responses to hypoxia and hypercapnia are reduced somewhat during NREM sleep and fall further during rapid eye movement (REM) sleep.20,21 However, several studies indicate that the decrement during NREM sleep is very likely a product of diminished resistive load compensation (reduced defense of ventilation in the presence of the normal physiologic increase in upper airway resistance associated with NREM sleep) rather than a true loss of chemosensitivity.22 Most investigators believe that chemoresponsiveness is reasonably well maintained during sleep, particularly NREM sleep, and is probably important in maintaining rhythmic ventilation during sleep.

Arterial Carbon Dioxide Tension and Breathing during Sleep In his classic studies, Bülow23 showed that periodic breathing during sleep was related to Pco2 in an important way. He observed that apnea or pronounced reduction of ventilation occurred “only when the preceding Pco2 was relatively low,” suggesting that a reduced Pco2 during sleep can decrease the drive to breathe to the point of apnea. Other studies have confirmed the prominent role played by Pco2 in maintaining rhythmic breathing during sleep. Skatrud and Dempsey18,24 showed that passive positivepressure hyperventilation of sleeping subjects yielded apnea by reducing Pco2 by only 3 to 6 mm Hg below the sleeping value. The actual Pco2 level associated with apnea was often only 1 to 2  mm  Hg below the awake value as Pco2 rose from wakefulness to sleep. Each subject had an “apnea threshold,” a Pco2 level below which apnea was commonly seen. It seemed, therefore, that the waking Pco2 level was at or near this apnea threshold, such that waking Pco2 levels may be inadequate to stimulate ventilation during sleep. It was also demonstrated that the periodic breathing during sleep that is often seen with prolonged hypoxia could be abolished by elevating the Pco2 above the predetermined apnea threshold. This finding suggests that the hypocapnia induced by hypoxia, not hypoxia itself, is the pivotal element in this periodic breathing. The authors19 concluded “that effective ventilatory rhythmogenesis in the absence of stimuli associated with wakefulness is critically dependent on chemoreceptor stimulation secondary to Pco2−[H+].” Subsequent studies by this same investigative group suggest that increased tidal volume (mediated by vagal mechanisms) might also be a primary mechanism inhibiting inspiration after a series of large breaths.25 However, the concept of hyperventilation ultimately leading to an inhibition of inspiratory effort as reflected by a central apnea (whether secondary to hypocapnia or vagal mechanisms), remains intact and is likely to be an important one in understanding the pathogenesis of central sleep apnea. Ventilatory Control Stability The mechanisms just described are all seemingly designed to maintain ventilatory stability during wakefulness and sleep, thus avoiding large swings in ventilatory pattern and arterial blood gases. However, abnormalities in the various components of this ventilatory control system can lead to ventilatory instability. This can best be understood by introducing the concept of loop gain, an engineering term that describes the gain of the negative feedback loop that regulates ventilation. Figure 100-2 is a block diagram showing the three major components of this loop: the plant, the circulation delay, and the controller. Plant refers to the lungs, blood, and body tissues where carbon dioxide is stored. Plant gain is the change in alveolar Pco2 for a given change in ventilation. The circulation delay is the time it takes for pulmonary capillary blood to reach the chemoreceptors and is primarily influenced by the cardiac output. The controller represents all the structures responsible for converting chemoreceptor stimuli into ventilation. Controller gain is the change in ventilation for a given change in arterial Pco2.



CHAPTER 100  •  Central Sleep Apnea and Periodic Breathing  1143 10

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PaCO2 (mm Hg) Figure 100-2  The chemical control feedback loop for PCO2. A decrease in ventilation [D Ventilation (disturbance)] produces an increase in alveolar PCO2 (ΔPACO2) as a function of the plant gain. The PACO2 signal gets delayed (circulation delay) and mixes with the existing blood in the heart and arteries before changing arterial PCO2 (PaCO2) in the vicinity of the chemoreceptors. This elicits an increase in ventilation [D Ventilation (response)] as a function of the controller gain, or chemoresponsiveness. Loop gain is calculated by dividing the magnitude of the response by the magnitude of the disturbance.

Loop gain, which is the product of the plant and controller gains, is defined as the ventilatory response to a disturbance of ventilation. For example, a reduction in ventilation [D Ventilation (disturbance)], (see Fig. 100-2) produces a change in alveolar Pco2, which, after a delay, produces a change in ventilation [D Ventilation (response)] at the controller. The ratio of the ventilatory response to the ventilatory disturbance is a measure of the stability of the ventilatory control system. A large ratio (high loop gain) indicates an unstable system prone to large swings in blood gases and ventilation. A small ratio, on the other hand, indicates a stable system that exhibits little or no ventilatory fluctuations in response to a disturbance. The dynamic aspects of loop gain that are important to ventilatory control stability are illustrated in Figure 100-3. In this figure, the ventilatory control system is disturbed by reducing ventilation slightly and holding it at a reduced level for several minutes. This produces an increase in the ventilatory drive to breathe. Note that it takes time for ventilatory drive (the response) to reach its final, steady-state value and that the ventilatory response to disturbance ratio is maximal when the response achieves a steady state. Thus, loop gain is not a single number, but rather it is a function of (1) the duration

Figure 100-3  Ventilatory response to disturbance ratio (loop gain) as a function of time. The ventilatory control system is disturbed by reducing ventilation (solid line) from the baseline of 6 L/min to 5 L/min. Therefore, the magnitude of the disturbance (downward arrow) is 1 L/min. This produces an increase in ventilatory drive, which is the ventilation desired by the ventilatory control system in response to the disturbance. Loop gain is calculated by dividing the magnitude of the response (upward arrows) by the magnitude of the disturbance. Note that this ratio depends on the time at which the response is measured. If the response is measured at time 60 seconds, then the loop gain ratio is 1.6. However, if the response is measured at time 120 seconds, then the loop gain ratio is 2.5.

of the disturbance and (2) the time it takes for the response to reach a steady state. In general, a more prolonged disturbance of ventilation means more time for the response to reach a new steady state, and thereby a higher loop gain. This has particular relevance to patients with Cheyne-Stokes respiration and congestive heart failure, in whom the prolonged circulation delay produces a slow cycle frequency (i.e., long apneas and long hyperpneas). Thus, there is more time for blood gases and ventilation to reach a steady state during the apnea and hyperpnea phases. A rapidly responsive ventilatory control system, in which the response achieves a steady state quickly, also tends to yield an elevated loop gain. This is the likely mechanism in high-altitude periodic breathing and hypoxia-induced periodic breathing. In these conditions, the fast-responding peripheral chemoreceptors are accentuated, and thus a near-steady state is more likely to be achieved when the ventilatory control system is disturbed. Sleep-Onset Central Apneas Ventilation is remarkably dependent on the metabolic control system during sleep and the primary stimulus to ventilation during sleep is arterial Pco2. As a consequence, central apneas can occur when the wakefulness drive is lost during the transition from wakefulness to sleep. The mechanism of sleep-onset central apnea is illustrated in Figure 100-4, which shows a plot of the CO2 controller gain during sleep and the metabolic hyperbola. During sleep, the intersection of the two lines marks the steady-state

1144  PART II / Section 13  •  Sleep Breathing Disorders 15

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Figure 100-4  Mechanism of sleep onset central hypopneas and apneas. A, During sleep in the steady state, ventilation and PCO2 are determined by the intersection of the controller curve with the metabolic hyperbola. During wakefulness, there is an additional (nonmetabolic) drive to breathe, and thus ventilation and PCO2 are to the left of the asleep steady state point. At sleep onset, the wakefulness drive (arrow) is withdrawn and a transient hypopnea occurs until PCO2 rises back to baseline. B, If the wakefulness drive is elevated, and thus the awake ventilation and PCO2 are even further to the left of the asleep steadystate point, a central apnea will occur at sleep onset. A rightward shift in the controller curve (C) or an increase in the controller gain (D) will also predispose to central apneas.

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Figure 100-5  Hypoventilation during sleep could be due to a reduction in controller gain without a change in the PCO2-apnea threshold (A), an increase in the apnea threshold without a change in controller gain (B), or a combination of the two. Note that the PCO2 (where the lines cross) is high in both conditions. However, an increase in ventilation is not likely to lower PCO2 below the apnea threshold in A. On the other hand, to the extent that hypoventilation is due to an increase in apnea threshold with a preserved controller gain (B), the likelihood of periodic central apneas increases.

ventilation and Pco2. During wakefulness, however, there is an additional drive to breathe (the wakefulness stimulus), and thus ventilation will be slightly higher (and Pco2 slightly lower) than during sleep. At sleep onset, when the wakefulness drive is withdrawn, central hypopnea or apnea can occur (Fig. 100-4A). A central apnea is likely if there is a large wakefulness drive to breathe (see Fig. 100-4B), if there is a rightward shift in the controller curve (see Fig. 100-4C), or if there is a high controller gain or a flat metabolic hyperbola (see Fig. 100-4D). To the extent that any of these factors are present, an excessive number of central events can occur at the wake-to-sleep transition, producing a pattern indistinguishable from idiopathic central sleep apnea. Likewise, any process that leads to frequent wake– sleep transitions over the course of the night (such as insomnia, obstructive sleep apnea, maladaptation to CPAP, or periodic leg movements) can increase the number of central apneas. It should be clear, however, that nonrepetitive central hypopneas and apneas in the wake-to-sleep transition are probably normal events.

nisms are no longer operative, there may be little residual drive to breathe, and thus significant hypoventilation can occur. Periodic central apneas, however, would be unexpected due to the low loop gain (Fig. 100-5A). This is generally the case in patients with disorders such as central alveolar hypoventilation (Ondine’s curse)26 and the obesity hypoventilation (pickwickian) syndrome.27 If, however, hypercapnia results from a general reduction in the drive to breathe without significant change in the controller gain—namely, a rightward shift in the controller gain line—then cycling central apneas would be expected (see Fig. 100-5B). This is likely to be the case in patients taking opioid medications, in whom central apneas in association with hypoventilation are common.28,29

Hypercapnic Respiratory Failure With loss of wakefulness, ventilation becomes completely dependent on metabolic control mechanisms. In persons with reduced controller gain (i.e., low or absent response to hypoxia or hypercapnia), breathing during wakefulness may be maintained by behavioral or wakeful stimuli. However, during sleep, when these wakefulness mecha-

Idiopathic Central Sleep Apnea By definition, the pathogenesis of idiopathic central sleep apnea is not entirely clear. A handful of studies30-33 have shown that these patients tend to have a high hypercapnic response and low arterial Pco2 levels during wakefulness, suggesting that an elevated loop gain may be responsible for the periodic central apneas. However,



CHAPTER 100  •  Central Sleep Apnea and Periodic Breathing  1145

careful examination of the actual ventilatory pattern in this disorder suggests that other mechanisms might be involved as well. A pure cycling of chemoreceptor (Pco2)-mediated respiratory output would yield a gradual waxing and waning of ventilation, with an apnea or hypopnea at the nadir as is seen in Cheyne-Stokes respiration (see later). In idiopathic central sleep apnea, the ventilatory pauses are often terminated with an abrupt, large breath, not with a gradual increment in ventilation. Although the explanation for this has not been fully elucidated, this pattern strongly suggests that the mechanisms involved in respiratory switching (expiration to inspiration) are affected by this disorder.34 The long expiratory pause that characterizes these central apneas seems to be a failure of the expiratoryto-inspiratory switch, which may be influenced by not only the chemoreceptors but other mechanisms as well (lung volume, chest wall mechanoreceptors, blood pressure). How these inputs individually contribute to this cycling ventilatory pattern is unclear. However, the pattern of central sleep apnea clearly suggests a different mechanism from that of Cheyne-Stokes breathing. Cheyne-Stokes Respiration It has long been recognized that congestive heart failure is associated with Cheyne-Stokes respiration during wakefulness and sleep, characterized by a crescendo–decrescendo pattern of tidal volume with a central apnea or hypopnea at the nadir. As stated earlier, this is quite different from the more-abrupt onset and offset of idiopathic central sleep apnea. This breathing pattern is almost entirely a product of ventilatory control system instability (high loop gain) resulting primarily from a prolonged circulation time. As previously discussed (see Ventilatory Control Stability), a prolonged circulation delay means that ventilatory disturbances (e.g., apnea or hyperpnea) go unrecognized, and therefore uncorrected, for a longer time. This leads to greater changes in blood gases and a larger ventilatory response-to-disturbance ratio. A prolonged circulation delay alone, however, is probably not sufficient in most patients to raise the loop gain high enough to produce Cheyne-Stokes respiration. In anesthetized animals, a several-fold increase in circulation time was needed to induce periodic breathing.35 Such an increase is probably greater than what commonly occurs with heart failure. Thus, an elevated controller gain36 or plant gain are probably also necessary. This might explain why the severity of heart failure does not alone account for the presence or absence of Cheyne-Stokes breathing. Cheyne-Stokes respiration has been reported in patients with neurologic disease as well, primarily cerebrovascular disorders37; however, the actual ventilatory pattern in these patients has been less well characterized than in patients with congestive heart failure, and the mechanisms remain less well understood. Neurologic Disorders and Central Sleep Apnea Ventilation during sleep is highly dependent on the metabolic control system, and as a result, any neurologic disorder affecting this system could influence the ventilatory pattern while the person is asleep, possibly leading to central sleep apnea. Various neurologic processes have been implicated in the development of central sleep apnea.

Patients with autonomic dysfunction,38 such as the ShyDrager syndrome, familial dysautonomia, or diabetes mellitus, often have apneas that are generally of central origin, although obstructive events are also reported. These patients have also been noted to have erratic breathing during sleep even when central apneas are not obvious. Because the brainstem is the primary source for generating ventilatory patterns and processing respiratory afferent input from chemoreceptors and intrapulmonary receptors, any disease process affecting this area could influence ventilation during sleep. An example is poliomyelitis, a disease well known to damage medullary neurons.39 In the early stages of the postpolio syndrome, respiration during wakefulness is normal, although short central apneas or mild hypoventilation can occur during sleep. With progression of this process (which can take decades), ventilation during sleep becomes progressively more abnormal, with longer, more frequent apneas and with greater hypoventilation as hypoventilation during wakefulness may become apparent. Finally, some patients actually require ventilatory support during sleep and wakefulness if the disease progresses that far. Other processes, such as tumor,40 infarction,41 hemorrhage, or encephalitis,42 can damage the medullary area, leading to breathing dysrhythmias during sleep, with central apneas being a prominent feature. In addition, if the neural pathways from these medullary respiratory neurons to the motoneurons of the ventilatory muscles are interrupted (without damage to the brainstem itself), the metabolic control of breathing may be affected. This interruption is not an uncommon event after cervical cordotomy,43 and central apnea is described after this procedure. Finally, chronic neuromuscular diseases, such as muscular dystrophy or myasthenia gravis, can lead to waking alveolar hypoventilation, with further hypoventilation during sleep. This is occasionally associated with central apneas, although hypoventilation is the more prominent disorder. In fact, as with most patients with postpolio syndrome, ventilation during sleep in patients with ventilatory muscle disease often deteriorates well before waking ventilation is affected. The treatment of the nocturnal hypoventilation with noninvasive ventilation can delay ventilatory failure during wakefulness. Complex Sleep Apnea The term complex sleep apnea has been used by some to describe patients who initially have obstructive sleep apnea during a diagnostic sleep study but develop more than five central apneas per hour of sleep during administration of therapeutic CPAP. The pathogenesis of this phenomenon is not known, but several hypotheses have been proposed. One is that patients with complex sleep apnea have an elevated loop gain in combination with a narrow upper airway. Thus, when CPAP is applied, it eliminates the upper airway obstruction but does not correct the ventilatory control instability. Hence, cyclic breathing with central apnea persists. However, if the definition of complex sleep apnea requires that disordered breathing be purely obstructive in the absence of CPAP, then a high loop gain is probably not responsible for the central apneas. A high loop gain, particularly one that is high enough to produce repetitive central apneas on CPAP, will almost surely produce some evidence of central, or at least mixed,

1146  PART II / Section 13  •  Sleep Breathing Disorders

events during the diagnostic study when there are large disturbances to the ventilatory control system due to arousals and upper airway obstruction. It is also unlikely that CPAP raises the loop gain per se. In addition, the central events occurring on CPAP in these patients are not as strongly periodic as one might expect if a high loop gain were the mechanism. Rather, the events are often aperiodic (or only weakly periodic). Thus, a high loop gain could be responsible for the persistence, but probably not the emergence, of central apneas on CPAP. Another possibility is that activation of the Hering-Bruer reflex by increased lung volume on CPAP produces prolonged expiration to the point of central apnea in some patients. Although this reflex is weak in humans during wakefulness, Hamilton, and colleagues44 showed that it is quite active during sleep and that an increase in lung volume of 1 to 1.5 L (roughly 10 to 15 cm H2O), can prolong expiration by several seconds. This is consistent with the fact that central apneas seem to be more common in patients who are overtitrated, in which the high lung volumes may be eliciting reflex prolongation of expiration. Lastly, central events on CPAP could potentially be due to maladaptation to the device, with frequent arousals causing hyperventilation and sleep-onset central apneas. The extent to which any or all of these mechanisms participate in the pathogenesis of complex sleep apnea awaits further study.

EPIDEMIOLOGY If central sleep apnea as a disorder is to be understood and recognized, it is important to determine how commonly central apneas occur in normal persons. The reported frequency of disordered breathing, and in particular the individual patterns, varies depending on the population studied, the methods used to detect apnea, and the threshold used to define abnormalities.45 Carskadon and Dement46 found that 37.5% of all subjects older than 62 years had apneas or hypopneas, and most of the time, “when determinations were possible, apneas were primarily of central type.” Other studies report an incidence of central sleep apnea of between 12% and 66%,47-50 depending on the population investigated. Lugaresi and colleagues51 stated that “central apneas lasting 5 to 15 seconds may appear during light and REM sleep” in normal subjects. With these limitations in mind, a frequency of more than five central apneas per hour of sleep is generally considered abnormal. Although most research-based studies require a greater frequency of events for inclusion, a report from the American Academy of Sleep Medicine in 2005 defined idiopathic (or primary) central sleep apnea as the presence of five or more central apneas per hour of sleep in patients who are excessively sleepy during the day, have frequent nocturnal arousals or awakenings, or awaken short of breath.52 This same report defined Cheyne-Stokes respiration as at least 10 central apneas and hypopneas per hour, with a crescendo–decrescendo tidal volume pattern, in a patient with a serious medical condition (congestive heart failure, stroke, or kidney failure).52 Thus, a standard now exists for defining these syndromes. In the four studies that specifically considered patients with symptomatic idiopathic central sleep apnea, no con-

sistent epidemiologic trends emerge. Guilleminault’s group,1 White’s group,53 and Bradley’s group30 reported a strong male predominance; Roehrs’s group9 observed central apneas more commonly in women. No explanation can be offered for this discrepancy. All studies, however, noted that this disorder occurred most commonly in middle-aged to older adults, although a few younger patients have been reported. In the case of Cheyne-Stokes respiration, a number of reports suggest that patients with congestive heart failure might have periodic breathing during sleep, particularly in men, persons older than 60 years, and patients with atrial fibrillation.54,55 One study suggests that 45% of patients with congestive heart failure (left ventricular ejection fraction 43 cm

Symptoms of OSA

Polysomnography

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Daytime sleepiness

Nonrespiratory cause of sleepiness

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Consider treatment for OSA/UARS

UARS

Figure 102-2  Algorithm for investigating snoring. ANC, adjusted neck circumstances AHI, apnea–hypopnea index; OSA, obstructive sleep apnea; UARS, upper airways resistance syndrome.

polysomnography. In patients with a low probability of obstructive sleep apnea, the decision to perform polysomnography depends on the presence of symptoms. Snorers with a history of sleep disruption, unrefreshing sleep, or daytime sleepiness should also have a polysomnogram (see Fig. 102-2). Patients with a low probability of obstructive sleep apnea and no symptoms could be treated without polysomnography, provided they are followed clinically for new-onset symptoms or weight gain. The ANC is derived from a sleep apnea clinical prediction rule, which Flemons and colleagues developed using multiple regression analysis.26 It has been validated in an independent sleep clinic population (published in abstract form),27 but results cannot be extrapolated to a general population. There are potential pitfalls with strict adherence to this approach. For example, a snorer with a small neck circumference but prominent craniofacial abnormalities might elude a diagnosis of obstructive sleep apnea. Some patients are also very poor perceivers of symptoms such as daytime sleepiness, and this could lead to a missed diagnosis of obstructive sleep apnea in a patient with otherwise low probability. Each case needs to be evaluated on its own merits, and the clinical prediction rule should be used as a guide, and not as a substitute, for sound clinical judgment. The vast majority of patients presenting to a sleep clinic with snoring still require some form of testing: Even an otherwise asymptomatic habitual snorer with a neck cir-

Treat nasal congestion (medical) Nasal steroids Nasal dilators Persistent snoring Evaluate for correctable obstruction Tonsillar/adenoidal hypertrophy Obvious nasal obstruction

Oral appliance CPAP Persistent snoring or intolerance of treatment

Surgical assessment Removal of enlarged tonsils/adenoids Correction of nasal obstruction Consider palatal procedure such as RFA Figure 102-3  Algorithm for management of snoring. CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea; RFA, radiofrequency ablation.

cumference of 40 cm (just under 16 inches) will be in the intermediate probability category. This underscores the need for easier and less costly methods of evaluating sleepdisordered breathing. With improvements in portable monitoring technology, unattended home studies—particularly those that allow manual review of raw data—are becoming an increasingly attractive option. We anticipate that in the future, portable monitors will take on a much greater role in evaluating the snoring patient; in fact, in many jurisdictions this is already the case, although standardizing measurement of snoring using unattended portable home monitoring equipment will continue to present a challenge.

TREATMENT Treatment options for nonapneic snoring and sleep apnea are similar. In broad terms, treatment can be divided into nonsurgical and surgical approaches. Nonsurgical treatments can be further subdivided into several categories: lifestyle modification, oral appliances, treatments targeting nasal congestion, and positive pressure therapy. Figure 102-3 contains an algorithm for treatment decisions, beginning with identifying and correcting risk factors and followed by using an oral appliance, using CPAP, and, finally, surgery. This general approach, which favors noninvasive treatments initially, can be applied to obese snorers who do not have an obvious anatomic



abnormality of the upper airway. However, treatment should be individualized on the basis of the clinical circumstances and the patient’s preference. For example, those who have hypertrophied tonsils might be referred early on for surgical assessment. Those who are considering surgery should not expect complete elimination of snoring, and even if snoring is initially improved, there is no guarantee that this favorable result will persist. Lastly, there is no reliable daytime assessment tool—such as Mallampati score, Freidman score,28 or nasopharyngoscopy combined with Müller maneuver—that would allow accurate prediction of postoperative success. Nonsurgical Treatments Lifestyle Modification W EIGHT L OSS Obesity is very common among snorers, and weight loss should be one of the first treatment recommendations, regardless of whether additional treatments are being contemplated. It is clinically observed that weight loss improves and sometimes cures snoring. Improvement with weight loss is almost uniformly demonstrated in studies of sleep apnea patients; for example, in one study of 123 patients (probably a mixed population of patients with sleep apnea and nonapneic snoring) who underwent bariatric surgery, the percentage of self-reported habitual snorers decreased from 82% to 14%, with a mean reduction in BMI from 46 kg/m2 to 35 kg/m2.29 However, this hypothesis remains unconfirmed in nonapneic snorers. It is also difficult to predict the amount of weight loss required to improve snoring in a given patient, but sometimes as little as a few kilograms is sufficient. A VOIDANCE OF A LCOHOL AND S EDATIVES Bed partners of snorers often report that ingesting alcohol before bed worsens snoring. Although moderate alcohol consumption (0.5 g/kg) did not affecct snoring intensity in habitual snorers in one study, other studies have shown that moderate alcohol consumption increases upper airway resistance and collapsibility of the pharynx, reduces nocturnal oxygen saturation, and increases the AHI.30,31 The deleterious effect of alcohol on breathing during sleep is related to the timing of alcohol ingestion, the amount ingested, and the person’s metabolism. The effect may be evident for up to 5 hours after ingestion. Snorers should be advised to avoid drinking alcohol within 2 to 5 hours of going to bed. Similarly, snorers should also avoid sedatives such as benzodiazepines. P OSITIONAL T RAINING Snoring is often worse in the supine position. Bed partners commonly observe that pushing or kicking the snorer to induce a change in position can lead to a temporary improvement in the snoring. This observation was validated in a review of the polysomnograms of 21 nonapneic snorers.32 There was a significant reduction in snoring time and intensity during sleep in the lateral position, as compared to the supine position. Maintaining the lateral position during sleep can be challenging: Even if patients intentionally start the night in the lateral position, many eventually end up supine. A

CHAPTER 102  •  Snoring  1177

number of homemade devices and commercially available products have been developed for the purpose of maintaining the lateral position during sleep. A tennis ball, sewn into a pocket over the back of a tee-shirt has been used, as well as backpacks, vests, and specialized pillows and sleepwear. Such devices have been used to treat positional sleep apnea. Although there are no studies demonstrating efficacy of these devices in nonapneic snorers, it stands to reason that such patients might derive some benefit. Partner Interventions If a tree falls in a forest and no one is around to hear it, does it still make a sound? In some cases, it may be simpler and more effective to have the snorer’s partner simply sleep in a separate room or wear ear plugs. Of course, this approach would not address any potential adverse physiologic effects of the snoring on the snorer. Treating Nasal Congestion P HARMACOLOGIC T REATMENTS Tissue lubricants have sometimes been used to treat snoring. A study using phosphocholinamin in a mixed population of 12 patients with sleep apnea and nonapneic snoring demonstrated a 25% reduction in snoring index (number of snores per hour of sleep), versus a 1% increase in snoring index in the placebo group.33 However, the long-term safety of nightly use of such preparations has not been established, and we do not recommend them. Intranasal corticosteroids are commonly prescribed in an attempt to reduce snoring. One study evaluated 13 patients with obstructive sleep apnea and 10 nonapneic snorers in a randomized, placebo-controlled, crossover study of intranasal fluticasone.34 Fluticasone reduced nasal airway resistance, but there was no change in polysomnographically measured snoring in either the sleep apnea subjects or the nonapneic snorers, compared to placebo. Hence, there is no evidence to support the use of intranasal corticosteroids for the treatment of snoring; however, given the reasonably benign nature of the treatment, a trial of 2 to 4 weeks might be reasonable in patients who also have symptoms of chronic rhinitis. Pseudoephedrine sulfate, a nasal decongestant, has also been put forth as a possible treatment for snoring. It was evaluated together with a prokinetic agent, domperidone, in a study of 30 healthy snorers.35 This placebo-controlled crossover study suggested a reduction in snoring intensity with treatment, based on partner reports. Some patients withdrew from the study because of the development of insomnia and palpitations. Pseudoephedrine should also be avoided in patients with hypertension and ischemic heart disease, and we do not usually suggest long-term treatment of snoring with these medications. N ASAL D ILATORS Two small randomized, controlled crossover trials have employed polysomnography to objectively examine the effects of an external nasal dilator on snoring. Patients had nonapneic snoring or mild obstructive sleep apnea and symptoms of chronic rhinitis or nocturnal nasal obstruction. The dilator consists of an adhesive band, bolstered by two elastic springs. Placed externally over the nose, it

1178  PART II / Section 13  •  Sleep Breathing Disorders

serves to pull the nares open. The first trial demonstrated that patients with chronic rhinitis experienced a reduction in snoring incidence compared to a placebo dilator, but with no change in snoring intensity.36 The second trial showed no difference in snoring duration or intensity compared to placebo.37 An internal nasal dilator has also been studied in a trial employing polysomnography in 10 patients.38 This device consists of a flexible plastic bar whose ends are placed inside the anterior nares, pushing them open via a springboard action. In this small study, there was a reduction in the incidence of snoring, compared to no treatment. Overall, it appears that nasal dilators may have a modest effect on nonapneic snoring, and given their innocuous nature, a trial of therapy could be of benefit in some patients. Oral Appliances Oral appliances, patented in the late 19th century for treatment of snoring, were at first relatively neglected because of the associated discomfort from wearing the device. More recently, however, there has been considerable progress in design, manufacturing techniques, and the ability to customize the appliance to an individual patient. They have become the treatment of choice in idiopathic nonapneic snorers when lifestyle modification is insufficient.39 A wide variety of appliances are available, but the most commonly used is the mandibular repositioning appliance. This device, usually customized to fit over the teeth, improves upper airway patency by inducing protrusion of the mandible. Oral appliances are covered in detail in Chapter 109. Most studies of oral appliances suggest that snoring is improved with the device. There has been one randomized, crossover, placebo-controlled trial of an oral appliance for the treatment of nonapneic snoring (polysomnography was not done, but all subjects had normal overnight oximetry).40 This study showed statistically significant improvement compared to a placebo device in partner reports of the incidence and loudness of snoring. On a five-point severity scale, snoring incidence went from a mean of 3.72 at baseline to 1.84 after 4 to 6 weeks of oral appliance therapy (versus 3.36 using the placebo device). Loudness of snoring went from a mean of 3.16 at baseline to 1.24 with the oral appliance (versus 2.76 using placebo). When constructed by dentists with specialized expertise, the appliances are relatively comfortable in the majority of patients. In our experience, if patients stop using the appliances, it is generally because of lack of effectiveness, rather than because of side effects. Compliance, defined as nightly or almost nightly use of the appliance, is on the average 62% at 30 months41; it may be as low as 27% and as high as 67% at 10-year follow up.42 Precise strategies regarding selection of candidates for treatment and titration protocols to determine the optimum mandibular protrusion are still under investigation. Continuous Positive Airway Pressure CPAP therapy for obstructive sleep apnea is described in Chapter 107. Studies on CPAP therapy rarely focus on

nonapneic snorers, but it is generally accepted that snoring can be eliminated with CPAP use in most patients. Whether a person with nonapneic snoring will use CPAP therapy, however, is largely a question of motivation. Those with daytime sleepiness (who, arguably, might actually have UARS) can experience symptomatic improvement from CPAP. Those whose partners are very bothered by the snoring might also have sufficient impetus for a trial of CPAP therapy. Surgical Treatments Surgery can seem an attractive option to nonapneic snorers, for several reasons. Many patients find lifestyle modification difficult and slow, and a quick fix may be more desirable. Patients are also often under the impression that surgery is a curative procedure that obviates the need for nightly intrusive interventions. Surgical procedures used for nonapneic snoring parallel those used to treat obstructive sleep apnea—to a point (see Chapter 108). Operations to optimize patency and stability of the nose and oropharynx are common to both conditions, whereas more complicated surgeries such as genioglossal advancement, hyoid myotomy, maxillomandibular osteotomy, and tracheostomy are reserved for patients with obstructive sleep apnea. Overall success rates with surgery are difficult to determine because of the heterogeneity of surgical procedures, and many studies are plagued by methodologic problems such as inconsistent or subjective assessment of endpoints, lack of longer-term follow-up, and selection bias. However, in general terms, the results of surgical treatment for idiopathic snoring (i.e., snoring not associated with discrete upper airway pathology) have been disappointing. Nasal Surgery Nasal obstruction promotes snoring by increasing negative intrathoracic pressure during sleep; this leads to a reduction in the pharyngeal cross-sectional area, pharyngeal collapse, turbulent flow, and vibration of pharyngeal structures. Data from the Wisconsin Sleep Cohort demonstrates a strong association between nocturnal nasal congestion and habitual snoring, with an odds ratio of 3.0.43 Despite this, there is little evidence in the literature to indicate that treating nasal obstruction surgically with septoplasty or turbinate reduction improves the snoring in nonapneic snorers. In what was probably a mixed population of nonapneic snoring and sleep apnea patients (mean apnea–hypopnea index of 13.6 events per hour), one study found no improvement in snoring time or intensity when measured before and after septoplasty with polysomnography, despite demonstrating improvement in nasal resistance.44 Based on the evidence available to date, nasal surgery cannot be generally recommended for treatment of nonapneic snoring. Pharyngeal Surgery A detailed discussion of upper airway surgery for obstructive sleep apnea is provided elsewhere in Chapter 108. In this section we review pharyngeal surgery specifically with respect to patients with nonapneic snoring.



U VULOPALATOPHARYNGOPLASTY Uvulopalatopharyngoplasty (UPPP) was first described in the early 1980s and quickly became the surgical treatment of choice for both sleep apnea patients and nonapneic snorers. A multitude of studies demonstrates impressive short-term improvement in subjective reports of snoring. An early review suggested success rates of up to 90%.45 However, data showing polysomnographically demonstrated improvement in snoring is lacking. One study showed that there was no difference in snoring index before and after surgery in 69 patients with snoring, some of whom had sleep apnea.46 Despite this, 78% of the patients reported reduction in snoring, highlighting the importance of objective testing in the assessment of surgical success rates. Furthermore, longer-term data on subjective snoring (using questionnaires) suggests that the initial improvements reported by patients often do not last. One survey study showed that the subjective success rate for resolution or improvement in snoring with UPPP fell from 76% in the immediate postoperative period to 45% 2 years after surgery. In this study, 61% of patients indicated that they would not have the operation again, although the retrospective nature of this study may certainly have introduced some bias.47 Airway assessment, during wakefulness and even during sleep, is unfortunately a poor predictor of surgical success. In general, younger, less heavy (BMI < 30 kg/m2), nonapneic snorers have a better success rate. The patient should be informed that UPPP might not result in complete abolition of snoring, and in fact there may be no improvement at all. Some patients have an intermediate result, with a reduction in sound intensity or a change in spectral frequency of the sound that is less objectionable to the bed partner. The surgery is generally quite painful, and longterm side effects from UPPP include velopharyngeal insufficiency, dry throat, and difficulty swallowing.48 L ASER- A SSISTED U VULOPLASTY Laser-assisted uvuloplasty (LAUP) was introduced in 1990 as an alternative to UPPP. It is an office procedure done under local anesthesia, which can be performed several times at 1- to 3-week intervals to achieve the desired effect. Less tissue is resected than during UPPP. The efficacy of this procedure for treatment of snoring is not higher than that of UPPP, and the main reason for selecting this procedure is to avoid administering a general anesthetic. In 2001, the Standards of Practice Committee of the American Academy of Sleep Medicine (AASM) published a review of the evidence for LAUP in sleep apnea and snoring.49 They concluded that “the long-term effectiveness of LAUP on treatment of snoring has not been convincingly established.” There are no controlled trials using objective snoring measures as an endpoint. In several case series reports, subjective improvements in snoring measures occurred in 43% to 90% of patients, but there was some recrudescence of snoring with longer follow-up periods. Since the AASM review, a prospective randomized trial has been published. Patients with nonapneic snoring or mild obstructive sleep apnea (AHI < 20) were randomized to either LAUP or a sham surgery followed by oral

CHAPTER 102  •  Snoring  1179

placebo.50 Reassessment 3 months after surgery with both subjective and objective measures of snoring revealed no difference between the groups in either snoring intensity on a visual analogue scale or in snoring index as measured by a laryngeal microphone. Macdonald and colleagues evaluated a number of preoperative measurements in hopes of finding predictors to a response to LAUP51; unfortunately, none of the measured variables of cephalometry, acoustic rhinometry, analysis of snoring sounds, or body mass index was of sufficient predictive value. Based on the available evidence, LAUP cannot be generally recommended as a treatment for snoring. I NJECTION S NOREPLASTY Injection snoreplasty, introduced in 2001, involves injecting a sclerotherapy agent into the submucosa of the soft palate. It can be performed with topical anesthesia on an outpatient basis. This procedure induces scarring and may serve to stiffen and shorten the palate, thereby reducing snoring. Injection snoreplasty using sodium tetradecyl sulfate has been evaluated in a case series of 17 patients and showed some subjective improvement in snoring.52 There was also an objective component to the snoring evaluation, using a portable monitoring device that measures the average loudness of snoring sounds in decibels but also assesses three parameters of palatal snoring (palatal loudness in decibels, proportion of total snoring originating from the soft palate, and palatal flutter frequency in hertz over the recording period). The authors reported statistically significant reductions in palatal flutter and palatal loudness, but there was no significant difference in average loudness of snoring or palatal flutter frequency. It is a bit difficult to judge the clinical significance of these results. Complications from the procedure have included self-limited palatal swelling and mucosal breakdown, as well as transient palatal fistulas. Further studies of this procedure are required. Although the technique has shown some promise, there is insufficient evidence to recommend injection snoreplasty at this time. R ADIOFREQUENCY A BLATION Radiofrequency ablation (RFA) is an outpatient procedure pioneered in 1998 by Powell and colleagues.53 Using a specialized probe, thermal (radiofrequency) energy can be applied to the pharyngeal tissues—the palate, tonsils, uvula, and base of the tongue. The tissues are heated to approximately 80° C, causing volume reduction and stiffening of the pharynx and making the walls less susceptible to vibration and collapse. Only topical anesthetic is required. Most publications on the use of RFA to treat snoring and sleep apnea are case series reports without placebo controls or objective measures of snoring. However, there have been two randomized, placebo-controlled trials of RFA. The first of these examined a population consisting of obstructive sleep apnea patients as well as nonapneic snorers, and it compared RFA to a sham procedure in which the radiofrequency probe was inserted but no energy was applied.54 There was no specific analysis for

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snoring, but the responses to a specific questionnaire,55 which targets symptoms of nocturnal obstruction, showed no difference between the RFA and sham procedure groups. The second study56 also compared RFA to a sham procedure in 23 patients with nonapneic snoring and mild obstructive sleep apnea (AHI < 15 events per hour). Snoring was evaluated by the bed partner using a 10-cm visual analogue scale. There was a reduction in snoring scores in the RFA group from 8.1 to 5.2, and the snoring score in the sham procedure group went from 8.4 to 8.0. The difference between the groups was statistically significant, suggesting that there may in fact be a moderate reduction in partner-reported snoring in this population with RFA. Larger studies using objective measures are needed before firm recommendations can be made, but based on this small study, RFA shows some promise in the treatment of nonapneic snoring. Side effects such as pain, difficulty swallowing, and pharyngeal irritation are generally rated low to moderate; mucosal blanching and erosions occur in 15% to 40%, and palatal fistula and excessive swelling occur in less than 1%. Hemorrhage occurs in 1.6%.57 P ALATAL I MPLANTS These cylindrical implants, measuring 18  mm in length and 1.6  mm in diameter, are made of a braided polyethylene terephthalate. Inserted with a specialized deployment device into the soft palate under local anesthesia, the implants cause an inflammatory reaction and formation of granulomatous tissue; the soft palate is stiffened as a result, in hopes of reducing snoring. The usual procedure is to insert three implants near the midline of the soft palate. Several case series reports describe the use of such palatal implants to treat snoring. One of the earliest studies, of 12 patients (AHI < 15 events per hour), showed a reduction in partner-based visual analogue scores of snoring, from a mean of 79/100 at baseline to 48/100 at 3 months after implantation. The implantation seemed to be associated with fairly mild discomfort, but spontaneous extrusion of the implant occurred in 17% of patients.58 Two subsequent case series reports (one with 3-month follow-up59 and another with 1-year follow up60) also showed improvement in partner-based visual analogue snoring scores, but neither study showed a change in objectively measured snoring. There was no control group in any of these studies. Though not yet done in nonapneic snorers, a randomized, double-blind, placebo-controlled trial of palatal implants has been published in patients with mild to moderate obstructive sleep apnea.61 This trial did not use objective measurement of snoring but demonstrated an improvement in subjective snoring on a visual analogue scale, compared to placebo. However, the study used only patient self-reports as the measurement of snoring. Some aspects of voice might change with implants.62 Overall, it seems that there are minimal side effects from the insertion of palatal implants, but objective improvement in snoring has yet to be demonstrated, and at this time there is insufficient evidence to recommend it.

T ONSILLECTOMY One occasionally comes across the adult snorer with bilateral severe tonsillar hypertrophy. There are no randomized, controlled trials of tonsillectomy in the treatment of nonapneic snoring adults. Case series reports in patients with obstructive sleep apnea suggest improvements in snoring.63 It is our feeling that tonsillectomy may be entertained as a treatment for snoring in selected cases, particularly in the presence of other indications for surgery such as recurrent infections.

CONCLUSION Snoring is a common complaint that brings the patient to a sleep laboratory. It is due to the vibrations of the walls of the upper airway—from the soft palate to below the base of the tongue. It is the most common symptom of obstructive sleep apnea. Although it may be disturbing to the bed partner, there is no convincing evidence that snoring alone, without sleep apnea, is associated with adverse health consequences. Treatment of nonapneic snoring needs to be individualized and generally involves lifestyle modification (weight loss, avoidance of alcohol), sleep position training, oral appliances, and nasal CPAP. Surgery should be reserved for patients in whom these techniques have failed or are not applicable and for patients with definite abnormalities of the upper airway. Because snoring is not localized to a particular airway segment, the patient should be aware that even if the abnormality is corrected, snoring might not be significantly improved.

❖  Clinical Pearl The diffuse involvement of the upper airway has complicated the treatment of patients with nonapneic snoring. Lifestyle modification and oral appliances may be of benefit; CPAP is effective but rarely used in nonapneic snorers. Surgical approaches are largely of unproved efficacy, but they may be considered in those with problematic snoring that persists despite noninvasive treatments.

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9. Janson C, Gislason T, De Backer W, Plaschke P, et al. Daytime sleepiness, snoring, and gastro-oesophageal reflux amongst adults in three European countries. J Intern Med 1995;237:277-285. 10. Norton PG, Dunn EV, Haight JSJ. Snoring in adults: some epidemiological aspects. Can Med Assoc J 1983;128:674-675. 11. Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome: Part I. Clinical features. Sleep 2002;25:409-416. 12. Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 1. Sleep disorders commonly found in older people. CMAJ 2007; 176:1299-1304. 13. Leung PL, Hui DS, Leung TN, et al. Sleep disturbances in Chinese pregnant women. BJOG 2005;112:1568-1571. 14. Ursavas A, Karadag M, Nalci N, et al. Self-reported snoring, maternal obesity and neck circumference as risk factors for pregnancyinduced hypertension and preeclampsia. Respiration 2008;76: 33-39. 15. Serrano E, Neukirch F, Pribil C, et al. Nasal polyposis in France: impact on sleep and quality of life. J Laryngol Otol 2005;119: 543-549. 16. Kohler M, Bloch KE, Stradling JR. The role of nose in the pathogenesis of obstructive sleep apnea and snoring. Eur Respir J 2007;30:1208-1215. 17. Gottlieb DJ, Yao Q, Redline S, et al. Does snoring predict sleepiness independently of apnea and hypopnea frequency? Am J Respir Crit Care Med 2000;162(4 Pt 1):1512-1517. 18. Nakano H, Furukawa T, Nishima S. Relationship between snoring sound intensity and sleepiness in patients with obstructive sleep apnea. J Clin Sleep Med 2008;4(6):551-556. 19. Lugaresi E, Coccagna G, Farnetti P, et al. Snoring. Electroencephalogr Clin Neurol 1975;39:59-64. 20. Bixler EO, Vgontzas AN, Lin HM, et al. Association of hyper tension and sleep-disordered breathing. Arch Intern Med 2000;160: 2289-2295. 21. Stradling JR, Crosby JH. Relation between systemic hypertension and sleep hypoxaemia or snoring: analysis in 748 men drawn from general practice. BMJ 1990;300(6717):75-78. 22. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365(9464):1046-1053. 23. Lee SA, Amis TC, Byth K, et al. Heavy snoring as a cause of carotid artery atherosclerosis. Sleep 2008;31(9):1207-1213. 24. El Badawey MR, McKee G, Heggie N, et al. Predictive value of sleep nasendoscopy in the management of habitual snorers. Ann Otol Rhinol Laryngol 2003;112:40-44. 25. Flemons WW. Obstructive sleep apnea. N Engl J Med 2002; 347(7):498-504. 26. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(5 Pt. 1):1279-1285. 27. Wyckoff CC, O’Donnell AE. Assessing the adjusted neck circumference sleep apnea screening score in patients clinically suspected to be at high risk of obstructive sleep apnea. Chest 2007;132(Suppl. 4):649S 28. Friedman M, Tanyeri H, La Rosa M, et al. Clinical predictors of obstructive sleep apnea. Laryngoscope 1999;109(12):1901-1907. 29. Dixon JB, Schachter LM, O’Brien PE. Sleep disturbance and obesity: changes following surgically induced weight loss. Arch Intern Med 2001;161(1):102-106. 30. Issa FG, Sullivan CE. Alcohol, snoring and sleep apnea. J Neurol Neurosurg Psychiatry 1982;45:353-359. 31. Mitler MM, Dawson A, Henriksen SJ, et al. Bedtime ethanol increases resistance of upper airways and produces sleep apneas in asymptomatic snorers. Alcohol Clin Exp Res 1988;12:801-805. 32. Nakano H, Ikeda T, Hayashi M, et al. Effects of body position on snoring in apneic and nonapneic snorers. Sleep 2003;26:169-172. 33. Hoffstein V, Mateika S, Halko S, Taylor R. Reduction in snoring with phosphocholinamin, a long-acting tissue-lubricating agent. Am J Otolaryngol 1987;8(4):236-240. 34. Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnea in patients with co-existing rhinitis. Thorax 2004;59:50-55. 35. Larrain A, Hudson M, Dominitz JA, Pope CE 2nd. Treatment of severe snoring with a combination of pseudoephedrine sulfate and domperidone. J Clin Sleep Med 2006;2(1):21-25.

CHAPTER 102  •  Snoring  1181 36. Pevernagie D, Hamans E, Van Cauwenberge P, Pauwels R. External nasal dilation reduces snoring in chronic rhinitis patients: a randomized controlled trial. Eur Respir J 2000:15(6):996-1000. 37. Djupesland PG, Skatvedt O, Borgersen AK. Dichotomous physiological effects of nocturnal external nasal dilation in heavy snorers: the answer to a rhinologic controversy? Am J Rhinol 2001;15(2): 95-103. 38. Höijer U, Ejnell H, Hedner J, et al. The effects of nasal dilation on snoring and obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1992;118(3):281-284. 39. John MT. Dentists should participate in the management of patients with obstructive sleep apnea and socially disruptive snoring— findings from a survey of Scottish sleep specialists. J Evid Based Dent Pract 2010;10(2):107-108. 40. Johnston CD, Gleadhill IC, Cinnamond MJ, Peden WM. Oral appliances for the management of severe snoring: a randomized controlled trial. Eur J Orthod 2001;23:127-134. 41. Chan ASL, Lee RWW, Cistulli PA. Dental appliance treatment for obstructive sleep apnea. Chest 2007;132:693-699. 42. Jauhar S, Lyons MF, Banham SW, et al. Ten-year follow-up of mandibular advancement devices for the management of snoring and sleep apnea. J Prosthetic Dentistry 2008;99:314-321. 43. Young T, Finn L, Palta M. Chronic nasal congestion at night is a risk factor for snoring in a population-based cohort study. Arch Intern Med 2001;161:1514-1519. 44. Virkkula P, Bachour A, Hytönen M, et al. Snoring is not relieved by nasal surgery despite improvement in nasal resistance. Chest 2006; 129(1):81-87. 45. Coleman J, Rathfoot C. Oropharyngeal surgery in the management of upper airway obstruction during sleep. Otolaryngol Clin North Am 1999;32:263-276. 46. Miljeteig H, Mateika S, Haight JS, et al. Subjective and objective assessment of uvulopalatopharyngoplasty for treatment of snoring and obstructive sleep apnea. Am J Respir Crit Care Med 1994;150(5 Pt. 1):1286-1290. 47. Hicklin LA, Tostevin P, Dasan S. Retrospective survey of long-term results and patient satisfaction with uvulopalatopharyngoplasty for snoring. J Laryngol Otol 2000;114(9):675-681. 48. Goh YH, Mark I, Fee WE Jr. Quality of life 17 to 20 years after uvulopalatopharyngoplasty. Laryngoscope 2007;117(3):503-506. 49. Littner M, Kushida CA, Hartse K, et al. Practice parameters for the use of laser-assisted uvulopalatoplasty: An update for 2000. Sleep 2001;24:603-608. 50. Larrosa F, Hernandez L, Morello A, et al. Laser-assisted uvulopalatoplasty for snoring: does it meet the expectations? Eur Respir J 2004;24(1):66-70. 51. Macdonald A, Drinnan M, Johnston A, et al. Evaluation of potential predictors of outcome of laser-assisted uvulopalatoplasty for snoring. Otolaryngol Head Neck Surg 2006;134(2):197-203. 52. Brietzke SE, Mair EA. Injection snoreplasty: extended follow-up and new objective data. Otolaryngol Head Neck Surg 2003;128(5): 605-615. 53. Powell NB, Riley RW, Troell RJ, et al. Radiofrequency volumetric tissue reduction of the palate in subjects with sleep-disordered breathing. Chest 1998;113(5):1163-1174. 54. Woodson BT, Steward DL, Weaver EM, Javaheri S. A randomized trial of temperature-controlled radiofrequency, continuous positive airway pressure, and placebo for obstructive sleep apnea syndrome. Otolaryngol Head Neck Surg 2003:128(6):848-861. 55. Piccirillo JF, Gates GA, White DL, et al. Obstructive sleep apnea treatment outcomes pilot study. Otolaryngol Head Neck Surg 1998:118(6):833-844. 56. Stuck BA, Sauter A, Hörmann K, et al. Radiofrequency surgery of the soft palate in the treatment of snoring. A placebo-controlled trial. Sleep 2005;28(7):847-850. 57. Main C, Liu Z, Welch K, et al. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs. Health Technol Assess 2009;13(3):1-208. 58. Ho WK, Wei WI, Chung KF. Managing disturbing snoring with palatal implants: a pilot study. Arch Otolaryngol Head Neck Surg 2004:130(6):753-758. 59. Maurer JT, Verse T, Stuck BA, et al. Palatal implants for primary snoring: short-term results of a new minimally invasive surgical technique. Otolaryngol Head Neck Surg 2005;132(1):125-131.

1182  PART II / Section 13  •  Sleep Breathing Disorders 60. Maurer JT, Hein G, Verse T, et al. Long-term results of palatal implants for primary snoring. Otolaryngol Head Neck Surg 2005; 133(4):573-578. 61. Friedman M, Schalch P, Lin HC, et al. Palatal implants for the treatment of snoring and obstructive sleep apnea/hypopnea syndrome. Otolaryngol Head Neck Surg 2008;138(2):209-216.

62. Akpinar ME, Kocak I, Gurpinar B, Esen HE. Effects of soft palate implants on acoustic characteristics of voice and articulation. J Voice 2010 Apr 30. [Epub ahead of print] 63. Verse T, Kroker B, Pirsig W, Brosch S. Tonsillectomy as a treatment of obstructive sleep apnea in adults with tonsillar hypertrophy. Laryngoscope 2000;110:1556-1559.

Genetics of Obstructive Sleep Apnea Susan Redline Abstract Patients with obstructive sleep apnea–hypopnea (OSAH) often have relatives—parents, siblings, and children—who have similar symptoms or a diagnosis of OSAH, or both. Related family members with OSAH often share similar anthropomorphic or craniofacial characteristics. In some instances, family resemblances appear strongest for weight and weight distribution (e.g., increased central adiposity); in others, family similarities are noted for jaw size and position (micro- or retrognathia) or face and head shape. These clinical observations are supported by studies demonstrating a familial aggregation of OSAH. Such studies have included reports of families with multiple affected members, twin and cohort studies, assessment of OSAH prevalence among relatives of affected probands, and quantification of the familial aggregation of OSAH by comparing the prevalence OSAH among relatives of affected probands with that in persons without affected relatives. There is clear evidence that a positive family history of OSAH is an important risk factor for an elevated apneahypopnea index (AHI) and associated symptoms such as

DEFINITION OF THE OBSTRUCTIVE SLEEP APNEA–HYPOPNEA PHENOTYPE As is the case with many other complex disorders, there is no standardized phenotypic definition of obstructive sleep apnea–hypopnea (OSAH). Clinically, OSAH is recognized as a syndrome that is defined by the occurrence of repetitive episodes of complete or partial upper airway obstruction during sleep; these episodes usually occur in association with loud snoring and daytime sleepiness. However, operationally, there is much variability in how specific respiratory events are identified, what threshold level for increased numbers of events is considered pathologic, and which other clinical and polysomnographic data are considered necessary for characterizing disease status. Most family and genetic studies of OSAH have used the apnea–hypopnea index (AHI) to define phenotype. The advantages of using the AHI include its relative simplicity, moderate to high night-to-night reproducibility,1 and widespread clinical use. In addition, it is often used clinically to diagnose cases and to justify third-party reimbursement for treatment, and it is often followed as a key outcome in OSAH treatment studies. Because the AHI has been shown to be moderately correlated with other indices of OSAH severity, such as nighttime oxygen desaturation and sleep fragmentation, it may provide information about several correlated traits that are important in disease expression. All genetic studies of OSAH that use the AHI as the outcome variable have demonstrated significant familial aggregation, suggesting that this measure captures useful information for quantifying genetic associations. Combining polysomnographic data with other information, including symptoms, signs, and outcome data, to

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103

snoring, daytime sleepiness, and apneas. Overall heritability estimates for the AHI are .30 to .40. Approximately 35% of the genetic variance in the AHI may be accounted for by genes that influence obesity (with 65% of the genetic variance likely due to genetic variants in other etiologic pathways). Linkage studies have identified several areas where biologically plausible candidate genes are located, including candidates for the metabolic syndrome, obesity, and sleep–wake control. A number of association studies also provide suggestive evidence for increased susceptibility to OSAH in persons who inherit variants for genes in pathways that might influence body fat distribution, metabolism, craniofacial structure, and ventilatory control. In this chapter, both general and specific approaches for investigating the genetic basis of OSAH are reviewed, and those candidate genes as well as intermediate traits that are likely important in determining the expression and severity of the syndrome are described. The latter knowledge might eventually help elucidate physiologically specific approaches for treating (and possibly preventing) OSAH and its common comorbidities.

derive a multidimensional phenotype is one approach for producing a more comprehensive description. In the Cleveland Family Study, a stronger relationship between familial risk and OSAH was observed when OSAH was defined by an AHI level greater than 15 plus reported daytime sleepiness than when disease was defined by AHI level alone.2 Additional power may be gained in future genetic studies of OSAH that use multidimensional phenotypes. As part of this effort, the polysomnographic variables that best identify specific phenotypes must be clarified. For example, alternatives to the AHI, such as indices of flow limitation during sleep or spectral analysis of sleep architecture, may prove to be superior markers for genetic studies. However, a phenotype must be feasible for use in the large numbers of subjects who are needed for genetic epidemiologic studies of complex traits. The choice of phenotype will be influenced by the cost, degree of invasiveness, and individual burden required for identifying and quantifying the phenotype and for applicability across the spectrum of age and body mass index (BMI), as well as by its accuracy and reliability.

INTERMEDIATE PHENOTYPES OSAH is a complex syndrome that is defined using clinically and physiologically relevant terms; identifying genes that determine intermediate phenotypes that are on a causal pathway leading to OSAH is one way to study it. Such intermediate traits may be more closely associated with specific gene products and may be less influenced by environmental modification than more complex (and downstream) phenotypes. A number of risk factors probably interact to increase propensity for repetitive upper airway collapse that occurs 1183

1184  PART II / Section 13  •  Sleep Breathing Disorders

during sleep in patients with OSAH. In a given person, the relevant attributes may be determined by anatomic and neuromuscular factors that influence upper airway size and function. Strong OSAH risk factors are obesity and male gender. Although it has been argued that the genetics of obesity cannot be separated from the genetics of OSAH, careful statistical modeling of AHI and BMI indicates that only about 35% of the genetic variance in AHI is shared with BMI, suggesting that a substantial portion of the genetic basis for OSAH is independent of obesity.3 Other pathoetiologic pathways include those that influence upper airway size, ventilatory control mechanisms, and possibly elements of sleep and circadian rhythm control. Thus, it is useful to consider at least four primary intermediate pathogenic pathways through which genes might act to increase susceptibility to OSAH: obesity and related metabolic syndrome phenotypes, craniofacial and upper airway morphometry, control of ventilation, and control of sleep and circadian rhythm4; these are discussed in more detail later. The limitation of this approach is that the genes so identified might not be sufficient to describe the clinically important phenotype, which might only occur in the context of other genetic and environmental factors. Specifically, susceptibility genes for intermediate traits associated with OSAH might not be equivalent to the susceptibility genes for OSAH.

OBESITY AND BODY FAT DISTRIBUTION Obesity increases risk of OSAH by 2- to 10-fold, with the strongest associations observed in middle-age.5 There are several pathways through which obesity predisposes to OSAH. Fat deposition in the parapharyngeal fat pads may directly narrow the upper airway and predispose it to collapse when neuromuscular activation of upper airway muscles declines with sleep (see Chapter 101). Fat deposition in the thorax and abdomen also increases the work of breathing, which can produce hypoventilation and reduce lung volumes, which in turn reduces parenchymal traction on the trachea, making the airway more collapsible. Reduced lung volumes also can increase propensity for oxygen desaturation to occur, increasing the likelihood that any given reduction in airflow may be classified as a hypopnea and increasing the severity of hypopnea-associated physiologic disturbances. In addition, low lung volumes can reduce oxygen stores and alter loop gain, which, in turn, can influence ventilatory instability. Finally, adipose tissue secretes hormones such as leptin that can influence ventilatory drive (see later). Central body fat distribution appears especially important in the pathogenesis of OSAH. It is unclear whether this is because of the mechanical effects of central fat on lung mechanics and ventilation or upper airway size or because visceral fat is metabolically active. Heritability estimates for obesity-associated phenotypes such as BMI, skinfold thickness, regional body fat distribution, fat mass, and leptin levels range between 40% and 70%, consistent with moderate to strong influences of genetic factors on these traits.6-8 Approximately 7% of cases of early-onset obesity have been estimated to be attributable to the effects of mutations in at least seven

genes influencing the leptin–melanocortin pathways, including melanocortin-4 receptor, leptin, leptin receptor, proopiomelanocortin, and tropomyosin-related kinase-B, which largely influence weight though alterations in appetite regulation.9 Mutations in melanocortin-4 receptor increase risk of severe childhood obesity by approximately 30% and also have been implicated in 0.5% of adult cases of obesity.10 Until recently, the genetic etiology of obesity in the general population was elusive. However, large-scale genome-wide association studies, which examine the variation of frequency of thousands of alleles with disease status in very large samples, have led to the discovery of FTO (fat mass and obesity–associated gene) as an obesitysusceptibility gene.11 These associations, which have been replicated across populations, indicate homozygotes for the risk allele weigh on average 3 to 4 kg more and have a 1.67-fold increased risk of obesity compared with persons without the risk allele. Although the functioning of this gene is not well understood, it is believed that FTO confers a risk of increased obesity risk through regulation of food intake, and possibly via mechanisms that influence stress responses. Other genetic variants, which might individually explain less than 4% of the phenotypic variation, include polymorphisms in genes involved in catecholamine function, mitochondrial respiration, and various pathways involved with insulin sensitivity.8

CRANIOFACIAL MORPHOLOGY Craniofacial morphology, which encompasses both bony and soft tissues, is believed to predispose to OSAH by reducing upper airway patency. Structural features that have been described in patients with OSAH using techniques such as cephalometry include reduction of the anterior-posterior dimension of the cranial base, a reduced nasion-sella-basion angle, reduction of the size of the posterior and superior airway spaces, inferior displacement of the hyoid, elongation of the soft palate, macroglossia, hypertrophy of adenoids and tonsils, increased vertical facial dimension with a disproportionate increase in the lower facial height, and mandibular retrognathia or micrognathia.12-14 (see Chapter 105). A brachycephalic head form, measured by anthropometry, is often found in association with reduced upper airway dimensions. This head form is associated with a small but significant increased risk of OSAH in whites, and it also identifies families at risk for both OSAH and sudden infant death.15 In African Americans, this head form is uncommon and does not appear to increase risk of OSAH. In humans, the genetic basis for craniofacial features is supported by both twin and family studies.16 Over one third of the variability in the volume of soft tissue airway structures including the tongue and lateral pharyngeal walls can be explained by familial factors.17 There are also at least 50 syndromes in which congenital malformations of mandibular and maxillary structure occur, many of which also are associated with respiratory impairment and upper airway obstruction. These include Pierre-Robin syndrome and Treacher Collins syndrome.18,19 Studies of various syndromes and genetic defects suggest potential roles of genes belonging to the fibroblast growth factor



(e.g., FGFR1, FGFR2, FGFR3), transforming growth factor beta (e.g., TGFBR1, TGFBR2), homeobox (e.g., MSX1, MSX2), and sonic hedgehog (e.g., PTCH, SHH) pathways. Other potentially relevant candidate genes are those that have been implicated in craniofacial development, including genes on the endothelin pathway (e.g., ECE1, EDN1, EDNRA),20-22 and TCOF1, the cause of Treacher Collins syndrome.23 Further understanding of homeobox genes and genes controlling growth factors might contribute to our clarifying the origins of craniofacial dysmorphisms found in OSAH. Inherited abnormalities of craniofacial structure appear to explain at least some of the familial aggregation of OSAH. Relatives of OSAH probands have been shown to have decreased total pharyngeal volumes and glottic crosssectional areas, retropositioned maxillas and mandibles, and longer soft palates compared with relatives of controls.24 Relatives of patients with OSAH have been shown by cephalometry to have a more retropositioned mandible and smaller posterior superior airway space compared to normative data.25 In the Cleveland Family Study, both hard tissue (e.g., head form, intermaxillary length) and soft tissue (e.g., soft palate length, tongue volume) factors predicted the AHI level in European Americans. In African Americans, soft tissue factors also predicted AHI levels, but hard tissue anatomic features appeared to be only weakly associated with OSAH.26 These data support the importance of structural features in increasing susceptibility to OSAH, but they also suggest that the anatomic underpinnings and the genes for upper airway anatomy might differ among ethnic groups. Magnetic resonance imaging (MRI) (see Chapter 101) studies have shown that the lateral pharyngeal wall and tongue are larger in OSAH patients compared with matched controls.27 More than one third of the variability in the volume of soft tissue airway structures including the tongue and lateral pharyngeal walls was estimated to be explained by familial factors.17 Although MRI precisely describes anatomic characteristics, its cost limits its utility for large-scale genetic epidemiology studies. An alternative approach is use of acoustic reflectometry, which is a noninvasive technique for assessing airway cross-sectional area as a function of airway distance, and has identified associations of OSAH with mean and minimal airway cross-sectional areas.28-31 The utility of acoustic reflectometry for phenotyping airway risk factors is supported by a study of 568 participants in the Cleveland Family Study. In this sample, the heritability estimate for minimal cross sectional area in both European Americans and African Americans was .37 (P < .05), which increased to .55 once only the highestquality curves were analyzed.32 These estimates were not appreciably changed after considering the influence of BMI, suggesting that between 30% and 55% of the familial similarities in airway dimensions may be explained by genetic factors apart from BMI. Future research needs to assess the ability of such techniques to identify subgroups of persons who inherit polymorphisms associated with genes on craniofacial as compared to other etiological pathways, and further investigation of how anatomic measurements performed awake and in the sitting position predict collapsibility during sleep.

CHAPTER 103  •  Genetics of Obstructive Sleep Apnea  1185

VENTILATORY CONTROL PATTERNS Potentially inherited abnormalities of ventilatory control may predispose to obstructive or central sleep apnea by affecting ventilation during sleep and promoting upper airway collapsibility. Ventilatory instability could result from blunted or augmented chemosensitivity, arousability, or load detection. In the presence of a blunted ventilatory drive, neural stimulation of the upper airway dilator muscles can become insufficient to overcome increases in upper airway resistance occurring during sleep and particularly during sleep in the recumbent posture. Conversely, an overly vigorous ventilatory drive can lead to instability of breathing with alternating cycles of hyperventilation and hypoventilation, most commonly recognized as periodic breathing. During the nadir of this cycling, reduction in chemical drive due to hypocapnia can reduce neural output to upper airway muscles to a level below the threshold required to keep the airway open. Mouse models have allowed genes to be identified that influence control of ventilation, including genes that determine respiratory timing, frequency, awake ventilation, chemosensitivity, and load responses. Clear strain differences have been observed for many of these phenotypes, with evidence of quantitative trait loci near plausible candidate genes. Knockout and transgenic mice also have helped identify the role of specific proteins and receptors in ventilatory chemoreception, neuromuscular transmission, and neural integration. Candidate genes identified from such studies include genes that sense hypoxia33-36; genes on the endothelin pathway,37,38 which also are important in craniofacial development; and genes that regulate neural crest migration,38-40 including PHOX2B, mutations of which cause congenital central hypoventilation.41,42 Population variability in the ventilatory neuromuscular responses might also influence propensity for OSAH and might also be inherited. Phenotypes that can both be inherited and influence OSAH propensity include ventilatory responses to the influences of state (sleep– wake), chemical drive (e.g., ventilatory response to hypoxia and hypercapnia), sensitivity of ventilatory load compensation (the degree to which an individual defends the tidal volume or minute ventilation in the presence of an imposed mechanical load to breathing such as an increased resistance or elastance), or arousal may result in different ventilatory responses to sleep-related stresses, shaping both the magnitude of ventilation and ventilatory pattern and the propensity for respiratory oscillations in sleep. The magnitude of ventilatory chemoresponsiveness appears to be subject to major genetic control; heritability estimates for chemoresponsiveness to oxygen saturation levels range from approximately 30% to 75%.43 Ventilatory responses are more strongly correlated between monozygotic than dizygotic twins.44-47 Population differences in ventilatory patterns and hypoxic sensitivity have been identified for populations that have adapted to living at high altitude.48,49 Abnormalities in hypoxic or hypercapnic ventilatory responsiveness have been described in the

1186  PART II / Section 13  •  Sleep Breathing Disorders

first-degree relatives of probands with unexplained respiratory failure,50 chronic obstructive pulmonary disease,51,52 and asthma.53 Unfortunately, further identification of the role of ventilatory control as an OSAH intermediate phenotype has been impeded by the overall complexity in measuring relevant ventilatory control abnormalities in humans. Challenges include making measurements during sleep, extrapolating awake responses to the sleep state, use of hypoxic and hypercapnic challenge testing to identify the role of peripheral and central chemoreceptors, respectively, and distinguishing responses that are a primary as compared to an acquired phenotype. An example of an acquired phenotype in this context may be one that results from drugs that alter ventilatory chemosensitivity or conditions in which translation of central nervous system ventilatory drive into the metric of drive, such as ventilation, is impaired by abnormal lung or chest wall function, as can occur in chronic obstructive pulmonary disease and ventilatory muscle weakness. No specific approach for measuring ventilatory control has yet been shown to reliably distinguish OSAH patients from controls. A potential role for inherited impairments of ventilatory control in influencing susceptibility to OSAH has been suggested by several studies of carefully characterized families. These studies have demonstrated blunted hypoxic responses and impairment in load compensation in the families of OSAH patients compared with controls. El Bayadi and colleagues reported the results of anatomic and physiologic studies performed in 10 subjects from three generations of a family with an affected proband with OSAH.54 OSAH was documented in 9 of the 10 family members, all of whom had a body mass index less than 30. Blunted responses to ventilatory challenge tests to progressive hypoxia were demonstrated in all five subjects who underwent ventilatory challenge testing. Cephalometry also showed variable degrees of upper airway anatomic compromise. These findings supported a family basis for OSAH, with evidence that inherited abnormalities in anatomic and physiologic risk factors both contributed to the disease severity. Significantly lower ventilatory responses to hypoxic challenge testing were demonstrated in a study that compared ventilatory control responses in 31 subjects from 12 families with two or more members with OSAH, compared to responses in nine age- and sex-matched controls.55 The selection of subjects from families showing familial aggregation for OSAH might have improved the ability to detect potentially inherited abnormalities in an intermediate phenotype. In another study, differences in responses to inspiratory resistive loading during sleep were examined in 10 apparently healthy (without OSAH) adult offspring of OSAH probands and in 14 control offspring of healthy parents.56 Both groups had similar load responses during wakefulness, but during sleep with inspiratory loading, the offspring of OSAH probands breathed at a lower tidal volume than controls, with development of hypopneas at lower levels of resistance, and were less likely to show EEG arousal with hypopneas than the controls. Similarly, nasal occlusion during sleep was demonstrated to precipitate more hypopneas in the healthy relatives of OSAH probands than controls.57 However, these studies could not

differentiate the extent to which differences in ventilatory patterns between the groups was due to differences in collapsibility versus ventilatory drive. Javaheri and colleagues tested for differences in chemoresponsiveness to progressive hypercapnia and to hypoxia in the healthy relatives of hypercapnic OSAH patients compared to eucapnic OSAH patients.58 Although the chemoresponses among relatives were correlated, the relatives of patients with and without hypercapnia did not differ. Thus, this study did not provide evidence for genetically determined differences in chemoresponsiveness influencing the propensity of hypercapnia in OSAH. The potential impact of deficits in ventilatory control on OSAH susceptibility is likely magnified in persons with anatomically comprised upper airways. With sleep onset, the central inspiratory drive to upper airway motor neurons, a major determinant of airway patency, is reduced or fluctuates.59,60 Any given reduction in central inspiratory drive results in greater increases in upper airway resistance in persons with anatomically compromised airways than in others.61 Conversely, persons with greater degrees of upper airway resistance (due to craniofacial or obesity risk factors) can require a high level of compensatory ventilatory drive to overcome sleep-associated airway collapse, and thus they may be especially vulnerable to the influence of genetically determined ventilatory control deficits. These observations underscore the potential importance of considering the interaction of genetic risk factors that influence more than one etiologic pathway.

CONTROL OF SLEEP AND CIRCADIAN RHYTHM Given the impact of sleep–wake state on respiratory motor neuron activation, insights into the susceptibility of upper airway muscles to collapse during sleep can require delineation of the genetics of sleep–wake control. Remarkable advances in our understanding of narcolepsy have provided important information on genes that might control sleep– wake regulation. Experimental studies in dogs and rodents have implicated deficiencies in the orexins (hypocretins; two polypeptides that are ligands for two G protein– coupled receptors in the brain) in causing the phenotypic abnormalities in sleep regulation that characterize narcolepsy. Abnormalities in orexin genes, or genes coding for their receptors, could be relevant to studies of OSAH because of the potential impact of these neuropeptides on arousal and muscle tone, both of which influence the behavior of respiratory systems, because of the close proximity of these neurons to central respiratory control centers, with potential interactions between arousal and respiratory centers. Orexins have also been shown to play a role in energy homeostasis and the regulation of feeding and projections to areas in the ascending cortical activating system, are involved with regulation of both appetite and sleep–wake states,62,63 as well as ventilatory control.64 Although this pathway has not been well studied in OSAH, orexin A levels are reported to be reduced in OSAH.65 Thus, abnormalities in orexin genes may be relevant to OSAH because of their influence on arousal, muscle tone, ventilatory control, and weight control. Data from the Cleveland



CHAPTER 103  •  Genetics of Obstructive Sleep Apnea  1187

Table 103-1  Familial Correlations for Apnea–Hypopnea Index

RELATIONSHIP

PARTIALLY ADJUSTED* FAMILIAL CORRELATION COEFFICIENT

BMI-ADJUSTED† FAMILIAL CORRELATION RELATIONSHIP P VALUE

COEFFICIENT

P VALUE

Parent–offspring

.21

.002

.17

.017

Sib-sib

.21

.003

.18

.008

age , age squared; BMI, body mass index. *Adjusted for age, age2, ethnic group, and gender. † Adjusted for BMI, age, age2, ethnic group, and gender. From Redline S, Tishler PV, Tosteson TD, et al. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:682-687. 2

Family Study indicate that an area on chromosome 6 that houses the orexin-2 receptor is linked with the AHI (see later). In addition to considering the impact of genetic abnormalities on processes that regulate sleep–wake state, it may be useful to consider how respiratory motor neuron control may be influenced by genetic processes that determine circadian clocks, which are known to drive important metabolic and behavioral rhythms. Studies of Drosophila and mouse models have identified a number of genes that influence periodicity and persistence of circadian rhythms,66-69 with evidence that similar mechanisms operate in humans.69,70 The relevance of these findings to OSAH is unclear. However, genetic variations in regulation of sleep–wake rhythm may be factors that influence the expression of OSAH (e.g., ability to compensate or show sleepiness in response to recurrent apneas and sleep disruption).

FAMILIAL AGGREGATION OF OBSTRUCTIVE SLEEP APNEA–HYPOPNEA Significant familial aggregation of AHI, or of symptoms of OSAH, has been observed in studies from the United States, Finland, Denmark, the United Kingdom, Israel, and Iceland.2,24,71-75 Studies have used a variety of designs, including cohorts, small and large pedigrees, twins, and case-control studies; they have included adults and children; and they have employed varying approaches for assessing phenotype. Despite study design and population differences, all studies have consistently shown familial aggregation of the AHI level and symptoms of OSAH in children and adults and in obese and nonobese subjects (Video 103-1). These studies have provided clear evidence that a positive family history of OSAH is an important risk factor for an elevated AHI and for associated symptoms such as snoring, daytime sleepiness, and apneas. However, the estimated magnitude of effects has varied greatly. Several large twin studies have shown that concordance rates for snoring, a cardinal symptom of OSAH, were significantly higher in monozygotic twins than in dizygotic twins.76-78 A study of adult male twins has shown significant genetic correlations for daytime sleepiness as well as snoring, and models were consistent with common genes underlying both symptoms.76 A subsequent report from this cohort showed significant heritability for objectively

measured AHI levels in this twin population.79 A large Danish cohort study showed that the age, BMI, and comorbidity-adjusted risk of snoring was increased threefold when one first-degree relative was a snorer, and it increased fourfold when both parents were snorers.80 The prevalence of objectively measured OSAH among first-degree relatives of OSAH probands has been reported to vary from 22% to 84%.2,24,72,73,75 Among the studies that included controls, the odds ratio (OR), which relates the odds of a person with OSAH in a family with affected relatives to that for someone without an affected relative, has varied from 2 to 46.2,24,72,73,75 Pedigree studies from the United States and Iceland have shown consistent associations; the overall recurrent risk for OSAH in a family member of an affected proband is approximately 2,2,72 which is lower than that reported from case-control studies, which may be subject to biases depending on the appropriateness of the selection of cases and controls. Heritability estimates for the AHI from both pedigree81,82 and twin studies79 are approximately 35% to 40%. Similar parent– offspring (r = .21, P = .002) and sib–sib correlations (r = 0.21, P = .003) have been observed, and they are greater than spouse–spouse correlations.2 OSAH has been described as occurring more commonly as a multiplex (affecting at least two members) than as a simplex (occurring in a single family member) disorder. Further evidence for a genetic basis for OSAH is derived from the observation that the odds of sleep apnea syndrome, defined as AHI greater than 15 and self-reported daytime sleepiness, increases with increasing numbers of affected relatives.2 Table 103-1 shows the odds for sleep apnea syndrome given one, two, or three affected relatives with these findings, as compared with OSAH patients who have no affected relatives, adjusted for age, gender, ethnicity, and BMI. These results support the utility of ascertaining family history as part of the evaluation of the patient for OSAH. Information on snoring, apneas, and sleepiness among first-degree relatives can be used to refine the likelihood of OSAH in any given patient. However, perhaps more importantly, such information can be used to make it easier to diagnose cases by identifying the need for other family members to seek sleep evaluations. Several studies have reported a co-aggregation of OSAH with sudden infant death syndrome (SIDS) or acute life threatening events (ALTEs).72,83,84 Members from families with both OSAH and SIDS cases have been reported to

1188  PART II / Section 13  •  Sleep Breathing Disorders

have anatomic features, such as brachycephaly, leading to upper airway narrowing, as well as reduced hypoxic ventilatory responsiveness.84 These observations suggest that the two disorders have a shared genetic predisposition acting via ventilatory control or craniofacial structure pathways. The demonstration of widespread serotoninergic brainstem abnormalities in SIDS victims,85 and the putative role of this pathway in respiratory drive, suggests an interesting biological basis for the potential genetic link between these disorders that might involve ventilatory mechanisms. The relationship between pediatric and adult OSAH is not clearly understood. However, pedigree studies show that the disease is transmitted across generations. The familial aggregation of appropriately age-adjusted AHI values suggests that common risk factors might influence OSAH susceptibility in children and adults. Although hypertrophy of the tonsils is a major risk factor for childhood OSAH, children of OSAH probands more often have residual OSAH after tonsillectomy compared to the offspring of adults without OSAH,86 suggesting the importance of underlying genetic susceptibility as a determinant of treatment response.

GENETIC ANALYSES Segregation Analysis Segregation analysis is an approach whereby statistical models that make alternative assumptions about the underlying mode of inheritance and the impact of environmental factors on a given trait are compared in an attempt to identify the model that best explains the underlying distribution of traits. These analyses are particularly useful in identifying potential patterns of inheritance. In the Tucson Epidemiologic Survey, segregation analyses of self-reported snoring in 584 pedigrees suggested a major gene effect; however, evidence for the connection weakened after adjustments were made for obesity and gender.87 Segregation analysis was applied to a sample of European Americans (177 families, 1202 members) and African Americans (123 families, 709 members) in the Cleveland Family Study. The analyses of AHI were consistent with the segregation of major genetic factors within both sets of families, although the results suggested possible ethnic differences in the mode of inheritance.74 In European Americans, analysis suggested recessive mendelian inheritance of the AHI, which accounted for 21% to 27% of the variance and an additional 8% to 9% of the variation caused by other familial factors, either environmental or polygenic.74 In African Americans, the BMI-adjusted and age-adjusted AHI gave evidence of segregation of a co-dominant gene with an allele frequency of 0.14 that accounted for 35% of the total variance of this trait. Adjustment of the AHI for BMI weakened the findings in the European Americans and strengthened them in the African Americans. These results provide support for an underlying genetic basis for OSAH in African Americans independent of the contribution of BMI. The analyses in European Americans suggested that a major gene for OSAH might be closely related to genes for obesity.

Molecular Genetic Studies The molecular genetics of OSAH has begun to be investigated using candidate gene approaches (association studies) and whole-genome screens. Candidate gene studies compare the frequency of genetic variants thought to relate to disease susceptibility in groups with and without OSAH. Marked advances in technology now permit fairly dense mapping of genetic markers across the genome, with some assays providing coverage of up to one million genetic variants (single nucleotide polymorphisms [SNPs]), providing the opportunity to discover genetic variants for a trait without prior knowledge of candidate genes. Such whole-genome scans can be applied to family members and analyzed with linkage analysis. Linkage analysis quantifies the co-segregation of a disease locus and a marker locus among family members. Typically, the strength of genetic associations is expressed as a LOD score (the log-odds quantifying the probability of receiving alleles at two loci). A LOD score of 3.0 or more usually is considered strong evidence for linkage. Whole-genome scans can also be used to quantify difference in frequencies of genetic variants in unrelated affected or unaffected persons (i.e., genome-wide association). These approaches have yielded novel discoveries of genetic variants that enhance susceptibility to major chronic diseases such as diabetes and inflammatory bowel disease.88 However, such large-scale studies have not yet been systematically performed for OSAH-related traits. A number of plausible candidate genes are found in pathways that influence the intermediate traits of obesity, craniofacial structure, and ventilatory control (Box 103-1). Candidate genes that have been examined in relationship to OSAH in humans include those for apolipoprotein E (APOE), angiotensin converting enzyme (ACE), serotoninergic pathways, and leptin pathways. Apolipoprotein E An allele of the APOE gene (e4) which was previously associated with increased risk for both cardiovascular disease and Alzheimer’s disease, was reported to be associated with OSAH in two cohort studies of predominantly white subjects.89,90 Two other studies, however, did not replicate this finding.91,92 The Cleveland Family Study reported evidence for linkage to AHI near the APOE locus on chromosome 19, using an initial set of genetic markers, with stronger evidence for linkage after inclusion of fine mapping markers.93 However, the APOE genotype did not explain the linkage findings and was not associated with OSAH status. These findings suggested that the susceptibility locus for OSAH is not to APOE but another locus close to it. A candidate gene in this area is hypoxia inducible factor 3, which plays a role in oxygen sensing. Angiotensin II Converting Enzyme Angiotensin II, an important vasoconstrictor, also appears to modulate afferent activity from the carotid body chemoreceptor and thus might influence ventilatory drive.94 Angiotensin II levels are regulated by the actions of ACE, which is encoded by the ACE gene. Several studies of



CHAPTER 103  •  Genetics of Obstructive Sleep Apnea  1189

Box 103-1  Candidate Genes* for Intermediate Phenotypes for Obstructive Sleep Apnea Obesity FTO (fat mass and obesity-associated gene) Melanocortin-4 receptor Leptin Proopiomelanocortin Melanocyte-stimulating hormone Neuropeptidase Y Prohormone convertase Neutrophic receptor TrkB Insulin-like growth factor Glucokinase Adenosine deaminase Tumor necrosis factor α Glucose regulatory protein Agouti signaling protein Beta-adrenergic receptor Carboxypeptidase E Insulin signaling protein Resistin Ghrelin Adiponectin Gamma-aminobutyric acid transporter Orexin Ventilatory Control RET protooncogene PHOX2B HOX IIL2 KROX-20 Receptor tyrosine kinase Neurotrophic growth factors • Brain-derived neurotrophic factor • Glia-derived neurotrophic factor • Neurotrophic factor-4 • Platelet-derived growth factor Neuronal synthase Acetylcholine receptor Dopaminergic receptor Substance P Glutamyl transpeptidase Endothelin-1 Endothelin-3 Leptin EN-1 GSH-2 Orexin Craniofacial Structure Class I homeobox genes Growth hormone receptors Growth factor receptors Retinoic acid Endothelin-1 Collagen types I and II Tumor necrosis factor α *Includes related proteins and receptors.

Chinese cohorts have reported an association between polymorphisms in the ACE gene and OSAH, particularly in persons with hypertension type.95-99 Data from the Wisconsin Sleep Cohort and the Cleveland Family Study did not show an association between ACE genotype and OSAH, but they showed variation of hypertension in asso-

ciation with level of OSAH and ACE genotype.100,101 In the Cleveland Family Study, after controlling for co-variates, hypertension risk was reduced in subjects who possessed the ACE deletion (D) polymorphism (OR, 0.63; 95% confidence interval [CI], 0.41-0.96, comparing those with 2 versus 0 D alleles). After stratifying by OSAH severity, the protective effect of the D allele was most evident in those with severe OSAH (OR, 0.47; 95% CI, 0.22-1.00), suggesting that the ACE deletion allele might protect against hypertension in the setting of OSAH. Serotoninergic Pathways Serotonin (5-hydroxytryptanmine [5-HT]) receptors are found in the carotid body and hypoglossal neurons, as well as in the brainstem near ventilatory control centers important for chemoreception. Research on animals suggests that serotoninergic neurotransmission, through peripheral actions at the level of the carotid body or hypoglossal nerve, or centrally, at medullary respiratory control centers, influences a wide range of functions relevant to OSAH, including upper airway reflexes, ventilation, and arousal, as well as sleep–wake cycling. Although the pharmacology is complex, with at least 14 receptor subtypes, there is growing evidence implicating the importance of this pathway in the pathogenesis of SIDS, which, as discussed earlier, might share common genetically determined risk factors with OSAH. Polymorphisms in three genes—SLC6A4 (encoding a serotonin transporter protein that clears serotonin from the synaptic space), HTR2A (encoding the 5-HT2A receptor), and HTR2C (encoding the 5-HT2C receptor)—each have been studied in relationship to OSAH.102-104 A polymorphism in the promoter region of SLC6A4, associated with variations in serotonin reuptake activity, was weakly associated with OSAH among men but not women in a small Turkish study, but this association was not confirmed in a Chinese cohort.102,103 Another polymorphism in SLC6A4, which has unclear functional significance, was weakly associated with OSAH in both studies. A polymorphism for HTR2A was also reported to be associated with OSAH among male, but not female, subjects in a small Turkish cohort,104 but this association was not replicated in a larger Japanese study.105 The latter study also did not identify a role for a polymorphism for HTR2C in OSAH. Leptin Signaling Animal studies suggest that leptin, an adipose-derived circulating hormone that influences appetite regulation and energy expenditure, not only influences body weight but also has important effects on ventilatory drive. Mice homozygous for a knockout mutation in leptin hypoventilate and have a blunted ventilatory response to hypercapnia.106 Leptin replacement improves the ventilatory responses to hypercapnia in both wakefulness and sleep in leptin-deficient mice.107 Leptin’s stimulatory effects on hypercapnic ventilatory response appear to be mediated through melanocortin, which is produced from a precursor polyprotein, proopiomelanocortin. As described earlier, the Cleveland Family Study reported suggestive evidence for linkage to an area on chromosome 2p that houses the proopiomelanocortin locus, an area also

1190  PART II / Section 13  •  Sleep Breathing Disorders Table 103-2  Evidence for Linkage for the Apnea Hypopnea Index and Body Mass Index, Cleveland Family Study (European American Subgroup) LOD Score CHR 6 6 10

cM 80.4

AHI

AHI ADJUSTED FOR BMI(5)

BMI

0.6

3.5

162

4.7

0.4

0.7 0.2

118.3

2.7

0.7

0.3

AHI, apnea–hypopnea index; BMI, body mass index; Chr, chromosome; cM, centimorgan. Adapted from Larkin EK, Patel SR, Elston RC, et al. Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index. Ann Hum Genet 2008;72(Pt. 6):762-773.

reported by others to be strongly linked to serum leptin levels.108 Thus, hypothalamic and pituitary pathways involved in leptin signaling may be important in influencing ventilatory control as well as obesity phenotypes relevant to OSAH. Linkage Analyses The only whole-genome screens available for OSAHrelated traits have been performed in the Cleveland Family Study.81,82 Preliminary linkage analyses, performed on the most informative subset of the cohort, identified candidate regions on chromosomes 1p, 2p, 12p, and 19p in whites and on 8q in African Americans. Subsequent linkage analyses were performed in 1275 members of 237 families.109 Several areas of significant linkage to AHI were identified (Table 103-2) that were not associated with coincident linkage for BMI. Notably, significant linkage was observed on chromosome 6 for the BMI-adjusted AHI level (LOD score: 3.5). This area houses the orexin 2 receptor. If this analysis is replicated, it would provide important data supporting pleiotropic effects of orexin on numerous phenotypes associated with sleep disorders.

SPECIAL CHALLENGES IN STUDYING THE GENETICS OF OBSTRUCTIVE SLEEP APNEA–HYPOPNEA The AHI has been the most common measure used in genetic studies of OSAH. However, it is not clear that this is the trait that has the highest degree of heritability or whether it provides an index of disease severity that is consistent across the population. As a count, it might not provide maximal information regarding severity of individual events (duration, associated hypoxemia, arousal) and event characteristics (e.g., extent of pleural pressure swings). An overall AHI in an older population might represent somewhat different physiologic perturbations than one derived in a younger population. Genetic determinants also can distinguish persons with a predominance of central events, in whom neural mechanisms might play a potentially greater role than do factors that more directly influence airway collapsibility. More

comprehensive physiologic data might better capture features that define clearer and more-specific phenotypes. The AHI as a trait-defining variable also presents special statistical challenges in genetic studies. Analyses of quantitative trait loci usually provide the greater statistical power in genetic analyses than analyses of binary traits (e.g., present or absent). These analyses are very sensitive to normality assumptions. However, the AHI follows an extremely skewed distribution that even extensive statistical transformations often do not fully normalize. Additionally, these distributions can vary by sex, with different mean values as well as variances for male and female subjects.74 These statistical challenges have required some studies to use specialized statistical transformations applied to each sex separately. Additionally, in the general population, AHI strongly correlates with BMI. Linkage studies suggest there are both common and independent genetic determinants for the AHI and BMI.109 Thus, strategies where the AHI is statistically adjusted for BMI might not be appropriate for identifying genes that causally affect both traits. On the other hand, analyses that do not account for BMI have limited interpretability regarding the specificity for OSAH of any observed genetic associations. Challenges also arise in association studies, where it is necessary to define specific thresholds for classifying disease status. The absolute threshold values that distinguish disease subgroups are very sensitive to the specific application of polysomnographic measurement techniques, and they can also vary according to the age and other characteristics of the population. Because the AHI has a strong age dependency, with marked increases with advancing age and in women after menopause, a single threshold disease-defining value might not be appropriate across the age span.

SUMMARY Despite the challenges in studying an inherently complex trait, there is growing evidence from clinical and epidemiologic studies that genetic factors influence the expression of OSAH. The largest pedigree and twin studies consistently estimate heritability for the AHI to be between 35% and 40%, with recurrent risk factors of approximately 2. Although obesity is the strongest risk factor for OSAH and has a clear genetic basis, causal modeling suggests that only 35% of the genetic variance in the AHI is shared with pathways that determine body weight. Thus, a majority of the genetic variance for the AHI is likely due to the influence of genes that influence other pathways, including those that influence craniofacial structure, ventilatory control, and possibly sleep–wake patterns. Investigating the genetic etiology of OSAH offers a means of better understanding its pathogenesis, with the goal of improving preventive strategies, diagnostic tools, and therapies. Molecular studies of OSAH still lag behind those of other chronic diseases. However, the application of genome-wide association studies to study the genetics of this disorder promise to further elucidate genetic pathways for this disorder, as has been accomplished for other major chronic illnesses.



CHAPTER 103  •  Genetics of Obstructive Sleep Apnea  1191

❖  Clinical Pearl A positive family history of OSAH (or of related symptoms) is useful in identifying patients at increased risk for the disorder. Craniofacial abnormalities and obesity can each have a genetic basis and are risk factors for sleep apnea. Clinicians should ask about sleep apnea symptoms in family members. Children who have undergone tonsillectomy for snoring who are the offspring of persons with sleep apnea may be at increased risk for recurrent sleep apnea, and careful monitoring of these children may be indicated.

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93. Larkin EK, Patel SR, Redline S, et al. Apolipoprotein E and obstructive sleep apnea: evaluating whether a candidate gene explains a linkage peak. Genet Epidemiol 2006;30(2):101-110. 94. Allen AM. Angiotensin AT1 receptor–mediated excitation of rat carotid body chemoreceptor afferent activity. J Physiol 1998;510 (Pt. 3):773-781. 95. Xiao Y, Huang X, Qiu C. Angiotension I converting enzyme gene polymorphism in Chinese patients with obstructive sleep apnea syndrome. Zhonghua Jie He He Hu Xi Za Zhi 1998;21(8): 489-491. 96. Xiao Y, Huang X, Qiu C, et al. Angiotensin I-converting enzyme gene polymorphism in Chinese patients with obstructive sleep apnea syndrome. Chin Med J 1999;112(8):701-704. 97. Zhang J, Zhao B, Gesongluobu Sun Y, et al. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism in hypertensive patients with different degrees of obstructive sleep apnea. Hypertens Res 2000;23(5):407-411. 98. Zhang LQ, Yao WZ, He QY, et al. Association of polymorphisms in the angiotensin system genes with obstructive sleep apnea– hypopnea syndrome. Zhonghua Jie He He Hu Xi Za Zhi 2004; 27(8):507-510. 99. Li Y, Zhang W, Wang T, et al. Study on the polymorphism of angiotensin converting enzyme genes and serum angiotensin II level in patients with obstructive sleep apnea hypopnea syndrome accompanied hypertension. Lin Chuang Er Bi Yan Hou Ke Za Zhi 2004;18(8):456-459. 100. Patel SR, Larkin EK, Mignot E, Lin L. The association of angiotensin converting enzyme (ACE) polymorphisms with sleep apnea and hypertension sleep. Sleep 2007;30(4):531-536.

CHAPTER 103  •  Genetics of Obstructive Sleep Apnea  1193 101. Lin L, Finn L, Zhang J, et al. Angiotensin-converting enzyme, sleep-disordered breathing, and hypertension. Am J Respir Crit Care Med 2004;170(12):1349-1353. 102. Ylmaz M, Bayazit YA, Ciftci TU, et al. Association of serotonin transporter gene polymorphism with obstructive sleep apnea syndrome. Laryngoscope 2005;115(5):832-836. 103. Yue WH, Liu PZ, Hao W, et al. Association study of sleep apnea syndrome and polymorphisms in the serotonin transporter gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005;22(5):533-536. 104. Bayazit YA, Yilmaz M, Ciftci T, et al. Association of the −1438G/A polymorphism of the 5-HT2A receptor gene with obstructive sleep apnea syndrome. J Otorhinolaryngol Relat Spec 2006;68(3): 123-128. 105. Sakai K, Takada T, Nakayama H, et al. Serotonin-2A and 2C receptor gene polymorphisms in Japanese patients with obstructive sleep apnea. Intern Med 2005;44(9):928-933. 106. Tankersley C, Kleeberger S, Russ B, et al. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol 1996; 81(2):716-723. 107. O’Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 1999;159(5 Pt 1):1477-1484. 108. Comuzzie A, Hixson J, Almasy L, et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997;15:273-276. 109. Larkin EK, Patel SR, Elston RC, et al. Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index. Ann Hum Genet 2008;72(Pt. 6):762-773.

Cognition and Performance in Patients with Obstructive Sleep Apnea Terri E. Weaver and Charles F.P. George Abstract Patients with obstructive sleep apnea (OSA) demonstrate variable degrees of cognitive and performance deficits such as difficulties with cognitive processing, sustaining attention, memory, executive functioning, and quality of life, with the deficits in these areas more apparent in those with moresevere disease (higher incidence of abnormal breathing events, greater hypoxemia). The mechanisms leading to such deficits and the relative contribution of sleep disruption, hypoxemia, reduced vigilance, and daytime sleepiness remain unclear. Treatment of OSA with continuous positive airway pressure (CPAP) results in consistent improvement in cognition

Sleep is chronically disturbed in untreated obstructive sleep apnea (OSA). Patients with OSA experience slowed thought processes, forgetfulness, delayed reaction time responses, and inability to concentrate, resulting in impaired daytime functioning. The cognitive and performance deficits experienced by patients with OSA are associated with decreased work performance,1 increased accidents,2 and diminished quality of life.3,4 The threat of impaired performance to the patient as well as the well-being of others presents legal and moral challenges to practitioners. Whether a person should be denied the privilege to operate a motor vehicle or work because of this risk is a matter of professional debate and legislative consideration. This chapter describes the cognitive and performance deficits in patients with OSA, considers the scope of this problem, proposes etiologic mechanisms, presents current methods of assessment, and describes the response to treatment. The legal ramifications of impaired functioning and practitioner liability are also addressed. Because respiratory disturbance index (RDI) and apnea–hypopnea index (AHI) are often used interchangeably in the literature, the term used in the cited literature will be the term applied in the chapter.

EPIDEMIOLOGY Cognitive and performance deficits (defined later) are clearly present in some patients with OSA, but the exact prevalence remains unknown. It has been estimated that approximately 80% of OSA patients complain of both excessive daytime sleepiness and cognitive impairments, and half also report personality changes.5 One in four patients with newly diagnosed OSA have appreciable neuropsychological impairments.6 In research studies examining memory, sustained attention, or executive function, memory impairments can be found in up to 9% of OSA subjects, 2% to 25% have problems with sustained attention, and 15% to 42% demonstrate difficulties with executive functioning.7 Traffic accidents and work-related accidents represent surrogate indicators of neurobehav1194

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and performance, although the magnitude of improvement is variable. The role of CPAP as first-line therapy in mild OSA is currently unknown, and its long-term effectiveness with regard to cognitive and performance deficits needs further study. Practically speaking, health care providers must be aware of the potential for cognitive and performance deficits in OSA patients and routinely ask about performance at work, ability to concentrate and maintain attention, irritability, and difficulties performing everyday tasks. It is the practitioner’s obligation to inform the patient of the risks associated with such deficits and protect the public through appropriate action until the patient is successfully treated.

ioral performance deficits.8 Compared to nonsnoring normal controls, those with OSA are 37 times more likely to complain of sleepiness, 7.5 times more likely to have difficulties with concentration at work, have a ninefold increase in difficulty learning new tasks, and are 20 times more likely to have problems performing monotonous tasks.1 Excessive daytime sleepiness is associated with greater work limitation in terms of difficulties with time management, mental tasks, interpersonal relationships, and work output.8,9 Beyond difficulties with performance, occupational accidents occur in 50% of male OSA patients; the risk of occupational accidents in women with OSA is six times greater than in controls.8,10 Motor vehicle drivers do not always perceive their impairment and continue to drive while sleepy.11 Overall, compared to normal controls, OSA patients are 2 to 13 times more likely to experience an accident.2 Such accidents are more likely to occur in those who manifest greater daytime sleepiness.2,4 However in some studies, OSA has been associated with motor vehicle crashes independent of daytime sleepiness.4 Sleepiness due to work schedules and sleepiness due to OSA are independent risk factors for accidents. For example, in commercial vehicle drivers, where both sleepiness-promoting conditions coexist, those with the highest level of sleepiness have a twofold increase in multiple accidents.12

DEFINITION, ASSESSMENT, AND IMPACT To understand the cognitive and neurobehavioral performance deficits that affect patients with OSA, it is helpful to consider them from a categorical perspective. The effects of sleep loss on performance include changes in cognitive performance, difficulty with working memory, slowing of response or inability to sustain attention across the duration of the task, declines in the best effort or fastest response, lapses (acts of omission), and false responses (acts of commission).13 In OSA, hypoxemia– reoxygenation cycles with attendant biochemical and cellular alterations cause dysfunction of the prefrontal cortex.



CHAPTER 104  •  Cognition and Performance in Patients with Obstructive Sleep Apnea  1195

This results in impaired executive function manifesting as false responses (e.g., responding when no stimulus is presented—an example of loss of behavioral inhibition), problems with working memory and contextual memory, problems with cognitive processing (analysis and synthesis) in addition to deficits in the pattern of responses (set shifting), and self-regulation of affect and arousal.14 Box 104-1 presents a description of the performance deficits

and commonly used assessment techniques in OSA patients. Tests that can easily be performed in the clinical setting include the Digit Symbol Substitution Task (90second test) to assess cognitive processing and the Psychomotor Vigilance Task (10-minute task) to evaluate the ability to sustain attention. Summary information regarding the neurobehavioral tests may be found elsewhere.15

Box 104-1  Definition and Assessment of Cognitive and Neurobehavioral Deficits Associated with Obstructive Sleep Apnea Cognitive Processing Behavior Decreased ability to digest information • Slowing on task • Increased errors • Decline in total number correct and/or completed per unit of time Measures Commonly Used to Assess Deficit Self-paced tasks of short duration (1 to 5 min), including arithmetic calculations, communication, or concept attainment • Paced Auditory Serial Addition task (PASAT) • Trailmaking A and B: sequencing numbers (A) or letters and numbers (B) • Category Test: six sets of items organized around different principles with a seventh set comprising previously shown items • Digit Symbol Substitution Test: supplying matching symbol given the corresponding number • Digit Backward: stating verbally provided numbers in reverse order • Letter Cancellation: cancellation of target alphabets from presentation of randomized alphabets Memory Behavior Decreased ability to register, store, retain, and retrieve information Measures Commonly Used to Assess Deficit Short-term memory: timed tasks of up to 10 min that require free recall of words, numbers, paragraphs, or figures • Probed, Recall Memory Task (words) • Digit Span Forward (numbers) • Wechsler Memory Scale Story Task (paragraph) • Rey Auditory-Verbal Learning Test (figure) Long-term memory: presenting the subject with lists of items that are longer than the 7-item memory capacity • California Verbal Learning Test Procedural memory: gradual acquisition and maintenance of motor skills and procedures • Mirror Tracing Task • Rotary Pursuit Task

• Reduction in the fastest optimal response times • Periods of delayed or no response (lapses) • Response to stimuli when none presented (false responses) Measures Commonly Used to Assess Deficit Short-duration tasks ( 15) compared to normal controls.21 These deficits are likely due to sleepiness, OSA or both. Memory Memory is defined as the ability to register, store, retain, and retrieve information.23 The psychological processes involved in memory include registration, short-term memory, rehearsal, long-term memory, and retrieval.15 Registration, or sensory memory, is the first recognition of a stimulus and serves as evidence of consciousness. Registered information is either processed as short-term memory or quickly decays.15 Short-term, or working, memory involves a limited capacity holding unit for storage of information and operates in conjunction with an executive system to hold and internalize information to direct behavior.15 When these components of memory malfunction, new information is immediately lost and there is a reduction in memory span.15 Repetitive mental processes, or rehearsal, increase the likelihood that the memory trace will endure or be maintained.15 Reduced learning efficiency and loss of new information occurs when there are deficits in rehearsal. Long-term information storage involves the process of consolidation, or the organization of information based on meaning. Neuropsychological deficits resulting from the inability to store information for the long-term result in the inability to learn, retain, or execute skills or functions.15 Retrieval involves recall of information; a deficit in retrieval



CHAPTER 104  •  Cognition and Performance in Patients with Obstructive Sleep Apnea  1197

produces difficulty with spontaneous recall.15 Procedural memory is the gradual acquisition and the maintenance of motor skills and procedures.23 Decreased alertness experienced by OSA patients potentially impairs registration and other aspects of memory, but the data remain unclear whether these patients have more difficulty with memory function than normal controls.21,24-26 Differences in study populations such as clinic versus broad population-based samples, level of disease severity, and the use of normal controls versus norm-referenced comparisons, might account for the lack of clarity in the literature regarding this issue. The type of memory assessed (episodic, procedural, short-term, working) might also account for differences among studies.25 Sustained Attention Attention is the composite of different capacities or processes that reflect how stimuli are received and processed.15 It can be sustained (or tonic), as in the case of vigilance, or it can be phasic, in which attention shifts in response to changing stimuli.15 Concentration refers to focused or selective attention to important stimuli while suppressing others.15 Sometimes used interchangeably with concentration, sustained attention is most affected by daytime sleepiness and probably the root cause of a significant source of OSA morbidity and mortality: motor vehicle crashes. With increased time on task, the ability to maintain attention becomes more taxed, producing uneven performance.27 There is a limit to attentional capacity such that engaging in one task requiring controlled attention can interfere with another task requiring the same processing requirements.15 Divided attention is the ability to respond to more than one task or stimulus and is sensitive to situations where there is reduced attentional capacity.15 OSA patients initially perform as well as normal controls during tasks of short duration (e.g., 10 minutes), but performance instability—uneven performance—occurs over the duration of the task with increasing response time, lapses or failure to respond, and responses without prior

stimuli (acts of commission) (Fig. 104-2).27 Deficits in sustained attention are greater in older OSA patients (older than 50 years) compared to younger patients with comparable OSA severity, showing longer reaction time and more lapses in attention in addition to differences compared to the performance of normal controls.28 The magnitude of the impact of OSA on sustained attention tasks ranges from small (effect sizes of 0.2) to very large (effect size of 3.0).3 As with other measures, the magnitude of results in clinic-based (smaller sample size) studies is less but still present when looking at larger community-based samples with lower levels of disease severity.4 To illustrate the effect of OSA on sustained attention using a meaningful example, performance on the psychomotor vigilance task (PVT) was measured in OSA patients and compared with normal controls who ingested alcohol to incrementally raise their blood alcohol level from zero to a mean of 0.80  g/210  L of breath.29 The PVT is a sustained-attention task that measures the speed with which a person responds (presses a button) to a presented stimulus (appearance of lighted numbers). OSA patients generally performed worse than inebriated subjects. For example, the performance of a 47-year-old patient with mild to moderate OSA is comparable to or worse than the performance of a healthy, nonsleepy 27-year-old with a blood-alcohol level above the legal limit in most states in the United States.29 On driving simulators, OSA patients hit more obstacles, have increased error in tracking and visual search, have increased response time to secondary stimuli, and drive out of bounds more times compared to control subjects (Fig. 104-3).30 In a large study of commercial drivers, across levels of disease severity, there were significant differences in lapses on the PVT and in tracking errors on a divided attention driving task.31 Executive Functions In contrast to assessment of cognitive functions in which the person is asked what he or she knows or can do,

Control Subjects

OSA Patients Pre-Tx 10000

msec

msec

10000

1000

1000

100

100 0

10

20

30

40

Consecutive RTs

50

60

0

10

20

30

40

50

60

Consecutive RTs

Figure 104-2  Comparison of performance of normal controls and sleep apnea patients on the Psychomotor Vigilance Task. Sleep apnea patients demonstrate increased reaction time, indicated by the bars, and lapses in response, indicated by the blank spaces. (From Chugh D, Dinges D. Mechanisms of sleepiness. In: Pack A, editor. Pathogenesis, diagnosis, and treatment of sleep apnea. New York: Marcel Dekker; 2002. p. 273.)

Tracking error (cm)

1198  PART II / Section 13  •  Sleep Breathing Disorders 600 500 400 300 200 100 0 Control

Alcohol

OSA

Narcolepsy OSA-Rx

Figure 104-3  Summary of tracking errors in different groups on the Divided Attention Driving Task. OSA, obstructive sleep apnea. (From George CF. Vigilance impairment: assessment by driving simulators. Sleep 2000;23(Suppl. 4):S115-S118, p. S116.)

evaluation of executive functions asks how or whether the person goes about accomplishing a task.15 Executive functions are facilities that produce purposive, independent, or self-serving action and represent frontal lobe functioning.15 There can be considerable loss in cognitive functioning, but if the executive functioning is preserved, the person will be able to be independent and productive.15 However, the reverse is not true, because the loss of executive functions renders the person incapable of performing self-care, working independently, or maintaining normal social relationships even though cognitive functioning remains intact.15 There can also be emotional lability or increased irritability, and impulsivity. Persons with impaired executive function lack motivation, are unable to initiate activity, and have problems with planning and carrying out activities that depict goal-directed behavior.15 The inconsistent finding of the impact of OSA on organization and retrieval aspects of memory, but not long-term storage, may be explained by deficits in executive function.24 Deficiencies in executive functioning in conjunction with difficulties with concentration, sustained attention, cognitive processing, and memory, might contribute to the decrements in functional status that have been reported in OSA patients, although this link has not been systematically studied.3 Although there is some inconsistency within the literature, executive functions may be the performance parameters that are most affected by OSA.14,32 As with other aspects of cognitive function, large effects tend to be found in clinic-based samples,4 and smaller or clinically insignificant findings are found in community-based samples.4 The variability in results can be accounted for both by the heterogeneity of the population studied and the lack of a standardized neuropsychological test battery that includes assessments of different domains of executive function.32 Impairments in executive function identified in the OSA population include problems with verbal fluency, planning, and sequential thinking; slowed information processing; and decreased short-term memory span and constructional ability.3,33

QUALITY OF LIFE Measuring the impact of illness on the patient’s ability to conduct everyday tasks and fulfill roles from the patient’s perspective is a key component in outcome management and the evaluation of treatment efficacy. Quality of life (QOL), health-related quality of life (HRQL), and func-

tional status, although conceptually distinct, have all been used to describe the effect of illness on everyday life.34 Although the term quality of life encompasses such attributes as standard of living, economic status, life satisfaction, quality of housing, health status, and job satisfaction, health-related quality of life comprises only domains considered to be affected by illness. Functional status, a component of quality of life, is multidimensional and defines the ability to carry out activities and tasks necessary to fulfill current life roles. Measures of quality of life are categorized as either generic or disease specific. Generic measures assess a wide variety of activities and domains and are designed to contrast the ability to conduct tasks and roles among heterogeneous populations, enabling crossillness comparisons (Table 104-1).34 Compared to generic measures, disease-specific measures provide greater depth of information regarding the aspects of daily functioning most likely to be affected by the illness or symptom of interest.34 Disease-specific measures that have been designed for use in assessing the impact of OSA include the Functional Outcomes of Sleep Questionnaire (FOSQ), Calgary Sleep Apnea Quality of Life Instrument (SAQLI), and OSA Patient-Oriented Severity Index.34 Because disease-specific measures of quality of life have recently been developed, the majority of research evaluating quality of life in untreated OSA has employed generic measures, such as the Medical Outcomes Study SF-36 (Short Form 36). Large community-acquired samples indicate that OSA affects quality of life with an impact similar to that experienced by persons with other chronic disorders of moderate severity.4 Even patients with mild OSA appear to have difficulties carrying out their daily activities, although whether there is a linear relationship with degree of sleep-disordered breathing is uncertain.4 However, several studies indicate that those with more-severe disease experience the greatest deficits, with an odds ratio of approximately 1.5 times those with less-severe disease.35 One small, limited study showed that the association between AHI and general physical and mental functioning reflected the escalation in AHI from 1 to 15, but no greater deficit was documented beyond that level, suggesting a threshold effect, although the nature and small size of the sample limit interpretation.35a Studies using clinical samples employing norm-referenced data or normal controls for comparison have demonstrated impaired quality of life in OSA patients on both generic and disease-specific measures.34,36 Studies using disease-specific questionnaires demonstrated a greater array of affected tasks and roles than generic measures.34 Patients reported problems in aspects of daily living beyond vigilance-related activities, indicating the pervasive effect of OSA.34 For example, OSA patients had greater deficits than normal controls by up to two standard deviations in all subscales of the FOSQ, reflecting the domains of general productivity, vigilance, activity level, social outcome, and sexual relationships.36 Although several studies have suggested a linear relationship between OSA severity (as measured by AHI) and components of quality of life, prediction of impaired daily functioning is not consistently found.3 For example, a dose-response relationship between scores on the vitality/ energy subscale of the generic SF-36 and OSA severity



CHAPTER 104  •  Cognition and Performance in Patients with Obstructive Sleep Apnea  1199

Table 104-1  Comparison of Domains Addressed by Quality-of-Life Instruments Instrument WHOQOLBREF

SICKNESS IMPACT PROFILE

FUNCTIONAL LIMITATIONS PROFILE

MEDICAL OUTCOME STUDY SF-36

NOTTINGHAM HEALTH PROFILE

EUROQOL

Physical functioning

x

x

x

x

x

x

Mental health

x

x

x

x

x

x

x

x

x

x

x

DOMAIN

Psychological distress Psychological well-being

x

Role functioning Social functioning

x

x

x

x

x

x

x

x

Health perceptions

x

Pain

x

x

Vitality

x

x

Mobility and travel

x

x

Sleep

x

x

Cognitive functioning

x

x

Eating

x

x

Recreation and hobbies

x

x

Communication

x

x

x

x

Environment Home management

x x

x

x

WHOQOL, World Health Organization Quality of Life. Data from Weaver TE. Outcome measurement in sleep medicine practice and research. Part 1: assessment of symptoms, subjective and objective daytime sleepiness, health-related quality of life and functional status. Sleep Med Rev 2001;5(2):103-128.

(controlling for age, body mass index [BMI], and other pertinent factors) was documented in one communitybased study, but only when oxyhemoglobin desaturation was included in the definition of disease severity.4 Selfreported sleepiness has been reported to affect quality of life, but the relationship depends on consideration of other critical factors such as chronic illness, BMI, and age.37-39

ETIOLOGY AND MECHANISMS It has been speculated that the cognitive and performance deficits associated with OSA are related to fragmented sleep, nocturnal hypoxemia, or both.14 Although sleep fragmentation and nocturnal hypoxemia have been linked to cognitive and neurobehavioral dysfunction, their relative contributions remain unclear.14 The relationship between the respiratory disturbance index and cognitive and neurobehavior have been either weak or not consistently statistically significant.3,4,40 Available evidence suggests that difficulties with attention and memory are related to excessive daytime sleepiness, and deficits in executive and motor function are attributed to hypoxemia, although hypoxemia can have an effect on all of these functions.19,20,41 The prefrontal model posits that the sleep disruption, intermittent hypoxemia, and hypercarbia experienced by OSA patients alters the normal restorative process that occurs during sleep, generating cellular and biochemical stresses that result in disruption of functional homeosta-

sis and altered neuronal and glial viability within certain brain regions, primarily the prefrontal regions of the brain cortex.14 This model has been proposed as a conceptual framework for the relationship between sleep disruption and nocturnal hypoxemia and primarily frontal deficits (cognitive and neurobehavioral dysfunction) (Fig. 104-4). These physiologic alterations destabilize the executive system, causing behavioral disturbance in inhibition, maintenance of performance, self-regulation of affect and arousal, working memory, analysis and synthesis, and contextual memory.14 Alterations in the executive system can adversely affect cognitive abilities, resulting in maladaptive types of behavior as depicted in Figure 104-4.14 It is important to emphasize that the impairments associated with OSA produce inefficient performance and not the inability to perform.14 When neural systems required for memory or divided attention attempt to perform but are debilitated, other brain systems are recruited in an effort to compensate. However if they too are affected by sleep disruption or hypoxemia, their contributions may be suboptimal. This might account for the increased activation of the prefrontal cortex under conditions of sleep deprivation documented by functional magnetic resonance imaging (fMRI).14 Deficits in performance of OSA patients are explained by impairments of elementary cognitive functions, specifically, sensory transduction, feature integration, or motor preparation and execution, which are required even in simple response-time tasks.41

1200  PART II / Section 13  •  Sleep Breathing Disorders OSA AND PREFRONTAL FUNCTIONING Intermittent hypoxia and hypercarbia

Sleep disruption

Disruption of restorative features of sleep

Disruption of cellular or chemical homeostasis

Prefrontal cortical dysfunction Dysfunction of cognitive executive system Behavioral inhibition

Set shifting

Self-regulation of affect and arousal

Working memory

Analysis/ synthesis

Contextual memory

Adverse daytime effects Problems in mentally manipulating information Poor planning and haphazard execution of plans Disorganization Poor judgment, decision making Rigid thinking Difficulty in maintaining attention and motivation Emotional lability (“mood swings”) Overactivity or impulsivity (especially in children)

Figure 104-4  The proposed prefrontal model. In this model, OSA-related sleep disruption and intermittent hypoxemia and hypercarbia alter the efficacy of restorative processes occurring during sleep and disrupt the functional homeostasis and neuronal and glial viability within particular brain regions, particularly the prefrontal regions of the brain cortex. OSA, obstructive sleep apnea. (From Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002;11:1-16, p 3.)

Magnetic resonance spectroscopy (MRS) studies have shown evidence of brain damage in patients with OSA correlating with the degree of disease severity as measured by AHI.20,42 Compared to MRS studies of healthy persons, the white matter, but not the cortex, of patients with OSA demonstrated decreases in the N-acetylaspartate/ choline ratio, an indicator of cerebral metabolic injury, as well as other signs of neuronal cellular chemical activity. These functional changes occurred despite no obvious structural abnormality as evidenced by a normal MRI.43,44 Frontal lobe white matter lesions have been associated with impaired executive function.44 Cold challenges showed aberrant responses on fMRI in patients with OSA compared to controls in several cortical areas in addition to other brain areas that may reflect neuronal loss in those sites.20,45 Regional volumetric MRI studies showed diminished gray matter loss, often unilateral, in multiple sites including the frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum.46,47 The unilateral loss in adequately perfused areas suggests neural deficits early in the onset of OSA.48 Perturbations in executive function and other cognitive functions associated with the prefrontal cortex may be associated with abnormalities in event-related potentials, indicating dysfunction of this brain region, in patients with OSA.49 Taken together, these findings suggest clear functional abnormalities of wide areas of the brain with less-obvious structural abnormalities.

Figure 104-5  Effects of sleep apnea on brain activation during a working memory task. Pretreatment random effects group activation map of 16 patients with obstructive sleep apnea, contrasted with 10 healthy subjects performing a similar working memory task. Activation in healthy subjects is more extensive, is bilateral, and involves areas well described in the literature: posterior parietal cortex, medial wall in the region of the anterior cingulate cortex, and dorsolateral prefrontal cortex. Sleep apnea patients do not show significant lateral prefrontal activation but do so in left posterior parietal and the medial wall. R, right; L, left. All activations are Bonferroni corrected for multiple comparisons, P < .05. Talairach space z-coordinate is 30. Statistical color scale: red, r = 0.4; yellow, r = 0.8. (From Thomas RJ, Rosen BR, Stern CE, et  al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol 2005;98:2226-34, p 2229.)

Functional MRI studies have shown differential brain activation associated with specific cognitive challenges in OSA patients compared to controls.50,51 Working memory speed was decreased compared to normal participants and associated with an absence of dorsolateral prefrontal activation not related to nocturnal hypoxia as illustrated in Figure 104-5. Performance of a verbal learning task was similar between OSA patients and normal controls, despite task-related increases in brain activation in several brain regions (bilateral inferior frontal and middle frontal gyri, cingulate gyrus, and areas at the junction of the inferior parietal and superior temporal lobes, thalamus, and cerebellum).51 This suggests an adaptive, compensatory recruitment response similar to that seen in young adults following total sleep deprivation.51 Collectively, findings from neuroimaging studies support the notion of OSA-associated neurofunctional impairments chiefly in the frontal lobes and hippocampus, which are consistent with models of central nervous system and cognitive dysfunction in OSA implicating the prefrontal cortex.43 They also indicate the presence of subtle cerebral metabolic insults such as neuronal loss, axonal injury, and gliosis, which have been demonstrated in animal models of intermittent hypoxemia.20,52 Studies have



CHAPTER 104  •  Cognition and Performance in Patients with Obstructive Sleep Apnea  1201

shown that hypoxemia is linked to attention, executive function, perceptual and organizational or motor speed, memory, and verbal fluency3 as well as a relationship between sleep disruption and executive function. Using factor analysis and by comparing the relative contributions of sleep disturbance, hypoxemia, and sleep quality, others have attempted to more directly isolate the mechanisms operative in producing cognitive and neurobehavioral deficits.40 It was hypothesized that a higher premorbid functional level as demonstrated by the higher intelligence provided a protective effect and compensated for the hypoxic brain damage or daytime sleepiness that may be etiologic factors associated with these deficits. This may be an example of cognitive reserve theory, where high intelligence might have a protective effect against OSArelated cognitive decline. A comparison of cognitive and neurobehavioral functioning in patients with chronic obstructive pulmonary disease, who also suffer from hypoxemia, and OSA patients showed that OSA patients were similarly impaired.6,53 Both types of patients showed problems with cognitive processing and memory, indicating a role for hypoxemia, and sleep apnea patients demonstrated more dysfunction on tests of sustained attention, sensitive to sleepiness.53 Other studies have suggested that sleepiness plays an important role in cognitive and neurobehavioral performance.53 These (and other) findings suggest that the small to moderate deficits in cognitive processing and large impairments in objective sleepiness indicate that sleepiness and decrements in performance share a common biological substrate.54 For example, in rodent models of long-term intermittent hypoxemia, the observed increased sleepiness is related to oxidative injuries to the wake-promoting regions of the forebrain.55

EFFECT OF TREATMENT Continuous positive airway pressure (CPAP) remains the primary treatment for OSA. Evaluating the evidence of the effectiveness of treatment on the cognitive and performance impairments exhibited by OSA patients is challenging because of differences across studies and patients with regard to adherence to and duration of therapy as well as study design issues including sample size, types of control populations, and the nature of placebos when they were employed. Response to treatment may be more clearly demonstrated when comparisons are made only in those who manifest deficits in cognitive processing and performance at baseline and in those more adherent to treatment (e.g., use of CPAP for 6 or more hours per night).56 The majority of controlled clinical trials evaluating the efficacy of CPAP treatment have predominantly involved patients with moderate to severe OSA. In these placebocontrolled studies the superiority of CPAP over placebo has not been demonstrated for cognitive functioning, sustained attention, or executive function.57,58 Despite these lack of changes, there was sufficient evidence of improvements in quality of life with CPAP treatment compared to placebo for the American Academy of Sleep Medicine in practice guidelines to recommend CPAP as a treatment option in this context.59

Few studies have examined the utility of CPAP treatment in patients with mild OSA.57 In patients with mild OSA, when comparing 8 weeks of CPAP treatment to conservative therapy, the only aspect of quality of life showing improvement was an increase in vitality.60 The variable results in these studies might reflect the fact that with milder disease severity there is less cognitive impairment and thus less potential for improvement following therapy.36,61 Improvements in cognitive and neurobehavioral performance might also be a function of baseline level of daytime sleepiness.58 Controlled studies that have examined treatment response in patients without subjective daytime sleepiness, but with mild60 or severe62 OSA have not found CPAP superior to conservative therapy60 or sham CPAP62 when looking at quality of life or cognitive outcomes. Several studies have compared the impact of CPAP treatment to other interventions on cognitive and neurobehavioral outcomes.58 Compared to supplemental oxygen, CPAP treatment of patients with moderate to severe OSA produces equivalent positive benefits for enhanced sustained attention and memory, with greater gains for cognitive processing in mild OSA.7 The effect of positional therapy is not different from CPAP treatment on cognitive performance or general health, but CPAP improved energy levels and positional therapy did not.63 Equivocal or inconsistent results regarding the benefit of oral appliances over CPAP or placebo have been shown for indices of quality of life and neurobehavior.64-66 Although there are a dearth of studies, in general, CPAP remains superior to surgery with respect to the outcomes of quality of life and neurobehavioral performance.67

MEDICAL AND LEGAL ASPECTS OF COGNITIVE AND PERFORMANCE DEFICITS The majority of accidental injuries or death can be explained by human error. Inattention or excessively dividing attention between tasks while driving (e.g., using a mobile telephone) is increasingly recognized as a cause of accidents.68 Functional MRI has provided evidence of reduced cortical activity in brain regions associated with driving, while subjects were listening to someone speaking,69 even though the two tasks (driving and auditory comprehension) draw on different and nonoverlapping cortical areas. These results provide neurobiological evidence for distraction creating inattention to a primary task like driving. Clearly, a motor vehicle operator has an obligation to drive safely in order to avoid foreseeable harm to others. However, the courts often agree that the driver is not criminally negligent when falling asleep while driving unless it appears that he or she continued to drive in reckless disregard of warning symptoms. Table 104-2 illustrates the legal consequence of cases of fall-asleep motor vehicle accidents. A recent and notable exception is in New Jersey, where the state enacted Maggie’s Law. Falling asleep at the wheel and fatigued driving now count as recklessness under the existing vehicular homicide law (NJS 2C:11-5). This legislation is the first bill in the United States to specifically address the issue of driving

1202  PART II / Section 13  •  Sleep Breathing Disorders Table 104-2  Case Details of Fall-Asleep Motor Vehicle Accidents OVERNIGHT SLEEP STUDY

MSLT OR MWT

ACCIDENT OUTCOME

LEGAL OUTCOME

REMAINED LICENSED?

OSA and PLMD

With CPAP: AI, 30; AHI, 10; PLMI, 20

MWT20, 4.75 min

2 vehicles, 1 fatality, 2 others injured

No-billed

Yes

OSA and UARS

AI, 41; AHI, 10

MSLT, 9.4 min

2 vehicles, 1 fatality, 2 others injured

No-billed

Yes

CASE

DIAGNOSIS

A

B

C (injured) Sleep deprivation

AHI, 2.4; AHI, 1 MWT40, 40 min

4 vehicles, 5 fatalities, several others

Acquitted

Yes; later withdrawn by RTA and then contested in court

D

OSA

AHI, 30

MWT40, 11 min

6 vehicles, 2 fatalities, 12 others injured

Found guilty, jailed

Yes

E

Idiopathic AHI, 0.4 hypersomnolence

MWT20, 8 min

5 vehicles, 1 fatality, 2 others injured

Pleaded guilty

Yes

F

OSA

AHI, 23

MSLT, 5.5 min

3 vehicles, 2 fatalities

Pleaded guilty, jailed

Yes

G

OSA

AHI, 17

Not 2 vehicles, 1 fatality performed

Found guilty, jailed

Yes; later withdrawn by judge

AHI, apnea–hypopnea index; AI, arousal index; CPAP, continuous positive airway pressure; MSLT, multiple sleep latency test; MWT, maintenance of wakefulness test; MWT20, MWT 20-minute protocol; MWT40, MWT 40-minute protocol; No-billed, not prosecuted; OSA, obstructive sleep apnea; PLMD, periodic limb movement disorder; PLMI, periodic limb movement index; RTA, Roads and Traffic Authority; UARS, upper airway resistance syndrome. Normal values: AHI, 0-5 per hour; AI, 0-10 per hour; MWT20 (sleep onset defined as the first occurrence of one epoch of any stage of sleep in 20-minute protocol), 11-20 minutes; MWT40 (sleep onset defined as three consecutive epochs of stage 1 sleep or any single epoch of another sleep stage in 40-minute protocol), 19-40 minutes; MSLT, 10-20 minutes; PLMI, 0-5 per hour. From Desai AN, Ellis E, Wheatley JR, Grunstein RR. Fatal distraction: a case series of fatal fall-asleep road accidents and their medicolegal outcomes. Med J Aust 2003;178:396-399.

while fatigued, where fatigue is defined as being without sleep for a period in excess of 24 consecutive hours. Other jurisdictions are considering similar legislation. As a result, physicians who believe that a patient is unfit to drive because of sleepiness should inform the patient of this opinion. Those patients who continue to drive and who are believed to be a public health risk should be reported by the physician to the authorities in jurisdictions where they are required to do so. Failure to report such patients can result in personal liability for clinicians. In the 1990s, two Ontario (Canada) Court of Appeal judgments found physicians liable because they had failed to report potentially unfit medical patients to the motor vehicle licensing authorities despite an existing statutory obligation to do so and the patients subsequently had traumatic car accidents.70,71 The courts emphasized the importance of the physicians’ statutory reporting duty to the public. This duty superseded the physicians’ private duty with regard to confidentiality and the dictates of the therapeutic relationship. The courts’ interpretation was a departure from earlier case law. In addition, the courts were unmoved by the physicians’ explanations for their failure to report. It was immaterial that the physicians deemed the medical conditions to be temporary or that they trusted their patients to comply with their medication regimen and instructions against driving. The courts have long recognized civil liability claims and defense for injury caused by loss of consciousness or diminished alertness in transportation-related accidents. Because sleepiness increases periods of inattention, it is not surprising that sleepiness has been linked to accidents on

the road and in occupational settings.72-74 Sleep-related civil liability issues have increased in frequency and complexity, and determining fitness to drive has been problematic for sleep clinicians, particularly in view of the varied laws and jurisdictions. It is therefore important for physicians to fulfill their statutory duties in a diligent yet sensible manner, reporting patients whom they believe have a medical condition that might reasonably make it dangerous to drive, especially where there is a mandatory reporting system. The data for sleep apnea and automobile crashes are numerous and consistent: As a group, OSA patients’ risk of motor vehicle collisions is increased twofold to fourfold (Videos 104-1 and 104-2). Still, not all patients have accidents, and as many as two thirds might never have a collision.75 A means to identify those OSA patients at greatest risk is still not clear based on available literature, and this complicates decision making from a medical and legal perspective. Accordingly, physicians must work to ensure that patients understand the balance between physician’s duty of care to the patient and their statutory duty under the law. They should educate patients about the increased risk of sleepy driving in sleep apnea, pointing out the patient’s civil responsibilities that accompany the privilege of having a driver’s license. Further, by instructing patients in proper sleep hygiene and effective countermeasures to sleepy driving (rest stops, caffeine, napping), physicians begin to modify the risks of drowsy driving. Although it may be argued that mandatory reporting of drivers with sleep apnea will discourage many sleepy drivers from being evaluated for OSA, data supporting this



CHAPTER 104  •  Cognition and Performance in Patients with Obstructive Sleep Apnea  1203

argument are lacking. There are data, however, supporting the concept that effective treatment of sleep apnea will reduce collision risk to normal and reduce health care use.75,76 Although mandatory physician reporting of sleep apnea is not uniform in North America or Europe, there are several efforts under way to increase this.77,78 Therefore, where mandatory reporting is in place, treating patients at the same time as notifying the motor vehicle authorities can discharge the clinician’s statutory duty while still maintaining the patient’s ability to drive and earn a living. This strategy assumes appropriate access to care, which regrettably is not yet universal.79 In situations where there is no mandatory reporting, and in cases where ongoing sleepiness is a major concern, physicians must balance the personal risk of litigation for disclosing private medical information without consent against the risk to public safety.

SUMMARY Patients with OSA demonstrate variable degrees of cognitive and performance deficits. Cognitive and performance deficits are more easily identified in those with more-severe disease. Patients with more-severe disease display deficits in cognitive processing, sustained attention, executive functioning, and quality of life, with mixed findings regarding memory. The mechanisms leading to such deficits with respect to the relative contribution of sleep disruption, hypoxemia, and daytime sleepiness are unclear. Although uncontrolled studies present a convincing picture of the positive impact of CPAP therapy, the benefit of this treatment is less persuasive in controlled trials, particularly those employing a sham placebo. The long-term effectiveness of CPAP with regard to reducing cognitive and performance deficits in patients with mild OSA remains undetermined and needs further exploration. Despite the need for more evidence regarding cognitive and performance deficits in community-acquired samples in sham CPAP–controlled studies, there is sufficient documentation to suggest that untreated and nonadherent patients are at risk for traffic- and occupation-related accidents. Legislation such as Maggie’s Law will increase public awareness of the hazard of driving sleepy. However, it is also the duty of the health care provider to assess the patient for cognitive and performance deficits by asking about performance at work, ability to concentrate, ability to maintain attention, irritability, and difficulties performing everyday tasks. It is the practitioner’s obligation to inform the patient of the risks associated with such deficits, protecting the public through appropriate action until the patient is successfully treated. ❖  Clinical Pearl Sleep fragmentation and hypoxemia due to sleep apnea influences cognitive ability and daytime performance. Awareness of these impairments and prompt treatment will reduce burden of illness on the patient and reduce individual and public risk.

REFERENCES 1. Ulfberg J, Carter N, Talback M, et al. Excessive daytime sleepiness at work and subjective work performance in the general population and among heavy snorers and patients with obstructive sleep apnea. Chest 1996;110:659-663. 2. Ellen RL, Marshall SC, Palayew M, et al. Systematic review of motor vehicle crash risk in persons with sleep apnea. J Clin Sleep Med 2006;2:193-200. 3. Sateia MJ. Neuropsychological impairment and quality of life in obstructive sleep apnea. Clin Chest Med 2003;24:249-259. 4. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239. 5. Guilleminault C, Hoed J, Mitler M. Clinical overview of the sleep apnea syndromes. In: Guilleminault C, Dement W, editors. Sleep apnea syndromes. New York: Allan R Liss; 1978. p 1-12. 6. Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea syndrome? J Sleep Res 2004;13:79-86. 7. Lim W, Bardwell WA, Loredo JS, et al. Neuropsychological effects of 2-week continuous positive airway pressure treatment and supplemental oxygen in patients with obstructive sleep apnea: a randomized placebo-controlled study. J Clin Sleep Med 2007;3:380386. 8. AlGhanim N, Comondore VR, Fleetham J, et al. The economic impact of obstructive sleep apnea. Lung 2008;186:7-12. 9. Mulgrew AT, Ryan CF, Fleetham JA, et al. The impact of obstructive sleep apnea and daytime sleepiness on work limitation. Sleep Med 2007;9:42-53. 10. Ulfberg J, Carter N, Edling C. Sleep-disordered breathing and occupational accidents. Scand J Work Environ Health 2000;26: 237-242. 11. George CF. Driving simulators in clinical practice. Sleep Med Rev 2003;7:311-320. 12. Howard ME, Desai AV, Grunstein RR, et al. Sleepiness, sleepdisordered breathing, and accident risk factors in commercial vehicle drivers. Am J Respir Crit Care Med 2004;170:1014-1021. 13. Dinges D. Probing the limits of functional capability: the effects of sleep loss on short-duration tasks. In: Ogilvie RBR, editor. Sleep, arousal, and performance. Cambridge: Birkhauser-Boston; 1992. p 176-188. 14. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002;11:1-16. 15. Lezak M. Neuropsychological assessment. New York: Oxford University Press; 1995. 16. Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988. 17. Engleman HM, Douglas NJ. Sleep. 4: Sleepiness, cognitive function, and quality of life in obstructive sleep apnoea/hypopnoea syndrome. Thorax 2004;59:618-622. 18. Aloia MS, Arnedt JT, Davis JD, et al. Neuropsychological sequelae of obstructive sleep apnea–hypopnea syndrome: a critical review. J Int Neuropsychol Soc 2004;10:772-785. 19. Alchanatis M, Zias N, Deligiorgis N, et al. Sleep apnea–related cognitive deficits and intelligence: an implication of cognitive reserve theory. J Sleep Res 2005;14:69-75. 20. El-Ad B, Lavie P. Effect of sleep apnea on cognition and mood. Int Rev Psychiatry 2005;17:277-282. 21. Quan SF, Wright R, Baldwin CM, et al. Obstructive sleep apnea– hypopnea and neurocognitive functioning in the Sleep Heart Health Study. Sleep Med 2006;7:498-507. 22. Redline S, Strauss ME, Adams N, et al. Neuropsychological function in mild sleep-disordered breathing. Sleep 1997;20:160-167. 23. Decary A, Rouleau I, Montplaisir J. Cognitive deficits associated with sleep apnea syndrome: a proposed neuropsychological test battery. Sleep 2000;23:369-381. 24. Beebe DW, Groesz L, Wells C, et al. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003;26:298-307. 25. Naegele B, Launois SH, Mazza S, et al. Which memory processes are affected in patients with obstructive sleep apnea? An evaluation of 3 types of memory. Sleep 2006;29:533-544.

1204  PART II / Section 13  •  Sleep Breathing Disorders 26. Daurat A, Foret J, Bret-Dibat JL, et al. Spatial and temporal memories are affected by sleep fragmentation in obstructive sleep apnea syndrome. J Clin Exp Neuropsychol 2007:1-11. 27. Chugh DK, Dinges DF. Mechanisms of sleepiness in obstructive sleep apnea. In: Pack A, editor. Pathogenesis, diagnosis, and treatment of sleep apnea. New York: Marcel Dekker; 2002. p 265-285. 28. Mathieu A, Mazza S, Decary A, et al. Effects of obstructive sleep apnea on cognitive function: a comparison between younger and older OSAS patients. Sleep Med 2008;9:112-120. 29. Powell NB, Riley RW, Schechtman KB, et al. A comparative model: reaction time performance in sleep-disordered breathing versus alcohol-impaired controls. Laryngoscope 1999;109:1648-1654. 30. George CF. Vigilance impairment: assessment by driving simulators. Sleep 2000;23(Suppl. 4):S115-S118. 31. Pack AI, Maislin G, Staley B, et al. Impaired performance in commercial drivers: role of sleep apnea and short sleep duration. Am J Respir Crit Care Med 2006;174:446-454. 32. Saunamaki T, Jehkonen M. A review of executive functions in obstructive sleep apnea syndrome. Acta Neurol Scand 2007; 115:1-11. 33. Verstraeten E, Cluydts R, Pevernagie D, et al. Executive function in sleep apnea: controlling for attentional capacity in assessing executive attention. Sleep 2004;27:685-693. 34. Weaver TE. Outcome measurement in sleep medicine practice and research. Part 1: assessment of symptoms, subjective and objective daytime sleepiness, health-related quality of life and functional status. Sleep Med Rev 2001;5:103-128. 35. Finn L, Young T, Palta M, et al. Sleep-disordered breathing and self-reported general health status in the Wisconsin Sleep Cohort Study. Sleep 1998;21:701-706. 35a.  Stepnowsky C, Johnson S, Dimsdale J, Ancoli-Israel S. Sleep apnea and health-related quality of life in African-American elderly. Ann Behav Med 2000;22:116-120. 36. Engleman HM, Kingshott RN, Wraith PK, et al. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159:461-467. 37. Baldwin CM, Griffith KA, Nieto FJ, et al. The association of sleepdisordered breathing and sleep symptoms with quality of life in the Sleep Heart Health Study. Sleep 2001;24:96-105. 38. Briones B, Adams N, Strauss M, et al. Relationship between sleepiness and general health status. Sleep 1996;19:583-588. 39. Bennett LS, Barbour C, Langford B, et al. Health status in obstructive sleep apnea: relationship with sleep fragmentation and daytime sleepiness, and effects of continuous positive airway pressure treatment. Am J Respir Crit Care Med 1999;159:1884-1890. 40. Naismith S, Winter V, Gotsopoulos H, et al. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol 2004;26:43-54. 41. Lis S, Krieger S, Hennig D, et al. Executive functions and cognitive subprocesses in patients with obstructive sleep apnoea. J Sleep Res 2008;17(3):271-280. 42. Kamba M, Inoue Y, Higami S, et al. Cerebral metabolic impairment in patients with obstructive sleep apnoea: an independent association of obstructive sleep apnoea with white matter change. J Neurol Neurosurg Psychiatry 2001;71:334-339. 43. Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med 2006;2:461-471. 44. Alchanatis M, Deligiorgis N, Zias N, et al. Frontal brain lobe impairment in obstructive sleep apnoea: a proton MR spectroscopy study. Eur Respir J 2004;24:980-986. 45. Macey PM, Macey KE, Henderson LA, et al. Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea. Respir Physiol Neurobiol 2003;138:275-290. 46. Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:1382-1387. 47. Morrell MJ, McRobbie DW, Quest RA, et al. Changes in brain morphology associated with obstructive sleep apnea. Sleep Med 2003;4:451-454. 48. Gale SD, Hopkins RO. Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc 2004;10:60-71.

49. Kotterba S, Rasche K, Widdig W, et al. Neuropsychological investigations and event-related potentials in obstructive sleep apnea syndrome before and during CPAP-therapy. J Neurol Sci 1998;159: 45-50. 50. Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol 2005;98:2226-2234. 51. Ayalon L, Ancoli-Israel S, Klemfuss Z, et al. Increased brain activation during verbal learning in obstructive sleep apnea. Neuroimage 2006;31:1817-1825. 52. Zhu Y, Fenik P, Zhan G, et al. Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci 2007;27:10060-10071. 53. Roehrs T, Merrion M, Pedrosi B, et al. Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD). Sleep 1995;18:382388. 54. Engleman HM, Kingshott RN, Martin SE, et al. Cognitive function in the sleep apnea/hypopnea syndrome (SAHS). Sleep 2000;23(Suppl 4):S102-S108. 55. Veasey SC, Davis CW, Fenik P, et al. Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleepwake brain regions. Sleep 2004;27:194-201. 56. Zimmerman ME, Arnedt JT, Stanchina M, et al. Normalization of memory performance and positive airway pressure adherence in memory-impaired patients with obstructive sleep apnea. Chest 2006; 130:1772-1778. 57. Gay P, Weaver T, Loube D, et al. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep 2006;29:381-401. 58. Giles TL, Lasserson TJ, Smith BH, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006;(3):CD001106. 59. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. Sleep 2006;29:375-380. 60. Redline S, Adams N, Strauss ME, et al. Improvement of mild sleepdisordered breathing with CPAP compared with conservative therapy. Am J Respir Crit Care Med 1998;157:858-865. 61. Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:773-780. 62. Barbe F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 2001;134:1015-1023. 63. Jokic R, Klimaszewski A, Crossley M, et al. Positional treatment vs continuous positive airway pressure in patients with positional obstructive sleep apnea syndrome. Chest 1999;115:771-781. 64. Barnes M, McEvoy RD, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:656-664. 65. Engleman HM, McDonald JP, Graham D, et al. Randomized crossover trial of two treatments for sleep apnea/hypopnea syndrome: continuous positive airway pressure and mandibular repositioning splint. Am J Respir Crit Care Med 2002;166:855-859. 66. Lim J, Lasserson TJ, Fleetham J, et al. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006/(4):CD004435. 67. Sundaram S, Bridgman SA, Lim J, et al. Surgery for obstructive sleep apnoea. Cochrane Database Syst Rev 2005:CD001004. 68. Administration NHTS. Driver cell phone use in 2006; 2007. 69. Just MA, Keller TA, Cynkar J. A decrease in brain activation associated with driving when listening to someone speak. Brain Res 2008;1205:70-80. 70. Wasserman Sv. 13 CCLT (2d) 267 (GD), [1998] OJ No.2470 (CA). 1992. 71. Foster Tv. OJ No.1413 (CA); 1994. 72. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999;340:847851. 73. Lindberg E, Carter N, Gislason T, et al. Role of snoring and daytime sleepiness in occupational accidents. Am J Respir Crit Care Med 2001;164:2031-2035.



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74. George CF, Nickerson PW, Hanly PJ, et al. Sleep apnoea patients have more automobile accidents. Lancet 1987;2:447. 75. George CF. Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 2001;56:508-512. 76. Hoffman B, Wingenbach DD, Kagey AN, et al. The long-term health plan and disability cost benefit of obstructive sleep apnea treatment in a commercial motor vehicle driver population. J Occup Environ Med 2010;52:473-477. 77. Hartenbaum N, Collop N, Rosen IM, et al. Sleep apnea and commercial motor vehicle operators: statement from the joint Task Force

of the American College of Chest Physicians, American College of Occupational and Environmental Medicine, and the National Sleep Foundation. J Occup Environ Med 2006;48:S4-S37. 78. Alonderis A, Barbe F, Bonsignore M, et al. Medico-legal implications of sleep apnoea syndrome: driving license regulations in Europe. Sleep Med 2008;9:362-375. 79. Flemons WW, Douglas NJ, Kuna ST, et al. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med 2004;169:668-672.

Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome Michelle T. Cao, Christian Guilleminault, and Clete A. Kushida Abstract Disorders involving disruption of normal breathing during sleep include obstructive sleep apnea and obstructive sleep hypopnea, grouped under the general term obstructive sleep apnea (OSA) and upper airway resistance syndrome (UARS). Obesity and craniofacial dysmorphism are major risk factors for these syndromes. Polysomnography distinguishes UARS from OSA, with the former characterized by the absence of obstructive apneas and hypopneas, an apnea–hypopnea index (AHI) of fewer than 5 events per hour, and an absence of oxygen desaturation less than 92%. Typical daytime symptoms of OSA include excessive daytime sleepiness, afternoon drowsiness, forgetfulness, impaired concentration and attention, personality changes, and morning headaches. UARS patients typically complain of insomnia and daytime fatigue

Obstructive sleep apnea (OSA) syndrome and the related upper airway resistance syndrome (UARS) are becoming increasingly recognized as leading causes of daytime sleepiness. Together they are referred to as sleep-disordered breathing (SDB). When apneas and hypopneas occur with a specified frequency during sleep and in conjunction with symptoms such as daytime somnolence, the term obstructive sleep apnea is applied,1 rather than the older terminology obstructive sleep apnea–hypopnea (OSAH). Obstructive apnea is defined as complete or nearcomplete cessation of airflow for a minimum of 10 seconds; obstructive hypopnea has been defined differently depending on the author and the type of equipment used to monitor nasal airflow. None of the currently available sleep scoring systems have adequately resolved the controversies surrounding the scoring criteria for an obstructive hypopnea. The American Academy of Sleep Medicine guideline1 for scoring an obstructive hypopnea recommends scoring the event based on the system used to monitor airflow at the nose, and this recommendation is based on consensus rather than objective data. The number of abnormal breathing events during nocturnal sleep is presented as apnea–hypopnea index (AHI), reflecting the number of apneas plus hypopneas per hour of sleep. Due to the variability of what is being measured, the term respiratory disturbance index (RDI) sometimes is used interchangeably and incorrectly with AHI; RDI refers to the number of apneas plus hypopneas plus respiratory effort– related arousals (RERAs) per hour of sleep. Obesity and certain craniofacial features are notable predisposing factors for SDB, and a thorough clinical evaluation can point toward the diagnosis. A definitive diagnosis however, requires the integration of clinical evaluation and an overnight sleep study. Obstructive sleep apnea is characterized by episodes of complete or partial upper airway obstruction during sleep. Upper airway obstruction during 1206

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rather than sleepiness, myalgias (similar to those reported by fibromyalgia patients), migrainelike headaches, postural hypotension, and dizziness. Nocturnal signs and symptoms of OSA and UARS include snoring, snorting, observed apneas, awakening with a sensation of choking or gasping, unexplained tachycardia, restless sleep, sweating during sleep, nocturia, bruxism, and nocturnal gastroesophageal reflux. Insomnia, disrupted sleep, sleepwalking, sleep terrors, and confusional arousals are more commonly expressed by UARS patients. The separation of OSA and UARS as two distinct syndromes is controversial. The important issue is to be aware that in the appropriate clinical context, a symptomatic patient who does not fulfill the diagnostic criteria for OSA might have UARS. None of the symptoms are sufficiently specific to be used as a diagnostic modality.

sleep is a polysomnographic finding. In this chapter we review the clinical features, the pathophysiology of OSA and discuss the current understanding regarding UARS.

EPIDEMIOLOGY OSA was first recognized during polysomnographic monitoring in severely obese patients with the pickwickian syndrome.2 Epidemiologic studies in the United States performed in the 1990s based on the general population or community-based cohorts consisting of primarily white persons between 30 and 60 years of age estimated the prevalence of OSA (defined by AHI ≥ 5) to be 24% in men and 9% in women. When complaints of sleepiness were taken into account, 4% of men and 2% of women had OSAS.3-9 More-recent studies after the explosion of the obesity epidemic in industrialized countries have changed these results. The incidence of OSA in whites in countries affected by the obesity epidemic has reached approximately 8%. Studies in other ethnic groups are also available. In Hong Kong the prevalence in the late 1990s was reported to be similar to the one seen in whites (4.1% in middleaged men and 2.1% in women). A study of Chinese subjects in Singapore reported an estimated prevalence of 15%, and the prevalence was reported to be 7.5% in urban middle-aged Indian men, 4.5% in Korean men and 3.2% in middle-aged Korean women, and 8.8% in Malaysian men and 5.1% in Malaysian women.10-12 The prevalence of OSA increases with aging.13,14 Obesity might also contribute the increased prevalence of OSA. In addition, techniques used to calculate prevalence might play a role in discrepancies between studies. The latest study performed on a representative sample of specific districts in the city of Sao Paulo from 2007 to 2008 is the only study in which more than 1100 participants were monitored with actigraphy for 1 week, underwent 1 night



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of polysomnography, answered multiple questionnaires, and had a complete physical evaluation. This Sao Paulo study examined a sample that is similar to residents from the midwestern United States, in particular with obesity, and found a prevalence for OSA to be about 15%.15 The prevalence of OSA is thus variable depending on geographic location, given that age and the degree of obesity also contribute to the prevalence. In addition, truncal or central obesity is associated with an abnormal adipocyte activity, leading to secretion of various peptides that contribute to metabolic abnormalities. Whether obesity is a comorbid condition associated with OSA or is actually the primary problem and OSA is a consequence of the obesity is still in question. Epidemiologic studies so far have not found complete answers to the questions raised regarding the relationship between obesity and OSA.

DEFINITION OF ABNORMAL BREATHING EVENTS An apnea is defined as complete or near cessation of airflow for a minimum of 10 seconds with or without associated oxygen desaturation or sleep fragmentation (arousal defined by electroencephalography [EEG]),16 although they are both usually present. The definition of a hypopnea is still under debate. Thermistors that monitor change in air temperature are considered less sensitive for detecting airflow compared to nasal cannula pressure transducers that mea­sure change in pressure induced by airflow. The nasal cannula pressure transducer is the recommended equipment used to monitor airflow because it is considered a more accurate indicator of change in the nasal flow curve. The nasal cannula pressure transducer permits inference regarding airway resistance through presentation of the inspiratory airflow wave contour.17,18 Normally, in the absence of upper airway narrowing or obstruction, the inspiratory airflow waveform is characterized by a rounded peak contour. In the setting of increased airway resistance, which is usually associated with increased inspiratory effort, there is a plateau or flattening of the peak or an abrupt decrease immediately following an initial peak in the wave contour. The American Academy of Sleep Medicine (AASM) has recommended that a hypopnea be defined by a 30% or greater reduction in the amplitude of the nasal wave contour from baseline and associated with at least 4% oxygen desaturation from the pre-event oxygen saturation, or a 50% or more decrease in the amplitude of the airflow wave contour from baseline in association with at least 3% oxygen desaturation from the pre-event oxygen saturation, or an EEG arousal. When reading the literature, it is important to recognize that even minor differences in event definitions can have a substantial impact on the study data. For example, using the criteria proposed by AASM in 1999 and 2007, a study comparing the scoring criteria of hypopneas with at least 30% decrease in flow amplitude and EEG arousal, or with at least 3% oxygen desaturation in 35 normal-weight 25- to 48-year-old subjects with suspected abnormal breathing during sleep reported that AHI scores could change from 26.9 ± 7.3 to 6.4 ± 3.1 events per hour of sleep when using EEG arousal versus oxygen desaturation criteria, respectively.19

Certain persons with daytime symptoms similar to those endorsed by OSA patients display a pattern indicating increased inspiratory effort, which, in the absence of the currently defined apneas and hypopneas, still leads to sleep disruption (e.g., arousal or awakening).20 It is believed that the sleep disruptions result in significant daytime symptoms such as excessive fatigue or sleepiness. The increase in inspiratory effort can be detected by esophageal manometry (gold standard) or inferred from the signal provided by the nasal cannula pressure transducer17,18 Esophageal pressure (Pes) provides a reflection of intrathoracic pressure fluctuations associated with breathing efforts. The greater the inspiratory effort, the greater the oscillations in Pes. Normally, the most negative Pes value generated during inspiration (measured from the end of expiration to the most negative pressure during inspiration) is 2 to 3  cm H2O in a small woman and 8 to 9  cm H2O in a healthy large man.21 Three patterns of increased inspiratory effort are recognized by Pes measurements. First, Pes crescendo22 reflects progressively more negative breath-by-breath swings in esophageal pressure terminating either with an alpha wave or a mixture of alpha and beta wave EEG arousal, or with a burst of delta wave activation.23 This entity that is formed by the alpha wave or alpha and beta wave bursts is referred to as a respiratory effort–related arousal.1 Second, a pattern of sustained continuous inspiratory effort is a relatively stable but persistent increase in Pes over time (several epochs) terminated with EEG patterns similar to Pes crescendo. Third, the pattern of Pes reversal is an abrupt drop in the esophageal pressure after a sequence of increased inspiratory efforts, independent of the EEG pattern seen (Figs. 105-1, 105-2, and 105-3).21 Historically, OSA has been defined by the AHI (the average number of apneas and hypopneas per hour of sleep). OSA syndrome is diagnosed when the patient has clinical symptoms and the most common is excessive daytime sleepiness in conjunction with an AHI greater than 5 events per hour. With recognition of the other respiratory patterns with increased respiratory effort, a new index was needed. Hence the RDI was introduced. The RDI is the number of apneas plus hypopneas plus RERAs per hour of sleep. Unfortunately, the terms AHI and RDI are used interchangeably in much of the literature, and it is difficult to assess which abnormal breathing events have been scored.

CLINICAL SIGNS AND SYMPTOMS The bed partner of an OSA patient often witnesses snoring (see Chapter 102), nocturnal snorting and gasping, and apneas.24 Nocturnal (sleep-related) symptoms and signs tend to be more specific for OSA than those expressed during diurnal wakefulness such as excessive daytime sleepiness, which is usually the result of abnormal sleep regardless of the cause. The OSA patient might report symptoms of tiredness, fatigue, or drowsiness rather than overt daytime sleepiness. Nighttime Signs and Symptoms Almost all OSA patients and many UARS patients snore. Snoring can be extremely loud and disruptive. A

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characteristic pattern in OSA is loud snoring or brief gasps alternating with intervals of silence that terminate with a loud snort or gasp reflecting resumption of breathing.24,25 The complaint of snoring often precedes the complaint of daytime sleepiness, and the intensity increases with weight gain and bedtime alcohol intake. Snoring can be a factor in marital discord; in one study, 46% of patients slept in separate bedrooms from their partners.24 Even though snoring is an important clue, the absence of its report does not exclude the presence of OSA. Pregnancy is associated with an increase in snoring due to the upward displacement of the diaphragm (which reduces lung volume and its stabilizing effect on the upper airway) and nasopharyngeal edema (see Chapter 101). Although up to 30% of pregnant women snore, overt OSA is uncommon. Chronic snoring is seen in 5 to 8% of all pregnant women (including those with preeclampsia). However, the relationship between OSA and preeclampsia is still unclear at this time. To date, despite preliminary data associating the development of early hypertension in

pregnant patients with SDB, no direct linkage has been demonstrated.26-30 Observed apneic episodes are reported by about 75% of bed partners.31 Persistent chest movements can usually be observed during periods of obstructive apneas. Observing apneic periods can cause the bed partner considerable anxiety, and many respond by shaking the patient for fear that breathing might not resume. Apneic episodes are usually terminated by gasps, chokes, snorts, vocalizations, or brief awakenings. Bed partners report a sudden cessation of snoring followed by a loud snort and resumed snoring. Although some patients awaken with a sensation of having stopped breathing, most are unaware of the apneas. A sensation of choking or dyspnea that interrupts sleep is reported by 18% to 31% of patients.24,32,33 On the other hand, particularly in the elderly, there is awareness of frequent unexplained awakenings, and this group tends to complain of insomnia and unrefreshing sleep. About half of OSA patients report restless sleep (tossing and turning) and diaphoresis, usually localized to the neck



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Figure 105-2  Continuous flow limitation indicated by nasal cannula–pressure transducer recording (channel 6 from top) but not reaching the criterion for hypopnea (i.e., decrease of flow by 30% from prior unobstructed recording) and leading to continuous increased effort (indicated by esophageal pressure [Pes] recording) (bottom channel) in an intermittent snorer with complaint of insomnia and fatigue. Note that the Pes reaches 10 cm H2O at peak end inspiration with each breath; there is no crescendo pattern but a continuous maintenance of the same amount of effort during the first part of the segment. When the patient has normal breathing in other parts of the recording, the Pes oscillates to a peak negative inspiratory Pes of −3 to −4 cm H2O. This is the normal respiratory effort during sleep for this subject. Note that there is minimal SaO2 change (1%) in this 60-second segment (channel 5 from top). In the last third of the recording (right) there is a short respiratory noise, not preceded by any prior snoring (microphone channel 4 from top) and an abrupt decrease in effort indicated by a less-negative peak Pes (Pes reversal). The nasal cannula, channel 6 from top, indicates a better nasal flow. Visual scoring of sleep performed at slower speed (30-second epoch) does not show presence of an electroencephalogram (EEG) arousal of 3 seconds or longer, but a high-amplitude slow wave is noted concomitant with the Pes reversal. Channel labeling from top to bottom: EEG with monopolar derivation, right eye lead (electrooculogram), chin EMG (electromyogram), microphone to record snoring, nasal cannula to record pressure fluctuations at the nose to reflect airflow, chest movement, abdominal movement, and esophageal pressure.

and upper chest area (Video 105-1).32,33 These symptoms are probably related to increased breathing effort during periods of upper airway obstruction. Bed partners readily attest to excessive body movements because movements can at times be violent. Bed covers may be noted to be disheveled the morning. During episodes of upper airway obstruction, progressively more vigorous inspiratory efforts lead to more negative intrathoracic pressure swings, with an increase in venous return to the right ventricle. Large negative intrathoracic pressure swings can also adversely affect left ventricular function. These circumstances can increase pulmonary capillary wedge pressure and contribute to the sensation of dyspnea.34 Because nocturnal dyspnea can also occur in patients with congestive heart failure (paroxysmal nocturnal dyspnea) in the absence of SDB, it is important to inquire about other symptoms in order to distinguish heart failure from OSA.35 However, it is not unusual for the two disorders to coexist. In our

experience, nocturnal dyspnea due to OSA usually resolves quickly upon awakening, whereas the paroxysmal nocturnal dyspnea that is characteristic of congestive heart failure takes much longer to resolve. Complaints that suggest nocturnal gastroesophageal reflux and to a lesser degree diurnal gastroesophageal reflux (e.g., heartburn) are often expressed by OSA patients. Vigorous respiratory efforts by the patient during periods of apnea and hypopnea result in greater negative intrathoracic pressure swings during inspiratory efforts while there is relatively increased intraabdominal pressure during expiration (measurements of abdominal muscle activity in have shown that there is an active participation of abdominal muscles during expiration in many OSA subjects). Reflux results when an increased gradient between intra-abdominal and intrathoracic pressures favors the movement of gastric contents cephalad into the esophagus. In our experience and that of others, reflux can lead to laryngospasm.36

1210  PART II / Section 13  •  Sleep Breathing Disorders

C3-A2 ROC-A1 Chin EMG MIC 89.1

89.0

88.9

88.9

88.9

89.1

90.0

SpO2

90.1

89.9

89.8

88.9

88.9

88.8

88.8

89.0 90.0 Min 88.7

Cannula Airflow Chest Abdomen PES

0 cm H2O –10 –20 –30

–9.8

Figure 105-3  Example of a continuous sustained effort. This recording is from a man with continuous snoring and absence of apneas. With normal breathing respiratory effort measured by esophageal pressure, recording is a maximum of 9 cm H2O. As can be seen with obstructed breathing, the patient presents a mild change in the nasal cannula–pressure transducer curve (channel 6 from top), but the respiratory effort is greatly increased as demonstrated by the peak end inspiratory pressure (Pes) (channel 10 from top). There is maintenance of the same amount of effort during the entire sequence of increased respiratory effort. The sequence lasted 3 minutes 46 seconds. There is no indication of change of electroencephalogram (EEG) in the 60 seconds presented here and thereafter. The termination of the sequence was indicated by a burst of delta waves. Channel labeling from top to bottom: EEG with monopolar derivation, right eye lead (electrooculogram), chin EMG (electromyogram), microphone to record snoring, nasal cannula to record pressure fluctuations at the nose to reflect airflow, chest movement, abdominal movement, and esophageal pressure.

Untreated reflux can make patients more susceptible to nocturnal aerophagy when treated with nasal continuous positive airway pressure (CPAP).37 Nocturia is relatively common in patients with OSA: 28% of patients report four to seven nightly trips to the bathroom.38 OSA can be an independent cause of frequent urination during sleep in elderly men, and patients might initially consult urologists and attribute their disrupted sleep to repeated nocturia.39 CPAP can significantly decrease the frequency of nocturia and improve quality of life.40 Rarely, an adult patient complains of enuresis. Increased intraabdominal pressure, confusion associated with arousals, and increased secretion of atrial natriuretic peptide40 are proposed contributors to nocturia and enuresis. About 74% of patients with OSA report dry mouth and the desire to drink water either during the night or in the morning.24 On the other hand, about 36% of patients with OSA complain of drooling. These symptoms are useful indicators of evidence for SDB, particularly in premenopausal women, who often have more limited and atypical clinical presentations.41 Dry mouth and drooling are most likely due to mouth breathing during sleep, which is com-

monly seen in patients with OSA. OSA is also commonly associated with nocturnal bruxism.42 Daytime Signs and Symptoms Daytime sleepiness or fatigue is the most common complaint in patients with OSA.24,31,32 The manifestations of sleepiness can have subtle consequences (midafternoon drowsiness during a group meeting or an occasional nap), severe consequences (falling asleep while eating or talking), or catastrophic consequences (falling asleep while driving) (see Video 104-1). In general, it is not normal to feel sleepy immediately after a meal or while watching television. Such drowsiness usually indicates some degree of sleep deprivation or fragmentation, and OSA may be the underlying factor. It is essential to inquire about sleepiness while operating a machine or motor vehicle because of the increased risk of accidents7-9,24,31-33,43-47 and concern regarding bystanders’ safety. In the sleep laboratory, pathologically short sleep latency, objectively assessed by the maintenance of wakefulness test, is associated with impaired driving in a simulator environment.45 Driving tests and simulations have shown that OSA patients might not be aware of their



CHAPTER 105  •  Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance  1211

degree of impairment while driving. Clinical evidence for impaired driving ranges from subtle to dramatic; some drivers recall an occasional honk from the car behind alerting them to the changing of traffic light; others report routinely rolling down the window or drinking coffee to stay awake,45 and others report falling asleep while in motion, resulting in riding on the berm or a crash. Some pathologically sleepy patients deny any problems with driving due to fear of restriction on their license. Studies have shown that there is a correlation between the Maintenance of Wakefulness Test (MWT) and the risk of impaired driving in OSA patients.46,47 However, one of the same studies showed that OSA patients with mildly abnormal results in the MWT had no driving impairment.47 Causes of sleepiness in OSA patients are multifactorial. Nocturnal disruption may be secondary to repetitive abnormal breathing events leading to arousals or complete awakenings in the middle of night or to early morning awakenings, with subsequent complaints of insomnia and reduced total sleep time. Mood disorders that are associated with disturbed nocturnal sleep can coexist with OSA. OSA and obesity often coexist, and whereas the former is associated with increased sleepiness, obesity per se has also been associated with sleepiness. In this regard, obesity may be responsible for the residual sleepiness that has been reported in obese patients who are otherwise appropriately treated for OSA with nasal CPAP.48 In a large survey of clinic patients, Stoohs and colleagues49 found that UARS patients had worse morning performance on the psychomotor vigilance task (PVT) compared to OSA patients who had apneic events that were longer in duration than the flow-limited events leading to sleep disturbance in UARS patients. Obstructive events may terminate with only increased delta on EEG rather than an EEG arousal.23 A study examining noise-induced brainstem activation versus EEG arousal during one nocturnal sleep period during which there were about 200 stimulations showed that the MSLT and PVT were impaired only when EEG arousals were present and not when brainstem activation was induced.50 Studies of sleep restriction lasting 1 week or longer have shown that responses were very different across subjects.51 It is postulated that genetic differences might explain why some subjects are more susceptible to nocturnal sleep disruption and restriction than others. While sleepiness might not be directly perceived by patients, they may complain of “tiredness” or “fatigue.” When asked to rest in a seated position with muscles relaxed to see if the feeling of fatigue could be improved, subjects denied improvement and differentiated between exercise-related fatigue and an overall feeling of fatigue. Subjects also complained that they experienced “lapses” while driving or performing monotonous tasks and reported lack of memory intermittently for a limited time period.45,47 Moreover, rather than, or in addition to sleepiness, patients may report cognitive dysfunction such as concentration, attention, memory, or judgment difficulties affecting their job performance (see Chapter 104). These complaints were most common in premenopausal women with a low AHI (mean, 13 events per hour of sleep) or UARS patients.41 In men performing manual work requiring attention and dexterity, unexplained periods of clumsi-

ness were mentioned in association with concentration difficulties. These issues may be sufficiently substantial that job performance or even the ability to maintain employment is adversely affected. Simple reaction time tests (such as the PVT) are affected, with slowing of response time and increasing frequency of erroneous responses. Neurocognitive functions have been investigated and results have shown that specific tests involving the prefrontal cortex may be affected by OSA, probably as a result of sleepiness. Most patients seem to respond favorably to treatment with nasal CPAP, with return to normal performance. However, some patients still complain of symptoms despite appropriate nasal CPAP use, and these patients need further investigation into the cause of their cognitive dysfunction. As is the case with the individual propensity to daytime sleepiness, it is not clear why some patients are more susceptible to cognitive dysfunction. Genetic influences might play a role; as an example, the APOE4 gene that is associated with neurodegenerative disorders has been clearly identified in OSA patients (see Chapter 103).52 However, the APOe-4 gene may not be directly linked to OSA specifically but may be a gene that favors neurodegenerative disease secondary to several different types of central nervous system insults. It is possible that specific genetic susceptibilities favor persistent neurocognitive dysfunction when exposed to an environmental condition such as OSA. Premenopausal women with a low AHI or UARS might have symptoms similar to attention-deficit/ hyperactivity disorder (ADHD), and may have received a mistaken diagnosis of adult ADHD.41 Personality changes including aggressiveness, irritability, anxiety, or depression may be observed. Treatment with continuous positive airway pressure (CPAP) has been shown to improve symptoms such as depression and fatigue.53,54 In our experience, a third of the patients report decreased libido or impotence that tends to improve with treatment. In addition, about 75% of OSAS patients with erectile dysfunction who have been treated with nasal CPAP report disappearance of difficulties with erection or ejaculation, resulting in significantly improved quality of life.55 Morning or nocturnal headaches are reported in about half of the patients and are often described as dull and generalized.56 Headaches usually last 1 to 2 hours and can prompt the ingestion of analgesics. A study from a clinic specializing in headaches found OSA to be the main cause of nocturnal or morning headaches.56 None of these patients had been previously investigated for OSA. Nocturnal headaches were controlled by OSA treatment.57 It is unlikely that all of these signs and symptoms will be reported by one person. There is a notable lack of specificity for most of these symptoms, and they overlap with other disorders such as depression or hypothyroidism.58 In many patients with depression, the presence of daytime sleepiness should prompt a sleep study to rule out coexisting OSA. With respect to thyroid abnormalities, one study detected hypothyroidism in 3 of 103 patients (2.9%) with OSA versus 1 of 135 control subjects (0.7%),59 and this difference was not significant. The authors concluded that routine thyroid function testing is not indicated in the absence of signs or symptoms of hypothyroidism,

1212  PART II / Section 13  •  Sleep Breathing Disorders

although an exception can be made for high-risk groups such as women older than 60 years.

UPPER AIRWAY RESISTANCE SYNDROME There is controversy regarding the classification of UARS separately from OSA, and the current International Classification of Sleep Disorders (2005) classifies UARS under OSA. Considering the multiple definitions regarding what constitutes a hypopnea, this leaves a number of patients with abnormal breathing during sleep who are undiagnosed and untreated. UARS has traditionally been diagnosed when the AHI is fewer than 5 events per hour, and the simultaneously calculated RDI is often, but not necessarily, more than 5 events per hour, the difference due to RERAs being included in the RDI. Hence, RERAs, including the phase A2 of the cyclic alternating pattern scoring system,60 are considered the diagnostic hallmark of UARS.20 The use of the nasal cannula pressure transducer and the esophageal pressure has allowed better recognition of the AASM-defined hypopneas. In light of recent studies showing that UARS has features that differ from OSA61-63 and with the availability of better sensors to monitor nasal flow, establishing the criteria for the diagnosis of UARS has become more significant.17 The definition of UARS has been elaborated upon, with emphasis on the differences among flow limitation, hypopnea, and apnea.64 The lowest oxygen saturation (>92%) during sleep that is acceptable for a diagnosis of UARS is now a part of the definition. The rationale behind these refinements for the definition is that it is important to differentiate what is related to an upper airway problem from SDB, and what is related to abdominal obesity that may be the cause of oxygen desaturation (the chest bellow in particular during physiologic REM sleep atonia is one example). In the latest definition64 an apnea is not seen and oxygen saturation is greater than 92% at termination of an abnormal breathing event. The abnormal breathing event does not meet criteria for a hypopnea, currently defined by AASM with duration of 10 seconds and a drop in amplitude of nasal flow of at least 30%, but it is associated with the presence of well-defined cyclical alternating patterns (CAPs)65 associated with EEG changes or alpha EEG arousal.1 Although symptoms of OSA can overlap with UARS, some important differences have been noted.66 Several studies have indicated that chronic insomnia tends to be much more common in patients with UARS than in those with OSA.41,61,67-69 Many UARS patients report nocturnal awakenings and find that it is difficult to return to sleep. Sleep-onset insomnia and sleep-maintenance insomnia have been reported in UARS. In younger subjects, parasomnias are more commonly reported.70,71 The most common parasomnia is sleepwalking, with or without sleep terrors. Sleep studies performed in persons with UARS and parasomnias show an increase in CAP (phases A2 and A3 CAP rate) indicating NREM sleep instability.71 The treatment of UARS usually eliminates parasomnias and abnormal CAP rates, a response not seen with pharmacologic and psychiatric treatment of the parasomnias in these subjects.70 Patients with UARS are more likely to complain of daytime fatigue rather than sleepiness, with abnormal

ratings in fatigue scales when compared to a normal range in response to the Epworth Sleepiness Scale (ESS).72,73 Postmenopausal women with UARS have higher fatigue scale scores than premenopausal women. Treatment of UARS returns these abnormal scores to normal range.67,74 Referrals for evaluation of abnormal breathing during sleep have also come from Rheumatology Clinics where subjects were seen for chronic fatigue and chronic myalgias. Polysomnography has shown that in these cases the presence of UARS and subsequent treatment is associated with the disappearance of these rheumatologic complaints.74 About half of UARS patients complain of cold hands and feet, usually during teenage years, and about a third have lightheadedness upon standing or bending abruptly. This latter complaint may be related to the observation that systolic blood pressure less than 105  mm  Hg and often below 90  mm  Hg is more often associated with UARS75 than with OSA, which is commonly associated with hypertension.76 Similarly, autonomic responses to abnormal breathing as seen in UARS, compared to OSA patients, showed a dominance of vagal responses in the UARS abnormal breathing pattern compared to a more dominant sympathetic response in OSA patients.75,77,78 This difference is not surprising because sympathetic activation is commonly secondary to hypoxemia and repetitive arousals, which is much less common in UARS than in OSA. Quantitative EEG analyses have shown that compared to age-matched OSA, UARS patients have different EEG spectra during the night and also a different CAP rate (an abnormal increase in phase A2 CAP rate) at visual scoring, which indicates more sleep disturbances compared to OSA subjects.65,79-81 The cyclic alternating pattern scoring system visually scores an arousal pattern (phase A2) that is not included in the two other international sleep scoring manuals, and computerized EEG analysis is better at detecting EEG frequency changes and arousals compared to visual scoring. Both techniques were concordant in showing a different sleep-disturbance pattern in UARS than in OSA. Studies have compared responses to autonomic stimulation and investigation of sensory inputs from the pharynx during nocturnal sleep in patients with UARS and patients with mild OSA. Investigation of palatal sensory response by the two-point discrimination test showed that responses were similar in UARS subjects and control subjects, and the test was significantly different, with demonstration of sensory impairment in OSA patients.82,83 The patency of the upper airway is related to the balance between negative transpharyngeal pressure during inspiration and a counteracting dilating force due to the contraction of the upper airway dilating muscles as well as mechanical forces associated with diaphragm descent and increasing lung volume.84,85 The reflexes involved in this activity are mediated at least in part through receptors embedded in the pharyngeal mucosa. Signs of local nerve lesions have been demonstrated in the pharyngeal mucosa in patients with OSA. The presence of local polyneuropathy83,86,88 has been well demonstrated using electrophysiology, histology, electron microscopy, histochemistry, and evoked potentials responses. However, a systematic search for local neuro-



CHAPTER 105  •  Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance  1213

logic lesions (local polyneuropathies83,86,88) in the upper airway is not a part of the systematic examination of patients with SDB despite demonstration of their existence and the development of a commercially available air-jet device in Europe to evaluate pharyngeal sensitivity.89 The authors who support a distinction between UARS and OSA base the difference in part on the clinical presentation and in part on the presence or on the decrease or absence of local sensory input due to local nerve lesions.82-83,86-88 Further efforts are required to evaluate them in a systematic fashion because this can have an impact on therapeutic indications, particularly soft palate surgery. Follow-up of untreated UARS patients for about 5 years has shown persistent complaints of insomnia associated with depressive mood and increased use of pharmacologic treatment (hypnotics and antidepressants). Patients with UARS who became overweight during the follow-up period were also subsequently found to have OSA and greater oxygen desaturation on follow-up polysomnography. As further studies are conducted on UARS, its relation to OSA will become clearer. For now it is important to know that the treatment options available to patients with UARS are similar to those for OSA patients, with more patients considering upper airway surgery (nasal surgery, pharyngoplasty with or without adenotonsillectomy) and dental appliances rather than nasal CPAP. Unfortunately, many UARS patients remain untreated and continue to experience worsening symptoms of insomnia, fatigue, and depressed mood.63

RISK FACTORS The presence of certain risk factors can strengthen the clinical suspicion of OSA. The strongest risk factors are obesity and age older than 65 years (Video 105-2). In one study, a body-mass index (BMI) of at least 25  kg/m2 had a sensitivity of 93% and a specificity of 74% for OSA.90 With the obesity epidemic increasing in industrialized countries, there is an ongoing evaluation regarding the association between OSA and android-type obesity (fat deposition predominantly in the neck and abdomen, in contrast to the gynecoid-type obesity with fat deposition in hips and legs). The question that is raised by the coexistence of OSA and obesity confounds assessment of the independent contribution of OSA to many associated health-related conditions. OSA as a comorbid condition of obesity is an important issue to consider because many of the clinical associations seen in overweight subjects who also have OSA could be the direct consequence of the weight problem rather than a result of upper airway narrowing. The association between android-type obesity and OSA leads to male gender being a risk factor for OSA. In community-based studies, the male-to-female ratio for OSA is 2-3 : 1, whereas in clinic-based studies the ratio is increased to 10-90 : 1. The risk for OSA in women increases with obesity and after menopause.91-93 This ratio might not be applicable to UARS patients, in whom, in our experience, the ratio is closer to 1 : 1. Most studies on postmenopausal women treated with hormone replacement therapy have not demonstrated significant improvement in OSA risk compared to those untreated.

A positive family history increases the risk of sleepdisordered breathing by twofold to fourfold.94-95 Firstdegree relatives of OSA patients have a 21% to 84% chance of having SDB compared with 10% to 12% of control subjects.94-95 This genetic predisposition is likely to be expressed through craniofacial anatomy that predisposes subjects to OSA, although the genetic predisposition for obesity has also been considered a potential heritable pathway for OSA (see Chapter 103). The craniofacial features that augment the risk for OSA include a high and narrow hard palate (i.e., abnormal nasomaxillary complex development), an elongated soft palate, a small chin, and an abnormal overjet (i.e., the distance between upper and lower incisors—a dental pattern indicating an abnormal growth pattern of the maxilla or mandible, or both) and can be passed on from parent to child. The anatomic features can become more pronounced as the child grows, especially if the growth period is interrupted by repetitive bouts of allergies, upper respiratory tract infections, and development of mouth breathing. Mouth breathing can contribute to the enlargement of tonsils, which is a common finding in childhood OSA.96 The lack of recognition and treatment for causes of childhood OSA may be the factor behind the clinical complaints of young adults. Several studies have shown that SDB is exacerbated by alcohol ingestion, especially around bedtime.97-98 Alcohol ingestion reduces the activity of the genioglossus muscle and other upper airway dilator muscles, and this can predispose to upper airway collapse and apneas. Additional risk factors include ethnicity (African Americans, Mexican Americans, Pacific Islanders, and East Asians99-102), disorders of craniofacial abnormalities such as Marfan syndrome, Down syndrome (Video 105-3), the Pierre-Robin syndrome, and other congenital craniofacial anomalies.103-104 Isolated studies have implicated tobacco use105 and a low vital capacity on pulmonary function testing as independent risk factors for SDB; however, currently there are insufficient data to include them as part of the accepted risk factors for OSA. Sleep-disordered breathing may be aggravated by certain factors such as sedatives, sleep deprivation, and supine posture.106 Respiratory allergies and nasal congestion can also aggravate snoring and SDB. Lesions caused by sensory impairment to the afferent sensory input (diabetes, chronic uremia, dysautonomia)107-108 can delay compensation to abnormal airway narrowing and can worsen or even lead to OSA. Further studies investigating the role of the autonomic nervous system impairments that are due to specific clinical syndromes are needed to confirm the currently available data in these regards. All of these factors should be identified during the initial clinical evaluation.

CLINICAL EXAMINATION A complete physical examination is required when assessing a patient with suspected OSA and UARS. Patients should be screened for other comorbidities including hypertension and signs of heart failure. Special attention however, must be given to the evaluation of body habitus and the upper airway.

1214  PART II / Section 13  •  Sleep Breathing Disorders

Obesity and Neck Circumference Height and weight, BMI, and neck circumference should be determined in every patient. Neck circumference has been reported to correlate better with the presence of obstructive apnea than BMI, and a circumference greater than 40 cm should lead to questions regarding presence of SDB. Katz and colleagues109 reported that the average neck circumference (measured at the superior border of the cricothyroid membrane with the patient in the upright position) was 43.7 ± 4.5 cm (mean ± SD) in patients with OSA and 39.6 ± 4.5 cm (mean ± SD) in patients without OSA (P = .0001). Another study found a correlation between neck circumference and the severity of OSA.110 In their morphometric model of OSA, Kushida and colleagues111 evaluated 423 patients referred to their sleep disorders clinic for suspected sleep-related breathing problems and observed that neck circumference at least 40 cm has a sensitivity of 61% and a specificity of 93% for OSA regardless of the patient’s sex. Upper Airway The purpose of the upper airway examination is to identify structures or abnormalities that potentially can narrow the airway and increase resistance in airflow during sleep, thus reflecting a risk for OSA. Some clinical indices suggesting the presence of OSA include retroposition of the mandible, a cranial base flexure with nasion-sella-basion more acutely flexed than expected, and displacement of the hyoid bone. The upper airway examination can also provide guidance in therapeutic decision making by providing insights into the possible outcome of specific interventions or suggesting benefit from specific combinations of treatment modalities, such as addressing nasal obstruction with septoplasty or radiofrequency treatment of inferior turbinates in a patient who is suboptimally treated with nasal CPAP. The patient should preferably be examined in both the seated and supine positions because the supine position can provide a relatively better reflection of the anatomy during sleep. The presence of retrognathia and dental overjet (a forward extrusion of the upper incisors beyond the lower incisors) should be identified. Analyzing the relative position of teeth on the maxilla and mandible helps classify a subject with a prognathic, orthognathic, or retrognathic mandible. The retrognathic mandible engenders risk of a narrow upper airway behind the base of the tongue. Craniofacial dysmorphism or disproportionate craniofacial anatomy leading to deficient maxilla or mandible (or both) that predisposes a patient to OSA can result from delayed growth of the maxilla or mandible, or both, narrowing the caliber of the upper airway and producing maxillary flattening or retrognathia.111 Dental malocclusion and overlapping teeth are indicators of a small oral cavity leading to tongue malposition, and dislocation of the temporomandibular joint during mouth opening can also contribute to an airway that is predisposed to collapse during sleep. Questions regarding the dental history during teenage years to early 20s and examination of teeth can provide further information. For example in a general population study, OSA has been found to be the most common association with bruxism, and signs of dental clenching and grinding can be noted.

Figure 105-4  Photograph of high arched palate.

The presence of bruxism should alert the clinician to the possibility of undiagnosed OSA. The role of bruxism in OSA is currently the subject of investigation, with the hypothesis that it may be a defense mechanism against repeated occlusion of the upper airway. Extraction of wisdom teeth early in life is usually to address impaction related to a small maxilla or mandible, which is a risk factor for a narrow upper airway. Therefore, a positive history of wisdom teeth removal in earlier years should again alert the clinician to the presence of OSA. The oropharynx should be examined for the presence of an abnormally large tongue or macroglossia, which can narrow the upper airway and predispose to airway obstruction during sleep. A visual estimate of the space between the back of the tongue and the posterior pharyngeal wall should be made because the retroglossal area is a common site of airway obstruction during sleep. The distinction between true macroglossia as opposed to a small oral cavity with relative macroglossia (in reality, a normal tongue size but deceptively large due a small oral cavity) can be difficult. The uvula and soft palate should be assessed for size, length, and height. These soft tissues represent the anterior limit of the upper airway. A small airway diameter increases the suspicion of greater susceptibility to collapse during sleep. The soft palate examination must always be coupled with an evaluation of the hard palate (Fig. 105-4) because the positions of the soft and hard palates are influenced by development of the maxilla early in life, and any abnormality suggests increased risk of oropharyngeal narrowing or collapse during sleep. Edema or erythema of the uvula can indicate repetitive vibratory trauma from chronic snoring. A low-lying redundant soft palate and uvula are commonly seen in patients. Accurate visualization of this area however, can require fiberoptic nasopharyngoscopy. When this procedure is performed in an awake patient, the mechanics of airway obstruction can be completely different from



CHAPTER 105  •  Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance  1215

those during sleep. Nasopharyngoscopy can be performed during the Müller maneuver, in which patients make a sustained inspiratory effort through an occluded mouthpiece with nostrils occluded to achieve a maximum pressure of −25 cm H2O within the upper airway (pressure is measured on the patient’s side of the occluded mouthpiece). This assessment is done to simulate conditions promoting upper airway obstruction during sleep and identifying regions of consequent narrowing or collapse. Fiberoptic examination is useful because it helps to estimate upper airway size in the supine position (in an awake patient) and serves as preoperative assessment for better visualization of potential sites of obstruction before surgical procedures for OSA such as palatopharyngoplasty or maxillomandibular advancement surgery. It is a relatively safe procedure done in the office setting with short-acting nasal local anesthesia. Somnonasopharyngoscopy employs sedation, such as propofol, to induce artificial sleep during endoscopy. Performed with and without simultaneous video recording, this procedure has been reported to be better at localizing regions of collapse in the upper airway. However, this requires specific precautions to ensure patient safety. Additionally, physiologic studies have demonstrated that anesthetics (including local anesthetics) per se, when applied to the upper airway mucosa influence sensory inputs that are involved in maintaining airway patency and timing of upper airway dilators thereby confounding the interpretation of the results. Clinical scores have been useful for standardizing an oropharyngeal clinical evaluation. The most commonly used is the Mallampati scale.112 As initially described, the evaluation is performed by visualizing the oropharynx with the mouth widely open and the tongue protruded. A modified Mallampati technique is performed with the mouth open and without protrusion of the tongue.113 In both cases, the respective positions of the soft palate, the tip of the uvula, the lateral tonsillar pillars, and the tongue are noted. The degree of oropharyngeal crowding is assigned a score between 1 and 4: 1 reflects an unobstructed, wide open oropharynx, with the uvula clearly above the tongue; 2 indicates visible pillars and part of the inferior segment of the uvula; 3 marks a much more limited visualization of the oropharynx, with the base of the uvula barely visible; and 4 indicates a very crowded oropharynx, with only the hard palate visible because the uvula is entirely masked by the tongue. Scores of 3 and 4 have been associated with a difficult intubation and usually imply an abnormally small oropharynx. Tonsils may be graded using the Friedman scale from 0 to 4, with 0 indicating complete absence of the tonsils and 4 indicating kissing tonsils that completely obstruct the oropharynx. It is a common finding to see hypertrophied tonsils in children with OSA. Hypertrophied tonsils are rarely seen in adults. The nose should also be closely examined for collapsibility of nasal valves, size and asymmetry of nares (Fig. 105-5), septal deviation, evidence of trauma, or enlarged inferior nasal turbinates that can lead to nasal obstruction and high nasal resistance to airflow. Although nasal obstruction alone is rarely the primary cause of OSA, it can contribute to increased airway resistance (increased

Figure 105-5  Abnormal nasal anatomy in a patient with upper airway resistance syndrome. Note the deviation of the septum, the asymmetrical size of the nares, and the collapse of the nasal external valves.

nasal airflow resistance plays a major role in mouth breathing in children, with secondary impact on craniofacial growth) and may be a more significant factor in patients with UARS. Kushida and colleagues111 described four measurements that characterize a narrow upper airway: palatal height, maxillary intermolar distance, mandibular intermolar distance, and overjet. Use of scales such as the Mallampati scale112 (developed to assess the likelihood of a difficult airway intubation) has been described to help predict the likelihood of OSA. Whether a scale is being used or not, routine visual examination of the upper airway in patients with and without SDB will quickly familiarize the clinician with the typical appearance of the narrow upper airway (see Fig. 105-4) where a high and narrow hard palate and overjet is seen. Figure 105-5 shows an abnormal nose in a patient with UARS. Gender Despite recognition that OSA is a prevalent disorder, the prevalence specifically in women was for a notable period incompletely examined.22 In the 1980s, rare reports of OSA in women emphasized obesity and that women were much more overweight compared to men for a similar AHI.92 This was later confirmed by the Wisconsin Sleep Cohort study.5 In a case-control study of 334 women between 30 and 60 years of age with SDB, the authors reported a significant difference in the duration of symptoms (mean, 9.7 years) associated with SDB and appropriate referral and diagnosis, compared to 100 men of similar age with SDB.22 This difference between men and women disappeared when BMI was greater than 30  kg/m2. In a large cohort, Young and colleagues6 found that women with an AHI more than 15 events per hour have symptoms similar to those of men with the same degree of apnea severity consisting of snoring, snorting, daytime sleepiness, and breathing pauses.

1216  PART II / Section 13  •  Sleep Breathing Disorders

Several authors22,41,114 have indicated that many women have symptoms of UARS and an AHI less than 5. There is a discrepancy between the recognition of SDB in women in the clinical setting versus in large cohorts or the general population. This is most likely due to the lack of recognition of specific symptomatology with which UARS patients present in conjunction with a low AHI, or evidence of increased upper airway resistance with associated arousals on polysomnography, that are not given proper pathologic significance in this context. Women with UARS usually complain of insomnia, fatigue, tiredness, morning headache, muscle pain mimicking fibromyalgia, and anxiety. These nonspecific symptoms are also shared by the functional somatic syndromes.61 When comparing men and women seen for SDB in a clinical setting, Shepertycky and colleagues115 found that women had a significantly higher incidence of depression (odds ratio [OR], 4.6), history of thyroid disease (OR, 5.6), and history of asthma or allergy (OR, 1.9). Guilleminault and colleagues22 noted a significantly greater degree of social isolation and depression in women with SDB; premenopausal women had increased reports of amenorrhea and dysmenorrhea. Thus, women often have a different clinical presentation than men for OSA. Women with SDB generally present with “atypical” symptoms, and therefore a thorough evaluation should be done so as not to miss a diagnosis of SDB. Predictive Value of Clinical Examination Hoffstein and Szalai studied 594 patients referred to their sleep laboratory and reported that clinical impression alone is insufficient to identify patients with OSA.31 Subjective impression had a sensitivity of 60% and a specificity of 63%. The positive predictive value for snoring was 49%, bed partner’s observation of apnea was 56%, and nocturnal choking was 44%. Physical examination of the pharynx revealed that 54% of the patients with OSA (AHI 36 ± 25) had an abnormal pharynx (bulky or long uvula that failed to elevate from the base of the tongue during phonation, large tonsils, or small and narrow pharyngeal orifice). In contrast, 35% of the patients without OSA had an abnormal pharynx. The authors concluded that history and physical examination (including blood pressure and BMI) can predict OSA in only about 50% of patients. Definitive diagnosis of OSA and UARS therefore requires a formal sleep study.

SUMMARY A thorough assessment for signs and symptoms and detailed craniofacial examination followed by a polysomnogram are necessary steps in the evaluation of a patient with SDB. As more physicians become familiar with the clinical presentation of OSA and UARS, diagnosis of these two disorders will increase. Further studies are required to clarify the nature and significance of UARS. As the link between SDB and a variety of medical and psychiatric diseases becomes more certain, referrals to sleep specialists will undoubtedly increase. Furthermore, the public is becoming increasingly more aware of the importance of sleep to a person’s health and social well-being. These are exciting times in the field of sleep medicine, and the role of the sleep specialist is likely to become much more prominent in the future.

❖  Clinical Pearls Clinicians should screen patients for signs and symptoms of SDB, including a bed partner’s report, if available. Confirmation or exclusion of a diagnosis of SDB requires objective assessment of breathing during sleep performed by a polysomnogram. Obesity and certain craniofacial features are notable predisposing factors for SDB, and a thorough clinical evaluation can strongly suggest the diagnosis. Obesity leading to OSA when seen in an overweight subject should be considered a complication of obesity itself and not an incident syndrome of obesity. A positive family history increases the risk of SDB by twofold to fourfold. This genetic predisposition is likely to be expressed through craniofacial anatomy that predisposes to OSA, although the genetic predisposition for obesity has also been considered a potential heritable pathway for OSA. Premenopausal women with normal weight present with atypical symptoms of SDB, and a high clinical suspicion is necessary for diagnosis. This group might present with UARS rather than OSA but can still have associated daytime clinical symptoms, and treatment of the SDB has been shown to improve or alleviate these symptoms.

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39. Guilleminault C, Lin CM, Gonçalves MA, Ramos E. A prospective study of nocturia and the quality of life of elderly patients with obstructive sleep apnea or sleep onset insomnia. J Psychosomat Res 2004;56:511-515. 40. Krieger J, Laks L, Wilcox I, Grunstein RR, et al. Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and during treatment with nasal continuous positive airway pressure. Clin Sci 1989;77:407-411. 41. Tantrakul V, Won C, Guilleminault C. Women and sleep-disordered breathing. Sleep 2007;30(Suppl. 1):A182. 42. Ohayon MM, Li KK, Guilleminault C. Risk factors for sleep bruxism in the general population. Chest 2001;119:53-61. 43. George CF, Nickerson PW, Hanly PJ, Millar TW, et al. Sleep apnoea patients have more automobile accidents. Lancet 1987;2:447. 44. Gonsalves MA, Paiva T, Ramos E, Guilleminault C. Obstructive sleep apnea syndrome, sleepiness and quality of life. Chest 2004; 125:2091-2096. 45. Philip P, Sagaspe P, Taillard J, Chaumet G, et al. Maintenance of wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64(4):410-416. 46. Sagaspe P, Taillard J, Chaumet G, Guilleminault C, et al. Maintenance of wakefulness test as a predictor of driving performance in patients with untreated obstructive sleep apnea. Sleep 2007;30: 327-330. 47. Philip P, Sagaspe P, Taillard J, Chaumet G, et al. Maintenance of wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64(4):410-416. 48. Guilleminault C, Philip P. Tiredness and somnolence despite initial treatment of obstructive sleep apnea. Sleep 1996;19:S117-S122. 49. Stoohs RA, Knaack L, Blum HC, Janicki J, et al. Differences in clinical features of upper airway resistance syndrome, primary snoring, and obstructive sleep apnea/hypopnea syndrome. Sleep Med 2008;9(2):121-128. 50. Guilleminault C, Abad VC, Stoohs R, Philip P. The effect of CNS stimulation versus EEG arousal during sleep on heart rate response and daytime test. Clin Neurophysiol 2006;117:731-739. 51. Guilleminault C, Powell NB, Martinez S, Kushida C, et al. Preliminary observations on the effect of sleep time in a sleep restriction paradigm. Sleep Med 2003;3: 177-184. 52. Kadotani H, Kadotani T, Young T, Peppard PE, et al. Association between apolipoprotein E-4 and sleep-disordered breathing in adults. JAMA 2001;285:2888-2890. 53. Greenberg GD, Watson RK, Deptula D. Neuropsychological dysfunction in sleep apnea. Sleep 1987;10:254. 54. Derderian SS, Bridenbaugh RH, Rajagopal KR. Neuropsychologic symptoms in obstructive sleep apnea improve after treatment with nasal continuous positive airway pressure. Chest 1988;94:1023-1027. 55. Gonçalves MA, Guilleminault C, Ramos E, Palha A, et al. Erectile dysfunction, obstructive sleep apnea syndrome and nasal CPAP treatment. Sleep Med 2005;6:333-339. 56. Paiva T, Farinha A, Martins A, Guilleminault C. Chronic headaches and sleep disorders. Arch Intern Med 1997;157:1701-1705. 57. Ohayon MM. Prevalence and risk factors of morning headaches in the general population. Arch Intern Med 2004;164:97-102. 58. Skjodt NM, Atkar R, Easton PA. Screening for hypothyroidism in sleep apnea. Am J Respir Crit Care Med 1999;160:732-735. 59. Rajagopal KR, Abbrecht PH, Derderian SS. Obstructive sleep apnea in hypothyroidism. Ann Intern Med 1984;101:471-474. 60. Cao M, Huynh N, Guilleminault C. Sleep-disordered breathing. In: Bone’s atlas of pulmonary medicine. 4th ed., Crapo JD (ed.) Philadelphia: Current Medicine; 2008. 61. Gold AR, Dipalo F, Gold MS, O’Hearn D. Symptoms and signs of upper airway resistance syndrome: a link to the functional somatic syndromes. Chest 2003;123:87-95. 62. Guilleminault C, Kim YD, Chowdhuri S, Horita M, et al. Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnea syndrome. Eur Respir J 2001; 17:838-847. 63. Guilleminault C, Kirisoglu C, Poyares D, Palombini L, et al. Upper airway resistance syndrome: a long-term outcome study. J Psychiatr Res 2006;40:273-279. 64. Bao G, Guilleminault C. Upper airway resistance syndrome 1 decade later. Cur Opin Pulm Med 2004;10:461-467. 65. Terzano MG, Parrino L, Chervin R, Sherieri A, et al. Atlas, rules and recording techniques for the scoring of the cyclical alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537-554.

1218  PART II / Section 13  •  Sleep Breathing Disorders 66. Guilleminault C, Black J, Palombini L, Ohayon M. Clinical investigation of obstructive sleep apnea syndrome and upper airway resistance syndrome patients. Sleep Med 2000;1:51-56. 67. Guilleminault C, Palombini L, Poyares D, Chowdhury S. Chronic insomnia, post-menopausal women and sleep-disordered breathing (SDB). Part 1: Frequency of SDB in a cohort. J Psychosomat Res 2002;53:611-615. 68. Guilleminault C, Palombini L, Poyares D, Chowdhury S. Chronic insomnia, post-menopausal women, and SDB. Part 2: comparison of nondrug treatment trials in normal breathing and UARS postmenopausal women complaining of insomnia. J Psychosomat Res 2002;53:617-623. 69. Guilleminault C, Davis K, Huynh NT. Prospective randomized study of patients with insomnia and mild sleep-disordered breathing. Sleep 2008;31:1527-1534. 70. Guilleminault C, Kirisoglu C, Bao G, Arias V, et al. Adult chronic sleepwalking and its treatment based on polysomnography. Brain 2005;128:1062-1069. 71. Guilleminault C, Kirisoglu C, da Rosa A, Lopes C, et al. Sleepwalking, a disorder of NREM sleep instability. Sleep Med 2006; 7:163-170. 72. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121-1123. 73. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-545. 74. Guilleminault C, Poyares D, da Rosa A, Kirisoglu C, et al. Chronic fatigue, unrefreshing sleep and nocturnal polysomnography. Sleep Med 2006;7:513-520. 75. Guilleminault C, Faul JL, Stoohs R. Sleep-disordered breathing and hypotension. Am J Respir Crit Care Med 2001;164: 1242-1247. 76. Peppard PE, Young T, Palta M, Skatrud J, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384. 77. Guilleminault C, Poyares D, Rosa A, Huang YS. Heart rate variability, sympathetic and vagal balance, and EEG arousal in upper airway resistance and mild OSA. Sleep Med 2005;6:451-457. 78. Guilleminault C, Rosa A, Ohayon M, Koester U. Arousal, EEG spectral power and pulse transit time in UARS and mild OSAS subjects. Clin Neurophysiol 2002;113:1598-1606. 79. Guilleminault C, Poyares D. Arousal and upper airway resistance. Sleep Med 2002;3:S15-S20. 80. Guilleminault C, Kim YD, Chowdhuri S, Horita M, et al. Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnea syndrome. Eur Respir J 2001;17:1-10. 81. Guilleminault C, Lopes MC, Hagen CC, da Rosa A. The cyclic alternating pattern demonstrates increased sleep instability and correlates with fatigue and sleepiness in adults with upper airway resistance syndrome. Sleep 2007;30:641-647. 82. Guilleminault C, Li K, Chen NH, Poyares D. Two-point palatal discrimination in patients with upper airway resistance syndrome, obstructive sleep apnea syndrome, and normal control subjects. Chest 2002;122(3):866-870. 83. Friberg D, Answed T, Borg K, Carlsson-Nordlander B, et al. Histological indications of a progressive snorer disease in upper airway muscle. Am J Respir Crit Care Med 1998;157:586-593. 84. Van De Graaff WB. Thoracic traction on the trachea: mechanisms and magnitude. J Appl Physiol 1991;70:1328-1336. 85. Van De Graaff WB. Thoracic influence on upper airway patency. J Appl Physiol 1988;65: 2124-2131. 86. Friberg D, Gazelius B, Holfelt T, Nordlander B, et al. Abnormal afferent nerve endings in the soft palatal mucosa of sleep apneics and habitual snorers. Regul Pept 1997;71:29-36. 87. Kimoff JR, Sforza E, Champagne V, Ofiara L, et al. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:250-255. 88. Affifi L, Guilleminault C, Colrain I. Sleep and respiratory stimulus specific dampening of cortical responsiveness in OSAS. Respir Physiol Neurobiol 2003;136:221-234. 89. Dematteis M, Lévy P, Pépin JL. A simple procedure for measuring pharyngeal sensitivity: a contribution to the diagnosis of sleep apnoea. Thorax 2005;60: 418-426. 90. Grunstein R, Wilcox I, Yang T, Gould Y, et al. Snoring and sleep apnoea in men: association with central obesity and hypertension. Int J Obes 1993;17:533-540.

91. Wilhoit SC, Suratt PM. Obstructive sleep apnea in premenopausal women: a comparison with men and with post-menopausal women. Chest 1987;91:654-658. 92. Guilleminault C, Quera-Salva A, Partinen M, Jamieson A, et al. Women and the obstructive sleep apnea syndrome. Chest 1988; 93:104-109. 93. Richmond RM, Elliot LM, Burns CM, Bearpark HM, et al. The prevalence of obstructive sleep apnoea in an obese female population. Int J Obes 1994;18:173-177. 94. Redline S, Tishler PV, Tosteson TD, Williamson J, et al. The familial aggregates of sleep apnea. Am J Respir Crit Care Med 1995;151:682-687. 95. Guilleminault C, Partinen M, Hollman K, Powell N, et al. Familial aggregates in obstructive sleep apnea syndrome. Chest 1995;107: 1545-1551. 96. Behlfelt K. Enlarged tonsils and the effect of tonsillectomy, characteristics of the dentition and facial skeleton, posture of the head, hyoid bone and tongue, mode of breathing. Swed Dent J 1990; 72(Suppl.):1-35. 97. Krol RC, Knuth SL, Bartlett D Jr. Selective reduction of genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir Dis 1984;129:247-250. 98. Scrima L, Broudy M, Nay KN, Cohn MA, et al. Increased severity of obstructive sleep apnea after bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action. Sleep 1982;5: 318-328. 99. Redline S, Hans M, Pracharktam N, Tishler PV, Hans MG, et al. Differences in the age distribution and risk factors for sleepdisordered breathing in blacks and whites. Am J Respir Crit Care Med 1994;149:577. 100. Schmid-Nowara WW, Coultas D, Wiggins C, Skipper BE, et al. Snoring in a Hispanic-American population: Risk factors and association with hypertension and other morbidity. Arch Intern Med 1990;150:597-601. 101. Grunstein RR, Lawrence S, Spies JM, et al. Snoring in paradise: the Western Samoa Sleep Survey. Eur Respir J 1989;2(S5):4015. 102. Li KK, Powell NB, Riley RW, Guilleminault C. Obstructive sleep apnea syndrome: a comparison between Far-East Asian and white men. Laryngoscope 2000;110:1689-1693. 103. Cistulli P, Sullivan CE. Sleep apnea in Marfan’s syndrome. Am Rev Respir Dis 1993;147:645-648. 104. Resta O, Barbaro MP, Giliberti T, Caratozzolo G, et al. Sleeprelated breathing disorders in adults with Down syndrome. Down Syndr Res Pract 2003;8:115-119. 105. Wetter D, Young T, Bidwall T, Badr MS, et al. Smoking as a risk factor for sleep disordered breathing. Arch Intern Med 1994;154: 2219-2224. 106. Roth T, Roehrs T, Zorick F, Conway W, et al. Pharmacological effects of sedative-hypnotics, narcotic analgesics, and alcohol during sleep. Med Clin North Am 1985;69:1281-1288. 107. Mondini S, Guilleminault C. Abnormal breathing patterns during sleep in diabetes. Ann Neurol 1985;17:391-395. 108. Resnick HE, Redline S, Shahar E, Gilpin A, et al. Diabetes and sleep disturbances: findings from the Sleep Heart Study. Diabetes Care 2003;26:702-709. 109. Katz I, Stradling J, Slutsky AS, Zamel N, et al. Do patients with obstructive sleep apnea have thick necks? Am Rev Respir Dis 1990;141:1228-1231. 110. Davies RJO, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J 1990;3:509-514. 111. Kushida CA, Efron B, Guilleminault C. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann Intern Med 1997;127:581-587. 112. Mallampati SR, Gatt SP, Gugino LD, Desai SP, et al. A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anesth Soc J 1985;32:429-434. 113. Friedman M, Tanyeri H, La Rosa M, Landsberg R, et al. Clinical predictors of obstructive sleep apnea. Laryngoscope 1999;109: 1901-1907. 114. Anttalainen U, Polo O, Saaresranta T. Is ‘MILD’ sleep-disordered breathing in women really mild? Acta Obstet Gynecol Scand 2010;89:605-611. 115. Shepertycky MR, Banno K, Kryger MH. Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 2005;28:309-314.

Medical Therapy for Obstructive Sleep Apnea

Charles W. Atwood, Jr., Patrick J. Strollo, Jr., and Rachel Givelber Abstract Positive airway pressure therapy, oral appliances, and surgery are considered the mainstays of sleep apnea therapy for obstructive sleep apnea (OSA), but a variety of medical therapies are occasionally appropriate as part of a primary therapy management strategy for obstructive apneas and hypopneas. In other cases, medical therapy may be a useful adjunct to positive airway pressure therapy in selected cases. Among these medical therapies is weight loss, which may the result of dietary manipulation or surgery. Weight loss can partially ameliorate or even reverse OSA. Alcohol and sedatives can also interact with OSA in a way that can worsen OSA symptoms, and consequently, these patients should refrain from these agents close to bedtime. Several medications are thought to affect OSA. Methylxanthines, progestational agents, selective serotonin reuptake inhibitors, and mixed serotonin receptor antagonists have each been studied with respect to OSA. Although positive studies exist, in aggregate the evidence provides no substan-

The principal therapy for obstructive sleep apnea (OSA) remains positive pressure delivered by a nasal or naso-oral interface (see Chapter 107). Oral appliances can also be useful in selected patients who cannot tolerate positive airway pressure (see Chapter 109). However, other medical options may be important as an adjunct to these treatment options or as a therapeutic intervention alone if the patient cannot accept or tolerate positive airway pressure or oral appliance therapy as a primary treatment. The focus of this chapter is to review these options.

BEHAVIORAL INTERVENTIONS Good medical care requires a comprehensive examination of the patient’s lifestyle and an understanding of how it may predispose to, or interact with, underlying medical problems. This is particularly true in patients with OSA. A number of lifestyle practices place persons at increased risk for OSA or worsen existing OSA. Modification of this behavior can favorably affect risk. These behavioral risks are described next. Multiple interventions may be appropriate in a given patient. Weight Loss A detailed discussion of upper airway physiology in OSA is provided in Chapter 101. To place the importance of weight reduction as a target for intervention in many OSA patients it is important to recognize the pathophysiologic contribution of obesity to this disorder. This issue is discussed in depth in Chapters 101 and 115. The adverse effect of obesity on upper airway function may be mediated through several pathways, one of which is a direct influence on upper airway geometry. Studies in animals have indicated that upper airway resistance is influenced by mass

Chapter

106

tial and consistent results that justify the use of these classes of medications for routine treatment of OSA. Administration of supplemental oxygen therapy has also been used to treat the hypoxemia in OSA. Oxygen therapy has not been proved to improve outcomes in OSA, although treatment of severe hypoxemia that cannot be achieved by interventions that are primarily directed at maintaining upper airway patency is generally considered to be reasonable. Caution is advisable in this circumstance because apneas may be longer during delivery of supplemental oxygen. Perhaps the most common and justifiable use of medication in OSA management is to improve alertness when sleepiness persists despite the successful amelioration of apneas and hypopneas with positive pressure therapy. Amphetamines and methylphenidate may be used for this purpose, but they have common side effects and can lead to dependence. A safer choice for promoting wakefulness in this setting is modafinil or armodafinil. These alertness promoting medications are approved for OSA patients who are adherent to CPAP therapy but still have excessive sleepiness.

loading of the anterior neck, which can simulate the clinical scenario of excessive adipose tissue deposits in this area.1 Further support for a significant pathophysiologic role of cervical obesity is provided by the observation that changes in pressure surrounding the neck are transmitted to the airway lumen and that cyclic pressure fluctuations in the pharyngeal fat pad coincide with intrapharyngeal pressure fluctuations.2,3 These data also support the importance of the observation that OSA patients have thick necks4 and that increased neck circumference is a predictive factor for OSA.5-7 Furthermore, velopharyngeal collapsibility increases with increasing neck circumference, at least in awake OSA patients.8 The presence of intrapharyngeal fat deposition may also be important in the pathophysiology of OSA (see Chapter 101). Several groups of investigators have observed increased intrapharyngeal adipose tissue or increased lateral fat pad size on computed tomography and magnetic resonance imaging of OSA patients.9-12 The significance of a space-occupying intrapharyngeal mass on pharyngeal function has been demonstrated in an animal model with increased upper airway resistance, which is related to the magnitude of inflation of a balloon catheter in the region of the upper airway lateral fat pad.3,13 In summary, upper airway closure during sleep partly depends airway size and shape as well as external tissue pressures from lateral pharyngeal fat pads exerting pressure on the airway lumen. Furthermore, to the extent that upper airway patency is increased by greater lung volume and reduced by decreased lung volume, greater truncal obesity leading to decreased lung volume may be another mechanism contributing to airway closure during sleep. It has been well documented that either medical or surgical weight reduction can have a substantial positive 1219

1220  PART II / Section 13  •  Sleep Breathing Disorders

ventilatory control. Several important questions about weight loss and OSA remain unanswered, such as the effectiveness of weight loss in patients with more severe degrees of OSA, the effect of CPAP therapy on weight homeostasis, and the amount of weight loss that should occur before a reevaluation for OSA is recommended. As discussed in detail in Chapter 115, bariatric surgery has gained popularity in the past decade as an alternative to diet and exercise for managing severe obesity. The preponderance of evidence to date suggests that this approach to weight loss brings short-term benefits for many obesityrelated medical problems, including OSA.25,26 The longterm result of gastric bypass surgery on OSA is less clear, but results from one study demonstrated a 75% reduction in the respiratory disturbance index.26 Longer-term data are needed, but the short-term results of gastric-bypass surgery are encouraging.

Mean change in AHI (events/hr)

6

4

2

0

–2

–4 −20% to 5 events per hour) is about 7% per year, and the incidence of developing an AHI of greater than 15 events per hour is about 2% per year.9 In addition to establishing the first incidence data for SDB, this study confirmed that with aging, male sex and BMI lose importance as risk factors for obstructive sleep apnea.3,9 After menopause, the incidence of SDB rises in women, and the prevalence difference between the sexes essentially vanishes.10 Genetic Influences Sleep-disordered breathing is seen more commonly in patients with a family history of SDB (see Video 103-1). In one study, 41% of the offspring of 45 randomly selected patients with OSAH syndrome had an AHI greater than 5, and 13.3% had an AHI greater than 20.11 Other large family studies have reported a much higher prevalence of OSAH syndrome among offspring of family members with OSAH when compared to the general population (see Chapter 103).8 Ethnicity also appears to play a role in the development of SDB. African Americans, Asians, and Latin Americans are at increased risk for sleep apnea, even controlling for other important risk factors such as BMI.2,8,12,13 Associated Medical Disorders Although it was recognized long ago that heart failure can result in repetitive central apneas (Cheyne-Stokes breathing—see Chapter 100), it is now clear that OSAH can contribute to left ventricular dysfunction and exacerbate congestive heart failure. Thus, SDB should be suspected in all cases of heart failure.14 OSAH also appears to be an independent risk factor for atrial fibrillation15 and stroke.16 Hypothyroidism is more prevalent in those with OSAH than in those without, and it can contribute to the development of SDB by several mechanisms, including obesity, increased tongue size, and reduced ventilatory drive.8,17 Nasal obstruction and rhinitis are also associated with increased snoring and SDB; unfortunately, however, surgery directed exclusively at the nose has a low therapeutic yield.18 Enlarged tonsils and adenoids can cause OSAH, particularly in children. OSAH should be strongly suspected in syndromes that are associated with altered craniofacial morphology, upper airway soft tissue anatomy, and airway caliber such as trisomy 21, achondroplasia, Arnold-Chiari malformation, mucopolysaccharidoses, and

Klippel-Feil, Pierre Robin, Alpert, Treacher Collins, and Marfan syndromes.8 Behavioral Factors Alcohol and sedative medications decrease neuromuscular drive to the upper airway dilator muscles, predisposing to recurrent upper airway collapse.8,19 Tobacco smoke causes an increase in nasal and pharyngeal irritation, resulting in narrowing of the upper airway. OSAH syndrome has been shown to be more prevalent in current smokers than in nonsmokers or ex-smokers.8,20-22

PATHOGENESIS Epidemiologic and genetic studies indicate that the inheritance of OSAHS is likely to be complex, and its development depends on environmental as well as genetic factors (see Chapter 103). Obesity increases the inspiratory work of breathing because the effort of displacing central obesity results in abnormally high levels of negative pressure (suction) against pliable tissues of the posterior pharyngeal space. Suction on the pliable, soft tissues of the upper airway can result in upper airway edema, which is exacerbated by the vibratory trauma of snoring. If there is nasal obstruction (polyps, septal deviation), then increased upstream airway resistance increases the effects of the increased downstream negative pressure (intrathoracic suction). A simple analogy is the collapse of a paper straw that is partially crimped along its length when a very strong suction is applied at one end. For more on the pathophysiology of sleep-disordered breathing, see Chapters 101 and 102. Several studies have also demonstrated that closure or narrowing of the upper airway occurs during inspiration in the breaths before obstructive events.23 CLINICAL FEATURES History Snoring Heavy snoring is the most common symptom in patients with SDB (Box 110-1, Videos 110-1, 110-2, and 110-3).

Box 110-1  Symptoms and Signs of Sleep-Disordered Breathing Symptoms Snoring Witnessed apneas Gasping for breath during sleep Sleepiness Enuresis, nocturia Mood, memory, or learning problems Impotence Recent weight gain Morning headache Dry mouth or dry throat in the morning Signs Obesity Hypertension Crowded oropharynx Retrognathia

1280  PART II / Section 13  •  Sleep Breathing Disorders

About 50% of men and 25% of women snore, but somewhat fewer than that have OSAH, so snoring alone is clearly not diagnostic. Snoring accompanied by a bed partner’s reports of observed apnea, snorting, gasping, and choking during sleep is predictive of OSAH.24-26 Witnessed apneas are more predictive of SDB than are patientreported episodes of waking up gasping for breath, which may be a symptom of other diseases such as congestive heart failure, gastroesophageal reflux disease, nocturnal asthma, and panic disorder. Nonetheless, a patient’s complaints of awakening with sensations of gasping or shortness of breath should be explored. Sleepiness Although excessive daytime sleepiness has many possible etiologies, this complaint should increase the suspicion for OSAH syndrome. Subjective sleepiness can be assessed by the Epworth Sleepiness Scale (see Chapter 143, which has been validated in clinical studies and correlates very roughly with objective measures of sleepiness.27 Patients underreport and overreport their sleepiness,28 so querying members of their household is also useful. An Epworth Sleepiness Scale score greater than 10 suggests significant daytime sleepiness, but this is not specific for OSAH syndrome. Sleepiness can be objectively measured with a multiple sleep latency test or with the maintenance of wakefulness test, but these tests are rarely indicated in the routine evaluation of persons with suspected or diagnosed OSAH syndrome. Patients who report falling asleep while driving or performing other safety-sensitive tasks should be evaluated for a variety of sleep disorders, including SDB (see Video 104-1). Because of the threat posed to the patient and others by this symptom, clinicians should have a low threshold for evaluation of patients who report this problem. Other Symptoms Nocturia,29 impotence,30 attention deficits, cognitive impairment (see Chapters 104 and 105), morning headache, dry or sore throat in the morning, and problems with vision31-33 are other symptoms that may be associated with OSAH syndrome. Gender and Symptoms Female patients with OSAH are much more likely than male patients to present with insomnia, and they are less likely to present with a history of observed apnea. Women with OSAH are much more likely than men to have a diagnosed mood disorder and hypothyroidism and are more likely than men to report symptoms of restless legs, nightmares, palpitations, and hallucinations.34 Alcohol and caffeine have been found to be used more by male than by female patients. Physical Findings The physical finding that is most predictive of OSAH syndrome is central obesity. BMI is a convenient but imperfect surrogate for central obesity. A BMI greater than 28 kg/m2 in both men and women reflects a risk factor and should increase the suspicion for OSAH syndrome. Approximately 40% of persons with a BMI greater than 40 and 50% of those with a BMI greater than 50 have significant SDB.2 Premenopausal women with OSAH are

generally much heavier than their male counterparts, and both obesity and sex become less important risk factors for OSAH after age 50 years.8 Measures of central obesity such as neck size are also very useful in predicting the presence of OSAH. Men with a neck circumference greater than 17 inches (43 cm) and women with a neck circumference greater than 16 inches (41  cm) are at particular increased risk for OSAH syndrome confirmed by overnight polysomnography.25,35,36 Nasal obstruction from any cause appears to be a risk factor for SDB, including snoring.37 Several diagnostic schemes are based on intraoral measurements, notably a narrowed posterior oropharynx.26,37,38 Measurement of systemic arterial blood pressure is, of course, a standard part of the physical examination. It is therefore noteworthy that several large epidemiologic studies have demonstrated that OSAHS is a risk factor for hypertension39-41 in a dose-dependent way. Analysis of data obtained from 6132 subjects in the SHHS revealed an odds ratio for hypertension of 1.37 (95% confidence interval [CI], 1.03 to 1.83), comparing the highest category of AHI (>30/hr) with the lowest (90% of baseline, lasting at least 10 seconds, with at least 90% of the event meeting the amplitudereduction criterion. Apneas are obstructive if there is continued or increased inspiratory effort, and they are central if there is not. The designation of mixed apnea is retained; mixed apnea is described as absent effort at the beginning, with resumption of effort before resumption of airflow. There are now two acceptable definitions of hypopnea according to the revised AASM scoring manual. The “classic” definition of hypopnea, which requires a nasal pressure transducer, is a reduction in nasal pressure excursion by more than 30% of baseline, lasting at least 10 seconds, with a greater than 4% oxyhemoglobin desaturation, with at least 90% of the event meeting the amplitude

reduction criterion. The “new,” alternative definition of hypopnea is a reduction in nasal pressure excursion of at least 50%, lasting at least 10 seconds, with a 3% desaturation or an arousal, with at least 90% of the event meeting the amplitude reduction criterion. It is useful to consider these definitions in light of the Sleep Heart Health Study (SHHS), which is a longitudinal follow-up of more than 6000 persons including in-home PSG.45 In this study, limited to middle-aged and older adults, apneas were identified by absence of airflow for greater than 10 seconds, and hypopneas were defined by a reduction of airflow (to 30% of baseline for apneas and to 70% of baseline for hypopneas) for longer than 10 seconds. In the SHHS, the definitions of apneas and hypopneas require an oxygen desaturation of 4% or more, and they do not include any measure of sleep disturbance or arousal.45-47 These criteria were adopted largely because they are both predictive of cardiovascular sequelae47 and are very reproducible.45,46

1282  PART II / Section 13  •  Sleep Breathing Disorders Box 110-2  Definitions

Box 110-3  Obstructive Sleep Apnea, Adult

Apnea A drop in the peak thermal sensor (this would be a thermocouple) excursion by >90% of baseline, lasting at least 10 seconds, with at least 90% of the event meeting the amplitude-reduction criterion. Apneas are obstructive if there is continued or increased inspiratory effort, and they are central if there is no inspiratory effort. The designation of mixed apnea is retained and is described as absent effort at the beginning, with resumption of effort before resumption of airflow.

A, B, and D or C and D satisfy the criteria A. At least one of the following applies: i. The patient complains of unintentional sleep episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue, or insomnia ii. The patient wakes with breath holding, gasping, or choking iii. The bed partner reports loud snoring, breathing interruptions, or both during the patient’s sleep B. Polysomnographic recording shows the following: i. Five or more scoreable respiratory events (i.e., apneas, hypopneas, or RERAs) per hour of sleep ii. Evidence of respiratory effort during all or a portion of each respiratory event (In the case of a RERA, this is best seen with the use of esophageal manometry) OR C. Polysomnographic recording shows the following: i. Fifteen or more scoreable espiratory events (i.e., apneas, hypopneas, or RERAs) per hour of sleep ii. Evidence of respiratory effort during all or a portion of each respiratory event (In the case of a RERA, this is best seen with the use of esophageal manometry) D. The disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use, or substance use disorder.

Hypopnea A reduction In nasal pressure excursion by >30% of baseline, lasting at least 10 seconds, with a >4% oxyhemoglobin desaturation, with at least 90% of the event meeting the amplitude reduction criterion or A reduction in nasal pressure excursion of at least 50%, lasting at least 10 seconds, with a 3% desaturation or An arousal, with at least 90% of the event meeting the amplitude-reduction criterion Respiratory Effort–Related Arousal A sequence of breaths lasting at least 10 seconds characterized by increasing respiratory effort or flattening of the nasal pressure waveform, leading to an arousal from sleep, when the sequence of breaths does not meet criteria for an apnea or hypopnea Obstructive Sleep Apnea Hypopnea Syndrome Five or more obstructed breathing events per hour of sleep with the appropriate clinical presentation Upper Airway Resistance Syndrome A clinical syndrome of sleepiness resulting from RERAs51 Respiratory Disturbance Index AHI, more or less (may include RERAs) Sleep-Disordered Breathing An ill-defined term used to encompass nonspecified respiratory disturbances during sleep; may include snoring, asymptomatic apneas, and full-blown sleep apnea AHI, apnea–hypopnea index; RERA, respiratory effort–related arousal.

Thus, there is a slight discrepancy between the definition of apnea proposed by the American Academy of Sleep Medicine (AASM),44 which does not require oxygen desaturation, and that used in the SHHS, which does. A careful retrospective analysis of SHHS data has demonstrated that only the only definition of hypopneas that includes at least a 4% oxyhemoglobin desaturation is associated with prevalent cardiovascular disease.48 This is not to say that different desaturation criteria would not be more predictive of other outcomes, such has glucose intolerance.49

Adapted from American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed. Diagnostic and coding manual. Westchester, Ill: American Academy of Sleep Medicine; 2005.

Diagnostic Criteria Obstructive Sleep Apnea–Hypopnea Syndrome According to the AASM, OSAH syndrome exists when a patient has five or more obstructed breathing events per hour of sleep, with an appropriate clinical presentation (Box 110-3).50 Centers for Medicare and Medicaid Services (CMS) reimburses for CPAP treatment for patients with an AHI greater than 15 or an AHI > 5, with associated hypertension, stroke, sleepiness, ischemic heart disease, or mood disorder (see below, page 1284, Indications).51 Although there is now some consistency in the definitions of SDB, considerable variation continues to exist in recording techniques for measures of airflow and respiratory effort (see Chapter 142).50,52 The innate inaccuracy and variability of current measurement techniques have almost certainly resulted in varying sensitivities for detection of SDB events. Upper Airway Resistance Syndrome The original description of the upper airway resistance syndrome (UARS) emanated from careful study of a small group of persons who had some of the clinical features of OSAH syndrome but negative sleep studies.53 In these patients, increased respiratory effort was identified by esophageal pressure nadirs (measured by esophageal pressure manometry) more negative than one standard deviation below the mean, followed by transient electroencephalography (EEG) arousals. These events were



CHAPTER 110  •  Management of Obstructive Sleep Apnea–Hypopnea Syndrome  1283

termed respiratory effort–related arousals (RERAs), and patients who had five or more such events per hour slept and complaints of sleepiness were deemed to have UARS. Patients with UARS require increased inspiratory effort to generate inspiratory airflow, and this is associated with frequent arousals but without overt apneas (see Videos 102-1 to 102-4). This fragmented sleep is believed to result in increased subjective and objective daytime sleepiness. Much of the current confusion and controversy surrounding UARS probably reflects the lack of standardized definitions and recording techniques. An AASM panel defined a RERA event as “a sequence of breaths characterized by increasing respiratory effort leading to an arousal from sleep, but which does not meet criteria for an apnea or hypopnea.”50 The revised scoring manual also defines RERAs using nasal pressure (they were originally defined using esophageal pressure) as “a sequence of breaths lasting at least 10 seconds characterized by increasing respiratory effort or flattening of the nasal pressure waveform leading to an arousal from sleep when the sequence of breaths does not meet criteria for an apnea or hypopnea.” In other words, both the measurement techniques and the precise definition of RERAs remain somewhat ill-defined. However, a perhaps oversimplified definition of UARS might be five or more RERAs (however defined) per hour of sleep with daytime sleepiness. Techniques that are currently used to detect RERAs in sleep laboratories vary greatly in clinical practice, but few clinical centers actually define and measure UARS as it was originally defined. Because there is no clear standard of diagnosis for this condition, it is probably both underdiagnosed and overdiagnosed (see Chapters 102 and 142). The RDI commonly includes apneas, hypopneas, and RERAs, however they are defined. Although it is possible that the use of the RDI instead of AHI and a wider definition of hypopnea could yield a higher prevalence number for OSAH syndrome, the definition of the disorder should be based on what is associated with adverse health outcomes. An additional issue for clinicians is that the changing definition of hypopnea. The potential replacement of the AHI with the RDI will inevitably lead to increased interrater and laboratory variability. Other Diagnostic Approaches Prediction Formulas and Questionnaires A variety of tools exist to identify persons at risk for OSAH syndrome. Questionnaires generally collect self-reported data from the patient about signs and symptoms, and formulas include physical measures such as blood pressure, BMI, or neck circumference. Because individual features from the history and physical diagnosis are often nondiagnostic, several groups have suggested the use of prediction formulas based on com­ binations of findings.24-26,36 Among the most useful of such findings are history of witnessed apneas, male sex, BMI, and neck circumference. The Berlin Questionnaire25 focuses on a limited set of known risk factors for OSAH including questions about snoring, daytime sleepiness, and high blood pressure, as well as age, weight, height, sex, and neck circumference (see Chapters 105 and 142).

Specific oropharyngeal measurements are also highly predictive.26,38 Investigators of prediction formulas typically analyze the ability of the proposed formula to predict a given AHI. However, because the AHI does not take into account the degree or duration of oxygen desaturation, sleep disturbance, or cardiac arrhythmias, it is a suboptimal gold standard. A more clinically relevant outcome for prediction formulas might be a positive response to CPAP treatment.43 In general, these formulas perform well when applied to persons with a high likelihood of severe SDB, but this is when such formalized algorithms are least needed by the clinician. Prediction formulas probably have a place in the expedited diagnosis or triage of patients with severe OSAH, particularly in patients with typical presentations, such as sleepy, obese, hypertensive, middleaged men. Home Sleep Testing A MBULATORY M ULTICHANNEL S TUDIES In the spring of 2008, the CMS announced its intent to pay for CPAP treatment on the basis of portable testing (home monitoring) and also announced that continued reimbursement for CPAP after the first 12 weeks of CPAP treatment will be contingent upon demonstration of benefit to the patient. The CMS statement also stipulated that patients should be evaluated by qualified clinicians.51 This decision came after a careful analysis of the available data, including an Agency for Health Quality (AHRQ) report that found that in-laboratory testing does not confer obvious benefit in patient outcomes compared with home testing.54 This national coverage decision (NCD) will be implemented regionally based on local coverage determinations (LCDs), and there is likely to be some regional variation in implementation and a gradual transition. Testing for sleep-disordered breathing is addressed in more detail in Chapter 142. Controversy continues about where sleep studies are best done (Video 110-4) and about the role of screening in general.55,56 Screening has the potential to actually delay diagnosis and to result in false-negative results. In general, screening for OSAH may be useful to screen a person in but not out. Clearly, not all patients will be good candidates for home testing, and the currently proposed reimbursement level for home studies is unlikely to result in a rapid transition from in-laboratory to home testing. Theoretically, home monitoring may result in increased accessibility, enhanced patient convenience, reduced cost, and better sleep in the familiar environment. However, equipment problems cannot be corrected, non-OSAH disorders cannot be detected, and CPAP titrations cannot be performed with home testing. Because autotitrating CPAP performs at least as well as in-laboratory titrated CPAP in patients who have the classic presentation of OSAH syndrome (see later and Chapter 107), the last concern is not particularly valid. The SHHS, using rigid protocols and a centralized PSG reading laboratory, demonstrated that home monitoring can produce reliable data with acceptable rates of data loss.45 The two nonapneic sleep disorders most likely to be identified by laboratory PSG are narcolepsy, which cannot be diagnosed by overnight study alone, and periodic limb movements during sleep. Periodic limb movements are

1284  PART II / Section 13  •  Sleep Breathing Disorders

extremely common in sleep disorders,57 often unassociated with sleepiness in the nonapneic patient,57 and in some patients may be a marker of SDB.58 A comparison of laboratory PSG and titration with home diagnosis and autotitration found no difference in CPAP compliance between groups, although the home testing group was evaluated more quickly and less expensively.59 Thus, although there are many unresolved issues about the large scale use of home sleep testing in the routine testing for OSAHS, CMS has clearly expanded the options for documenting OSAHS and starting CPAP treatment. At present, home sleep testing is most applicable to confirm the diagnosis of OSAH syndrome in persons with a high likelihood of the disorder.

Box 110-4  Consequences of Untreated Sleep Apnea Impaired cognitive function Impaired quality of life Daytime sleepiness Increased risk of automobile accidents Increased health care costs Hypertension Cardiovascular disease Worsened glucose tolerance Increased mortality rates Impotence

O THER D IAGNOSTIC T OOLS Several other tools have been developed to aid in the evaluation of SDB. Among them are measures of movement such as actigraphy62 and static charge-sensitive bed assessment.63 Also being developed are measures of heart rate variability and pulse pressure, Holter monitoring, and measures of sympathetic nervous system tone.64-66

predictors of progression. Unfortunately, however, the worsening of AHI with a weight gain is greater than the reduction in AHI with a comparable degree of weight loss, and weight gain is much more likely to occur than weight loss in persons with sleep-disordered breathing.81 A report in 1997 estimated that 93% of women and 82% of men with moderate to severe SDB had not received a clinical diagnosis.82 At this point, the need for aggressive diagnosis and treatment of severe, symptomatic SDB is widely recognized. The next frontier is likely to be an understanding of the risks and natural progression associated with milder levels of SDB. This will necessarily involve developing more precise tools and definitions for its identification. At present, even “simple” snoring is associated with some of the risks known to result from unequivocal OSAH syndrome (see Chapter 83).83,84 This is likely to be because the tools that we use to assess breathing disturbances during sleep and their sequelae are very imprecise. Sleep-disordered breathing is a spectrum (Fig. 110-2), and it is not yet clear where to draw the line between normal and pathologic. This likely varies by individual and is influenced by factors such as age and underlying illness. Although some data on cardiovascular morbidity are emerging from the SHHS,46 much more needs to be known about the consequences of “mild” SDB. Because of the burden of illness associated with this disorder, and because the risk of vehicular crashes makes it a public health problem, increasing efforts toward effective diagnosis and cure are appropriate. The National Center for Sleep Disorders Research has published and is continually updating a research blueprint for OSAH syndrome and other sleep disorders.85

CLINICAL COURSE AND PREVENTION Several large studies controlling for obesity and for other confounders have established that SDB is a risk factor for hypertension,39,41,67 car crashes,68,69 neurocognitive dysfunction,70,71 and cardiovascular disease,47,72,73 including strokes and death.16,74 Other likely sequelae include impotence,30 depression,75 glucose intolerance,76,77 reduced quality of life,4,78 and increased health care costs (see Chapters 104 and 105) (Box 110-4).79 Substantial progression of SDB can occur over relatively short time periods.9,80 In the Wisconsin Sleep Cohort, the overall mean AHI increased by 2.6 events per hour of sleep in 8 years. Both snoring and obesity appear to be

TREATMENT Indications The AASM and the CMS have published very similar criteria for treatment of patients with sleep-disordered breathing. CMS reimburses for CPAP treatment for patients with an AHI greater than 15, or with an AHI greater than 5 and concurrent hypertension, stroke, sleepiness, ischemic heart disease, or mood disorders (Box 110-5).51,51a Although there is some debate about whether or not treatment benefits those who have milder degrees of sleep-disordered breathing but who are not sleepy,86 there appears to be a high mortality risk associated with severe sleep-disordered breathing irrespective of sleepiness.46,74,74a,74b

O XIMETRY Because the CMS NCD addressing CPAP treatment of OSAHS covers even the simplest (2-channel) home studies, some regions may stipulate that oximetry is sufficient to diagnose OSAH, so long as one other parameter (typically, heart rate) is also recorded. Oximetry results are the basis for the current definitions of SDB, in that oxygen desaturation of varying degrees are included or required criteria for measures of SDB, notably hypopneas.46,47,50-52 Oximetry has better interrater reliability, and it is a better predictor of the response to CPAP treatment than is the AHI.60,61 In general, patients with significant sleep apnea have a greater fluctuation in oxygen saturation (and heart rate) than do those without. However, thinner, younger patients without lung disease can have significant breathing and sleep disturbance without remarkable oxygen desaturation. Patients with underlying lung disease can have oxygen desaturation without OSA. Thus, oximetry is neither sensitive nor specific for SDB. Several studies have investigated it as a screening or diagnostic tool for OSAH, but their conclusions often conflict. In general, like prediction models, oximetry performs best with more severely affected patients.



CHAPTER 110  •  Management of Obstructive Sleep Apnea–Hypopnea Syndrome  1285

Box 110-5  CMS Indications for CPAP Reimbursement to Patients with Obstructive Sleep Apnea CPAP therapy is covered for adults who have sleepdisordered breathing and the following symptoms or disorders: • AHI >15, or • AHI >5 with any of the following: • Hypertension • Stroke • Sleepiness • Ischemic heart disease • Insomnia • Mood disorders AHI, apnea-hypopnea index; CMS, Centers for Medicare and Medicaid Services; CPAP, continuous positive airway pressure. Information obtained from Centers for Medicare and Medicaid Services.

General Measures Behavior not consistent with health has a major role in causing OSAH, and modifying unhealthful behavior has a major role in treating OSAH. Weight loss can be curative, and even modest weight loss (10%) can relieve mild SDB.70 The relationship among weight, sleep, and appetite is complex, probably mediated in part by leptin, cortisol, insulin, and metabolic rate (see Chapter 86). Patients with newly diagnosed OSAH have a greater increase in weight in the year before diagnosis than do their weight-matched controls, and patients who comply with CPAP treatment tend to gain weight.87,88 All obese patients should be counseled about the potential benefits of weight loss, and those with SDB should be counseled about the potential benefits specifically in this regard. Unfortunately, weight loss through dietary modification takes time, and only a minority of patients can maintain weight loss (bariatric surgery is discussed later). In the long run, simple advice about caloric intake and output may be most effective. The two pharmacologic approaches that are still available in the United States have respectable long-term (2-year) weight loss results of 8% to 10%. One commercially available program (Weight Watchers) has been shown to promote and maintain weight loss more effectively than self-help or other approaches.89,90 Some adults with OSAH have chronic rhinitis. Intra­ nasal corticosteroid therapy might improve their apnea severity, but not necessarily their snoring or sleep quality,91 so the usefulness of this treatment as sole therapy is not established. Although the data are inconsistent, cigarette smoking has been implicated as a risk factor for snoring and for OSAH, as well as for chronic obstructive pulmonary disease (COPD).4,19 In addition, nicotine disrupts sleep. In general, smokers have more sleep disturbances than nonsmokers.92 Smoking cessation advice should be routine in the management of all patients who smoke. Muscle relaxants, including alcohol and sleeping pills, can make apneas longer by reducing airway tone and by increasing the arousal threshold. Moderate alcohol drink-

ing has been clearly shown to exacerbate OSAH and should be discouraged.93 A subset of patients (usually thinner, older, and with milder disease) have supine position–dependent apnea. In these persons, sleeping on the side can totally eliminate SDB. Unfortunately, the state of the art of position training is still in its infancy. A variety of devices are commercially available, though none has been rigorously tested or Food and Drug Administration (FDA) approved. A tennis ball in a pocket in the back of a T-shirt is often recommended, but it can result in back pain in our experience. Most clinicians are uncomfortable using this technique to treat a condition known to have serious cardiovascular and public health consequences. Continuous Positive Airway Pressure The first line of treatment for OSAH is CPAP (see Chapter 107) (Video 110-5). Typically applied in the range of 5 to 15  cm H2O through a nasal or oronasal mask, CPAP splints open the entire airway (from nares to alveoli), increases functional residual capacity, can increase pharyngeal dilator activity, and reduces afterload on the heart. CPAP is often titrated in a sleep laboratory, with mask fitting and CPAP adjustment done in the second half of the night after the diagnosis of OSAH is established. Diagnosing SDB and titrating CPAP in one night, or splitnight testing, is currently the standard approach. CPAP is begun at 3 to 5 cm H2O, and it is gradually increased until all measures of SDB, including snoring and arousals, are eliminated. CPAP requirements vary across patients and tend to be higher in more-obese patients, during REM sleep, in the supine position, and when alcohol or other muscle relaxants have been consumed. For this reason, achieving a perfect CPAP pressure in a single night’s (or half night’s) titration is more difficult than it sounds. A majority of patients are adequately treated with CPAP pressures between 8 and 12 cm H2O. Autotitrating CPAP machines are now available.94-97 Although the performance algorithms are proprietary and differ among manufacturers, in general these devices infer upper airway narrowing or collapse (e.g., apnea or hypopnea) by real-time assessment of flow or flow profile with detection of reduced patient-generated airflow as well as vibration of upper airway tissues (e.g., snoring). In response to these conditions, the device augments the pressure delivered to the upper airway to restore or optimize upper airway patency and eliminate the vibration (snoring). Autotitrating CPAP machines might not all be equally effective.78 However, most have been validated in studies of small numbers of patients with classic features of OSAH in both laboratory and home studies. Currently, no guidelines exist about how to remedy an inadequate attempt at CPAP titration on a split-night study. Autotitrating CPAP is a cost-effective alternative to laboratory titration for some patients. However, for patients who have severe oxygen desaturation or sleep disruption, have problems with mask leaks or sleep with their mouth open, or have hypoventilation or possible central apnea, laboratory titration with a technician in attendance is recommended. A third approach to establishing CPAP pressure is arbitrary pressure.98 Given that a majority of patients do well

1286  PART II / Section 13  •  Sleep Breathing Disorders

with CPAP set at 8 to 12 cm H2O, Hukins demonstrated that basing initial CPAP pressures on BMI (8 cm H2O if BMI is P > 0.10). The death rate is, of course, higher at night than by day in the general population, but this averages only a 5% increase between midnight and 8 am, in contrast to the 28% increase observed in these asthmatic patients.51 Excess nocturnal mortality could result from many factors, including the inability of hypoxia,52 hypercapnia,53 or increased airflow resistance54 to awaken sleeping subjects rapidly, with resultant delays in taking treatment; reluctance to summon family or medical help at night; and delay in the arrival of medical assistance. Eight of 10 ventilatory arrests in asthmatic patients in the hospital occurred in the early morning,55 suggesting that unavailability of medical assistance is not a major factor. One of the most important causes of nocturnal death seems to be nocturnal bronchospasm. The two asthmatic patients who died at night during a prospective study were both morning dippers,56 which suggests that nocturnal bronchoconstriction can be life threatening. Thus, the morning dip pattern of asthma should be sought and recognized as potentially dangerous when it is marked in patients with unstable asthma. Diagnosis Nocturnal asthma comprises a combination of relevant symptoms—nocturnal wheeze, cough, and breathlessness—associated with a greater than 10% fall in overnight peak flow rate. Peak flow rates should be measured in triplicate, and the highest value taken, at least three times a day for at least 2 weeks. A consistent overnight fall in peak flow rate of greater than 15% is strong evidence of nocturnal asthma. Treatment Nocturnal bronchoconstriction is a sign of inadequately controlled asthma, and the new development of nocturnal wheeze in a patient must be regarded as a dangerous sign requiring monitoring and urgent treatment. Nocturnal

wheeze often responds to increasing conventional daytime maintenance treatment with either prophylactic agents or bronchodilators, and recent evidence indicates that inhaled steroids can help overnight airway narrowing within 12 hours.57 Only when optimal daytime control does not abolish nocturnal symptoms should additional treatment be directed at nocturnal wheeze. Inhalation of bronchodilators immediately before sleep, repeated whenever the patient is awakened by wheeze, is the initial treatment of choice; side effects are few. However, conventional inhaled beta2 agonists last only around 4 hours, and most people sleep for longer than that. Inhaled ipratropium or tiotropium lasts longer, but this increased duration has proved disappointing in clinical practice. In patients for whom these treatments are insufficient, long-acting bronchodilators—either inhaled or oral— should be used. Salmeterol improves symptoms, overnight peak flow rates, and sleep quality58 and also quality of life59 in nocturnal asthma (Fig. 111-5). Formoterol, another long-acting inhaled agent, has been shown to improve overnight lung function.60 In terms of oral bronchodilators, there appears to be little to choose, from the bronchodilation point of view, between oral theophyllines61 and oral beta2 agonists.62 Both can markedly reduce nocturnal symptoms, and the choice will largely be determined by whether the patient develops side effects. These agents can often be taken effectively once a day immediately before going to bed, thus reducing daytime side effects.61 Theophylline absorption tends to be lower at night than in the morning. This is not due to diurnal variations in theophylline absorption or disposition but probably results from differences between nocturnal and morning gastric content, physical activity, and posture.

200

Time (mins)

underlines the importance of improving therapy in patients with nocturnal asthma.

** P < 0.02 * P < 0.05

**

100

* 0 0+1

2

3

4

5

Sleep stages Figure 111-5  Mean (standard error [SE]) time spent in each sleep stage by 18 asthmatic patients receiving placebo (green bar) or salmeterol 50  µg (red bar) or 100  µg (yellow bar) twice daily. (Redrawn from Fitzpatrick MF, Mackay T, Driver H, Douglas NJ. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled β2 agonist. BMJ 1990;301:1365-1368.)

CHAPTER 111  •  Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease  1299

However, it is important to be aware of this difference, because larger dosages can be given at night. Oral theophylline can disturb sleep, as judged by the EEG in patients with nocturnal asthma, despite improving nocturnal symptoms and overnight changes in flow rates.63 However, there was no evidence of sleep disturbance in a medium-term study of normal subjects taking theophylline.64 There have been relatively few studies comparing longacting inhaled beta2 agonists with other agents in the management of nocturnal asthma.65,66 One study showed no major difference in efficacy between salmeterol and oral theophylline, although there were marginal benefits in favor of salmeterol in terms of frequency of arousals from sleep and improved quality of life.65 Another study showed that salmeterol resulted in less deterioration in nighttime lung function and improvement in subjective sleep quality compared with theophylline.66 Salmeterol was superior to oral slow-release terbutaline in terms of the number of nights free of awakenings, morning peak flow rates, and assessment of clinical efficacy.67 Salmeterol 50  µg twice daily was similar in efficacy to fluticasone 250  µg twice daily in improving nocturnal asthma.68 Inhaled long-acting bronchodilators have taken over from oral long-acting bronchodilators, as side effects are fewer.69 However, the U.S. Food and Drug Administration requires that, for safety reasons, long-acting beta agonists be used in combination with inhaled corticosteroids.69a The role of proton pump inhibitors remains unclear.18,16 Their continued widespread use constitutes, at best, a non– evidence-based approach. Patients who do not respond to these measures require oral steroid therapy. A very small minority might need further immunosuppression such as methotrexate, which can improve symptoms and FEV1. In the small minority of asthmatic patients whose nocturnal airway narrowing relates to their snoring or obstructive apneas, weight loss, if appropriate, and CPAP should be tried.28 In my experience and that of others,70 such therapy does not often improve nocturnal asthma. Conclusions Although there have been advances in our understanding of both pathophysiology and therapeutics, overnight wheeze remains a problem for many patients with asthma. Overnight wheeze is caused by a circadian rhythm in airway caliber that is at least partially controlled by neural factors. Long-acting inhaled bronchodilators have simplified the management of these symptoms.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE Chronic obstructive pulmonary disease (COPD) is an umbrella term describing a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Patients with COPD become more hypoxemic during sleep than when awake—even more hypoxemic than during exercise.71 They become slightly more hypoxemic as they fall into non-REM (NREM) sleep and much more hypoxemic in REM sleep, when oxygen

100

REM sleep

90 80 Oxygen saturation (%)



70 60 50 40 30 20 10 0 1 AM

2 AM

3 AM

4 AM

5 AM

6 AM

Time Figure 111-6  Overnight oxygen saturation in a patient with chronic obstructive pulmonary disease. Shaded areas represent REM sleep during which marked oxygen desaturation occurs.

saturation can fall to extremely low levels,72 especially in those whose oxygenation is poorest when awake (Fig. 111-6). This sleep-related hypoxemia affects the cardio­ vascular and hematologic systems and so is clinically significant. Sleep becomes fragmented (Videos 111-2 to 111-5). Pathogenesis of Hypoxemia during Sleep Many causes of hypoxemia during sleep in COPD have been proposed, including hypoventilation, a decrease in functional residual capacity, and ventilation–perfusion mismatching. Hypoventilation Minute ventilation decreases during all sleep stages compared with wakefulness in normal subjects23 and in patients with COPD.73 The reduction in ventilation from wakefulness to NREM sleep is 20%,73,74 but during REM sleep, there is intermittent marked hypoventilation.23,73 In normal subjects, this hypoventilation is most severe during periods of frequent eye movements,75 when tidal volume falls substantially. The typical REM sleep–related desaturation in COPD is accompanied by hypoventilation and not by apneas (Fig. 111-7).76,77 Breathing pattern during REM sleep is similar in patients with COPD and normal subjects.76 Alveolar ventilation in normal subjects is about 40% lower during bursts of eye movements in REM sleep than during wakefulness. Direct measurements made in patients with COPD sleeping with 4 cm H2O CPAP are compatible with these estimates.73 Because patients with COPD have increased physiologic dead space, the rapid shallow breathing during bursts of eye movements in REM sleep produces an even greater decrease in alveolar ventilation than occurs in normal subjects. This contributes significantly to their REM sleep–related hypoxemia and could account for all the hypoxemia observed in REM sleep in patients with COPD.78

Wake 1 2 3 4

W 1 2 3 4

REM sleep 100

50

VT

O2 saturation

Sleep stage

1300  PART II / Section 13  •  Sleep Breathing Disorders

0

5

10 Time (minutes)

Figure 111-7  Tidal volume (VT), O2 saturation, and sleep stage in a patient with chronic obstructive pulmonary disease illustrated in the drop in O2 saturation and irregular hyperventilation during REM sleep. (Redrawn from Fletcher EC, Gray BA, Levin DC. Nonapneic mechanisms of arterial oxygen desaturation during rapid-eye movement sleep. J Appl Physiol 1983;54:632-639.)

Many factors contribute to hypoventilation during sleep. In NREM sleep, ventilation falls in normal subjects despite an increase in respiratory effort as measured by occlusion pressure.79 It is likely that this hypoventilation in NREM sleep is in part due to the increased in upper airway resistance.80 Furthermore, the ventilatory response to added respiratory resistance is impaired during NREM sleep,81 which allows hypoventilation to occur. There is also loss of the wakefulness drive to breathing, which contributes to hypoventilation during NREM sleep52 and an effect from the fall in basal metabolic rate during sleep.82 The marked intermittent hypoventilation during REM sleep seems unlikely to be due to further increases in upper airway resistance because overall airway resistance is no greater in REM sleep than in NREM sleep, at least in normal subjects.80 Furthermore, although few measurements have been made, it appears that the ventilatory response to inspiratory resistance is similar in NREM and REM sleep.81 During REM sleep, there is altered brainstem function, with phasic activity of respiratory neurons and diminution in central respiratory output, which may be a major factor in producing REM sleep–related hypoventilation. During REM sleep, there is also hypotonia of postural muscles, including the intercostal muscles, so that they contribute less to ventilation.83 This further decreases ventilation during REM sleep in hyperinflated patients with COPD, in whom the flattened diaphragm pulls in the flaccid lower chest wall, with resultant highly inefficient ventilation. This might explain why patients with COPD become relatively more hypoxemic during sleep than do patients with pulmonary fibrosis.84 In addition, the postural muscle hypotonia of REM sleep involves not only the intercostal muscles but also the accessory muscles of respiration,85 which may be important

in maintaining adequate ventilation in awake patients with COPD. The hypoventilation of REM sleep is accompanied by a marked diminution of both the hypoxic52 and hypercapnic53 ventilatory responses. The normal defense mechanisms of the body to the resulting hypoxemia and hypercapnia are diminished. Decrease in Functional Residual Capacity Functional residual capacity decreases during REM sleep in normal subjects.80 However, body plethysmographic studies indicate that functional residual capacity does not change during sleep in patients with COPD, although these data were gathered in only five patients.86 Ventilation–Perfusion Mismatching It is inevitable that additional ventilation–perfusion mismatching occurs in patients with COPD during the marked hypoventilation of REM sleep. This is supported by evidence that cardiac output is maintained during these episodes of hypoventilation, which indicates changes in global ventilation–perfusion matching.87 Unfortunately, technology does not allow assessment of the importance of ventilation–perfusion matching relative to the other mechanisms involved. Techniques for quantifying ventilation–perfusion mismatch rely on a steady state of both ventilation and metabolism; certainly, the former does not occur during REM sleep, when ventilation is extremely variable.87 This negates many of the arguments previously advanced for the importance of ventilation–perfusion mismatching. For example, it has been suggested that the greater decrease in alveolar Po2 compared with the rise in arterial Pco2 indicates the importance of ventilation– perfusion changes during REM sleep in patients with COPD. However, because the body stores of carbon



CHAPTER 111  •  Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease  1301

dioxide are much larger than those of oxygen, the transient episodes of hypoventilation that occur during REM sleep produce much greater decreases in Po2 than rises in Pco2, which is exactly what has been observed.87 COPD Combined with OSAH Syndrome Both COPD and obstructive sleep apnea–hypopnea (OSAH) syndrome are common. These two conditions coexist in some patients, although the prevalence of the OSAH in patients with COPD seems to be no greater than the prevalence of OSAH88,89 in the normal population. In a small minority of patients with COPD, perhaps about 2%,89 nocturnal hypoxemia results from obstructive apneas or hypopneas, in addition to REM sleep–related hypoventilation. Viewed in a different way, one study suggested that 10% of patients with OSAH might have some degree of coexisting COPD.90 In patients with both conditions, the pattern of nocturnal desaturation is different; frequent desaturation results in a broad-band saturation trace rather than the relatively clearly defined spike desaturation typically found in REM sleep (see Fig. 111-6). Hypercapnic patients with COPD may be heavier and have narrower upper airways when awake, predisposing them to OSAH.91 Summary Hypoventilation is the major cause of hypoxemia during REM sleep in patients with COPD. There may be additional contributions from ventilation–perfusion mismatching and a decrease in functional residual capacity. In a small minority of patients with COPD, there may also be coexisting OSAH. Clinical Consequences of Sleep Hypoxemia Hypoxemia during sleep in patients with COPD has significant cardiovascular and neurophysiologic effects, might have hematologic consequences, and might contribute to the incidence of nocturnal death. Cardiac Dysrhythmias Patients with COPD have increased ventricular ectopic beats during sleep. Although in most patients there is no direct relation between ventricular ectopic frequency and oxygen saturation,92 in a minority of the most hypoxic patients a significant relation could be found between ventricular ectopic frequency and nocturnal oxygen saturation. Hemodynamics Pulmonary arterial pressure rises as oxygen saturation falls during REM sleep. Coccagna and Lugaresi93 observed in 12 patients with COPD that mean pulmonary arterial pressure rose from 37 to 55 mm Hg during REM sleep as the average arterial oxygen tension fell from 56 to 43  mm  Hg. Boysen and colleagues94 observed an inverse correlation between oxygenation and mean pulmonary arterial pressure, and although individual values varied widely, on average a 1% fall in oxygen saturation led to a rise of 1 mm Hg in mean pulmonary arterial pressure. The clinical significance of these transient episodes of pulmonary arterial pressure elevation is unknown; however, in rats, intermittent hypoxemia induced by breathing 12%

oxygen for as little as 2 hours each day for 4 weeks significantly elevated right ventricular mass, even when individual episodes of hypoxia were as short as 30 minutes.95 It thus seems probable that the intermittent REM sleep hypoxemia in patients with COPD has similar effects on the human myocardium. Polycythemia Intermittent hypoxemia in rats results in an elevation of red cell mass95; the nocturnal desaturation in patients with COPD might also stimulate erythropoiesis. Morning erythropoietin levels are raised in some patients with COPD.96 A study compared red cell mass and pulmonary hemodynamics of 36 patients with COPD who experienced desaturation at night to at least 85% with more than 5 minutes spent below 90% saturation with those of 30 patients who did not so desaturate.97 Those with nocturnal desaturation had significantly higher daytime pulmonary arterial pressures and red cell mass than did the nondesaturators. Although these differences could have resulted from the nocturnal events, the nocturnal desaturators also had significantly poorer daytime oxygenation levels, which could explain the hemodynamic and hematologic differences. Nocturnal erythropoietin rises only in patients with COPD whose oxygen saturations fall below 60% at night.96 This suggests that the relatively minor degree of nocturnal desaturation may be of little hematologic consequence. Sleep Quality Both subjective and objective98 assessments indicate that patients with COPD sleep poorly compared with healthy subjects. Although arousals and sleep fragmentation are common during episodes of desaturation,98 the extent of sleep disruption is at least as great in relatively normoxic patients with COPD. Despite these reports of poor sleep, there is no objective evidence of daytime sleepiness as assessed by the multiple sleep latency test in patients with COPD.99 Consequences of COPD Combined with OSAH Syndrome Patients with both COPD and OSAH are more likely to develop pulmonary hypertension, right-sided heart failure, and carbon dioxide retention than are patients with OSAH alone.100 Indeed, these complications develop earlier in patients with COPD and OSAH than in patients with COPD alone, and many patients who have these complications with both COPD and OSAH have relatively good lung function. This is probably due to their having two causes for nocturnal hypoxemia, resulting in more-severe nocturnal hypoxemia than would have occurred if they had only COPD alone or OSAH alone. Prediction of Nocturnal Oxygenation Oxygenation during wakefulness in patients with COPD is the major predictor of both the mean and lowest levels of oxygenation during sleep and the extent of desaturation during sleep.89,101 Because the hypoxemic complications of pulmonary hypertension and polycythemia relate to the patient’s absolute arterial oxygenation rather than to the

1302  PART II / Section 13  •  Sleep Breathing Disorders 100 P < 0.0001 r = 0.75

Lowest SaO2 asleep (%)

80

60

40

20

0 60

70

80

90

100

Mean SaO2 awake (%) Figure 111-8  Relationship between mean oxygen saturation (SaO2) awake and lowest oxygen saturation during sleep in 97 patients with COPD. (Redrawn from Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138:341-345.)

change in saturation, the more important relation is that between absolute levels of nocturnal oxygenation and measurements that can be taken during wakefulness. Several different equations relating these variables have been derived, but their clinical significance is limited because the scatter around the regression lines is wide,89 especially for the more severely hypoxemic patients (Fig. 111-8). Regression relations show that the extent of nocturnal hypoxemia relates not only to daytime oxygenation but also to daytime arterial carbon dioxide tension and to the duration of REM sleep.89 Similarly the predictors of the extent of transcutaneous CO2 rise during sleep were found to be arterial Pco2 awake, amount of REM sleep, and body mass index.102 Clinical Value of Sleep Studies Studying breathing and oxygenation during sleep by either polysomnography or more-limited techniques in patients with COPD could be of clinical relevance by • Detecting unsuspected cases of OSAH • Detecting which patients had clinically important excess nocturnal hypoxemia

• Guiding which patients might benefit from nocturnal oxygen therapy • Determining the optimal inspired oxygen concentration for nocturnal oxygen therapy. The last two roles are discussed in the section “Treatment of Nocturnal Hypoxemia.” There is no evidence that the prevalence of OSAH is increased in patients with COPD.76,88,103 When OSAH syndrome and COPD coexist, the typical symptoms of OSAH are present, and it appears that sleep studies do not yield unsuspected cases of OSAH.89 Thus, all patients with COPD should be questioned about the occurrence of symptoms of OSAH syndrome. If major symptoms are elicited, polysomnography should be performed; oximetry alone studies are difficult to interpret in hypoxemic patients. Oxygenation during sleep can be predicted on the basis of awake arterial blood gas tensions.89 These predictions leave considerable unexplained residual variance, but it is unclear whether this is of clinical significance. Measurement of the extent of nocturnal hypoxemia in such patients has been held to be a useful guide for treatment. To clarify the clinical importance of this variability among patients in the extent of nocturnal hypoxemia, Connaughton and colleagues89 studied the relation between nocturnal oxygen saturation and survival in 97 patients with severe COPD followed up for a median of 70 months. Both the mean nocturnal oxygen saturation and the lowest nocturnal oxygen saturation were significantly related to survival; the lower the nocturnal oxygenation, the worse the prognosis. However, neither nocturnal measure significantly improved the prediction of survival that could be obtained from the easier and cheaper measurements of oxygen saturation or vital capacity when awake.89 These data89 were also analyzed to determine the significance of the scatter around the regression relation between measurements of oxygen saturation and Paco2 when awake and oxygen saturation during sleep. The patients were divided into those who had excess nocturnal hypoxemia, defined as those whose oxygen saturation during sleep was lower than that predicted on the basis of their awake oxygen saturation and arterial Pco2, and those who became less hypoxemic at night than predicted. There was no difference in survival rates at a median of 70 months between those with excess nocturnal hypoxemia and those who became less hypoxemic at night than might be predicted based on the awake oxygenation and Paco2 (Fig. 111-9). Thus, measurement of nocturnal oxygenation does not yield useful prognostic information in addition to that obtained during wakefulness. Another study in a group of patients with daytime arterial oxygen tension 56 to 69 mm Hg found no significant relation between the magnitude of nocturnal hypoxemia and the development of pulmonary hypertension or worsening of arterial blood gas tensions.104 This, again, suggests that the contribution of the additional hypoxemia during sleep to overall daytime pulmonary arterial pressure is relatively small. There is also no evidence that nocturnal desaturators have impaired quality of life or subjective sleep quality.105 There seems to be no clinical advantage, therefore, in performing routine polysomnography in patients with COPD, although undoubtedly there are many research



CHAPTER 111  •  Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease  1303

proven role for studies of breathing and oxygenation during sleep to aid selection of patients for nocturnal oxygen therapy. Studies in patients with daytime arterial tensions of greater than 55  mm  Hg but with nocturnal desaturation reported that nocturnal oxygen therapy did not improve patient survival rates.107 The only patients in whom I suggest that polysomnography be performed in relation to oxygen therapy in COPD are those who develop morning headaches with oxygen therapy, because this can indicate coexisting OSAH syndrome. I do not believe there is any indication or evidence base for oxygen therapy only at night in patients with COPD, whereas there is a strong evidence base for continuous oxygen therapy in patients with daytime hypoxemia.

100 Mean nocturnal oxygen saturation More hypoxic than predicted

Percent surviving

80

P = 0.19

60

Less hypoxic than predicted

40

20

0 0

2

4

6

8

Time after sleep study (yrs) Figure 111-9  Survival curves for patients who are more hypoxic than predicted from their awake oxygen saturation and carbon dioxide level compared with those who are less hypoxic than predicted. There was no significant difference in the survival curves in the two groups. (Redrawn from Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138:341-5.)

areas requiring clarification by this technique. I believe clinical polysomnography is only indicated in patients with COPD if OSAH syndrome is suspected because of symptoms of OSAH syndrome or the development of hypoxemic complications—cor pulmonale and polycythemia—in patients whose daytime arterial oxygen tension is greater than 60  mm  Hg. Equally, there is no evidence that recording overnight oxygenation in patients with COPD adds evidence to daytime oxygenation data that either helps their management or the prediction of their prognosis.89,104 Treatment of Nocturnal Hypoxemia Oxygen Therapy Not surprisingly, nocturnal oxygen therapy improves oxygenation during sleep in patients with COPD.72 Some nocturnal desaturation still occurs, particularly during REM sleep, but the hypoxemia is not so profound. A few patients report morning headaches due to carbon dioxide retention as a result of nocturnal oxygen therapy. This may be a particular problem in patients with coexisting OSAH syndrome106 and is as an indication for polysomnography. The patients who become most severely hypoxemic at night are those with the greatest daytime hypoxemia.89 Long-term domiciliary oxygen therapy remains the only treatment shown by controlled clinical trials to prolong life in such patients. Because the period of oxygen administration almost always includes the night, it is possible that some of the benefit of oxygen therapy is due to preventing nocturnal hypoxemia. Long-term domiciliary oxygen therapy is based on data where oxygen treatment depended solely on measurement of arterial blood gas tensions when awake. There is no

Lung Volume Reduction Surgery In patients suitable for lung volume reduction surgery, the procedure can improve objective sleep and nocturnal oxygenation.108 Almitrine The use of the respiratory stimulant almitrine can raise arterial oxygen tension in patients with COPD. In a randomized, double-blind study, 50  mg of almitrine twice daily for 2 weeks improved oxygenation during sleep in patients with COPD.109 The role of almitrine in patients with COPD is limited,110 and the drug is not available in some countries because side effects, especially peripheral neuropathy, have caused it to be withdrawn. Protriptyline Tricyclic agents suppress REM sleep and might thus improve oxygenation. The results of a nonrandomized, nonblinded trial111 suggested that protriptyline might improve daytime arterial oxygen and carbon dioxide tensions in patients with COPD, but side effects were common, causing cessation of therapy within 10 weeks in 4 of 14 patients. I would not advocate the use of protriptyline to improve oxygenation in patients with COPD. Medroxyprogesterone Acetate Despite suggestions that medroxyprogesterone acetate might be beneficial as a respiratory stimulant, in a doubleblind, placebo-controlled trial, Dolly and Block112 found no significant change in the lowest oxygen saturation during sleep in 19 patients with COPD who were taking medroxyprogesterone acetate. In addition, medroxyprogesterone acetate can cause troublesome side effects, including impotence in many patients. The clinical role of the drug in COPD is limited, although there may be some benefit in postmenopausal women.113 Theophylline The use of oral theophylline can improve overnight oxygen saturation and transcutaneous carbon dioxide levels.114 However, the benefits of this bronchodilator are limited and are often outweighed by the side effects. Beta Agonists and Anticholinergic Bronchodilators The use of oral sustained-release salbutamol had no effect on sleep, oxygenation, or morning FEV1 in 14 patients with moderately severe COPD.115 Randomized studies

1304  PART II / Section 13  •  Sleep Breathing Disorders

found that the anticholinerigc agents ipratropium bromide116 and tiotropium117 improved oxygenation, and ipratropium also improved sleep quality.116 Intermittent Positive-Pressure Ventilation by Mask Long-term use of nocturnal intermittent positive-pressure ventilation (NIPPV) via a nasal or face mask at home was developed for patients with chest wall or neuromuscular disorders. Some patients with COPD find this technique acceptable, and it has a theoretical advantage over longterm oxygen therapy of reducing, rather than raising, arterial carbon dioxide tension. In patients who can tolerate NIPPV, improvements in arterial blood gas tensions and sleep may be achieved, but nocturnal oxygenation is improved more with nocturnal oxygen therapy than with NIPPV alone.118 Simultaneous nasal NIPPV and nocturnal oxygen therapy produced greater improvements in arterial blood gas tensions and quality of life than did oxygen therapy alone in randomized, controlled trials.119,120 A more detailed review of NIPPV is given in Chapter 113. NIPPV has a role in the treatment of hypoxemic patients with COPD, especially in those who continue to smoke or who have troublesome headaches on long-term oxygen therapy as well as in those with coexisting OSAHS (see next). Treatment of COPD Combined with OSAH Syndrome — the Overlap Syndrome There are remarkably few data indicating how to treat patients who have both COPD and OSAH syndrome (Videos 111-6 and 111-7). A nonrandomized study found that patients with both conditions improved their daytime arterial blood gas tensions (Fig. 111-10) and pulmonary arterial pressures when they were adequately treated for OSAH but not when they received domiciliary oxygen therapy in the absence of adequate therapy for OSAH.121 The overlap syndrome results in increased risk of death and hospitalization and CPAP treatment is associated with improved survival and decreased hospitalizations in these patients.122 Hypnotics in COPD Hypnotics should be used with care in all patients with COPD to avoid inducing respiratory depression. Indeed, the counsel of perfection is that they should never be used, and, if used, in the lowest possible dose. Studies on a selective melatonin MT1/MT2 receptor agonist showed improved sleep duration and quality without impairing gas exchange in patients with mild to moderate and also severe COPD,123 but further data are required before their widespread use could be encouraged.124 Conclusions Patients with COPD become hypoxemic during sleep, particularly during episodes of dense eye movements in REM sleep. The measurement of nocturnal hypoxemia and breathing patterns in individual patients does not provide prognostic information that significantly adds to the simpler measurements of oxygenation and lung function during wakefulness. In a small minority of patients with COPD, OSAH syndrome coexists, and any patient with COPD and a history suggesting OSAH syndrome should

100 Tracheostomy 90

No tracheostomy

80 P < 0.005

70 PO2

NS

60 50 PCO2

NS P < 0.001

40 30 Baseline

Follow up

Figure 111-10  Arterial oxygen (PO2) and carbon dioxide (Pco2) tensions (in mm Hg) in patients with both COPD and sleep apnea at baseline and subsequent follow-up. Open circles indicate those who were treated with tracheostomy, and closed circles indicate those who were treated by other techniques, which largely consisted of long-term oxygen therapy. The P values indicate significant improvements in arterial blood gas tensions in the patients treated with tracheostomy. NS, not significant. (Redrawn from Fletcher EC, Schaaf JW, Miller J, et al. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987;135: 525-533.)

undergo full polysomnography. Those found to have OSAH syndrome should be aggressively treated. Domiciliary oxygen therapy is the treatment of choice for patients with COPD who are hypoxemic at day and night, but the role of NIPPV via a nasal mask could grow. REFERENCES 1. Connolly CK. Diurnal rhythms in airway obstruction. Br J Dis Chest 1979;73:357-366. 2. Floyer J. A treatise on the asthma. London, 1698. 3. Clark TJ, Hetzel MR. Diurnal variation of asthma. Br J Dis Chest 1977;71:87-92. 4. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977;71:73-86. 5. Hetzel MR, Clark TJ. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 1980;35: 732-738. 6. Catterall JR, Rhind GB, Stewart IC, et al. Effect of sleep deprivation on overnight broncho-constriction in nocturnal asthma. Thorax 1986;41:676-680. 7. Ballard RD, Saathoff MC, Patel DK, et al. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol 1989;67:243-249. 8. Hetzel MR, Clark TJ. Does sleep cause nocturnal asthma? Thorax 1979;34:749-754. 9. Whyte KF, Douglas NJ. Posture and nocturnal asthma. Thorax 1989;44:579-581. 10. Woodcock A, Forster L, Matthews E, et al. Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N Engl J Med 2003;349:225-236. 11. Davies RJ, Green M, Schofield NM. Recurrent nocturnal asthma after exposure to grain dust. Am Rev Respir Dis 1976;114: 1011-1019.



CHAPTER 111  •  Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease  1305 12. Platts-Mills TA, Tovey ER, Mitchell EB, et al. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982;2:675-678. 13. Ryan G, Latimer KM, Dolovich J, et al. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre. Thorax 1982;37:423-429. 14. Kerr HD. Diurnal variation of respiratory function independent of air quality: experience with an environmentally controlled exposure chamber for human subjects. Arch Environ Health 1973;26: 144-152. 15. Chen WY, Chai H. Airway cooling and nocturnal asthma. Chest 1982;81:675-680. 16. Kiljander TO, Salomaa ER, Hietanen EK, et al. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999;116:1257-1264. 17. Nagel RA, Brown P, Perks WH, et al. Ambulatory pH monitoring of gastro-oesophageal reflux in “morning dipper” asthmatics. BMJ 1988;297:1371-1373. 18. Kiljander TO, Harding SM, Field SK, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006;173:1091-1097. 19. Littner MR, Leung FW, Ballard ED, et al. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005;128:1128-1135. 20. Gervais P, Reinberg A, Gervais C, et al. Twenty-four-hour rhythm in the bronchial hyperreactivity to house dust in asthmatics. J Allergy Clin Immunol 1977;59:207-213. 21. Smolensky MH, Reinberg A, Queng JT. The chronobiology and chronopharmacology of allergy. Ann Allergy 1981;47:234-252. 22. Kales A, Beall GN, Bajor GF, et al. Sleep studies in asthmatic adults: relationship of attacks to sleep stage and time of night. J Allergy 1968;41:164-173. 23. Douglas NJ, White DP, Pickett CK, et al. Respiration during sleep in normal man. Thorax 1982;37:840-844. 24. Tabachnik E, Muller NL, Levison H, et al. Chest wall mechanics and pattern of breathing during sleep in asthmatic adolescents. Am Rev Respir Dis 1981;124:269-273. 25. Catterall JR, Douglas NJ, Calverley PM, et al. Irregular breathing and hypoxaemia during sleep in chronic stable asthma. Lancet 1982;1:301-304. 26. Ballard RD, Irvin CG, Martin RJ, et al. Influence of sleep on lung volume in asthmatic patients and normal subjects. J Appl Physiol 1990;68:2034-2041. 27. Kraft M, Pak J, Martin RJ, et al. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001;163: 1551-1556. 28. Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988; 137:1502-1504. 29. Chinn S. Asthma and obesity: where are we now? Thorax 2003;58:1008-1010. 30. Sulit LG, Storfer-Isser A, Rosen CL, et al. Associations of obesity, sleep-disordered breathing, and wheezing in children. Am J Respir Crit Care Med 2005;171:659-664. 31. Catterall JR, Rhind GB, Whyte KF, et al. Is nocturnal asthma caused by changes in airway cholinergic activity? Thorax 1988;43:720-724. 32. Morrison JF, Pearson SB, Dean HG. Parasympathetic nervous system in nocturnal asthma. Br Med J (Clin Res Ed) 1988; 296:1427-1429. 33. Barnes P, FitzGerald G, Brown M, et al. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Engl J Med 1980;303:263-267. 34. Mackay TW, Hulks G, Douglas NJ. Non-adrenergic, noncholinergic function in the human airway. Respir Med 1998;92: 461-466. 35. Soutar CA, Carruthers M, Pickering CA. Nocturnal asthma and urinary adrenaline and noradrenaline excretion. Thorax 1977; 32:677-683. 36. Morrison JF, Teale C, Pearson SB, et al. Adrenaline and nocturnal asthma. BMJ 1990;301:473-476. 37. Jarjour NN, Busse WW, Calhoun WJ. Enhanced production of oxygen radicals in nocturnal asthma. Am Rev Respir Dis 1992; 146:905-911.

38. Kraft M, Martin RJ, Wilson S, et al. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999;159:228-234. 39. Mackay TW, Wallace WA, Howie SE, et al. Role of inflammation in nocturnal asthma. Thorax 1994;49:257-262. 40. Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143:351-357. 41. ten Hacken NH, Postma DS, Bosma F, et al. Vascular adhesion molecules in nocturnal asthma: a possible role for VCAM-1 in ongoing airway wall inflammation. Clin Exp Allergy 1998;28: 1518-1525. 42. Kraft M, Striz I, Georges G, et al. Expression of epithelial markers in nocturnal asthma. J Allergy Clin Immunol 1998; 102:376-381. 43. ten Hacken NH, Timens W, Smith M, et al. Increased peak expiratory flow variation in asthma: severe persistent increase but not nocturnal worsening of airway inflammation. Eur Respir J 1998; 12:546-550. 44. Jarjour NN, Busse WW. Cytokines in bronchoalveolar lavage fluid of patients with nocturnal asthma. Am J Respir Crit Care Med 1995;152:1474-1477. 45. Oosterhoff Y, Kauffman HF, Rutgers B, et al. Inflammatory cell number and mediators in bronchoalveolar lavage fluid and peripheral blood in subjects with asthma with increased nocturnal airways narrowing. J Allergy Clin Immunol 1995;96:219-229. 46. Raherison C, Abouelfath A, Le Gros V, et al. Underdiagnosis of nocturnal symptoms in asthma in general practice. J Asthma 2006;43:199-202. 47. Mastronarde JG, Wise RA, Shade DM, et al. Sleep quality in asthma: results of a large prospective clinical trial. J Asthma 2008;45:183-189. 48. Teodorescu M, Consens FB, Bria WF, et al. Correlates of daytime sleepiness in patients with asthma. Sleep Med 2006;7:607-613. 49. Fitzpatrick MF, Engleman H, Whyte KF, et al. Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance. Thorax 1991;46:569-573. 50. Weersink EJ, van Zomeren EH, Koeter GH, et al. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med 1997;156: 1144-1150. 51. Douglas NJ. Asthma at night. Clin Chest Med 1985;6:663-674. 52. Douglas NJ, White DP, Weil JV, et al. Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 1982;125:286-289. 53. Douglas NJ, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982;126: 758-762. 54. Gugger M, Molloy J, Gould GA, et al. Ventilatory and arousal responses to added inspiratory resistance during sleep. Am Rev Respir Dis 1989;140:1301-1307. 55. Hetzel MR, Clark TJ, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977;1: 808-811. 56. Bateman JR, Clarke SW. Sudden death in asthma. Thorax 1979; 34:40-44. 57. Frezza G, Terra-Filho J, Martinez JA, et al. Rapid effect of inhaled steroids on nocturnal worsening of asthma. Thorax 2003; 58:632-633. 58. Fitzpatrick MF, Mackay T, Driver H, et al. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled beta 2 agonist. BMJ 1990;301:1365-1368. 59. Lockey RF, DuBuske LM, Friedman B, et al. Nocturnal asthma: effect of salmeterol on quality of life and clinical outcomes. Chest 1999;115:666-673. 60. Maesen FP, Smeets JJ, Gubbelmans HL, et al. Formoterol in the treatment of nocturnal asthma. Chest 1990;98:866-870. 61. Barnes PJ, Greening AP, Neville L, et al. Single-dose slow-release aminophylline at night prevents nocturnal asthma. Lancet 1982; 1:299-301. 62. Crompton GK, Ayres JG, Basran G, et al. Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. Am J Respir Crit Care Med 1999;159:824-828. 63. Rhind GB, Connaughton JJ, McFie J, et al. Sustained release choline theophyllinate in nocturnal asthma. Br Med J (Clin Res Ed) 1985;291:1605-1607.

1306  PART II / Section 13  •  Sleep Breathing Disorders 64. Fitzpatrick MF, Engleman HM, Boellert F, et al. Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects. Am Rev Respir Dis 1992; 145:1355-1358. 65. Selby C, Engleman HM, Fitzpatrick MF, et al. Inhaled salmeterol or oral theophylline in nocturnal asthma? Am J Respir Crit Care Med 1997;155:104-108. 66. Wiegand L, Mende CN, Zaidel G, et al. Salmeterol vs theophylline: sleep and efficacy outcomes in patients with nocturnal asthma. Chest 1999;115:1525-1532. 67. Brambilla C, Chastang C, Georges D, et al. Salmeterol compared with slow-release terbutaline in nocturnal asthma. A multicenter, randomized, double-blind, double-dummy, sequential clinical trial. French Multicenter Study Group. Allergy 1994;49:421-426. 68. Weersink EJ, Douma RR, Postma DS, et al. Fluticasone propionate, salmeterol xinafoate, and their combination in the treatment of nocturnal asthma. Am J Respir Crit Care Med 1997;155: 1241-1246. 69. Tee AK, Koh MS, Gibson PG, et al. Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2007;(3)CD001281. 69a.  U.S. Food and Drug Administration. Postmarket drug safety information for patients and providers. Available at: http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm200776. 70. Lafond C, Series F, Lemiere C. Impact of CPAP on asthmatic patients with obstructive sleep apnoea. Eur Respir J 2007; 29:307-311. 71. Mulloy E, McNicholas WT. Ventilation and gas exchange during sleep and exercise in severe COPD. Chest 1996;109:387-394. 72. Douglas NJ, Calverley PM, Leggett RJ, et al. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1979;1:1-4. 73. Becker HF, Piper AJ, Flynn WE, et al. Breathing during sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med 1999;159:112-118. 74. O’Donoghue FJ, Catcheside PG, Eckert DJ, et al. Changes in respiration in NREM sleep in hypercapnic chronic obstructive pulmonary disease. J Physiol 2004;559:663-673. 75. Gould GA, Gugger M, Molloy J, et al. Breathing pattern and eye movement density during REM sleep in humans. Am Rev Respir Dis 1988;138:874-877. 76. Catterall JR, Douglas NJ, Calverley PM, et al. Transient hypoxemia during sleep in chronic obstructive pulmonary disease is not a sleep apnea syndrome. Am Rev Respir Dis 1983;128:24-29. 77. George CF, West P, Kryger MH. Oxygenation and breathing pattern during phasic and tonic REM in patients with chronic obstructive pulmonary disease. Sleep 1987;10:234-243. 78. Catterall JR, Calverley PM, MacNee W, et al. Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 1985;59:1698-1703. 79. White DP. Occlusion pressure and ventilation during sleep in normal humans. J Appl Physiol 1986;61:1279-1287. 80. Hudgel DW, Martin RJ, Johnson B, et al. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol 1984;56:133-137. 81. Wiegand L, Zwillich CW, White DP. Sleep and the ventilatory response to resistive loading in normal men. J Appl Physiol 1988;64:1186-1195. 82. White DP, Weil JV, Zwillich CW. Metabolic rate and breathing during sleep. J Appl Physiol 1985;59:384-391. 83. White JE, Drinnan MJ, Smithson AJ, et al. Respiratory muscle activity during rapid eye movement (REM) sleep in patients with chronic obstructive pulmonary disease. Thorax 1995;50:376-382. 84. Midgren B. Oxygen desaturation during sleep as a function of the underlying respiratory disease. Am Rev Respir Dis 1990; 141:43-46. 85. Johnson MW, Remmers JE. Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984;57:1011-1017. 86. Ballard RD, Clover CW, Suh BY. Influence of sleep on respiratory function in emphysema. Am J Respir Crit Care Med 1995; 151:945-951. 87. Catterall JR, Calverley PM, MacNee W, et al. Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 1985;59:1698-1703.

88. Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleepdisordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med 2003;167:7-14. 89. Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138: 341-344. 90. Chaouat A, Weitzenblum E, Krieger J, et al. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:82-86. 91. Chan CS, Bye PT, Woolcock AJ, et al. Eucapnia and hypercapnia in patients with chronic airflow limitation. The role of the upper airway. Am Rev Respir Dis 1990;141:861-865. 92. Shepard Jr JW, Garrison MW, Grither DA, et al. Relationship of ventricular ectopy to nocturnal oxygen desaturation in patients with chronic obstructive pulmonary disease. Am J Med 1985;78: 28-34. 93. Coccagna G, Lugaresi E. Arterial blood gases and pulmonary and systemic arterial pressure during sleep in chronic obstructive pulmonary disease. Sleep 1978;1:117-124. 94. Boysen PG, Block AJ, Wynne JW, et al. Nocturnal pulmonary hypertension in patients with chronic obstructive pulmonary disease. Chest 1979;76:536-542. 95. Moore-Gillon JC, Cameron IR. Right ventricular hypertrophy and polycythaemia in rats after intermittent exposure to hypoxia. Clin Sci (Lond) 1985;69:595-599. 96. Fitzpatrick MF, Mackay T, Whyte KF, et al. Nocturnal desaturation and serum erythropoietin: a study in patients with chronic obstructive pulmonary disease and in normal subjects. Clin Sci (Lond) 1993;84:319-324. 97. Fletcher EC, Luckett RA, Miller T, et al. Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 1989;95: 757-764. 98. Fleetham J, West P, Mezon B, et al. Sleep, arousals and oxygen desaturation in chronic obstructive pulmonary disease. The effect of oxygen therapy. Am Rev Respir Dis 1982;126:429-433. 99. Orr WC, Shamma-Othman Z, Levin D, et al. Persistent hypoxemia and excessive daytime sleepiness in chronic obstructive pulmonary disease (COPD). Chest 1990;97:583-585. 100. Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985;131: 835-839. 101. Zanchet RC, Viegas CA. Nocturnal desaturation: predictors and the effect on sleep patterns in patients with chronic obstructive pulmonary disease and concomitant mild daytime hypoxemia. J Bras Pneumol 2006;32:207-212. 102. O’Donoghue FJ, Catcheside PG, Ellis EE, et al. Sleep hypoventilation in hypercapnic chronic obstructive pulmonary disease: prevalence and associated factors. Eur Respir J 2003;21:977-984. 103. Weitzenblum E, Chaouat A, Kessler R, et al. Overlap syndrome: obstructive sleep apnea in patients with chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:237-241. 104. Chaouat A, Weitzenblum E, Kessler R, et al. Outcome of COPD patients with mild daytime hypoxaemia with or without sleeprelated oxygen desaturation. Eur Respir J 2001;17:848-855. 105. Lewis CA, Ferguson W, Eaton T, et al. Isolated nocturnal desaturation in COPD: prevalence and impact on quality of life and sleep. Thorax 2009;64:133-138. 106. Goldstein RS, Ramcharan V, Bowes G, et al. Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N Engl J Med 1984;310:425-429. 107. Chaouat A, Weitzenblum E, Kessler R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999;14:1002-1008. 108. Krachman SL, Chatila W, Martin UJ, et al. Effects of lung volume reduction surgery on sleep quality and nocturnal gas exchange in patients with severe emphysema. Chest 2005;128:3221-3228. 109. Connaughton JJ, Douglas NJ, Morgan AD, et al. Almitrine improves oxygenation when both awake and asleep in patients with hypoxia and carbon dioxide retention caused by chronic bronchitis and emphysema. Am Rev Respir Dis 1985;132:206-210. 110. Saas-Torres J, Domingo C, Moron A, et al. Long-term effects of almitrine bismesylate in COPD patients with chronic hypoxaemia. Respir Med 2003;97:599-605.



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111. Series F, Cormier Y. Effects of protriptyline on diurnal and nocturnal oxygenation in patients with chronic obstructive pulmonary disease. Ann Intern Med 1990;113:507-511. 112. Dolly FR, Block AJ. Medroxyprogesterone acetate and COPD. Effect on breathing and oxygenation in sleeping and awake patients. Chest 1983;84:394-398. 113. Saaresranta T, Aittokallio T, Utriainen K, et al. Medroxyprogesterone improves nocturnal breathing in postmenopausal women with chronic obstructive pulmonary disease. Respir Res 2005;6:28. 114. Mulloy E, McNicholas WT. Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148:1030-1036. 115. Veale D, Cooper BG, Griffiths CJ, et al. The effect of controlledrelease salbutamol on sleep and nocturnal oxygenation in patients with asthma and chronic obstructive pulmonary disease. Respir Med 1994;88:121-124. 116. Martin RJ, Bartelson BL, Smith P, et al. Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD. Chest 1999;115:1338-1345. 117. McNicholas WT, Calverley PM, Lee A, et al. Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD. Eur Respir J 2004;23:825-831. 118. Lin CC. Comparison between nocturnal nasal positive pressure ventilation combined with oxygen therapy and oxygen monotherapy

in patients with severe COPD. Am J Respir Crit Care Med 1996;154:353-358. 119. Clini E, Sturani C, Rossi A, et al. The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients. Eur Respir J 2002;20:529-538. 120. Meecham Jones DJ, Paul EA, Jones PW, et al. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med 1995;152:538-544. 121. Fletcher EC, Schaaf JW, Miller J, et al. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987;135:525-533. 122. Martin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010;182:325-331. 123. Kryger M, Wang-Weigand S, Zhang J, et al. Effect of Ramelteon, a selective MT1/MT2-receptor agonist, on respiration during sleep in mild to moderate COPD. Sleep Breath 2008;12: 243-250. 124. Kryger M, Roth T, Wang-Weigand S, Zhang J. The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Sleep Breath 2009;13:79-84.

Restrictive Lung Disorders Juan F. Masa and Meir H. Kryger

Abstract Diseases of structures adjacent to the lungs, such as obesity and kyphoscoliosis, lead to extrapulmonary lung restriction and frequently result in breathing problems during sleep and consequent daytime symptoms, as well as significant physiologic perturbations. The most severe cases engender hypoventilation and cardiorespiratory failure. In addition to potentially imposing mechanical limitation on the chest wall, obesity also increases risk for upper airway obstruction and obstructive sleep apnea. Obesity also increases the risk for hypercapnia during wakefulness, known as obesity hypoventilation syndrome. This syndrome is usually treated with continuous positive airway pressure or noninvasive intermittent mechanical ventilation (NIMV), with additional efforts directed toward

Resting lung volume (the volume at the end of a normal exhalation) is determined by the balance between the elasticity and inward recoil of the lung and the outward recoil properties of the chest wall. The former tends to reduce lung volume. Forces that tend to preserve or increase lung volume include the normal, inherent mechanical tendency of the chest wall (considered to consist of three components: the thoracic cage, diaphragm, and abdomen) to recoil outward, as well as tonic inspiratory muscle activity. Restriction of lung expansion may thus be the result of disorders of the lung parenchyma (intrapulmonary restriction) or disorders of structures adjacent to the lungs, such as the skeletal and soft tissue components of the chest wall (extrapulmonary restriction). The physiologic consequences of these two types of restriction are different and result in different effects on respiratory control mechanisms. In general, intrapulmonary restriction is characterized by stimulation of pulmonary vagal receptors, with subsequent tachypnea (e.g., rapid, shallow breathing) and hyperventilation. Patients with extrapulmonary restriction may exhibit blunted ventilatory chemosensitivity and hypoventilation. On the basis of differences during the awake state, one would expect these two groups to behave differently during sleep. Extrapulmonary restriction is most commonly associated with obesity, kyphoscoliosis, neuromuscular diseases, and pregnancy, and intrapulmonary restriction with interstitial lung disease and lung resection. Sleep disorders during pregnancy are reviewed in detail in Chapter 139, and neuromuscular diseases are reviewed in Chapter 88.

OBESITY Definition, Epidemiology, and Risk Factors Obesity is a condition that occurs when body fat exists in excess to the extent that health is impaired.1 The most common clinical measure of obesity in adults and children is the body mass index (BMI).1,2 In adults, the BMI thresholds for overweight and obesity are 25 kg/m2 (Asians, 23) and 30  kg/m2 (Asians, 27), respectively. Children are 1308

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weight loss. Kyphoscoliosis, which is associated with reduced chest wall compliance and ventilatory muscle inefficiency resulting in hypoventilation, is usually treated with NIMV. Diffuse pulmonary parenchymal diseases resulting in intrapulmonary lung restriction have many causes, the most common being idiopathic pulmonary fibrosis or cryptogenic fibrosing alveolitis. In these cases, stimulation of pulmonary receptors results in a rapid, shallow breathing pattern and hyperventilation, which also serves to mitigate hypoxemia to varying degrees. Daytime symptoms such as dyspnea predominate, but significant hypoxemia may occur especially during sleep. The most common treatment for sleep hypoxemia in these cases is oxygen therapy. Sleep apnea is uncommon in this group, although its frequency may be higher in those who are also obese.

overweight when their BMI is greater than or equal to the sex- and age-specific 95th percentile.2 In addition, waist circumference can be used to determine central obesity, which appears to be a better predictor of obesity-related diseases.3,4 Thresholds of 102 cm for men and 88 cm for women define central obesity. In the United States, the prevalence of obesity in adults increased from 13% to 32.9% between the 1960s and 2003-2004. In 2003-2004, 66% of adults and 16% of children and adolescents were overweight.5 Similar data were reported for Europe6 and other developed countries. However, more recent U.S. data do not show a statistical difference in prevalence of obesity between the 2003-2004 survey (32.9%) and the 2005-2006 survey (34.2%).7 Numerous studies have shown that obesity increases morbidity and mortality.1,4 Obesity is the second leading preventable cause of disease and death in the United States, surpassed only by tobacco use. Overweight and obesity are associated with significant pathophysiologic alterations and clinically relevant consequences including insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, certain forms of cancer, steatosis hepatitis, gastroesophageal reflux, obstructive sleep apnea (OSA), degenerative joint disease, gout, lower back pain, and polycystic ovarian syndrome.8 Some of these conditions are components of metabolic syndrome. A significant subset of obese people are considered metabolically healthy: they appear to be protected from obesity-related metabolic abnormalities9 and have a less abnormal inflammation profile.10 Obstructive sleep apnea syndrome (OSAS) has been reported in about 51% of people with obesity11 and in a majority of people with morbid obesity.12 OSAS has been hypothesized to be a predisposing factor for the development of metabolic syndrome.13 Pathogenesis Obese patients have compromised respiratory function while awake and seated. Their ventilatory function may become worse when they assume the supine position, and



it may deteriorate further during sleep. However, the compromise of respiratory function is not the same in all types of obesity.14 Predominantly abdominal adiposity (central obesity) may restrict the descent of the diaphragm and limit lung expansion to a greater degree than adipose tissue mass in other locations. Breathing during Wakefulness Obesity is associated with increased metabolic demands,  O2) and carbon reflected by increased oxygen uptake ( V  dioxide production ( VCO2). Thus, to sustain normal arterial blood gas tensions (Pao2 and Paco2), these individuals must maintain an elevated level of alveolar ventilation. Moreover, the work required to maintain the augmented ventilation is greater for obese individuals, mainly because of increased stiffness (reduced compliance) and reduced mobility of the thoracic cage. In obese patients, the load on the chest wall caused by adipose tissue reduces the capacity to recoil outward. Thus, resting lung volume (measured as functional residual capacity [FRC]) is reduced in these patients, with consequent reduction of oxygen stores in the lungs. In addition, during expiration, when lung volume falls below a certain level, airways at the lung bases begin to close, reducing ventilation to the alveoli subtended by these airways. Perfusion may continue to these poorly ventilated lung units and result in an imbalance between ventilation and perfu leading to a reduced V  ratio and causing  Q),  Q sion ( V hypoxemia. Breathing in the Supine Position In the supine position, the abdominal hydrostatic force is applied through the diaphragm to the lungs. In addition, the chest wall in obese patients (particularly in central obesity) is stiffer in the supine than in the upright position. Thus, FRC is further lowered in the supine compared with the seated or upright positions, which promotes greater   Q and more widespread regional reduction of the V ratio and greater consequent hypoxemia. Moreover, varying degrees of increased upper airway resistance during sleep further increases the work of breathing. This would be the case even in the absence of obstructive apnea, given the normal increase in airway resistance that usually accompanies sleep (see Chapters 23 and 101). Breathing during Sleep Obese patients may present with the following breathing abnormalities during sleep: • Heavy snoring without obstructive upper airway events or hypoxemia. Nocturnal hypoxemia and OSA are frequent in obese patients,11 although some of these individuals (generally those with lesser degrees of overweight or obesity) demonstrate only snoring as a sleep disturbance. • Hypoxemia with no demonstrable obstructive upper airway events. As discussed earlier, obesity-associated respiratory alterations are exacerbated when the patient lies down, especially in the supine position, leading to  mismatch and hypoxemia. Moreover, the abnor Q V mal respiratory system mechanics that may accompany obesity, in conjunction with normal sleep physiology such as the tendency for reduced ventilation (relative

CHAPTER 112  •  Restrictive Lung Disorders  1309

to wakefulness), hypotonia of the intercostal muscles, and lower lung volume (see Chapter 22), can lead to oxyhemoglobin desaturation and hypercapnia in about 10% of obese subjects even in the absence of OSA.11 Sleep Apnea and Hypoventilation Obesity is the greatest risk factor for developing OSA. Indeed, apneas and hypopneas or respiratory effort–related arousals15 can be observed together or with predominance of one of these events. Although many obese patients develop repetitive sleep obstructive events, some do not. Increased weight alone is not sufficient to cause OSA, and differences in neuromuscular control of upper airway muscles and variations in ventilatory control mechanisms can play a role. In obese individuals, the accumulation of fat in the lateral parts of the pharynx increases the extraluminal pressure and may alter the geometry of the upper airway, predisposing to the collapse.16 The variability in upper airway fat deposition may be related to sex and genetic17 factors. Nocturnal hypoventilation without daytime hypercapnia occurs in 29% of nonselected obese subjects and is frequently associated with OSA.8 Sometimes hypoven­ tilation is also present during wakefulness, reflecting obesity–hypoventilation syndrome (OHS), which may also be a component of the pickwickian syndrome (see later discussion of obesity–hypoventilation syndrome). OSA is discussed in detail in other chapters of this section. Clinical Features The clinical presentations of people with obesity reflect obesity-related comorbidities that can also affect sleep. For example, they might have diabetes, cardiovascular disease, joint diseases, or sleep breathing disorders. Many patients have combinations of symptoms related to several of these conditions. Diagnosis As previously discussed, the BMI is used to diagnose obesity.1,2 Cutoff points of 25 and 30 kg/m2 in white adults identify overweight and obesity, respectively. Waist circumference, waist-to-hip ratio, and neck circumference are other metrics of adiposity and body fat distribution. Waist circumference is a better predictor of associated cardiometabolic disorders than BMI, and it could be an additional indicator for monitoring changes in obesity (Table 112-1).3 Diagnoses of breathing-related sleep disorders should be confirmed by performing comprehensive polysomnography with or without monitoring of end-tidal or transcutaneous CO2 tension (Pco2tc).18 Less complete polysomnography or a cardiopulmonary sleep study (in hospital or at home) may be considered in selected patients with suspected OSA (see Chapter 105). Treatment Achieving and maintaining normal weight is a challenge, and strategies for treating obesity are beyond the scope of this chapter. Several institutions, medical societies, and national health departments have guidelines for management and prevention of obesity.19,20

1310  PART II / Section 13  •  Sleep Breathing Disorders Table 112-1  Parameters of Overweight and Obesity, and Relationship to Disease Risk Disease Risk* Relative to Normal Weight and Waist Circumference†

Underweight

BODY MASS INDEX (KG/M2)

OBESITY CLASS

102 CM (40 IN) WOMEN: >88 CM (35 IN)

—

—

Normal

18.5-24.9

—

—

—

Overweight

25.0-29.9

—

Increased

High

Obesity Extreme obesity

30.0-34.9

I

High

Very high

35.0-39.9

II

Very high

Very high

40.0+

III

Extremely high

Extremely high

*Disease risk for type 2 diabetes, hypertension, and cardiovascular disease. † Increased waist circumference can also be a marker for increased risk in persons of normal weight.

Dietary weight loss is recommended for overweight and obese patients with OSAS. However, lack of adherence to diet,21 regain of lost weight, and interindividual improvement variability are frequent.22 Large, randomized, placebo-controlled outcome studies are necessary for a full evaluation of the role of weight loss through dieting in OSAS patients. There are no randomized and controlled studies of the efficacy of bariatric surgery in sleep breathing disorders, but information from prospective long-term clinical series is now available. Accordingly, weight loss, secondary to bariatric surgery, leads to improvement in sleep quality and apnea-hypopnea index (AHI).23 Although a 1-year follow-up study showed complete resolution of OSA in only 1 of 24 patients,24 a metaanalysis reported a high resolution rate of sleep apnea (86%).25 Therefore, although more information is necessary, bariatric surgery may play a role in the treatment of morbidly obese patients with OSA, as an adjunct to less invasive and rapidly applicable first-line therapies (see Chapter 111).

OBESITY–HYPOVENTILATION SYNDROME Definition, Epidemiology, and Risk Factors The term obesity–hypoventilation syndrome describes the concurrence of diurnal hypoventilation (Paco2 > 45  mm  Hg) and obesity (BMI > 30) when other causes of alveolar hypoventilation, such as severe obstructive or restrictive pulmonary disease, significant kyphoscoliosis, severe hypothyroidism, neuromuscular diseases, or other central hypoventilation syndromes, can be excluded. Although OHS can exist without sleep apnea, approximately 90% of patients with OHS have OSA.26,27 Some confusion exists regarding the term pickwickian syndrome. Although it is a well-characterized entity that entails obesity, hypercapnic respiratory failure, periodic breathing, polycythemia, and cor pulmonale, sometimes it is inaccurately used to mean OHS plus sleep apnea regardless of other components of this syndrome.

The prevalence of OHS is unknown, but it is believed to affect a minority of the obese population. The prevalence of OHS in subjects with suspected sleep apnea varies from 10% to 30%, depending on the study method, BMI score, geographic location (where the patients were selected), and the AHI cutoff point used to diagnose sleep apnea.28 Morbid obesity (BMI > 40) is associated with a higher prevalence of OHS.29 This type of obesity is considered more common in women than in men, and some studies have identified a higher prevalence of OHS in women.30-32 Nevertheless, when several series of patients were examined together,33 OHS was diagnosed more frequently in men (66%). There are no clear risk factors for development of OHS in obese subjects except morbid obesity. Pathogenesis The mechanisms by which diurnal hypoventilation develops in patients with obesity are complex and not fully understood. Abnormal respiratory mechanisms (including respiratory muscle dysfunction), abnormal central responses to hypercapnia and hypoxia, neuro­ hormonal dysfunction (e.g., leptin resistance), and sleep disordered breathing have all been proposed. Respiratory Mechanics As discussed, the mechanical alterations on the respiratory system produced by obesity can cause respiratory muscle dysfunction34 and daytime hypercapnia. Control of Breathing Diminished responses in both hypercapnia and hypoxia have been observed in patients with OHS,35 but it is not entirely clear if the origin is primary (central) or is secondary to mechanical load. Some studies indicate that there is no genetic predisposition to diminished chemosensitivity,36 and that it can improve with noninvasive intermittent mechanical ventilation (NIMV),35,37 suggesting that a secondary origin is more probable. Because the mechanical alterations caused by obesity do not change with NIMV, the improvement in chemosensitivity would depend on other secondary factors (e.g., reduced buffering and muscle



fatigue). On the other hand, the assessment of central neural drive presents some interpretative difficulties. First, ventilatory pump (e.g., the chest wall, including ventilatory muscles) dysfunction may prevent evaluation of the central neural control of breathing because the dysfunction may impair translation of the central drive to breathe into measured ventilation. Second, the increased buffering capacity to chronic elevation of Paco2 could have a secondary effect on central “real” neural drive. These difficulties contribute to the absence of clear evidence to determine if reduced chemosensitivity has a primary or secondary origin. The hormone leptin, produced by fat cells and thought to reduce appetite, may also act in the nervous system to increase ventilation. Thus hypoleptinemia, or central ner­ vous system resistance to leptin’s ventilation-promoting effects, may promote daytime hypercapnia. Although leptinemia is elevated in obese subjects and OSA patients, the leptin level is almost twice as high in patients with OHS (obesity and daytime hypercapnia) as in patients with obesity without daytime hypercapnia, when measurements of AHI and obesity are similar.38 On the other hand, leptinemia decreases with NIMV treatment39 in the same way as daytime hypercapnia. Thus, some studies have showed correlation between leptinemia and daytime hypercapnia38,40 and between leptinemia and reduction of hypercapnic ventilatory response.41 Given that leptinemia is very high in patients with OHS and is associated with hypercapnia, the respiratory failure present in patients with OHS may result from leptin resistance in the central nervous system. Sleep When apneic events are present during sleep, they can cause transitory nocturnal hypoventilation (Videos 112-1 and 112-2). Daytime hypercapnia in patients with OSA has been associated with the ratio of event duration to interevent duration, which would indicate that diurnal and nocturnal hypercapnia depends on insufficient recovery from the hypoventilation produced by apneic events, especially during rapid eye movement (REM) sleep.42 Transitory hypercapnia would cause higher daytime serum bicarbonate (which results in increased blood buffering capacity) and consequent blunting of the central CO2 response.28 A similar mechanism can happen when nocturnal hypoventilation (especially during REM sleep) occurs without apneas and hypopneas. As most of the previous mechanisms are interconnected, the combined action of all (or the majority) of them is a more realistic explanation for daytime hypercapnia in patients with OHS (Fig. 112-1). Clinical Features The common clinical features of patients with OHS are obesity, a plethoric complexion, dyspnea, cyanosis, and evidence of right heart failure including peripheral edema.29 Such patients may not complain of dyspnea even when hypoxemia and hypercapnia are present. If OSA is present, other symptoms, such as loud snoring, nocturnal choking episodes with witnessed apneas, excessive daytime sleepiness, morning headaches, and tiredness, can be evidenced.

CHAPTER 112  •  Restrictive Lung Disorders  1311

Obesity

↑ Mechanical load

↑ Work breathing

Breathing sleep disorders

Leptin resistance

↑ Threshold arousal

Muscle deficiency

REM hypoventilation

Sleep apnea

Sleep hypercapnia Chemoreceptors blunting

↑ Serum bicarbonate

Daytime hypercapnia Figure 112-1  Potential mechanisms explaining how obesity can lead to daytime hypercapnia.

Diagnosis Clinicians should consider OHS in obese patients (BMI > 30) with daytime hypercapnia (Paco2 > 45 mm Hg) without the existence of other diseases that might cause hypercapnia, such as severe obstructive or restrictive pulmonary disease, significant kyphoscoliosis, severe hypothyroidism, neuromuscular diseases, or other central hypoventilation syndromes. Pulmonary function tests can be normal, but more commonly they show a mild to moderate restrictive disorder associated with the mechanical alterations of obesity. Laboratory testing should include thyroid function tests to exclude severe hypothyroidism, and a complete blood count to rule out secondary erythrocytosis. An electrocardiogram and echocardiogram can demonstrate right ventricular hypertrophy, right atrial enlargement, or pulmonary hypertension.26,30 An overnight sleep study may demonstrate a spectrum of findings: episodes of upper airway obstruction, sleep fragmentation, transitory oxygen desaturation and significant hypoventilation (increase in Paco2 of more than 10 mm Hg and oxygen desaturation) during REM sleep.31 In patients without relevant OSA, hypoventilation is the main finding (Fig. 112-2). There are no studies that recommend a limited cardiopulmonary sleep study (portable monitoring), instead of complete polysomnography, for the diagnosis of OSA in OHS. Treatment There are no established guidelines for treatment of OHS. The following paragraphs review the most frequently used therapies. Weight Loss The ideal treatment is weight loss. Return to a normal weight reverses respiratory insufficiency, pulmonary hypertension, and sleep disorders.43 However, it is difficult

% SAT O2

PCO2tc (mm Hg)

1312  PART II / Section 13  •  Sleep Breathing Disorders

trials that show which of these two treatments is more effective in nonselected patients, or if they are more effective than the ideal treatment, which is weight loss. Neither are there controlled trials that show whether the reper­ cussions of OHS (arterial and pulmonary hypertension, cardiovascular events, hospital admissions, and mortality) decrease at all with treatment or decrease more with one type of treatment over another.

100

0 100

0 W REM 1 2 3 4 MT

0

1

2

3

4

5

6

7

8

Figure 112-2  Transcutaneous PCO2 (PCO2tc), oxygen saturation (SATO2), and hypnogram in a patient with obesity–hypoventi­ lation syndrome without a significant number of apneas and hypopneas. MT, sleep recording loss resulting from movement; W, awake. (From Masa JF, Celli BR, Riesco JA, et al. Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest 1997;112:207-213, with permission.)

for these patients to achieve and maintain physiologically meaningful weight loss. Limited data exist about the effect of bariatric surgery in OHS44 and it is an alternative for only a minority of patients because of increased morbidity and mortality.45 Nevertheless, moderate weight loss (10 kg) achieves a decrease in Paco2, although this result has not been demonstrated over the long term.43 Ventilatory Support NIMV consists of the application of intermittent positive pressure ventilation, including fixed bilevel pressure devices, using nasal or naso-oral masks, with the objective of improving alveolar ventilation and letting the ventilatory muscles rest (Video 112-3). Series of cases have shown improvement in clinical markers, arterial blood gases, and sleep disorders with this treatment.32,46,47 In uncontrolled longitudinal studies, decreases in days of hospital admission have been observed.30,47 There are no controlled trials that have evaluated mortality, and decreased mortality is seen only in series of treated patients compared with other studies in which they were not treated.48 One small series of cases reported decreased mortality in treated patients versus patients who refused treatment.27 Although continuous positive airway pressure (CPAP) can correct nocturnal apneic events in patients with OHS, daytime Paco2 does not return to normal in all cases. At present, only one controlled and randomized study has assessed and compared the short-term efficacy of CPAP and NIMV treatments in 36 patients with OHS, selected for their acceptance and favorable response to an initial night of CPAP treatment.49 Clinical, Paco2, and polysomnographic improvements were similar in both groups. However, there are no randomized, controlled

Oxygen Therapy In a group of obese patients with nocturnal hypoventilation (and with normal daytime Paco2), oxygen therapy increased transcutaneous Pco2 during sleep when compared with NIMV.46 However, there are no randomized trials that evaluate the benefits of long-term oxygen therapy in patients with OHS, or oxygen therapy together with weight loss. Furthermore, oxygen treatment has not been compared with CPAP or NIMV in these patients. Although oxygen is frequently added to the circuits in patients in whom NIMV does not entirely resolve hypoxemia, data on the long-term benefits of adding nocturnal oxygen to CPAP or NIMV have not been published. If a trial of oxygen therapy is initiated, close monitoring of Paco2 is mandated to detect worsening of hypercapnia and potential acidosis. Drug Therapy Progesterone increases the chemical drive to breathe without altering lung mechanics. Few patients with classic OHS have been reported as receiving treatment with medroxyprogesterone acetate (MPA).50 Whether MPA is clinically useful in the long term is unclear. MPA might be used for patients with OHS who have an inadequate response to (or are unable to use) CPAP or NIMV, taking into account the secondary effects such as feminization in men and deep vein thrombosis. In summary, on the basis of the present state of knowledge, weight loss, CPAP to initial responders, and NIMV should be considered the most effective OHS treatments.

KYPHOSCOLIOSIS Definition, Epidemiology, and Risk Factors Scoliosis refers to a lateral curvature of the spine, whereas kyphosis refers to anteroposterior curvature of the spine. Kyphoscoliosis, a combination of the two that causes thoracic cage deformity, is usually (in 80% of cases) idiopathic in origin but may be the consequence of many diseases, including paralytic poliomyelitis, neurofibromatosis, Pott’s disease, ankylosing spondylitis, Marfan syndrome, and the mucopolysaccharidoses. Chest wall deformity is more common in females than males. Very severe kyphoscoliosis occurs in about 1 in 10,000 people. Pathogenesis Depending on the cause and degree of spinal curvature, kyphoscoliosis can produce ventilatory failure at ages ranging from adolescence to late adulthood. About 100 degrees of scoliotic curvature is present in patients with



kyphoscoliosis and respiratory failure; in most of the studies reporting on sleep in kyphoscoliosis, the spinal deformity has been of this magnitude.51,52 Respiratory Mechanics During wakefulness, these patients have the rapid, shallow breathing pattern typical of a marked restrictive defect. This pattern is adopted because it is associated with the reduced work of breathing in the context of the stiff chest wall associated with kyphoscoliosis. In addition, the ventilatory muscles, abnormally positioned because of the chest wall deformity, are inefficient. This also promotes the development of a breathing pattern that operates with the greatest efficiency. An important tradeoff is engendered by a rapid, shallow breathing pattern, because it is associated with relatively increased ventilation of the anatomic dead space (the larger, more central airways that do not participate in gas exchange) with a smaller percentage of the inspired tidal volume getting to the alveoli. The deformity also causes an abnormal distribution of inspired air, with   Q) consequent atelectasis and ventilation–perfusion ( V mismatching. The small tidal volumes probably also promote airway closure and thus perpetuate the atelectasis and its consequent hypoxemia.Another factor that may play a role is low FRC. Patients with a low FRC have reduced oxygen stores in the lungs. If such a patient becomes apneic, oxygen uptake from the lungs into the pulmonary circulation will continue with abnormally rapid depletion of oxygen stores, thus causing a precipitous drop in alveolar Po2. Compared with obesity, which is also an extrathoracic restrictive disorder, kyphoscoliosis shows a more rapid and shallow pattern of breathing. Control of Breathing Control of ventilation in patients with kyphoscoliosis may be abnormal for two reasons. First, the kyphoscoliosis might be caused by poliomyelitis, in which the defect in the respiratory drive may be secondary to involvement of the respiratory control system in the medulla oblongata, or it may be the result of weakness of the respiratory muscles. Second, the blunting of the drive may be acquired (e.g., related to a substantial mechanical load impairing translation of neural drive into output of the chest wall pump). Respiratory failure may first occur in patients with postpoliomyelitic kyphoscoliosis 20 to 30 years after acute infection and recovery. The ventilatory response to hypercapnia may be markedly reduced. This blunting of the hypercapnic drive may result from mechanical impairment (e.g., chest wall deformity, ventilatory muscle weakness) alone. However, when hypercapnia is present, peak ventilation remains well below the patient’s maximal voluntary ventilation, which suggests a primary defect in the ventilatory drive, although it might also result from ventilatory muscle fatigue or adaptation to minimize the work of breathing. The hypoxic ventilatory drive may also be blunted in some patients. Therefore, although in kyphoscoliosis without other secondary diseases (e.g., poliomyelitis) a primary defect in respiratory center cannot be ruled out, the most probable event is a secondary impairment due to mechanical load.

CHAPTER 112  •  Restrictive Lung Disorders  1313

Alterations during Sleep During sleep, especially during REM sleep, the physiologic tendency to hypoventilate and the change in mechanical properties, combined with the increased mechanical load produced by kyphoscoliosis (see earlier), cause increases respiratory muscular effort, which might lead to muscle fatigue, leading to hypoventilation and oxygen desaturation and increasing Paco2. These sleep abnormalities can promote or maintain daytime respiratory failure caused by muscle fatigue or blunting of the respiratory center.53 Accordingly, a positive correlation between awake Paco2 and nocturnal increases in Paco2 has been observed in some studies.54 That is, the greater the degree of hypercapnia is during wakefulness, the greater is the increase in Paco2 during sleep. The influence of sleep state on daytime hypoventilation occurs because most kyphoscoliotic patients treated only with nocturnal NIMV normalize their daytime Paco2.47,55 Clinical Features Although hypoventilation during wakefulness is chronic in patients with severe cases of kyphoscoliosis, in less severe cases it appears to be episodically precipitated by infections and, to a lesser extent, by pulmonary emboli or respiratory depressant agents, such as hypnotics or opiates. Patients with chronic hypoventilation show the effects of chronic hypoxemia, including polycythemia, pulmonary hypertension,56 and cor pulmonale. Patients may complain of excessive daytime sleepiness and disrupted nocturnal sleep.51 Some have severe nocturnal or morning headaches, probably caused by CO2 retention during sleep. Both hypercapnia and hypoxia are known to increase cerebral blood flow by vasodilation, which is the likely mechanism by which these headaches occur. Probably the physiologic alterations during sleep precede (and even cause) the awake manifestations, allowing, in theory, a potential preventive treatment with NIMV, especially in symptomatic patients.46,57 Diagnosis Kyphoscoliosis is easily diagnosed by physical examination, and its impact on physiology is documented by testing lung function and arterial blood gases. A Paco2 of greater than 45 mm Hg frequently involves treatment with NIMV (see later). In the most severe cases, sleep symptoms (nocturnal or morning headaches, sleepiness) and cardiorespiratory failure are common. Comprehensive polysomnography is normally indicated when OSA or nocturnal hypoventilation is suspected. Different respiratory patterns have been observed: CheyneStokes respiration (i.e., a periodic breathing pattern with or without apneas; see Chapter 100), central apneas, hypoventilation (primarily during REM sleep),52 and obstructive apneas.51 Apnea duration is substantially greater in REM sleep than in non-REM sleep. Nevertheless, in patients not selected for suspected sleep apnea, the most common clinical finding is a low number of obstructive events.54,55 Common findings include sleep fragmentation,52 desaturation, and Paco2 rise, especially in REM sleep (Fig. 112-3). The lowest oxyhemoglobin saturation (Sao2) during the night is less than 60% in most reported

1314  PART II / Section 13  •  Sleep Breathing Disorders 100

0

0

100

100

0

0

W REM 1 2 3 4 MT

W REM 1 2 3 4 MT

% SAT O2

PCO2tc (mm Hg)

100

0

1

2

3

4

5

6

7

0

1

2

3

4

5

6

7

Figure 112-3  Transcutaneous PCO2 (PCO2tc), oxygen saturation (SATO2), and hypnogram in a patient with kyphoscoliosis. Left: Before treatment with noninvasive intermittent mechanical ventilation. Right: After treatment. MT, sleep recording loss resulting from movement; W, awake. (From Masa Jiménez JF. Mechanical ventilation at home: current perspectives. Arch Bronconeumol 1994;30:29-39, with permission.)

cases.51,52 Patients with the most severe drops in Sao2 are more likely to develop cor pulmonale.52 Treatment Untreated patients with kyphoscoliosis, respiratory failure, and cor pulmonale have a poor prognosis. Tracheostomy alone, which was used in the past in an attempt to reduce anatomic dead space, is now probably indicated on rare occasions. The use of tracheostomy does not result in consistent improvement in respiratory failure unless it is accompanied by mechanical ventilation58 (see Other Treatments, later). Continuous Positive Airway Pressure Because of the stiffness of the chest wall, continuous pressure alone may, when increasing end-expiratory volume, adversely influence the patient’s ability to breathe in and thus may cause distress or worsen gas exchange. CPAP is therefore not recommended unless that OSAS is documented. Noninvasive Intermittent Mechanical Ventilation NIMV used at home can be expected to be effective, and excellent long-term results have been reported47,55 (see Chapter 114). With such treatment, improvements can be expected in clinical symptoms, quality of life,59 nocturnal hypoventilation, and quality of sleep (see Fig. 112-3), as well as improvement or reversal of the hypercapnic respiratory failure. Other studies have found improvement in muscular performance,55 exercise capacity, and reduction in hospitalization days.47 There is no information about mortality with NIMV treatment, because no controlled and randomized clinical trials have been performed. However, such trials are not considered ethically feasible because of the cumulative favorable clinical and physiologic results reported in clinical series. Today, NIMV is indicated in patients with hypercapnic respiratory failure

or exclusively nocturnal hypoventilation with significant related clinical symptoms.46,57 In the latter case, NIMV could possibly be a preventive treatment. Like patients with severe chronic obstructive pulmonary disease,60 kyphoscoliotic patients who are chronic users of NIMV exhibit clinical and physiologic improvement during exercise.61 Other Treatments Because of the presence of a ventilation–perfusion imbalance caused by mechanical alteration, long-term oxygen therapy was historically considered an alternative to invasive mechanical ventilation. Although oxygen admini­ stration increases Sao2 during sleep, dyspnea, morning headache, and sleepiness are not always improved.46 Some longitudinal studies have shown better survival with NIMV (or with NIMV plus oxygen) than long-term oxygen therapy alone.62,63 When ventilatory support is not possible with noninvasive modalities, a tracheostomy may become necessary in severe disease. Tracheostomy and appropriate nighttime ventilation have resulted in dramatic improvements in Paco2 and in Pao2 during wakefulness, and in a normalization of hematocrit,59 as well as in better survival than long-term oxygen therapy.62 If invasive or noninvasive ventilator supports are not possible, oxygen is an alternative, although a somewhat unattractive one, because daytime and nocturnal Pco2 can rise. Thus, appropriate monitoring is indicated.

INTERSTITIAL LUNG DISEASE Definition, Epidemiology, and Risk Factors The common factor in this group of diseases reflecting intrathoracic restriction is the accumulation of abnormal cells, tissues, or fluid in the interstitial space of the lung.



This alters the mechanical properties of the lung, making it substantially stiffer and increasing its recoil, which reduces lung volume. Although diffuse interstitial lung disease (ILD) can be caused by over a hundred diseases, the most commonly responsible are idiopathic pulmonary fibrosis (also called cryptogenic fibrosing alveolitis), sarcoidosis, occupational dust exposures, malignancy, and reactions to drugs. Pathogenesis Respiratory Mechanics Patients with ILD have a rapid, shallow breathing pattern thought to be related to stimulation of receptors in the lung by the pathologic process in the lungs resulting in increased vagal afferent activity. The resultant level of ventilation is usually excessive for the level of CO2 production, which causes hypocapnia to occur.64 Alterations during Sleep Breathing frequency tends to remain high, but it may decrease during sleep. Hypoxemia during sleep is common in these patients,65 in particular during REM sleep.66,67 Lung volume is reduced in patients with ILD during wakefulness, and it may be further reduced during REM sleep. Transcutaneous Pco2 can remain at the same levels as during wakefulness,68 or it may increase, as seen in normal subjects.58 Severe hypoventilation does not seem to occur, at least until there is advanced impairment of pulmonary function.58,67 Therefore, hypoxemia may be caused by decreased lung volume during REM sleep and physiologic hypoventilation, because Sao2 and Pao2 during wakefulness are, at least in part, maintained by the hyperventilation. The degree that oxygenation worsens will depend on the starting position over the oxyhemoglobin dissociation curve, resulting in larger swings in Sao2 in response to changes in ventilation than during wakefulness.69 Sleep apnea has been uncommonly reported in patients with ILD.66 However, in a more recent study of patients with cryptogenic fibrosing alveolitis who were selected for the presence of symptoms of OSA, a 61% prevalence rate of OSA was reported.70 In the same study, AHI was correlated with BMI and forced vital capacity (FVC). Obesity is the main risk factor for developing OSA, but low lung volume produces upper airway instability,71 favoring obstructive events during sleep. In a study of patients with sarcoidosis, the prevalence of OSA was 17% as opposed to 3% in the control group.72 It is probable that weight increase caused by corticosteroid treatment plays a role. In other words, ILD is more likely to be associated with OSA in the subgroup of patients who have lower lung volume or obesity (ILD overlap). Clinical Features During wakefulness, patients with ILD have dyspnea, which may become quite severe with exercise. Nonproductive cough is another common symptom. Patients with ILD have symptoms related to sleep alteration. Disrupted sleep can lead to impaired quality of life, mainly associated with hypoxemia (Video 112-4).61,73 Because corticosteroid treatment may lead to obesity, clinicians must be aware of and be prepared to identify

CHAPTER 112  •  Restrictive Lung Disorders  1315

patients with ILD and OSA, as they may benefit from CPAP treatment. Diagnosis Several methods may be used to determine the physiologic impact of ILD (lung function tests, exercise oximetry) and for diagnosis (chest radiograph, computerized tomography, and lung biopsy). Daytime symptoms, especially dyspnea, can be quite severe, so in general these patients are not referred to a sleep laboratory, and therapy is directed toward attempts to reverse the lung disease and toward the use of oxygen (depending on arterial blood gases, or sometimes exercise oximetry). Nevertheless, it could be appropriate to monitor nocturnal Sao2 in patients without significant awake hypoxemia but with compli­ cations suggestive of chronic hypoxemia, such as cor pulmonale or polycythemia.74 Polysomnography has documented that patients with ILD have very disrupted sleep, with more arousals, sleepstage changes, sleep fragmentation, and periodic leg movement than normal individuals.66,75 Patients with an Sao2 of less than 90% had more disrupted sleep than did those with an Sao2 of greater than 90%. Sleep stages were also redistributed, with a marked increase in stage 1 and a reduction in REM sleep. Hypoxemia, especially during REM, can provoke arousal and sleep disruption.64 These hypoxemic episodes tend to be brief, so mean sleep Sao2 values may fall only slightly from awake values. Desaturation will decrease as the wakeful baseline Sao2 decreases.67 The maximal drop in Sao2 is similar to that seen during maximal exercise.76 In addition, a subgroup of patients could have ILD overlap and related symptoms of both ILD and OSA.70,72 Nocturnal oximetry can be applied to evaluate the oxygenation level in patients with cor pulmonale or polycythemia without important daytime hypoxemia and to properly adjust the oxygen flow. Polysomnography should be performed when OSA is clinically suspected. Treatment In view of the high drive to breathe and the low incidence of apnea, it is unlikely that nocturnal oxygen therapy would cause either significant apneas or hypoventilation. There are no randomized clinical trials examining the use of oxygen in patients with ILD. In the absence of any literature dealing with indications for nocturnal oxygen therapy in this group, it seems prudent to start with the criteria of the Nocturnal Oxygen Therapy Trial group.77 Supplemental oxygen would thus be used if awake Pao2 is less than 55 mm Hg, or if it is less than 60 mm Hg in the presence of hypoxemic complications (polycythemia or peripheral edema). However, because many of these patients desaturate rapidly with minimal exercise, criteria for home oxygen therapy should be more liberal, and many centers use exercise oximetry as a guide in determining the need for and flow of home oxygen. Some patients may need oxygen therapy only with exercise. Another possible indication for oxygen therapy could be significant desaturation during sleep. As mentioned, nocturnal hypoxemia provokes arousals and sleep fragmentation, and it has been correlated with impairment of quality of life.65 However, oxygen administration improved

1316  PART II / Section 13  •  Sleep Breathing Disorders

Sao2 and decreased heart rate and breathing frequency, but it had little effect on sleep efficiency or arousal rate.78 Moreover, nocturnal hypoxemia depends on the level of awake oxygenation,65,67 so for most patients, significant hypoxemia during sleep is an indication for oxygen therapy according to conventional recommendations. Even so, it could be indicated in patients without significant awake hypoxemia (Pao2 > 60) and complications suggesting chronic hypoxemia, such as cor pulmonale or polycythemia. CPAP should be the treatment of choice for symptomatic patients with ILD overlap, but only if testing has confirmed a positive treatment effect. Some of these patients may tolerate bilevel devices better than fixed continuous-pressure devices. ❖  Clinical Pearls Patients with extrapulmonary lung restriction may develop severe hypoventilation during sleep, resulting in cardiorespiratory failure. Treatment with noninvasive mechanical ventilation can result in improved clinical status and even resolution of daytime hypo­ ventilation. Patients with intrapulmonary restriction generally hyperventilate, and OSA is uncommon unless they have additional risk factors, such as obesity caused by corticosteroid treatment.

REFERENCES 1. World Health Organization: Obesity: preventing and managing the global epidemic—report of a WHO consultation on obesity. Geneva, World Health Organization, 1998. p. 1-276. 2. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data 2000;314:1-27. 3. Klein S, Allison DB, Heymsfield SB, et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America’s health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Obesity (Silver Spring) 2007;15(5):1061-1067. 4. Zhang C, Rexrode KM, Van Dam RM, et al. Abdominal obesity and the risk of all-cause, cardiovascular and cancer mortality: sixteen years of follow-up in US women. Circulation 2008 Apr 1;117 (13):1658-1667. 5. Wang Y, Beydoun MA. The obesity epidemic in the United States: gender, age, socio-economic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev 2007;29:6-28. 6. James PT, Rigby N, Leach R. The obesity epidemic metabolic syndrome and future prevention strategies. Eur J Cardiovasc Prev Rehabil. 2004;11(1):3-8. 7. Overweight and obesity: overweight and obesity trends among adults. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/index.htm. Accessed September 1, 2008. 8. Haslam DW, James WP. Obesity. Lancet 2005;366:1197-1209. 9. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population. (NHANES 1999-2004). Arch Intern Med 2008;168(15):1617-1624. 10. Karelis AD, Faraj M, Bastard JP, et al. The metabolically healthy but obese individual presents a favorable inflammation profile. J Clin Endocrinol Metab 2005;90:4145-4150. 11. Resta O, Foschino-Barbaro MP, Legari G, et al. Sleep-related breathing disorders, loud snoring and excessive daytime sleepiness in obese subjects. Int J Obes Relat Metab Disord 2001;25:669-675.

12. Valencia-Flores M, Orea A, Castano VA, et al. Prevalence of sleep apnea and electrocardiographic disturbances in morbidly obese patients. Obes Res 2000;8:262-269. 13. Kono M, Tatsumi K, Saibara T, et al. Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest 2007;131:1387-1392. 14. Ochs-Balcom HM, Grant BJB, Muti P, et al. Pulmonary function and abdominal adiposity in the general population. Chest 2006; 129:853-862. 15. Exar EN, Collop NA: The upper airway resistance syndrome. Chest 1999;115:1127-1139. 16. Crummy F, Piper AJ, Naughton MT. Obesity and the lung: 2. Obesity and sleep-disordered breathing. Thorax 2008;63(8): 738-746. 17. Lam B, Ip MS, Tench E, et al. Craniofacial profile in Asian and white subjects with obstructive sleep apnoea. Thorax 2005;60(6): 504-510. 18. Iber C, Ancoli-Israel S, Chesson A, Quan SF, for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, Ill: American Academy of Sleep Medicine; 2007. 19. National Institutes of Health: Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Bethesda, Md: NIH, 1998. Available at: http://www.nhlbi.nih.gov/ guidelines/obesity. Accessed September 1, 2008. 20. Lau DC, Douketis JD, Morrison KM, et al, for Obesity Canada Clinical Practice Guidelines Expert Panel. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children. CMAJ 2007:176(Suppl. 8):S1-S13. Available at: http:// www.cmaj.ca/cgi/content/full/176/8/S1. 21. Lam B, Sam K, Mok WY, et al. Randomized study of three nonsurgical treatments in mild to moderate obstructive sleep apnea. Thorax 2007;62:354-359. 22. Schwartz AR, Gold AR, Schubert N, et al. Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am Rev Resp Dis 1991;144:494-498. 23. Haines KL, Nelson LG, Gonzalez R, et al. Objective evidence that bariatric surgery improves obesity-related obstructive sleep apnea. Surgery 2007;141:354-358. 24. Lettieri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med 2008;4(4): 333-338. 25. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724-1728. 26. Kessler R, Chaovat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive case. Chest 2001;120:369-376. 27. Perez del Llano LA, Golpe R, Ortiz Piquer M, et al. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005;128: 587-594. 28. Mokhlesi B, Tulaimat A, Faibursowitsch I, et al. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007;11:117-124. 29. Mokhlesi B, Kryger MH, Grustein RR. Assessment and management of patients with obesity hypoventilation syndrome. Proc Am Thorac Soc 2008;15:218-225. 30. Berg G, Delaise K, Manfreda J, et al. The use of health-care resources in obesity-hypoventilation syndrome. Chest 2001;120: 377-383. 31. Berger KI, Ayappa I, Chatr-Amontri B, et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest 2001;120:1231-1238. 32. Masa JF, Celli BR, Riesco JA, et al. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001;119:1102-1107. 33. Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest 2007;132:1322-1336. 34. Kress JP, Pohlman AS, Alverdy J, et al. The impact of morbid obesity on oxygen cost of breathing (VO2RESP) at rest. Am J Respir Crit Care Med 1999;160:883-886. 35. Chouri-Pontarollo N, Borel JC, Tamisier R, et al. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: impact of noninvasive ventilation. Chest 2007;131:148-155.

36. Jokic R, Zintel T, Sridhar G, et al. Ventilatory responses to hypercapnia and hypoxia in relatives of patients with the obesity hypoventilation syndrome. Thorax 2000;55:940-945. 37. De Lucas-Ramos P, De Miguel-Diez J, Santacruz-Siminiani A, et al. Benefits at 1 year of nocturnal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Respir Med 2004;98:961-967. 38. Phipps PR, Starritt E, Caterson I, et al. Association of serum leptin with hypoventilation in human obesity. Thorax 2002;57:75-76. 39. Yee BJ, Cheung J, Phipps P, et al. Treatment of obesity hypoventilation syndrome and serum leptin. Respiration 2006;73:209-212. 40. Shimura R, Tatsumi K, Nakahara Y, et al. Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest 2005;127:543-549. 41. Campo A, Frühbeck G, Zulueta JJ, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J 2007;30:223-231. 42. Ayappa I, Berger KI, Norman RG, et al. Hypercapnia and ventilatory periodicity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166:1112-1115. 43. Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005;118:948-956. 44. Martí-Valeri C, Sabaté A, Masdevall C, et al. Improvement of associated respiratory problems in morbidly obese patients after open roux-en-y gastric bypass. Obes Surg 2007;17:1102-1110. 45. Surgeman HJ, Fairman RP, Sood RK, et al. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr 1992;55:5975-6015. 46. Masa JF, Celli BR, Riesco JA, et al. Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest 1997;112:207-213. 47. Janssens JP, Derivaz S, Breitenstein E, et al. Changing patterns in long-term non-invasive ventilation: a 7-years prospective study in the Geneva lake area. Chest 2003;123:67-79. 48. Budweiser S, Riedl SG, Jörres RA, et al. Mortality and prognostic factors in patients with obesity-hypoventilation syndrome undergoing non-invasive ventilation. J Intern Med 2007;261:375-383. 49. Piper AJ, Wang D, Yee BJ, et al. Randomized trial of CPAP vs bi-level support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation. Thorax 2008;63:395-401. 50. Hudgel DW, Thanakitcharu S. Pharmacologic treatment of sleepdisordered breathing. Am J Respir Crit Care Med 1998;158:691-699. 51. Guilleminault C, Kurland G, Whikle R, et al. Severe kyphoscoliosis, breathing, and sleep: the “Quasimodo” syndrome during sleep. Chest 1981;79:626-630. 52. Mezon BL, West P, Israel J, et al. Sleep breathing abnormalities in kyphoscoliosis. Am Rev Respir Dis 1980;122:617. 53. McNicholas WT. Impact of sleep in respiratory failure. Eur Respir J 1997;10:920-933. 54. Sawika EH, Branthwaite MA. Respiration during sleep in kyphoscoliosis. Thorax 1987;42:801-808. 55. Gonzalez C, Ferris G, Diaz J, et al. Kyphoscoliotic ventilatory insufficiency: effects of long-term intermittent positive-pressure ventilation. Chest 2003;124:857-862. 56. Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005;172:1072-1077. 57. Clinical indications for non-invasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease COPD, and nocturnal hypoventilation—a consensus conference report. Chest 1999;116:521-534. 58. Hoeppner VH, Cockcroft DW, Dorman JA, et al. Night-time ventilation improves respiratory failure in secondary kyphoscoliosis. Am Rev Respir Dis 1984;129:240-243.

CHAPTER 112  •  Restrictive Lung Disorders  1317 59. Windisch W, Freidel K, Schucher B, et al. The Severe Respiratory Insufficiency (SRI) Questionnaire: a specific measure of healthrelated quality of life in patients receiving home mechanical ventilation. J Clin Epidemiol 2003;56:752-759. 60. Van’t Hul A, Gosselink R, Hollander P, et al. Acute effects of inspiratory pressure support during exercise in patients with COPD. Eur Respir J 2004;23:34-40. 61. Vila B, Servera E, Marin J, et al. Noninvasive ventilatory assistance during exercise for patients with kyphoscoliosis: a pilot study. Am J Phys Med Rehabil 2007;86:672-677. 62. Chailleux E, Fauroux B, Binet F, et al. Predictors of survival in patients receiving domiciliary oxygen therapy or mechanical ventilation. A 10-year analysis of ANTADIR observatory. Chest 1996; 109:741-749. 63. Gustafson T, Franklin KA, Midgren B, et al. Survival of patients with kyphoscoliosis receiving mechanical ventilation or oxygen at home. Chest 2006;130:1828-1833. 64. Lourenco RV, Turino GM, Davidson LA, et al. The regulation of ventilation in diffuse pulmonary fibrosis. Am J Med 1965;38: 199-216. 65. Clark M, Cooper B, Sigh S, et al. A survey of nocturnal hypoxemia and cryptogenic fibrosing alveolitis. Thorax 2001;56:482-486. 66. Perez-Padilla R, West P, Lertzman M, et al. Breathing during sleep in patients with interstitial lung disease. Am Rev Respir Dis 1985;132:224-229. 67. Tatsumi K, Kimuar H, Kunitomo F, et al. Arterial oxygen desaturation during sleep in interstitial pulmonary disease: correlation with chemical control of breathing during wakefulness. Chest 1989;95:962-967. 68. Shea SA, Winning AJ, McKenzie E, et al. Does the abnormal pattern of breathing in patients with interstitial lung disease persist in deep, non-rapid eye movement sleep? Am Rev Respir Dis 1989; 139:653-658. 69. McNicholas WT. Impact of sleep on ventilation and gas exchange in chronic lung disease. Monaldi Arch Chest Dis 2003;59:212215. 70. Mermigkis C, Chapman J, Polychronopoulus V, et al. Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis. Lung 2007;185:173-178. 71. Heinzer RC, Stanchina ML, Malhotra A, et al. Lung volume and continuous positive airway pressure requirements in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:11-117. 72. Turner GA, Lower EE, Corser B, et al. Sleep apnea in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1997;14:61-64. 73. Mermigkis C, Stagaki E, Amfilochiou A, et al. Sleep quality and associated daytime consequences in patients with idiopathic pulmonary fibrosis. Med Princ Pract 2009;18(1):10-15. 74. Fletcher EC, Luckett RA, Miller T, et al. Pulmonary vascular hemodynamics in chronic lung diseases patients with and without oxyhemoglobin desaturation during sleep. Chest 1989;95:757-766. 75. Prado G, Allen R, Trevisani V, et al. Sleep disruption in systemic sclerosis (scleroderma) patients: clinical and polysomnographic findings. Sleep Med 2002;2:341-345. 76. Midgren B, Hansson L, Eriksson L, et al. Pulmonary vascular hemodynamics in chronic lung diseases patients with and without oxyhemoglobin desaturation during sleep. Thorax 1987;42: 353-356. 77. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Intern Med 1980;93:391-398. 78. Vazquez JC, Perez-Padilla R. Effect of oxygen on sleep and breathing in patients with interstitial lung disease at moderate altitude. Respiration 2001;68:584-589.

Noninvasive Ventilation to Treat Chronic Ventilatory Failure Dominique Robert, Patrick Leger, and Mark W. Elliott Abstract Early experience with long-term home mechanical ventilation using either tracheostomy or negative pressure ventilation revealed that even patients with essentially no ventilatory function could be continuously supported, and individuals who retained partial ventilatory function could do well with intermittent (e.g., during sleep) ventilatory assistance. Recognition that noninvasive means of providing ventilatory support (e.g., using noninvasive interfaces such as nasal and oronasal masks and mouthpieces) often obviate or postpone the requirement for tracheostomy has resulted in the availability of this alternative for an increasing number of patients who now benefit from long-term ventilation. Patients with all categories of chronic respiratory diseases and consequent alveolar hypoventilation may benefit from

The first patient populations to receive long-term mechanical ventilation were those with sequelae of poliomyelitis or Duchenne’s muscular dystrophy (DMD). Either noninvasive (negative pressure body ventilators or positive pressure via mouthpiece) or invasive (tracheotomy) ventilation was used.1-3 Early experience revealed that even individuals with essentially no ventilatory function could be continuously supported, and patients who retained partial ventilatory function could be managed successfully with intermittent (e.g., during sleep) ventilatory assistance.2 It is now recognized that intermittent positive pressure ventilation can be delivered comfortably using a noninvasive interface.4 In light of its successful application, use of noninvasive positive pressure ventilation (NPPV) for long-term mechanical ventilation has increased substantially, both in patients with pulmonary restrictive disorders resulting from neuromuscular or chest wall disorders and, to a lesser degree, in patients with lung parenchymal disorders such as chronic obstructive pulmonary disease (COPD), although there are clear differences in practice in different countries.5 This chapter addresses the treatment of patients, other than those with sleep apnea, who require NPPV during sleep to achieve physiologic and clinical improvement while asleep as well as during wakefulness. In addition, we will contrast NPPV and negative pressure modalities.

INDICATIONS FOR NOCTURNAL NPPV Use of NPPV reflects a balance of (1) the disease process and its rate of progression, (2) the disease severity, and (3) the patient’s willingness to undertake this therapy. Diseases The principal diseases that may be successfully addressed using NPPV therapy are shown in Box 113-1. All may 1318

Chapter

113

chronic, noninvasive ventilatory assistance, but those with neuromuscular or chest wall disorders experience the best results and the longest extension of life. Clear evidence of benefit is still lacking for patients with chronic obstructive pulmonary disease. Careful choice and adjustment of masks and ventilator settings are key requisites for clinical success. Volume and pressure preset modes both provide good results, but pressure preset modes, which provide better leak compensation, are better suited for noninvasive ventilation. For some patients, such as those with advanced neuromuscular disorders, who need diurnal as well as nocturnal ventilatory assistance, noninvasive ventilation may be applied during wakefulness using mouthpiece interfaces. Although some patients can be continuously ventilated using noninvasive strategies (using either a mask or a mouthpiece, or both), ventilation via tracheostomy remains a treatment option.

become sufficiently severe to be life-threatening, or to cause alveolar hypoventilation that impairs quality of life. Factors to bear in mind when considering initiating nocturnal NPPV therapy include (1) the relative contributions of chest wall abnormalities, ventilatory muscle weakness, and pulmonary parenchymal pathology to hypoventilation, (2) the natural history of the disease progression (to anticipate the likelihood of evolution from NPPV use exclusively during sleep to requirement of diurnal ventilatory assistance), and (3) the associated comorbidities that may dominate the prognosis. Clinical Severity The presence of clinical symptoms (Box 113-2) or physiologic markers of hypoventilation are useful in identifying disease severity as it relates to deciding when to initiate nocturnal NPPV. The symptoms may be subtle, insidious, and not attributed to nocturnal hypoventilation by patients or nonspecialist health care providers. On close questioning, patients who present with life-threatening ventilatory failure may be found to have exhibited warning symptoms suggestive of nocturnal hypoventilation for some time. Education of patients at risk and those involved in their care is very important; patients should be advised to seek specialist advice if they develop any of the symptoms listed in Box 113-1. Hypoventilation is defined by an abnormally elevated arterial carbon dioxide tension (Paco2) and high serum bicarbonate levels with an associated reduction of arterial oxygen tension (Pao2). There are no validated values at which NPPV is definitely indicated, but many clinicians consider treating patients with nonneuromuscular disorders who have an awake Paco2 of greater than 50 to 55 mm Hg and a Pao2 of less than 65 mm Hg, and patients with a neuromuscular disorder with a Paco2 of greater than 45 mm Hg even with a Pao2 of greater than 65 mm Hg on room air.6 The degrees of severity at which NPPV may be considered are presented in Table 113-1.



CHAPTER 113  •  Noninvasive Ventilation to Treat Chronic Ventilatory Failure  1319

Box 113-1  Disorders for Which Benefit May Be Obtained from NPPV Therapy, Grouped by Clinical Category and PFT Profile Extrapulmonary Restrictive Disorders: ↓* VC, ↓* FEV1, ↔* FEV1/VC, ↓ RV, ↓ TLC Chest Wall Disorders Kyphoscoliosis Sequelae of thoracoplasty for tuberculosis Neuromuscular Disorders Spinal muscular atrophy Acid maltase deficit (Duchenne’s muscular dystrophy) Myotonic myopathy Amyotrophic lateral sclerosis Obstructive Lung Diseases: ↔ or ↓ VC, ↓ FEV1, ↓ FEV1/VC, ↑ RV, ↑ TLC Chronic obstructive pulmonary disease Bronchiectasis Cystic fibrosis Abnormal Central Ventilatory Control but Normal Lung Function; Normal PFT Idiopathic hypoventilation Obesity–hypoventilation syndrome *Symbols indicate actual compared with theoretical values: ↓ or ↑, decrease or increase; ↔, normal. FEV1, forced expiratory volume in 1 second; NPPV, noninvasive positive pressure ventilation; PFT, pulmonary function test; RV, residual volume; TLC, total lung capacity; VC, vital capacity.

Box 113-2  Clinical Features of Alveolar Hypoventilation • Shortness of breath during activities of daily living in the absence of paralysis • Orthopnea in patients with disordered diaphragmatic dysfunction* • Poor sleep quality: insomnia, nightmares, frequent arousals* • Nocturnal or early morning headaches* • Daytime fatigue and sleepiness, loss of energy* • Decrease in intellectual performance • Loss of appetite and weight loss • Appearance of recurrent complications: respiratory infections • Cor pulmonale *This symptom indicates an overnight polygraphy or polysomnography when clear diurnal hypoventilation does not exist.

Chronic daytime hypoventilation is an important indicator of a very low respiratory reserve and reflects an unstable state with increased susceptibility to life-threatening acute ventilatory failure that may be triggered by what may otherwise be trivial additional factors. Sleep-related hypoventilation is invariably present and precedes diurnal hypoventilation. Thus, a primary reason for overnight respiratory polygraphy or full polysomnography (PSG), which additionally allows sleep staging in patients with diurnal hypoventilation, is to rule out obstructive apnea, particularly in patients who are obese or have central apnea and chronic heart failure. In patients with mild or moderate underlying disease (e.g., a neuromuscular disorder) but no evidence of hypoventilation or hypercapnia during wakefulness (see Table 113-1), a sleep study is required to rule out sleep apnea and to document nocturnal hypoventilation, which may occur in all sleep stages but in some cases occur exclusively during rapid eye movement (REM) sleep, justifying a trial of NPPV. When full polysomnography is unavailable, an overnight recording of oxygen saturation by pulse oximetry (Spo2) (and, if possible, transcutaneous CO2 tension or end-tidal CO2 tension), as well as ribcage and abdominal excursion, may be useful in detecting hypoventilation-associated reduced ventilatory effort and to rule out upper airway obstruction. However, this strategy has not been subjected to high-quality, systematic study and should not be used to exclude sleep-related alveolar hypoventilation. Pulmonary function tests help define and quantify the ventilatory or respiratory disease and are a very useful guide to the possible presence of sleep-related hypoventilation, but they have poor predictive values in individual patients, for whom management requires expertise in sleep medicine and experience with NPPV. In clinical practice, NPPV is initiated either electively or in the context of acute ventilatory failure. In the latter circumstance, the long-term necessity for NPPV should be reevaluated during follow-up, because the need for NPPV may change as the clinical condition stabilizes.7 Indications for NPPV are listed in Table 113-2. NPPV is indicated in patients with restrictive diseases (including chest wall and neuromuscular disorders but not lung parenchymal disorders such as fibrosis) in the presence of clinical symptoms attributable to either diurnal or nocturnal hypoventilation.6,8 With increasing ventilator dependency, the daily duration of NPPV may be progressively extended from sleep time alone to throughout the 24-hour period.3 Alternatively, a tracheostomy may be performed

Table 113-1  Disease Severity at Which Noninvasive Positive Pressure Ventilation (NPPV) Can Be Considered CLINICAL SIGNS AND SYMPTOMS*

DIURNAL HYPOVENTILATION†

NOCTURNAL HYPOVENTILATION‡

+

Yes

Yes

Severe

+/−

No

Yes

Moderate

+/−

No

Yes

Mild

*See Box 113-1. † PaO2 < 65 mm Hg, and PaCO2 > 50-55 mm Hg. ‡ Proven at least with overnight SpO2, and possibly with CO2 recording (transcutaneous or end-tidal capnography).

SEVERITY

1320  PART II / Section 13  •  Sleep Breathing Disorders Table 113-2  Indications for Nocturnal Noninvasive Positive Pressure Ventilation (NPPV) According to Disease and Severity of Hypoventilation

DISEASE OR CONDITION

CLINICAL SIGN* + DIURNAL AND NOCTURNAL HYPOVENTILATION†

CLINICAL SIGN + ONLY NOCTURNAL HYPOVENTILATION‡

NOCTURNAL HYPOVENTILATION ONLY

NEITHER CLINICAL SIGNS NOR HYPOVENTILATION

MAINTENANCE ON NOCTURNAL NPPV (YR) >10-20

Scoliosis

Yes

Yes

Perhaps

No

Tuberculosis

Yes

Yes

No

No

10

  Stable or slowly progressive

Yes

Yes

Perhaps

No

10-15

  Intermediate progression

Yes

Yes

Yes

No

5

  Severe or rapidly progressive

Yes

Yes

Yes

No

0-5

Chronic obstructive pulmonary disease

Perhaps

No

No

No

1-5

Bronchiectasis, cystic fibrosis

Yes

Perhaps

No

No

1-5

Obesity– hypoventilation syndrome

Yes

Yes

Perhaps

No

>10-20

Neuromuscular disease

*Symptoms of chronic ventilatory failure (see Box 113-1). † PaO2 < 65 mm Hg, and PaCO2 > 50-55 mm Hg. ‡ Proven at least with overnight SpO2, and possibly with CO2 recording (transcutaneous or end-tidal capnography).

to facilitate ventilatory assistance.9 On the other hand, for patients with COPD, even with essentially the same symptoms (see Box 113-1), the evidence does not provide unequivocal support for benefit from NPPV. Observational cohorts treated with NPPV plus supplemental O2 did not experience improved survival. This was confirmed by two randomized control trials that did not show substantial benefits, although the studies were underpowered for this endpoint.10,11 One trial provides a possible small positive survival effect but at the cost of worsening quality of life.11a As a result, this question remains open, as parameters other than the survival, such as quality of life or hospitalization days, may have improved. Currently, NPPV may be considered as an option for patients with significant symptoms of hypoventilation or recurrent acute hypoventilation, superimposed on chronic ventilatory failure requiring hospitalization and treatment with NPPV, provided that all aspects of medical therapy, particularly long-term oxygen therapy, have been optimized. In cases of isolated sleep hypoventilation (i.e., in the absence of clinical symptoms during wakefulness and diurnal hypercapnia), NPPV may be indicated for diseases known to rapidly worsen, such as typically amyotrophic lateral sclerosis, but also for primary congenital neuromuscular disorders.8 All at-risk patients must receive regular follow-ups, and both patients and caregivers should be regularly reminded of warning symptoms and signs suggesting impending decompensation. There are limited data regarding the use of NPPV as prophylaxis to prevent acute ventilatory failure or to increase survival in patients who do not have chronic ventilatory failure. However, although frequently criticized

on methodological grounds, one study reported that there was no benefit of such use in patients with muscular dystrophy.12 Patients Needing Continuous NPPV With time, many patients, particularly those with progressive neuromuscular disease, require ventilatory assistance during wakefulness as well as during sleep. At this point, the clinician must reconsider the suitability of NPPV. An interface such as a nasal mask, which functions well during sleep, may be inappropriate during wakefulness. However, a mouthpiece may be a useful interface for intermittent daytime ventilation, and some patients can be ventilated overnight using a mouthpiece held in place with head straps and designed to limit leaks, making it an option for those requiring continuous ventilatory support.13 Another option is to vary the type of interface with the period of use—for example, nasal NPPV at night and NPPV via mouthpiece during the day (Fig. 113-1). This has been reported by different teams in stable but severely impaired neuromuscular patients, such as those with sequelae of poliomyelitis, high-level spinal cord injury, or Duchenne’s muscular dystrophy.14 Nevertheless, some clinicians prefer to create a tracheostomy when the need for ventilatory support approaches 24 hours a day, often because it ensures access to the airway and facilitates secretion removal. Continuation of NPPV assumes that the medical team, patient, family, and caregivers understand assisted cough and secretion removal techniques, especially because secretion clearance may be difficult under the best of circumstances when providing NPPV. There is no clear answer as to whether and beyond what



CHAPTER 113  •  Noninvasive Ventilation to Treat Chronic Ventilatory Failure  1321

Neurologic disorders that make it difficult for a patient to apply or adjust the interface increase the complexity of use at home, but success can be achieved by trained caregivers, who have an essential role in providing home care to severely impaired patients. Persistent or repeated difficulties with secretion clearance, resulting in chronically obstructed airways and infection, may be a contraindication to NPPV, but this can often be addressed by coughassisting techniques that can be routinely and efficiently applied by caregivers at home.9,17 Patients with secretion clearance problems caused by airway disease, however, usually have an effective cough in terms of mechanics, but their sputum is excessively viscid, so these devices are not effective.18

Figure 113-1  A patient requiring continuous ventilatory assistance is using only noninvasive ventilation. He uses a nasal mask during sleep and a mouthpiece during the day. The mouthpiece is positioned close to his mouth. He alternates between receiving insufflations from the ventilator (on the back of the wheelchair) and breathing spontaneously.

duration patients who require mechanical ventilatory assistance are better or more safely served by tracheostomy or NPPV. In our experience, patients with DMD who have been using NPPV for 16 to 20 hours per day and subsequently converted to ventilatory assistance via tracheostomy demonstrate weight gain and psychological improvement. This may be because during the daytime, ventilatory assistance that is consistently delivered via the tracheostomy frees the patient from having to repeatedly access a mouthpiece for a few assisted breaths and then release it. The most difficult cases involve patients with motor neuron disease, which usually devastates all muscle function within a few years of diagnosis. NIPPV or tracheostomy, or both, may prolong life despite further muscle loss, leading to a locked-in state or a state of minimal communication in 50% of these patients.15 This debate will probably continue, and, ultimately, the decision to convert to tracheostomy depends on the patient and the family environment and preferences as well as on the philosophy and capabilities of the clinical team. Discussion of such issues should begin early in the disease course, well before a crisis precipitates hasty decisions that are subsequently regretted, and an expert team should be involved for longterm mechanical ventilation. Contraindications There are no absolute contraindications to NPPV other than a patient’s unwillingness to use the equipment (e.g., because of claustrophobia) or a major deformity of the face or upper airway that precludes the use of noninvasive interfaces. Dynamic upper airway dysfunction leading to swallowing difficulties and aspiration (particularly frequent in patients with bulbar amyotrophic lateral sclerosis) makes acceptance of NPPV more difficult and may raise interest in switching to a tracheostomy. Nevertheless, many of these patients can still benefit from NPPV.16

Negative Pressure for Noninvasive Ventilation Negative pressure ventilators function by alternatively applying subatmospheric (negative) and atmospheric (zero) pressures around the thorax and the abdomen. The result is negative intrathoracic pressure that simulates spontaneous inspiration with airflow into the airway and lungs. Three categories of negative pressure ventilators are available.19 With the typical iron lung, the entire body, except the head, is exposed to negative pressure. The chest cuirass (a rigid shell) and wrap-type system (nylon poncho surrounding a semicylindrical tentlike support) are simply enclosures that allow application of negative pressure to the thorax. Because the efficacy in generating tidal volume is related to the degree of body surface area that is exposed to negative pressure, it is greater with the iron lung type than with cuirass or poncho type of negative pressure ventilators. Negative pressure ventilation was successfully and predominantly used for long-term mechanical ventilation until the mid-1980s,3,20,21 but then interest waned, partly because NPPV is more efficacious in patients with altered pulmonary or chest wall mechanics and in those who have comorbid obstructive sleep apnea–hypopnea. In addition, negative pressure ventilation may precipitate upper airway obstruction (i.e., obstructive sleep apnea–hypopnea).22 Furthermore, from a patient-use perspective, negative pressure modalities are cumbersome and relatively impractical.

TECHNICAL CONSIDERATIONS FOR NPPV Interfaces Selecting an appropriate interface and fitting it properly have a significant impact on the quality of ventilation and the patient’s sleep, comfort, tolerance, and compliance with therapy. Table 113-3 summarizes the advantages of, disadvantages of, and indications for a wide variety of interfaces. Nasal Interfaces Many nasal interfaces are commercially available, and they are frequently the first choice offered to the patient. Practical suggestions include (1) follow the manufacturer’s suggestions for proper sizing, using a gauge when supplied; (2) use the smallest mask size that encompasses the nose

1322  PART II / Section 13  •  Sleep Breathing Disorders Table 113-3  Interfaces for Noninvasive Positive Pressure Ventilation INTERFACE

ADVANTAGES

DISADVANTAGES

INDICATION

Nasal mask

Allows usual physiologic breathing Natural humidification Patient can speak and expectorate

Damage to nasal bridge Mouth leaks

First choice

  Commercially made

Large choice Easy to size

—

More preferred

  Custom made

Large contact area with face limits skin damage

Time consuming Risk of nares compression when internal space of the mask is too tight

Less preferred Better for volume-preset than pressure-preset ventilation

Mouthpiece (commercially available lip seal or customized)

Better control of leaks

Patient cannot expectorate or talk Aerophagia Initial hypersalivation Dental pain Orthodontic problem Nasal leaks No physiologic humidification

Nasal obstruction Massive oral air leaks Intermittent daytime ventilation

Oronasal mask (industrial or customized)

Control of oral air leaks

Less choice available for long-term use Difficult to size Claustrophobia Dead space Facial skin necrosis

Nocturnal use Massive air leaks

without pinching the nares; (3) use forehead supports; (4) avoid overtightening head straps to overcome air leaks, and tolerate minimal air leaks; (5) check the skin regularly, and if signs of a pressure sore develop, use mask or skin barriers, or alternate different types of interfaces (e.g., masks versus prongs). Cleaning the mask and skin before a ventilation session increases mask adhesion and limits leaks. Using the correct head gear for the interface and the right size for the patient is essential. Customized, made-to-measure nasal masks are an option for patients who present unusual challenges and have even been used routinely by some teams.4 Usually, such masks are directly molded on the face with formable material, such as silicone paste or thermoplastic, and they then maintain their shape. Making these masks requires skill and regular practice. When tidal-volume preset modes of ventilation are used, custom nasal interfaces have been found to limit leaks and dead space better than commercially available nasal masks.23 Nasal pillows or prongs can be useful when there is abrasion on the nasal bridge or when a nasal mask is considered too obtrusive. Some patients with limited arm movement have also found these interfaces to be easier to put on and remove. Oronasal (Full-Face) Masks When mouth leaks are significant and prevent adequate ventilatory support, a full-face or oronasal mask may be indicated. Oronasal mask ventilation is used extensively during acute ventilatory failure, and some clinicians estimate that as many as 30% to 40% of their patients receiving chronic ventilatory assistance use this type of interface.24 As with nasal masks, proper sizing minimizes

leaks and increases tolerance. Oronasal masks can add significant dead space, and ventilator settings need to be adjusted accordingly. To reduce CO2 rebreathing, the exhalation port has to be positioned properly, and during expiration, flow through the circuit should be maintained at an expiratory positive airway pressure (EPAP) level of at least 4  cm H2O.25,26,28,28a Oronasal interfaces should incorporate a safety valve to permit entrainment of fresh air in case of ventilator failure. The clinician must also consider the risk associated with vomiting and aspiration when the patient uses an oronasal interface. Patients should be counseled regarding this risk and advised to contact their physician if circumstances arise that would predispose to such events. Oral Interfaces Used during Sleep Some clinicians have had success using an oral interface (e.g., a mouthpiece) to apply noninvasive ventilation in patients with postpoliomyelitis.1 The oral interface may be either a commercial or a custom-made model. The main indications for a trial of this interface include unmanageable mouth leaks during nasal ventilation, and nasal obstruction. As with oronasal masks, major drawbacks of this type of interface include swallowing difficulties and potential aspiration risk, particularly in patients with esophageal reflux or vomiting, and the inability to speak. Furthermore, its use may be associated with swallowing difficulties. Clinicians should consider break-away head gear that will permit the patient to expel the mouthpiece, and they should incorporate a safety valve to permit entrainment of fresh air in case of ventilator failure. Since the development of better full-face masks, nocturnal mouthpiece ventilation is rarely used by most teams.



CHAPTER 113  •  Noninvasive Ventilation to Treat Chronic Ventilatory Failure  1323

Daytime Use of an Oral Interface An oral interface is primarily used for daytime ventilation and may be an excellent adjunct to nocturnal ventilation for patients who are unable to maintain acceptable diurnal arterial blood gases after nocturnal ventilation alone. For patients with neuromuscular diseases, the mouthpiece can be positioned close to the mouth, where it may be intermittently captured to take a few assisted breaths from the ventilator and then released (see Fig. 113-1). Thus, the patient needing assistance night and day may use a combination of interfaces. Ventilators Ventilators use one of two basic methods to deliver, assist in delivering, or augment tidal volume: volumepreset and pressure-preset (Table 113-4). A volume-preset ventilator always delivers the tidal volume that is set by the clinician, regardless of the patient’s pulmonary system mechanics (compliance, resistance, and active inspiration); however, leaks in the system (e.g., leaks at the skin–mask interface, or mouth leaks when using a nasal interface) reduce the volume received by the patient. On the other hand, with pressure-preset ventilators, changes in pulmonary mechanics directly influence the flow and possibly the delivered tidal volume; within limits, and depending on the type of ventilator, there is some compensation for leaks. With volume-preset delivery, two ventilator modes may be applied: either fully controlled (called control mode), in which the beginning and end of inspiration are uniquely initiated by the ventilator, or partially controlled (called assist-control), in which the patient can initiate (trigger) inspiration or, in the event of failure, the minimal rate set on the ventilator will deliver the breath. In pressure-preset delivery, an additional mode (called spontaneous) is available and is initiated when the end of inspiration occurs at a certain percentage (either determined automatically by the ventilator or set by the physician) of the maximal flow observed at the beginning of inspiration. Compared with conventional ventilators with the classical circuitry, including an expiratory valve, bilevel ventilators are simpler and therefore lend themselves to home

mechanical ventilation.27 These devices provide both inspiratory positive airway pressure and expiratory positive airway pressure (IPAP and EPAP) delivered via a single tubing circuit that incorporates an intentional, calibrated leak located close to the patient. The risk of CO2 rebreathing with such a circuit is decreased by using an EPAP of 2 to 4  cm H2O or more.25,28,28a In bilevel ventilators, the EPAP may be equated with positive end-expiratory pressure (PEEP), as used in more sophisticated critical care ventilators. In general, the modes and settings usually used in the intensive care unit are available for home ventilation. The objective in providing many possible settings is to be able to adapt and optimize patient–machine synchronization. Although this is conceptually attractive, not enough studies have been performed to document or refute the advantages of such complexity in the context of home ventilation.29 Some ventilators may analyze ventilation in real time, keep it in an internal memory, and provide data for future assessment. Few studies have compared volume- and pressure-preset ventilators. The results of short-term investigations show no major differences in the correction of hypoventilation in patients with neuromuscular and chest-wall restrictive disorders or COPD.30-32 These studies suggest that volume-preset ventilators are usually efficient, but that some patients respond better than others. Many clinicians prefer the pressure-preset ventilator for most patients, believing it offers better synchronization and is better able to compensate for leaks. However, clinicians should be flexible and try alternative approaches if problems occur with either type of ventilator. Assisted Coughing Techniques Techniques to assist secretion clearance are intended to mimic the physiologic cough. They provide inspiratory assistance consisting of high inspiratory volume followed by a high expiratory flow (or velocity) that serves to clear the airways. In patients with a neuromuscular disease, inspiration must be mechanically assisted by stacking normal tidal volumes without exhaling between them (thus requiring normal glottis functioning), or by delivering one

Table 113-4  Indications for Volume-Preset and Pressure-Preset Ventilators for Home Mechanical Ventilation VOLUME PRESET

PRESSURE PRESET

Advantages

Tidal volume always delivered Internal batteries provide long-duration electrical autonomy

Comfort Responsive to patient demand PEEP Leak compensation Tidal volume variable

Disadvantages

Decrease of tidal volume in presence of leaks No compensation for leaks Poor response to patient demand Desynchronization

Decrease of tidal volume when resistance increases Failure to maintain pressure and to cycle in presence of massive leaks Variability of FIO2

First choice

For patients with neuromuscular disease (battery needed in case of quite total ventilator dependency or if patient is wheelchair bound)

For patients with COPD, chest wall disease, or tuberculosis

Second choice

When pressure preset is insufficiently efficient or poorly tolerated

When volume preset is insufficiently efficient or poorly tolerated

COPD, chronic obstructive pulmonary disease; FIO2, fraction of inspired O2; PEEP, positive end-expiratory pressure.

1324  PART II / Section 13  •  Sleep Breathing Disorders

large tidal volume. Cough assistance techniques should be initiated when expiratory peak flow during cough is below 270 L/min.7 Patients and caregivers must be educated about the techniques. Cough assistance can be provided by using an inflating bag, a ventilator to provide an augmented inspiratory volume (which in turn results in a higher peak cough flow), or an insufflation–exsufflation device. In addition to the high expiratory flow velocity generated by respiratory system recoil after a high-volume inspiration, the effectiveness of the exhalation may be augmented by simultaneously pushing on the upper abdomen and chest wall. Alternatively, when an insufflation– exsufflation device is used, it applies a negative pressure to the airways during exhalation to augment airflow velocity and secretion-clearance capability. When patients are quite totally ventilator dependent and particularly prone to airway plugging and atelectasis, it is recommended to initiate cough assistance techniques very early before clinical obstruction with secretions becomes obvious, or when awake Spo2 is less than 95%.9,17 Initiation and Settings of NPPV NPPV is usually initiated in the hospital, either electively to start ventilation or after a situation requiring acute NPPV. However, a recent randomized controlled study showed that outpatient initiation of home mechanical ventilation was feasible, and that the outcome was equivalent in the outpatient and the inpatient groups.33 The goals of NPPV include patient comfort, synchrony with the ventilator, improvement of sleep, and improvement in arterial blood gases with and without ventilatory assistance. It is good practice to select and adjust the ventilator settings for the first couple of hours while the patient is awake, to ensure physiologic adequacy and patient comfort. One study found that using clinical observation to set the ventilator parameters is as successful as using physiologic measurements, including esophageal pressure.34 Next, the adequacy of ventilatory assistance during sleep (either a nap or nocturnal sleep) should be assessed. Ideally, expiratory tidal volume, airway pressure, and arterial blood gas measurements should be made to confirm delivery of the intended degree of support. However, the invasive nature of and the resources required for frequent arterial blood sampling has led most clinicians to monitor Spo2, transcutaneous CO2 tension (Pco2tc) or end-tidal CO2 tension (Pco2et), and ribcage and abdomen excursion, which, together with sleep staging, permit assessment of efficacy. When resources are not available to perform these detailed recordings, it is recommended that Spo2 and Pco2tc, or at the least Spo2, be recorded. Although there are no clearly established values defining efficient nocturnal ventilation, it is generally acknowledged that, in the context of restrictive diseases, assistance is efficient when an Spo2 of less than 90% occurs less than 5% of the time, and when an improvement of at least 10 mm Hg of Pco2tc (compared with unassisted sleep values) is seen during at least 70% of the night.33 Clearly, this does not hold true for Spo2 if oxygen is added to the ventilator circuit.35 In addition, data related to patient tolerance, comfort, and changes in sleep quality and well-being should be obtained. Reduction of awake Paco2, assessed after 3 hours off the ventilator, of at least 10 mm Hg with

a normal blood bicarbonate level measured in a sample of arterial blood after several nights, confirms the efficacy of NPPV.36 If the results are not satisfactory, alterations must be made to the settings and their effects checked again. In patients with COPD, it is frequently not possible to achieve such improvements. If pressure-preset ventilation is used, 10  cm H2O of inspiratory pressure support (i.e., above the EPAP or PEEP) is a suggested starting point. If necessary, the pressure level is progressively increased to achieve evidence of improvement assessed by clinical symptoms (night comfort, morning rest), overnight Spo2, and awake, unassisted Paco2. Although increased pressures are associated with increased leak, there is still a worthwhile increase in ventilation and reduction in the work of breathing.37 However, inspiratory pressure support higher than 20  cm H2O is rarely necessary in patients with COPD, the addition of positive end-expiratory pressure (PEEP in ventilators with an expiratory valve, or EPAP in bilevel devices) should conceptually improve patient triggering when intrinsic PEEP exists, but there is no long-term study proving its clinical usefulness.38 Depending on the ventilator capabilities and observations of how patient and ventilator interact together, more subtle settings involving triggers, initial flow, and inspiratory time limit (to 1 to 1.5 seconds) could be tried. A backup frequency set close to the spontaneous frequency of the patient during sleep is reasonable to accommodate the inspiratory trigger failure sometime induced by decreased Paco2 under the apnea threshold39 or in the presence of a transient leak that impairs proper cycling to the inspiratory pressure. When using a volume preset ventilator, the initial settings may be established by adjusting the frequency of ventilator-delivered breaths so that it approximates the patient’s spontaneous breathing frequency during sleep, an inspiratory time per total breathing cycle time of between 0.33 and 0.5, and a tidal volume of around 10 mL/kg. Supplemental O2 should be added into the ventilator circuit for patients requiring oxygen while awake because of lung parenchymal disease (e.g., COPD). In the absence of parenchymal disease, it is only after trying to optimize all technical parameters that nocturnal residual desaturation may justify additional O2 bled into the ventilator circuit, provided there is maintenance of an acceptable Paco2 (or an appropriately valid surrogate) during sleep. The minimal O2 supplementation that provides acceptable therapy must be identified by assessing overnight Spo2. Use of Alarms with NPPV Therapy The decision to use alarms to indicate power failure, unacceptable leaks, and patient disconnection during NPPV must depend on the severity of the patient’s physiologic and clinical impairment and consequent risk assessment. Unfortunately, no study of this issue has provided definitive guidance. In general, no particular alarms are mandatory when providing NPPV to patients who retain the capacity to maintain adequate spontaneous ventilation for at least 30 minutes. When ventilator dependency is of a more continuous nature, alarms are theoretically mandatory but require a ventilator that incorporates them in the device or circuit, or for which special adaptation is feasible. Downsides of alarm systems include the



CHAPTER 113  •  Noninvasive Ventilation to Treat Chronic Ventilatory Failure  1325

potential for alarms in response to non–life-threatening or minor conditions, which may significantly disturb patients’ and caregivers’ rest and reduce their enthusiasm for adherence to NPPV. Clinicians must weigh issues of security regarding device malfunction, interface leaks, and disconnections in the context of the patient’s clinical condition against the potential disruptive influence of inappropriate alarms. Further study is required to provide guidance in assessing patient risk and defining risk versus benefit in patients across the spectrum of severity of various disorders, as well as to request that industry develop alarms that are specifically suitable for the home NPPV patient. When Should Patients Use NPPV? NPPV is mainly used at night for physiologic and practical reasons, but use should also be encouraged during daytime naps, even in individuals without awake hypoventilation. It has been shown that in the short term, awake ventilatory support provided results that were very similar to 8 consecutive hours during the night; this included similar effects on overnight Spo2.40 Substantial improvements in diurnal arterial blood gas tensions and exercise tolerance have been shown in sham controlled studies of 3 hours of ventilation by day for 5 days a week over 3 weeks.41 Daytime (awake) ventilatory assistance, although less convenient as it encumbers the patient during a considerable part of the day, is an option for individuals who are unable to sleep with a ventilator and are prepared to use it in this way. Follow-Up Clinical follow-up should be conducted and daytime arterial blood gas should be obtained once or twice a year. When possible, recordings during sleep on NPPV, identical to those used when initiating NPPV, are useful. At any time, when there are indications of unsatisfactory results, particularly a recurrence of clinical symptoms or an indication of hypoventilation on the arterial blood gas, inadequate NPPV must be suspected and an objective evaluation during sleep undertaken. At the very least, nocturnal oxim­ etry must be done. When NPPV is determined to be suboptimal, a change in ventilator modality or setting may be indicated after ensuring that there is no damage to the ventilator tubing, mask, or other part. It is also worth ensuring that the patient has not changed the ventilator settings and that a different machine has not been substituted, as significant changes in performance of machines from the same manufacturer and differences between prescribed and delivered parameters have been reported. Increasing the total duration of NPPV use per day should also be considered, particularly when the underlying disease has progressed. Interfaces should be checked, and changed or adapted as needed.

MANAGEMENT OF COMPLICATIONS DURING NPPV Air Leaks To some degree, leaks are present when using NPPV during sleep in all patients. The major potential adverse effects of such leaks are reduced efficiency of ventilation

and sleep fragmentation.42-44 A variety of measures have been suggested to address problematic mouth leaks, and their effectiveness must be confirmed during a sleep recording. These include using preset pressure ventilation, preventing neck flexion, having the patient assume a semirecumbent position, using a chin-strap or a cervical collar to discourage the mouth from opening and the mandible from falling, decreasing the peak inspiratory pressure, and using a full-face mask. If upper airway obstruction is documented or suspected, judicious addition of PEEP, preferably during polysomnographic recording, may be tried. Nasal Dryness, Congestion, and Rhinitis Nasal dryness, congestion, and rhinitis are addressed in Chapter 107. In our experience, humidification during NPPV is usually not necessary, but for some patients nasal and mouth dryness (usually related to leaks) can increase nasal airway resistances and be a source of discomfort.45 In a study of normal subjects, expired tidal volume fell and nasal resistance increased after 5 minutes of intentional mouth breathing, and this was attenuated by heated humidification.46 Comfort scores were also higher with humidification when there was significant leak. A passover, or heated humidifier, can be use in this situation or for patients with high sputum production (e.g., with bronchiectasis, cystic fibrosis). Heat or moisture exchangers are not very useful in the presence of leaks, as the “dry” flow from the ventilator is higher than the “dampened” flow returning from the patient. Aerophagia Aerophagia, or swallowing air, is frequently reported by patients but is rarely intolerable during NPPV.47 It usually depends on the level of inspiratory pressure and is more commonly seen when using volume or mouthpiece ventilation. The incidence decreases considerably if the peak inspiratory pressure is kept below 25 cm H2O pressure.

OUTCOMES OF NOCTURNAL NPPV Effects of NPPV during Ventilatory Assistance During ventilatory assistance, gas exchange is improved as reflected by increased overnight Spo2 and decreased Pco2tc.32,48-50 Nevertheless, significant episodes of transient hypoventilation may persist and, assuming the ventilator settings are otherwise appropriate, these appear to be related to mouth leaks.42-44 Sleep duration slightly increases during NPPV especially in patients with restrictive disorders.51-56 Among five series studying COPD, three have shown increased and two have shown decreased sleep duration. The two series reporting outcomes in patients with restrictive disorders have shown increases of sleep duration. In patients with COPD and those with a restrictive disorder, sleep efficiency was similar with and without NPPV (70 ± 9% and 73 ± 11%, respectively).10,49,51,57 No significant changes were reported in percentage of non-REM sleep, REM sleep, and arousals in any disease groups.43,48,55,56 Thus, NPPV improves nocturnal hypoventilation, but improvement in sleep quality is inconsistent. A recent study

1326  PART II / Section 13  •  Sleep Breathing Disorders

comparing subjective sleep quality in patients with postpoliomyelitis showed than those who had undergone tracheostomy had better results than those who received NPPV.58

2. Resetting of the chemoreceptors. It has been suggested that in response to chronic hypercapnia, the respiratory control centers change their set point, which perpetuates the hypoventilation, rather than trying to generate nonsustainable ventilatory muscle effort.60-62 A study of 20 patients with restrictive chest wall disease reported that an increase in CO2 sensitivity was the predominant mechanism by which noninvasive ventilation improved diurnal blood gas tensions.63 In obesity–hypoventilation syndrome, the mechanism seems more complex because of the coexistence of obstructive apnea and primary hypoventilation.64 3. Decreased ventilatory load. This hypothesis suggests that NPPV is associated with improved respiratory system compliance or stiffness, thereby reducing the ventilatory load and increasing the efficiency of the muscles during spontaneous breathing. Some studies suggest a possible minor role of this mechanism in both restrictive and COPD diseases.65,66 Even if the mechanisms that explain the efficacy of nocturnal assisted ventilation are unknown, it is evident that improvement is more or less related to the normalization, or at least the improvement, of alveolar ventilation during

Effects of NPPV on Daytime Respiratory Function during Spontaneous Breathing This discussion focuses on patients who use nocturnal NPPV but are able to breathe spontaneously (i.e., without ventilatory assistance) for at least 8 hours during the day (Tables 113-5 and 113-6). Although arterial blood gases and pulmonary function tests improve in patients with restrictive disorders, it appears that NPPV is associated with little or no improvement in patients with COPD. Three main hypotheses have been proposed to explain the improvements of diurnal arterial blood gases during spontaneous breathing following initiation of NPPV during sleep in patients with restrictive disorders: 1. Improved respiratory muscle strength. It has been suggested that ventilatory assistance rests the respiratory muscles with consequent reversal of fatigue. However, no study has confirmed this hypothesis.

Table 113-5  Blood Gas Composition of Spontaneous Breathing in Response to Noninvasive Mechanical Ventilation Arterial Blood Gases (mm Hg) PaO2 DISEASE/CONDITION

PATIENTS/STUDIES

BASELINE

PaCO2

CHANGE

BASELINE

CHANGE

Chronic obstructive pulmonary disease

314/16*

56 ± 16

5±5

54 ± 7

−3 ± 4

Scoliosis, tuberculosis

543/16†

54 ± 9

10 ± 5

54 ± 5

−13 ± 10

Neuromuscular disorder

179/14‡

65 ± 7

13 ± 6

57 ± 3

−10 ± 5

Obesity–hypoventilation syndrome

110/1§

58 ± 12

56 ± 8

−14 ± 5

7 ± 11

*Noninvasive positive pressure ventilation (NPPV) references 4, 10, 11, 49, 51, 56, 70, 71, 78-84. † NPPV references 32, 40, 42, 48, 52, 62, 71, 79, 81, 85-88. ‡ NPPV and negative pressure ventilation references 50, 70, 71, 89-95. § NPPV reference 74.

Table 113-6  Responses to Noninvasive Positive Pressure Ventilation: Vital Capacity and Maximal Inspiratory Pressure Vital Capacity (mL or %) DISEASE OR CONDITION

PATIENTS/STUDIES

BASELINE

35/3*

1980 ± 228

Scoliosis, tuberculosis

178/6†

1097 ± 219

Obesity– hypoventilation syndrome

111/1‡

64 ± 16%

Chronic obstructive pulmonary disease

*References 49, 51, 84. † References 40, 42, 85-87, 96. ‡ Reference 74. § References 51, 78, 82, 83. ¶ References 31, 40, 48, 51, 52, 54, 82, 83, 85, 86, 97.

Maximal Inspiratory Pressure (cm H2O) CHANGE 57 ± 143 110 ± 98 15%

PATIENT/STUDY

BASELINE

CHANGE

52/4

§

−48 ± 2

−1 ± 11

112/6¶

−39 ± 6

−14 ± 10

—

—

—



CHAPTER 113  •  Noninvasive Ventilation to Treat Chronic Ventilatory Failure  1327

NPPV.49 In general, it is likely that, in addition to reducing the burden of breathing during use in patients with chest wall or neuromuscular diseases, NPPV has a favorable impact on ventilatory mechanics or muscle function during spontaneous breathing, despite intrinsic neuromuscular abnormality. Effects on Hospitalization The home care system in France allows precise tabulation of the days that patients spend in the hospital. Comparison between the year before and the first and second years after beginning nocturnal NPPV reveals a significant reduction in the number of days of hospitalization: 34 days versus 6

during the first year and 5 during the second for patients with scoliosis; 31 days versus 10 and 9 for patients with the sequelae of tuberculosis; and 18 versus 7 and 2 for patients with DMD. In contrast, the number of hospital days for patients with COPD decreased significantly during the first year on NPPV, from 49 days at baseline to 17 and 25 days at 1 and 2 years after NPPV, respectively.4 This reflects a modest long-term effect of NPPV in patients with COPD. In the two control studies on COPD, hospitalizations are not significantly decreased with NPPV.10,11 For patients with bronchiectasis, there was no statistical change in the number of hospital days after initiation of NPPV.4,67

Table 113-7  Long-term Issues for Patients on Noninvasive Positive Pressure Ventilation (NPPV) DISEASE, PRIMARY AUTHOR (REF)

PATIENTS (NO./ AVERAGE AGE)

NPPV CONTINUATION (% AT 5 YR)

NPPV WITHDRAWAL* NO. (%)

TRACHEOSTOMY NO. (%)

DEATHS NO. (%)

Scoliosis Simonds (70) Leger (98) Janssens (71)

47/49

79

1 (2)

NA tech

105/57

73

7 (7)

5 (5)

2 (10)

0 (0)

19/60

71

129/62

NA

Simonds (70)

20/61

94

0 (0)

NA tech

Leger (98)

80/64

68

1 (1)

11(14)

Laub (73)†

NA

NA

7 (9) 15 (14) 3 (16) 34 (26)

Tuberculosis

Janssens (71)

23/75

40

Laub (73)†

98/73

NA

30/51

100

0 (0) NA

1 (5) 17 (21)

1 (4)

11 (48)

NA

47 (48)

Poliomyelitis Simonds (70) Janssens (71) Laub (73)†

12/67

40

141/67

NA

0 (0)

NA tech

0 (0)

1 (8)

NA

NA

0 (0) 5 (42) 39 (29)

Duchenne Muscular Dystrophy Leger (98)

16/21

47

0 (0)

7 (44)

2 (13)

Simonds (72)

23/20

73

0 (0)

NA tech

5 (22)

Chronic Obstructive Pulmonary Disease Simonds (70)

33/57

43

5 (15)

NA tech

Leger (98)

50/63

31

4 (8)1

12 (24)

Sivasothy (24)

26/66

68

0 (0)

—

Janssens (71)

58/63

28

4 (7)

0 (0)

188/65

26

13 (7)

Simonds (70)

13/41

102  cm) in men and greater than 35 inches (>88 cm) in women, is an independent predictor of risk for type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease in adults with a BMI between 25 and 34.9 kg/m2.1 Overweight and obesity are a result of a complex interplay of genetic and sociocultural forces that lead to long-term positive energy balance.2 Obesity is associated with myriad complications, including obstructive sleep apnea (OSA). Obesity is one of the most important risk factors for OSA.3 Excessive body weight may increase propensity for upper airway narrowing during sleep by altering the function and the geometry of the pharynx.3 In addition, obesity may alter ventilatory control and respiratory muscle function, leading to obesity hypoventilation syndrome (OHS), which is characterized by the combination of obesity, chronic hypercapnia (in the absence of another identifiable cause), and usually some component of OSA (see Chapter 112).4 Treatment for OSA includes continuous positive airway pressure (CPAP), oral appliances, upper airway surgeries, and risk factors modifications, including weight loss. For patients who are motivated to lose weight, the initial treatments include dietary modifications to reduce energy intake, enhanced physical activity to increase energy expenditure, and behavioral therapies to overcome barriers to compliance.1 Pharmacotherapy may be considered for patients with a BMI of 30 kg/m2 or more, or for those with a BMI of 27  kg/m2 or more and obesity-related disease who fail to achieve their weight loss targets after 6 months of diet and lifestyle changes.1 Surgical therapy for obesity, or bariatric surgery, is indicated for morbidly obese, wellmotivated individuals who have failed other attempts at nonsurgical approaches to weight control. Some bariatric

Chapter

115

tions that restrict caloric intake or absorption, or both. Approximately 200,000 bariatric operations were performed in the United States in 2007. This chapter focuses on bariatric surgery, an appropriate issue for the provider of sleep medicine care given the frequency with which coexistent obesity and sleep-disordered breathing are encountered in routine clinical sleep practice and the important role for the sleep specialist in a comprehensive perioperative bariatric care program.

procedures restrict food intake and others induce malabsorption or maldigestion.5 The number of bariatric procedures being performed has increased dramatically as a result of the rise of severe obesity and refinement of operative techniques. This chapter explores the epidemiology of overweight and obesity, potential mechanisms linking overweight and obesity with OSA, indications for bariatric surgery, technical aspects of common bariatric procedures, perioperative management of OSA, and outcomes of bariatric surgery, including its impact on OSA.

EPIDEMIOLOGY Epidemiology of Overweight and Obesity According to the latest National Health and Nutrition Examination Survey (NHANES), 66.2% of U.S. adults are overweight, 32.9% are obese, and 4.8% have class 3 obesity (see Table 115-1).6 Between 1980 and 2007 the prevalence of obesity doubled (15% to 31%), and the prevalence of class 3 obesity nearly quadrupled (1.4% to 5%).7 Figure 115-1 shows further worsening of the state-specific prevalence of obesity in 2009.8 By 2015, an estimated 75% of United States adults will be overweight or obese, and 41% will be obese.9 Obesity rates are highest amongst nonHispanic black adults, followed by Mexican Americans and then non-Hispanic whites.6 Obesity prevalence is much lower among Asian Americans, and rates in Native Americans are similar to those in non-Hispanic blacks.10 Data from the Framingham Heart Study attributed a reduction in life expectancy of 7.1 years in nonsmoking women and 5.9 years in nonsmoking men at age 40 to obesity,11 with the increased mortality resulting primarily from cardiovascular disease.12 Epidemiologic Association between Overweight/Obesity and OSA Cross-sectional analyses of clinical and population samples have demonstrated notable co-localization of OSA and obesity.3 OSA has been found in 50% to 80% of obese clinical patients,3 and 60% to 90% of adults with OSA may be overweight.13 In the Wisconsin Sleep Cohort, an increase of 1 standard deviation in BMI was associated with a fourfold risk of an apnea–hypopnea index (AHI) of 5 or 1339

1340  PART II / Section 13  •  Sleep Breathing Disorders

greater.14 Furthermore, the Sleep Heart Health Study reported a dose-dependent relationship between increasing BMI and OSA, as the prevalence of an AHI of 15 or greater was 10% in the lowest BMI quartile (16 to 24  kg/m2) as opposed to 32% in the highest quartile (32 to 59 kg/m2).15 Longitudinal population and clinical samples also indicate that weight and AHI change congruently. In the Wisconsin Sleep Cohort, each 1% increase (decrease) in weight was associated with a 3% increase (decrease) in AHI, and in individuals with mild obstructive sleep apnea (AHI, 5 to 15) at baseline, a 10% weight gain led to a

Table 115-1  Classification of Overweight and Obesity by Body Mass Index BODY MASS INDEX kg/m2 Underweight Normal Overweight

50  kg/m2). Today, RYGB is most commonly performed via a minimally invasive laparoscopic, rather than open, approach. Most weight is lost in the first year, with long-term weight loss stabilizing at 2 to 3 years. Typically, 80% of patients experience weight stabilization slightly above weight nadir approximately 3 years after surgery. The remaining patients slowly regain more excess weight over longer-term followup, and they risk becoming surgical failures. Another bariatric procedure that has grown increasingly popular worldwide is the strictly restrictive laparoscopic adjustable gastric banding procedure. The gastric band is an inflatable silicone prosthetic device that is placed around the top portion of the stomach, just below the esophagus (Fig. 115-3). The band is attached to a reservoir, with a port placed under the skin on the abdominal wall, and the inner lining of the band is a balloon that is adjustable by the addition or removal of saline from the reservoir port. Inflation of the band increases the restriction of gastric

outlet size and food flow. Postoperative management for adjustable gastric band patients requires frequent followup visits for band adjustments and strict adherence to dietary guidelines and lifestyle modification to achieve consistent weight loss. The weight loss trajectory after banding procedures is more gradual than weight loss after bypass and continues for a period of 3 years, but the two procedures result in similar long-term weight loss results. The favorable aspects of this procedure are that it is less invasive, requires less operating time, and is both adjustable and removable. The less commonly used biliopancreatic diversion (BPD) and BPD with duodenal switch (BPDDS) are extremely malabsorptive procedures for the treatment of the very “superobese” patients. BPD combines a partial, subtotal gastrectomy and a very long Roux-en-Y anastomosis with a short common channel for nutrient absorption. With this procedure, patients can eat much larger quantities of food and still achieve and maintain weight loss. Disadvantages to the procedure include loose and foul smelling stools, intestinal ulcers, anemia, vitamin and mineral deficiencies, and possible protein-calorie malnutrition. Because of these potential problems, BPD patients require lifelong supplementation and close follow-up. With similar weight loss and complications, the BPDDS is a hybrid operation that combines a gastric sleeve resection (70% greater-curve gastrectomy) with a long intestinal bypass in the Roux-en-Y configuration. In this procedure, ulcer rate is reduced and dumping syndrome (the constellation of nausea, vomiting, abdominal pain or cramping, diarrhea, bloating, fatigue, palpitations, lightheadedness, sweating, and anxiety beginning within 15 to 30 minutes after eating) is eliminated by leaving the first portion of the intestine in the alimentary stream. Both the BPD and BPDDS can also be performed laparoscopically. BPD and BPDDS procedures are clearly the most major and technically difficult procedures performed for weight loss and consequently should be offered only by experienced surgeons and should entail lifelong comprehensive surgical weight loss programs.

Figure 115-2  Roux-en-Y gastric bypass.

Figure 115-3  Gastric band procedure.

1344  PART II / Section 13  •  Sleep Breathing Disorders

Despite a substantive body of literature, debate still continues regarding the selection of procedure type for any given patient. Patients are provided with general guidelines about the different mechanisms of action, percent weight loss over time, and morbidity profile between procedures when making a final decision toward surgery. The optimal choice of procedure depends, in part, on the expertise of the surgeon and the institution, patient preference, and risk stratification.35

CLINICAL COURSE Management of OSA Immediately after Bariatric Surgery Many details of optimal care of the bariatric patient with OSA immediately after surgery remain unclear. The following general recommendations are based on experience, consensus expert opinion for generic surgical care published by the AASM45 and the American Society of Anesthesiologists,46 and limited peer-reviewed literature. Airway extubation after bariatric surgery should be performed only when the patient is fully awake and alert and has demonstrated evidence of returned neuromuscular function (as evidenced by sustained head-lift for more than 5 seconds) and adequate vital capacity and peak inspiratory pressure.45 Removal of the endotracheal tube should take place in the operating room, PACU, or special care unit so that airway control can be monitored closely and expertly addressed if lost.45 The patient should be maintained in the semiupright or lateral, not supine, position and should undergo continuous cardiorespiratory monitoring. Immediate application of PAP with or without a nasopharyngeal airway will help prevent upper airway collapse. PACU staff must be capable of monitoring and responding to PAP therapy, including addressing interface leaks and observing diligently for signs of breakthrough upper airway obstruction despite PAP, such as snoring, choking, witnessed apneas, cardiac dysrhythmias, or frequent desaturation. In the first 24 postoperative hours, patients are the most vulnerable with respect to the potential for OSArelated complications,37 although OSA propensity may be increased for at least several days after bariatric surgery because of the aggregate effects of ongoing sleep deprivation, rapid eye movement sleep rebound, and medication synergies.45 Fortunately, the length of hospital stay is usually short (3.5 days and 1.6 days for gastric bypass and restrictive procedures, respectively47). Nevertheless, providers must keep OSA in mind as they consider postoperative analgesia, monitoring, oxygenation, and patient positioning46 for the duration of the hospitalization. Systemic opioids should be used cautiously because of their ability to depress the respiratory drive and cause subsequent oxygen desaturation. The use of patient-controlled analgesia is controversial, although it may be option if it is used without a basal rate and with restricted dosing. Nonsteroidal antiinflammatory agents may help decrease opioid dosing as recovery progresses but should be used cautiously in the postsurgical patient because of the enhanced potential for bleeding complications. Benzodiazepines should be avoided because of their negative effects on the respiratory control and upper airway mus-

culature. Access to PAP should be available at all times44 during recovery, a seemingly obvious recommendation but one that may be overlooked by busy house staff, nurses unfamiliar with PAP, and patients distracted by their debilitation. Properly trained health care staff should be readily available to assist patients in PAP placement, to troubleshoot interface problems, to observe for breakthrough upper airway obstruction, and to reassure patients struggling with PAP. Continuous pulse oximetry monitoring after discharge from the PACU is recommended for as long patients are deemed at increased risk, which may be defined as the duration of intravenous opioid use. Oximetry data should be continuously observed at the bedside in a critical care or stepdown unit, by telemetry on a hospital ward, or by a dedicated, trained observer in the patient’s room. Choosing the optimal monitoring site will depend on the interplay of the severity of underlying OSA or OHS, opioid requirements, and availability of local resources. Incentive spirometry should be encouraged. If desaturations despite PAP are noted, supplemental oxygen should be added while the provider searches for an explanation, such as transient worsening of upper airway obstruction requiring a PAP adjustment, venous thromboembolic event, atelectasis, aspiration, pneumonia, or anastomotic leak. Use of supplemental oxygen without PAP during sleep should be avoided, as this provides no protection against upper airway obstruction and will blunt detection of a disordered-breathing event by oximetry monitoring. Patients should avoid the supine position and instead keep the head of the bed elevated in a semi-Fowler position (to at least 30 degrees) at all times. Venous thromboembolic disease, which can occur after laparoscopic and open procedures, is the most common cause of postoperative mortality,48 so thromboprophylaxis is indicated with low-molecular-weight heparin, low-dose unfractionated heparin three times daily, or fondaparinux, with or without intermittent pneumatic compression stockings.49 In the University HealthSystem Consortium evaluation, a review of the bariatric programs at 29 academic medical centers in the United States, 7.7% of patients undergoing gastric bypass and 1.1% of patients undergoing a restrictive procedure required intensive care unit (ICU) support postoperatively.5 Clinical practice guidelines for bariatric surgery35 conclude that “no consensus exists about which type of patient should be considered for admission to the ICU after bariatric surgery.” It would seem reasonable to consider ICU care for the first 24 to 48 hours for bariatric patients with one or more of the following features: age greater than 50, BMI greater than 60  kg/m2, significant comorbid cardiopulmonary disease, brittle diabetes mellitus, worrisome record of PAP compliance, sluggish emergence from anesthesia, and intraoperative complications. Some patients may not require an ICU stay.49a Prolonged respiratory failure after bariatric surgery is uncommon, occurring in less than 1% of cases.48 Benefits of Bariatric Surgery Postoperative weight loss is typically reported as the mean percentage of excess weight loss, defined by the following formula:

( weight loss ÷ excess weight ) × 100,



CHAPTER 115  •  Obstructive Sleep Apnea, Obesity, and Bariatric Surgery  1345

where excess weight equals total preoperative weight minus ideal weight. In a review of 136 studies involving 22,000 bariatric surgery patients, Buchwald and colleagues50 reported that the mean percentage of excess weight loss with bariatric surgery was 61.2%: 47.5% for gastric banding, 68.2% for gastric bypass (principally Roux-en-Y gastric bypass [RYGB]), and 70.1% for BPD and BPDDS.50 The mean decrease in BMI was 14.2  kg/ m2, whereas the mean decrease in absolute weight was 39.7  kg, similar to the 20- to 30-kg weight loss reported in the meta-analysis by Maggard and colleagues.51 Comorbidities correspondingly improved. Diabetes mellitus completely resolved in 76.8%, hyperlipidemia improved in 70%, and hypertension improved or resolved in 78.5%.50 A retrospective cohort study comparing long-term mortality among 7925 patients who underwent gastric bypass and 7925 age-, sex-, and BMI-matched controls demonstrated a 40% reduction in adjusted long-term mortality with bariatric surgery during a mean follow-up of 7.1 years.52 No large randomized trials have compared bariatric surgery with medical management of obesity. The Swedish Obesity Study53 was a large, prospective, nonrandomized, controlled trial that compared 2010 obese subjects treated with bariatric surgery, and 2037 contemporaneously matched obese controls treated conventionally. At 2 years, weight had decreased by 23.4% in the surgery group but had increased by 0.1% in the control group, and after 10 years, the weight had decreased by 16.1% in the surgery group but had increased by 1.6% in controls (P < .001 at both time points). Improvements in diabetes, hypertriglyceridemia, and hypertension were more favorable in the surgery group, and the surgery group had lower 2- and 10-year incident rates of diabetes than controls. Maximal weight losses in the surgical group were observed after 1 to 2 years, and at 10 years the maximal average losses were 32% for gastric bypass, 25% for vertical banded gastroplasty, and 20% for banding.53 Overall mortality was lower in the surgery group.54 Long-Term Impact of Bariatric Surgery on OSA Weight loss induced by bariatric surgery is consistently associated with reductions in AHI.55 Buchwald and coworkers’ meta-analysis50 of selected bariatric surgery outcomes reported that OSA resolved or improved in 83.6%. The weighted mean change in the AHI was 40, with a range of 16 to 52.8. Enthusiasm over these results must be tempered by several methodological concerns. Improvement and resolution with respect to OSA were not explicitly defined. The studies included in the meta-analysis are not entirely specified but a review of studies from the inclusion period (1990 to June 2003) reveals that symptomatic reduction was probably sufficient in some studies to assess OSA response (i.e., postoperative polysomnography was not required in all subjects), the timing of polysomnography after surgery was nonuniform, and the results were most likely variably reported (e.g., only preoperative and postoperative apnea indices were described, not AHIs). Studies published since June 200356-60 corroborate earlier series reporting that surgically induced weight loss is associated with improvement in OSA approximately 1 year or longer after surgery. However, many patients have residual

OSA. Even though bariatric surgery resulted in a mean AHI reduction of 23.4, Lettieri and colleagues60 found that 23 patients (96%) still met criteria for OSA (AHI > 5), 20 (83%) continued to experience transient nocturnal hypoxia (oxyhemoglobin saturation < 90%), and 13 (54%) had persistent sleepiness (Epworth Sleepiness Scale scores, >10) despite an average weight loss of 54 kg at a mean of 418 days postoperatively. In the series of Valencia-Flores,57 15 patients (54%) had a postoperative AHI of greater than 5. A pervasive limitation of these studies is the lack of followup polysomnography in all patients (24% to 60% followup polysomnogram rates), which may introduce selection bias. Health care providers must therefore remain vigilant for persistent OSA with a systematic postoperative followup program, as dramatic changes in weight and symptoms do not guarantee cure of OSA. The optimal timing for postoperative polysomnography is not clear, but it depends, in part, on the patient’s weight loss evolution. The CPAP requirement for residual OSA is likely to fall by at least 2 to 4  cm H2O in the year after surgery.59-61 Autotitrating CPAP after surgery may bridge the patient to their polysomnogram and obviate empiric pressure reductions or serial sleep studies.61 The AASM concluded that bariatric surgery may be adjunctive in the treatment for OSA, but it rates this recommendation as an option, meaning that bariatric surgery is of uncertain clinical use for OSA.62 This designation is based on the lack of data at the Sackett level of evidence I to III, the potential for perioperative complications, and a recognition of the possibility for long-term OSA recurrence without concurrent weight gain.63 Risks and Complications of Bariatric Surgery According to the meta-analysis by Buchwald and colleagues,50 operative mortality, defined as death within the first 30 days, was 0.1% for purely restrictive procedures, 0.5% with gastric bypass, and 1.1% with BPD or BPDDS. Factors that increase risk for mortality include surgical inexperience, greater patient age, BMI of 50  kg/m2 or greater, and comorbidities.5 The University HealthSystem Consortium evaluation, which included 1143 bariatric surgery procedures performed between October 2003 and March 2004, revealed a 30-day mortality rate of 0.4% for gastric bypass procedures (76% performed laparoscopically) and 0% for restrictive procedures (92% performed laparoscopically).47 For gastric bypass procedures, the 30-day readmission rate was 6.6% and the overall complication rate was 16%. For restrictive procedures, the 30-day readmission rate was 4.3% and the overall complication rate was 3.2%.47 Box 115-1 lists the postoperative adverse events from bariatric surgery, which can be grouped as early and late phenomena. A dreaded complication is anastomotic leak. In the University HealthSystem Consortium evaluation,47 the anastomotic leak rate for gastric bypass procedures was 1.6%. The extent to which OSA is linked to complications after bariatric surgery is not fully known. In a review of more than 3000 patients, OSA was found to be an independent predictor for anastomotic leak,64 whereas OSA, hypertension, and surgeon experience were identified as predictors of postoperative complications in a series of

1346  PART II / Section 13  •  Sleep Breathing Disorders Box 115-1  Complications of Bariatric Surgery Complications Common to All Bariatric Procedures Early (30 days) Incisional and internal hernias Bowel obstruction from adhesions Nutritional deficiencies Anastomotic strictures and marginal ulcers or erosions Cholelithiasis Anemia Persistence/recurrence of obstructive sleep apnea Need for body contouring Weight regain Procedure-Unique Complications Roux-en-Y Gastric Bypass Dumping syndrome Laparoscopic Adjustable Gastric Banding Band slippage or erosion Port or device malfunction Biliopancreatic Diversion Loose, foul-smelling stools Protein-calorie malnutrition

more than 300 bariatric surgery patients.65 Accordingly, OSA has been linked to increased cost of postoperative care66 and higher risk for prolonged postoperative hospital stay.67 However, other investigators have not identified OSA as an independent predictor of complications after bariatric surgery.68-70 These reports are challenging to interpret and compare because of operative differences and uncertainty over how OSA was managed postoperatively.

PITFALLS AND CONTROVERSY Although a PAP regimen starting before surgery and continued immediately after extubation can markedly reduce the negative effects of sleep-disordered breathing, concerns exist regarding the use of PAP after upper intestinal surgery. Some have avoided application of PAP immediately after surgery because of concern that high levels of positive pressure may inflate the stomach and intestinal loops and increase the risk for anastomotic disruption and leakage. However, in a large prospective series of 1067 bariatric surgery patients, 159 of whom were receiving

CPAP treatment after bariatric surgery for known OSA, there was no increase in anastomotic leak related to CPAP use.71 In another series,72 an increase in number of anastomotic leaks was not reported with empiric bilevel PAP after gastric bypass. Therefore, it appears that PAP immediately after surgery is safe for the bariatric surgery patient with known OSA.

SUMMARY Obesity is a leading cause of preventable disease and death, and its prevalence is increasing. Sixty-six percent of Americans are currently overweight or obese, and the percentage is likely to reach 75% by 2015. Rates of overweight and obesity are higher in Mexican Americans and nonHispanic black Americans than in non-Hispanic whites. Excess weight is the strongest risk factor for OSA because of adverse impacts on upper airway neuromuscular function and anatomy. Bariatric surgery, a variety of procedures that limit food absorption or restrict intake (or both), is indicated for severely obese patients who have instituted but failed an adequate exercise and diet program and who have either a BMI of 40 kg/m2 or more, or a BMI of 35 kg/m2 or more in conjunction with one or more obesity-related severe comorbid conditions. The mean percentage of excess weight loss with bariatric surgery is approximately 60%, and major obesity-related conditions, such as diabetes mellitus and hypertension, consistently improve. Thirty-day mortality of bariatric surgery is less than 1%, and adverse events occur in approximately 20% of cases. ❖  Clinical Pearls The sleep clinician should be mindful that bariatric surgery patients are likely to have OSA, which requires careful consideration during preoperative evaluation as well as in the immediate postoperative and perioperative periods. Bariatric surgery patients should be expected to lose 20 to 50  kg at 1 to 2 years, which contemporary studies indicate should be accompanied by a 50% to 75% reduction in AHI and a drop in PAP levels. Autotitrating CPAP may be a useful management modality as weight falls after surgery. Despite dramatic weight loss, OSA may persist in many patients.

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32. Thut DC, Schwartz AR, Roach D, et al. Tracheal and neck position influence upper airway airflow dynamics by altering airway length. J Appl Physiol 1993;75:2084-2090. 33. American Society of Metabolic and Bariatric Surgery. Metabolic and bariatric surgery fact sheet. Available at: http://www.asmbs.org/ Newsite07/media/asmbs_fs_accesstocare.pdf. 34. Livingston EH. Hospital costs associated with bariatric procedures in the United States. Am J Surg 2005;190:816-820. 35. Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society of Metabolic and Bariatric Surgery medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Endocr Pract 2008;14(Suppl 1):1-83. 36. Frey WC, Pilcher J. Obstructive sleep-related breathing disorders in patients evaluated for bariatric surgery. Obes Surg 2003;13: 676-683. 37. Gupta RM, Parvizi J, Hanssen AD, Gay PC. Postoperative complications in patients with obstructive sleep apnea syndrome undergoing hip or knee replacement: a case-control study. Mayo Clin Proc 2001;76:897-905. 38. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(5):1279-1285. 39. Gali B, Whalen FX Jr, Gay PC, et al. Management plan to reduce risks in perioperative care of patients with presumed obstructive sleep apnea syndrome. J Clin Sleep Med 2007;3:582-588. 40. Kushida CA, Littner MR, Morgenthaler TI, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 2005;28:499-521. 41. Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable monitoring task force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737-747. 42. Weaver TE, Kribbs NB, Pack AI, et al. Night-to-night variability in CPAP use over the first three months of treatment. Sleep 1997;20:278-283. 43. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. An American Academy of Sleep Medicine report. Sleep 2006;29: 375-380. 44. Hillman DR, Loadsman JA, Platt PR, Eastwood PR. Obstructive sleep apnoea and anesthesia. Sleep Med Rev 2004;8:459-471. 45. Meoli AL, Rosen CL, Kristo D, et al. Upper airway management of the adult patient with obstructive sleep apnea in the perioperative period-avoiding complications. Sleep 2003;26:1060-1065. 46. American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Obstructive Sleep Apnea. Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Obstructive Sleep Apnea. Anesthesiology 2006; 104:1081-1093. 47. Nguyen NT, Silver M, Robinson M, et al. Result of a national audit of bariatric surgery performed at academic centers: a 2004 University HealthSystem Consortium benchmarking project. Arch Surg 2006;141:445-450. 48. Pieracci FM, Barie PS, Pomp A. Critical care of the bariatric patient. Crit Care Med 2006;34:1796-1804. 49. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism. American College of Chest Physicians evidencebased clinical practice guidelines (8th edition). Chest 2008;133: 381S-453S. 49a.  Grover BT, Priem DM, Mathiason MA, et al. Intensive care unit stay not required for patients with obstructive sleep apnea after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis 2010;6: 165-170. 50. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724-1737. 51. Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: surgical treatment of obesity. Ann Intern Med 2005;142:547-559. 52. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357:753-761.

1348  PART II / Section 13  •  Sleep Breathing Disorders 53. Sjostrom L, Lindroos A-K, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683-2693. 54. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741-752. 55. Veasey SC, Guilleminault C, Strohl KP, et al. Medical therapy for obstructive sleep apnea: a review by the medical therapy for obstructive sleep apnea task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep 2006;29: 1036-1044. 56. Guardiano SA, Scott JA, Ware JC, Schechner SA. The long-term results of gastric bypass on indexes of sleep apnea. Chest 2003;124:1615-1619. 57. Valencia-Flores M, Orea A, Herrera M, et al. Effect of bariatric surgery on obstructive sleep apnea and hypopnea syndrome, electrocardiogram, and pulmonary arterial pressure. Obes Surg 2004; 14:755-762. 58. Dixon JB, Schachter LM, O’Brien PE. Polysomnography before and after weight loss in obese patients with severe sleep apnea. Int J Obesity 2005;29:1048-1054. 59. Haines KL, Nelson LG, Gonzalez R, et al. Objective evidence that bariatric surgery improves obesity-related obstructive sleep apnea. Surgery 2007;141:354-358. 60. Lettierri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med 2008;4: 333-338. 61. Lankford DA, Proctor CD, Richard R. Continuous positive airway pressure (CPAP) changes in bariatric surgery patients undergoing rapid weight loss. Obes Surg 2005;15:336-341. 62. Morgenthaler TI, Kapen S, Lee-Chiong T, et al. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep 2006;29:1031-1035.

63. Pillar G, Peled R, Lavie P. Recurrence of sleep apnea without concomitant weight increase 7.5 years after weight reduction surgery. Chest 1994;106:1702-1704. 64. Fernandez AJ, DeMaria EJ, Tichansky DS, et al. Experience with over 3000 open and laparoscopic bariatric procedures: multivariate analysis of factors related to leak and resultant mortality. Surg Endosc 2004;18:193-197. 65. Perugini RA, Mason R, Czerniach DR, et al. Predictors of complication and sub-optimal weight loss after laparoscopic Roux-en-Y gastric bypass: a series of 188 patients. Arch Surg 2003;138:541-546. 66. Cooney RN, Haluck RS, Ku J, et al. Analysis of cost outliers after gastric bypass surgery: what can we learn? Obes Surg 2003; 13:29-36. 67. Ballantyne GH, Svahn J, Capella RF, et al. Predictors of prolonged hospital stay following open and laparoscopic gastric bypass for morbid obesity: body mass index, length of surgery, sleep apnea, asthma and the metabolic syndrome. Obes Surg 2004;14:1042-1050. 68. O’Rourke RW, Andrus J, Diggs BS, et al. Perioperative morbidity associated with bariatric surgery: an academic center experience. Arch Surg 2006;141:262-268. 69. Fernandez AZ Jr, Demaria EJ, Tichansky DS, et al. Multivariate analysis of risk factors for death following gastric bypass for treatment of morbid obesity. Ann Surg 2004;239:698-702. 70. Campos GM, Ciovica R, Rogers SJ, et al. Spectrum and risk factors of complications after gastric bypass. Arch Surg 2007;142:969-975. 71. Huerta S, DeShields S, Shpiner R, et al. Safety and efficacy of postoperative continuous positive airway pressure to prevent pulmonary complications after Roux-en-Y gastric bypass. J Gastrointest Surg 2002;6:354-358. 72. Joris JL, Sottiaux TM, Chiche JD, et al. Effect of bi-level positive airway pressure (BiPAP) nasal ventilation on the postoperative pulmonary restrictive syndrome in obese patients undergoing gastroplasty. Chest 1997;111:665-670.

Cardiovascular Disorders

Section

Shahrokh Javaheri 116  Sleep and Cardiovascular Disease:

Present and Future 117  Sleep-Related Cardiac Risk 118  Cardiac Arrhythmogenesis during Sleep: Mechanisms, Diagnosis, and Therapy 119  Cardiovascular Effects of Sleep-Related Breathing Disorders

120  Systemic and Pulmonary Hypertension

14

in Obstructive Sleep Apnea 121  Coronary Artery Disease and Obstructive Sleep Apnea 122  Heart Failure

Sleep and Cardiovascular Disease: Present and Future Shahrokh Javaheri Abstract Cardiovascular disorders are very common, affecting 26% of the population. They are associated with excess morbidity and mortality, and huge economic costs. One of the most signifi-

CARDIOVASCULAR DISEASE Cardiovascular disorders have a high prevalence and are associated with excessive morbidity and mortality, and huge economic costs (Table 116-1).1 Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, updates statistics on the morbidity and mortality of cardiovascular disease. According to the 2009 update, approximately 80 million people—38% of the U.S. population—have some form of cardiovascular disease. This has increased from the 2005 edition, when the prevalence was about 23%. Hypertension alone, a disorder that has been proven to be caused by obstructive sleep apnea (see Chapter 120), affects 74 million Americans. Many of these patients are erroneously diagnosed as having essential hypertension. Congestive heart failure and stroke, disorders frequently associated with both central and obstructive sleep apnea, are also highly prevalent, each affecting approximately 6.0 to 6.5 million Americans (see Table 116-1). According to the 2009 update, cardiovascular disorders accounted, in 2005, for approximately 865,000 deaths, which is 35% of all deaths in the United States. When the cases in which cardiovascular disease was a contributing factor to mortality are counted, the mortality was 1.4 million, or 56% of all mortalities. In fact, since 1900, cardiovascular disease has been the number one killer every year except 1918. In 2009, the annual cost of cardiovascular diseases is estimated to be $475 billion (compared with $368 billion

Chapter

116

cant recent developments in the field has been the recognition that sleep disorders such as sleep apnea can cause or worsen cardiovascular disease, and furthermore that cardiovascular disease can cause sleep disorders.

in 2004), and for congestive heart failure, the figure is approximately $37 billion (see Table 116-1). Since polysomnography became a common tool and sleep apnea was recognized as a medical disorder, perhaps the most important development in this field has been the recognition of the association of sleep apnea, both obstructive and central, with cardiovascular disorders (Fig. 116-1, Box 116-1, and Video 116-1).2-7

SLEEP APNEA There has been an explosion of basic science and physiologic studies in both experimental animals and humans, as well as epidemiologic and clinical studies, that support the bidirectional linking of sleep apnea to a variety of cardiovascular disorders (see Fig. 116-1 and Box 116-1) (see Chapters 117 through 122).2-7 Although much more research needs to be done in this area, it is interesting to note that cor pulmonale was recognized as a feature of pickwickian syndrome before it became known that the underlying pathologic process of cor pulmonale is a sleep disorder. Obstructive sleep apnea is associated with a number of biochemical and cellular abnormalities. Obstructive apnea results in neurohormonal activation; release of inflammatory mediators such as cytokines; increased expression of adhesion molecules, resulting in attachment of white blood cells to endothelial cells and their transmigration; and oxidative stress (see Chapter 116). Through increased production of reactive oxygen species,8 a number of transcription factors are activated, increasing the expression of redox-sensitive genes and resulting in the production of 1349

1350  PART II / Section 14  •  Cardiovascular Disorders Table 116-1  Prevalence, Mortality, and Economic Burden of Cardiovascular and Cerebrovascular Disorders in the United States POPULATION GROUP

PREVALENCE 2006

MORTALITY 2005

HOSPITAL DISCHARGES 2006

COST 2009

Total

80 Million (36%)

865,000 (39% of all deaths)

7 Million

475 Billion

  Women

41 Million (35%)

502,200 (54%)

4 Million

—

  Men

39 Million (38%)

390,600 (46%)

3 Million

—

  Age ≥ 60 yr

38 Million (47% of 80 million)

—

—

—

Hypertension

74 Million

—

514,000

Coronary heart disease

17 Million

450,000

1.8 Million

165 Billion

  Myocardial infarction

8 Million

—

—

—

10 Million

—

—

—

  Angina Congestive heart failure

6 Million

Stroke

6.5 Million

59,000* 144,000

73 Billion

1.1 Million

37 Billion

890,000

69 Billion

Numbers are rounded. Data from American Heart Association: Heart disease and stroke statistics—2009 update. Circulation 2009;119: e1-e161. *Total reported mortality, 290,000.

Box 116-1  Potential Cardiovascular and Cerebrovascular Complications of Obstructive Sleep Apnea Primary

Secondary

Sleep apneas and hypopneas

Cardiovascular pathology

Secondary

Primary

Figure 116-1  The relationship between obstructive sleep apnea (a primary sleep disorder), which secondarily could result in cardiovascular diseases, and a primary cardiovascular disease, specifically congestive heart failure, which secondarily could result in sleep-related breathing disorders.

vasoactive and inflammatory proteins. These reactions underlie the pathologic processes involved in endothelial dysfunction syndrome, the underlying pathophysiological mechanism for atherosclerosis, hypertension, stroke, heart failure, and coronary artery disease (Fig. 116-2). Because of the aforementioned abnormalities, and along with cyclic changes in blood pressure resulting in wall stress, changes in coronary and cerebral blood flow, and diminished oxygen delivery, obstructive sleep apnea could play a causative role or contribute to the development of atherosclerosis (see Fig. 116-2). In this context, treatment of obstructive sleep apnea with nasal continuous positive airway pressure (CPAP) devices results in reversal of a number of biochemical abnormalities, indicating a causal relationship (see Chapter 107). Furthermore, a number of studies also demonstrate that in patients with obstructive sleep apnea, treatment with CPAP results in a reduction in systemic and pulmonary hypertension (see Chapter 120).4,9,10 In the previous edition of this book, I expressed

Endothelial dysfunction Hypertension Systemic Pulmonary (cor pulmonale) Heart failure (systolic and/or diastolic) Arrhythmias Coronary artery disease Carotid artery atherosclerosis Stroke; transient ischemic attack Neuropsychological dysfunction Dementia Death (including sudden death)

the hope that long-term treatment of obstructive sleep apnea would be reflected in the prevention of cardiovascular and cerebrovascular diseases. Indeed, studies published since then strongly suggest not only that obstructive sleep apnea is a cause of mortality but also that treatment with CPAP decreases mortality, and this decrease is related primarily to the contribution of cardiovascular disorders. With regard to systemic hypertension, studies show a significant drop in blood pressure with even short-term use of CPAP. The most beneficial therapeutic effects are observed in patients with severe obstructive sleep apnea who are compliant with the CPAP regimen (see Chapter 107).9,10 Importantly, it has been shown that even small reductions in blood pressure over the long term significantly decrease the incidence of cerebrovascular and cardiovascular diseases.11 In prospective studies of 420,000 patients, with a mean follow-up of 10 years, drops in diastolic blood pressure of 5, 7.5, and 10 mm Hg were associated with, respectively, at least 34%, 46%, and 56% less stroke and at least 21%, 29%, and 37% less coronary heart disease.11 Therefore, in patients with obstructive sleep apnea, even a small drop in blood pressure, which could be maintained with long-term use of CPAP, is clinically



CHAPTER 116  •  Sleep and Cardiovascular Disease  1351

Primary events

Intermediary mechanisms

Consequences

ygenation/hypocapn ia Reox ia ↓ . rcapn DO e p y h t a 2; ↓ /h Symp etic overactivity a i and m ↑C oxe rtension e p y h l a n r p u i d ↓ d y a n n a BF d l a ↑ wa H n r u t l l te No c Alterations in CBF nsi ↓ and on ↑

Sleep apnea and hypopnea

Adhe sion

Negative swings in intrathoracic pressure

mole

cules Trans cription fa ctors Oxida Pla tive stress tele t agg regatio n/coagulopathy Meta bolic dysregula tion

tion Inflamma tion Inflamma RO S

osis e Thromb tanc resis n i t p Insulin/le

Endothelial dysfunction Systemic HTN Pulmonary HTN Systolic HF Diastolic HF Arrythmias Atherosclerosis CAD TIA Stroke

Cardiovascular mortality

Figure 116-2  The mechanisms by which sleep apnea may result in endothelial dysfunction and cerebrovascular and cardiovascular  , oxygen delivery; HF, heart failure; HTN, hypertendisorders. CAD, coronary artery disease; CBF, coronary/cerebral blood flow; DO 2 sion; ROS, reactive oxygen species; TIA, transient ischemic attacks; ↑, increase; ↓, decrease. (From McNicholas WT, Javaheri S. Pathophysiological mechanisms of cardiovascular disease in obstructive sleep apnea. Clin Sleep Med 2007;2(4):539-547.)

meaningful. Furthermore, treatment of obstructive sleep apnea with CPAP may afford additional protection against vascular disorders, because obstructive sleep apnea may contribute to cardiovascular and cerebrovascular disease by a variety of mechanisms in addition to hypertension (see Fig. 116-2).

abnormalities associated with metabolic syndrome. Longitudinal studies should be conducted to determine whether early recognition and treatment of obstructive sleep apnea as a companion of metabolic syndrome will have a preventive effect on cerebrovascular and cardiovascular diseases.

METABOLIC SYNDROME With the emergence of metabolic syndrome (see Chapter 114), a precursor of incident cerebrovascular and cardiovascular diseases, a new epidemic is evolving.12-14 This syndrome, characterized by hypertension, hyperglycemia, insulin resistance, and hypertriglyceridemia, goes handin-hand with obesity. Metabolic syndrome is a proinflammatory and prothrombotic condition with increased serum concentrations of high-sensitivity C-reactive protein, fibrinogen, and von Willebrand’s factor, and increased platelet aggregation. Metabolic syndrome has a high prevalence, affecting 24% of all adults.14 Its prevalence increases with age, reaching approximately 45% in those 60 years or older.14 Because metabolic syndrome is a precursor of cerebrovascular and cardiovascular disorders, its early recognition and targeted therapy have been emphasized by different medical societies.13-15 However, obstructive sleep apnea also accompanies obesity, and it shares a large number of biochemical abnormalities that are markers of metabolic syndrome (see Chapter 114). As an example, through sympathetic stimulation, obstructive sleep apnea contributes to insulin resistance and hypertension. Therefore, metabolic syndrome, obesity, and obstructive sleep apnea together are components of a vicious cycle. In concert with an emphasis on early recognition of metabolic syndrome,13-15 early recognition of obstructive sleep apnea as a comorbid condition also needs to be emphasized, particularly because treatment of obstructive sleep apnea with CPAP has been shown to reverse some of the

SLEEP IN PATIENTS WITH HEART FAILURE Another major development in the field is the rediscovery of central sleep apnea and Cheyne-Stokes breathing in patients with congestive heart failure and systolic dysfunction (see Chapter 122),16 although the discovery of this disorder dates back to John Hunter,17,18 37 years before John Cheyne’s description in 1818. There has been an explosion of physiologic and clinical research studies in this field.19 Many studies show that both central and obstructive sleep apnea are common in patients with congestive heart failure,19 and preliminary studies have shown that treatment of sleep apnea improves mortality in patients with heart failure.20 IMPACT For two major reasons, the recognition of the association of sleep-related breathing disorders and cardiovascular diseases is important. First, as noted previously (see Table 116-1), cardiovascular disorders pose a great burden to patients and society. Second, recent studies show that treatment of obstructive and central sleep apnea results in improvement in the cardiovascular morbidity and probably mortality as well. However, long-term longitudinal studies that are randomized and adequately powered to prove that sleep apnea is a cause of cardiovascular mortality are lacking. Meanwhile, the design of such studies is complicated by a number of factors, such as inclusion and

1352  PART II / Section 14  •  Cardiovascular Disorders

exclusion criteria: For example, should the most severe cases—patients with preexisting hypertension or excessive daytime sleepiness—be excluded? Yet such subjects may be the most compliant with CPAP therapy and their response to treatment may have the most favorable impact on mortality, the primary end point of the study. Other factors that complicate a long-term randomized clinical trial of obstructive sleep apnea include cost, compliance with CPAP (particularly when patients do not feel shortterm symptomatic benefit from it), and ethical issues, such as whether to use sham CPAP as a placebo in the control group. Because of the importance of the relationship between sleep-related breathing disorders (both obstructive and central sleep apnea) and cardiovascular disorders, this fifth edition of this book again devotes a series of chapters to cardiovascular diseases and sleep. In Chapters 117 and 118, a number of cardiovascular disorders related to sleep but unrelated to sleep apnea are reviewed. The emphasis in Chapter 117 is on nocturnal myocardial ischemia and infarction, and in Chapter 118, on arrhythmias as they relate to changes in autonomic nervous system and sleep stages. The remaining chapters in the series are devoted to obstructive and central sleep apnea and their relationship to cardiovascular diseases. Much research remains to be done in this field. Some studies have shown that treatment of obstructive sleep apnea reduces some cardiovascular morbidities in OSA patients with cardiovascular disorders, for example hypertension and arrhythmias.21-24 Large future studies will determine impact on cardiovascular mortality. Similarly, prospective therapeutic studies will determine whether treatment of sleep apnea, both central and obstructive, will influence the natural history of left ventricular dysfunction in systolic and diastolic heart failure. There have been no large systematic studies of diastolic heart failure, which is the most common form of left ventricular heart failure in the older population, in whom sleep apnea is also common. Furthermore, there is ample pathophysiologic evidence that the consequences of sleep apnea can cause left ventricular diastolic dysfunction.

❖  Clinical Pearls Cardiovascular disorders are highly prevalent and associated with excess morbidity and mortality and huge economic costs. Sleep-related breathing disorders are common in patients with cardiovascular disorders and may either play a causative role or contribute to the progression of the cardiovascular pathologic process. Observational studies suggest that obstructive sleep apnea is a cause of mortality, and that treatment with CPAP improves survival. Similarly, both central and obstructive sleep apnea may contribute to mortality of patients with systolic heart failure, and effective treatment with CPAP may improve survival.

REFERENCES 1. American Heart Association. Heart disease and stroke statistics—2009 update. Circulation 2009;119:e1-e161. 2. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384. 3. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829-1836. 4. Marrone O, Bonsignore MR. Pulmonary hemodynamics in obstructive sleep apnea. Sleep Med Rev 2002;6:175-193. 5. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 6. Koehler U, Fus E, Grimm W, et al. Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment. Eur Respir J 1998;11:434-439. 7. Javaheri S. Sleep-related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2004, p. 471-487. 8. Lavie L. Obstructive sleep apnoea syndrome: an oxidative stress disorder. Sleep Med Rev 2003;7:35-51. 9. Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68-73. 10. Pepperell JC, Randassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomized parallel trial. Lancet 2002;359:204-210. 11. MacMahon S, Peto R, Culter J, et al. Epidemiology: blood pressure, stroke, and coronary artery disease: Part 1. Prolonged differences in blood pressures: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-774. 12. Ninomiya JK, L’Italien G, Criqui MH, et al. Association of the metabolic syndrome with history of myocardial infarction and stroke in Third National Health and Nutrition Examination Survey. Circulation 2004;109:42-45. 13. Deedwania PC. Metabolic syndrome and vascular disease: is nature or nurture leading to new epidemic of cardiovascular disease? Circulation 2004;109:2-4. 14. Ford ESF, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359. 15. Grundy SM, Hansen B, Smith SC. Clinical management of metabolic syndrome: report of the American Heart Association/ National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004;109:551-556. 16. Cheyne J. A case of apoplexy, in which the fleshy part of the heart was converted into fat. Dublin Hosp Rep Commun 1818;2: 216-223. 17. Ward M. Periodic respiration: a short historical note. Ann R Coll Surg Engl 1973;52:330-334. 18. Allen R, Truk JL, Muricy R. The case books of John Hunter, FRS. New York: Parthenon; 1993. 19. Levy P, Pepin JL, Tamisier R, et al. Prevalence and impact of central sleep apnea in heart failure. Sleep Med Clin 2007;2:615-621. 20. Debacker W, Javaheri S. Treatment of sleep apnea in heart failure. Sleep Med Clin 2007;2:631-638. 21. Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens 2010; July. In press. 22. Di Guardo A, Profeta G, Crisafulli C, et al. Obstructive sleep apnoea in patients with obesity and hypertension. Br J Gen Pract 2010;60: 325-328. 23. Abe H, Takahashi M, Yaegashi H, et al. Efficacy of continuous positive airway pressure on arrhythmias in obstructive sleep apnea patients. Heart Vessels 2010;25:63-69. 24. Barbé F, Durán-Cantolla J, Capote F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181:718-726.

Sleep-Related Cardiac Risk Richard L. Verrier and Murray A. Mittleman

Abstract The brain, in subserving its need for periodic re-excitation during rapid eye movement (REM) sleep and dreaming, imposes significant demands on the heart by inducing bursts of sympathetic nerve activity, which reaches levels higher than during wakefulness. In patients with cardiac disease, such neural activity may compromise coronary artery blood flow, as metabolic demand outstrips supply, and may trigger sympathetically mediated life-threatening arrhythmias in response to functional myocardial ischemia. An additional challenge is presented by non-REM sleep, when hypotension may lead to malperfusion of the heart and brain as a result of a lowered blood pressure gradient through stenosed vessels. Impairment of ventilation by sleep-related breathing disor-

In healthy individuals, sleep is usually salutary and restorative. Ironically, during sleep in patients with respiratory or heart disease, the brain can precipitate breathing disorders, myocardial ischemia, arrhythmias, and even death. Our observation that 20% of myocardial infarctions (MIs) and 15% of sudden deaths occur during the period from midnight to 6:00 am projects to an estimated 300,000 nocturnal MIs and 48,750 nocturnal sudden deaths annually in the U.S. population.1 The latter figure is equivalent to 87% of the number of U.S. fatalities due to automobile accidents and is more than 2.5 times the number of U.S. deaths resulting from human immunodeficiency virus infection. Thus, sleep is not a fully protected state. Furthermore, the nonuniform distribution of deaths and MIs during the night is consonant with provocation by pathophysiologic triggers. The two main factors implicated in nocturnal cardiac events are sleep state–dependent surges in autonomic activity2 and depression of respiratory control mechanisms,3 which affect a vulnerable cardiac substrate. Precise characterization of their interaction in precipitating nocturnal cardiac events is, however, incomplete. Although sudden death during sleep can be presumed to be painless, in many cases it is premature because it occurs in infants and adolescents and in adults with ischemic heart disease, for whom the median age is 59 years. Populations at risk for nocturnal cardiorespiratory events include several large patient groups (Table 117-1). For example, atrial fibrillation is common in sleep apnea.1a-1f It is an insidious component of the problem of nocturnal risk that many people are unaware of their respiratory or cardiac distress at night and therefore take no corrective action. Thus, sleep presents unique autonomic, hemodynamic, and respiratory challenges to the diseased myocardium that cannot be monitored by daytime diagnostic tests. The importance of nocturnal monitoring of patients with cardiac disease extends beyond identifying sleep state–dependent triggers of cardiac events because nighttime myocardial ischemia, arrhythmias, autonomic activity, and respiratory disturbances carry predictive value for daytime events (Box 117-1).

Chapter

117

ders, including obstructive sleep apnea and central sleep apnea, which afflict millions of Americans, can generate reductions in arterial oxygen saturation and other pathophysiologic sequelae. Obstructive sleep apnea has been strongly implicated, when severe, in the etiology of hypertension, myocardial ischemia, arrhythmias, myocardial infarction, heart failure, and sudden death in individuals with coexisting ischemic heart disease. Similarly, central sleep apnea has been associated with a variety of atrial and ventricular arrhythmias. Atrial fibrillation may be triggered by autonomic or respiratory disturbances during sleep in certain patient populations. Medications that cross the blood–brain barrier may alter sleep structure and provoke nightmares with severe cardiac autonomic discharge.

In this chapter we discuss the pathophysiologic mechanisms responsible for sleep-related cardiac morbidity and mortality. For a review of mechanisms and treatment of nocturnal arrhythmias, see Chapter 118. Effects of sleepdisordered breathing and apnea on the cardiovascular system are discussed in Chapter 119.

AUTONOMIC ACTIVITY AND CIRCULATORY FUNCTION DURING SLEEP The generalized decrease in mean heart rate and arterial blood pressure at the onset of sleep and throughout non– rapid eye movement (NREM) sleep, which occupies 80% of sleep time, has prompted the assumption that sleep is a period of relative autonomic inactivity. NREM sleep, the initial stage, is characterized by marked stability of autonomic regulation with a high degree of parasympathetic neural tone and prominent respiratory sinus arrhythmia.2,4 Baroreceptor gain is high and contributes to the stability of arterial blood pressure and to overall cardiovascular homeostasis.5 Muscle sympathetic nerve activity is stable, falls with the transition from awake to NREM sleep, and decreases progressively with depth of sleep,2,6 reaching half the awake value during stage 4.2 Short-lasting increases in muscle sympathetic nerve activity, heart rate, and arterial blood pressure accompany the appearance of high-amplitude K-complexes during stage 2.2,6 Heart rate accelerations may even precede the electroencephalographic arousals of stage 2 and REM sleep.7 During transitions from NREM to REM sleep, bursts of vagus nerve activity may result in pauses in heart rhythm and frank asystole. Transitions between REM and NREM sleep elicit posture shifts that are associated with varying degrees of autonomic activation and attendant changes in heart rate and arterial blood pressure.8 These shifts in body position increase in frequency as individuals age and sleep becomes fragmented. Autonomic nervous system activity is dramatically altered when REM sleep is initiated (Fig. 117-1). REM 1353

1354  PART II / Section 14  •  Cardiovascular Disorders Table 117-1  Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events INDICATION (U.S. PATIENTS/YR)

POSSIBLE MECHANISM

Angina, myocardial infarction (MI), arrhythmias, ischemia, or cardiac arrest at night; 20% of myocardial infarctions (~300,000 cases/yr) and 15% of sudden deaths (~48,750 cases/yr) occur between midnight and 6:00 AM.

The nocturnal pattern suggests a sleep state–dependent autonomic trigger or respiratory distress.

Unstable angina, Prinzmetal angina

Nondemand ischemia and angina peak between midnight and 6:00 AM

Acute MI (1.5 million)

Disturbances in sleep, respiration, and autonomic balance may be factors in nocturnal arrhythmogenesis. Nocturnal onset of MI is more frequent in older and sicker patients and carries a higher risk of congestive heart failure.

Heart failure (5.3 million)

Sleep-related breathing disorders are pronounced in the setting of heart failure and may contribute to its progression and to mortality risk.

Spousal or family report of highly irregular breathing, excessive snoring, or apnea in patients with coronary disease (5 to 10 million patients with apnea).

Patients with hypertension or atrial or ventricular arrhythmias should be screened for the presence of sleep apnea.

Long QT syndrome

The profound cycle-length changes associated with sleep may trigger pause-dependent torsades de pointes in these patients.

Near-miss or siblings of victims of sudden infant death syndrome (SIDS)

SIDS commonly occurs during sleep with characteristic cardiorespiratory symptoms.

Brugada syndrome in Western populations; Asians with warning signs of sudden unexplained nocturnal death syndrome (SUNDS)

SUNDS is a sleep-related phenomenon in which night terrors may play a role. It is genetically related to the Brugada syndrome.

Atrial fibrillation (2.5 million)

Twenty-nine percent of episodes occur between midnight and 6:00 AM. Respiratory and autonomic mechanisms are suspected.

Patients on cardiac medications (13.5 million patients with cardiovascular disease)

Beta-blockers and calcium channel blockers that cross the blood–brain barrier may increase nighttime risk because poor sleep and violent dreams may be triggered. Medications that increase the QT interval may conduce to pause-dependent torsades de pointes during the profound cycle-length changes of sleep. Because arterial blood pressure is decreased during non–rapid eye movement sleep, additional lowering by antihypertensive agents may introduce a risk of ischemia and infarction due to lowered coronary perfusion.

sleep is marked by profound muscle sympathetic nerve activation, in terms of both frequency and amplitude,2,6 which attains levels significantly higher than in wakefulness.2 Sympathetic nerve activity is concentrated in short, irregular periods that are most striking when accompanied by intense eye movements.2 These bursts trigger intermittent increases in heart rate and arterial blood pressure to levels similar to those in wakefulness, with increased variability.2,6,7 Significant surges and pauses in heart rate during REM sleep have been described in several species, including humans.6,7 Cardiac efferent vagal tone and baroreceptor regulation5 are generally suppressed during REM sleep, and breathing patterns may become highly irregular and may lead, in susceptible individuals, to oxygen desaturation. Thus, while subserving the neurochemical functions of the brain, REM sleep can disrupt cardiorespiratory homeostasis. The brain’s increased excitability during REM sleep can also trigger major surges in sympathetic nerve activity to the skeletal muscular beds, accompanied by muscular twitching,2 which interrupts the generalized skeletal atonia of REM.8 The peripheral autonomic status

characterized by muscle sympathetic nerve recording is compatible with reduced neuronal activity in the brainstem and other regions of the brain and reduced cerebral blood flow during NREM sleep and, during REM sleep, with increased brain activity in several discrete regions to levels higher than waking values.9 The decline in autonomic activity during sleep is also evident in peroneal muscle sympathetic nerve activity2,6 and peripheral levels of epinephrine and norepinephrine, and mirrors the generalized sleep-induced decline in heart rate and arterial blood pressure.10 A nocturnal nadir in plasma catecholamines is evident at 1 hour after sleep onset. Plasma cortisol is also depressed during sleep; increased levels are initiated at 5:00 am. In the absence of readily achieved, direct measures of cardiac-bound nerve activity, analysis of heart rate variability (HRV) has emerged as a widely accepted method for measuring cardiac sympathetic versus parasympathetic neural dominance. High-frequency (HF) HRV is a general indicator of cardiac parasympathetic tone and includes the effects of respiration. The low- to high-frequency



• Because parasympathetic nerve activity is elevated during sleep in healthy individuals, lack of circadian pattern of heart rate variability and baroreflex sensitivity may be readily monitored for increased risk of cardiac events. • Nondemand nocturnal ischemic episodes may disclose a critical underlying coronary lesion, coronary vasospasm, or transient coronary artery stenosis. • In elderly subjects, nighttime multifocal ventricular ectopic activity predicts increased mortality from cardiac causes independent of clinically evident cardiac disease. • Sleep apnea, which may be screened by heart rate variability analysis, conduces to hypertension, ischemia, and atrial and ventricular arrhythmias, and is a risk factor for lethal daytime cardiac events, including myocardial infarction. • Hypertensive patients with less than a 10% nocturnal decline in blood pressure (remaining higher than 101/65 mm Hg) are at increased risk of total and cardiovascular mortality and all cardiovascular endpoints, myocardial ischemia, frequent or complex ventricular arrhythmias, cerebrovascular insult, and increased organ damage, including cardiac hypertrophy. • Elevated nocturnal heart rates are associated with increased mortality.

(LF/HF) ratio is widely accepted as an approximation of cardiac-bound sympathetic nerve activity, as validated by studies involving beta-adrenergic receptor blocking agents. Decreased HRV, indicating a decline in parasympathetic nerve activity, is an established indicator of risk for sudden cardiac death after MI. HRV analysis reveals a generalized increase in vagus nerve activity and a decrease in cardiac sympathetic nerve activity across the sleep period,11,12 probably reflecting the dominance of total sleep time by NREM sleep. HRV studies using 5-minute intervals provide results consistent with muscle nerve recording, indicating increased HF and decreased LF (or parasympathetic nerve dominance) in NREM sleep, but decreased HF and increased LF (or predominant sympathetic nerve activity) in REM sleep and during wakefulness.7 In healthy individuals, the increase in HRV measures of cardiac sympathetic nerve activity at onset of REM sleep is initiated before7,12 the transition from NREM sleep as classically defined from the polysomnographic record. The typical circadian pattern of decreased nocturnal cardiac sympathetic nerve activity as described by heart rate and HRV studies is altered in patients with coronary artery disease,13,14 MI,11,15 and diabetes,16 suggesting either increased nocturnal cardiac sympathetic nerve activity or decreased parasympathetic nerve activity compared with healthy subjects. The HF component has been observed to decrease approximately 10 minutes before onset of nocturnal myocardial ischemia.14 In unmedicated patients with a recent MI, the LF/HF ratio was significantly increased

40

*

30 20 *

10

*

0 Awake 1

2

3

4

REM

250 Burst amplitude (%)

Box 117-1  Predictive Value of Nocturnal Cardiorespiratory Status

Burst frequency (bursts/min)

CHAPTER 117  •  Sleep-Related Cardiac Risk  1355

*

200 150 100 50

*

*

3

4

0 Awake 1

2

REM

Figure 117-1  Sympathetic nerve burst frequency and amplitude during wakefulness, non–rapid eye movement (NREM) sleep (eight subjects), and REM sleep (six subjects). Sympathetic nerve activity was significantly lower during stages 3 and 4 (P < .001). During REM sleep, sympathetic nerve activity increased significantly (P < .001). Values are means ± standard error of the mean. (From Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993;328:303-307. Copyright 1993 Massachusetts Medical Society. All rights reserved.)

during both REM and NREM sleep, in contrast to healthy subjects, in whom this ratio during REM sleep is similar to awake levels and higher than during NREM sleep (Fig. 117-2).11 The conclusions were reached that MI decreases the capacity of the vagus nerve to be activated during sleep, resulting in unbridled cardiac sympathetic nerve activity,11 and that loss of rise in the HF component is characteristic of patients after an MI and with residual myocardial ischemia.15 These sleep state–dependent profiles of autonomic activity have significant potential to affect coronary function and cardiac electrical stability in patients with ischemic heart disease.

NOCTURNAL CARDIOVASCULAR EVENTS Nocturnal Myocardial Ischemia and Angina Accurate assessment and treatment of nocturnal angina has been a subject of concern for more than 2 centuries. Heberden in 1768 described angina that “will often oblige [the patients] to rise up out of their bed every night for many months altogether.” John Hunter, the well-known 18th-century surgeon, reported chest pains that “seized

1356  PART II / Section 14  •  Cardiovascular Disorders

12 10

Post-MI

8 LF/HF

*

Controls

*

6 4 2 0 Awake

NREM

REM

Figure 117-2  Bar graphs indicating low- to high-frequency (LF/ HF) ratio of heart rate variability during the awake state (left), during non–rapid eye movement (NREM) sleep (middle), and during REM sleep (right) in healthy subjects and in post-myocardial infarction (MI) patients (P < .01 when comparing control subjects and post-MI patients). Values are means ± standard error of the mean. (From Vanoli E, Adamson PB, Ba-Lin, et  al. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation 1995;91:1918-1922.)

him in his sleep so as to awaken him.”17 As early as 1923, MacWilliam18 postulated that the mechanisms of nocturnal ventricular fibrillation and angina were stimulation of sympathetic nerves and increased arterial blood pressure. He described “reflex excitations, dreams, nightmares, etc., sometimes accompanied by extensive rises of arterial blood pressure (hitherto not recognized), increased heart action, changes in respiration, and various reflex effects” and noted “the suddenness of development of the functional disturbances in arterial blood pressure, heart action, etc., in the dreaming state.” He documented greater stress on the circulatory system during dreaming than during wakefulness, with arterial blood pressures reaching 200 mm Hg. In the middle of the 20th century, the renowned cardiologists Paul Dudley White and Samuel Levine remarked on the frequency of MI and angina in sleep and suggested an association with dreams. Ischemic activity is an important prognostic marker in patients with cardiac disease, and characteristics of both REM and NREM sleep may conduce to nocturnal myocardial ischemia and angina. The few studies in patients with cardiac disease that have used sleep staging have concluded that in the absence of significant depression of left ventricular function, nocturnal ischemic events occur primarily during REM sleep,19,20 which is characterized by increased sympathetic nerve activity, metabolic demands, and heart rate surges. In patients with stable coronary artery disease, myocardial ischemia is largely attributable to bouts of sympathetically mediated surges in heart rate and resultant metabolic demands in flow-limited, stenotic coronary arteries.4,14,20-24 Nowlin and coworkers20 attributed nocturnal angina to heightened blood pressure after performing detailed, multisession polysomnographic analysis of four patients with advanced coronary artery disease and nocturnal angina pectoris. They established that

attacks of nocturnal angina occurred predominantly during REM sleep (32 of 39 recordings) and were associated with heart rate acceleration. Dream content, in patients who could describe it, included awareness of chest pain and involved strenuous physical activity or emotions of fear, anger, or frustration. Nocturnal myocardial ischemia may be generated by mechanisms in addition to sympathetic nerve activity and unsatisfied metabolic demands. This possibility is suggested by the finding that nighttime ischemic events remain, although they are less frequent, in patients receiving beta-adrenergic receptor blockade therapy, the primary therapy that effectively reduces the overall incidence of and suppresses the morning peak in cardiac events by containing sympathetic nerve activity and demand-related myocardial ischemia.24,25 The main factors that may contribute to nondemand-related myocardial ischemia during NREM sleep are decreased coronary perfusion pressure as the result of hypotension4,24-27 and increased coronary vasomotor tone.26 These influences decrease the metabolic threshold for induction of nocturnal myocardial ischemia, which has a nadir between 1:00 am and 3:00 am.21,26,28 During these hours in patients with stable coronary disease, Benhorin and colleagues26 observed that myocardial ischemia can be provoked at heart rates of 83 beats per minute (bpm), in contrast to 96 bpm during midday, and that its incidence was not affected by beta-adrenergic receptor blockade. Patel and colleagues25 noted that nocturnal myocardial ischemia is attended by heart rate elevations of 6  bpm or less in patients with unstable angina receiving beta-adrenergic receptor blocking agents. Mancia4 hypothesized that the hypotension of NREM sleep is a major contributor to nocturnal myocardial ischemia and MI because it “reduces the volume and velocity of blood flow, favoring the development of thrombi and embolic and ischemic phenomena before and after arousal.” It has also been postulated that myocardial ischemia provoked by transient thrombus formation29 is attributable to the nocturnal nadir in endogenous fibrinolytic activity,29 as well as to peaks in serum levels of plasminogen activator inhibitor29 and tissue plasminogen activator antigen, increasing blood viscosity or hypercoagulability at night, and freeradical generation. Nondemand nocturnal myocardial ischemia is prevalent among patients with more severe coronary disease,24,28,30 acute coronary syndromes,15 or diabetes, populations with significant endothelial dysfunction. Indeed, it has been concluded that nondemand nocturnal ischemic episodes disclose a critical underlying coronary lesion, coronary vasospasm, or transient coronary artery stenosis.25 Patel and colleagues25 documented a nocturnal peak in ischemic events in their study of 256 hospitalized patients with the acute coronary syndromes of unstable angina and non– Q-wave MI (Fig. 117-3). Electrocardiograms were recorded within hours after patients’ admission for chest pain to the coronary care unit for new-onset angina, sudden acceleration of previously stable angina, or angina within 1 month of MI. In hospital, they received optimal medical therapy aimed at containing demand-related myocardial ischemia. It is important to note, however, that the peak in out-of-hospital onset of the syndromes followed the usual circadian pattern, as reported by Cannon and



CHAPTER 117  •  Sleep-Related Cardiac Risk  1357

25 UA Non-Q

No. of episodes

20 15 10 5 0 0-2

2-4

4-6

6-8

8-10

10-12

12-14

14-16

16-18

18-20

20-22

22-24

Time of day (2-hour blocks)

coworkers31 in the Thrombosis in Myocardial Infarction (TIMI) III Study of 3318 patients. By contrast, in patients with longstanding diabetes or with documented autonomic nervous system dysfunction, there is no nocturnal decrease in myocardial ischemia or onset of acute MI. Demand-related ischemic episodes can be effectively contained by beta-adrenergic receptor blockade,25 but antihypertensive treatment does not reduce the nocturnal incidence of nondemand-related myocardial ischemia.32 The use of vasodilators to treat nondemand episodes resulting from endothelial dysfunction is the subject of debate. The lack of sleep staging and arterial blood pressure monitoring in patients with nocturnal myocardial ischemia leaves unidentified any contribution by autonomic and hemodynamic activity dictated by sleep states. Such monitoring would also disclose the prevalence of the established proischemic influences of nocturnal arousal and rising from bed.13,33 Post-Myocardial Infarction Patients During the first weeks after MI, sleep is significantly disturbed,27,34 and nocturnal oxygen desaturation, especially in patients with impaired left ventricular function, may be generalized or episodic and may directly provoke tachy­ cardia, ventricular premature beats, and ST-segment changes (Fig. 117-4).34-37 Both the duration and number of nighttime ischemic events are increased, consonant with increased cardiac sympathetic nerve activity25,38 or decreased parasympathetic nerve activity (see Fig. 117-2),11 particularly in patients with residual myocardial ischemia.15 Nocturnal levels of norepinephrine are increased, and nocturnal secretion of melatonin, an endogenous hormone that suppresses sympathetic nerve activity, is impaired.39 These symptoms become normal over time so that within the first 6 months, ventricular tachycardia during sleep is relatively rare.

Oxygen saturation (%)

Figure 117-3  The circadian variation of ischemic activity based on 2-hour time blocks for the in-hospital study population. There is a single peak of ischemic activity at night between 10:00 PM and 8:00 AM, and no morning peak in ischemic activity is apparent. More than 64% of episodes occurred during this period (P < .001 compared with daytime). The circadian distribution of ischemic episodes in unstable angina (UA) and non–Q-wave myocardial infarction (Non-Q) is similar to the overall pattern of ischemic activity. (From Patel DJ, Knight CJ, Holdright DR, et al. Pathophysiology of transient myocardial ischemia in acute coronary syndromes: characterization by continuous ST-segment monitoring. Circulation 1997;95:1185-1192.)

100 80 60 0130

0145

0200

0215

0230

Time

0201 0202 0203 0204 0205 Time Continuous ECG

Figure 117-4  Importance of monitoring nocturnal oxygen saturation in patients who have sustained a myocardial infarction. Nonsustained ventricular tachycardia (bottom) and hypoxemia measured by pulse oximetry (top) occurred simultaneously in a patient on the third night after infarction. The patient died on the following day of cardiogenic shock. ECG, electrocardiogram. (From Galatius-Jensen S, Hansen J, Rasmussen V, et  al. Nocturnal hypoxemia after myocardial infarction: association with nocturnal myocardial ischaemia and arrhythmias. Br Heart J 1994;72:23-30.)

The most detailed study to date of sleep in post-MI patients was performed in 1978 by Broughton and Baron,27 who reported on the sleep and cardiovascular condition of 12 patients, aged 33 to 70 years, after severe MI, first during their stay in the intensive care unit and then in the hospital ward. They noted a “marked disturbance of nocturnal sleep patterns … characterized by high amounts of wakefulness, stage 1, and number of awakenings, and REM density and low amounts of REM sleep, shorter

1358  PART II / Section 14  •  Cardiovascular Disorders

REM periods with prolonged REM latencies. Sleep efficiency was substantially reduced.”27 All of these sleepquality parameters improved in parallel with time after MI until on day 9 the only remaining abnormal feature was a high content of NREM sleep stages 3 and 4. REM density peaked on postinfarction nights 3 and 4 and NREM sleep on night 4. On subsequent hospital visits after discharge, the patients described terrifying dreams, suggesting that REM suppression was followed by REM rebound more than 2 weeks after the crisis. Importantly, Broughton and Baron observed that NREM sleep provoked nocturnal angina and awakening. They postulated that the hypotension associated with NREM sleep resulted in a diminution in perfusion pressure of the major coronary and collateral vessels supplying the mechanically compromised myocardium. The decreased heart rates typical of NREM sleep, however, were not observed, and heart rates were higher in NREM sleep than in wakefulness on half the nights recorded, indicating enhanced cardiac sympathetic nerve activity even in NREM sleep. In half of the cases, the electrocardiogram amplitude decreased during anginal attacks. In the context of nighttime monitoring, it is of interest to note that T-wave alternans, an electrocardiographic (ECG) phenomenon indicating vulnerability to lethal arrhythmias,40-42 has been recorded in the nighttime electrocardiogram of a patient with left dysfunction enrolled in the ambulatory ECG arm of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (Fig. 117-5).41

the myocardial oxygen supply–demand relationship or alpha-adrenergically mediated coronary vasoconstriction. Alternatively, in a starkly opposite manner, the hypotension of slow-wave sleep may lead to malperfusion of the myocardium because of reduced coronary perfusion pressure through stenotic vessel segments (Fig. 117-6).44 Several investigators25,45,46 have attributed nocturnal MI and myocardial ischemia to the relative hypotension of NREM sleep, which “reduces the volume and velocity of blood flow, favoring the development of thrombi and embolic and ischemic phenomena before and after arousal.”4 Mancia4 therefore advocated avoiding drugs that enhance the hypotension of NREM sleep and prescribing antihypertensive medications only for daytime therapy. He echoed the argument of Floras,32 who observed that antihypertensive treatment did not reduce the incidence of nocturnal MI and myocardial ischemia. Further evidence of the risk of hypotension-induced infarction has been provided by Kleiman and colleagues,45 who reported that the incidence of subendocardial MI clustered at 2:00 am to 4:00 am, simultaneously with the nadir in arterial blood pressure. Other factors known to contribute to MI are operative during sleep, including increased ventricular diastolic pressures and volumes caused by the fluid shifts resulting from assuming a supine posture, unfavorable alterations in the balance of fibrinolytic and thrombotic factors,29 and chronic or episodic oxygen desaturation.27,34-37 Specific patient groups experience an increased incidence of nighttime MIs, particularly those with poor ventricular function, advanced age, or diabetes.47,48 The risk for development of congestive heart failure is higher for nighttime than daytime MIs,49 potentially because of either the pathologic process or a delay in obtaining high-quality care.

Nocturnal Myocardial Infarction Although only 20% of MIs occur between midnight and 6:00 am, their nonuniform distribution implicates pathophysiologic triggers.1 The dynamic perturbations in autonomic nervous system activity both independent of and in conjunction with apnea43 are likely to constitute important triggers of MI at night. REM-induced surges in sympathetic nerve activity have the potential to provoke tachycardia and hypertension, alterations that carry the potential for inducing MI secondary to coronary artery plaque rupture as well as to inappropriate decreases in

IV

IV

IV

Hypertension Patients whose nighttime arterial blood pressure declines less than 10% from day to night (called “nondippers”) are at increased risk for total and cardiovascular mortality,50 as well as all cardiovascular end points,51 frequent or complex ventricular arrhythmias,52 myocardial ischemia,53

IV

IV

IV

IV

IV

IV

IV

IV

25 m/sec 10 m/mV

75 m/sec 100 m/mV

25 m/sec 10 m/mV 25 m/sec 10 m/mV

03-Jul-2007 04 26 15

62 BPM

Figure 117-5  High-resolution template showing T-wave alternans (65  µV) in precordial lead V3 in superimposed electrocardiographic (ECG) waveforms from a nighttime ambulatory ECG recording of a patient with heart failure and left ventricular dysfunction enrolled in the ambulatory electrocardiographic (AECG) substudy of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). The associated ECG strip is also provided. (From Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS Study. J Cardiovasc Electrophysiol 2008;19:1037-1042.)



CHAPTER 117  •  Sleep-Related Cardiac Risk  1359

Coronary stenosis

Baseline 300

20 sec

HR (bpm) 0 200 AP (mm Hg) 0 200 CBF (ml/min) 0 +5000

x2

dP/dt (mm Hg/sec) -5000 11.7 PWT (mm) 6.9 15.8 AWT (mm) 7.9 Non-REM sleep

REM sleep

Figure 117-6  Representative tracings for hemodynamic variables at baseline (prior to stenosis) and during non–rapid eye movement (non-REM) (single arrow) and REM sleep (double arrow) in the presence of coronary stenosis. Non-REM sleep initiated a decrease in arterial pressure (AP), resulting in akinesis in the anterior wall (stenotic region). REM sleep induced a rapid increase in heart rate (HR), AP, and dP/dtmax (rate of change of left ventricular pressure). The onset of REM sleep increased coronary blood flow, which returned anterior wall function to the poststenotic condition prior to the onset of non-REM sleep (see expanded tracing in box). AWT, anterior wall thickness; CBF, coronary blood flow; PWT, posterior wall thickness. (From Kim SJ, Kuklov A, Kehoe RF, et al. Sleep-induced hypotension precipitates severe myocardial ischemia. Sleep 2008;31:1215-1220.)

cerebrovascular insult,54 and increased organ damage, including cardiac hypertrophy.55 The absence of a nocturnal decline in blood pressure may be an important marker of complications among patients with type 1 diabetes,56 and it may be reflected in the significant incidence of death at 2:00 am to 4:00 am among hypertensive women reported by Mitler and colleagues (Fig. 117-7).57 Faulty baroreceptor activation may account for the fact that arterial blood pressure during sleep remains significantly elevated in these hypertensive patients, who typically show evidence of central hypersympathetic nerve activity with an increased number of microarousals, a reduced length and depth of NREM sleep, and a shortened REM latency. Blunted endothelium-dependent vasodilation is also implicated. Heart Failure Excess mortality risk attends chronic congestive heart failure, particularly among the 40% to 80% of heart failure patients with either obstructive or central sleep apnea. These sleep-related breathing disorders may contribute to the severity of disease—specifically, to remodeling of cardiac chambers and left ventricular diastolic dysfunction as well as to T-wave alternans, a marker of vulnerability to ventricular arrhythmias and sudden cardiac

death.42,56 In patients with systolic heart failure, central sleep apnea, severe right ventricular systolic dysfunction, and low diastolic blood pressure are associated with increased mortality risks.59 Treatment of apnea with continuous positive airway pressure, medications, or devices frequently lessens heart failure symptoms and mortality risk. Diagnostic and treatment strategies are discussed in Chapter 122. Elderly Patients Elderly individuals’ (particularly women’s) reports of daytime sleepiness, suggesting poor quality of sleep, are associated with mortality, cardiovascular morbidity and mortality, MI, and congestive heart failure.60 Depression, poor health, daytime angina, a limited activity level, and cardiac arrhythmias may accompany disturbed sleep in elderly individuals. Initiating a moderately intense exercise program significantly improves sleep quality61 and autonomic status62 in formerly sedentary older people. Nocturnal myocardial ischemia is not uncommon in older patients with vascular disease who experience regular episodes of oxygen desaturation and increased heart rate. Conflicting evidence has been presented of increased risk for nighttime compared with daytime MI and sudden

1360  PART II / Section 14  •  Cardiovascular Disorders

FEMALE DEATHS FROM HYPERTENSIVE DISEASE 10 9

n = 52

Deaths/ 2 hr interval

8 7 6 5 4 3 2 1 0 12 to 2

2 to 4

4 to 6

6 to 8

8 to 10

10 to noon

Noon to 2

2 to 4

4 to 6

6 to 8

8 to 10

10 to 12

Time Figure 117-7  The temporal distribution of female deaths attributed to hypertensive disease peaked at 2:00 AM to 4:00 AM. The temporal concentration was statistically significant (P < .01). Data were derived from a 4600-person (>8%) sample of deaths due to disease in New York City in 1979. (Reprinted from Mitler MM, Hajdukovic RM, Shafor R, et al. When people die: cause of death versus time of death. Am J Med 1987;82:266-274, copyright 1987, with permission from Excerpta Medica, Inc.)

cardiac death in the elderly.46,47,63 Impaired baroreceptor sensitivity,64 a measure of the capacity for reflex vagus nerve activation,5 and increased low-frequency power of HRV65 are evident at night in susceptible elderly patients. Given this autonomic background, it is not surprising that nighttime multifocal activity in elderly patients is a predictor of cardiac mortality.

❖  Clinical Pearls Sleep exerts a major impact on the health of the patient with cardiac disease, through both direct cardiovascular influences and sleep-disordered breathing.66 In a sense, the diseased heart and lungs are unwitting victims of the needs of the sleeping brain, which commands dramatic alterations in autonomic and respiratory activity. A sizeable population experiences cardiac events during sleep, with identifiable high-risk groups (see Table 117-1). Sleep also presents unusual opportunities to monitor the patient with cardiac disease, because there is growing appreciation of the fact that nighttime heart rate, blood pressure, myocardial ischemia, arrhythmias, and respiratory disturbances carry predictive value for daytime events (see Box 117-1). Daytime tests cannot substitute for nighttime monitoring of the patient with cardiac disease, because exercise treadmill testing and daytime ambulatory monitoring cannot replicate the autonomic, hemodynamic, or respiratory challenges that uniquely accompany sleep. Improved identification of the precise triggers of nocturnal cardiac events may be anticipated when technologies are integrated for monitoring sleep state, respiration, oxygen desaturation, and cardiovascular variables.

Acknowledgments The authors thank Sandra Verrier for her editorial contributions. REFERENCES 1. Lavery CE, Mittleman MA, Cohen MC, et al. Nonuniform nighttime distribution of acute cardiac events: a possible effect of sleep states. Circulation 1997;5:3321-3327. 1a.  Padeletti M, Vignini S, Ricciardi G, et al. Sleep disordered breathing and arrhythmia burden in pacemaker recipients. Pacing Clin Electrophysiol 2010 Aug 24. [Epub ahead of print] 1b.  Matiello M, Nadal M, Tamborero D, et al. Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients. Europace 2010;12:1084-1089. 1c.  Pedrosa RP, Drager LF, Genta PR, et al. Obstructive sleep apnea is common and independently associated with atrial fibrillation in patients with hypertrophic cardiomyopathy. Chest 2010;137:10781084. 1d.  Monahan K, Storfer-Isser A, Mehra R, et al. Triggering of nocturnal arrhythmias by sleep-disordered breathing events. J Am Coll Cardiol 2009;54:1797-1804. 1e.  Bitter T, Langer C, Vogt J, et al. Sleep-disordered breathing in patients with atrial fibrillation and normal systolic left ventricular function. Dtsch Arztebl Int 2009;106:164-170. 1f.  Mehra R, Stone KL, Varosy PD, et al. Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009;169:1147-1155. 2. Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993;328: 303-307. 3. Young T, Palta M, Dempsey J, et al. The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-1235. 4. Mancia G. Autonomic modulation of the cardiovascular system during sleep. N Engl J Med 1993;328:347-349. 5. Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity. Circ Res 1969;24:109-121. 6. Hornyak M, Cejnar M, Elam M, et al. Sympathetic muscle nerve activity during sleep in man. Brain 1991;114:1281-1295.

7. Bonnet MH, Arand DL. Heart rate variability: sleep stage, time of night, and arousal influences. Electroencephalogr Clin Neurophysiol 1997;102:390-396. 8. Hobson JA, Spagna T, Malenka R. Ethology of sleep studied with time-lapse photography: postural immobility and sleep-cycle phase in humans. Science 1979;201:1251-1253. 9. Maquet P, Peters J, Aerts J, et al. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 1996; 383:163-166. 10. Dodt C, Breckling U, Derad I, et al. Plasma epinephrine and norepinephrine concentrations of healthy humans associated with nighttime sleep and morning arousal. Hypertension 1997;30:71-76. 11. Vanoli E, Adamson PB, Ba-Lin, et al. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation 1995;91:1918-1922. 12. Otzenberger H, Simon C, Gronfier C, et al. Temporal relationship between dynamic heart rate variability and electroencephalographic activity during sleep in man. Neurosci Lett 1997;229:173-176. 13. Huikuri HV, Niemela MJ, Ojala S, et al. Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease: effects of arousal and upright posture. Circulation 1994;90:121-126. 14. Vardas PE, Kochiadakis GE, Manios EG, et al. Spectral analysis of heart rate variability before and during episodes of nocturnal ischaemia in patients with extensive coronary artery disease. Eur Heart J 1996;17:388-393. 15. Cerati D, Nador F, Maestri R, et al. Influence of residual ischaemia on heart rate variability after myocardial infarction. Eur Heart J 1997;18:78-83. 16. Aronson D, Weinrauch LA, D’Elia JA, et al. Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy. Am J Cardiol 1999;84:449-453. 17. Home E. Life of John Hunter. In: Major RH, editor: Classic descriptions of disease. 4th ed. Springfield, Ill: Charles C Thomas; 1955. p. 423. 18. MacWilliam JA. Blood pressure and heart action in sleep and dreams: their relation to haemorrhages, angina, and sudden death. BMJ 1923;22:1196-2000. 19. Kales A, Kales JD. Evaluation, diagnosis, and treatment of clinical conditions related to sleep. JAMA 1970;213:2229-2232. 20. Nowlin JB, Troyer WG Jr, Collins WS, et al. The association of nocturnal angina pectoris with dreaming. Ann Intern Med 1965;63:1040-1046. 21. Quyyumi AA, Wright CA, Mockus LJ, et al. Mechanisms of nocturnal angina pectoris: Importance of increased myocardial oxygen demand in patients with severe coronary artery disease. Lancet 1984;1:1207-1209. 22. Deedwania PC, Nelson JR. Pathophysiology of silent myocardial ischemia during daily life: hemodynamic evaluation by simultaneous electrocardiographic and blood pressure monitoring. Circulation 1990;92:1296-1304. 23. Behar S, Reicher-Reiss H, Goldbourt U, et al. Circadian variation in pain onset in unstable angina pectoris. Am J Cardiol 1991;67: 91-93. 24. Andrews TC, Fenton T, Toyosaki N, et al., for the Angina and Silent Ischemia Study Group (ASIS): subsets of ambulatory myocardial ischemia based on heart rate activity: circadian distribution and response to anti-ischemic medication. Circulation 1993;98:92-100. 25. Patel DJ, Knight CJ, Holdright DR, et al. Pathophysiology of transient myocardial ischemia in acute coronary syndromes: characterization by continuous ST-segment monitoring. Circulation 1997; 95:1185-1192. 26. Benhorin J, Banai S, Moriel M, et al. Circadian variations in ischemic threshold and their relation to the occurrence of ischemic episodes. Circulation 1993;97:808-814. 27. Broughton R, Baron R. Sleep patterns in the intensive care unit and on the ward after acute myocardial infarction. Electroencephalogr Clin Neurophysiol 1978;45:348-360. 28. Figueras J, Cinca J, Balda F, et al. Resting angina with fixed coronary artery stenosis: nocturnal decline in ischemic threshold. Circulation 1986;74:1248-1254. 29. Bridges AB, McLaren M, Scott NA, et al. Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischemic heart disease. Br Heart J 1993;69:121-124.

CHAPTER 117  •  Sleep-Related Cardiac Risk  1361 30. Selwyn AP, Fox K, Eves M, et al. Myocardial ischaemia in patients with frequent angina pectoris. BMJ 1978;2:1594-1596. 31. Cannon CP, McCabe CH, Stone PH, et al. Circadian variation in the onset of unstable angina and non-Q-wave acute myocardial infarction (the TIMI III Registry and TIMI IIIB). Am J Cardiol 1997;79:253-258. 32. Floras JS. Antihypertensive treatment, myocardial infarction, and nocturnal myocardial ischaemia. Lancet 1988;2:994-996. 33. Parker JD, Testa MA, Jimenez AH, et al. Morning increase in ambulatory ischemia in patients with stable coronary artery disease: importance of physical activity and increased cardiac demand. Circulation 1994;99:604-614. 34. Galatius-Jensen S, Hansen J, Rasmussen V, et al. Nocturnal hypoxemia after myocardial infarction: association with nocturnal myocardial ischaemia and arrhythmias. Br Heart J 1994;72:23-30. 35. Spudge DD, Seires SF, Maron BJ, et al. Prevalence of arrhythmias during 24-hour Holter electrocardiographic monitoring and exercise testing in patients with obstructive and nonobstructive hypertrophic cardiomyopathy. Circulation 1979;59:866-875. 36. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation 2000;101:392-397. 37. Cripps T, Rocker G, Stradling J. Nocturnal hypoxia and arrhythmias in patients with impaired left ventricular function. Br Heart J 1992;68:382-386. 38. Mickley H, Pless P, Nielsen JR, et al. Circadian variation of transient myocardial ischemia in the early out-of-hospital period after first acute myocardial infarction. Am J Cardiol 1991;67:927-932. 39. Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet 1995;345:1408. 40. Verrier RL, Nearing BD, LaRovere MT, et al. Ambulatory ECGbased tracking of T-wave alternans in post-myocardial infarction patients to assess risk of cardiac arrest or arrhythmic death. J Cardiovasc Electrophysiol 2003;14:705-711. 41. Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECGbased T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS Study. J Cardiovasc Electrophysiol 2008;19:1037-1042. 42. Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective [Invited review]. Heart Rhythm 2009;6(3):416422. 43. Hung J, Whitford EG, Parsons RW, et al. Association of sleep apnoea with myocardial infarction in men. Lancet 1990;336: 261-264. 44. Kim SJ, Kuklov A, Kehoe RF, et al. Sleep-induced hypotension precipitates severe myocardial ischemia. Sleep 2008;31:1215-1220. 45. Kleiman NS, Schechtman KB, Young PM, et al., and the Diltiazem Reinfarction Study Investigators. Lack of diurnal variation in the onset of non-Q-wave infarction. Circulation 1990;91:548-555. 46. Hansen O, Johannsson BW, Gullberg B. Circadian distribution of onset of acute myocardial infarction in subgroups from analysis of 10,791 patients treated in a single center. Am J Cardiol 1992; 69:1003-1008. 47. Hjalmarson A, Gilpin EA, Nicod P, et al. Differing circadian patterns of symptom onset in subgroups of patients with acute myocardial infarction. Circulation 1989;90:267-275. 48. Rana JS, Mukamal KJ, Morgan JP, et al. Circadian variation in the onset of myocardial infarction: effect of duration of diabetes. Diabetes 2003;52:1464-1468. 49. Mukamal KJ, Muller JA, Maclure M, et al. Increased risk of congestive heart failure among infarctions with nighttime onset. Am Heart J 2000;140:439-442. 50. Fagard RH, Celis H, Thijs L, et al. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension 2008;51:55-61. 51. Staessen JA, Thijs L, Fagard R, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA 1999;282:539-546. 52. Schillaci G, Verdecchia P, Borgioni C, et al. Association between persistent pressure overload and ventricular arrhythmias in essential hypertension. Hypertension 1996;28:284-289. 53. Pierdomenico SD, Bucci A, Costantini F, et al. Circadian blood pressure changes and myocardial ischemia in hypertensive patients with coronary artery disease. J Am Coll Cardiol 1998;31:1627-1634.

1362  PART II / Section 14  •  Cardiovascular Disorders 54. Schwartz GL, Bailey KR, Mosley T, et al. Association of ambulatory blood pressure with ischemic brain injury. Hypertension 2007; 49:1228-1234. 55. Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990;91:523-536. 56. Lurbe E, Redon J, Kesani A, et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002;347:797-805. 57. Mitler MM, Hajdukovic RM, Shafor R, et al. When people die: cause of death versus time of death. Am J Med 1987;82:266-274. 58. Takasugi N, Nishigaki K, Kubota T, et al. Sleep apnoea induces cardiac electrical instability assessed by T-wave alternans in patients with congestive heart failure. Eur J Heart Fail 2009;11:1063-1070. 59. Javaheri S, Shukla R, Zeigler H, et al. Central sleep apnea, right ventricular dysfunction and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007;49: 2028-2034. 60. Newman AB, Spiekerman CF, Enright P, et al. Daytime sleepiness predicts mortality and cardiovascular disease in older adults: the Cardiovascular Health Study Research Group. J Am Geriatr Soc 2000;48:115-123. 61. King AC, Oman RF, Brassington GS, et al. Moderate-intensity exercise and self-rated quality of sleep in older adults: a randomized controlled trial. JAMA 1997;277:32-37.

62. Stein PK, Ehsani AA, Domitrovich PP, et al. Effect of exercise training on heart rate variability in healthy older adults. Am Heart J 1999;138:567-576. 63. Aronow WS, Ahn C. Circadian variation of primary cardiac arrest or sudden cardiac death in patients aged 62 to 100 years (mean 82). Am J Cardiol 1993;71:1455-1456. 64. Parati G, Frattola A, Di Rienzo M, et al. Effects of aging on 24-h dynamic baroreceptor control of heart rate in ambulant subjects. Am J Physiol 1995;268:H1606-H1612. 65. Yamasaki Y, Kodama M, Matsuhisa M, et al. Diurnal heart rate variability in healthy subjects: effects of aging and sex difference. Am J Physiol 1996;271:H303-H310. 66. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. In Collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118:1080-1111.

Cardiac Arrhythmogenesis during Sleep: Mechanisms, Diagnosis, and Therapy Richard L. Verrier and Mark E. Josephson Abstract The pronounced sleep state–dependent changes in autonomic nervous system activity and respiration can provoke both atrial and ventricular arrhythmias in patients with cardiovascular disease. Mortality is most common during sleep in the distinct syndromes of sudden infant death, sudden unexplained nocturnal death, and the Brugada syndrome, each of which has been linked to genetic abnormalities. Because the etiology of nocturnal arrhythmias is multifactorial, their man-

Cardiac arrhythmias are prevalent in the 13.5 million Americans with heart disease, with potentially severe consequences. Approximately 15% of sudden cardiac deaths, which result from lethal ventricular arrhythmias, occur during sleep, and most atrial arrhythmias in patients younger than 61 years have their onset at nighttime. Sleep apnea profoundly alters autonomic nervous system activity and increases risk of arrhythmia, hypertension, and myocardial infarction. (See Chapter 119.) Lack of streamlined technology for concurrent monitoring of sleep state, electrocardiogram, oxygen saturation, and respiration continues to hamper diagnosis and evaluation of therapy of these arrhythmias. We will review the current state of knowledge regarding epidemiology, risk factors, pathogenesis, and treatment options for each nocturnal arrhythmia type.

VENTRICULAR ARRHYTHMIAS Malignant ventricular arrhythmias are usually suppressed during sleep, as is evidenced by the nocturnal trough in incidence of myocardial infarction, sudden cardiac death, implantable cardioverter–defibrillator discharge, myocardial ischemic events, and arrhythmias in patients with ischemic heart disease.1,2 This decrement coincides with lessened metabolic demands during non–rapid eye movement (NREM) sleep, which occupies approximately 80% of sleep time. However, sleep is not entirely free of risk because the nocturnal incidence of sudden cardiac death, which is attributable to ventricular fibrillation, has been calculated at approximately 15%,3 or 48,750 cases annually in the United States alone. Moreover, the nonuniformity of the nighttime distribution of these events (Fig. 118-1)3 suggests physiologic triggering that may be amenable to monitoring for improved diagnosis and therapy. Surges in cardiac sympathetic nerve activity during REM sleep have been implicated in nocturnal ventricular arrhythmias and myocardial ischemia4-7 (see Chapter 19). The specific mechanisms of REM-induced cardiac events include direct effects on electrophysiologic status or indirect consequences of heart rate and arterial blood pressure accelerations, which may disrupt plaques and lead to intraarterial platelet aggregates, releasing proarrhythmic con-

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agement necessitates a comprehensive approach and consideration of a host of cardiovascular and respiratory factors. Treatment must be tailored to contain neurally induced arrhythmias while avoiding exacerbation of the hypotension of non–rapid eye movement sleep. The proarrhythmic potential of class III antiarrhythmic agents (potassium channel blockers) for patients with significant heart rate pauses and the sleep-disrupting effect of medications must be considered.

stituents such as thromboxane A2.8 Myocardial ischemia or other changes in cardiac substrate and mechanical function resulting from disease,9 infarction,10 or ageing11 can amplify nocturnal electrical instability. Oxygen desaturation may trigger nighttime ventricular tachycardia in patients with cardiac disease in the subacute phase after myocardial infarction10 or in those with heart failure.9 Hypoxemia and tachycardia frequently occur together during sleep after major surgery and may promote myocardial ischemia.12 Frequent or complex arrhythmias are also characteristic of hypertensive patients in whom the typical nocturnal trough in blood pressure is not observed.13 The nocturnal increase in QT-interval dispersion among survivors of sudden cardiac death,14 acute myocardial infarction,15 and heart failure15 provides evidence of their increased vulnerability to cardiac arrhythmias at night. REM-related nocturnal arrhythmogenesis may have a significant affective component. REM sleep dreams, which may be vivid, bizarre, and emotionally intense, commonly generate the emotions of anger and fear. Because these emotions have been linked in wakefulness to the onset of myocardial infarction and sudden death,16 it is reasonable to hypothesize that when these affective states are evoked during dreaming, they may trigger lethal events. This possibility is illustrated by a case report of recurrence of ventricular fibrillation in a 39-year-old man with normal coronary arteries and cardiac function while sleeping. A subsequent sleep study determined that ventricular premature beats were substantially increased during REM and that dreams at the same hour that fibrillation had occurred were emotionally charged.17 In some cases, arrhythmia frequency may be enhanced during NREM sleep, when latent automatic foci are exposed by the generalized reduction in heart rate after withdrawal of overdrive suppression, or when hypotension exacerbates impaired coronary perfusion. Therapy In most cases, an electrically unstable substrate underlies the propensity to develop nocturnal ventricular arrhythmias, and treatment is similar to that for daytime arrhythmias. If surges in sympathetic nerve activity, which typically 1363

1364  PART II / Section 14  •  Cardiovascular Disorders

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occur during REM sleep and dreaming, are suspected, beta-adrenergic receptor blockade therapy may prove helpful, with careful attention to avoiding medications that disrupt sleep.18 In treating hypertensive patients, it is important to appreciate Mancia’s19 suggestion that pharmacologic therapy that exacerbates the hypotensive effect of NREM sleep may introduce the potential risk of thrombosis and embolism in patients with stenotic lesions in the heart or brain. Floras20 determined that the nocturnal incidence of myocardial infarction was not diminished in patients treated with antihypertensive agents and suggested that the agents induced nocturnal hypotension. Thus, special attention should be given to the hemodynamic effects of antihypertensive drugs and vasodilators to avoid precipitating cardiac events by inducing profound hypotension. The importance of ruling out “white coat” hypertension is underscored because more than 30% of individuals with

elevated blood pressure readings in the physician’s office or hospital prove to be normotensive during daily life as documented by ambulatory blood pressure monitoring.21 Nighttime onset of ventricular arrhythmias may also indicate provocation by disturbed breathing, which can be treated by continuous positive airway pressure.

NOCTURNAL ASYSTOLE AND QT-INTERVAL PROLONGATION Sinus pauses of less than 2 seconds, prolonged atrioventricular (AV) conduction, Wenckebach AV block, and bradycardia are well documented in normal populations during sleep and are attributed to effects of increased parasympathetic activity on AV node conduction.22,23 These asystoles are more frequent in individuals who are young24,25 or physically fit, such as athletes26,27 and heavy laborers.28 More extreme cases were observed by Guilleminault and colleagues,29 who reported periods of sinus arrest of up to 9 seconds during REM sleep in young adults with apparently normal cardiac function. It was concluded that the nocturnal asystoles were the result of exaggerated, if not abnormally elevated, vagal tone, because muscarinic receptor blockers significantly reduced the duration of the nocturnal asystoles but did not prevent them. No further therapeutic intervention was warranted. However, in patients with cardiac disease, especially those taking class III antiarrhythmic drugs (potassium channel–blocking agents), nocturnal asystolic events can set the stage for ventricular arrhythmias. Such prolongation of cycle length can facilitate the development of early afterdepolarizations and the lethal arrhythmia torsades de pointes. In patients with damaged endothelium resulting from coronary atherosclerosis, the acetylcholine released by surges in vagus nerve activity could result in vasoconstriction rather than vasodilation because of impaired release of endothelium-derived relaxing factor.30 Nocturnal heart rate pauses may be particularly arrhythmogenic in subsets of patients with the long QT syndrome, specifically LQT2 and LQT3, who have mutations on the sodium channel, voltage-gated, type V, alpha gene (SCN5A).31 The lethal arrhythmias occur almost exclusively at rest or during sleep, when the QT interval is typically prolonged32 (see Sudden Infant Death Syndrome, later). Therapy Ascertaining whether patients exhibit nocturnal heart rate pauses is important when treating individuals for whom class III antiarrhythmic drugs (potassium channel blockers) are the primary option.

ATRIAL FIBRILLATION In the 2.5 million U.S. patients with atrial fibrillation, which has serious consequences in terms of increased morbidity and mortality,33 it is likely that 10% to 25% of the arrhythmias are facilitated by vagal influences. This has been termed vagally mediated atrial fibrillation. Several investigators have reported nocturnal peaks in onset of paroxysmal atrial fibrillation.34-36 A significant midnight to 2:00 am peak in atrial fibrillation onset and a higher average nocturnal incidence were documented

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by Rostagno and colleagues in their review of records from 10 years of responses by mobile coronary care units staffed by cardiologists in Florence, Italy.34 This arrhythmia was also found to exhibit a peak in frequency of onset at midnight in a Japanese population 60 years of age or younger. The maximal duration of the arrhythmia (77 ± 27 minutes per episode) was also greatest between midnight and 6:00 am (Fig. 118-2).35 Other investigators characterized a 4:00 am to 5:00 am peak in onset of paroxysmal atrial fibrillation that was refractory to antiarrhythmic drugs in a 3-month study of 67 patients with implantable cardioverters.36 The 514 recorded episodes with an atrial rate of greater than 220 beats per minute lasted more than 1 minute before termination by pacing or spontaneous reversion. A potential contribution of sympathetic nerve activity is implicated by the timing of these bouts of atrial fibrillation, which occurred during a period of sleep when REM typically emerges. However, the potential of REM sleep to trigger the arrhythmia was not discussed. Records of concurrent monitoring of sleep and nocturnal onset of atrial fibrillation are rare (Fig. 118-3).37 In the case illustrated, disruption of the nocturnal trough in heart rate disclosed sleep-related atrial fibrillation. Available evidence indicates that nocturnal atrial fibrillation is provoked during periods of intense vagus nerve activity, as indicated by heart rate variability studies,38,39 and the presence of bradycardia,40 in individuals with structurally normal hearts. Enhanced adrenergic activity may interact in a complex manner with changes in vagal tone to affect atrial refractoriness and dispersion of repolarization and alter intraatrial conduction, thus increasing the propensity to develop this arrhythmia.33,40 The high level of vagus nerve tone maintained during slow-wave sleep has the capacity to exacerbate atrial fibrillation in patients whose atria are particularly prone to the arrhythmogenic influence of acetylcholine.33

(1 min. HR – 83)

B Figure 118-3  A, Heart rate (HR) trend from an ambulatory electrocardiogram (AECG) showing a normal circadian rhythm with a sleep-induced decrease in heart rate. B, Heart rate trend from an AECG in our patient shows a nocturnal increase in heart rate caused by paroxysmal atrial fibrillation at the onset of sleep and a drop in heart rate after awakening resulting from spontaneous conversion to sinus rhythm. The ECG (below) documents atrial fibrillation during the sleep period. (From Singh J, Mela T, Ruskin J. Images in cardiovascular medicine: sleep [vagal]-induced atrial fibrillation. Circulation 2004;110: e32-e33.)

1366  PART II / Section 14  •  Cardiovascular Disorders

Risk of atrial fibrillation is doubled if breathing during sleep is disordered,41 because apnea can provoke nocturnal hypoxemia, sympathetic nerve activity, and hemodynamic stress.42-42d Obstructive apnea–induced surges in blood pressure distend atrial chambers and can activate stretch receptors. Incidence of atrial fibrillation is strongly predicted by nocturnal oxygen desaturation in subjects less than 65 years old and by heart failure in older subjects.43 Therapy Medical therapy is similar to that for patients whose arrhythmias occur during the day, including therapy to control rate or terminate the arrhythmia pharmacologically or with an atrial cardioverter–defibrillator. As nighttime atrial fibrillation is classed as “vagally mediated,” anticholinergic agents such as disopyramide or flecainide are sometimes helpful to prevent recurrences; adrenergic blocking drugs or digitalis sometimes worsen symptoms.44 In addition, individuals with nocturnal onset of atrial fibrillation should be monitored for the presence of sleep-disordered breathing, which can be effectively treated by continuous positive airway pressure. Treatment of the atrial fibrillation alone in a patient with untreated sleep disordered breathing may result in an unfavorable outcome.44a

SUDDEN INFANT DEATH SYNDROME Sudden infant death syndrome (SIDS), the leading cause of mortality in infants between 1 week and 1 year of age, occurs during sleep.45 The syndrome is a diagnosis of exclusion; that is, it includes all causes that remain unexplained after a thorough case investigation, including an autopsy, examination of the death scene, and review of the clinical history. Thus, SIDS, which took a toll of 2234 infants in 2001 in the United States46 or 8.1% of infant deaths, may be attributable to a variety of etiologies that challenge the developing cardiorespiratory system. The fatal event in SIDS victims is characterized by hypotension and bradycardia47 and appears to be attributable to a deficit in the normal reflex coordination of heart rate, arterial blood pressure, and respiration during sleep.48 This failure to respond to cardiorespiratory challenges during sleep may result from a binding deficit in the arcuate nucleus of SIDS infants,48 because muscarinic cholinergic activity in this structure at the ventricular medullary surface is postulated to be involved in cardiorespiratory control. Heart rates in infants who later died of SIDS are generally higher and exhibit a reduced range, suggesting altered autonomic control.49 Autonomic instability has also been documented in NREM sleep in infants with aborted SIDS events.50 Repolarization abnormalities have also been observed. Recent evidence from a 19-year, prospective, multicenter observational study of 34,442 infants determined that significant prolongation (35 msec or more) of the QT interval characterized the 24 (0.07%) infants who died of SIDS within the first year of life.51 These results suggest that some SIDS cases may be attributed to a genetic defect that produces a developmental abnormality in cardiac sympathetic innervation and alters repolarization to increase the risk of ventricular arrhythmia. These repolarization abnormalities typify infants and children with the long QT syndrome genotype linked to chromosome 3 (LQT3). Mutations in the sodium channel gene SCN5A are the most common causes

of long QT syndrome and are responsible for the arrhythmias and reduced heart rates. The genetic locus of the defect and the length of the QT interval are independent predictors of risk.52 T-wave alternans, an electrocardiographic indicator of heightened vulnerability to sudden cardiac death,53 has been reported in infants who became SIDS victims54,55 or who were successfully treated with pacing56 or beta-blockade therapy.57,58 The latter therapy diminished T-wave alternans, indicating antiarrhythmic efficacy. Among environmental influences, the increased risk of SIDS during the winter season is well documented59,60 and is not related to bronchiolitis.61 A genetic susceptibility that may interact with environmental factors has been implicated by a 5.8-fold increase in recurrence of SIDS within families.62 Tishler and colleagues63 reported a significant incidence of deficits in ventilatory responses to hypoxia in families with apnea. Conflicting evidence has been provided regarding the relative increase in risk attributable to prone (face-down) sleeping.64-68 Passive cigarette smoking is a highly significant modifiable risk factor in SIDS. A reduction of 61% in the number of SIDS deaths has been projected if smoking were eliminated from infants’ environments.63-66,69 A dose-dependent effect has been demonstrated.64 Maternal smoking during gestation is also implicated.69-71 Established SIDS risk factors of preterm birth and low birth weight increased risk more than 15-fold among smokers71 but not at all among nonsmokers. Illegal drug use increases risk of SIDS by more than fourfold.69 The mechanisms may include impairment in chemoreceptor responsiveness resulting from decreased sensitivity to carbon dioxide in infants of substance-abusing mothers.72 The increase in SIDS due to passive smoking may be attributable to nicotine’s adverse effect on chemoreceptor activation of respiration,73 dulling the arousal response to hypoxia.74 Nicotine and its metabolites have been found at autopsy in the pericardial fluid of SIDS infants.75,76 Epicardial nicotine is associated with hypopnea77 and affects the sinoatrial node and epicardial neural fibers to induce hypotension and bradycardia,78,79 the documented symptomatology of the final event in SIDS infants.47 Therapy This profile suggests some straightforward opportunities for intervention, including placing infants in a supine (face-up) position for sleeping and avoidance of maternal smoking during gestation and passive smoking during infancy. Theoretically, sodium channel blockade31 or cardiac pacing31,56 might be useful in treating infants diagnosed with the long QT3 syndrome, but prospective studies are required. Beta-blockade is the current treatment of choice.31,57,58 Assessment of vulnerability to arrhythmias by QT-interval prolongation has been suggested in a prospective study,51 and by T-wave alternans in multiple clinical reports based on ambulatory electrocardiographic (AECG) records.54-58

THE BRUGADA SYNDROME AND SUDDEN UNEXPLAINED NOCTURNAL DEATH The striking phenomenon of sudden death during sleep has been reported in Western adults diagnosed with the Brugada syndrome, which strikes men almost exclusively,



and in young, apparently healthy Southeast Asian men with the sudden unexplained nocturnal death syndrome (SUNDS). The latter syndrome is named lai-tai (“sleep death”) in Laos, pokkuri (“sudden and unexpected death”) in Japan, and bangungut (“to rise and moan in sleep”) in the Philippines. These syndromes probably represent the same disorder, which is characterized by right precordial ST segment elevation.80,81 Deaths are due to lethal ventricular arrhythmias. The Brugada syndrome is considered responsible for 4% to 12% of all sudden cardiac deaths and for approximately 20% of deaths in patients with structurally normal hearts.80 The electrocardiographic abnormality is estimated to be present in approximately 5 per 10,000 inhabitants, and, apart from accidents, in geographic regions where it is widespread, this inherited syndrome is the leading cause of death of men younger than 50 years of age. A single sodium channel mutation in the SCN5A gene identified in an eightgeneration kindred with a high incidence of nocturnal sudden cardiac death, QT-interval prolongation, and Brugada-like electrocardiogram characterizes 20% of Brugada patients; other mutations are suspected. Genetic defects in the sodium channel are also associated with progressive conduction system disease attended by bradycardia. A mechanistic link with enhanced presynaptic norepinephrine recycling has been described.82 Presynaptic sympathetic cardiac dysfunction has been hypothesized based on abnormal iodine-123 metaiodobenzylguanidine (123IMIBG) uptake, with bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, conduction abnormalities, and absence of ventricular ectopy.83 In the United States, 117 SUNDS deaths were registered among male Southeast Asian immigrants or their descendants from 1981 to 1988.84 Autopsies of those who died of SUNDS have established that cardiovascular disease is absent, but, in some instances, that conduction pathways are developmentally abnormal.81 Companions have reported that the immediate symptoms are onset of agonal respirations during sleep along with vocalization; violent motor activity; nonarousability; rapid, irregular deep breathing; perspiration; heart rate surges; and severe autonomic discharge. Several victims revived by vigorous massage reported sensations of airway obstruction, chest discomfort or pressure, and numb and weak limbs. When these symptoms recurred within weeks to months, they culminated in death.85 Three victims who had been resuscitated from ventricular fibrillation then experienced recurring fibrillation in the hospital during sleep accompanied by similar moaning vocalizations. In these three patients, there was no evidence of atherosclerosis or structural abnormalities and no sleep apnea, but creatine kinase levels were markedly elevated and potassium was depressed. Vagal tone is lower in SUNDS survivors than in healthy individuals, particularly at night.86 Cases have also been reported of lethal ventricular arrhythmias during sleep in adults with other variants of long QT syndrome (LQT7 or type 1 Andersen-Tawil syndrome).87 Therapy Development of effective therapy for these syndromes has been particularly challenging. Currently, implantation of cardioverter–defibrillators appears to be the most effective

CHAPTER 118  •  Cardiac Arrhythmogenesis during Sleep  1367

approach in patients with Brugada syndrome80 or SUNDS.81

SLEEP-DISRUPTING EFFECTS OF CARDIAC MEDICATIONS Several important medications that are widely prescribed for patients with cardiac disease, including antihypertensive agents and beta-blockers that cross the blood–brain barrier, have the potential to disrupt sleep.18 In particular, the lipophilic beta-blockers (pindolol, propranolol, and metoprolol) increase the total number of awakenings and total wakefulness compared with placebo and with the nonlipophilic atenolol. Penetration of the blood–brain barrier occurs with prolonged therapy, when these distinctions may become less apparent. In addition, pindolol, which has intrinsic sympathomimetic activity, increases REM latency and, as a result, decreases REM sleep time. Sleep disruption may provoke daytime fatigue and lethargy, symptoms widely reported by patients taking beta-blockers, which may prompt discontinuation of the medication or noncompliance. It has been postulated that the mechanism of sleep disruption by beta-blocking agents is their wellknown tendency to deplete endogenous melatonin,88 a key sleep-regulating hormone that modulates sympathetic nerve activity. An additional important side effect of these beta-blockers18 is their potential to provoke nightmares. Despite these effects, it is the lipophilic beta-blockers (propranolol, metoprolol, carvedilol) that have been shown to reduce the risk of sudden cardiac death. Sleep disturbance has also been documented in conjunction with the widely used antiarrhythmic agent amiodarone.89,90 Neurologic side effects were attributed to amiodarone in 20% to 40% of patients. Optimal antiarrhythmic management with this agent to minimize side effects dictates prescription of lower dosages and close patient monitoring and follow-up. ❖  Clinical Pearl

Diagnosing and treating patients with nocturnal arrhythmias have been hampered by a paucity of information about concurrent autonomic nervous system activity, cardiac electrical instability, oxygen desaturation, and breathing disturbances. It is now possible to assess autonomic nervous system activity by AECG monitoring of noninvasive markers such as heart rate variability, a measure of autonomic nervous system tone, and heart rate turbulence, an indicator of baroreceptor function based on the pattern of heart rhythm recovery after a ventricular premature beat.91 Simultaneous measurement of these indicators, along with clinical history and analysis of cardiac electrical instability with QT-interval dispersion14,15 or T-wave alternans,53,92,93 also possible with AECG monitoring, promises to provide valuable information regarding vulnerability to nocturnal arrhythmias and potential provocation by the autonomic nervous system. Concurrent monitoring of oxygen saturation and respiratory patterns will provide essential information. Increased survival from in-hospital nighttime cardiac arrest can be anticipated with improved monitoring.94

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Rep 1996;45:859-863. 46. National Center for Health Statistics. Deaths: final data for 2001. National Vital Statistics Report 2003;52. Available at http://www. cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf. 47. Meny RF, Carroll JL, Carbone MT, et al. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 1994;93:43-49. 48. Kinney HC, Filiano JJ, Sleeper LA, et al. Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome. Science 1995;269:1446-1450. 49. Schechtman VL, Harper RK, Harper RM. Aberrant temporal patterning of slow-wave sleep in siblings of SIDS victims. Electroencephalogr Clin Neurophysiol 1995;94:95-102. 50. Pincus SM, Cummins TR, Haddad GG. Heart rate control in normal and aborted-SIDS infants. Am J Physiol 1993;264:R638-R646. 51. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709-1714. 52. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-1874. 53. Verrier RL, Nearing BD, LaRovere MT, et al. Ambulatory ECGbased tracking of T-wave alternans in post-myocardial infarction patients to assess risk of cardiac arrest or arrhythmic death. J Cardiovasc Electrophysiol 2003;14:705-711. 54. Smith TA, Mason JM, Bell JS, et al. Sleep apnea and QT interval prolongation: a particularly lethal combination. Am Heart J 1979:97:505-507. 55. Weintraub RG, Gow RM, Wilkinson JL. The congenital long QT syndromes in childhood. J Am Coll Cardiol 1990;16:674-680. 56. Tanel RE, Triedman JK, Walsh EP, et al. High-rate atrial pacing as an innovative bridging therapy in a neonate with congenital long QT syndrome. J Cardiovasc Electrophysiol 1997;8:812-817. 57. Mache CJ, Beitzke A, Haidvogl M, et al. Perinatal manifestations of idiopathic long QT syndrome. Pediatr Cardiol 1996;17:118-121. 58. Bosi G, Cappato R, Priori SG, et al. Complex electrocardiographic findings in a neonate with long QT syndrome. Ital Heart J 2002; 3:605-607. 59. Haglund B, Cnattingius S, Otterblad-Olausson P. Sudden infant death syndrome in Sweden, 1983-1990. Season at death, age at death, and maternal smoking. Am J Epidemiol 1995;142:619-624. 60. Douglas AS, Allan TM, Helms PJ. Seasonality and the sudden infant death syndrome during 1987-9 and 1991-3 in Australia and Britain. BMJ 1996;312:1381-1383. 61. Gupta R, Helms PJ, Jolliffe IT, et al. Seasonal variation in sudden infant death syndrome and bronchiolitis: a common mechanism? Am J Respir Crit Care Med 1996;154:431-435. 62. Oyen N, Skjaerven R, Irgens LM. Population-based recurrence risk of sudden infant death syndrome compared with other infant and fetal deaths. Am J Epidemiol 1996;144:300-305. 63. Tishler PV, Redline S, Ferrette V, et al. The association of sudden unexpected infant death with obstructive sleep apnea. Am J Respir Crit Care Med 1996;153:1857-1863. 64. Dwyer T, Ponsonby AL, Blizzard L, et al. The contribution of changes in the prevalence of prone sleeping position to the decline in sudden infant death syndrome in Tasmania. JAMA 1995; 273:783-789. 65. Klonoff-Cohen HS, Edelstein SL. A case-control study of routine and death scene sleep position and sudden infant death syndrome in Southern California. JAMA 1995;273:790-794. 66. Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, et al. The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome. JAMA 1995;273:795-798. 67. Fleming PJ, Blair PS, Bacon C, et al. Environment of infants during sleep and risk of the sudden infant death syndrome: Results of 19931995 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential enquiry into stillbirths and deaths regional coordinators and researchers. BMJ 1996;313:191-195. 68. Brooke H, Gibson A, Tappin D, et al. Case-control study of sudden infant death syndrome in Scotland, 1992-5. BMJ 1997;314:1516-1520. 69. Blair PS, Fleming PJ, Bensley D, et al. Smoking and the sudden infant death syndrome: results from 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. BMJ 1996;313:195-198. 70. MacDorman MF, Cnattingius S, Hoffman HJ, et al. Sudden infant death syndrome and smoking in the United States and Sweden. Am

CHAPTER 118  •  Cardiac Arrhythmogenesis during Sleep  1369 J Epidemiol 1997;146:249-257. 71. Schellscheidt J, Oyen N, Jorch G. Interactions between maternal smoking and other prenatal risk factors for sudden infant death syndrome (SIDS). Acta Paediatr 1997;96:857-863. 72. Wingkun JG, Knisely JS, Schnoll SH, et al. Decreased carbon dioxide sensitivity in infants of substance-abusing mothers. Pediatrics 1995;95:864-867. 73. Slotkin TA, Lappi SE, McCook EC, et al. Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for sudden infant death syndrome. Brain Res Bull 1995;38:69-75. 74. Cutz E, Ma TK, Perrin DG, et al. Peripheral chemoreceptors in congenital central hypoventilation syndrome. Am J Respir Crit Care Med 1997;155:358-363. 75. Milerad J, Majs J, Gidlund E. Nicotine and cotinine levels in pericardial fluid in victims of SIDS. Acta Pediatr 1994;93:59-62. 76. Rajs J, Rasten-Almqvist P, Falck G, et al. Sudden infant death syndrome: postmortem findings of nicotine and cotinine in pericardial fluid of infants in relation to morphological changes and position at death. Pediatr Pathol Lab Med 1997;17:83-97. 77. Evans RG, Ludbrook J, Michalicek J. Use of nicotine, bradykinin and veratridine to elicit cardiovascular chemoreflexes in unanesthetized rabbits. Clin Exp Pharmacol Physiol 1991;18:245-254. 78. Staszewska-Barczak J. Prostanoids and cardiac reflexes of sympathetic and vagal origin. Am J Cardiol 1983;52:36A-45A. 79. Barber MJ, Mueller TM, Davies BG, et al. Phenol topically applied to canine left ventricular epicardium interrupts sympathetic but not vagal afferents. Circ Res 1984;55:532-544. 80. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659-670. 81. Nademanee K, Veerakul G, Mower M, et al. Defibrillator versus beta-blockers for unexplained death in Thailand (DEBUT): a randomized clinical trial. Circulation 2003;107:2221-2226. 82. Kies P, Wichter T, Schafers M, et al. Abnormal myocardial presynaptic norepinephrine recycling in patients with Brugada syndrome. Circulation 2004;110:3017-3022. 83. Wichter T, Matheja P, Eckardt L, et al. Cardiac autonomic dysfunction in Brugada syndrome. Circulation 2002;105:702-706. 84. National Center for Health Statistics. Update: sudden unexplained death syndrome among Southeast Asian refugees—United States. MMWR Morb Mortal Wkly Rep 1988;37:568-570. 85. Munger RG. Sudden death in sleep of Laotian-Hmong refugees in Thailand: a case-control study. Am J Public Health 1987;77: 1187-1190. 86. Krittayaphong R, Veerakul G, Bhuripanyo K, et al. Heart rate variability in patients with sudden unexpected cardiac arrest in Thailand. Am J Cardiol 2003;91:77-81. 87. Garcia-Touchard A, Somers VK, Kara T, et al. Ventricular ectopy during REM sleep: implications for nocturnal sudden cardiac death. Nature Clin Pract Cardiovasc Med 2007;4:284-288. 88. Garrick NA, Tamarkin L, Taylor PL, et al. Light and propranolol suppress the nocturnal elevation of serotonin in the cerebro spinal fluid of rhesus monkeys. Science 1983;221:474-476. 89. Bucknall CA, Keeton BR, Curry PV, et al. Intravenous and oral amiodarone for arrhythmias in children. Br Heart J 1986;56:278-284. 90. Hilleman D, Miller MA, Parker R, et al. Optimal management of amiodarone therapy: efficacy and side effects. Pharmacotherapy 1998;18:138S-145S. 91. Bauer A, Malik M, Schmidt G, et al. Heart rate turbulence: standards of measurement, physiological interpretation, and clinical use: International Society for Holter and Noninvasive Electrophysiology Consensus. J Am Coll Cardiol 2008;52:1353-1365. 92. Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECGbased T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS Study. J Cardiovasc Electrophysiol 2008;19:1037-1042. 93. Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective [Invited review]. Heart Rhythm 2009;6:416-422. 94. Peberdy MA, Ornato JP, Larkin GL, et al. Survival from in-hospital cardiac arrest during nights and weekends. JAMA 2008;299:785-792.

Cardiovascular Effects of SleepRelated Breathing Disorders Virend K. Somers and Shahrokh Javaheri Abstract The cycle of apnea and recovery causes hypoxemia/ reoxygenation, hypercapnia/hypocapnia, changes in intrathoracic pressure, and arousals. These consequences of sleep apnea, both obstructive and central apnea, adversely affect

Hemodynamic changes have been most studied in patients with obstructive sleep apnea (OSA), and in these studies, acute apnea-induced hemodynamic changes have been documented. Chronic exposure may also result in left ventricular systolic and diastolic dysfunction, and in increased atrial volume. A limited number of studies have shown that treatment of OSA with nasal continuous positive airway pressure (CPAP) devices or tracheostomy can result in reversal of left ventricular dysfunction and arrhythmias. Whether treatment of sleep apnea reduces cardiovascular events or cardiovascular mortality remains to be demonstrated in randomized control trials. However, several observational studies have reported that treatment of sleep apnea improves survival primarily because cardiovascular events are reduced. Periodic breathing is characterized by cyclic changes in tidal breathing with intervening episodes of obstructive or central apnea or hypopnea. These disordered breathing events result in three basic pathophysiologic consequences: (1) intermittent arterial blood gas abnormalities characterized by hypoxemia/reoxygenation and hypercapnia/ hypocapnia, (2) arousals and a shift to light sleep stages, and (3) large negative swings in intrathoracic pressure (Fig. 119-1).1-3 These pathophysiologic consequences of apnea and hypopnea, both obstructive and central, adversely affect cardiovascular function, acutely and chronically.

ARTERIAL BLOOD GAS ABNORMALITIES AND THEIR CONSEQUENCES Periodic breathing consists of cyclic changes in breathing pattern that include episodes of apnea and hypopnea, resulting in hypoxemia and hypercapnia. After apnea and hypopnea, hyperpnea ensues, resulting in reoxygenation and hypocapnia. These alterations in blood gases affect the cardiovascular system in different ways. Hypoxemia and Reoxygenation Hypoxemia has direct (decreased myocardial oxygen delivery) and indirect (activation of sympathetic nervous system, promotion of endothelial cell dysfunction, and pulmonary arteriolar vasoconstriction) cardiac and vascular effects. Hypoxemia with reoxygenation may be analogous to ischemia with reperfusion, and reoxygenation may cause additional damage through further production of free radical species. Biochemical injury due to hypoxemia– 1370

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119

cardiovascular function. The cardiovascular effects of sleep apnea may be mediated by redox-sensitive gene activation, altered autonomic nervous system activity, oxidative stress, and release of inflammatory mediators. Pathophysiologic consequences of sleep apnea elicit acute and chronic cardiovascular changes.

reoxygenation has considerable relevance to sleep apnea– hypopnea, where intermittent and profound alterations in the partial pressure of oxygen (Po2) may occur hundreds of times during sleep. Direct Effects of Hypoxia on Myocardium Decreased myocardial oxygen delivery may result in an imbalance between myocardial oxygen consumption and demand, resulting in myocardial hypoxia, particularly if there is already coronary artery disease. Potential clinical consequences include nocturnal angina, nocturnal myocardial infarction,4 arrhythmias, and even nocturnal sudden death.5 Hypoxia may also impair myocardial contractility and cause diastolic dysfunction.6 Hypoxemia–Reoxygenation and Coronary Endothelial Dysfunction Coronary vessel endothelial cells play a central role in vasoregulation, coagulation, and inflammation.7 Blood flow and coagulation are modulated by production and release of vasoactive substances that include vasodilators and platelet deaggregators (e.g., nitric oxide, prostacyclin), and vasoconstrictors and platelet aggregators (e.g., endothelin and thromboxane). The balance between vasoregulatory agents is important in modulating coronary blood flow and coagulation status in both health and disease. Through activation of certain transcription factors such as hypoxia-inducible factor-1 and nuclear factor-κB,8,9 hypoxia increases the expression of a number of genes such as those encoding endothelin-1, a potent vasoconstrictor with proinflammatory properties, vascular endothelial growth factor, and platelet-derived growth factor. In contrast, it suppresses the transcriptional rate of endothelial nitric oxide synthase,10 resulting in decreased production of nitric oxide, which is vasodilatory and has antimitogenic properties. Hypoxia also enhances expression of adhesion molecules and promotes leukocyte rolling and endothelial adherence,11 and it is involved in induction of endothelial and myocyte apoptosis.12 Some of the aforementioned adverse effects of sustained hypoxia have also been observed with intermittent hypoxia (i.e., hypoxia–reoxygenation).13-23 In this context, intermittent hypoxia has been proposed to be more deleterious than sustained hypoxia.18,19 Reoxygenation through delivery of oxygen molecules provides a substrate for additional production of oxygen radicals and may contribute to oxidative stress.



CHAPTER 119  •  Cardiovascular Effects of Sleep-Related Breathing Disorders  1371

H/R ↑ PCO2

Sleep apnea and hypopnea

Arousals

↓ Ppl

↓ O2 delivery

Organ dysfunction

Endothelial dysfunction syndrome

Vasoconstriction Thrombosis Inflammation

Hypoxic and hypercapnic pulmonary vasoconstriction

↑ RV afterload

Sympathetic activation

↑ SVR/other adverse effects

↑ Transmural P of L and R ventricles, and pulmonary microvascular bed

Changes in R and L ventricular preload and afterload ↑ Lung H2O

Figure 119-1  Pathophysiologic consequences of sleep apnea and hypopnea. Pleural pressure (Ppl) is a surrogate of the pressure surrounding the heart and other vascular structures. H/R, hypoxia-reoxygenation; L, left; P, pressure; R, right; RV, right ventricular; SVR, systemic vascular resistance; ↑, increased; ↓, decreased. (Adapted from Javaheri S. Sleeprelated breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2003. p. 478.)

The pathophysiologic consequences of hypoxemia– reoxygenation could lead to vascular inflammation and remodeling, similar to atherosclerosis.7,23 Endothelial dysfunction has been demonstrated in a number of cardio­ vascular disorders, including hypertension, myocardial infarction, and stroke. Interestingly, these disorders have been also associated with OSA. It is therefore conceivable that endothelial dysfunction caused by sleep-related breathing disorders may contribute to worsening of atherosclerosis, atherothrombosis, and left ventricular dysfunction.1,24 The inflammatory and neurohormonal (see Obstructive Sleep Apnea and Systolic Heart Failure, later) consequences of altered blood gas chemistry have been best studied in patients with OSA, which is associated with increased sympathetic activity, high concentrations of endothelin, adhesion molecules, inflammatory cytokines, activation of white blood cells, oxidative stress, and hypercoagulopathy.1,22,24-39 These biochemical alterations may be reversed with use of nasal CPAP to treat OSA. However, such systematic studies are lacking for central sleep apnea, with the exception of studies showing increased overnight and morning sympathetic activity and increased concentration of endothelin and brain natriuretic peptide in patients with heart failure with central sleep apnea compared with those without central sleep apnea (for details, see Chapter 122).40 Hypoxemia–Hypercapnia and the Autonomic Nervous System Sleep apneas and hypopneas, both obstructive and central (Figs. 119-2 and 119-3), increase sympathetic activity through complex mechanisms. Hypoxemia stimulates the

peripheral arterial chemoreceptors in the carotid bodies, triggering reflex increases in sympathetic activity.41,42 Hypercapnia acts primarily on the central chemoreceptors located in the region of the brainstem, also increasing sympathetic activity. Both hypoxemia and hypercapnia increase ventilation, which, acting via thoracic afferents, buffers the increases in sympathetic drive during hypoxemia, and to a lesser extent during hypercapnia.41,42 Thus, when hypoxemia or hypercapnia occurs during apnea, the absence of ventilatory inhibition results in a potentiation of sympathetic activation and consequent vasoconstriction and blood pressure surges. In this context, and especially when there are potentiated chemoreflex responses to hypoxemia– hypercapnia,43,44 the sympathetic and consequent pressor responses to hypoxemia–hypercapnia, particularly in the absence of inhibitory effects of breathing, are marked. Alveolar Hypoxia–Hypercapnia and Pulmonary Arteriolar Vasoconstriction Alveolar hypoxia, in part through release of endothelin, and hypercapnia cause pulmonary arteriolar vasoconstriction and hypertension, which could adversely affect right ventricular function (see Chapter 120). Hypocapnia Episodes of hyperpnea after apneas and hypopneas result in hypocapnia. Hypocapnia may impair myocardial oxygen delivery and uptake by coronary artery vasoconstriction45 and shifting of the oxygen–hemoglobin dissociation curve to the left. Hypocapnia may also contribute to arrhythmogenesis. Arousals, Shift to Light Sleep Stages, and the Autonomic Nervous System Compared with wakefulness, the balance of activity of sympathetic and parasympathetic nervous system reverses in normal sleep.46,47 Normally, there is a progressive reduction in sympathetic nerve traffic, heart rate, and blood pressure during the deepening stages of non–rapid eye movement (non-REM) sleep, such that sympathetic activity, heart rate, and blood pressure in stage 4 sleep are substantially lower than during supine resting wakefulness.46,47 During phasic REM sleep, there is an abrupt increase in sympathetic activity, resulting in intermittent and brief surges in blood pressure and heart rate. On average, blood pressure and heart rate during REM sleep are similar to levels recorded during wakefulness. Thus, during normal sleep, there is a well-regulated pattern of alteration in autonomic and hemodynamic measures, modulated by changes in sleep stage. These organized responses to normal sleep are disrupted in patients with sleep-related breathing disorders, both obstructive and central sleep apnea. Sleep architecture is dramatically altered in patients with OSA–hypopnea, and also in patients with heart failure and central sleep apnea. There is a shift to light sleep stages. Most important, however, apneas and hypopneas commonly result in arousals that are also associated with an increase in sympathetic activity and a decrease in parasympathetic activity,47,48 and increasing blood pressure and heart rate. In OSA, arousals occur at the end of the apnea and with resumption of breathing. In patients with central

1372  PART II / Section 14  •  Cardiovascular Disorders AWAKE

CONTINUOUS POSITIVE AIRWAY PRESSURE THERAPY DURING REM SLEEP

Sympathetic nerve activity

Respiration 150 Blood 100 pressure 50 mm Hg 0

150 100 50 0 10 sec OBSTRUCTIVE SLEEP APNEA (OSA) DURING REM SLEEP

Sympathetic nerve activity

Respiration OSA

OSA

250 200 Blood 150 pressure 100 mm Hg 50 0 Figure 119-2  Recordings of sympathetic nerve activity, intraarterial blood pressure, and breathing in a normotensive patient with obstructive sleep apnea (OSA) during resting normoxic wakefulness (top left). The patient was free of any other overt cardiovascular disease and on no medications. Note the high levels of sympathetic nerve traffic even in the absence of apneic events. During rapid eye movement (REM) sleep (bottom), the repetitive hypoxemia and hypercapnia elicit chemoreflex-mediated sympathetic activation and vasoconstriction. At the end of apneas, with increases in cardiac output and severe vasoconstriction, intraarterial blood pressure can reach levels from 130/60  mm  Hg during wakefulness to a peak of 220/130  mm  Hg during apneas. At the end of apneas, there also is abrupt inhibition of sympathetic traffic because of the increase in blood pressure acting through the baroreflexes and the sympathetic inhibitory effects of the thoracic afferents. After treatment of OSA with continuous positive airway pressure (top right), there is a marked reduction in sympathetic traffic and in blood pressure. (From Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904.)

sleep apnea and Hunter-Cheyne-Stokes breathing pattern, arousals occur at the peak of hyperventilation. In addition to arousals, sleep-related breathing disorders may increase sympathetic activity by hypoxemia, hypercapnia, and changes in ventilation, as noted previously. There are multiple adverse cardiac consequences of sympathetic activation. These include increased systemic vascular resistance and left ventricular afterload, venoconstriction with increased right ventricular preload, increased myocardial contractility, hypertrophy, tachycardia, and

arrhythmias. Furthermore, increased myocardial norepinephrine may cause myocyte toxicity and apoptosis.49,50 Central sleep apnea and OSA increase sympathetic activity as measured by either microneurography or blood and urinary norepinephrine levels.51-56 Treatment of obstructive54-56 and central sleep apnea52,57 decreases sympathetic activity, with important implications. First, with regard to central sleep apnea in heart failure, increased sympathetic activity is associated with poor survival; therefore, a reduction in sympathetic activity should have



CHAPTER 119  •  Cardiovascular Effects of Sleep-Related Breathing Disorders  1373

Figure 119-3  Recordings of breathing (top), beat-by-beat blood pressure (middle), and muscle sympathetic nerve activity (MSNA) (bottom) in a patient with severe congestive heart failure, during normal breathing on the left and during Cheyne-Stokes breathing on the right. Oxygen saturation was 94% during normal breathing and oscillated between 97% and 90% during Cheyne-Stokes breathing. MSNA total burst amplitude increased from 1533 arbitrary units per minute during normal breathing to 1759 arbitrary units per minute during Cheyne-Stokes breathing. Mean blood pressure was 70  mm  Hg during normal breathing and peaked at 82  mm  Hg during the hyperventilation that followed central apnea. Patients with heart failure have high levels of sympathetic drive even during normal breathing. During central apneas, there is a modest but significant further increase in sympathetic activity. (From Van de Borne P, Oren R, Abouassaly C, et al. Effect of Cheyne-Stokes respiration on muscle sympathetic nerve activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1998;81:432-436.)

favorable prognostic implications. OSA causes nocturnal increases in sympathetic activity and blood pressure, which carry over into the daytime. OSA is a known cause of hypertension, and in some patients blood pressure decreases relatively quickly with effective treatment of OSA with CPAP (see Chapter 120). In summary, pathophysiologic consequences of sleeprelated breathing disorders, such as increased periods of wakefulness (interruption insomnia), arousals, hypoxemia, and hypercapnia, collectively contribute to increased sympathetic activity. Exaggerated Negative Intrathoracic Pressure and Its Consequences Large negative intrathoracic pressures are generated during episodes of obstructive apnea. In central sleep apnea, relatively large negative pressure deflections occur during hyperpnea, particularly in the face of less compliant (stiff) lungs (due to heart failure). However, pleural pressure changes are usually more pronounced in obstructive than in central sleep apnea. A number of studies have addressed the cardiovascular consequences of both negative and positive pressure deflections affecting right and left ventricular function.58,59 Negative intrathoracic pressure increases the transmural pressure (pressure inside minus pressure outside) (Fig. 119-4) of the intrathoracic vascular structures, including aorta, pulmonary vascular bed, and ventricles. According to Laplace’s law, increased transmural myocardial pressure increases wall tension and myocardial oxygen consumption. Furthermore, negative intrathoracic perivascular pressure could increase extravascular lung water by favoring fluid transudation across the pulmonary microvascular bed and by diminishing lymph outflow from the lung.60 This may account in part for cases of flash pulmonary edema reported in OSA, and sleep apnea may contribute to excess lung water and pulmonary edema in congestive heart failure. In addition, decreased intra­ thoracic pressure increases venous inflow, resulting in

increased right ventricular diastolic filling, which in turn may decrease left ventricular compliance and volume, a phenomenon called ventricular interdependence. Application of nasal CPAP to treat sleep apnea, both obstructive and central, reduces transmural pressure by two mechanisms. First, and most important, it decreases or eliminates apneas, desaturation, and arousals, which collectively increase sympathetic activity and result in cyclic surges in arterial blood pressure. Second, nasal CPAP not only attenuates steep surges in intrathoracic pressure, it actually increases the pleural pressure, thus decreasing transmural pressures across intrathoracic structures (see Fig. 119-4).

ACUTE HEMODYNAMIC EFFECTS OF SLEEP APNEA The circulatory responses to individual apneas and hypopneas are governed by the interaction of stresses and physiologic consequences described previously.61,62 Hemodynamic changes are related to development of hypoxemia, hypercapnia, presence or absence of breathing, changes in intrathoracic pressure, and the consequent mechanical effects. Hemodynamic changes have been best studied in human OSA.61,63,64 The evolution of a cycle of apnea and recovery is complex and represents an unsteady hemodynamic state. For these reasons, hemodynamic changes occur during the course of an apnea, and these changes are different from those occurring during the immediate or late postapneic periods. During recovery, arousals and ventilation further affect hemodynamics. Cyclic changes in heart rate and systemic and pulmonary arterial blood pressure paralleling periodic breathing occur commonly.61,63-66 In some patients, there is a very clear and progressive bradycardia toward the end of apnea, with abrupt development of tachycardia with resumption of breathing, because of the vagolytic effects of lung inflation and arousals. This manifests as a pattern of repetitive bradycardias or tachycardias during sleep, which may be evident on Holter monitoring and

1374  PART II / Section 14  •  Cardiovascular Disorders

Pr LV Tm

100 – (0.0) = 100

+10

–40

0.0

0.0

140 – (0.0) = 140

100

100

140

100

Ppl

Ppl

Ppl

Ppl

100

100

140

100

CPAP

UAO

Hypertension

Normal

100 – (–40) = 140

100 – (+10) = 90

Figure 119-4  Transmural (Tm) pressure (Pr) of the left ventricle (LV) during systole. Because of an obstructive apnea (UAO, upper airway occlusion), a negative pleural pressure (Ppl) of −40 mm Hg is generated. This increases left ventricular transmural pressure from 100 to 140 mm Hg, which is equivalent to an increase in systolic aortic blood pressure from 100 to 140 mm Hg. Note the reduction in left ventricular transmural pressure with application of nasal continuous positive airway pressure (CPAP). (Adapted from Javaheri S. Sleep-related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2003. p. 480.)

may signify the presence of OSA. In experimental sleep apnea, decreases in heart rate are more severe during central than obstructive apnea, reflecting lack of activation of thoracic afferents.62 The bradycardias may be especially severe,65,66 and they are elicited because of activation of the diving reflex by the combination of hypoxemia and apnea. Episodes of up to 10 seconds or more of sinus arrest may occur because of the chemoreflex-mediated vagal activation. The consequent absence of perfusion, because of asystole, may have implications for patients with preexisting severe cerebral or cardiac ischemia. At the termination of obstructive apneas, there are surges in blood pressure. This cyclic change in blood pressure is one of the most consistent hemodynamic findings in patients with OSA. Multiple mechanisms are involved. During apnea, the increased hypoxemia and hypercapnia, acting through the chemoreflexes, progressively elicit sympathetic activation and vasoconstriction.53 With resumption of breathing, because of the inspiratory increase in right ventricular filling, stroke volume may increase. Vagolytic effects of inspiration result in tachycardia. The increased stroke volume and heart rate result in an increased cardiac output entering a vasoconstricted peripheral circulation, with consequent acute increases in blood pressure.53 However, just after termination of an obstructive apnea, there is abrupt inhibition of sympathetic activity to the peripheral blood vessels, in part because the deep breathing inhibits sympathetic activity through thoracic afferents, and in part because of baroreflex inhibition of sympathetic activity secondary to the postapneic blood pressure surge. Nevertheless, despite the interruption in sympathetic nerve traffic, vasoconstriction persists for several seconds after termination of the sympathetic nerve discharge because of the kinetics of norepinephrine uptake, release, and washout at the neurovascular junction. Another consistent finding is a mild reduction in stroke volume during obstructive apnea, which has been documented using noninvasive techniques for measuring beatto-beat cardiac output.61 This probably results from a decrease in left ventricular preload and an increase in afterload. Changes in stroke volume after termination of the apnea depend on where in the recovery cycle it is being measured.61

Obstructive Sleep Apnea, Left Ventricular Dysfunction, and Heart Failure The relationship between central sleep apnea and heart failure is discussed in Chapter 122. In this section, we review OSA as a cause of heart failure. Obstructive Sleep Apnea and Systolic Heart Failure In a canine model mimicking severe OSA,67 within a 1- to 3-month period of exposure to apneas during sleep, left ventricular systolic dysfunction developed. Left ventricular ejection fraction, measured during the daytime, decreased significantly because of an increase in left ventricular systolic volume. In humans, there are two kinds of studies relating left ventricular systolic dysfunction and OSA—first, studies in which patients with OSA have been assessed for the presence of left ventricular dysfunction,68-71 and second, studies in patients with established left ventricular systolic dysfunction who have been assessed to determine the prevalence of OSA.72,73 In some studies,74-76 changes in left ventricular ejection fraction in response to treatment for OSA have been also described. Results of studies assessing left ventricular systolic function in OSA patients are conflicting.68-70 However, in the two studies69,70 in which technetium-99m was used to assess left ventricular systolic function, OSA was associated with left ventricular systolic dysfunction. Use of radionuclide ventriculography to assess left ventricular function is important because in obese subjects, echocardiography, which has been used in some studies, may be associated with technical difficulties. Alchanatis and colleagues69 studied 29 patients with severe OSA (apnea–hypopnea index [AHI] greater than 15/ hr; mean AHI, 54/hr; lowest arterial oxygen saturation, 62%) and 12 control subjects (AHI, 9/hr; lowest saturation, 92%). The subjects were without known cardiovascular disease. The mean left ventricular ejection fraction was significantly lower in patients with OSA compared with the control group (53% versus 61%; P < .003). Six months after treatment with CPAP, left ventricular ejection fraction increased significantly to 56% (P < .001). Left ventricular diastolic dysfunction also improved significantly (see later). In a large study70 of 169 patients with OSA (AHI greater than 10/hr; mean AHI, 47/hr), 13 subjects (8%) had left



CHAPTER 119  •  Cardiovascular Effects of Sleep-Related Breathing Disorders  1375

Table 119-1  Effects of PAP Therapy on Left Venticular Ejection Fraction in Patients with Obstructive Sleep Apnea and Systolic Heart Failure VARIABLE

KANEKO OPEN

MANSFIELD OPEN

EGEA DB

SMITH DB

KHAYAT OPEN

KHAYAT OPEN

n

12

19

20

23

11

13

AHI (n/h)

40

25

44

36

30

34

LVEF (%)

25

35

29

30

29

26

Increase in LVEF (%)

9*

5*

2.2*

0.0

0.5

8.5*

Duration

4 wk

3 mo

3 mo

6 wk

3 mo

3 mo

PAP titration Compliance (hr)

CPAP yes 6.2

CPAP yes 5.6

CPAP yes NR

Auto CPAP 3.5

CPAP yes 3.6

Bilevel yes 4.5

*Indicates a statistically significant change. Data from Kaneko Y, Flores JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 003;348:1233-1241; Mansfield DR, Gollogly, NC, Kaye DM, et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea in heart failure. Am J Respir Crit Care Med 2004;169:361-366; Egea, CJ, Aizpuru F, Pinto JA, et al. Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study. Sleep Medicine 2008;9:660-666; Schmidt LA, Vennelle M., Gardner RS, et al. Autotitrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnea: a randomized placebo controlled trial. Eur Heart J 2007;28:1221-1227; Khayat RN, Abraham WT, Patt B, et al. Cardiac effects of continuous and bilevel crowded airway pressure for patients with heart failure and obstructive sleep apnea: a pilot study. Chest 2008;134:1162-1168. AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure; DB, double blind; NR, not reported; PAP, positive airway pressure.

ventricular systolic dysfunction (range, 32% to 50%). Left ventricular systolic dysfunction was not the result of ischemic disease as evidenced by echocardiography and dipyridamole stress testing. In seven patients who were treated for OSA (six with CPAP and one with upper airway surgery), 1 year after therapy, mean left ventricular ejection increased significantly from 44% to 63%.70 In the cross-sectional analysis of more than 6000 patients enrolled in the Sleep Health Heart Study,71 the presence of OSA increased the likelihood of having a history of heart failure by an odds ratio of 2.5. Furthermore, there was a significant dose-dependent correlation between AHI and the prevalence of heart failure. In studies of patients with established left ventricu­lar systolic dysfunction undergoing polysomnography (re­ viewed in Chapter 122), the prevalence of OSA, defined as an AHI of at least 15/hour, ranged from 5% to 32%. This wide range is not particularly surprising. The prevalence depends on a number of factors, including the number of obese patients with heart failure enrolled in each study and the different polysomnographic criteria used by various investigators for diagnosis of OSA. In a prospective study72 of 81 patients with known systolic dysfunction and in whom no question was asked regarding snoring or other symptoms associated with OSA, 11% had OSA with a mean AHI of 36/hour and a lowest arterial oxygen saturation of 72%. In a retrospective study73 of 450 patients with systolic dysfunction who were referred for a sleep study because of loud snoring and other symptoms of sleep apnea, 32% had OSA. From the aforementioned studies, however, it cannot be determined whether OSA preceded heart failure. Yet, as is discussed later, treatment of OSA with nasal CPAP increases left ventricular ejection fraction, indicating that OSA contributes to worsening of left ventricular systolic dysfunction. The mechanisms by which OSA may impair left ventricular systolic function are multiple. Hypoxemia plays a critical role, both by impairing myocardial contractility and through a host of neurohormonal mechanisms. In

addition, increases in left ventricular wall stress and transmural pressure occur because of additive effects of the excess negative juxtacardiac pressure (during obstructive apneas) and development of hypertension. The effects of positive airway pressure therapy on left ventricular ejection fraction in patients with OSA and systolic heart failure has been reported in five randomized clinical trials, two of which have been double blind (Table 119-1). In three of the studies in which CPAP was used, including the only two double-blind randomized clinical trials, the rise in left ventricular fraction was minimal or not at all. It should be noted, however, that in at least two of these studies compliance with CPAP was also limited. In the two open studies in which compliance hours with CPAP were more than those in the double-blind studies, ejection fraction increased between 5% and 9%. In one open randomized clinical trial of CPAP versus abilevel device, the ejection fraction increased significantly only with bilevel therapy. Obstructive Sleep Apnea and Diastolic Heart Failure Isolated left ventricular diastolic heart failure with relative preservation of left ventricular systolic function is the most common form of heart failure in elderly subjects. The pathophysiologic consequences of this form of heart failure relate to a hypertrophied, noncompliant left ventricle, shifting the pressure–volume curve upward and to the left. Therefore, for a given left ventricular volume, left ventricular end-diastolic pressure increases, resulting in elevated left atrial and pulmonary capillary pressure, and pulmonary congestion and edema. As noted previously, hemodynamic studies63,64 of patients with OSA have documented that pulmonary capillary pressure increases during the course of an obstructive apnea, indicating development of diastolic dysfunction. During obstructive apnea, left ventricular transmural wall tension increases because of an increase in aortic blood pressure and a simultaneous decrease in juxtacardiac pressure.

1376  PART II / Section 14  •  Cardiovascular Disorders

Arrhythmias in Obstructive Sleep Apnea Obstructive Sleep Apnea Predisposing to an Arrhythmogenic Substrate Repetitive nocturnal apneas elicit severe derangements in cardiovascular homeostasis. Hypoxemia, hypercapnia, acidosis, adrenergic activation, increased afterload, and rapid fluctuations in cardiac wall stress would reasonably be expected to be conducive to tachycardia–brachycardia oscillations and atrial and ventricular arrhythmias (Figs. 119-5 and 119-6). A variety of atrioventricular arrhythmias, including complete heart block and ventricular asystole during sleep, have been observed in patients with OSA84-86 and have been eliminated by either tracheostomy or use of nasal CPAP.84,85 Profound OSA-induced arrhythmias can occur in the absence of any major structural abnormalities in the conduction system.86a Although the normal heart would be less likely to manifest malignant arrhythmias in the setting of severe obstruc-

BP (mm Hg) CVP (mm Hg)

250 125

10 5 0

0

ECG

SNA RESP Apnea

10 sec

Figure 119-5  Recordings of intraarterial blood pressure (BP), central venous pressure (CVP), electrocardiogram (ECG), sympathetic nerve activity (SNA), and respiratory patterns (RESP) in a healthy subject during voluntary end-expiratory apnea. During apnea, there is a progressive increase in the RR interval on the ECG with eventual sinus pause and atrioventricular block. Accompanying this is increased sympathetic activity. The simultaneous sympathetic activation to peripheral blood vessels and vagal activation of the heart is characteristic of the diving reflex. Note the rapid increase in heart rate and sympathetic inhibition during resumption of breathing. This occurs in part because thoracic afferents activated by inspiration inhibit both sympathetic traffic and vagal cardiac drive. (From Somers VK, Dyken ME, Mark AL, Abboud FM. Parasympathetic hyperresponsiveness and brady arrhythmias during apnea in hypertension. Clin Auton Res 1992;2:171-176.)

ECG RESP 200 BP (mm Hg)

Furthermore, hypoxemia may impair left ventricular relaxation, further impairing diastolic function.77 Repeated exposure to nocturnal hypertension and hypoxemia, and consequent development of OSA-induced systemic hypertension and increased left ventricular mass, may also contribute to left ventricular diastolic dysfunction. Most studies show that OSA is associated with an increase in left ventricular mass,78-81 and suggest that the OSA-related cardiac structural changes may resolve with CPAP treatment.80 An early study78 reported that OSA may cause left ventricular hypertrophy even in the absence of daytime systemic hypertension. This finding was later supported by another study79 comparing patients with OSA (AHI greater than 20/hr) with those without OSA (AHI less than 20/hr). In the largest study,81 consisting of 2058 Sleep Heart Health Study participants, left ventricular mass was associated with both apnea–hypopnea and hypoxemia indices after adjustment for age, sex, ethnicity, study site, body mass index, smoking, systolic blood pressure, antihypertensive medication use, diabetes mellitus, myocardial infarction, and alcohol consumption. Although there are some data regarding the prevalence of sleep apnea in patients with systolic heart failure,72,73,82 the prevalence and the impact of OSA in diastolic heart failure need to be determined. In one study,83 approximately half of 20 patients with diastolic heart failure had sleep apnea. As noted earlier, isolated diastolic heart failure is highly prevalent in elderly subjects. Furthermore, elderly subjects have a high prevalence of OSA. It is speculated that OSA could be the cause of diastolic heart failure, or the presence of OSA could contribute to the worsening of left ventricular diastolic dysfunction. In this regard, a preliminary study reported that treatment of OSA improves left ventricular diastolic dysfunction,69 an observation confirmed by the only randomized, placebo (sham CPAP)-controlled trial80 showing that after 12 weeks on effective CPAP therapy, there was a significant increase in E/A ratio (the ratio of early to late diastolic filling), and a significant decrease in isovolumic relaxation and mitral deceleration. These observations are similar to the improvement seen in systolic function when patients with heart failure and OSA are treated with CPAP (see Table 119-1).74-76

100 0

10 sec

Figure 119-6  A patient with sleep apnea manifesting prolonged and profound bradyarrhythmias with absence of either atrial or ventricular contraction. The beat-by-beat blood pressure (BP) recording confirms the absence of any perfusion during the bradycardia. ECG, electrocardiogram; RESP, respiratory pattern. (From Somers VK, Dyken ME, Mark AL, Abboud FM. Parasympathetic hyperresponsiveness and brady arrhythmias during apnea in hypertension. Clin Auton Res 1992;2:171176.)

tive apnea, the ischemic, hypertrophied, or failing heart may be more susceptible.87 Nevertheless, activation of the diving reflex66,88 during apneas can often elicit severe bradyarrhythmias, even in the setting of a normal myocardium and normal cardiac electrophysiologic function. Tachycardia–Bradycardia Oscillations Patients undergoing Holter monitoring may be noted to have repetitive cyclic episodes of tachycardias and bradycardias during the night.89,90 These cyclic fluctuations may be attributable to obstructive apneas, although this cannot be confirmed because standard Holter monitoring does not incorporate simultaneous measurements of either breathing pattern or oxygen saturation.



CHAPTER 119  •  Cardiovascular Effects of Sleep-Related Breathing Disorders  1377

These oscillations in cardiac rate are for the most part explained by changes in cardiac autonomic drive related to breathing pattern. During the course of apnea, incremental hypoxemia elicits the diving reflex so that bradycardia becomes progressively more marked. With termination of apnea, hyperpnea occurs with consequent activation of thoracic afferents, which is vagolytic.91 Thus, with resumption of breathing, abrupt lung inflation interrupts vagal drive to the heart, resulting in rapid-onset tachycardia. Furthermore, increased cardiac-bound sympathetic drive and withdrawal of parasympathetic activity because of arousals should also contribute to the tachycardia seen with termination of obstructive apnea. It is interesting that tachycardia persists even though blood pressure increases strikingly with termination of apnea. The vagolytic effects of inspiration and the arousal-associated changes in the autonomic nervous system not only interrupt the chemoreflex-mediated cardiac vagal drive but also blunt the expected cardiac vagal drive that would occur secondary to baroreflex activation by the postapneic surge in blood pressure. Because of the repetitive nature of nocturnal apneas, Holter or other electrocardiographic monitoring at night manifests as a tachycardia–bradycardia pattern. This cardiac rate oscillation is less apparent in patients with autonomic dysfunction, such as patients with long-standing diabetes, or cardiac transplant recipients with denervated hearts. Although the changes in cardiac rate are predominantly reflex-mediated, breathing-related changes in cardiac filling, as well as rapid changes in cardiac transmural pressures resulting from the Müller maneuver, also modulate heart rate by variations in stretch of cardiac conduction tissue. Bradyarrhythmias The primary response to hypoxia is bradycardia.88 When hypoxia is accompanied by the action of breathing, the bradycardic response is masked because of inhibition of cardiac vagal drive by ventilation.66 The sympathetic response to hypoxemia, although evident to some extent during breathing, is also attenuated by ventilation and is therefore potentiated during apnea.92,93 Patients with OSA may be particularly susceptible to hypoxia-induced bradyarrhythmias because their peripheral chemoreflex is heightened, so that even during voluntary apneas, hypoxemia elicits greater bradycardia than is seen in closely matched control subjects.94 The arterial baroreflexes serve as an important buffer to diminish chemoreflex gain.95 Impaired baroreflex sensitivity, such as is seen in hypertension96 and heart failure,97 may be associated with further increased chemoreflex drive. Thus, patients with hypertension or heart failure who have OSA may manifest even greater sympathetic, and perhaps bradycardic, responses to obstructive apneas. Profound bradyarrhythmias may have important consequences, particularly in patients with underlying cardiovascular disease. As an example, in the absence of recognition of OSA as a potential cause of the bradyarrhythmia, patients may receive pacemaker implantation, even though their cardiac conduction system may be completely normal and the bradyarrhythmias could be abolished by effective treatment with CPAP.83,84,98 Second, prolonged episodes of asystole result in absence of perfusion (see Fig. 119-6). Absence of perfusion in the setting of apnea-induced hypoxemia, occurring repetitively

through the night, may have important implications for ischemic damage to end organs in which there may already be preexisting circulatory compromise. Ventricular Arrhythmias There is an extensive literature on sleep apnea inducing nocturnal angina and cardiac ischemia evidenced by STsegment depression.99,100 Thus, there is a potential con­ tribution of OSA to ventricular arrhythmias through ventricular ectopy during profound bradycardia, as well as polymorphic ventricular tachycardia due to cardiac hypoxia/ischemia. These episodes occur primarily with severe desaturation,83,84 are more common in patients with coronary heart disease,86 and are virtually eliminated with treatment.83,84,98 The prevalence of these arrhythmias is low in patients without premorbid cardiorespiratory disease or severe desaturation.101 Atrial Fibrillation In patients cardioverted for atrial fibrillation, those with polysomnographically proven OSA who were not receiving effective CPAP treatment had a 12-month recurrence rate of 82%, compared with a 42% recurrence rate in patients with OSA receiving effective CPAP.102 In patients cardioverted for atrial fibrillation in whom no sleep study had been done, the recurrence rate was 53%. This risk for recurrence in the patients with atrial fibrillation without a previous sleep study suggests that undiagnosed OSA may be present in a large proportion of patients with atrial fibrillation. In addition, among the untreated patients with OSA, those experiencing a recurrence of atrial fibrillation had more severe nocturnal hypoxemia than those without a recurrence. Furthermore, the increased recurrence in patients with untreated OSA could not be explained by factors such as antiarrhythmic medication, body mass index, hypertension, cardiac function, or atrial size. Mooe and colleagues103 observed that after coronary artery bypass surgery, patients with OSA were more likely to experience postoperative atrial fibrillation. However, it is not clear whether this was explained by other variables in the patients with OSA. In a recent longitudinal study of several thousand patients, those with OSA had an increased risk of developing new-onset atrial fibrillation as compared with those who did not have OSA. This risk was evident in patients aged 65 or younger, and it was especially marked in those with more severe nocturnal hypoxemia.104 There are many reasons why OSA may be conducive to atrial fibrillation. Hypoxemia, pressor surges, and sympathetic activation are all potential mechanisms leading to atrial fibrillation. High levels of C-reactive protein may also independently predict the development of atrial fibrillation.105 Patients with OSA may have increased levels of C-reactive protein.106-108a Furthermore, abrupt and dramatic changes in intrathoracic negative pressures may especially affect the atria, with their relatively thin walls compared with the ventricles. Increased pressure gradients with consequent increased atrial wall stretch, occurring repetitively through the night, may be expected to induce mechanical and electrical changes that are also conducive to atrial fibrillation.109-111 Indeed, about 50% of patients presenting for cardioversion have a high risk for sleep

1378  PART II / Section 14  •  Cardiovascular Disorders

apnea, compared with 30% of patients from a general cardiology clinic.112

SUMMARY Sleep-related breathing disorders affect cardiovascular function in a variety of ways. OSA and central sleep apnea act through multiple mechanisms to elicit acute circulatory responses, which have implications for the development of chronic vascular and cardiac dysfunction. The acute responses to apnea are mediated in large part by the effects of apnea on blood gas chemistry, which exerts important cardiovascular effects directly on the myocardium and blood vessels, and also acts through reflex mechanisms. Acute neural, circulatory, endothelial, inflammatory, and other responses to repetitive nocturnal hypoxemia and hypercapnia may act to induce long-term damage to the myocardium and to the coronary and other vascular beds. With the development of functional and structural cardiovascular disease, the consequences of acute apneas are magnified. For example, severe hypoxemia in the setting of sleep apnea is more easily tolerated by an overtly healthy cardiovascular system compared with one where myocardial ischemia or left ventricular dysfunction is present, with consequent diminished cardiovascular reserve. Small, short-term studies have suggested that effective prevention of recurrent apneas may favorably affect surrogates of cardiovascular disease outcome, such as sympathetic activity, blood pressure, and left ventricular ejection fraction. ❖  Clinical Pearls Apnea and recovery cycles result in three basic abnormalities: alterations in blood gases, arousals, and changes in intrathoracic pressure. Hypoxemia–reoxygenation has deleterious effects on the cardiovascular system. This activates redoxsensitive genes, resulting in synthesis of vasoconstrictor and inflammatory mediators; increases sympathetic activity; and causes oxidative stress. These alterations have been best studied in patients with OSA. Untreated OSA may increase the risk of recurrence of atrial fibrillation after cardioversion. Sleep apnea can induce severe bradyarrhythmias, including prolonged periods of asystole and heart block, even in the setting of a normal myocardium and cardiac electrophysiologic function. OSA should be considered in patients who have ST-segment depression or angina occurring primarily at night. Heart failure may be significantly linked to the presence of either central sleep apnea or OSA.

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1380  PART II / Section 14  •  Cardiovascular Disorders 75. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233-1241. 76. Mansfield DR, Gollogly NC, Kaye DM, et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169:361-366. 77. Cargill JI, Keily DG, Liworth BJ. Adverse effects of hypoxemia on diastolic filling in humans. Clin Sci 1995;89:165. 78. Hender J, Enjell H, Caidahl K. Left ventricular hypertrophy independently of hypertension in patients with obstructive sleep apnea. J Hypertens 1990;8:941-946. 79. Noda A, Okada T, Yasuma F, et al. Cardiac hypertrophy in obstructive sleep apnea syndrome. Chest 1995;107:1538-1544. 80. Arias MA, Garcia-Rio F, Alonso-Fernandez A, et al. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation 2005;112:375-383. 81. Chami HA, Devereux RB, Gottdiener JS, et al. Left ventricular morphology and systolic function in sleep-disordered breathing. The Sleep Heart Health Study. Circulation 2008;117:2599-2607. 82. Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 2007;49:1625-1631. 83. Chan J, Sanderson J, Chan W, et al. Prevalence of sleep-disordered breathing in diastolic heart failure. Chest 1997;111:1488-1493. 84. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 85. Koehler U, Fus E, Grimm W, et al. Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment. Eur Respir J 1998;11:434-439. 86. Grimm W, Hoffmann J, Menz V, et al. Electrophysiologic evaluation of sinus node function and atrioventricular conduction in patients with prolonged ventricular asystole during obstructive sleep apnea. Am J Cardiol 1996;77:1310-1314. 86a.  Koehler U, Glaremin DT, Junkermann H, et al. Nocturnal myocardial ischemia and cardiac arrhythmia in patients with sleep apnea with and without coronary heart disease. Klin Wochenschr 1991;69:474-482. 87. de Burgh Daly M, Elsner R, Angel-James JE. Cardiorespiratory control by carotid chemoreceptors during experimental dives in the seal. Am J Physiol 1977;232:H508-H516. 88. de Burgh Daly M, Angell-James J, Elsner R. Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. Lancet 1997;1:764-767. 89. Roche F, Gaspoz J-M, Court-Fortune I, et al. Screening of obstructive sleep apnea syndrome by heart rate variability analysis. Circulation 1999;100:1411-1415. 90. Stein PK, Domitrovich PP. Detecting OSAHS from patterns seen on heart-rate tachograms. Comput Cardiol 2000;27:271-274. 91. Anrep GV, Pascual W, Rossler R. Respiratory variations of the heart rate: II. The central mechanism of the respiratory arrhythmia and the interrelations between the central and reflex mechanisms. Proc R Soc Lond Ser B 1936;119:218-230. 92. Somers VK, Zavala DC, Mark AL, et al. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol 1989;67:2101-2106. 93. Somers VK, Zavala DC, Mark AL, et al. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol 1989;67:2095-2210. 94. Narkiewicz K, van de Borne P, Pesek C, et al: Selective potentiation of peripheral chemoreceptor sensitivity in obstructive sleep apnea. Circulation 1999;99:1183-1189.

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Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea Terry Young, F. Javier Nieto, and Shahrokh Javaheri Abstract Findings from investigations based on diverse populations and different study designs have consistently supported a role for obstructive sleep apnea (OSA) in systemic and pulmonary hypertension. Both cross-sectional and prospective populationbased epidemiology studies have shown that persons with polysomnographically indicated OSA (15 or more apnea or hypopnea events per hour of sleep) have 2 to 3 times greater odds of having systemic hypertension or of developing new systemic hypertension than persons who do not have OSA. The associations are only partly explained by confounding factors such as increased body mass index (BMI), sex, or age. Some studies suggest that the strength of the link between OSA and hypertension varies by age, BMI, and sex, but nonetheless, the link between OSA and hypertension is consistently found across subgroups, including children and different ethnic groups. A dose-dependent association for OSA and hypertension is seen in the mild to moderate OSA range, but the

Although the clinical association between hypertension and obstructive sleep apnea (OSA) has long been reported1-3 in sleep medicine, the potential importance of OSA in patients with elevated blood pressure and cardiovascular disease is gaining recognition beyond the field of sleep research. In the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, OSA is recognized as an identifiable cause of hypertension.4 Similarly, the World Health Organization has recognized OSA as a cause of secondary pulmonary arterial hypertension.5 Increasing evidence that OSA has a causal role in the development of hypertension has been discussed in two recent task force statements.6,7 Although an accurate estimate of the fraction of systemic hypertension that can be causally attributed to OSA is lacking and data on OSA and pulmonary hypertension are sparse, it is clear that clinical recognition of the high prevalence of systemic and pulmonary hypertension in people with OSA,8,9 as well as the high occurrence of OSA in hypertensive patients,10-12 is imperative. The aim of this chapter is to present the epidemiologic data in support of a role of OSA in systemic and pulmonary hypertension and to describe the clinical issues in identification and treatment of patients with OSA and hypertension.

SYSTEMIC HYPERTENSION Epidemiologic Evidence for a Role of OSA in Systemic Hypertension The early observations of hypertension in patients with sleep apnea stimulated several cross-sectional clinic- and community-based studies that attempted to determine whether there was an association between OSA and hypertension that was not explained by excess body weight or other factors common to both OSA and hypertension (see Chapter 61).9 Results were mixed, but many of the studies

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association appears to plateau with more severe OSA. The associations are seen during both sleep and wake. Pulmonary hypertension, ranging from mild to severe, is prevalent in patients with OSA. Mild pulmonary arterial hypertension (PAH) may occur in patients with OSA without daytime hypoxemia or chronic obstructive pulmonary disease, but these comorbidities are more common in patients with severe OSA. Although definitive randomized clinical trials have not been completed, most studies of both systemic and pulmonary arterial blood pressures before and after continuous positive airway pressure (CPAP) have shown decreases in blood pressure. Intervention trials have generally shown modest reductions in systemic blood pressure with CPAP use (2 to 10  mm  Hg), and the largest effects are seen in effectively treated patients with severe OSA. Importantly, such small changes in blood pressure, if maintained, have the potential of significantly decreasing the population incidence of cerebrovascular and cardiovascular disease.

had some methodological shortcomings, such as inadequate sample size, flawed comparison groups, measurement error, or limited statistical analysis.13,14 Since then, findings from both population and clinical studies have shed important new light on this association. Reports from several well-designed epidemiology studies, summarized in Table 120-1, have consistently shown that significant associations of polysomnographically determined OSA and hypertension, defined by blood pressure thresholds or use of antihypertensive medication, remain after adjustment for potential confounding factors.15-17 The strongest epidemiologic evidence for a causal association comes from longitudinal analyses of data from the ongoing Wisconsin Sleep Cohort Study of middle-aged state employees, reported by Peppard and colleagues.18,19 The incidence of new hypertension, defined as systolic blood pressure at least 140  mm  Hg, diastolic blood pressure at least 90  mm  Hg, or use of antihypertensive medication at follow-up, was significantly dependent on baseline level of OSA. The 4-year hypertension incidence increased from 10% in those with no sleep-disordered breathing at baseline, to 32% for those with moderate sleep-disordered breathing at baseline. After considering confounding factors, the probability of developing new hypertension over 4 years was twofold greater for those with an apnea–hypopnea index (AHI) of 5 to 15, and threefold greater for those with an AHI of greater than 15 at baseline, compared with participants without OSA at baseline (i.e., AHI < 1). Cross-sectional analyses of baseline data from three other population cohorts (Southern Pennsylvania,20 Spain,21 and the U.S. multicenter Sleep Heart Health Study22) using measurements, definitions, and statistical adjustment models similar to those used in the Wisconsin Sleep Cohort, have also shown OSA to be a statistically 1381

1382  PART II / Section 14  •  Cardiovascular Disorders Table 120-1  Association of Polysomnographically Determined Sleep-Disordered Breathing and Hypertension in Four Population Studies Odds Ratio* for Hypertension† (95% CI) AHI CATEGORY PARTICIPANTS (N)

STUDY DESIGN 1. Wisconsin Sleep Cohort Study, state employees, ages 30 to 65 years,16 prospective, 4-8 years follow-up

20/hr 17% had mean PAP > 20 mm Hg 8% had mean PAP ≥ 25 mm Hg Patients with PH had more severe OSA, higher Paco2 and BMI, lower Pao2, and a more obstructive and restrictive defect Paco2 and FEV1 were independent predictors of PAH Laks L, Lehrhaft B, Grunstein RR, et al. (Reference 69) 100 consecutive Australian patients with AHI > 20/hr 42% had mean PAP > 20  mm  Hg; range, 20 to 52 mm Hg Paco2, Pao2, and FEV1 accounted for 33% of the variability in PH Six patients with PAH had normal Pao2 Sanner BM, Doberauer C, Konermann M, et al. (Reference 70) 92 consecutive German patients with OSA and AHI > 10/hr; range, 10 to 100/hr COPD was an exclusion criterion 20% had mild PH; range, 20 to 25 mm Hg Eight patients had increased PCWP; all had systemic hypertension PCWP and time spent at 5/hr COPD was an exclusion criterion 27% had PH with mean pressure ≥ 28.5 mm Hg 18% had mean PAP ≥ 25 mm Hg AHI, apnea–hypopnea index; BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure.



CHAPTER 120  •  Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea  1389

met this criterion; in 23 patients (62%), the mean pressure exceeded 40 mm Hg. In an Australian study69 of 100 consecutive patients with an AHI of 20 or more, 42% had PH, with the mean pulmonary artery pressure ranging from about 20 to 52 mm Hg. In several of these patients, the mean pressure was more than 25 mm Hg. In this study, Paco2, Pao2, and FEV1 accounted for about 33% of variability in pulmonary artery pressure. Six patients with PH had normal Pao2. In a German study70 of 92 consecutive patients with an AHI of greater than 10 and with COPD as an exclusion criterion, 20% had mild PH with a mean pulmonary artery pressure of 20 to 25  mm  Hg. Eight patients had increased pulmonary capillary wedge pressure, and all of these patients had systemic hypertension that was presumably causing left ventricular diastolic dysfunction. Pulmonary capillary wedge pressure and time spent with a saturation of below 90% were the independent variables predicting PH. The presence of PH in patients with OSA but without COPD was also confirmed in another French study (see Box 120-1).71 In this study, however, COPD was defined by an FEV1 of less than 70% predicted and a ratio of FEV1 to forced vital capacity (FVC) of less than 60% predicted. The study involved 44 patients, 12 of whom (27%) had precapillary PH. The authors reported that mean pulmonary artery pressure was positively correlated with BMI and negatively correlated with Pao2. Patients with PH had significantly lower values for FVC and FEV1. The mechanisms by which BMI positively correlated with PH could have been multifactorial and related to restrictive lung defect and hypoxemia. In conclusion, mild PH is common in patients with OSA and may occur in the absence of COPD and daytime hypoxemia. However, severe OSA, severe hypoxemia, and obstructive or restrictive lung defects are more commonly associated with PH and contribute to its severity. In addition, as noted, PH either becomes manifest or is augmented by exercise and can cause dyspnea and exercise intolerance.72 Mechanisms of Pulmonary Hypertension in Patients with OSA Multiple mechanisms mediate nocturnal rises in pulmonary artery pressure. These include alterations in blood gases, cardiac output, lung volume, intrathoracic pressure, compliance of pulmonary circulation, and left ventricular diastolic dysfunction. Diurnal PH in patients with OSA could be precapillary, capillary, or postcapillary, depending in part on comorbid disorders that may contribute to the development of PH (Box 120-2). Postcapillary PH (pulmonary venous hypertension) results primarily from left ventricular hypertrophy and diastolic dysfunction caused by diurnal systemic hypertension. However, left ventricular hypertrophy could be present in patients with OSA even in the absence of daytime systemic hypertension,75 presumably because of cyclic changes in systemic artery blood pressure and hypoxemia74 during sleep. In the presence of a hypertrophied, noncompliant left ventricle, end-diastolic pressure increases, resulting in an increase in pulmonary capillary and pulmonary artery systolic and diastolic pressures (post-

Box 120-2  Mechanisms of Pulmonary Hypertension in Obstructive Sleep Apnea Precapillary Pulmonary Hypertension Hypoxemia Hypercapnia Endothelial dysfunction or remodeling* Changes in intrathoracic pressure Postcapillary Pulmonary Hypertension Left ventricular hypertrophy and diastolic dysfunction *See Tilkian AG, Guilleminault C, Schroeder JS, et al. Hemodynamics in sleep-induced apnea: studies during wakefulness and sleep. Ann Intern Med 1976;85:714-719.

capillary PH). Left ventricular diastolic dysfunction may become unmasked when cardiac output increases. This may account for the high prevalence of PH with exercise in patients with OSA. Loss of vascular surface area, as may occur in patients with COPD, is an important cause of capillary PH, and it may significantly contribute to PH in patients with OSA. Several studies67-69 have shown that COPD and a low FEV1 are predictors of PH in patients with OSA. COPD could also contribute to PH by way of arteriolar vasoconstriction due to hypoxemia and hypercapnia resulting in precapillary PH (see next paragraph). An important mechanism mediating PH in patients with OSA is the presence of factors that cause constriction of pulmonary arterioles, leading to precapillary PH. The best-known stimulus is alveolar hypoxia, and it is not surprising that hypoxemia is an independent predictor of PH in OSA (see Box 120-1). However, hypercapnia could also increase pulmonary arterial blood pressure. The molecular mechanisms of PH in general are complex and multifactorial. Both acquired and genetic factors are involved. Disordered endothelial cell function, in part caused by hypoxia (and reoxygenation) and manifested biochemically by an imbalance between concentrations of local vasodilators (e.g., nitric oxide and prostacyclins) and vasoconstrictors (e.g., endothelin-1, thromboxane, serotonin), as occurs in endothelial dysfunction syndrome, appears to mediate the development of PH.76,77 It is also conceivable that if OSA is long-standing, pulmonary vascular remodeling similar to that in COPD could occur, as a number of mediators such as vascular endothelial growth factor are proliferative and angiogenic. Even though cyclic PH occurs regularly with episodes of apnea during sleep, it is not clear why only some patients with OSA develop diurnal PH. The same is true for systemic hypertension. Genetic predisposition, however, may confer an increased risk for the occurrence of PH in some patients. In familial inherited PH, mutations in the gene for bone morphogenetic protein receptor type 2 (BMPR2) have been reported.8 Furthermore, aberrant production of angiopoietin-1 has been reported in a variety of disorders with acquired PH,78 including thromboembolic disease, scleroderma, and mitral regurgitation. The expression of angiopoietin-1 messenger RNA and the protein itself were unregulated in the lungs of these patients, and it correlated directly with the severity of the disease. Angiopoietin-1 is

1390  PART II / Section 14  •  Cardiovascular Disorders

an angiogenic factor that recruits smooth muscle cells to the endothelial vascular network during the embryogenic stage. However, after development is completed, angiopoietin-1 is expressed only minimally in normal human lung. In contrast, in patients with the various forms of acquired PH, the level of angiopoietin-1 is increased.78 Although the mechanisms leading to upregulation of angiopoietin-1 are unclear, it is conceivable that its upregulation could also contribute to PH in some patients with OSA. In summary, the consequence of OSA on pulmonary circulation may vary from those of cyclic nocturnal PH, which occurs in virtually all patients, to daytime PH, right ventricular dysfunction, and eventually cor pulmonale, a feature of pickwickian syndrome. However, even in the absence of cor pulmonale, which is the manifestation of long-standing severe PH, presence of PH increases right ventricular afterload and myocardial oxygen consumption. If PH develops as a result of increases in cardiac output, for example with exercise, it may cause dyspnea and exercise intolerance. Changes in Pulmonary Artery Pressure after CPAP Treatment of OSA Because mechanisms of PH in OSA are multifactorial (see Box 120-2), the behavioral response of pulmonary circulation to therapy for OSA probably depends on several factors. For example, if loss of vascular surface area due to the presence of COPD or other comorbid pulmonary disorders is contributing to PH in OSA, this component is irreversible.79 Similarly, if remodeling of the pulmonary vascular bed has occurred, long-standing effective therapy is necessary to effect any reversal (reverse remodeling). Therefore, if CPAP is used to treat OSA, long-term compliance with therapy is critical and needs to be confirmed by covert monitoring. Large, long-term systematic studies considering these important factors are necessary to determine the effects of treatment of OSA on pulmonary circulation. Lack of such considerations may lead to serious underestimation of effects. Effective treatment of OSA improves PH. Both Fletcher and colleagues79 and Motta and coworkers80 have reported that with tracheostomy, PH is virtually eliminated. Alchanatis and colleagues81 used Doppler echocardiography to estimate pulmonary artery pressure before and after 6 months of effective treatment with CPAP in 29 patients with OSA and without COPD. In six patients who had mild PH, the mean pulmonary artery pressure decreased significantly, from about 26 to 20  mm  Hg, 6 months after treatment with CPAP. In the study by Sforza and colleagues,82 eight patients had mild PH (mean ± SEM = 23 ± 1 mm Hg). After treatment with CPAP for a year, the mean pulmonary artery pressure was 21 (±1) mm Hg. For such a small change to be statistically significant, a large sample of patients is imperative. Sajkov’s group,83 using Doppler echocardiography, studied pulmonary hemodynamics in 20 patients with OSA (average AHI, 49 or greater) before and 4 months after treatment with CPAP. In this study, CPAP compliance was objectively monitored, and the average was 5 hours per night. Patients had normal lung function. Five patients who had mild PH (range, 20 to 32  mm  Hg) showed the most dramatic decrease in the pulmonary artery pressure,

all decreasing to less than 20  mm  Hg after 4 months of effective treatment with CPAP. In a subject who was not compliant with CPAP, there was no change in pulmonary artery pressure. Although this was a single observation, this finding and those reported for systemic hypertension strongly indicate that effective use of CPAP is necessary to lower systemic and pulmonary artery pressures. There is only one randomized clinical trial regarding therapy of pulmonary hypertension in patients with OSA. Arias and colleagues84 randomized 23 middle-aged patients with severe OSA (AHI, 44/hr or greater) to either sham CPAP or CPAP therapy. In this crossover trial, after 12 weeks of CPAP therapy, pulmonary artery systolic pressure decreased significantly from a mean of about 30 to 24  mm  Hg. The reduction was greatest (8.5  mm  Hg) in patients with pulmonary hypertension defined as pulmonary artery systolic pressure of 30 or more determined by echocardiography. ❖  Clinical Pearls Epidemiologic studies support a causal role of OSA in systemic hypertension independent of BMI, measures of fat distribution, age, sex, and other possible confounding factors. Randomized double-blind placebo (sham CPAP)controlled trials of patients with hypertension demonstrate that effective treatment of OSA with CPAP lowers blood pressure. A decrease in blood pressure is most pronounced in those with the most severe OSA and who are the most compliant. Even small decrements in blood pressure, maintained for the long term, have been shown to significantly lessen the incidence of cerebrovascular and cardiovascular diseases. Thus, the potential lowering of blood pressure from CPAP treatment holds promise for decreasing cerebrovascular or cardiovascular disease. However, adequate control of OSA and compliance with CPAP, particularly in patients with severe OSA, are critical. Several observational studies show that OSA is a cause of mortality, particularly when severe. Treatment with CPAP improves mortality. Obstructive sleep apnea is a cause of secondary pulmonary hypertension, and this has been recognized by international health organizations. PH is usually mild, although it could be severe, particularly in the presence of comorbid disorders such as COPD. Treatment of OSA with CPAP may improve PH.

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1392  PART II / Section 14  •  Cardiovascular Disorders 51. Ip M, Tse H, Lam B, et al. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004; 169:348-353. 52. Arias MA, Garcia-Rio F, Fernandez AA, et al. Obstructive sleep apnea affects left ventricular diastolic function. Circulation 2005; 112:375-383. 53. Bazzano LA, Khan Z, Reyonlds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50(2):417-423. 54. Campos-Rodriguez F, Perez-Ronchel J, Grilo-Reina A, et al. Longterm effect of continuous positive airway pressure on BP in patients with hypertension and sleep apnea. Chest 2007;132:1847-1852. 55. Robinson GV, Langford BA, Smith DM, Stradling JR. Predictors of blood pressure fall with continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea (OSA). Thorax 2008;63: 855-859. 56. Cross MD, Mills NL, Al-Abri M, et al. Con­tinuous positive airway pressure improves vascular function in obstructive sleep apnoea/ hypopnoea syndrome: a randomised controlled trial. J Am Col Cardiol 2004;43:5S-12S. 56a.  Jaimchariyatam N, Rodriguez CL, Budur K. Does CPAP treatment in mild obstructive sleep apnea affect blood pressure? Sleep Med 2010 Aug 16. [Epub ahead of print] 56b.  Calhoun DA, Harding SM. Sleep and hypertension. Chest 2010; 138:434-443. 56c.  Aihara K, Chin K, Oga T, Takahashi KI, et al. Long-term nasal continuous positive airway pressure treatment lowers blood pressure in patients with obstructive sleep apnea regardless of age. Hypertens Res 2010 Jul 29. [Epub ahead of print] 57. Ogha E, Tomita T, Wada H, et al. Effects of obstructive sleep apnea on circulating I-CAM-1, IL-6, and MCP1. J Appl Physiol 2003;94:179-184 58. Montserrat JM, Barbe F, Rodenstein DO. Should all sleep apnoea patients be treated? Sleep Med Rev 2002;6:7-14. 59. Levy P, Pepin JL, McNicholas WT. Should all sleep apnoea patients be treated? Yes. Sleep Med Rev 2002;6:17-26. 60. Pack AI, Maislin G. Who should get treated for sleep apnea? Ann Intern Med 2001;134:1065-1067. 61. Logan AG, Tkacova R, Perlikowski SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 2003;21:241-247. 62. Marshall NS, Wong KK, Liu PY, et al. Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study. Sleep 2008;31:1079-1085. 63. Young T, Finn L, Peppard P, et al. Sleep disordered Breathing and mortality: eighteen-year follow-up of the Wisconsin Sleep Cohort. Sleep 2008;31:1071-1078. 64. MacMahon S, Peto R, Cutler J, et al. Epidemiology: blood pressure, stroke, and coronary heart disease; Part 1, prolonged difference in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-774. 65. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Col Cardiol 2004;43:5S-12S. 66. Atwood CW Jr, McCrory D, Garcia JGN, et al. Pulmonary artery hypertension and sleep-disordered breathing. Chest 2004;126: 72S-77S.

67. Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985;131:835-839. 68. Chaouat A, Weitzenblum E, Krieger J, et al. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Chest 1996;109: 380-386. 69. Laks L, Lehrhaft B, Grunstein RR, et al. Pulmonary hypertension in obstructive sleep apnea. Eur Respir J 1995;8:537-541. 70. Sanner BM, Doberauer C, Konermann M, et al. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997;157:2483-2487. 71. Bady E, Achkar A, Pascal S, et al. Pulmonary arterial hypertension in patients with sleep apnea syndrome. Thorax 2000;55: 934-939. 72. Hetzel M, Kochs N, Woehrle H, et al. Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension. Lung 2003;181:157-166. 73. Podszus T, Bauer W, Mayer J, et al. Sleep apnea and pulmonary hypertension. Klin Wochenschr 1986;64:131-134. 74. Marrone O, Bonsignore MR. Pulmonary hemodynamics in obstructive sleep apnea. Sleep Med Rev 2002;6:175-193. 75. Hedner J, Enjell H, Caidahl K. Left ventricular hypertrophy independently of hypertension in patients with obstructive sleep apnea. J Hypertens 1990;8:941-946. 76. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-165. 77. Sommer N, Dietrich A, Schermuly RT, et al. Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms. Eur Respir J 2008; 32:1639-1651. 78. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 2003;348:500-509. 79. Fletcher EC, Schaaf JW, Miller J, Fletcher JG. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease: Am Rev Respir Dis 1987;135:525-533. 80. Motta J, Guilleminault C, Schroeder JS, et al. Tracheostomy and hemodynamic changes in sleep-induced apnea. Ann Int Med 1978;89:454-458. 81. Alchanatis M, Tourkohoriti G, Kakouros S, et al. Daytime pulmonary hypertension in patients with obstructive sleep apnea. Respiration 2001;68:566-572. 82. Sforza E, Krieger J, Weitzenblum E, et al. Long-term effects of treatment with nasal continuous positive airway pressure on daytime lung function and pulmonary hemodynamics in patients with obstructive sleep apnea. Am Rev Respir Dis 1990;141: 866-870. 83. Sajkov D, Wang T, Saunders NA, et al. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002; 165:152-158. 84. Arias MA, Garcia-Río F, Alonso-Fernández A, et al. Pulmonary hypertension in obstructive sleep apnea: effects of continuous positive airway pressure—a randomized, controlled crossover study. Eur Heart J 2006;27:1106-1113.

Coronary Artery Disease and Obstructive Sleep Apnea Jan Hedner, Karl A. Franklin, and Yüksel Peker

Chapter

121

Abstract Recurrent apneas during sleep lead to a sequence of events that, independently or in concert with other recognized risk factors, are likely to have harmful effects on vascular structure and function. The epidemiologic support for a causal relationship between obstructive sleep apnea (OSA) and coronary artery disease (CAD) is rapidly increasing but is not yet fully confirmed. This relationship is stronger in clinical cohorts than in the general population, which suggests that comorbid OSA in obese, hypertensive, smoking, and hyperlipidemic subjects may provide an additive or synergistic risk factor for development of CAD. OSA-related phenomena including hypoxemia, reoxygenation, and recurrent vascular wall stress may induce CAD, and the events may by themselves aggravate already-existing compromised coronary artery flow reserve.

Epidemiologic data suggest that obstructive sleep apnea (OSA) is overrepresented in patients with coronary artery disease (CAD). On the other hand, evidence suggests that the clinical course of CAD is initiated or accelerated by the presence of the breathing disorder. A rapidly evolving field of experimental data demonstrates that OSA, by phenomena such as hypoxemia and reoxygenation, may trigger a sequence of events involved in the development of atherosclerotic disease. Development of vascular disease and CAD is influenced by a number of genotypic and phenotypic risk factors, several of which have been associated with OSA. Sleep apneic events induce a state of increased cardiac oxygen demand but are also often associated with low oxygen reserve because of lack of ventilation. Nocturnal angina can therefore be triggered by sleep apneas in patients with CAD. There is growing evidence that elimination of sleep apnea can benefit patients with OSA at risk of CAD in the immediate and long term. Other data suggest that treatment of OSA may improve prognosis in patients undergoing coronary revascularization. This chapter reviews the evidence of an association between these two conditions.

EPIDEMIOLOGY The risk of experiencing angina pectoris or an acute coronary syndrome such as unstable angina, acute myocardial infarction (MI), or sudden cardiac death has long been known to be increased during the late hours of sleep or in the hours after awakening.1 This association may be explained by occurrence of OSA. A retrospective analysis showed an overrepresentation of peak time in sudden death from the cardiac causes during the sleeping hours in patients with OSA, which contrasted with a nadir in sudden death from cardiac causes in subjects without OSA and in the general population.2 A small prospective study addressing the time of onset of myocardial infarction showed a higher likelihood of having OSA in those with an onset of

Patients with CAD, including nocturnal angina, should therefore be considered for sleep recording, because elimination of apneas by nasal continuous positive airway pressure during sleep has been shown to reduce angina attacks and nocturnal myocardial ischemia. The long-term tentative causal association between OSA and CAD is supported by experimental data suggesting endothelial dysfunction, acceleration of vascular inflammation, and development of atherosclerotic disease as a result of the breathing disorder. Increased recognition of the adverse impact of OSA on vascular disease may open a perspective of new primary and secondary prevention models for CAD that involve identification and elimination of the OSA.

myocardial infarction during midnight hours.3 Besides this evidence of an immediate detrimental effect of apneas in patients with existing CAD, there is rapidly growing epidemiologic support for a causal relationship between OSA and CAD development. However, this association is yet not fully confirmed. In general, there is a stronger relationship between OSA and CAD in clinical cohorts than in the general population because clinical cohort studies are particularly influenced by comorbidity and confounding factors, including obesity, hypertension, smoking, and hyperlipidemia. This circumstance may also suggest that OSA constitutes an additive or synergistic risk factor for development of CAD. Prevalence of OSA and CAD in the General Population Snoring, a common symptom of OSA, is associated with up to a fivefold risk increase for MI.4,5 It has been claimed that snoring is a relatively insensitive measure of sleepdisordered breathing. However, the strength of these data is that snoring is an accessible symptom in large-scale studies, permitting appropriate adjustment for confounding risk factors. Snoring per se is a hard-to-quantify and observer-dependent phenomenon, but intrathoracic pressure changes typical of snoring may play an important role in the pathogenesis of CAD. This speculation is supported by a smaller-scale community study of 441 subjects,6 with sleep recordings showing an increased prevalence of CAD in nonapneic snorers (12%) compared with nonsnorers (7%), and there was a further increase (20%) in apneic snorers. The largest study to date addressing OSA and CAD is the Sleep Heart Health Study.7 The investigators performed a cross-sectional analysis of 6132 subjects undergoing unattended polysomnography. There was a modest risk increase (peaking at an odds ratio [OR] of 1.27) for self-reported CAD when the highest and lowest apnea– hypopnea index (AHI) quartiles were compared. The weak association in this prevalence study may be explained by a 1393

1394  PART II / Section 14  •  Cardiovascular Disorders

proportionally high age and a low median AHI in the investigated population. Prevalence of CAD in Patients with OSA Clinical studies of CAD in sleep clinic cohorts generally involve patients with OSA and with daytime symptoms. Consequently, compared with studies in the general population, these studies selectively deal with symptomatic patients, those likely to suffer from more severe sleep apnea, and potentially also patients with more obesity and other cardiovascular comorbidities. Available data in this area are to a large extent based on uncontrolled studies. For example, in a sleep clinic cohort of 386 subjects,8 CAD was present in almost one fourth of subjects with OSA, and the percentage of patients with CAD was high among those with moderate to severe OSA. Simultaneous polysomnography and electrocardiographic recordings demonstrated that episodes of nocturnal ischemia were more common in patients with OSA who also had CAD, and mainly so during rapid eye movement (REM) sleep, during episodes of high apnea activity, and during sustained hypoxemia.9 Moreover, ST-segment depression on electrocardiography was not uncommon during sleep in patients with OSA but without a history of CAD, and these changes were eliminated by continuous positive airway pressure (CPAP).10 Studies using invasive measures, including angiography, verified CAD in more than 20% of investigated subjects with OSA,11 and an even higher prevalence (68%) was reported in a slightly larger study of unselected patients with OSA.12 Collectively these data suggest a proportionally high prevalence of CAD in sleep clinic cohorts. Prevalence of OSA in CAD Sleep-disordered breathing appears to be common in patients with CAD.13a An early small study13 demonstrated OSA or central sleep apnea with Cheyne-Stokes respiration in more than 75% of subjects with CAD. A subsequent Australian case-control study that investigated middle-aged male survivors of acute MI and age-matched controls14 provided the first clinic-based epidemiologic evidence of an increased prevalence of OSA in patients with CAD. OSA (AHI ≥ 5) was found in approximately one third of the patients compared with only 4% of controls and constituted an independent predictor of MI after adjustment for traditional risk factors. A larger case-control study15 provided a similar OSA prevalence (approximately 30%), whereas the prevalence in the control group was 20%. In this population, an AHI of 20 was associated with a history of MI (odds ratio, 2.0). Finally, in a tightly matched Swedish case-control study of 62 patients, OSA provided an independent odds ratio of 3.1 for CAD.16 There are also data that suggest that the OSA and CAD association may also be influenced by sex and age. In patients with angiographically verified CAD, an AHI of greater than 10 was almost twice as common in men17 but three times more common in women18 younger than 70 years, compared with age-matched controls. An uncontrolled follow-up study found OSA (AHI > 10) in 57% of 89 subjects with acute coronary syndrome undergoing percutaneous coronary intervention (PCI).19 A similar

high prevalence of OSA (66%) was reported in another investigation.20 The possibility that OSA may trigger episodes of nocturnal angina in patients with disabling CAD was addressed in an interventional study.21 OSA was found in 9 of 10 investigated patients with CAD who had nocturnal angina, and episodes of ischemia were reversed after elimination of the apneic events with CPAP treatment. A subsequent larger cross-sectional study found signs of silent nocturnal myocardial ischemia in 31% of 226 patients with CAD22 but failed to demonstrate a general and immediate temporal relationship between OSA and episodes of myocardial ischemia. However, a direct association could be documented in a small subgroup of patients, and, in general, episodes of silent ischemia appeared to be more frequent in those with more severe OSA. A retrospective evaluation of more than 200 patients undergoing electron-beam computer tomography within 3 years of an overnight sleep recording addressed the occurrence of subclinical coronary artery calcification.23 With multivariate adjustment, the OR for coronary artery calcification was 3.3 in the most severe AHI quartile (mean, 63.4 events/hr). The impact of OSA on the prognosis of CAD has been addressed in several studies. In a study of patients with CAD who were undergoing elective PCI, concomitant OSA was significantly related with increased late lumen loss and restenosis after an average follow-up time of 7 months.24 In another study,19 the incidence of adverse cardiac events (cardiac death, reinfarction, and target vessel revascularization) was reported to be almost 24% among patients with OSA, compared with 5% among those without OSA during a 6-month follow-up. Moreover, patients with CAD who had concomitant OSA were found to have an increased risk of cardiovascular mortality over a 5-year period.25,26 However, another study demonstrated no impact of OSA on readmission rate of PCI-treated patients with CAD who had concomitant OSA during a 6-month follow-up period20 and no significant difference regarding the 10-year survival rate for patients with CAD and with OSA compared with those without OSA at baseline.27,28 The incidence of stroke was also increased in patients with CAD who had concomitant OSA (and an AHI of at least 5 events/hr).28 Stroke occurred in 18% of patients with CAD and sleep apnea, compared with 5% of those without sleep apnea, during 10 years of follow-up after a coronary angiography was performed. After adjustments for confounders, including hypertension and atrial fibrillation, the patients with sleep apnea had an adjusted hazard of 2.9 (95% confidence interval [CI], 1.4 to 6.1) for a stroke.28 Hence, OSA is common in patients with MI, but their mean AHI is relatively low in most published reports (Table 121-1).9,13,16-20,29-32 Moreover, the prevalence of OSA is higher in patients with MI than in those with angina pectoris. This finding may be explained by the occurrence of Cheyne-Stokes respiration as a result of reduced ejection fraction.22 Nocturnal angina may be associated with severe OSA in patients with CAD. Available studies of the OSA prevalence in the CAD populations (see Table 121-1) include 776 patients, and more than 40% of those had an AHI exceeding 10. Moreover, the majority of the available data suggests that concomitant



CHAPTER 121  •  Coronary Artery Disease and Obstructive Sleep Apnea  1395

Table 121-1  Prevalence of Sleep Apnea in Patients with Coronary Artery Disease FIRST AUTHOR REF (YEAR)

PATIENTS (NO.)

SEX

PATIENTS WITH AHI ≥ 10 (%)

CONTROLLED

De Olazabal 13 (1982)

17

Male

76

No

Andreas 29 (1996)

50

Male, female

50

No

Mooe 17 (1996)

142

Male

37

Yes

Mooe 18 (1996)

102

Female

30

Yes

Koehler 9 (1996)

74

Male

35

No

Peker 16 (1999)

62

Male, female

31

Yes

Moruzzi 30 (1999)

22

Male, female

9

No

Sanner 31 (2001)

49

Male, female

27

No

Mehra 20 (2006)

104

Male, female

66

No

Takama 32 (2007)

65

Male, female

45

No

Yumino 19 (2007)

89

Male, female

57

No

—

42

—

Total or mean

776

OSA provides a worsening of long-term outcome in patients with CAD. Incidence of CAD in Longitudinal Studies The incidence of CAD has been investigated in three large studies with focus on snoring habits. In a Finnish cohort of 4388 men aged 40 to 69 years, snoring provided a 1.9fold increased risk of CAD during a 3-year follow-up.4 The association was somewhat weakened after CAD risk-factor adjustment. A subsequent smaller prospective study33 in 400 subjects suggested that snoring worsened the prognosis of patients with already-known risk factors for cardiovascular disease but did not constitute an independent or predictive risk factor in itself. A large Danish prospective investigation on self-reported snoring habits in middleaged men34 failed to identify an increased incidence of CAD, although a trend was seen in the younger half of the cohort. These data are supported by a well-controlled 4-year prospective Spanish study,35 which showed a tripled risk for acute MI in snorers compared with nonsnorers. Self- or relative-reported heavy snoring has also been identified as a risk factor for case fatality and poor short-term prognosis after MI in a follow-up study.36 Moreover, a large followup study37 showed an almost tripled risk of cardiovascular death when the symptom of daytime sleepiness was added to snoring. The association was stronger in men younger than 60 years. As mentioned, it is likely that snoring provides only a nonspecific measure of OSA. These studies are likely to contain a variable contribution of patients with OSA, and it remains unknown if any specific aspect of snoring, such as profound negative intrathoracic pressures, may be involved in CAD development. Incident CAD data from the longitudinal analysis of the Sleep Heart Health Study has yet not been published. A smaller, retrospective sleep laboratory cohort study reported incident CAD in almost a quarter of untreated patients with OSA during a 7-year follow-up period.38 The corresponding numbers in treated sleep apnea patients and nonapneic snorers were 4% and 6%, respec-

tively. Moreover, more than 50% of a normotensive cohort not treated for OSA developed at least one cardiovascular disease during the 7-year follow-up (Fig. 121-1). New cases of patients with CAD were also found among those maintaining normotension.39 These findings suggest that development of CAD may be in part independent of diurnal systemic hypertension induced by OSA. A larger observational study of a sleep laboratory cohort, containing close to 1300 subjects with OSA, with a mean follow-up of 10 years, found a three to four times higher incidence of fatal and nonfatal cardiovascular events in patients with severe OSA compared with simple snorers.40 Multivariate analysis showed that the risk of fatal cardiovascular events was significantly increased in severe untreated patients with OSA (OR, 3.17; 95% CI, 1.12 to 7.51) compared with healthy controls. Similarly, the 18-year follow-up study of the population-based Wisconsin Sleep Cohort sample reported an adjusted hazard ratio of 5.2 (95% CI, 1.4 to 19.2) for cardiovascular mortality in severe (AHI > 30) patients with OSA and not using CPAP, versus those without OSA.41 Impact of Elimination of OSA on CAD Continuous positive airway pressure is the first-line treatment for reduction of daytime sleepiness and quality of life improvement in patients with OSA.42 A retrospective analysis of 55 patients with OSA and with concomitant CAD over an average follow-up time of 7.3 years showed a significantly lower occurrence of the composite endpoint of cardiovascular death, acute coronary syndrome, hospitalization for cardiac failure, or need for revascularization in those successfully treated with CPAP.43 In another followup study over 7.5 years, deaths from cardiovascular disease were reported to be less common in patients with OSA and treated with CPAP compared with those without treatment.44 Moreover, a review of 371 revascularized patients with OSA with concomitant CAD suggested a significantly lower cardiac death rate (3%) among 175 patients treated with CPAP, compared with 10% among 196 untreated patients during a follow-up period of 5 years.45 In the investigation of the sleep clinic cohort

1396  PART II / Section 14  •  Cardiovascular Disorders 60 Incompletely treated OSA (n = 37) Efficiently treated OSA (n = 15) Non-OSA (n = 123)

50

%

40 30 20 10 0 Cardiovascular disease

Hypertension

Coronary artery disease

Cardiovascular event

Figure 121-1  Incidence of cardiovascular disease during a 7-year follow-up in middle-aged men otherwise healthy at baseline. The fraction of individuals with incidence of cardiovascular disease, hypertension, coronary artery disease (CAD), and cardiovascular event (stroke, myocardial infarction [MI], or cardiovascular death) is shown. Depicted are data from patients without OSA (non-OSA) as well as from those incompletely or efficiently treated for their sleep and breathing disorder. (Reprinted from Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a seven-year follow-up. Am J Respir Crit Care 2002;166:159-165.)

(mentioned earlier),40 treatment with CPAP significantly reduced cardiovascular risk in patients with severe OSA. Plenty of evidence suggests that CPAP treatment reduces the number of ischemic events in patients with nocturnal angina and concomitant OSA in the short term.21 However, some patients with CAD and with OSA may not experience daytime sleepiness (i.e., they are asymptomatic), and less is known regarding the adherence to CPAP therapy in these patients. However, a study of a sleep clinic cohort with concomitant CAD suggested a comparable compliance between sleepy and nonsleepy patients.46 Randomized clinical outcome trials are needed in this area. An ongoing study47 investigating the combined rate of cardiovascular mortality, stroke, MI, and the need for a new revascularization over a 3-year period in revascularized patients with CAD and with concomitant OSA may add further insights.

PATHOGENESIS Obstructive sleep apnea is associated with considerable immediate hemodynamic change (see Chapter 119). During the cycle of the apneic event, there is increased work of breathing, considerable negative intrathoracic pressure, recurrent hypoxia and reoxygenation, and fluctuating autonomic activity (see Chapter 119). Heart rate and blood pressure also fluctuate considerably through the cycle, but the absolute contribution of each of these changes to development of cardiovascular disease is unknown. Increased oxygen demand and reduced oxygen supply (i.e., hypoxemia) after sleep-disordered breathing may trigger an attack of angina pectoris in patients with CAD, who already have reduced coronary flow reserve.21 Nocturnal oxygen desaturations have been related to the severity of coronary atherosclerosis in patients with CAD48 and may be an important contributor to coronary restenosis in patients with CAD who are treated with PCI.49 Another study reported signs of apnea-induced ischemia

predominantly during REM sleep,9 a finding that may be explained by the often more prolonged and severe apneic events that commonly occur in this sleep stage. OSA is also associated with long-term alteration of cardiac structure, hemodynamic reflex function, and vascular structure or function. The disorder leads to immediate and sustained sympathetic activation.50 Baroreceptor and chemoreceptor responsiveness is altered,51 and vascular reactivity in terms of responsiveness to hypoxemia or vasoconstrictors appears to be elevated.52 A series of studies demonstrated that vascular endothelial function, expressed in terms of nitric oxide vascular dilating capacity, appears to be reduced in OSA.53 Changes are specific to OSA in the sense that they are reversed by CPAP (see Chapter 119).54-57 The mechanisms responsible for endothelial cell damage and dysfunction are not entirely understood. However, investigations have shown that oxidative stress, potentially as a result of periodic hypoxia and reperfusion, is enhanced in patients with OSA.55 Oxidative stress results in compromised nitric oxide bioavailability and leads to an activation of redox-sensitive gene expression. Ensuing steps in this chain of events include increased expression of adhesion molecules by an activated endothelium and leukocytes, which finally leads to acceleration of vascular inflammatory cascades and a promotion of atherogenesis and vascular dysfunction. This hypothesis (see Chapter 117)58 is supported by data from patients with OSA demonstrating increased free radical production,55 increased plasma-lipid peroxidation, increased adenosine and uric acid levels,58 and increased levels of redox-sensitive gene expression products including vascular endothelial growth factor59 and inflammatory cytokines.60 Interestingly, there was an improvement of endothelial function in patients with OSA following inhibition of xanthine oxidase by allopurinol61 or supplemental vitamin C.62 Moreover, circulating levels of adhesion molecules63 as well as adhesion molecule–dependent monocyte-to-endothelial-cell avidity appear to be increased in



CHAPTER 121  •  Coronary Artery Disease and Obstructive Sleep Apnea  1397

OSA.64 Finally, sleep apnea appears to provide an additive stimulus for adhesion molecule expression in patients with CAD.65 Increased levels of circulating markers of inflammation including tumor necrosis factor (TNF)-α66 and C-reactive protein67 have been inconsistently found to be increased in OSA. It may be that determinants of these markers are, besides OSA, also influenced by multiple circumstances including comorbid risk factors for cardiovascular disease, lifestyle, environmental factors, and genetics. In fact, a study suggested an aggregation of premature CAD and related mortality in patients with OSA compared with controls.68 The tentative association between OSA and CAD is therefore supported by experimental data suggesting endothelial dysfunction, acceleration of vascular inflammation, and development of atherosclerotic disease as a result of the breathing disorder. Atherosclerotic plaque formation may jeopardize coronary flow reserve and generate symptoms of nocturnal angina during periods of increased flow demand. Such episodes occur repeatedly in sleep apnea, and they are associated with hypoxemia that further enhances the vulnerability for ischemia. On the other hand, the majority of heart attacks (i.e., acute MI, sudden cardiac death) stem from sudden rupture of less-obtrusive plaques, which triggers thrombus formation in coronary vessels.69 As earlier mentioned, it is suggested that sleepdisordered breathing influences the circadian acute coronary event distribution. OSA may lead to a disproportionate number of events that occur during or soon after the sleeping period. Although there is scientific support for a considerable impact of OSA on vascular structure and function, it is likely that development of CAD and other forms of vascular disease is determined by multiple genotypic and phenotypic factors. The absolute role of OSA in this concerted influence should evidently be better clarified. However, with the increasing recognition of OSA as an independent, additive, or even synergistic risk factor for CAD, we are facing a need for early identification of high-risk persons and a consensus on well-defined treatment strategies in such patients.

CLINICAL COURSE AND PREVENTION Early recognition and treatment of OSA may be beneficial in terms of CAD prevention. A retrospective analysis of a sleep laboratory cohort followed over 7 years found a reduction (relative risk, 0.29; CI, 0.10 to 0.82) of incident CAD in effectively treated OSA compared with ineffectively treated or untreated patients.38 On the other hand, in a group of patients with CAD followed for 5 years, mortality was higher in those with comorbid OSA (38%) than in those with no OSA (9%).25 Although the higher mortality was in part explained by the presence of other traditional risk factors, there was an independent influence by the breathing disorder. Another study followed 408 patients with stable angina and angiographically verified CAD during 5 years after sleep apnea recordings. The risk for a cerebrovascular event, including stroke and transient ischemic attack, was tripled in patients with CAD and concomitant OSA.26,28

Patients with CAD and nocturnal angina should be considered for sleep recording, because nasal CPAP reduces angina attacks and nocturnal myocardial ischemia.21 In the study of 10 severely disabled patients with a history of frequent nocturnal angina, 9 had sleep apnea.21 Treatment with CPAP reduced episodes of nocturnal ischemia. There is no evidence to suggest that medication used for treatment of CAD affects the severity of the breathing disorder. A double-blind crossover study of nitrates in patients with OSA with or without CAD found lower oxygen saturation during apnea-associated ischemic episodes than during ischemia not associated with apnea (77.3% versus 93.1%), and nitrate administration did not reduce the number of ischemic episodes associated with apnea.70 ❖  Clinical Pearls Recurrent apneas during sleep lead to a sequence of events that independently or in concert with other recognized risk factors are likely to have harmful effects on vascular structure and function. Not only may phenomena such as hypoxemia, reoxygenation, and recurrent vascular wall stress induce CAD but also the events themselves may aggravate already-existing compromised coronary artery flow reserve. The adverse health effects of OSA in terms of CAD development, progression, and proneness to complications are likely to depend on genotypic and phenotypic factors. Markers or predictors for identification of high-risk persons in this context are still lacking. Approximately a third of patients with CAD have OSA defined according to conventional criteria. A large fraction of these patients do not exhibit daytime sleepiness. Additional data on compliance with CPAP treatment, especially for nonsleepy patients with OSA and CAD, is needed. OSA identifies patients at risk for CAD and may represent a highly prevalent and modifiable risk factor. Recognition of the adverse impact of OSA on vascular disease will open a perspective of new primary and secondary prevention models for CAD that involve identifying and eliminating the sleep and breathing disorder.

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1398  PART II / Section 14  •  Cardiovascular Disorders 7. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19-25. 8. Maekawa M, Shiomi T, Usui K, et al. Prevalence of ischemic heart disease among patients with sleep apnea syndrome. Psychiatry Clin Neurosci 1998;52:219-220. 9. Koehler U, Dubler H, Glaremin T, et al. Nocturnal myocardial ischemia and cardiac arrhythmia in patients with sleep apnea with and without coronary heart disease. Klin Wochenschr 1991;69: 474-482. 10. Hanly P, Sasson Z, Zuberi N, et al. ST-segment depression during sleep in obstructive sleep apnea. Am J Card 1993;71:1341-1345. 11. Akasaka K, Akiba Y, Ishii Y, et al. Association between sleep apnea syndrome and coronary artery disease. Nippon Kyobu Shikkan Gakkai Zasshi 1997;35:16-21. 12. Bauer T, Ewig S, Schafer H, et al. Heart rate variability in patients with sleep-related breathing disorders. Cardiology 1996;87:492-496. 13. De Olazabel JR, Miller MJ, Cook WR, et al. Disordered breathing and hypoxia during sleep in coronary artery disease. Chest 1982;82:548-552. 13a.  Prinz C, Bitter T, Piper C, Horstkotte D, Faber L, Oldenburg O. Sleep apnea is common in patients with coronary artery disease. Wien Med Wochenschr 2010;160:349-355. 14. Hung J, Whitford EG, Parsons RW, et al. Association of sleep apnoea with myocardial infarction in men. Lancet 1990;336: 261-264. 15. Schafer H, Koehler U, Ewig S, et al. Obstructive sleep apnea as a risk marker in coronary artery disease. Cardiology 1999;92:79-84. 16. Peker Y, Kraiczi H, Hedner J, et al. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179-184. 17. Mooe T, Rabben T, Wiklund U, et al. Sleep-disordered breathing in men with coronary artery disease. Chest 1996;109:659-663. 18. Mooe T, Rabben T, Wiklund U, et al. Sleep-disordered breathing in women: occurrence and association with coronary artery disease. Am J Med 1996;101:251-256. 19. Yumino D, Tsurumi Y, Takagi A, et al. Impact of obstructive sleep apnea on clinical and angiographic outcomes following percutaneous coronary intervention in patients with acute coronary syndrome. Am J Cardiol 2007;99:26-30. 20. Mehra R, Principe-Rodriguez K, Kircher HL, et al. Sleep apnea in acute coronary syndrome: high prevalence but low impact on 6-month outcome. Sleep Med 2006;7:521-528. 21. Franklin KA, Nilsson JB, Sahlin C, et al. Sleep apnea and nocturnal angina. Lancet 1995;345:1085-1087. 22. Mooe T, Franklin KA, Wiklund U, et al. Sleep-disordered breathing in patients with coronary artery disease. Chest 2000;117:1597-1602. 23. Sorajja D, Gami AS, Somers VK, et al. Independent association between obstructive sleep apnea and subclinical coronary artery disease. Chest 2008;133:927-933. 24. Steiner S, Schueller PO, Hennersdorf MG, et al. Impact of obstructive sleep apnea on the occurrence of restenosis after elective percutaneous coronary intervention in ischemic heart disease. Respir Res 2008 June 3;9:50 (Epub ahead of print). 25. Peker Y, Hedner J, Kraiczi H, et al. Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med 2000;162:81-86. 26. Mooe T, Franklin KA, Holmström K, et al. Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001;164:1910-1913. 27. Hagenah GC, Gueven E, Andreas S. Influence of obstructive sleep apnea in coronary artery disease: a 10-year follow-up. Respir Med 2006;100:180-182. 28. Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients with coronary artery disease and sleep apnea: a 10-year follow-up. Circulation 2008;118:955-960. 29. Andreas S, Schulz R, Werner GS, et al. Prevalence of obstructive sleep apnoea in patients with coronary artery disease. Coron Artery Dis 1996;7:541-545. 30. Moruzzi P, Sarzi-Braga S, Rossi M, et al. Sleep apnoea in ischaemic heart disease: differences between acute and chronic coronary syndromes. Heart 1999;82:343-347. 31. Sanner BM, Konermann M, Doberauer C, et al. Sleep-disordered breathing in patients referred for angina evaluation-association with left ventricular dysfunction. Clin Cardiol 2001;24:146-150.

32. Takama N, Kurabayashi M. Possibility of close relationship between sleep disorder breathing and acute coronary syndrome. J Cardiol 2007;49:171-177. 33. Zaninelli A, Fariello R, Boni E, et al. Snoring and risk of cardiovascular disease. Int J Cardiol 1991;32:347-352. 34. Jennum P, Hein HO, Suadicani P, et al. Risk of ischemic heart disease in self-reported snorers. A prospective study of 2,937 men aged 54 to 74 years: the Copenhagen male study. Chest 1995;108: 138-142. 35. Zamarron C, Gude F, Otero Otero Y, et al. Snoring and myocardial infarction: a 4-year follow-up study. Respir Med 1999;93:108-112. 36. Janszky I, Ljung R, Rohani M, et al. Heavy snoring is a risk factor for case fatality and poor short-term prognosis after a first acute myocardial infarction. Sleep 2008;31:801-807. 37. Lindberg E, Janson C, Svärdsudd K, et al. Increased mortality among sleepy snorers: a prospective population based study. Thorax 1998;53:631-637. 38. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006; 28:596-602.28. 39. Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a seven-year follow-up. Am J Respir Crit Care 2002;166:159-165. 40. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcome in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-1053. 41. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-1078. 42. Basner RC. Continuous positive airway pressure for obstructive sleep apnea. N Engl J Med 2007;356:1751-1758. 43. Milleron O, Pilliére R, Foucher A, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J 2004;25:728-734. 44. Doherty LS, Kiely JL, Swan V, et al. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127:2076-2084. 45. Cassar A, Morgenthaler TI, Lennon RJ, et al. Treatment of obstructive sleep apnea is associated with decreased cardiac death after percutaneous coronary intervention. J Am Coll Cardiol 2007;50: 1310-1314. 46. Sampol G, Rodés G, Romero O, et al. Adherence to nCPAP in patients with coronary disease and sleep apnea without sleepiness. Respir Med 2007;101:461-466. 47. Peker Y, Glantz H, Thunstrom E, et al. Rationale and design of the Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnoea—RICCADSA trial. Scand Cardiovasc J 2009;43: 24-31. 48. Hayashi M, Fujimoto K, Urushibata K, et al. Nocturnal oxygen desaturation correlates with the severity of coronary atherosclerosis in coronary artery disease. Chest 2003;124:936-941. 49. Hayashi M, Fujimoto K, Urushibata K, et al. Nocturnal oxygen desaturation as a predictive risk factor for coronary restenosis after coronary intervention. Circ J 2005;69:1320-1326. 50. Hedner J, Ejnell H, Sellgren J, et al. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertension 1988;6(Suppl. 4):529-531. 51. Parati G, Di Rienzo M, Bonsignore MR, et al. Autonomic cardiac regulation in obstructive sleep apnea syndrome: evidence from spontaneous baroreflex analysis during sleep. J Hypertension 1997;15 (12 Pt. 2):1621-1626. 52. Kraiczi H, Hedner J, Peker Y, et al. Increased vasoconstrictor sensitivity in obstructive sleep apnea. J Appl Physiol 2000;89:493498. 53. Carlson JT, Rangemark C, Hedner JA. Attenuated endotheliumdependent vascular relaxation in patients with sleep apnoea. J Hypertension 1996;14:577-584 54. Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand 2003;177:385-390. 55. Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000;162:566-570.



CHAPTER 121  •  Coronary Artery Disease and Obstructive Sleep Apnea  1399

56. Noda A, Nakata S, Koike Y, et al. Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome. Hypertens Res 2007;30:669-676. 57. Ip MS, Tse HF, Lam B, et al. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:348-353. 58. Lavie L. Obstructive sleep apnoea syndrome-an oxidative stress disorder. Sleep Med Rev 2003;7:35-51. 59. Lavie L, Kraiczi H, Hefetz A, et al. Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med 2002; 165:1624-1628. 60. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129-1134. 61. El Solh AA, Saliba R, Bosinski T, et al. Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study. Eur Respir J 2006;27:997-1002. 62. Grebe M, Eisele HJ, Weissmann N, et al. Antioxidant vitamin C improves endothelial function in obstructive sleep apnea. Am J Respir Crit Care Med 2006;173:897-901.

63. Ohga E, Tomita T, Wada H, et al. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 2003; 94:179-184. 64. Dyugovskaya L, Lavie P, Lavie L. Phenotypic and functional characterization of blood γδ T cells in sleep apnea. Am J Respir Crit Care Med 2003;168:242-249. 65. El-Solh AA, Mador MJ, Sikka P, et al. Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest 2002;121:1541-1547. 66. Kataoka T, Enomoto F, Kim R, et al. The effect of surgical treatment of obstructive sleep apnea syndrome on the plasma TNF-alpha levels. Tohoku J Exp Med 2004;204:267-272. 67. Shamsuzzaman AS, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462-2464. 68. Gami AS, Rader S, Svatikova A, et al. Familial premature coronary artery disease mortality and obstructive sleep apnea. Chest 2007; 131:118-121. 69. Libby P. Atherosclerosis: the new view. Sci Am 2002;286:46-55. 70. Schafer H, Koehler U, Ploch T, et al. Sleep-related myocardial ischemia and sleep structure in patients with obstructive sleep apnea and coronary heart disease. Chest 1997;111:387-393.

Heart Failure Shahrokh Javaheri

Abstract Heart failure is a common disorder that has a significant economic impact and is associated with excess morbidity and mortality. Because of increased average life spans and improved therapy for hypertension and ischemic coronary artery disease, the incidence and prevalence of heart failure remain high. One factor that may contribute to the progressively declining course of heart failure is the occurrence of periodic breathing, with repetitive episodes of apnea, hypopnea, and

Heart failure has been known for more than 2 centuries to be associated with abnormal breathing patterns, and John Cheyne and William Stokes have been credited for its description—hence the eponym Cheyne-Stokes breathing.1,2 However, 37 years earlier, John Hunter,3,4 a British physician, was the first to describe this breathing pattern, which is characterized by gradual crescendo– decrescendo changes in tidal volume, commonly with an intervening central apnea (Fig. 122-1).5-9 We therefore refer to this pattern as Hunter-Cheyne-Stokes breathing. Periodic breathing is a pattern of breathing characterized by cyclic fluctuations in the amplitude of tidal volume.10 It consists of recurring cycles of apnea or hypopnea, or both, followed by hyperpnea. The apneas and hypopneas may be obstructive (i.e., the result of upper airway occlusion) or central.10 Obstructive sleep apnea–hypopnea is the most common form of periodic breathing in persons without heart failure. However, in patients with heart failure, both obstructive and central periodic breathing occur, although central sleep apnea– hypopnea is predominant. Hunter-Cheyne-Stokes breathing (HCSB) is a form of periodic breathing with central sleep apnea that occurs in patients with systolic heart failure and has a long cycle time.11 The latter is an important feature of HCSB breathing and reflects the prolonged circulation time that is a pathologic feature of systolic heart failure. HCSB is a subjective description and is not readily quantifiable. For these reasons, the term central sleep apnea is preferable, and it also avoids misrepresentation, as credit for the discovery of breathing pattern has not been given to the original discoverer. Central sleep apnea observed in awake patients with heart failure has been considered a rare entity and potentially an indicator of a terminal prognosis. However, like obstructive apnea, central apnea occurs primarily during sleep, and polysomnographic studies have reported a high prevalence of this disorder in ambulatory patients with stable heart failure.8,9,12-14 1400

Chapter

122 hyperpnea. Episodes of apnea, hypopnea, and the following hyperpnea collectively cause hypoxemia and reoxygenation, hypercapnia and hypocapnia, changes in intrathoracic pressure, and sleep disruption and arousals. These pathophysiologic consequences of sleep-related breathing disorders have deleterious effects on the cardiovascular system, and they may be most pronounced in the setting of established heart failure and coronary artery disease. Diagnosis and treatment of sleep-related breathing disorders may therefore improve morbidity and mortality rates for patients with heart failure.

EPIDEMIOLOGY OF HEART FAILURE AND SLEEP-RELATED BREATHING DISORDERS Heart Failure Heart failure is approaching epidemic proportions and has become a major public health problem.15 It is estimated that it may contribute directly or indirectly to 266,400 deaths each year. The death rate increases progressively with advanced symptomatology, approaching 30% to 40% annually in patients with heart failure in New York Heart Association class IV. It is the largest single Medicare expenditure because it is the leading cause of hospitalization for patients older than age 65 years. Not surprisingly, therefore, the economic impact of heart failure is also huge, with an estimated cost of $29 billion in 2004 and $37 billion in 2009 (see Chapter 116, Table 116-1).15 Left ventricular myocardial failure is the most common cause of heart failure in adults, and it could be predominantly diastolic or manifested by combined systolic and diastolic dysfunction. The underlying pathology in diastolic heart failure is a stiff, noncompliant left ventricle with preserved systolic function. The principal hallmark of diastolic dysfunction, therefore, is an elevation in left ventricular end-diastolic pressure and consequently in pulmonary capillary pressure, resulting in pulmonary congestion, pulmonary edema, and shortness of breath (backward failure). In contrast, the hallmark of left ventricular systolic dysfunction is a depressed ejection fraction, which is commonly associated with an increase in left ventricular enddiastolic and systolic volumes. The symptoms, which result from both diminished cardiac output and the concomitant diastolic dysfunction, include fatigue, shortness of breath, and exercise intolerance. It is estimated that 1.5% to 2% of the U.S. population has heart failure.15 Heart failure is a disorder of elderly persons, and its prevalence increases to approximately 6% to 10% in those older than 65 years. Furthermore, it is estimated that 20 million people may have asymptomatic



CHAPTER 122  •  Heart Failure  1401

LEOG REOG C3A2 O1A2 Chin LEMG ECG *FLOW *CHEST *ABDO SAO2 STAGE

95 97 96 93 90 90 93 97 97 94 91 90 92 96 98 95 93 90 90 95 98 97 93 90 90 94 97 97 94 91 90 92 96 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 60"

120"

180"

240"

300

Figure 122-1  A 10-minute epoch of a patient with systolic heart failure and Hunter-Cheyne Stokes breathing. Note recurrent hypoxia/reoxygenation as a result of central sleep apnea. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)

Table 122-1  Prevalence of Sleep Apnea in Recent Studies of Systolic Heart Failure COUNTRY OF STUDY, YEAR (REF)

PATIENTS (N)

AHI ≥10/HR (%)

AHI ≥15/HR (%)

CSA (%)

OSA (%)

PATIENTS ON BETA-BLOCKERS (%)

United States, 2006 (16)

100

—

49

37

12

10

United States, 2008 (28)*

108

—

61

31

30

82

Canada, 2007 (23)

287

—

47

21

26

80

China, 2007 (25)

126

71

—

46

25

80

55

—

53

38

15

78

Germany, 2007 (27)*

700

52

33

19

85

85

Germany, 2007 (29)*

203

71

28

43

90

90

Germany, 2007 (26)*

102

54

37

17

80

80

United Kingdom, 2007 (24)

*In these studies, brain waves were not recorded. AHI, apnea–hypopnea index (the threshold used to define the presence of the disorder in each study); CSA, central sleep apnea; OSA, obstructive sleep apnea. From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.

cardiac dysfunction, and with time, these persons are likely to become symptomatic. Because of the increased average life span and improved therapy for ischemic coronary artery disease and hypertension, which are risk factors for heart failure, it is predicted that incidence and prevalence of heart failure will continue to rise in the 21st century. Sleep Apnea in Systolic Heart Failure The prevalence of sleep-related breathing disorders has been systematically studied in patients with systolic heart failure.5 Polysomnographic studies6-14,16-25 and studies using respiratory channels26-29 show a high prevalence of sleep apnea in this population. Most recent large studies of con-

secutive patients with systolic heart failure are depicted in Table 122-1. High prevalence rates have been reported in patients who have systolic heart failure and are awaiting transplantation,17 those with valve heart disease,18 and those with an implanted cardiac defibrillator.19,20 The most systematic prospective study of systolic heart failure16 involved 100 ambulatory male patients with stable, treated heart failure. Using an apnea-hypopnea index (AHI) of 15 events per hour or greater as the threshold, 49 patients (49% of all patients) had moderate to severe sleep apnea–hypopnea, with an average AHI of 44. In comparison, a population study of subjects without heart

1402  PART II / Section 14  •  Cardiovascular Disorders

failure30 showed that 9% of working men and women aged 30 to 60 years had an AHI of greater than 15. An AHI of 5 or greater has been used to define the presence of a significant number of disordered-breathing events in obstructive sleep apnea–hypopnea syndrome.23 Therefore, with a much higher prevalence of sleep apnea observed in patients with heart failure than in the general population, systolic heart failure should be the leading risk factor for sleep apnea in the general population. In our studies,9,16 about 10% of the patients were on beta-blockers; however, recent studies continue to show a high prevalence of sleep apnea, both central and obstructive, despite the use of beta-blockers. Table 122-1 shows the prevalences of central and obstructive sleep apnea in the largest recent studies.16,23-29 Combining the results of these recent series, which used an AHI of 15 per hour of sleep as the threshold, 52% of 1250 patients with systolic heart failure have moderate to severe sleep apnea, 31% have central sleep apnea (CSA), and 21% have obstructive sleep apnea (OSA) (Fig. 122-2). However, there has been considerable variation in the prevalence of these two forms of sleep apnea in patients with systolic heart failure (see Table 122-1) which depends on a number of issues. The major reasons are the criteria used to define hypopnea, the accuracy of classification of disordered-breathing events (obstructive versus central, particularly in regard to hypopneas), the criteria used to define predominant obstructive versus central sleep apnea, the number of obese patients with heart failure enrolled, the level of arterial Pco2, and the severity of left ventricular systolic dysfunction. Sleep Apnea in Isolated Diastolic Heart Failure Isolated left ventricular diastolic dysfunction (LVDD) with relative preservation of left ventricular systolic function is the most common form of heart failure in elderly patients. The pathophysiologic consequence of LVDD relates to a hypertrophied, noncompliant left ventricle shifting the pressure volume curve upward and to the left.

PREVALENCE OF SLEEP APNEA IN SHF (n = 1250) 60 50

%

40 30 20 10 0 AHI < 15

AHI ≥ 15

CSA

OSA

Figure 122-2  Prevalence of sleep apnea in systolic heart failure (SHF). The data presented combine a series of world sleep studies (see Table 122-1). AHI, apnea–hypopnea index; CSA, central sleep apnea; OSA, obstructive sleep apnea. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)

Therefore, for a given left ventricular (LV) volume, LV end-diastolic pressure increases, resulting in elevated left atrial and pulmonary capillary pressures, pulmonary congestion, and edema. Hemodynamic studies show that pulmonary capillary pressure increases during the course of obstructive apnea, indicating the development of LVDD (see Chapter 120). Chronic repetitive exposure to negative swings in intrathoracic pressure, cyclic nocturnal hypertension and hypoxemia, and diurnal systemic hypertension could eventually result in LV hypertrophy and LVDD and failure. Studies30-32 suggest that OSA is associated with an increase in LV mass and that OSA-related cardiac structural changes may resolve with continuous positive airway pressure (CPAP) treatment. In the largest study,32 consisting of 2058 Sleep Heart Health Study participants, LV mass was associated with both apnea–hypopnea and hypoxemia indices after adjustment for age, sex, ethnicity, body mass index, smoking, systolic blood pressure, antihypertensive medication use, diabetes mellitus, prevalent myocardial infarction, and alcohol consumption. Furthermore, studies31,33 suggest that treatment with CPAP results in reversal of diastolic dysfunction.33 This has been confirmed by a randomized placebo (sham CPAP)-controlled trial, showing that after 12 weeks on effective CPAP therapy, there was a significant increase in the early-to-atrial filling velocity (E/A) ratio and a significant decrease in isovolemic relaxation and mitral deceleration time. Overall, little is known about the prevalence of sleeprelated breathing disorders and their impact in patients with isolated diastolic heart failure.34,35 Yet both disorders are prevalent in the older population, and the major consequences of sleep-related breathing disorders such as sympathetic activation, nocturnal hypertension, and hypoxemia could impair LV diastolic function. It is, therefore, conceivable that sleep-related breathing disorders are a cause of diastolic dysfunction or contribute to its progression. Epidemiologic and therapeutic studies are needed to define the relationship of these two disorders, particularly in the older population, and the impact of treatment of sleep apnea on the natural history of isolated diastolic heart failure. Sex and Sleep-Related Breathing Disorders in Systolic Heart Failure In the general population, the prevalence of OSA is significantly higher in men than in women. This also holds true for CSA in systolic heart failure. Combining the results of several studies of patients with systolic heart failure,12-14,17,18 40% of the male patients and 18% of the female patients have CSA (Fig. 122-3). A similar trend was found for OSA. The results of population studies of subjects without heart failure (reviewed by Young and colleagues36) suggest that menopause may be a risk factor for OSA, and that the risk is probably reduced by hormone replacement therapy. In women with congestive heart failure and systolic dysfunction, the risk of CSA was six times higher in those aged 60 years or older than in those younger than 60 years.12 A similar difference was also reported for obstructive sleep apnea–hypopnea before and after age 60 years.12 Thus,



CHAPTER 122  •  Heart Failure  1403

P = .0001

40

% of each gender

35

P = .1

30 25

Male OSA: (169/496) CSA: (197/496) Female OSA: (25/96) CSA: (17/96)

20 15 10 5 0 OSA

CSA

Figure 122-3  Prevalence of obstructive sleep apnea (OSA) and central sleep apnea (CSA) in men and women with systolic heart failure. The prevalence of CSA is much lower in women than in men. A similar trend is found in OSA, though it is not statistically significant. (From Javaheri S. Sleep related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2004. pp. 471-487.)

female hormonal status plays a role in the development of sleep-disordered breathing in women with and without heart failure. Progesterone is a known respiratory stimulant, and its effects on the respiratory system may in part explain the lower prevalence of central and obstructive sleep apnea in menstruating women. Progesterone increases ventilation37 and the tone of the dilator muscles of the upper airway.38 Furthermore, premenopausal women have a significantly lower apneic threshold than men.39 This should decrease the probability of developing central apnea during sleep in female subjects (see Mechanisms of Central Sleep Apnea, later).

MECHANISMS OF SLEEP-RELATED BREATHING DISORDERS IN HEART FAILURE Mechanisms of Central Sleep Apnea The mechanisms of periodic breathing and central sleep apnea in heart failure are complex and multifactorial (see Chapter 100).5,40-42 In heart failure, alterations occur in various components of the negative feedback system controlling breathing that increase the likelihood of developing periodic breathing, during both sleep and wakefulness. In addition, there are specific sleep-related mechanisms that explain the genesis of CSA and the reason periodic breathing becomes so prevalent during sleep. Mathematical models of the negative feedback system predict that increased arterial circulation time (which delays the transfer of information regarding changes in Po2 and Pco2 from pulmonary capillary blood to the chemoreceptors), enhanced gain of the chemoreceptors, and

enhanced plant gain (e.g., decreased functional residual capacity) collectively increase the likelihood of periodic breathing.5,40-42 Delay in transfer of information plays a fundamental role in destabilization of a negative feedback system.11,43 It has the potential to convert a negative feedback system to a positive feedback system. In heart failure, arterial circulation time may be increased for a variety of reasons including dilation of cardiac chambers, increased pulmonary blood volume, and decreased cardiac output. However, patients with systolic heart failure invariably have increased circulation time. Therefore, although increased circulation time is necessary to develop periodic breathing, it does not explain why only some heart failure patients have periodic breathing. The second factor that increases the likelihood of occurrence of periodic breathing (and also central apnea during sleep) is the gain of the chemoreceptors.44 In persons with increased sensitivity to CO2 (or hypoxia), the chemoreceptors elicit a large ventilatory response whenever the Pco2 rises (or the Po2 decreases). The consequent intense hyperventilation, by driving the Pco2 below the apneic threshold, results in central apnea. As a result of central apnea, Pco2 rises (and Po2 falls) and the cycles of hyperventilation and hypoventilation (hypopnea) or central apnea are maintained.44 Differences in the gain of the chemoreceptors among patients with heart failure may in part explain why only some patients develop periodic breathing and central sleep apnea. The third factor that may contribute to the development of periodic breathing in heart failure is decreased functional residual capacity, which results in underdamping.5,40-42 This means that for a given change in ventilation (e.g., a pause in breathing), changes in the controlled variables—namely Po2 and Pco2—will be augmented. In turn, the augmented changes in Po2 and Pco2 result in a pronounced compensatory ventilatory response, and overcompensation tends to destabilize breathing. Patients with heart failure may have decreased functional residual capacity for a variety of reasons, including pleural effusion, cardiomegaly, and decreased compliance of the respiratory system. Functional residual capacity may decrease further in the supine position, facilitating development of periodic breathing in this position. The aforementioned mechanisms underlying periodic breathing are present during both sleep and wakefulness. However, in the supine position and during sleep, further changes, such as reduction in functional residual capacity, metabolic rate, and cardiac output, occur that will augment the likelihood of developing periodic breathing beyond that observed during wakefulness. Meanwhile, like obstructive apnea, central apnea usually occurs during sleep or when a subject is dozing. The genesis of CSA during sleep relates specifically to the removal of the nonchemical drive of wakefulness on breathing and to the unmasking of the apneic threshold—the level of Pco2 below which rhythmic breathing ceases.42,45 The difference between two Pco2 set points—the prevailing Pco2 minus the Pco2 at the apneic threshold, referred to as Pco2 reserve—is a critical factor for occurrence of CSA. The smaller this difference, the greater is the likelihood of occurrence of apnea (discussed later).

1404  PART II / Section 14  •  Cardiovascular Disorders

Normally, with the onset of sleep, ventilation decreases and Pco2 increases. As long as the prevailing Pco2 is above the apneic threshold, rhythmic breathing continues. However, in some patients with heart failure, the awake prevailing Pco2 does not significantly rise with onset of sleep.46,47 In addition, heart failure patients who develop central apnea have increased CO2 chemosensitivity below eupnea.46 Because of this and the proximity of the prevailing Pco2 to the apneic threshold, the likelihood of developing central apnea increases during sleep. The reason for the lack of the normally observed rise in Pco2 in some patients with heart failure is not clear. It could result from the lack of the normally observed sleepinduced decrease in ventilation. Conceivably, because of increased venous return in the supine position, and in the presence of a stiff left ventricle, pulmonary capillary pressure could rise. This results in an increase in respiratory rate and ventilation, preventing the normally observed rise in Pco2. Several studies48-50 have shown that patients with heart failure and low arterial Pco2 have a high probability of developing central apnea during sleep. Predictive value of a low steady-state arterial Pco2 ( or =50 years. BJU Int 2005;95: 346-349. 101. Nicholson AN, Stone BM. Antihistamines: impaired performance and the tendency to sleep. Eur J Clin Pharmacol 1986;30: 27-32. 102. Larsen JP, Tandberg E. Sleep disorders in patients with Parkinson’s disease: epidemiology and management. CNS Drugs 2001;15: 267-275. 103. Grimsley SR, Jann MW. Paroxetine, sertraline, and fluvoxamine: new selective serotonin reuptake inhibitors. Clin Pharm 1992;11: 930-957. 104. Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol Psychiatry 2005;58:510-514. 105. Wang D, Teichtahl H, Drummer O, Goodman C, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest 2005;128:1348-1356. 106. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336: 186-195. 107. Moraes Wdos S, Poyares DR, Guilleminault C, et al. The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study. Sleep 2006;29: 199-205. 108. Schredl M, Hornung O, Regen F, Albrecht N, et al. The effect of donepezil on sleep in elderly, healthy persons: a double-blind placebo-controlled study. Pharmacopsychiatry 2006;39:205-208. 109. Riemann D, Gann H, Dressing H, Muller WE, et al. Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep. Psychiatry Res 1994;51:253-267. 110. Grant BF. Prevalence and correlates of alcohol use and DSM-IV alcohol dependence in the United States: results of the National Longitudinal Alcohol Epidemiologic Survey. J Stud Alcohol 1997; 58:464-473. 111. Atkinson R. Substance abuse. In: Coffee C, Cummings J, editors. Textbook of geriatric neuropsychiatry. Washington DC: American Psychiatry Press; 2000. p. 367-400. 112. Brower KJ, Aldrich MS, Hall JM. Polysomnographic and subjective sleep predictors of alcoholic relapse. Alcohol Clin Exp Res 1998;22:1864-1871. 113. Aldrich MS, Shipley JE, Tandon R, Kroll PD, et al. Sleep-disordered breathing in alcoholics: association with age. Alcohol Clin Exp Res 1993;17:1179-1183. 114. Curless R, French JM, James OF, Wynne HA, et al. Is caffeine a factor in subjective insomnia of elderly people? Age Ageing 1993;22:41-45. 115. Brown SL, Salive ME, Pahor M, Foley DJ, et al. Occult caffeine as a source of sleep problems in an older population. J Am Geriatr Soc 1995;43:860-864. 116. LaCroix AZ, Lang J, Scherr P, Wallace RB, et al. Smoking and mortality among older men and women in three communities. N Engl J Med 1991;324:1619-1625. 117. Phillips BA, Danner FJ. Cigarette smoking and sleep disturbance. Arch Intern Med 1995;155:734-737. 118. McCurry SM, Logsdon RG, Teri L, Vitiello MV, et al. Sleep disturbances in caregivers of persons with dementia: contributing factors and treatment implications. Sleep Med Rev 2007;11: 143-153. 119. Happe S, Ludemann P, Berger K. The association between disease severity and sleep-related problems in patients with Parkinson’s disease. Neuropsychobiology 2002;46:90-96.

CHAPTER 133  •  Medical and Psychiatric Disorders  1535 120. Kochar J, Fredman L, Stone KL, Cauley JA, et al. Sleep problems in elderly women caregivers depend on the level of depressive symptoms: results of the Caregiver-Study of Osteoporotic Fractures. J Am Geriatr Soc 2007;55:2003-2009. 121. McKibbin CL, Ancoli-Israel S, Dimsdale J, Archulcta C, et al. Sleep in spousal caregivers of people with Alzheimer’s disease. Sleep 2005;28:1245-1250. 121a.  Mausbach BT, Ancoli-Israel S, von Kanal R, Patterson TL, et al. Sleep disturbance, norepinephrine, and d-dimer are all related in elderly caregivers of people with Alzheimer’s disease. Sleep 2006; 29:1347-1352. 122. Hope T, Keene J, Gedling K, Fairburn CG, et al. Predictors of institutionalization for people with dementia living at home with a carer. Int J Geriatr Psychiatry 1998;13:682-690. 123. Tranmer JE, Minard J, Fox LA, Rebelo L, et al. The sleep experience of medical and surgical patients. Clin Nurs Res 2003;12: 159-173. 124. Vinzio S, Ruellan A, Perrin AE, Schlienger JL, et al. Actigraphic assessment of the circadian rest–activity rhythm in elderly patients hospitalized in an acute care unit. Psychiatry Clin Neurosci 2003;57:53-58. 124a.  Lee CY, Low LP, Twinn S. Older men’s experiences of sleep in the hospital. J Clin Nurs 2007;16:336-343. 125. Friese RS. Sleep and recovery from critical illness and injury: a review of theory, current practice, and future directions. Crit Care Med 2008;36:697-705. 126. Hugel H, Ellershaw JE, Cook L, Skinner J, et al. The prevalence, key causes and management of insomnia in palliative care patients. J Pain Symptom Manage 2004;27:316-321. 127. Mystakidou K, Parpa E, Tsilika E, Pathiaki M, et al. The relationship of subjective sleep quality, pain, and quality of life in advanced cancer patients. Sleep 2007;30:737-742. 128. Hajjar RR. Sleep disturbance in palliative care. Clin Geriatr Med 2008;24:83-91, vii. 129. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S, et al. Incidence of and risk factors for falls and injurious falls among the communitydwelling elderly. Am J Epidemiol 1993;137:342-354. 130. Campbell AJ, Robertson MC, Gardner MM, Norton RN, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999;47:850-853. 131. Avidan AY, Fries BE, James ML, Szafara KL, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53:955-962. 132. Stone KL, Ancoli-Israel S, Blackwell T, Ensrud KE, et al. Actigraphy-measured sleep characteristics and risk of falls in older women. Arch Intern Med 2008;168:1768-1775. 133. Bergeron N, Dubois MJ, Dumont M, Dial S, et al. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med 2001;27:859-864. 134. Marquis F, Ouimet S, Riker R, Cossette M, et al. Individual delirium symptoms: do they matter? Crit Care Med 2007;35: 2533-2537. 135. Meagher DJ, Moran M, Raju B, Gibbons D, et al. Phenomenology of delirium. Assessment of 100 adult cases using standardised measures. Br J Psychiatry 2007;190:135-141. 136. Jacobson SA, Dwyer PC, Machan JT, Carskadon MA, et al. Quantitative analysis of rest–activity patterns in elderly postoperative patients with delirium: support for a theory of pathologic wakefulness. J Clin Sleep Med 2008;4:137-142.

Obstructive Sleep Apnea in the Elderly Barbara A. Phillips

Abstract The prevalence of obstructive sleep apnea increases with age, but the peak prevalence of clinically diagnosed obstructive sleep apnea–hypopnea (OSAH) syndrome is in middle age. Differences in the clinical presentation and manifestations of

More than half of older adults report sleeping difficulty.1-5 Because sleep complaints are so prevalent in older people, clinicians sometimes discount them. However, sleep complaints in the geriatric population correlate with health complaints, depression, and mortality.1-6 This is likely because some sleep symptoms in the elderly result from sleep-disordered breathing, which is both clinically important and treatable. Sleep disorders are thus important in geriatrics.6a-6c Although studies of clinical populations identify peak prevalence of clinically significant sleep-disordered breathing in middle age, population-based studies have shown that sleep-disordered breathing increases with age.7,8 This observation is of particular interest given known decreases in obesity with increasing age.9 One disorder leading both to sleep disturbance and to increased mortality is sleep apnea. Longitudinal and cross-sectional studies have also shown that the prevalence of sleep apnea increases with increasing age.10-14 This chapter focuses on obstructive sleep apnea (OSA) in the older patient. For discussion of central sleep apnea, see Chapters 100, 113, 116, and 122.

EPIDEMIOLOGY AND DEFINITIONS Estimates of the prevalence of OSA in older people depend on how it is defined. For example, there has been considerable variation in the definitions and measurements of respiratory events (such as apneas, hypopneas, and respiratory effort–related arousals [RERAs]) used to identify sleep-disordered breathing. Further, which respiratory events to count toward the threshold used to define sleep apnea has also varied. The apnea–hypopnea index (AHI) typically includes only apneas and hypopneas, but the respiratory disturbance index (RDI) may include other events, such as RERAs. The demarcation between normal and abnormal has also been somewhat fluid. In populationbased studies, about one third of those older than 65 years have AHIs of 5 or more events per hour of sleep,15,16 and about two thirds have RDIs of 10 or more events per hour.16,17 Although measures of sleep-disordered breathing events alone do not establish a diagnosis of OSA, the classically associated symptoms of the disorder (sleepiness, hypertension, cognitive dysfunction) increase in prevalence with aging. Thus, a majority of older persons who meet laboratory-defined criteria for OSA also have a finding that is commonly associated with the syndrome; for this reason, 1536

Chapter

134

obstructive sleep-disordered breathing between older and younger persons likely account for the gap in prevalence and established diagnosis. It is not clear that older adults with OSAH suffer the same consequences as do younger persons. Diagnosis and treatment of OSAH in older patients is similar to that of younger patients.

defining clear-cut criteria for sleep apnea in older persons is difficult. However, the Centers for Medicare and Medicaid Services (CMS), the primary provider of health care coverage for people older than 65 years in the United States, defines OSA as an AHI greater than 15, or an AHI greater than 5 in persons with hypertension, stroke, sleepiness, ischemic heart disease, or mood disorder.18

CLINICAL MANIFESTATIONS AND PRESENTATION Most studies of the clinical presentation and manifestations of OSA have focused on middle-aged subjects. In the older patient with OSA, cognitive impairment is more severe, and erectile dysfunction, cardiac arrhythmias, and heart failure are more common.18a-18d Thus it is becoming increasingly clear that the phenotype of OSA can be quite different between younger and older populations. Perhaps most striking is the change in sex as a risk factor for sleep-disordered breathing in aging. Prospective data from the Wisconsin Sleep Cohort have demonstrated male sex is no longer an important risk factor for OSA after the age of about 50 years,19 confirming work from other studies.8 At least part of the reason for this phenomenon is that the prevalence of OSA rises strikingly for women as they go through menopause, which occurs at about age 50 years.20-23 As a consequence, some investigators have reported a male-to-female ratio of 1 : 1 for older people.19 In addition to the loss of effect of male sex as a risk for OSA with aging, there is reduced importance of obesity as a risk factor. Beginning at about age 60 years, obesity is no longer a statistically significant risk factor for sleep-disordered breathing.19,21 Some data suggest that obesity is a more important risk factor for men than for women, but aging, perhaps specifically achieving menopause, is a more important risk factor for women than for men.19,21,22,24 However, in an 18-year follow-up of 427 communitydwelling elderly persons, Ancoli-Israel and colleagues found that the changes in RDI that occurred were associated only with changes in body mass index (BMI) and were independent of age.25 The authors pointed out that this finding underscores the importance of managing weight for older adults, particularly those with hypertension. Studies of obstructive sleep apnea–hypopnea (OSAH) syndrome in older persons have tended to report milder disease, with lower AHIs, and better-preserved oxygen saturation than that seen in younger adults.10,15,21



CHAPTER 134  •  Obstructive Sleep Apnea in the Elderly  1537

In a study of nearly 100 community-dwelling adults aged 62 to 91 years, Endeshaw found that almost one third (equally divided between men and women) had an AHI of 15 or more per hour of sleep and that the traditional risk factors such as snoring, BMI, and neck circumference were not significantly associated with OSAH in this group. Rather, those with an AHI of at least 15 were more likely to report not feeling well rested in the morning, to have higher Epworth sleepiness scores, and to have greater frequency of nocturia.26 This confirms earlier work from the Sleep Heart Health Study, which reported that witnessed apneas are much less often reported in older patients than in younger ones.14 In short, the classic presenting symptoms of OSA are uncommon in older persons, which might account in part for the reduced prevalence of clinical diagnosis of the disorder in this population. Table 134-1 presents an overview of some of the differences in sleep apnea’s presentation and consequences between older and younger patients.

Data specifically focusing on the consequences of OSAH in older persons is scant. Notably, although OSAH increases the risk of death in younger populations, it has not been associated with increased mortality in older groups.29,30 The reasons for this are unknown, but they might include a survivor effect, the generally reduced severity of sleep-disordered breathing in older people, competing causes of mortality, or some combination of these factors. Lavie speculates that the reduced effect of OSAH on mortality in older people is a result of ischemic preconditioning resulting from the nocturnal cycles of hypoxiareoxygenation and points out that in patients with sleep-disordered breathing, there is an association of ischemic preconditioning with increased levels of vascular endothelial growth factor and increased production of reactive oxygen species, heat shock proteins, adenosine, and tumor necrosis factor α (TNF-α).31 However, several manifestations of sleep-disordered breathing appear to be particularly significant in aging populations, including nocturia, cognitive dysfunction, and cardiac disease. OSAH is strongly associated with cardiovascular disease in middle-aged populations, but there is very little evidence about the relationship between sleepdisordered breathing and heart disease in the elderly. The best-proved association and evidence for benefit is with hypertension, and the data are largely derived from middle-aged populations.

PATHOPHYSIOLOGY The pathophysiology of OSA may be different in older persons than in younger persons. Chapter 101 outlines the pathophysiology of OSA in adults. With aging, loss of tissue elasticity can also contribute for airway collapse. For older women, declining levels of sex hormones appear to be partly responsible for increased collapsibility of the posterior oropharynx.27,28 CLINICAL CONSEQUENCES A majority of studies of the consequences of OSAH have been undertaken in clinical samples of middle-aged people.

Nocturia Nocturia is a particularly troublesome symptom of aging, and it appears to be related to the severity of sleepdisordered breathing. Because older persons with significant sleep-disordered breathing might not manifest classic

Table 134-1  Differences between Younger and Older Patients with Obstructive Sleep Apnea–Hypopnea RISK FACTORS

OLDER PATIENTS (>60 yr)

YOUNGER PATIENTS ( 5

30%-40%

9% for women, 24% for men

RDI > 10

62%

10%

Nocturia, impaired cognition, atrial fibrillation

Death, ischemic cardiac disease, hypertension, cerebrovascular disease, depression, metabolic consequences

CPAP pressure

May require lower CPAP pressures

May require higher CPAP pressures

Compliance

No difference in tolerance or adherence

No difference in tolerance or adherence

Demographics

Clinical Features

Prevalence

Consequences Morbidity and mortality

Treatment

AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure; RDI, respiratory disturbance index.

1538  PART II / Section 17  •  Sleep Medicine in the Elderly

symptoms of OSAH, the presence of nocturia in the older patient should heighten the clinical suspicion for OSAH. Indeed, nocturnal urination of more than three times per night had a positive and negative predictive values of 0.71 and 0.62 for severe OSA in one study.32 The postulated mechanism of nocturia in OSAH is that the negative intrathoracic pressures resulting from occluded breaths cause distention of the right atrium and ventricle. This right-sided cardiac distention results in release of atrial natriuretic peptide (ANP), which inhibits the secretion of antidiuretic hormone (ADH) and aldosterone and causes diuresis through its effect on glomerular filtration of sodium and water.33 Several studies have demonstrated improvement in nocturia with use of continuous positive airway pressure (CPAP).34-36 CPAP might improve nocturia by allowing the normal nocturnal rise in ADH, resulting in increased resorption of sodium and water from the collecting tubules and production of lower volumes of more-concentrated urine.37 In a retrospective review of 196 patients whose mean age was 49 years, predictors of nocturia included increasing age and diabetes mellitus. Although a complaint of nocturia was equally likely to occur in patients with and without OSAH, frequency of nocturia was significantly related to age, diabetes, and severity of sleep-disordered breathing in patients who had OSAH. Patients with OSAH and nocturia who were treated with CPAP experienced significant reductions in the frequency of nocturnal voiding.38 In a study of 21 women with a mean age of 65 years, the same group of investigators reported that OSAH is present in a majority of women with nocturia and that the presence of diluted nighttime urine in a patient with nocturia is a sensitive marker for OSA.39 Impaired Cognition Impaired cognition, including sleepiness, impaired vigilance, worsened executive function, and dementia, increase in prevalence with aging. Neuropsychological assessment of patients with OSAH demonstrates declines in cognition similar to that of aging. For example, patients with OSAH have sleepiness,40 impaired executive function,41 working memory,42 alertness,43 and attention.44 In general, the association between sleep-disordered breathing and impaired cognition has been best studied in middle-aged persons. Because of the association with aging itself on impaired cognition, the effects, if any, of OSAH on cognitive function in older people are of great importance.18a In a small study of persons older than 55 years who had OSA, Aloia and coworkers found that the degree of sleepdisordered breathing, especially oxygen desaturation, was associated with delayed verbal recall and constructional abilities. After 3 months, those who were compliant with CPAP had greater improvements in attention, psychomotor speed, executive functioning, and nonverbal delayed recall than those who were not compliant.45 Despite the logical notion that cognitive impairment associated with OSAH in older people might be more severe than in younger people because of cumulative effects of age and sleep-disordered breathing, Mathieu’s group were unable to demonstrate any group-by-age interaction for any neuropsychological variable. In a study of

matched older and younger patients with and without OSAH, they found that performance on most tasks deteriorated with advancing age in both controls and OSAH patients without evidence of a compounded effect.46 The mechanism by which sleep-disordered breathing impairs neurocognitive function remains incompletely understood. Some authors have suggested that sleep fragmentation is the primary culprit,47 and others maintain that hypoxemia is the primary cause. It is likely that different functions are affected by hypoxemia than by sleep deprivation, as suggested by Sateia: “Disturbances in general intellectual function and executive function show strongest correlations with measures of hypoxemia. Not unexpectedly, alterations in vigilance, alertness, and, to some extent, memory seem to correlate more with measures of sleep disruption.”48 Information about the effects CPAP treatment on cognition is rare, and data about CPAP’s effects on cognition in older persons is even rarer. In a small group of patients whose mean age was 56 years, CPAP resulted in normalization in attention, visuospatial learning, and motor performances after 15 days, but there was no further improvement after 4 months of treatment. CPAP did not improve performance on tests evaluating executive functions and constructional abilities.49 A meta-analysis of randomized, placebo-controlled, crossover studies of CPAP treatment involving 98 sleep apnea patients demonstrated mostly trends for better performance on CPAP than on placebo.50 In a group of middle-aged subjects with significant OSAH, Zimmerman demonstrated that memory normalized for the group that used CPAP at least 6 hours a night,51 but it did not improve in those who were not adherent to CPAP treatment. In a review of CPAP adherence and benefits for older patients, Weaver and Chasens noted that in general, older adults have increased alertness; improved neurobehavioral outcomes in cognition, memory, and executive function; and decreased sleep disruption.52 They also noted that older patients might require lower CPAP pressures than younger ones, and they tolerate CPAP well, with similar rates of adherence. Thus, although there are differences in the clinical presentation and impact of sleep apnea in the elderly, CPAP treatment is likely to be well tolerated and beneficial in symptomatic patients.53,54 A final concern about cognitive dysfunction and sleepdisordered breathing is that there are likely to be variations in susceptibility. Alchantis and colleagues have proposed that high intelligence can protect against cognitive decline caused by sleep-disordered breathing, perhaps due to increased cognitive reserve.55 One large study reported that severity of SDB was not associated with indices of sleep-related symptoms or sleeprelated quality of life in community-dwelling older women, suggesting that this group may be resistant to OSAH’s adverse effects on cognition.56 Given the facts that improvement in cognition likely depends on CPAP adherence, that there may be gender and intelligence influences on susceptibility to impaired cognition, and that most studies addressing this issue have not included geriatric OSAH patients and objectively measured adherence, firm conclusions about the reversibility



CHAPTER 134  •  Obstructive Sleep Apnea in the Elderly  1539

of cognitive deficits in older OSAH patients are impossible to draw at present. With regard specifically to Alzheimer’s disease, the prevalence of OSAH in patients with is higher than in nondemented seniors, and sleep-disordered breathing is believed to contribute to cognitive dysfunction in those with Alzheimer’s disease. A randomized, double-blind, placebo-controlled crossover trial of CPAP in patients with OSA and Alzheimer’s disease demonstrated a significant improvement in cognition following 3 weeks of CPAP.57 In addition to improving cognition, CPAP treatment can improve sleepiness in Alzheimer’s disease patients with OSAH.58

colleagues found that OSA was a risk factor for stroke, controlling for other important variables.71 Treatment did not affect the risk of either stroke or death in this study.

Cardiovascular Disease Sleep-disordered breathing is strongly linked to cardiovascular disease including hypertension, congestive heart failure, stroke, cardiac arrhythmias, ischemic events, and pulmonary artery hypertension.59 Very few studies of the relationship between OSAH and cardiovascular disease are prospective and control for confounding variables such as obesity. Even fewer have been conducted in older adults. However, hypertension, atrial fibrillation, and stroke are particularly relevant comorbidities of OSAH in older patients because of their prevalence and clinical importance in that population. The evidence that sleep-disordered breathing causes hypertension has been established by several studies, including prospective and CPAP sham-controlled trials.6067 In general, CPAP has modest effects on blood pressure in patients with OSAH, but it is most effective in those who have significant hypertension and are most adherent with its use.60,67 Atrial fibrillation is strongly both with aging and with OSA.59,68,68a The Sleep Heart Health Study investigators found that those with severe sleep-disordered breathing had double or quadruple the risk of complex cardiac arrhythmias that those with no sleep-disordered breathing had, controlling for multiple relevant confounders.68 In this study, atrial fibrillation was the arrhythmia most strongly associated with sleep-disordered breathing. Gami and coworkers reported that both obesity and nocturnal oxygen desaturation were independent predictors of incident atrial fibrillation, but only in subjects younger than 65 years.69 In a small, retrospective study of patients with atrial fibrillation, some of whom had treated sleep apnea and some of whom did not, the patients with untreated OSAH had a higher recurrence of atrial fibrillation after cardioversion than did the patients without sleep apnea.70 Treatment with CPAP in the sleep apnea patients was associated with lower recurrence of atrial fibrillation at 1 year of follow-up. This study is particularly relevant to older patients because the mean age of the study population was about 66 years. At present, however, sleep apnea cannot be definitively stated to be a cause of atrial fibrillation. Stroke The prevalence of stroke increases with age. In a 6-year follow-up study of more than a thousand patients whose mean age at enrollment was about 60 years, Yaggi and

Other Effects In middle-aged men, OSAH is associated with increased health care costs, which decrease following treatment.72 CPAP treatment is a cost-effective treatment for severe sleep apnea in middle-aged people.73 Among sleep apnea patients, expenditures for health care in older people are about twice as high as they are for middle-aged patients. After adjusting for age, BMI, and AHI, cardiovascular disease and use of psychoactive drugs were important determinants of health care costs for older sleep apnea patients in one study.74 OSA may mask anemia of aging.74a Sex likely influences the effects of sleep-disordered breathing in older people, just as it does for younger persons. For example, a significant relationship between SDB and hypertension, history of diabetes, and low HDL cholesterol has been reported in women older than 65 years, but these effects were not demonstrable in older men.75

TREATMENT Continuous Positive Airway Pressure As with younger adults, CPAP is the treatment of choice in the older patients. Because most studies of effects of CPAP have been done in clinical (e.g., middle-aged) populations, evidence of the benefits of CPAP for older persons is not robust. Complex sleep apnea appears to be more prevalent in older than in younger people. Complex sleep apnea is characterized as OSA in which central apneas and periodic breathing develop when CPAP is applied.76,77 This phenomenon appears to be more prevalent in older men with congestive heart failure, and its clinical significance is unclear. In many patients, these treatment-emergent central apneas simply resolve over time. In a convenience sample of a variety of sleep-disordered breathing syndromes resistant to CPAP, the mean age of 72 years was much higher than typically observed in clinical populations of sleep apnea patients. In that cohort, adaptive servoventilation (ASV) appeared to be effective and well tolerated in about half.78 Because complex or treatment-emergent central apnea appears to be more prevalent in older persons, formal, in-laboratory titrations may be more important for this group. Compliance with CPAP in older patients may be affected by factors such as cognitive impairment, medical and mood disturbances, nocturia, lack of a supportive partner, and impaired manual dexterity. However, older age per se does not affect adherence to CPAP treatment,52,79 and behavioral interventions can improve CPAP adherence in the elderly.80 The major predictors of CPAP nonadherence in older sleep apnea patients are nocturia, current cigarette smoking, lack of resolution of symptoms, and advanced age at the time of diagnosis.81 Older men with nocturia can find CPAP particularly confining, and they may be particularly likely to have

1540  PART II / Section 17  •  Sleep Medicine in the Elderly

difficulty with its use, although CPAP can actually improve nocturia.79 Patients with OSA who have dementia, even including Alzheimer’s disease, have been demonstrated to tolerate CPAP, although depressive symptoms appear to predict worsened adherence in demented seniors with sleep apnea.82 Oral Appliances Oral appliances are effective in treating snoring and mild to moderate OSA.83-86 Although they are not as effective as CPAP, these agents improve sleep-disordered breathing, sleepiness, nocturnal oxygen saturation, and blood pressure. There are two basic types of oral appliances: mandibular repositioners and tongue-retaining devices. Mandibular repositioners pull the mandible (and with it, the tongue) forward. Tongue-retaining devices adhere to the tongue by suction and pull it forward. Because these are not approved by the FDA for treating sleep apnea, they are used much less commonly in clinical practice. See Chapter 109 for a detailed discussion of the use of oral appliances. No studies address the use of these devices specifically in older persons. Common side effects of oral appliances include dry mouth, increased salivation, tooth soreness, and jaw muscle or jaw joint discomfort. Pain is occasionally severe enough that patients discontinue the use of the appliance.86 Bite changes, (e.g., the inability to close on the back teeth) combined with heavy contact of the front teeth upon removal of the appliance in the morning are also reported, but these changes generally resolve when the device is removed. Oral appliances can be made to fit over false teeth, although this is not optimum. The use of oral appliances in edentulous patients may be attempted with a tongueretaining device, but these devices are not FDA approved, and the efficacy of this approach is unknown. Surgery As with younger adults, surgery is not a particularly effective treatment for OSA in older patients, and it can carry an especially increased morbidity in the elderly.87 Pharmacologic Treatment Several medications have been applied to the treatment of SDB. In general, no drug is effective enough to recommend as first-line treatment. Antidepressants, nasal steroids, hormone replacement therapy (HRT), and modafinil have all been studied in younger patients. In the 1980s, protriptyline was demonstrated to show modest efficacy in treating apnea, probably because it reduces REM sleep, when apnea is worst.88 There is some early experimental work with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of sleep apnea, but results have not been promising in humans.89 SSRIs can suppress REM sleep, but not as much as the tricyclic antidepressants. Nasal steroids have been demonstrated to have modest efficacy in the treatment of sleep-disordered breathing.90 In the Sleep Heart Health Study, women who were on HRT were less likely to have sleep apnea, but overall lifestyle and health care are significant confounders in drawing

conclusions about the efficacy of HRT for OSA.91 Although estrogen is an option to consider, it would need to be discussed carefully with the patient because of recognized complications of HRT. Modafinil has been evaluated as an adjunct to CPAP in patients who remain sleepy while being treated with CPAP.92,93 This application is limited to those who are actually using and compliant with CPAP. Body Position The supine sleeping position predisposes to airway collapse and to reduced lung volume, and it has long been known to exacerbate OSA. Indeed, some patients have obstructive events exclusively when sleeping on their backs.94,95 Upper airway size decreases with increasing age in both men and women, and upper airway collapsibility while supine increases with aging.96 In my experience, position-related obstructive apnea is prevalent in older persons. Position therapy has not been well studied for any group of patients, but it shows promise as treatment for the older patient with mild disease.93,97

DRIVING AND THE OLDER PATIENT WITH OSAH Untreated OSAH is a well-established risk for crash in drivers (see Chapter 104) and might be expected to affect older drivers as well. In a review of conditions increasing crash risk in older drivers, Marshall found that several conditions were believed to be associated with increased risk of crash in older persons, including alcohol abuse and dependence, cardiovascular disease, cerebrovascular disease, depression, dementia, diabetes mellitus, epilepsy, use of certain medications, musculoskeletal disorders, schizophrenia, vision disorders, and, finally, OSA. He noted that these “conditions can serve as potential warnings for reduced fitness to drive, but many persons with these medical conditions would still be considered safe to continue driving.”98 SUMMARY Sleep-disordered breathing increases in prevalence with aging, but it can confer a lower risk of mortality. However, the morbidity and impact of SDB in the older patient is significant, and it clearly responds to treatment in adherent patients. Consideration and treatment of sleep apnea in the older population can improve health and quality of life.

❖  Clinical Pearl Older people with OSA present differently than their middle-aged counterparts, and thus their sleep apnea may be overlooked by clinicians. Female gender and obesity are less important risk factors in older people than they are in younger people. Symptoms of sleep apnea change with aging: Whereas the classic symptoms of OSA are witnessed apneas and sleepiness, older patients are more likely to present with nocturia and cognitive dysfunction.



REFERENCES 1. Foley DJ, Monjan AA, Brown SL, et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18: 425-432. 2. Rao V, Spiro JR, Samus QM, et al. Sleep disturbances in the elderly residing in assisted living: findings from the Maryland Assisted Living Study. Int J Geriatr Psychiatry 2005;20:956-966. 3. Voyer P, Verreault R, Mengue PN, et al. Prevalence of insomnia and its associated factors in elderly long-term care residents. Arch Gerontol Geriatr 2006;42:1-20. 4. Manabe K, Matsui T, Yamaya M, et al. Sleep patterns and mortality among elderly patients in a geriatric hospital. Gerontology 2000; 46:318-322. 5. Kripke DF, Garfinkel L, Wingard DL, et al. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 2002;59: 131-136. 6. Phillips BA, Mannino DM. Does insomnia kill? Sleep 2005;28: 965-971. 6a.  Bloom HG, Ahmed I, Alessi CA, et al. Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am GeriatrSoc 2009;57:761-789. 6b.  Bombois S, Derambure P, Pasquier F, Monaca C. Sleep disorders in aging and dementia. J Nutr Health Aging 2010;14:212-217. 6c.  Cherniack EP, Cherniack NS. Obstructive sleep apnea, metabolic syndrome, and age: will geriatricians be caught asleep on the job? Aging Clin Exp Res 2010;22:1-7. 7. Bliwise DL, Feldman DE, Bliwise NG, et al. Risk factors for sleep disordered breathing in heterogeneous geriatric populations. J Am Geriatric Soc 1987;35:132-141. 8. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239. 9. Phillips B, Cook Y, Schmitt F, et al. Sleep apnea: prevalence of risk factors in a general population. South Med J 1989;82:10901092. 10. Bliwise D, Carskadon M, Carey F, Dement W. Longitudinal development of sleep-related respiratory disturbance in adult humans. J Gerontol 1984;39:290-293. 11. Phoha RL, Dickel MJ, Mosko SS. Preliminary longitudinal assessment of sleep in the elderly. Sleep 1990 13:425-429. 12. Hoch CC, Reynolds CF, Monk TH, et al. Comparison of sleepdisordered breathing among healthy elderly in the seventh, eighth and ninth decades of life. Sleep 1990;13:502-511. 13. Bader GG, Turesson K, Wallin A. Sleep-related breathing and movement disorders in healthy elderly and demented subjects. Dementia 1996;7:279-287. 14. Young T, Shahar E, Nieto FJ, and the Sleep Heart Health Study Research Group. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Intern Med 2002;162:893-900. 15. Phillips BA, Berry DT, Schmitt FA, et al. Sleep-disordered breathing in the healthy elderly. Clinically significant? Chest 1992;101: 345-349. 16. Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep-disordered breathing in community-dwelling elderly. Sleep 1991;14:486495. 17. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230-1235. 18. Centers for Medicare and Medicaid Services. Decision memo for continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) (CAG-00093R2). Available at: https://www.cms. hhs.gov/mcd/viewdecisionmemo.asp?from2=viewdecisionmemo. asp&id=204&. Accessed December 12, 2009. 18a.  Ayalon L, Ancoli-Israel S, Drummond SP. Obstructive sleep apnea and age: a double insult to brain function? Am J Respir Crit Care Med 2010;182:413-419. 18b.  Andersen ML, Santos-Silva R, Bittencourt LR, Tufik S. Prevalence of erectile dysfunction complaints associated with sleep disturbances in Sao Paulo, Brazil: A population-based survey. Sleep Med 2010 Apr 26. [Epub ahead of print] 18c.  Pedrosa RP, Drager LF, Genta PR, et al. Obstructive sleep apnea is common and independently associated with atrial fibrillation in patients with hypertrophic cardiomyopathy. Chest 2010;137: 1078-1084.

CHAPTER 134  •  Obstructive Sleep Apnea in the Elderly  1541 18d.  Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352360. 19. Tishler PV, Larkin EK, Schluchter MD, et al. Incidence of sleepdisordered breathing in an urban adult population. JAMA 2003; 289:2230-2237. 20. Young T, Finn L, Austin D, et al. Menopausal status and sleep-disordered breathing in the Wisconsin sleep cohort study. Am J Respir Crit Care Med 2003;167:1181-1185. 21. Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163(3 Pt. 1):608-613. 22. Dancey DR, Hanly PJ, Soong C, et al. Impact of menopause on the prevalence and severity of sleep apnea. Chest 2001;120:151-155. 23. Resta O, Bonfitto P, Sabato R, et al. Prevalence of obstructive sleep apnoea in a sample of obese women: effect of menopause. Diabetes Nutr Metab 2004;17:296-303. 24. Kirkness JP, Schwartz AR, Schneider H, et al. Contribution of male sex, age, and obesity to mechanical instability of the upper airway during sleep. J Appl Physiol 2008;104:1618-1624. 25. Ancoli-Israel S, Gehrman P, Kripke DF, et al. Long-term follow-up of sleep disordered breathing in older adults. Sleep Med 2001;2: 511-516. 26. Endeshaw Y. Clinical characteristics of obstructive sleep apnea in community-dwelling older adults. J Am Geriatr Soc 2006;54: 1740-1744. 27. Popovic RM, White DP. Upper airway muscle activity in normal women: influence of hormonal status. J Appl Physiol 1998;84: 1055-1062. 28. Malhotra A, Huang Y, Fogel R, et al. Aging influences on pharyngeal anatomy and physiology: the predisposition to pharyngeal collapse. Am J Med 2006;119:72.e9-e14. 29. He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94:9-14. 30. Lavie P, Lavie L, Herer P. All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age. Eur Respir J 2005;25:514-520. 31. Lavie L, Lavie P. Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea. Med Hypotheses 2006;66:1069-1073. 32. Kaynak H, Kaynak D, Oztura I. Does frequency of nocturnal urination reflect the severity of sleep-disordered breathing? J Sleep Res 2004;13:173-176. 33. Umlauf M, Chasens E, Greevy R. et al. Obstructive sleep apnea, nocturia and polyuria in older adults. Sleep 2004;27:139144. 34. Kiely L, Murphy M, McNicholas WT. Subjective efficacy of nasal CPAP therapy in obstructive sleep apnoea syndrome: a prospective controlled study. Eur Respir J 1999;13:1086-1090. 35. Kramer NR, Bonitati AE, Millman RP. Enuresis and obstructive sleep apnea in adults. Chest 1998;114:634-637. 36. Guilleminault C, Lin C, Goncalves M, Ramos E. A prospective study of nocturia and the quality of life in elderly patients with obstructive sleep apnea or sleep onset insomnia. J Psychosomat Res 2004; 56:511-515. 37. Asplund R, Aberg H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern Med 1991;229:131-134. 38. Fitzgerald MP, Mulligan M, Parthasarathy S. Nocturic frequency is related to severity of obstructive sleep apnea, improves with continuous positive airways treatment. Am J Obstet Gynecol 2006;194: 1399-1403. 39. Lowenstein L, Kenton K, Brubaker L, et al. The relationship between obstructive sleep apnea, nocturia, and daytime overactive bladder syndrome in women. Am J Obstet Gynecol 2008;198:598; e1-e5. 40. Guilleminault C, Partinen M, Quera-Salva MA, et al. Determinants of daytime sleepiness in obstructive sleep apnea. Chest 1988;24: 32-37. 41. Naegele B, Thouvard V, Pepin JL, et al. Deficits of cognitive executive functions in patients with sleep apnea syndrome. Sleep 1995; 18:43-52. 42. Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Apply Physiol 2005;98:2226-2234.

1542  PART II / Section 17  •  Sleep Medicine in the Elderly 43. Mazza S, Pepin JL, Naegele B, et al. Most obstructive sleep apnea patients exhibit vigilance and attention deficits on an extended battery of tests. Eur Respir J 2005;25:75-80. 44. Verstraten E, Cluydts R. Executive control of attention in sleep apnea patients: theoretical concepts and methodological considerations. Sleep Med Rev 2004;8:257-267. 45. Aloia MS, Ilniczky N, Di Dio P, et al. Neuropsychological changes and treatment compliance in older adults with sleep apnea. J Psychosom Res 2003;54:71-76. 46. Mathieu A, Mazza S, Decary A, et al. Effects of obstructive sleep apnea on cognitive function: a comparison between younger and older OSAS patients. Sleep Med 2008;9:112-120. 47. Verstraeten E, Cluydts R, Pevernagie D, Hoffmann G. Executive function in sleep apnea: controlling for attentional capacity in assessing executive attention. Sleep 2004;27:685-693. 48. Sateia MJ. Neuropsychological impairment and quality of life in obstructive sleep apnea. Clin Chest Med 2003;24:249-259. 49. Ferini-Strambi L, Baietto C, Di Gioia MR, et al. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP). Brain Res Bull 2003;61:87-92. 50. Engleman HM, Kingshott RN, Martin SE, Douglas NJ. Cognitive function in the sleep apnea/hypopnea syndrome (SAHS). Sleep 2000;23(Suppl. 4):S102-S108. 51. Zimmerman ME, Arnedt JT, Stanchina M, et al. Normalization of memory performance and positive airway pressure adherence in memory-impaired patients with obstructive sleep apnea. Chest 2006;130:1772-1778. 52. Weaver TE, Chasens ER. Continuous positive airway pressure treatment for sleep apnea in older adults. Sleep Med Rev 2007; 11:99-111. 53. Launois SH, Pepin J, Levy P. Sleep apnea in the elderly: a specific entity? Sleep Med Rev 2007;11:87-97. 54. Ancoli-Israel S. Sleep apnea in older adults—is it real and should age be the determining factor in the treatment decision matrix? Sleep Med Rev 2007;11:83-85. 55. Alchanatis M, Zias N, Deligiorgis N, et al. Sleep apnea–related cognitive deficits and intelligence: an implication of cognitive reserve theory. J Sleep Res 2005;14:69-75. 56. Kezirian EJ, Harrison SL, Ancoli-Israel S, and the Study of Osteoporotic Fractures Research Group. Behavioral correlates of sleepdisordered breathing in older women. Sleep 2007;30:1181-1188. 57. Ancoli-Israel S, Palmer BW, Cooke JR, et al. Effect of treating sleep disordered breathing on cognitive functioning in patients with Alzheimer’s disease: a randomized controlled trial. J Am Geriatr Soc 2008;56:2076-2081. 58. Chong MS, Ayalon L, Marler M, et al. Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer’s disease with sleep disordered breathing. J Am Geriatr Soc 2006;54:777-781. 59. Somers VK, White DP, Amin R, and the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology; American Heart Association Stroke Council; American Heart Association Council on Cardiovascular Nursing; American College of Cardiology Foundation. Sleep apnea and cardiovascular disease: an American Heart Association/American College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118: 1080-1111. 60. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000;320: 479-482. 61. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829-1836. 62. Grote L, Ploch T, Heitmann J, et al. Sleep-related breathing disorder is an independent risk factor for systemic hypertension. Am J Respir Crit Care Med 1999;160:1875-1882. 63. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384.

64. Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea. A 7-year follow-up. Am J Respir Crit Care Med 2002;166: 159-165. 65. Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271-2277. 66. Chobanian AV, Bakris GL, Black HR and the National Heart Lung and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572. 67. Alajmi M, Mulgrew AT, Fox J, et al. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007;185:67-72. 68. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing. The Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910-916. 68a.  Mehra R, Stone KL, Varosy PD, et al. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009 Jun 22;169(12):1147-1155. 69. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49:565-571. 70. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;27: 2589-2594. 71. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353: 2034-2041. 72. Albarrak M, Banno K, Sabbagh AA, et al. Utilization of healthcare resources in obstructive sleep apnea syndrome: a 5-year follow-up study in men using CPAP. Sleep 2005;28:1306-1311. 73. Guest JF, Helter MT, Morga A, et al. Cost-effectiveness of using continuous positive airways pressure in the treatment of severe obstructive sleep apnoea/hypopnoea syndrome in the UK. Thorax 2008;63:860-865. 74. Tarasiuk A, Greenberg-Dottan S, et al. The effect of obstructive sleep apnea on morbidity and healthcare utilization of middle-aged and older adults. J Am Geriat Soc 2008;56:247-254. 74a.  Khan AM, Ashizawa S, Hlebowicz V, Appel DW. Anemia of aging and obstructive sleep apnea. Sleep Breath 2010 Feb 17. [Epub ahead of print] 75. Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001;154:50-59. 76. Pusalavidyasagar SS, Olson EJ, Gay PC, et al. Treatment of complex sleep apnea syndrome: a retrospective comparative review. Sleep Med 2006;7:474-479. 77. Morgenthaler TI, Kagramanov V, Hanak V, et al. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 2006;29: 1203-1209. 78. Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest 2007;132:1839-1846. 79. Pelletier-Fleury N, Rakotonanahary D, Fleury B. The age and other factors in the evaluation of compliance with nasal continuous positive airway pressure for obstructive sleep apnea syndrome. A Cox’s proportional hazard analysis. Sleep Med 2001;2:225-232. 80. Aloia MS, Di Dio L, Ilniczky N, et al. Improving compliance with nasal CPAP and vigilance in older adults with OAHS. Sleep Breath 2001;5:13-21 81. Russo-Magno P, O’Brien A, Panciera T, et al. Compliance with CPAP therapy in older men with obstructive sleep apnea. J Am Geriatr Soc 2001;49:1205-1211. 82. Ayalon L, Ancoli-Israel S, Stepnowsky C, et al. Adherence to continuous positive airway pressure treatment in patients with Alzheimer’s disease and obstructive sleep apnea. Am J Geriatr Psychiatry 2006;14:176-180. 83. Kushida CA, Morgenthaler TI, Littner MR, et al. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240-243.



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84. Giles T, Lasserson T, Smith B, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006:CD001106. 85. Ferguson KA, Cartwright R, Rogers R, Schmidt-Nowara W. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2005;29:244-262. 86. Pantin CC, Hillman DR, Tennant M. Dental side effects of an oral device to treat snoring and obstructive sleep apnea. Sleep 1999;22: 237-240 87. Jones TM, Earis JE, Calverley PM, et al. Snoring surgery: a retrospective review. Laryngoscope 2005;115:2010-2015. 88. Brownell LG, West P, Sweatman P, et al. Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med 1982;307:10371042. 89. Dumont GJ, de Visser SJ, Cohen AF, and the German Association for Applied Human Pharmacology. Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol 2005;59:495-510. 90. Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax 2004;59:50-55. 91. Shahar E, Redline S, Young T, et al. Hormone replacement therapy and sleep-disordered breathing. Am J Crit Care Med 2003;167: 1186-1192.

92. Schwartz JR, Hirshkowitz M, Erman MK, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study. Chest 2003;124:2192-2199. 93. Morgenthaler TI, Kapen S, Lee-Chiong T, and the Standards of Practice Committee, American Academy of Sleep Medicine. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep 2006;29:1031-1035. 94. Malhotra A, Trinder J, Fogel R, et al. Postural effects on pharyngeal protective reflex mechanisms. Sleep 2004;27:1105-1112. 95. Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5:144-153. 96. Martin SE, Mathur R, Marshall I, Douglas NJ. The effect of age, sex, obesity and posture on upper airway size. Eur Respir J 1997;10:2087-2090. 97. Skinner MA, Kingshott RN, Filsell S, Taylor DR. Efficacy of the “tennis ball technique” versus nCPAP in the management of position-dependent obstructive sleep apnoea syndrome. Respirology 2008;13:708-715. 98. Marshall SC. The role of reduced fitness to drive due to medical impairments in explaining crashes involving older drivers. Traffic Inj Prev 2008;9:291-298.

Insomnia in Older Adults Sonia Ancoli-Israel and Tamar Shochat

Abstract Insomnia is a complaint of difficulty initiating or maintaining sleep or of nonrestorative sleep resulting in significant daytime consequences. Chronic insomnia is prevalent in about 10% of the adult population; however, increasing age is a risk factor for the development of insomnia, especially in women. Although late-life insomnia is usually attributed to medical and psychiatric morbidity rather than to age-related changes per se, underlying age-related physiologic changes in sleep–

Insomnia is a complaint of difficulty initiating sleep, difficulty maintaining sleep, or experience of nonrestorative sleep occurring at least three times a week and lasting at least 1 month.1 Typically, insomnia may be a chronic condition lasting for several years. In the elderly population, a chronic insomnia complaint is common, and it is often related to medical or psychiatric comorbidity. Owing to the widespread notion that insomnia is an inevitable consequence of aging, it is often not recognized or properly treated. However, growing evidence suggests that insomnia is not only a symptom consequent to morbidity but also a potential contributor to subsequent morbidity.2 Thus, increasing the awareness of clinicians and older adults regarding the significance of identifying and managing insomnia is imperative for improving sleep and health in this population.

EPIDEMIOLOGY AND RISK FACTORS The prevalence rate of insomnia increases with age, and it has been shown to be higher in women.3 In a sample of more than 5000 adults from the Sleep Heart Health Study (SHHS), older age was significantly related to poor sleep in men, particularly reduction in slow-wave sleep and increased stages 1 and 2, whereas in women, older age was related to subjective sleep complaints.4 It has been suggested that when categorizing studies based on the definition of insomnia used, studies focusing on symptoms of insomnia have shown an increased prevalence with age, and studies focusing on global sleep dissatisfaction and on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) diagnosis for insomnia were not age dependant.5 This hypothesis is supported by a study of more than 13,500 participants aged 47 to 69 years, assessing the prevalence of three major insomnia complaints and their correlates.3 Twenty-two percent of the sample complained of difficulty falling asleep, 39% complained of difficulty staying asleep, and 35% complained of nonrestorative sleep. In a multivariate analysis, increasing age was significantly associated only with a complaint of difficulty staying asleep, whereas depression and heart disease were associated with all three complaints. Other factors related to the sleep complaints were medical illnesses, lower socioeconomic status and 1544

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wake regulation—circadian rhythms and sleep homeostasis— have been identified. Other factors associated with insomnia in the elderly include medications or other substances and primary sleep disorders. Key elements in appropriate evaluation and management include considering the type of insomnia complaint and assessing sleep patterns, including daytime napping, daytime consequences, and comorbidity. Behavioral treatment should be considered first, and when necessary, the newer hypnotic medications may be added.

education, and unhealthy behavior such as current or former alcohol use and cigarette smoking. Other studies have also examined insomnia in the elderly population. In a sample of more than 9000 participants aged 65 years and older from the National Institute of Aging’s Established Populations of Epidemiological Studies of the Elderly (EPESE), more than 50% reported at least one sleep complaint, and 35% to 40% reported disorders of initiating or maintaining sleep (or both) on a chronic basis.6 In a 3-year follow-up of this sample, an annual incidence rate of 5% was reported.7 Incidence rates were highest in those with chronic medical conditions such as heart disease, stroke, and diabetes. Remission occurred in nearly half of those with insomnia at baseline, and it was related to improvements in perceived health. Similarly, in a representative sample of general practice patients aged 65 years and older, the annual incidence rate for late-life insomnia was 3.1%.8 Significant and independent risk factors in this sample were depressed mood, poor physical health, and intermediate to low physical activity. Based on the National Sleep Foundation survey from 2003, depression, heart disease, bodily pain, and memory problems were the disorders most commonly associated with insomnia.9 In fact, in studies using rigorous exclusion criteria for comorbidities, prevalence of insomnia is very low in healthy older adults. These findings lend further support to the epidemiologic evidence demonstrating that the bulk of geriatric sleep complaints and disorders is not the result of age per se, but rather co-segregates with medical and psychiatric disorders and related health burdens and even gender.10,10a One problem with insomnia in the elderly is that it is often unrecognized by physicians. In a study of older adults in primary care practices in the midwest United States, 69% of patients endorsed at least one sleep problem, 40% endorsed at least two sleep problems, and 45% endorsed symptoms of insomnia, but these complaints were identified in the medical charts only 19% of the time.11 In this same study, the two questions that best identified those with poor sleep at risk for medical and psychiatric problems were “Do you feel excessively sleepy during the day?” and “Do you have difficulty falling asleep, staying asleep, or being able to sleep?” These two questions would be easy for physicians to integrate into their standard history.



CONSEQUENCES OF INSOMNIA The reason it is so important to identify insomnia in older adults is that poor sleep can result in serious consequences. Studies have assessed the health consequences of insomnia as well as the effect of insomnia on physical functioning and performance. In a study of several thousand older men, lighter and more fragmented sleep were associated with poorer performance, particularly in age-adjusted models. Shorter total sleep time, sleep efficiency below 80%, and more than 90 minutes of wake time were associated with lower grip strength, slower walking speed, inability to stand from a chair without assistance, and inability to complete a narrow walk course.12 Results of multiple surveys have shown that insomnia in adults can result in decreased cognitive performance, such as difficulty sustaining attention, slowed response time, and memory problems. In a controlled laboratory study comparing patients with insomnia and good sleepers, performance impairments such as decreased vigilance, working memory, and motor control, as well as mood disturbances, concentration difficulties, and fatigue were evident in the insomnia group.13 Changes in cognition are of particular concern in the elderly population, where cognitive decline depends on age and may be an early sign of dementia.14 In a 2-year prospective study assessing relationships between snoring, sleep duration, and sleep difficulties with cognitive functioning in elderly women, short sleep duration (≤5 hours) and insomnia complaints were related to lower scores on cognitive tests at baseline but not at 2-year follow-up.15 In a 3-year longitudinal study, chronic insomnia was found to be an independent risk factor for cognitive decline in older men but not in older women,16 suggesting that cognitive decline in insomnia might correlate with sex. Alternatively, daytime sleepiness may be the underlying factor for cognitive decline, rather than insomnia. In a longitudinal study, daytime sleepiness, but not insomnia, was related to incident dementia and cognitive decline in men.17 On the other hand, in the Study of Osteoporotic Fractures (SOF), cognitive decline in close to 3000 elderly women age 70 years and older was associated with poor sleep based on actigraphically measured sleep efficiency of 70% or less, long sleep latency, and increased wake after sleep onset.18 In a study of more than 1000 older men and women, cognitive impairment was associated with short sleep duration of less than 6 hours and daytime nap of longer than 1 hour.19 Additionally, studies on the consequences of insomnia have identified reduced measures of health-related quality of life (HR-QOL), increased psychological distress, lower medical status and increased utilization of health services.20-22 Further consequences are related to reduced professional performances, such as increased absenteeism, decreased work performance, increased risk for road accidents, poor self-esteem, and less job satisfaction.23 Several studies have found that poor sleep is associated with increased risk of falls, even after controlling for relevant factors including benzodiazepine use.24,25 In the SOF study, less than 5 hours of sleep per night and sleep efficiency of 70% or less were independent risk factors for

CHAPTER 135  •  Insomnia in Older Adults  1545

falls in elderly women, but use of benzodiazepines did not increase the risk.25 Insomnia also increases the risk of mortality. In a study of older adults followed for close to 5 years, those with initial sleep latencies of longer than 30 minutes or sleep efficiency less than 80% had close to twice the risk for mortality.26 Similar results were found in the SOF study of older women. After adjusting for clinical and demographic factors, subjects who slept less than 5 hours a night and who had a sleep efficiency less than 65% or who napped for more than 2 hours a day had an increased risk of mortality at follow-up.27 For these reasons, it is imperative for physicians to be able to recognize and treat insomnia in older adults.

ETIOLOGY Underlying factors involved in the development of late-life insomnia include age-related changes in homeostatic and circadian sleep–wake regulation, psychiatric and medical comorbidities, medications and other substances, and primary sleep disorders. Evidence for each of these factors is reviewed separately. Age-Related Changes in Sleep Regulation Developmental changes in sleep in the elderly are characterized by advanced sleep phase, including earlier bedtimes and earlier wake times, reduced sleep consolidation, and altered sleep architecture, indicating a transition to lighter sleep. To understand the basis for these changes, it is necessary to understand some of the basic mechanisms of human sleep regulation. Sleep regulation is based on an interaction between the homeostatic pressure for sleep and the output of the circadian pacemaker. Homeostatic sleep pressure reflects the increasing need for sleep that accumulates during the waking hours and dissipates during sleep, as marked by increased EEG slow waves at the beginning of the nocturnal sleep episode, which gradually decrease throughout the night. The endogenous circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus regulates the synchronous timing of several physiologic variables including hormone secretion, core body temperature, and sleep–wake states. Regulation of the timing of sleep and wake states is achieved by promoting a signal of increased wakefulness throughout the day and a signal of increased sleep consolidation throughout the night.28,29 In young adults, daytime wakefulness and nighttime sleep consolidation are high due to both of these bioregulatory mechanisms. However, both homeostatic and circadian mechanisms change with age. Advanced age has been associated with a marked reduction in slow-wave sleep (SWS) and an increase in lighter sleep. This reduction in SWS indicates weaker homeostatic sleep pressure in the elderly.30 Under entrained conditions, timing of the circadian rhythm of core body temperature and habitual wake times are advanced to an earlier hour in the elderly, and the amplitude of the circadian rhythm of core body temperature is decreased, indicating a reduced circadian signal promoting sleep in the early morning hours.31 The circadian signal for wakefulness is also reduced,32 as reflected

1546  PART II / Section 17  •  Sleep Medicine in the Elderly

in sleep episodes and reports of sleepiness in the early evening hours. In summary, reductions in both the homeostatic drive for sleep and in the strength of the circadian signal for sleep in the early morning hours and for wakefulness in the early evening hours have been implicated as underlying factors for reduced sleep consolidation, advanced sleep phase, and early-morning awakenings in the elderly. Medical and Psychiatric Comorbidities Many chronic medical conditions and illnesses are known to disrupt sleep. These include arthritis, angina pectoris, congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, end-stage renal disease, diabetes, asthma, stroke, gastroesophageal reflux disease, dementia and Alzheimer’s disease, Parkinson’s disease, cancer, and menopause. In a study of more than 1000 older adults aged 60 to 101 years, poor health was associated with short sleep duration, long sleep latency (longer than 80 minutes) and going to bed late and waking early.19 In a large survey of older adults, those with heart disease, lung disease, stroke, or depression were more likely to report difficulties with sleep. In addition, the more medical conditions subjects reported, the worse the sleep complaint and the more likely subjects were to rate their sleep as poor.9 In a group of older adults who are likely to have multiple medical or psychiatric conditions, poor sleep is a likely comorbid condition. In a study examining sleep and health in 1500 adults older than 60 years in 11 primary care offices, complaints of poor sleep and excessive daytime sleepiness were significantly associated with both poor physical and poor mental health–related quality of life.11 Other studies have also shown an association between poor mental health, especially depression and anxiety, and late-life insomnia.6,33 Insomnia has also been implicated as a risk factor for heart disease,34 although the mechanism mediating this relationship is yet to be determined. The authors hypothesized that insomnia may be part of a larger syndrome including poor health and depression, or it may be a marker of chronic stress and autonomic dysfunction. Collectively, the evidence indicates that insomnia may be a cause or a consequence of comorbidity. Thus, comorbid insomnia has been suggested as the more appropriate term.35 Such a distinction has important implications not only in determining causal relationships between insomnia and comorbidity but also for considering treatment strategies. Treatment and management should focus not only on comorbid illnesses but also on insomnia as a distinct entity. Medications and Substances Polypharmacy is a serious problem in older adults, and the use of multiple medications also contributes to insomnia. Prescription medications known to be related to insomnia include antidepressants, such as bupropion, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs) except for amitriptyline and venlafaxine.36 Other medications prescribed for medical conditions that are associated with insomnia include bronchodilators, beta-blockers, central nervous system (CNS) stimulants, gastrointestinal drugs, and cardiovascular drugs. Concomitant use of

several types of medication (polypharmacy) further increases the risk of sleep disturbances in this age group. Adjustment of the timing and dosing and the contraindications between medications in elderly persons can lead to improvements in their sleep.36 Moderate alcohol consumption in elderly persons has been related to sleep disturbances including insomnia and sleep-disordered breathing (SDB).37 Other substances known to be related to insomnia include caffeine and nicotine. Although the effects of these substances are yet to be investigated in the elderly population, it is unlikely that they would not also disrupt sleep in the elderly. Primary Sleep Disorders Insomnia is often related to a primary sleep disorder. Common primary sleep disorders in the elderly include SDB, periodic limb movements in sleep (PLMS), and restless leg syndrome (RLS). Relationships between insomnia and each of these disorders are discussed. In addition, the development of insomnia as a primary sleep disorder is discussed. Sleep-Disordered Breathing Sleep-disordered breathing is a respiratory dysfunction syndrome during sleep, characterized by partial (hypopnea) to complete (apnea) airway collapse causing pauses in breathing that occur repeatedly during the night. These respiratory events reduce blood oxyhemoglobin saturation and terminate in partial arousals. Symptoms of SDB include excessive daytime sleepiness and heavy snoring. The prevalence of SDB is 4% to 9% in men and women,38 and the incidence increases considerably with age to as much as 45% to 62% in older adults.39 Other risk factors include obesity, male sex, and hypertension. Treatment of choice for SDB is positive airway pressure (PAP), a nasal mask attached via a hose that allows the continuous flow of positive air pressure through the nose, thereby eliminating respiratory events and associated outcomes. Insomnia and SDB often appear together in sleep clinic populations.40,41 Other variables associated with the insomnia complaint included female sex, psychiatric diagnosis, chronic pain, and restless legs symptoms. Collectively, these studies suggest that insomnia is highly prevalent in SDB and is associated with poor sleep and psychiatric distress; however, the underlying relationship between these two prevalent sleep disorders is currently unknown. Conversely, SDB may be veiled in older patients with insomnia who had initially been screened by clinical intake and did not have traditional signs and symptoms of SDB.42 In a sample of 80 adults with insomnia aged 59 years and older who had undergone rigorous screening for SDB, 29% had an apnea–hypopneas index (AHI) greater than 15, indicating significant SDB. These findings confirm that clinical interview alone might not suffice for identifying veiled SDB in the older adult population. Periodic Limb Movements in Sleep Periodic limb movements in sleep (PLMS) is a disorder characterized by involuntary leg jerks during sleep appearing in repetitive clustered episodes, often leading to brief awakenings from sleep. PLMS has traditionally been associated with insomnia or excessive daytime sleepiness. A



CHAPTER 135  •  Insomnia in Older Adults  1547

PLM index (the number of limb movements per hour of sleep) greater than 5, accompanied by arousals, indicates clinical diagnosis of PLMS. The prevalence of PLMS has been shown to increase with age. Prevalence rates reported in community-dwelling elderly persons for a PLM index greater than five events per hour range between 37% and 66%.43,44 A long-term follow-up study of an elderly sample showed no overall change in PLMS with increasing age.45 Despite its high prevalence, studies on the pathologic significance of PLMS in the elderly have yielded inconsistent results. In two studies on the prevalence and clinical significance of the PLMS in community-dwelling elderly persons, investigators found no relationship between PLMS severity and any measurement of sleep disturbance.46,47 However, in a large study of community-dwelling older women, PLMS accompanied by arousals was related to indicators of disturbed sleep that are associated with insomnia.44

comorbid conditions such as medical or psychiatric illness, medications being taken, poor sleep hygiene, and other sleep disorders. The assessment of insomnia does not necessitate overnight PSG monitoring; however, symptoms and signs of comorbid sleep disorders, especially sleep-disordered breathing, do warrant a PSG study. Based on AASM standard guidelines, actigraphy is indicated in insomnia patients, including the elderly and institutionalized elderly, for the assessment of circadian rhythms and sleep–wake patterns and their disturbances, as well as for monitoring treatment for insomnia and circadian rhythm disturbances.53 Actigraphy is considered a more reliable measurement tool compared to sleep logs (although sleep logs are often used to complement actigraphy) and is particularly useful in populations that might not tolerate PSG, such as the institutionalized elderly.54

Restless Legs Syndrome Restless legs syndrome is a neurologic disorder characterized by dysesthesia in the legs and an irresistible urge to move them in order to relieve the discomfort. Symptoms of RLS increase during the evening and at night, usually when the patient is in a relaxed or restful state, resulting in a sleep disturbance. PLMS is a common finding in 80% of RLS cases and is also implicated as a major cause of sleep disturbance in RLS patients. PLMS and related sleep disturbance can also occur without RLS symptoms.48 Pharmacologic treatment studies for PLMS and RLS have included adults older than 65 years; however, despite the marked prevalence of these disorders in the elderly population, no studies thus far have been dedicated exclusively to older adults. Treatment strategies for both conditions, PLMS and RLS, are similar, and they should be limited to symptomatic persons with comorbid insomnia or daytime sleepiness. In the United States, the only treatments approved by the Food and Drug Administration for the treatment of RLS are the dopamine agonists pramipexole and ropinorole. Other medications are often used off-label, such as levodopa with the dopa decarboxylase inhibitor carbidopa. However, in the elderly these medications can increase daytime sleepiness, and therefore monitoring and follow-up are recommended. Second-line, off-label treatments include sedative-hypnotics, anticonvulsants, opioids, and adrenergic medications.49

TREATMENT The effectiveness of pharmacologic and nonpharmacologic treatments has been demonstrated for late-life insomnia. The evidence for their efficacy as well as specific considerations for their use in the elderly are reviewed in here.

EVALUATION AND DIAGNOSIS Despite its widespread prevalence, insomnia is underrecognized and often inadequately treated in the health care system.11,50 Guidelines for evaluating insomnia in the adult population, based on the Standards of Practice Committee of the American Academy of Sleep Medicine (AASM),51 call for a thorough sleep history and determination of the specific sleep complaint: sleep-onset or sleep-maintenance insomnia. Useful information when taking a sleep history in the elderly includes questions on the timing of bedtime and wake time, number and length of nocturnal awakenings, use of hypnotic medication, daytime sleepiness, the timing and duration of daytime naps, and effects of insomnia on daytime functioning.52 It is essential to identify

Nonpharmacologic Nonpharmacologic treatments for insomnia include cognitive behavioral therapy, and bright-light treatments (Box 135-1). In an update of the AASM practice parameters for psychological and behavioral treatments of insomnia,55 stimulus control, relaxation training, and cognitive behavior therapy (CBT) were recommended treatments for chronic insomnia with a high level of evidence from clinical trials. Treatments reaching moderate levels of evidence for efficacy included sleep-restriction therapy, multicomponent therapy (without cognitive therapy), biofeedback, and paradoxical intention. These treatments have been found to be effective in older adults and in patients who chronically use hypnotics. There was insufficient evidence regarding the efficacy of sleep hygiene, imagery training, and cognitive therapy. Cognitive behavior therapy has proved successful for older adults with primary and comorbid insomnia and for those with dependency on hypnotics. For example, in a clinical ambulatory PSG trial with 6-week and 6-month follow-ups, CBT was compared with zopiclone and placebo in elderly patients with chronic insomnia. For the CBT group, wake time was significantly reduced, and sleep efficiency and SWS were significantly increased at both 6-week and 6-month follow-ups compared to the zopiclone and placebo groups.56 In a sample of patients aged 31 to 92 years who had insomnia and who chronically used hypnotic medication, CBT maintained efficacy at 3-, 6-, and 12-month follow-ups, including improved reported global sleep quality and reduced use of hypnotics.57 Importantly, these improvements were not age dependent, indicating that even older insomnia patients who are chronic hypnotic medication users can benefit from CBT. In another study on late-life insomnia, comparing the effects of CBT with a sedative-hypnotic medication (temazepam) and with both treatments combined (CBT

1548  PART II / Section 17  •  Sleep Medicine in the Elderly Box 135-1  Instructions for Nonpharmacologic Therapies for Late-Life Insomnia Stimulus Control The patient is instructed to go to bed only when sleepy. If sleep is not obtained in 20 minutes, the patient leaves the bedroom and returns to bed only when sleepy. This process is repeated as needed until sleep is obtained. Wake time is normal and naps are not allowed. Sleep Restriction Time in bed is restricted to self-estimated total sleep time. Sleep efficiency (ratio between time asleep and time in bed) is assessed weekly. Time in bed may gradually be increased following increases in sleep efficiency. No naps are allowed. Cognitive Behavioral Therapy Dysfunctional beliefs regarding the distinction between normal and abnormal sleep are identified, addressed, and redefined to induce positive changes in sleep-related cognitions and associated behavioral and emotional outcomes. Stimulus control and/or sleep restriction are initiated to deal with maladaptive behaviors. Sleep Hygiene Education Based on sleep history, ineffective habits and behavior related to poor sleep are targeted and clear guidelines for better sleep are provided, such as creating a stable sleep–wake schedule and a sleep-inducing bedroom environment, minimizing napping, avoiding sleep-inhibiting substances and activities at night, including caffeine, nicotine, and alcohol; heavy meals and high fluid intake; worrisome thoughts; and clock watching. Relaxation Training Various relaxation techniques are used, including meditation, muscle relaxation, and biofeedback for reducing somatic and cognitive arousal. Paradoxical Intention The patient is instructed to lie in bed and attempt to remain awake with eyes open for as long as possible. The bedroom should be dark and quiet, and the patient must not engage in other activities other than the continuous endeavor to remain awake. Bright Light Patients are exposed either to a bright-light box or to natural outdoor light in the evening hours.* *Indicated for advanced sleep phase and early morning awakenings.

and temazepam), good short-term efficacy was reported for all three treatments compared to placebo, with a small increased benefit for the combined treatment.58 However, at a 2-year follow-up, sustained long-term gains were achieved only in the CBT groups, especially in the CBTonly group, indicating that CBT alone is superior to combined therapy. Therefore, CBT provides a particularly promising alternative for this age group. In the 2005 NIH State-of-the-Science Conference on Insomnia, CBT was found to be as effective as prescription medications for brief treatment of chronic insomnia, with indications that

beneficial effects of CBT, in contrast to those produced by medications, may last well beyond termination of treatment.35 Evening bright light exposure has been indicated for the treatment of advanced circadian sleep phase syndrome (ASPS) and insomnia characterized by early-morning awakening, both which are common in elderly persons. In one study, 2 evenings of bright-light treatment significantly delayed circadian rhythms of core body temperature and melatonin, and based on actigraphy and sleep diaries collected for 1 month, they reduced night awakenings, increased total sleep time, and tended to delay morning wake times.59 The practical usefulness of bright light treatment in late-life insomnia, however, is still under study. Pharmacologic Hypnotic medication use is highest and most chronic in older adults.60 General guidelines for the use of sedative hypnotics in the elderly include selection of the appropriate drug (short acting versus long acting), considering the type of insomnia complaint (sleep-onset versus sleepmaintenance insomnia), starting with a low dose and increasing as needed, considering drug-drug interactions, and monitoring for adverse effects, particularly residual effects of daytime sleepiness and cognitive performance. It is important to keep in mind that the adverse consequences of sedative hypnotic use can outweigh the benefits, particularly in those with cognitive impairment. Commonly used hypnotic prescription medications for the treatment of insomnia include traditional benzo­ diazepine sedative hypnotics (temazepam, estazolam, flurazepam, quazepam, triazolam), newer selective nonbenzodiazepine sedative “Z drug” hypnotics (eszopiclone, zaleplon, zolpidem, and zolpidem MR), and the melatonin receptor agonist ramelteon. Sedating antidepressants (e.g., trazodone or doxepin), antipsychotics (e.g., quetiapine) and antihistamines (diphenhydramine) are also used off label, despite limited efficacy data. Self-treatments for insomnia include over-the-counter medications such as herbal or dietary supplements. In the 2005 State-of-the-Science conference on insomnia, the panel concluded that the risks of these off-label drugs outweigh the benefits, and therefore they did not recommend the use of antidepressants, antihistamines, or antipsychotics for the treatment of insomnia.35 The NIH also concluded that the new agents, particularly the Z drugs, are safer and more effective than the older benzodiazepines. All the selective nonbenzodiazepine hypnotics have been investigated in the older population. In a sample of 549 elderly insomnia patients, both zaleplon (5 or 10 mg per night) and zolpidem (5 mg per night) significantly improved sleep parameters.61 Rebound effects were observed following discontinuation for zolpidem but not for zaleplon. In a subsequent open-label trial with follow-up at 6 to 12 months, long-term use of 5 or 10 mg of nightly zaleplon was safe and effective, improved sleep measures were maintained, and there was no rebound insomnia upon discontinuation.62 The efficacy of two doses of eszopiclone (1 or 2  mg/ night) was evaluated in 231 elderly primary insomnia patients for 2 weeks.63 A dose of 1  mg was sufficient to significantly shorten sleep latency, and a dose of 2  mg significantly shortened sleep latency, increased total sleep



CHAPTER 135  •  Insomnia in Older Adults  1549

time, reduced wake after sleep onset, and improved sleep quality. Daytime improvements included decreased napping, alertness, and a sense of physical well-being. A 12-month study also showed safety and efficacy in the older adult.63a Ramelteon is a selective agonist for melatonin subtype 1 and 2 receptors. Assessment of the efficacy of ramelteon 8  mg per night with placebo over 5 weeks in 800 older adults with chronic insomnia has demonstrated significantly decreased sleep latency, with no withdrawal or rebound insomnia after discontinuation based on patient reports.64 These findings were supported by a PSG repeated-measures design with two treatment days for each treatment phase (8 mg and placebo) and an intervening washout period.65 PSG results demonstrated reduced latency to persistent sleep, increased total sleep time, and increased sleep efficiency for both doses compared to placebo. No residual effects were found for next day cognitive and psychomotor performance.65

SUMMARY Symptoms of insomnia are highly common in the elderly population and are largely underrecognized and undertreated. Increasing evidence of the significant consequences of insomnia warrants careful assessment and appropriate treatment strategies for this population. Proper treatment of insomnia in this age group is effective and can improve overall physical and mental health, well-being, and quality of life in the elderly patient. Further research is required in selected elderly subjects to understand the mechanisms underlying the development of insomnia and its related comorbidities and consequences and to determine how these processes can be effectively treated or prevented. ❖  Clinical Pearl Insomnia is very common in older adults, but is generally related to medical and psychiatric illness, medication, circadian rhythm changes, and other primary sleep disorders and not to aging per se. Clinicians should routinely screen for problems with sleep and initiate appropriate treatment.

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6. Foley DJ, Monjan AA, Brown SL, et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18:425-432. 7. Foley DJ, Monjan A, Simonsick EM, et al. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep 1999;22:S366-S372. 8. Morgan K, Clarke D. Risk factors for late-life insomnia in a representative general practice sample. Br J Gen Pract 1997;47: 166-169. 9. Foley DJ, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res 2004; 56:497-502. 10. Vitiello MV, Moe KE, Prinz PN. Sleep complaints cosegregate with illness in older adults: clinical research informed by and informing epidemiological studies of sleep. J Psychosom Res 2002;53: 555-559. 10a.  Jaussent I, Dauvilliers Y, Ancelin ML, et al. Insomnia symptoms in older adults: associated factors and gender differences. Am J Geriatr Psychiatry 2010 Jun 10. [Epub ahead of print] 11. Reid KJ, Martinovich Z, Finkel S, et al. Sleep: a marker of physical and mental health in the elderly. Am J Geriatr Psychiatry 2006; 14:860-866. 12. Dam TT, Ewing SK, Ancoli-Israel S, et al. Association between sleep and physical function in older men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2008;56:1665-1673. 13. Varkevisser M, Kerkhof GA. Chronic insomnia and performance in a 24-h constant routine study. J Sleep Res 2005;14:49-59. 14. Chen P, Ratcliff G, Belle SH, et al. Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001;58:853-858. 15. Tworoger SS, Lee S, Schernhammer ES, et al. The association of self-reported sleep duration, difficulty sleeping, and snoring with cognitive function in older women. Alzheimer Dis Assoc Disord 2006;20:41-48. 16. Cricco M, Simonsick EM, Foley DJ. The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc 2001;49: 1185-1189. 17. Foley D, Monjan A, Masaki K, et al. Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc 2001;49:1628-1632. 18. Blackwell T, Yaffe K, Ancoli-Israel S, et al. Poor sleep is associated with impaired cognitive function in older women: the Study of Osteoporotic Fractures. J Gerontol Med Sci 2006;61:405-410. 19. Ohayon MM, Vecchierini MF. Normative sleep data, cognitive function and daily living activities in older adults in the community. Sleep 2005;28:981-989. 20. Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II. Sleep 1999;22:S354-S358. 21. Hatoum HT, Kong SX, Kania CM, et al. Insomnia, health-related quality of life and healthcare resource consumption. A study of managed-care organisation enrollees. Pharmacoeconomics 1998;14: 629-637. 22. Leblanc M, Beaulieu-Bonneau S, Merette C, et al. Psychological and health-related quality of life factors associated with insomnia in a population-based sample. J Psychosom Res 2007;63:157-166. 23. Leger D, Massuel MA, Metlaine A. Professional correlates of insomnia. Sleep 2006;29:171-178. 24. Avidan AY, Fries BE, James MC, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53: 955-962. 25. Stone KL, Ancoli-Israel S, Blackwell T, et al. Poor sleep is associated with increased risk of falls in older women. Arch Intern Med 2008;168:1768-1775. 26. Dew MA, Hoch CC, Buysse DJ, et al. Healthy older adults’ sleep predicts all-cause mortality at 4 to 19 years of follow-up. Psychosom Med 2003;65:63-73. 27. Stone KL, Ewing SK, Ancoli-Israel S, et al. Self-reported sleep and nap habits and risk of mortality in a large cohort of older women. J Am Geriatr Soc 2009;57(4):604-611. 28. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526.

1550  PART II / Section 17  •  Sleep Medicine in the Elderly 29. Shochat T, Luboshitzky R, Lavie P. Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J Physiol 1997;273: R364-R370. 30. Dijk DJ, Duffy JF, Riel E, et al. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol (London) 1999;516: 611-627. 31. Duffy JF, Dijk DJ, Klerman EB, Czeisler CA. Later endogenous circadian temperature nadir relative to an earlier wake time in older people. Am J Physiol 1998;275:R1478-R1487. 32. Munch M, Knoblauch V, Blatter K, et al. Age-related attenuation of the evening circadian arousal signal in humans. Neurobiol Aging 2005;26:1307-1319. 33. Paudel M, Taylor B, Diem S, et al. Association between depressive symptoms and sleep disturbances among community-dwelling older men. J Am Geriatr Soc 2008;56:1228-1235. 34. Schwartz S, McDowell AW, Anderson W, et al. Insomnia and heart disease: a review of epidemiologic studies. J Psychosomatic Res 1999;47:313-333. 35. National Institutes of Health State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep 2005;28:1049-1057. 36. Ancoli-Israel S. Insomnia in the elderly: a review for the primary care practitioner. Sleep 2000;23:S23-S30. 37. Dufour MC, Archer L, Gordis E. Alcohol and the elderly. Clin Geriatr Med 1992;8:127-141. 38. Young T, Palta M, Dempsey J, et al. The occurrence of sleep disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230-1235. 39. Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep disordered breathing in community-dwelling elderly. Sleep 1991;14(6): 486-495. 40. Lavie P. Insomnia and sleep-disordered breathing. Sleep Med 2007;8(Suppl. 4):S21-S25. 41. Smith S, Sullivan K, Hopkins W, Douglas J. Frequency of insomnia report in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS). Sleep Med 2004;5:449-456. 42. Lichstein KL, Riedel BW, Lester KW, Aguillard RN. Occult sleep apnea in a recruited sample of older adults with insomnia. J Consult Clin Psychol 1999;67:405-410. 43. Ancoli-Israel S, Kripke DF, Klauber MR, et al. Periodic limb movements in sleep in community-dwelling elderly. Sleep 1991;14(6): 496-500. 44. Claman DM, Redline SS, Blackwell T, et al. Prevalence and correlates of periodic limb movements in older women. J Clin Sleep Med 2006;2:438-445. 45. Gehrman P, Stepnowsky C, Cohen-Zion M, et al. Long-term followup of periodic limb movements in sleep in older adults. Sleep 2002;25:340-346. 46. Dickel MJ, Mosko SS. Morbidity cut-offs for sleep apnea and periodic leg movements in predicting subjective complaints in seniors. Sleep 1990;13(2):155-166. 47. Youngstedt SD, Kripke DF, Klauber MR, et al. Periodic leg movements during sleep and sleep disturbances in elders. J Gerontol 1998;53:M391-M394. 48. Stiasny K, Oertel WH, Trenkwalder C. Clinical symptomatology and treatment of restless legs syndrome and periodic limb movement disorder. Sleep Med Rev 2002;6:253-265. 49. Hening WA, Allen RP, Earley CJ, et al. Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American

Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004;27:560-583. 50. Shochat T, Umphress J, Israel AG, Ancoli-Israel S. Insomnia in primary care patients. Sleep 1999;22:S359-S365. 51. Chesson AL Jr, Anderson WM, Littner M, et al. Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 1999;22:1128-1133. 52. Ancoli-Israel S, Cooke JR. Prevalence and co-morbidity of insomnia and impact on functioning in elderly populations. J Am Geriatr Soc 2005;53:S264-S271. 53. Morgenthaler T, Alessi C, Friedman L, et al. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep 2007;30:519-529. 54. Ancoli-Israel S, Cole R, Alessi CA, et al. The role of actigraphy in the study of sleep and circadian rhythms. Sleep 2003;26:342-392. 55. Morgenthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine report. Sleep 2006; 29:1415-1419. 56. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295:2851-2858. 57. Morgan K, Dixon S, Mathers N, et al. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use. Health Technol Assess 2004;8:iii-68. 58. Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late life insomnia. JAMA 1999;281:991-999. 59. Lack L, Wright H, Kemp K, Gibbon S. The treatment of earlymorning awakening insomnia with 2 evenings of bright light. Sleep 2005;28:616-623. 60. Glass J, Lanctot KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005;331:1169-1176. 61. Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M, Zaleplon Clinical Study Group. Zaleplon, a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999;1: 114-120. 62. Ancoli-Israel S, Richardson GS, Mangano R, et al. Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med 2005;6:107-113. 63. Scharf MB, Erman M, Rosenberg R, et al. A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep 2005;28:720-727. 63a.  Ancoli-Israel S, Krystal AD, McCall WV, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010;33:225-234. 64. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patientreported sleep latency in older adults with chronic insomnia. Sleep Med 2006;7:312-318. 65. Roth T, Seiden D, Wang-Weigand S, Zhang J. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007;23:1005-1014.

Sleep in Independently Living and Institutionalized Elderly Donald L. Bliwise Abstract Although not a mainstream source of patients in most sleep clinics, an ever-increasing proportion of the population residing in institutional settings necessitates that sleep medicine specialists be comfortable with and understand issues that affect sleep in those settings. Many patients residing in assisted living facilities or nursing homes meet criteria for dementia, and sleep-related syndromes such as sleep-disordered breathing, nocturnal incontinence, falls, agitation, and wandering are very common comorbidities in those patients. Medication to improve nocturnal sleep or to enhance daytime alertness should be considered, but it must be judiciously

This chapter is organized around common clinical problems commonly seen by the sleep medicine specialist who encounters geriatric patients, including those living independently, but especially those residing in assisted living and nursing homes. For many older persons, loss of cognitive capacities in late life overlay the multiple medical morbidities and syndromes (e.g., nocturia, incontinence, wandering, agitation) that constitute problems with sleep in this population. Treatment considerations must be made viewing the frailty of the patient, evaluating the riskto-benefit ratio, and, ultimately, the cost and feasibility of implementing treatment. Elucidation of central nervous system pathophysiology underlying disturbed sleep in specific dementing conditions is covered in greater detail elsewhere (see Chapter 91). This chapter focuses on issues related to interventions, including their efficacy and rationale.

SLEEP PROBLEMS IN DEMENTED NURSING HOME PATIENTS Clinicians encountering patients with sleep problems in institutional environments face innumerable challenges. Considerable heterogeneity exists in the range of dementing conditions that are present. Patients are most likely to carry a diagnosis of Alzheimer’s disease (AD), but dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), Parkinson’s disease with dementia (PDD), and vascular dementia (VasD) are likely to be present in sizeable proportions of the nursing home population as well (see Chapter 91 for a more-detailed description of these conditions). Many patients are placed in long-term care without the benefit of well-documented neurologic evaluations and neuroimaging, and chart notes are unlikely to contain sufficient detail to ascertain which specific diagnoses may be present in a given patient. With the possible exceptions of DLB (see Nocturnal Wandering, later) and VasD (see Sleep Apnea, later), the specific diagnosis of dementia subtype is unlikely to affect treatment decisions.

Chapter

136

implemented and carefully monitored. Sleep apnea interventions, such as nasal continuous positive airway pressure, can also be considered in some cases, especially in the presence of an engaged caregiver or spouse. Appropriate expectations should be fostered regarding the value of treating sleep apnea in late life. In certain cases, the sleep medicine specialist plays a critical role at the institutional level by educating staff about identifying specific sleep disorders (sleep apnea, restless legs syndrome), relevant sleep pharmacology, and principles of nonpharmacologic management, including optimizing the sleep environment. Treatment of sleep and sleep disorders in nursing home patients can benefit both patients and their caregivers and significantly affect quality of life.

THE NURSING HOME ENVIRONMENT AS A CHALLENGE TO SLEEP INTEGRITY A major challenge to the integrity of sleep–wake in the nursing home is the environment itself. The typical nursing home patient receives little or no high-intensity light to synchronize circadian rhythms, may be confined or put to bed for long periods, may be subject to little or no daytime stimulation, and may be subjected to noise and light disruptions at night. Transfer from noninstitutional to institutional settings is associated with longer time in bed, increased daytime napping, and earlier bedtimes, even within a period of several months,1 although there are huge differences between facilities in terms of how much time patients are placed in bed during the daytime hours.2 Lower ratios of staff to resident may be a relevant factor,3 but time in bed in the nursing home is a complex issue. Nursing home patients experiencing more pain may spend more time in bed but have poorer sleep.4 A study encompassing 53 nursing homes across the United States showed that facilities placing patients in bed during the daytime were reported to have residents who exhibited lower rates of agitated behavior when compared to facilities that that did not use daytime bedrest,5 which demonstrates the complexity of implementing good sleep hygiene in these environments. Apart from staffing issues, if nursing home personnel believe that their patients “need rest” for fatigue during the daytime hours6 and that such practices reduce disruptive behavior, it may be difficult to convince them otherwise. In the outpatient setting, daytime sleepiness in the dementia patient is seldom viewed as problematic by the caregiver.7 Institutionally based data have linked peak agitation to the time when nursing staff shift (typically 4 pm)8 and imply that staff change is disruptive for patient’s behavior. A broader perspective comes from a nursing home study that based ratings of negative and positive behavior based on observations made in the hours before and after sunset 1551

1552  PART II / Section 17  •  Sleep Medicine in the Elderly

and noted that frequencies of both kinds of behavior appeared to increase in the hours before sunset.9 Such more-generalized behavioral activation might represent a manifestation of the wake-maintenance zone in cognitively impaired patients. In the United States, many nursing facilities continue to interpret the Centers for Medicare and Medicaid Services (CMS) guidelines, established in the1987 Omnibus Budget and Reconciliation Act, as providing a mandate for nightly bedchecks and awakenings on a 2-hour basis for all nursing home patients at risk for developing pressure ulcers because of incontinence. The logic is that dementia patients, if not periodically awakened and repositioned and having their bedding changed, would more readily develop erythema and frank bedsores and be subject to their corresponding morbidity.10 However, 66% of incontinent bedridden patients demonstrated spontaneous mobility during the night, both at the shoulder and hip, at rates in excess of one turn per hour,11 thus potentially obviating the need to enforce awakenings in at least some patients. Not surprisingly, such staff-induced nocturnal awakenings have been shown to induce agitation in nursing home patients.1 More-profound levels of dementia, both within and outside of the nursing home setting, are associated with greater daytime sleepiness.12 This appears to be the case for assisted living facilities as well.13 Considerable descriptive evidence, relying upon behavioral observation14 and actigraphy15 in the institutional setting and relying on caregiver report16 in the home setting, suggest that daytime sleepiness and napping might have functional consequences for participation in social activities, occupational therapy, and even independence in selected activities of daily living. Lower amounts of REM sleep at night have been related to higher levels of observed sleep in nursing home patients.17 Actigraphic data also suggest that longer sleep durations per 24-hour period were associated with more-profound dementia in the nursing home,18 these data being compatible with loss of the wake-promoting function of the mammalian suprachiasmatic nucleus.19

TREATMENT Pharmacologic Sedative-Hypnotics Controversy exists over the use of medication for sleep in the nursing home. Injurious falls and hip fracture remain one of the most serious risks ascribed to such medications. Reluctance of many physicians to prescribe certain types or classes of medication was codified with the publication of the consensually derived Beers list of undesirable medications for older patients. The modified Beers list20 includes several older benzodiazepine sedative-hypnotics, consisting of all dosages of flurazepam and temazepam (doses >15 mg) and triazolam (doses >0.25 mg). Both short-half life and intermediate half-life benzodiazepines are discouraged in geriatric patients with a history of syncope or falls. Gamma-aminobutyric acid A (GABAA) selective agonists (zolpidem, zolpidem MR, zaleplon, eszopiclone) were not specified on the list. Diphenhydramine was included, and a study of acutely hospitalized geriatric patients demonstrated an exceptionally high risk for delirium with its

use.21 Anticholinergics have been known for years to cause delirium.22 A Finnish nursing home study suggested that as of 2003, the most commonly misused drug on the Beers list for nursing home patients was temazepam, used at doses greater than 15 mg.23 As of early 2009, there are no published randomized, placecbo-controlled clinical trials of the newer sedative-hypnotics (eszopiclone, ramelteon, sustained-release zolpidem) specifically studying demented, institutionalized patients. Some trials cited in this chapter have included zolpidem and zaleplon. A widely cited meta-analysis24 looked at 24 randomized clinical trials of sedative-hypnotics in elderly persons living independently, in various types of senior living facilities, and in nursing homes; five of the studies used zolpidem or zaleplon encompassing about 15,800 patient nights. The meta-analysis concluded that although sedative hypnotics as a group improved sleep time by an average of about 25 minutes, such medication increased the risks for altered cognition (odds ratio [OR], 4.78) and daytime fatigue or sleepiness (OR, 3.82). The effects on falls and psychomotor impairment (OR, 2.25; 95% confidence interval [CI], 0.93-5.41) did not reach significance; no falls were associated with zolpidem or zaleplon. Of the eight falls occurring across all these trials, none specified the time of day when the fall occurred. Apart from such meta-analyses, most knowledge of potential efficacy and adverse effects of sedative-hypnotics in demented nursing home populations derive from retrospective analyses of various administrative databases. Such data often represent relatively crude summaries of specific times when medications are ingested and when adverse events occur. They also cannot track when and for how long use of a sedative-hypnotic may be successful. For example, apparent lack of efficacy of sleep medications25 or even worse sleep26 with sedative-hypnotics in institutionalized patients have frequently been noted, though other databases suggest that hypnotics may be effective in many patients.27 Wang and colleagues28 examined 1-year risk of hip fracture in association with zolpidem in a retrospective casecontrol study of elderly community-dwelling patients undergoing surgical treatment for a hip fracture. Apparent zolpidem use was associated with nearly double the risk, but the specific ingestion of zolpidem related to the index event (hospital admission date) was inferred on the basis of adequate supply of zolpidem, not documented ingestion of a particular dose at specified time of day. The authors later argued further that residual confounding (i.e., patients most likely to be at risk for hip fracture were those most likely to ingest zolpidem) did not account for their findings,29 but they presented no data on time of drug intake or time of day of fall leading to hospital admission date to clarify their original finding. Although a substantial amount of epidemiologic literature beginning in the late 1980s has demonstrated that psychotropic medications generally (and sedative-hypnotic medications specifically) are associated with increased risk for falls and hip fracture, these observational studies, often derived from either community-dwelling30 or institutionalized31 populations, cannot be considered definitive for several reasons. First, not all population-based studies uniformly have reported such effects,32 implying that the



CHAPTER 136  •  Sleep in Independently Living and Institutionalized Elderly  1553

Table 136-1  Prediction of Incident Falls in State of Michigan Nursing Homes (N = 34,163) BASELINE INSOMNIA

OR

95% CL

Not using hypnotics

1.55

1.41-1.71

Using hypnotics

1.32

1.02-1.70

Using hypnotics (implied effective treatment)

1.11

0.94-1.31

CI, confidence interval; OR, odds ratio. Data from Avidan AY, Bries BE, James ML, Szafara KL, Wright GT, Chervin RD. Insomnia and hypnotic use, recorded in the Minimum Data Set as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53:955-962.

effects may be specific to population, medication, or database. Second, virtually every study fails to account for the time of day the fall or injury occurs. This is highly relevant because such information on timing and dose of medication in relation to when the fall occurred is essential to establish whether a plasma level could reasonably be assumed to be present. An exception to this is the study of Ray and coworkers33 who examined medication dose and half-life and time of day (daytime versus nighttime) as predictors of falls in 2500 Tennessee nursing home patients and showed that acute use of short elimination half-life medications (primarily temazepam, and much smaller numbers using oxazepam, zolpidem, and triazolam) were associated with falls only in the nighttime hours. Avidan and colleagues, using the Minimal Data Set (MDS), an administrative database of Medicare and Medicaid patients, examined successful and unsuccessful use of sedative-hypnotic medication in relation to falls in 34,000 Michigan nursing home patients.27 In these analyses, insomnia (derived from a single item on the MDS) and sedative-hypnotic use were examined as separate predictors of falls. Insomnia per se was associated with increased risk for falls regardless of medication use, and sedativehypnotic use without concurrent insomnia (implying efficacious treatment) was not associated with falls (Table 136-1). Although such use of the MDS has been severely criticized and could not be validated by reference to actigraphic measurements in a separate analysis of about 180 patients,34 the Michigan nursing home data provide a broader perspective for interpretation of administratively derived databases. In that regard, perhaps the most compelling reasons to suspect that falls data may be more parsimoniously interpreted as bedrise episodes associated with an inability to sleep through the night, come from studies of nocturia and incontinence. Both nocturia35 and urge incontinence have been associated with falls,36 though the latter studies also fail to specify the time of day when falls occurred. An Australian study of elderly women demonstrated that daytime sleepiness and urge incontinence independently contributed to the likelihood of falling,37 and in a United States population, daytime sleepiness38 and short nocturnal sleep duration39 were associated with falls. Although interventional studies at the level of health care systems are difficult to implement, a quasiexperimen-

tal study of hip fracture offered some perspective on the implementation of the New York State triplicate benzodiazepine prescription policy for elderly Medicaid enrollees by comparing hip fracture rates over a similar period for comparable Medicaid recipients in New Jersey.40 Although prescriptions showed a dramatic reduction in New York (unlike New Jersey), hip fracture rates showed few changes during that interval and were comparable between states, again raising the possibility that medications are not likely to be the primary cause of such events. Cholinesterase Inhibitors, Antipsychotics, and Stimulants It is well recognized that the most widely used class of medications for the cognitive impairments of AD, the cholinesterase inhibitors, have disrupted sleep as a side effect, which leads to higher than expected concurrent use of sedative-hypnotics.41 Many patients report increased frequency of unpleasant dreaming with this medication class, perhaps reflecting the stimulation of cholinergic systems controlling rapid eye movement (REM) sleep. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is also approved for moderate to severe cognitive loss in AD, but no studies have specifically reported on its effects on sleep. Some retrospective data analyses derived from the MDS suggest that despite disrupting sleep, cholinesterase inhibitors were associated with lower use of antipsychotics.42 Another study demonstrated that although antipsychotics were not specifically prescribed for sleep in nursing home patients, their withdrawal was associated with lower sleep efficiency as measured with actigraphy.43 Judicious use of antipsychotics in dementia is strongly advised, because this constitutes an off-label use of such drugs. Essentially, promotion of nocturnal sleep by these agents represents an opportunistic use of the side effect of sleepiness (at a rate approaching three times that of placebo as estimated by meta-analysis),44 otherwise cast as an adverse effect. When administered to elderly dementia patients, older-generation antipsychotics (haloperidol, thioridizine)45 and newer atypical antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole) increase risk for sudden death, and the FDA has issued a black-box warning for their use in such populations, the latter supported by meta-analysis of clinical trials46 and by a case-control study involving more than 13,000 matched patient pairs.47 Use of stimulant medication in dementia, targeting the daytime sleepiness and the apathy that characterizes dementia, has been the subject of several small-scale studies in nursing home patients48 and community-dwelling49 AD patients. Results suggested good tolerance and some improvement in apathy. A double-blind, placebo-controlled trial of methylphenidate for AD confirmed these improvements, though some adverse events (restlessness, agitation) were problematic,50 suggesting cautious use of this drug class. There are no published randomized trials with modafinil in institutionalized or noninstitutionalized AD patients, though a small case series in mixed-dementia patients suggested some benefit at 100 to 200 mg.51 Controlled trials in outpatients with PD at doses up to 400 mg have shown only mixed results in increasing daytime alertness.52

1554  PART II / Section 17  •  Sleep Medicine in the Elderly

Nonpharmacologic A large number of randomized clinical trials employing nondrug interventions to improve sleep in institutionalized patients have shown mixed success with such approaches. In contrast, multifaceted behavioral treatment programs involving engaged caregivers of dementia patients have shown better rates of success, extending out as long as 6 months subsequent to the intervention.53 The nursing home studies have employed parallel group designs involving hundreds of demented nursing home residents, have incorporated credible control treatments, and have employed a variety of measures attempting to assess sleep, using wrist actigraphy and systematic behavioral observations. Many studies have included secondary outcomes of importance such as mood, functional status, and nurses’ ratings of residents’ behavior. Sloane’s group54 employed relatively high intensity (2500 lux) lights embedded in existing fixtures in common rooms, such as dining areas, in two geriatric facilities for 3 weeks across four lighting conditions: customary, bright light in the morning (7 am to 11 am), bright light in the evening (4 pm to 8 pm), bright light all day (7 am to 8 pm). Sleep durations improved modestly (about 15 minutes) for morning and all-day exposures. The amplitude of wrist actigraphic rhythms did not change substantially, though some changes in phase were noted. Two other studies failed to find markedly beneficial effects of bright light in nursing home patients. Alessi and colleagues55 combined 5 consecutive days of morning outdoor light exposure (documented at >10,000 lux) with an intensive program to limit time in bed during the day, increase daytime physical activity, and reduce nursing home noise and light at night. Effects were dramatic reductions in daytime sleep but no significant change in hours of nighttime sleep or number of awakenings. Dowling and coworkers56 used a much longer treatment period (10 weeks of active treatment), but combined light treatment (1 hour morning exposure at 2500 lux) with 5 mg melatonin. As in the Alessi55 study, the most dramatic effects were seen in reducing daytime sleep, but nighttime sleep did not show differential improvement relative to control condition. Dowling’s group56 demonstrated marked improvements in the actigraphically measured rest–activity rhythm (e.g., amplitude, improved cosine goodness of fit), which the authors interpreted as compatible with functional improvements. The most ambitious attempt at improving sleep in demented nursing home patients was a 3.5-year trial comparing fixture-based light alone (1000 lux administered from 10 am to 6 pm), melatonin alone (2.5  mg mediumfast release), combined light and melatonin versus a dim light (300 lux), and a placebo-control condition.57 Although the study design was straightforward, the analyses were complicated to interpret because residents entered and left the study at various periods; only 7 of 189 residents completed the entire study. Many participants entered the protocol after the baseline period was completed, and only about 30% completed even the 6-month follow-up. Intent-to-treat analyses employing last observation carried forward, an approach of questionable utility in dementia

studies,58 were employed, but analyses were offered only for 3.5- and 1.5-year follow-ups. Given these constraints, the authors’ results were difficult to interpret. For example, light significantly improved sleep duration by 10 minutes and melatonin significantly improved sleep duration by 27 minutes, but the combined interventions did not produce a significant effect on sleep time. Other notable nonsleep outcomes were decreases in mood and greater behavioral withdrawal associated with melatonin and improved mood and cognition with light. The latter extrapolated to an improvement of less than 1 point over 3.5 years on the Mini Mental State Examination (MMSE). Taken together, these results did not suggest dramatic improvements. The melatonin results in particular are difficult to interpret given the large scale (n = 157) multisite National Institutes of Health study of AD outpatients,59 which demonstrated few beneficial effects on sleep of melatonin at a dose of 2.5  mg (sustained release) or 10  mg (immediaterelease) in an 8-week trial using actigraphic measurements. This trial had few drop outs (6%) and showed no change in Hamilton Depression Rating Scale score. Similar negative results were reported in a smaller randomized clinical trial using a single dose of combined 8.5  mg immediate release and 1.5  mg sustained-release melatonin administered for 10 days.60 Perhaps the most intriguing manipulation attempting to improve sleep was an individualized social activity intervention applied daily for 3 weeks in 147 demented nursing home patients.61 The intervention was tailored thoughtfully to the specific background and (often former occupational) interests of the residents and compared to usual nursing home care. Because of broadly defined entry criteria, many patients slept more than 7 hours at baseline (as recorded by actigraph). When analyses were limited to subjects with low baseline sleep efficiencies ( 30) in infirm, very old patients residing in nursing homes approximates 20%,77 and pulse oximetry screening indicates an oxygen desaturation index (ODI) of at least 4% more than 5 events per hour in greater than 40% of nursing home patients.78 Even the most casual observer of sleeping patients in a nursing home can grasp how common sleep apnea is in this population.79 The high prevalence undoubtedly reflects the myriad of risk factors that predispose elderly patients in general to high rates of SDB. These can be described generally as the operation of a relatively less stable respiratory control system that leads to interruptions in breathing and a subsequent tendency for upper airway collapse, perhaps accentuated by greater compliance of the upper airway and decreased lung volumes80 and less so the effect of adiposity or high body mass index (see Chapter 3). These somewhat distinctive potential contributing mechanisms are emphasized further by the associations of sleep apnea to measures of frailty,81 an important phenomenon in geriatric medicine, which predicts multiple morbidities82 as well as mortality.83 The observed association between sleep apnea and frailty probably reflects dysfunction of the respiratory pump and upper airway musculature. Whether sleep apnea in aged populations is associated with adverse outcomes has been a matter of considerable debate. Elsewhere in this volume (see Chapters 3 and 134)

1556  PART II / Section 17  •  Sleep Medicine in the Elderly

the case has been made that the strength of the associations seen in middle age may only be slightly diminished, if dampened at all, in old age. In addition to cardiovascular outcomes, such as hypertension84 and nondipping of blood pressure,85 some outcomes, such as nocturia,86 urge incontinence or overactive bladder,87 falls,88 poorer physical function,89 behavioral agitation,90 and stroke,91 may be particularly relevant for elderly persons residing in nursing homes. Incident stroke in relation to sleep apnea in a community population appeared more likely in older than younger persons.92 Untreated sleep apnea may be a risk for recurrent stroke,93 and treatment with continuous positive airway pressure (CPAP) can reduce the risk for recurrence.94 Specifically in nursing home populations, nocturnal incontinence may be associated, either biochemically or mechanically, with episodes of sleep apnea,95 and, at least in noninstitutionalized populations, reduction of nocturia episodes was associated with successful treatment of sleep apnea with CPAP.96 Treatment trials for sleep apnea in nursing home patients are nonexistent, and the condition remains grossly underdiagnosed and unrecognized in nursing facilities within the United States.97 If sleep apnea represents a risk for dementia in geriatric patients, it probably does so by virtue of its impact on cardiovascular and cerebrovascular function.98 Although many clinicians who work with dementia patients routinely consider sleep apnea as a cause of dementia99 and others go so far as to add sleep apnea to their rule-out list of causes of AD,100 the role of sleep apnea in late-life dementia is still unsettled. One consideration is that dementia, defined as the decline of multiple cognitive abilities, including memory, that interfere with social or occupational function,101 is a broad diagnosis that encompasses many different conditions (see Chapter 91), and it is conceivable that sleep apnea could be preferentially related to some specific forms of dementia rather than others. For example, some neuropsychological data have suggested that the pattern of cognitive deficits seen in severe obstructive sleep apnea fit better with the constellation of deficits seen in VasD, even more than AD,102 and the International Consensus Criteria for Vascular Dementia considers sleep apnea a recognized cause of dementia in late life.103 However, many patients with clinically diagnosed AD have a substantial number of microvascular lesions when their brains are examined neuropathologically,104 thus blurring the distinction between VasD and AD. Furthermore, analyses from major cohorts, such as the Atherosclerosis Risk in Communities105 study, have all suggested that midlife cardiovascular risk factors predispose to moresevere cognitive loss in late life, such as AD. These data represent long-term follow-ups from 6 to 30 years. If broadly defined cardiovascular disease is a harbinger not only for frank cerebrovascular disease (e.g., VasD, stroke) but also AD in later life, sleep apnea could easily be a mediator or moderator in those associations by virtue of its role in cardiovascular disease in midlife. Although no studies have systematically attempted to treat sleep apnea in demented nursing home patients, one systematic and otherwise heroic clinical trial in noninstitutionalized patients with mild to moderate AD (mean MMSE score, 24.5) provides invaluable guidance and experience on the potential value of initiating such treat-

ments in such cognitively impaired populations. AncoliIsrael and colleagues compared 3 to 6 weeks of CPAP use to placebo CPAP and found rates of adherence not lower than might be expected in noninstitutionalized populations,106 improvements in sleep architecture107 and selfreports of sleepiness,108 but negligible improvement in cognition.109 However, data pooled from the intervention group and the control group (crossed over with 3 weeks of active treatment) showed significant improvement in a composite neuropsychological test score and several individual tests (Trailmaking B, verbal learning), leaving open the possibility that treatment might be beneficial in this domain as well. The study was underpowered for a parallel groups design, and allowing for type I error given the number of psychometrics employed, the results certainly did not indicate dramatic clinical significance. The types of changes seen were no greater and may have even been less than what is typically seen with cholinesterase inhibitors, which themselves have been reported to have modest benefit in treating sleep apnea in Alzheimer’s disease.110 On the other hand, data from this important clinical trial should not be construed as diminishing the value of treating sleep apnea in a demented patient living in the community or in a nursing home. First, preliminary data on a follow-up of five patients using CPAP over an entire year suggested that rate of decline in some functions may be partially ameliorated over a longer exposure to CPAP.111 Additionally, in nondemented patients, numerous other clinical trials have demonstrated unequivocally that sleep apnea treatment is associated with substantial improvement in cognitive function,98 and in view of the brunt of epidemiologic evidence suggesting that vascular disease plays a role in stroke and VasD as well as in AD in late life,105 the modest findings in the cognitive domain require reframing. It may well be that treating sleep apnea in midlife, rather than late life, provides the greatest chance of affecting long-term cognitive function. The clinical trials of therapy with CPAP or oral appliances encompassing decades of treatment that would be required to detect such effects simply do not exist at this time. Weighing the currently available scientific evidence bearing upon whether sleep apnea might represent a causal risk for AD is complex. Together with the equivocal changes in cognition from the clinical trial just cited,106-109 several studies of small numbers of high-functioning, healthy elderly subjects (see reference 112 for a review) and broader population-based studies involving cognitive correlates of snoring,113 polysomnographically defined SDB,114 and brainstem115 and nonbrainstem116 MRI-measured white matter hyperintensities, these negative findings have all been interpreted by some as casting doubt on whether there is any risk conferred by SDB for more-severe forms of cognitive impairment, such as dementia.117 However, such a perspective ignores a diverse matrix of converging studies that provide repeated validation for the presence of an association and offer substantial and plausible evidence for its neuronal substrates. To summarize these findings: 1. In contrast to the aforementioned studies, other epidemiologic data in elderly subjects have shown that sleep apnea–type symptoms (e.g., daytime sleepiness, snoring) are associated with incident cognitive impairments.118



CHAPTER 136  •  Sleep in Independently Living and Institutionalized Elderly  1557

2. At least two other population-based studies of community-dwelling older persons—the Study of Osteoporotic Fractures (SOF) (in women) and the Osteoporotic Fractures in Men Sleep Study (MrOS)— has demonstrated an association between polysomnographically measured sleep apnea and cognitive impairment.119,120 3. Specifically within a nursing home population (heterogeneous for types of dementias, but probably including sizeable numbers of both AD and VasD patients),112 severity of physiologically measured SDB is modestly associated (r2 effect size of about .21) with severity of cognitive impairment.77 4. Studies comparing caregiver reports about sleep in well-characterized AD outpatients in relation to nondemented controls showed significantly greater endorsements of snoring, irregular breathing in sleep, and daytime napping in the AD patients, all suggesting sleep apnea.71 5. In fully ambulatory middle-aged populations, a broad array of cognitive skills, including executive abilities and memory (typical deficits of dementia patients) but also more subcortically mediated functions such as psychomotor and fine motor speed,98 have been related to sleep apnea, though the absolute level of impairments are not nearly as great as those seen in dementia.112 6. Numerous studies employing structural brain neuroimaging techniques, such as magnetic resonance imaging (MRI), have shown that sleep apnea is associated with lower hippocampal volumes (see reference 121 for review), a key region known to show marked atrophy in AD. Additional studies using even more sensitive diffusion tension imaging (DTI) have suggested reduced volumes in nearby structures such as the mammillary bodies,122 as well as widespread interruption of white matter fiber tracts involving cingulate cortex, corpus callosum, internal capsule, and selected cerebellar nuclei.123 7. Functional neuroimaging studies have suggested enhanced blood oxygen level–dependent (BOLD) activation on fMRI during verbal memory tasks involving activation of left frontal and temporal regions in sleep apnea patients relative to controls124 and absence of activation during working memory tasks in the dorsolateral prefrontal cortex relative to controls,125 an effect that did not resolve with 8 weeks of CPAP treatment. In an uncontrolled study of never-treated sleep apnea patients, increased BOLD activation during a serial addition task requiring working memory was particularly widespread and involved prefrontal cortex, thalamus, basal ganglia, cerebellum, and brainstem.126 These findings are all highly relevant because progressive memory impairment is one of the defining characteristic of dementias, especially AD. 8. Dementia as a concurrent diagnosis of sleep apnea within the limits of a closed health care system (Veterans Administration)127 occurs significantly above chance. 9. Animal models of intermittent hypoxia indicate larger behavioral deficits, hippocampus cell loss, and apoptosis in older, relative to younger, animals, thus suggest-

ing at least one plausible pathophysiologic mechanism for CNS damage.128 10. Among nondementia carriers of the apolipoprotein type 4 (APOE4) allele, the most common genotype predisposing to AD,129 measures of sleep apnea severity were also associated with extent of cognitive impairment,130 a result partially replicated by others131 and one that may be mediated by sleepiness.132 The presence of the APOE4 allele also predicted a stronger relationship between sleep apnea and cognitive impairment in the SOF study.119 The association between sleep apnea and APOE4 appears to be age-dependent (i.e., confined to persons younger than 65 years)133 and might merely represent a coding region in strong linkage disequilibrium with other more-relevant satellite markers.134 However, the APOE4 allele is associated with more guarded prognosis after stroke,135 worse cognitive outcome after coronary artery bypass surgery,136 and poorer recovery from head injury.137 This suggests that even if sleep apnea did not lie on a causal pathway for cognitive impairment in old age, the genotype could still represent a relevant vulnerability for neurobehavioral manifestations of sleep apnea in old age. Genotype was not available in the clinical trial results,106-109 so whether this factor might have affected the largely negative findings on cognition is unknown. How considerations regarding genotypes or specific dementia subtypes would play out in the day-to-day care of the typical nursing home patient, who may be less likely to have undergone genotyping or extensive neuroimaging, are uncertain, though the sleep specialist asked to provide input into the diagnosis or treatment of sleep apnea in such patients should be aware of the many potential causal factors operating here. Ultimately, the clinician undertaking CPAP or oral appliance treatment for sleep apnea in the demented nursing home patient must come to grips with whether the purpose of the intervention is to treat the dementia itself, the excess disability associated with the dementia (e.g., somnolence, nocturia, or incontinence), or both. If treatment is undertaken primarily with the aim of ameliorating the dementia, it should be emphasized to family members that CPAP will probably not represent a “miracle cure.” Realistically, the level of improvement in the cognitive arena may be on a par with that seen with cholinesterase inhibitors. On the other hand, as emphasized repeatedly throughout this chapter, improved alertness and engagement with the environment are far from trivial quality-of-life endpoints for the institutionalized dementia patient and deserve full consideration in treatment planning. Anecdotal AD cases showing substantial cognitive improvement have been noted.112

SUMMARY With the inevitable aging of the population, the likelihood increases that sleep medicine specialists will be asked to offer expertise regarding the care of geriatric patients residing in institutions. To that end, an understanding of the conditions and syndromes that can affect end-of-life care in the broadly defined dementia patient, particularly when these conditions and syndromes involve SDB,

1558  PART II / Section 17  •  Sleep Medicine in the Elderly

nocturnal incontinence, falls, agitation, and wandering, can benefit patients and their caregivers. Appropriate and judicious pharmacologic implementation, albeit still limited by lack of trials of newer sedative-hypnotic medications, may be warranted in some cases. Treatments for sleep apnea should also be considered; poor adherence should never be assumed, especially in the presence of an engaged spouse or caregiver. Furthermore, introduction of knowledge at the institutional or staffing level regarding not only specific sleep disorders (sleep apnea, RLS) but also basic sleep hygiene and principles of nonpharmacologic management of inadequate nocturnal sleep, can enhance health and quality of life. Rudimentary understandings of basic principles of chronobiology should also be sought. The sleep and well-being of the institutionalized dementia patient should not be considered beyond the range of care of the sleep medicine specialist.

❖  Clinical Pearl Patients residing in nursing homes can present with many significant sleep-related problems that affect the quality of life of those patients and those who care for them. These issues should not be considered beyond the range of care of the sleep medicine specialist. Consultative advice regarding appropriate medication use, including drug interactions, may be significant when issues arise involving falls, nocturnal agitation and wandering, and daytime sleepiness. Sleep apnea and its treatment should not be considered beyond the realm of possibility for the nursing home patient as long as expectations are clear and warranted. The inevitable aging of the population raises the likelihood that many sleep medicine specialists will be asked to provide input regarding sleep in such patients.

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1560  PART II / Section 17  •  Sleep Medicine in the Elderly 81. Endeshaw YE, Unruh ML, Kutner M, et al. Sleep disordered breathing and frailty in the Cardiovascular Health Study Cohort. Am J Epidemiol 2009;170:193-202. 82. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006;54:991-1001. 83. Fried LP, Tangen CM, Walston J, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56: M146-M156. 84. Endeshaw YE, Bloom HL, Bliwise DL. Sleep-disordered breathing and cardiovascular disease in the Bay Area Sleep Cohort. Sleep 2008;31:563-568. 85. Endeshaw YE, White WB, Kutner M, et al. Sleep-disordered breathing and 24-hour blood pressure pattern among older adults. J Gerontol A Biol Sci Med Sci 2009;64:280-285. 86. Endeshaw YE, Johnson TM, Kutner MH, et al. Sleep disordered breathing and nocturia in older adults. J Am Geriatr Soc 2004; 52:957-960. 87. Kemmer H, Mathes AM, Dilk O, et al. Obstructive sleep apnea syndrome is associated with overactive bladder and urgency incontinence in men. Sleep 2009;32:271-275. 88. Stone KL, Blackwell T, Ensrud KE, et al. Sleep disordered breathing increases the risk of falls in older men. Sleep 2006;29(Abstract Supplement):A104. 89. Dam T-T L, Weing S, Ancoli-Israel S, et al. Association between sleep and physical function in older men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2008;56:1665-1673. 90. Gehrman PR, Martin JL, Shochat T, et al. Sleep-disordered breathing and agitation in institutionalized adults with Alzheimer’s disease. Am J Geriatr Psychiatry 2003;11:426-433. 91. Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea as a risk of ischemic stroke in the elderly. Stroke 2006;37: 2317-2321. 92. Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005;172:1147-1151. 93. Dziewas R, Humpert M, Hopmann B, et al. Increased prevalence of sleep apnea in patients with recurring ischemic stroke compared with first stroke victims. J Neurol 2005;252:1394-1398. 94. Martinez-Garcia MA, Galiano-Blancart R, Roman-Sanchez P, et al. Continuous positive airway pressure treatment in sleep apnea prevents new vascular events after ischemic stroke. Chest 2005;128: 2123-2129. 95. Bliwise DL, Adelman CL, Ouslander JG. Polysomnographic correlates of spontaneous nocturnal wetness episodes in incontinent geriatric patients. Sleep 2004;27:153-157. 96. Margel D, Shochat T, Getzler O, et al. Continuous positive airway pressure reduces nocturia in patients with obstructive sleep apnea. Urology 2006;67:974-977. 97. Resnick HE, Phillips B. Documentation of sleep apnea in nursing homes: United States 2004. J Am Med Dir Assoc 2008;9:260-264. 98. Aloia MS, Arnedt JT, Davis JD, et al. Neuropsychological sequelae of obstructive sleep apnea–hypopnea syndrome: a critical review. J Int Neuropsychol Soc 2004;10:772-785. 99. Panegyres PK, Frencham K. Course and causes of suspected dementia in young adults: a longitudinal study. Am J Alzheimer Dis Other Demen 2007;22:48-56. 100. Abrams B. Add Alzheimer’s to the list of sleep apnea consequences. Med Hypotheses 2005;65:1201-1202. 101. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994. 102. Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea? J Sleep Res 2004;13:79-86. 103. Roman GC. Vascular dementia prevention: a risk factor analysis. Cerebrovasc Dis 2005;20(Suppl. 2):91-100. 104. Schneider JA, Arvanitakis Z, Bang W, et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007;69:2197-2204. 105. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;56:42-48.

106. Ayalon L, Ancoli-Israel S, Stepnowsky C, et al. Adherence to continuous positive airway pressure treatment in patients with Alzheimer’s disease and obstructive sleep apnea. Am J Geriatr Psychiatry 2006;14:176-180. 107. Cooke J, Liu L, Fiorentino L, et al. CPAP improves sleep in patients with Alzheimer’s disease and sleep disordered breathing. Sleep 2007;30(Abstract Supplement):A105. 108. Chong MS, Ayalon L, Marler M, et al. Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer’s disease with sleep disordered breathing. J Am Geriatr Soc 2006;54:777-781. 109. Ancoli-Israel S, Palmer BW, Cooke JR, et al. Cognitive effects of treating obstructive sleep apnea in Alzheimer’s disease. J Am Geriatr Soc 2008;56:2076-2081. 110. Moraes W, Poyares D, Sukys-Claudino L, et al. Donepezil improves obstructive sleep apnea in Alzheimer’s disease. Chest 2008;133: 677-683. 111. Cooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med 2009;5:305-309. 112. Bliwise DL. Sleep apnea, APOE4 and Alzheimer’s disease: 20 years and counting? J Psychosom Res 2002;53:539-546. 113. Tworoger SS, Lee S, Schernhammer ES, et al. The association of self-reported sleep duration, difficulty sleeping, and snoring with cognitive function in older women. Alzheimer Dis Assoc Disord 2006;20:41-48. 114. Boland LL, Shahar E, Iber C, et al. Measures of cognitive function in persons with varying degrees of sleep-disordered breathing: the Sleep Heart Health Study. J Sleep Res 2002;11:265-272. 115. Ding J, Nieto FJ, Beauchamp NJ Jr, et al. Sleep-disordered breathing and white matter disease in the brainstem in older adults. Sleep 2004;27:474-479. 116. Robbins J, Redline S, Ervin A, et al. Associations of sleep-disordered breathing and cerebral changes on MRI. J Clin Sleep Med 2005; 1:159-165. 117. Quan SF, Wright R, Baldwin CM, et al. Obstructive sleep apneahypopnea and neurocognitive functioning in the Sleep Heart Health Study. Sleep Med 2006;7:498-507. 118. Foley D, Monjan A, Masaki K, et al. Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc 2001;49:1628-1632. 119. Spira AP, Blackwell T, Stone KL, et al. Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc 2008;56:45-50. 120. Stone K, Blackwell T, Yaffe K, et al. The relationship of sleep disordered breathing and cognition: the MROS sleep study. Sleep 2007;30(Abstract Supplement):A105. 121. Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med 2006;2:461-471. 122. Kumar R, Birrer BVX, Macey PM, et al. Reduced mammillary body volume in patients with obstructive sleep apnea. Neurosc Lett 2008;438:330-334. 123. Macey PM, Kumar R, Woo MA, et al. Brain structural changes in obstructive sleep apnea. Sleep 2008;31:967-977. 124. Ayalon L, Ancoli-Israel S, Klemfuss Z, et al. Increased brain activation during verbal learning in obstructive sleep apnea. Neuroimage 2006;31:1817-1825. 125. Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol 2005;98:2226-2234. 126. Archbold KH, Borghesani PR, Mahurin RK, et al. Neural activation patterns during working memory tasks and OSA disease severity. J Clin Sleep Med 2009;5:21-27. 127. Sharafkhaneh A, Giray N, Richardson P, et al. Association of psychiatric disorders and sleep apnea in a large cohort. Sleep 2005; 28:1405-1411. 128. Gozal D, Row BW, Kheirandish L, et al. Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function. J Neurochem 2003;86: 1545-1552. 129. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921-923. 130. O’Hara R, Schroder CM, Kraemer HC, et al. Nocturnal sleep apnea/hypopnea is associated with lower memory performance in APOE e4 carriers. Neurology 2005;65:642-644.



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131. Cosentino FII, Bosco P, Drago V, et al. The APOE e4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea. Sleep Med 2008;9:831-839. 132. Caselli RJ, Reiman EM, Hentz JG, et al. A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes. Sleep 2002;25:447-453. 133. Gottlieb DJ, DeStefano AL, Foley DJ, et al. APOE ε4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study. Neurology 2004;63:664-668. 134. Larkin EK, Patel SR, Redline S, et al. Apolipoprotein E and obstructive sleep apnea: evaluating whether a candidate gene explains a linkage peak. Genet Epidemiol 2006;30;101-110.

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Women’s Health

Section

Kathryn A. Lee 137  Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms 138  Sleep Disturbances and Sleep-Related Disorders in Pregnancy 139  The Postpartum Period 140  Menopause

Sex Differences and MenstrualRelated Changes in Sleep and Circadian Rhythms

Fiona C. Baker, Louise M. O’Brien, and Roseanne Armitage Abstract There are sex differences in sleep from a very early age. Girls report longer sleeping periods and begin the adolescent decline in slow-wave (delta) activity (SWA) earlier than boys. Women report a poorer sleep quality and have an increased risk for insomnia than do men. However, women have a better sleep efficiency and higher SWA during non-rapid eye movement (NREM) sleep. Sex is an important factor when considering sleep disturbances associated with disorders such as major depressive disorder; depressed men have lower SWA whereas depressed women have lower synchronization between sleep electroencephalographic (EEG) frequency bands compared with healthy controls. These results highlight the importance of sex in sleep and circadian rhythm research studies and have broader implications for women’s health issues relating to these topics. Within groups of women, sleep

SEX DIFFERENCES IN SLEEP FROM INFANCY TO ADULTHOOD Sexual dimorphism describes morphologic differences between the sexes, although it also describes any biological process that differs between men and women. Extensive evidence from fruit flies to humans demonstrates sexual dimorphism in structure, function, and regulation of the brain. Differences between male and female brains are believed to result from the actions of gonadal secretions during a critical period of brain development. Data from animal models show that androgens produced by the testes in fetal and neonatal life induce sex differences in the neural structure and function of the brain, and such sex differences are also apparent in humans. Gonadal secretion is not the only mechanism: Gene expression in neuronal cells also plays a role in sexual dimorphism of the brain before gonadal secretion occurs. There is provocative evidence that even mechanisms of cell death in fetal or newborn brains are not identical between male and female infants.1 Other examples of sexual dimorphism include circadian clock genes, respiratory control, stress responses 1562

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may be affected by variation in reproductive hormones, such as occurs over the menstrual cycle. The menstrual cycle is associated with changes in circadian rhythms and sleep architecture, most notably a blunted amplitude of the body temperature rhythm and increased spindle frequency activity during sleep in the luteal phase compared with the follicular phase. Women with polycystic ovary syndrome are at risk for developing sleep-disordered breathing, which can contribute to insulin resistance and other metabolic abnormalities. Women with severe premenstrual syndrome or dysmenorrhea (painful menstrual cramps) can have transient sleep disturbances or insomnia coupled with their other mood and/or physical symptoms before and during menstruation. Assessment of sleep complaints in women should include an investigation of any association between symptoms and menstrual cycle phase or menstrual-related disorders.

and hypothalamic-pituitary-adrenal axis, density of hypothalamic nuclei and sex hormone receptors in the suprachiasmatic nucleus (SCN), and the action of sex and reproductive hormones on sleep-regulatory mechanisms, all of which have implications for sleep and circadian rhythm regulation. Despite this, research into sex differences in sleep and circadian rhythm regulation lags behind other studies of sex differences in both humans and animal models. The following sections highlight current literature in sleep and circadian rhythms from infancy to adulthood, focusing on differences between the sexes. Major findings are summarized in Table 137-1.

INFANCY In humans, circadian rhythms exhibit a cyclic tendency, with a periodicity of approximately 24 hours. Circadian rhythms undergo a gradual developmental course after birth, strengthening from interaction with a 24-hour light– dark cycle, social cues, and other environmental conditions. In healthy newborns, robust circadian rhythms are usually entrained by 2 to 3 months of age.



CHAPTER 137  •  Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms  1563

Table 137-1  Sex Differences in Sleep throughout the Life Cycle Objective Measures AGE GROUP

SUBJECTIVE REPORTS

VIDEO

ACTIGRAPHY

POLYSOMNOGRAPHY

Infants

Poor sleepers are more likely to be boys

Girls have a longer sleep period and more quiet sleep than boys

Children

Girls sleep longer than boys

Girls sleep longer than boys

Girls have a higher sleep efficiency than boys

Adolescents

Girls take longer to get to sleep and have more sleep than boys

Girls have a more efficient sleep and fewer awakenings than boys

Girls begin the decline in NREM delta power earlier than boys Depressed boys have greater sleep disturbance than depressed girls

Adults

Women report more sleep difficulties than men Women are more likely to have insomnia than men

Women have better sleep quality and sleep more than men

Women have a shorter sleep latency, better sleep efficiency, and more sleep than men Women have higher delta power during NREM

Boys have more infraslow activity (