Atlas of Clinical Sleep Medicine 9780323654036, 0323654037

Table of contents :
Front Cover
Inside front cover
Front matter
Atlas of Clinical Sleep Medicine Third Edition
Copyright
Contributors
Foreword
Preface
Technical details
Polysomnogram recordings
Acknowledgments
Table of Contents
Video contents
Section 1 Sleep in Visual Arts and Literature
1 Sleep in art and literature
Mythology
Religion
Rest
Innocence
Dreams, danger, and death
Bibliography
Section 2 History of Sleep Medicine and Physiology
2 History of sleep medicine and physiology
Timeline
References
Bibliography
Section 3 The Biology of Sleep
3 Sleep mechanisms
Arousal systems
Sleep-promoting systems
Sleep drive
Control of rapid eye movement sleep
Control of the timing of sleep
Bibliography
4 Localization and neurochemistry of sleep-wake physiology and pathophysiology
Introduction
Wake-promoting neurotransmitters
Sleep-promoting neurotransmitters
NREM sleep
REM sleep
External sleep-wake regulation (two-process model)
Homeostasis
Circadian rhythms
Explanatory diagrams
The waking state
NREM sleep
REM sleep
Sleep-wake regulation
Sleep-wake dysregulation in pathologic states
REM behavior disorder
Narcolepsy type 1
Acknowledgment
References
5 Circadian rhythms regulation
Bibliography
6 Physiologic regulation in sleep
Dynamics of individual systems and functional changes in sleep and wake states and across sleep stages
Coupling and network interactions among physiologic systems during sleep and wake states
Acknowledgments
Bibliography
7 Cytokines, host defense, and sleep
Overview of the immune system
Effect of sleep deprivation
Sleep, immune function, and disease
Bibliography
8 Control of breathing
Normal sleep
Sleep apnea
9 Central and autonomic regulation in cardiovascular physiology
Overview
Heart rate surges
Heart rhythm pauses
Physiologic mechanisms underlying nocturnal cardiac events
Summary
Bibliography
10 Interactive regulation of sleep and feeding
Shared brain circuits of sleep and feeding regulation
Shared somatic signaling between sleep and feeding regulation
Metabolic organs modulate sleep-wake activity and feeding
Bidirectional relationship between feeding/metabolic status and sleep-wake activity
Bibliography
11 Endocrine physiology
Overview of endocrine physiology
Ultradian and circadian mechanisms that control hormone secretion across the 24-hour day
Temporal variations of plasma levels of hormones
Glucose regulation and hunger
Conditions that affect hormones and metabolism
Aging
Disease states that reduce slow-wave sleep
Sleep deprivation
Acknowledgments
References
Bibliography
Section 4 Normal Sleep and Its Variants
12 Sleep in mammals
Bibliography
13 Normal sleep in humans
What is sleep?
What is the function of sleep?
Current theories about why we sleep
Restorative theory
Energy conservation theory
Adaptation theory
Memory consolidation theory
Thermoregulatory function theory
Synaptic homeostasis theory
Glymphatic theory
How much sleep is enough?
Neurophysiology of sleep and wakefulness
Wakefulness
Transition between wakefulness and sleep
Sleep mechanisms: From wakefulness to sleep
Transition from wakefulness to non–rapid eye movement sleep
Staging of sleep
Normal circadian function
Normal sleep
Factors that affect sleep
Sleep changes in children
Sleep changes with aging
Sleep characteristics that change with age and their possible neurophysiologic mechanisms
Circadian characteristics that change with age
Bibliography
14 Sleep restriction
Sleep restriction
Recovery from sleep restriction
Individual differences in vulnerability to sleep restriction
Bibliography
15 Sleep and athletic performance
Disordered sleep in athletes
Screening athlete populations for sleep problems
Overscheduling and overtraining
Obstructive sleep apnea
Insomnia and other sleep disorders
Sleep extension
Addressing the sleep needs of athletes
References
Bibliography
16 Dreaming in normal and disrupted sleep
What is dreaming?
Brain basis of dream experience
Factors that influence dream content
Disruption of dreaming pathologic conditions
Sleep disorders
Psychiatric disorders
References
Section 5 Pharmacology
17 Pharmacology
Drugs with hypnotic properties
Zolpidem
Zopiclone and eszopiclone
Zaleplon
Ramelteon
Doxepin
Suvorexant
Diphenhydramine
Sedating antidepressants
Atypical antipsychotics
Ethanol
Agents in development
Wakefulness-promoting medications
Amphetamines and related compounds
Modafinil
Sodium oxybate
Solriamfetol
Pitolisant
Caffeine
Bibliography
Section 6 Impact, Presentation, and Diagnosis
18 Impact, presentation, and diagnostic considerations
Impact
Presentation and diagnostic considerations
Clinical evaluation
History of the present illness
Sleep-disordered breathing symptoms.
Insomnia symptoms.
Excessive daytime sleepiness.
Abnormal sleep-related behaviors and movements.
Medical history
Physical examination
Sleep assessment instruments
Evaluating sleepiness.
Evaluating duration and timing of sleep.
Obstructive sleep apnea risk assessment.
Diagnostic testing
Future considerations: Telemedicine, remote patient monitoring, and beyond
Bibliography
Section 7 Circadian System Disorders
19 Circadian rhythm disorders
Delayed sleep-wake phase disorder
Advanced sleep-wake phase disorder
Non–24-hour sleep-wake rhythm disorder
Irregular sleep-wake rhythm disorder
Shift-work disorder
Jet lag disorder
Summary
Bibliography
20 Circadian desynchrony and health
Circadian system and circadian disruption
Cardiovascular disease
Metabolism
Microbiota
Gastrointestinal disease
Cancer
Conclusions
Bibliography
Section 8 Insomnia
21 Insomnia
Overview
Classification
Epidemiology
Pathophysiology of insomnia
Types of insomnia
Insomnia and comorbidities
Insomnia and other sleep disorders
Isolated insomnia disorder
Management of insomnia
Bibliography
Section 9 Neurologic Disorders
22 Central disorders of hypersomnolence
Overview
Classification and prevalence
Clinical features and epidemiology
Cataplexy
Sleep paralysis and hallucinations
Excessive daytime sleepiness
Disrupted nocturnal sleep
Kleine-levin syndrome
Pathophysiology
Evaluation and diagnosis
Epworth sleepiness scale and fatigue severity scale
Overnight polysomnography, multiple sleep latency test, and maintenance of wakefulness test
Cerebrospinal fluid hypocretin measurement and human leukocyte antigen typing
Other workup
Treatment
Bibliography
23 Movement disorders in sleep
Overview
Restless legs syndrome
Prevalence and clinical significance
Evaluation and diagnosis
Evaluation of severity
Medical evaluation: Iron status
Biology and pathophysiology
Iron
Dopamine
Glutamate
Adenosine
Opioids
Genetics
Treatment
Periodic limb movements during sleep and periodic limb movement disorder
History and definition
Prevalence and clinical significance
Evaluation and treatment
Biology and pathophysiology
Bruxism
Clinical significance
Evaluation
Biology and pathophysiology
Treatment
Sleep-related rhythmic movement disorder
Sleep-related leg cramps
Bibliography
24 Sleep and epilepsy
Introduction
Epilepsy and seizures
Electroencephalography
Types of sleep-related epilepsies
Sleep-related hypermotor epilepsies
Childhood epilepsy with centrotemporal spikes
Childhood epilepsy with occipital paroxysms
Epileptic encephalopathy with continuous spikes and waves during slow sleep
Landau-kleffner syndrome
Primary generalized epilepsies
Normal variants and nonepileptic behaviors
Differentiating interictal discharges from normal variants
Differentiating parasomnia and epilepsy
Other sleep disorders in epilepsy
Conclusion
Bibliography
25 Cerebrovascular disease and sleep
Overview
Breathing patterns after stroke
Pathogenesis of obstructive sleep apnea in stroke
Effect of stroke on sleep
Obstructive sleep apnea as a risk factor for stroke
Bidirectional relationship between obstructive sleep apnea and stroke
Impact of obstructive sleep apnea on stroke outcomes
Diagnosis and treatment of sleep apnea
Impact of obstructive sleep apnea treatment
Summary and future directions
Bibliography
26 Sleep and other neurologic diseases
Introduction
Parkinson disease
Sleep symptoms
Laboratory findings
Treatment
Alzheimer disease
Sleep symptoms
Treatment
Multiple system atrophy
Progressive supranuclear palsy
Huntington disease
Hereditary ataxias
Multiple sclerosis
Paraneoplastic syndromes
Prion disease
Fatal familial insomnia
Creutzfeldt-Jakob disease
Spinal cord injury
Traumatic brain injury
Headache
COVID-19
Conclusion
Bibliography
27 Sleep and neuromuscular disease
Introduction
Impaired respiratory physiology in neuromuscular disease
Common neuromuscular diseases
Motor neuron disease
Spinal cord injury
Peripheral nerve disease
Postpolio syndrome/infectious motor neuropathy
Phrenic nerve injury, neuralgic amyotrophy, parsonage turner syndrome
Neuromuscular junction disease
Muscle diseases
Duchenne muscular dystrophy
Myotonic dystrophy
Chest wall disorders and scoliosis
Compromised breathing mechanics during sleep
Polysomnography findings in neuromuscular disease
Impaired pulmonary physiology and symptoms
Noninvasive ventilation benefits in neuromuscular disease: Physiology and sleep
Longitudinal management of noninvasive ventilation in neuromuscular disease
Conclusion
Bibliography
Section 10 Parasomnias
28 Parasomnias
Overview
Pathophysiology of parasomnias
Disorders of arousal: NREM parasomnias
Rapid eye movement sleep parasomnias
Rapid eye movement sleep behavior disorder
Sleep paralysis
Experiential parasomnias
Sleep enuresis
Nocturnal seizures
Bibliography
Section 11 Sleep Breathing Disorders
29 Examination of the patient with suspected sleep breathing disorders
Overall inspection of the patient
Facial and jaw structures
Inspection of the face
Bony structures
Pervasive facial abnormalities
Maxillary and mandibular insufficiency
Small lower jaw
Nasal airway
Diseases of the nose and nares
Trauma to the nose and nares
Traumatic injury to the nose
Examination of the palate
Examination of the pharynx
Mallampati classification
Examination of the tonsils
Variants and abnormal airway pharyngeal findings
Examination of the neck
Examination of the abdomen
Examination of the extremities
Peripheral edema
Bibliography
30 Sleep apnea in the adolescent and adult
Overview
Definitions
Risk factors
Obstructive sleep apnea
Central sleep apnea
Clinical assessment
Symptoms
Examination
Laboratory evaluation
Data obtained in polysomnography
Scoring of respiratory events with polysomnography
Home sleep apnea testing
Nonapneic respiratory events
Adolescent sleep-disordered breathing
Treatment
General measures
Continuous positive airway pressure
Oral appliance therapy
Surgery
Bibliography
31 Sleep breathing disorders in children
Congenital central hypoventilation syndrome
Obstructive sleep apnea in children
History and physical examination
Historical symptoms of obstructive sleep apnea in children
Common physical examination findings
Technical considerations
Definitions
Obstructive sleep apnea
Mixed sleep apnea
Central sleep apnea
Hypopnea
Respiratory effort–related arousal
Obstructive hypoventilation
Expiratory apnea/hypopnea
Diagnostic considerations
Treatment options for childhood obstructive sleep apnea
References
32 Respiratory diseases and the overlap syndromes
Obstructive pulmonary diseases
Restrictive lung diseases
Extrapulmonary lung restriction
Extrathoracic upper airway obstruction
Bibliography
Section 12 Other Medical and Psychiatric Disorders
33 Cardiovascular diseases
Impact of cardiovascular diseases
Effect of sleep disorders on cardiovascular physiology
Obstructive sleep apnea as a cause of cardiac arrhythmias
Obstructive sleep apnea as a cause of coronary artery disease
Obstructive sleep apnea as a cause of systemic hypertension
Heart failure
Clinical features
Epidemiology
Abnormal breathing patterns in heart failure
Treatment of the abnormal breathing pattern in heart failure
Central sleep apnea
Obstructive sleep apnea
Bibliography
References
34 Thyroid disease
Hyperthyroidism
Hypothyroidism
Thyroid mass lesions
Bibliography
35 Diseases of the pituitary gland
Anatomy
Growth hormone hypersecretion
Pathophysiology
Clinical findings
Diagnosis
Treatment
Hypersecretion of adrenocorticotropic hormone
Pathophysiology
Clinical findings
Diagnosis
Treatment
Bibliography
36 Gastrointestinal disorders
Introduction
Upper gastrointestinal tract
Intestinal motility and lower bowel disorders
Advanced liver disease
Mild liver disease
Bibliography
37 Diabetes mellitus
Sleep quantity and quality and diabetes mellitus
Obstructive sleep apnea and type 2 diabetes mellitus
Prevalence and incidence of concomitant sleep apnea and diabetes mellitus
Mechanisms of development and progression of diabetes mellitus in sleep apnea
Common risk factors and bidirectional relationship between diabetes mellitus and obstructive sleep apnea
Impaired glucose metabolism and pathogenesis of diabetes mellitus in sleep apnea
Complications
Impact of obstructive sleep apnea treatment on glucose homeostasis and diabetes mellitus
Impact of weight loss on obstructive sleep apnea and type 2 diabetes mellitus
Type 1 diabetes mellitus and obstructive sleep apnea
Gestational diabetes mellitus and obstructive sleep apnea
Conclusion
Bibliography
38 Sleep disorders in chronic kidney disease
Background
Definitions and prevalence
Morbidity and mortality
Respiratory sleep disorders
Obstructive sleep apnea
Pathophysiology
Diagnosis
Treatment
Improvement of kidney function.
Improvement of upper airway stability.
Central sleep apnea
Pathophysiology
Diagnosis
Treatment
Improvement of kidney function.
Improvement of ventilatory stability.
Nonrespiratory sleep disorders
Restless legs syndrome and periodic limb movement disorder
Pathophysiology
Diagnosis
Treatment
Insomnia
Pathophysiology
Diagnosis
Treatment
Hypersomnia
Pathophysiology
Diagnosis
Treatment
Bibliography
39 Sleep and psychiatric disease
Overview
Sleep and depression
Sleep architecture
Treatment of depression and sleep problems
Sleep and mania
Sleep, nightmares, and posttraumatic stress
Sleep architecture
Treatment of nightmares in posttraumatic stress
Sleep and generalized anxiety disorder
Sleep and alcohol dependence
Sleep and schizophrenia
Screening for sleep disorders and other medical conditions
Conclusion
Bibliography
40 Sleep and ophthalmologic disorders
Sleep and ophthalmologic disorders
The eye and sleep
Sleep-disordered breathing and ophthalmologic disorders
Circadian rhythm disorders and vision
Insomnia and the eye
Bibliography
41 Sleep and pain
Introduction
Association between sleep and pain
Experimental studies
Restorative sleep and pain
Clinical application
Sleep and pain: Mechanisms
Neurobiology
Psychosocial factors
Polysomnography and pain
Sleep architecture
Electroencephalography power spectral analysis
Circadian regulation of sleep and pain
Conclusion
Bibliography
42 COVID-19 and sleep
Sleep in uninfected individuals during the pandemic
Sleep in those infected with SARs-COV-2
Respiratory system infection
Long-haul respiratory outcomes
Neurologic effects
Long-haul neurologic and psychiatric outcomes
Cardiovascular system
Long-haul cardiovascular outcomes
COVID-19–related sleep symptoms and disorders
Insomnia or Hypersomnia
Sleep-disordered breathing
Therapeutic considerations
Role of other preexisting sleep disorders
Changes in the practice of sleep medicine
The future
Bibliography
Section 13 Women’s Health
43 The menstrual cycle
Menstrual cycle physiology
Sleep across the menstrual cycle
Pubertal maturation
Menstrual cycle and Insomnia symptoms
Impact of the menstrual cycle on other sleep disorders
Polycystic Ovarian syndrome
Impact of sleep on menstrual function
Bibliography
44 Pregnancy and postpartum
First trimester
Second trimester
Third trimester
Sleep-disordered breathing
Restless legs syndrome
Labor and delivery
Postpartum sleep
Postpartum sleep and mental health
Narcolepsy and pregnancy
Summary
Bibliography
45 Midlife transition and menopause
Sleep disturbance during menopause
Vasomotor symptoms
Management options for sleep disturbance
Bibliography
46 Fibromyalgia and chronic fatigue syndrome
Introduction
Fibromyalgia
Clinical presentation and diagnosis
Pathogenesis
Sleep
Treatment
Myalgic Encephalomyelitis/Chronic Fatigue syndrome
Clinical presentation and diagnosis
Pathogenesis
Sleep
Treatment
Bibliography
Section 14 Diagnostic Assessment Methods in Adults
47 Polysomnography and home sleep test assessment methods in adults
Overview
Sleep staging
Recording
Electroencephalogram for brain activity
Eye movements
Electromyogram for skeletal muscle tone
Staging
Classification
Waves
Stages
Stage W.
Stage N1.
Stage N2.
Stage N3.
Stage R.
Smoothing rules
Arousal scoring
Electroencephalogram speeding and central nervous system arousals
Cyclic alternating pattern
Sleep-related breathing disorders
Recording technique
Definitions and scoring rules
Sleep apnea
Hypopnea
Respiratory effort–related arousals
Movements
Leg movement recording technique
Periodic leg movement scoring rules
Other movements
Electrocardiogram
Home sleep testing
Overall assessment
Sleep stage changes across the night
Sleep stage changes as a function of age
Parameters, pathophysiology, and interpretation
Other assessments and interpretation
Multiple sleep latency test
Maintenance of wakefulness test
Suggested immobilization test
Actigraphy
Summary
Bibliography
Section 15 Media Galleries
48 Gallery of polysomnographic recordings
Obstructive sleep apnea (OSA)
Central sleep apnea
Mixed and complex sleep apnea
Heart failure
Cardiac rhythm abnormalities
Neurologic diseases
Movement disorders
Genetic disorders
Stroke
Narcolepsy
REM sleep behavior disorder
Seizures
Head trauma
Multiple sclerosis
Artifacts in sleep recordings
49 Gallery of patient interview videos
Sleep-related breathing disorders
An 8-year-old male patient with sleep apnea (Video 49.1)
An 82-year-old female patient with sleep apnea (Video 49.2)
A 43-year-old female patient with down syndrome (Video 49.3)
Apnea with cardiovascular comorbidities (Video 49.4)
Apnea presenting as restless sleep (Video 49.5)
Apnea in a truck driver (Video 49.6)
Explaining the results (Video 49.7)
Teaching and CPAP mask fitting (Video 49.8)
Neurologic and other disorders
Undiagnosed narcolepsy patient with cataplexy (Video 49.9)
Thirty-five years of undiagnosed narcolepsy (Video 49.10)
Hallucinations in a male narcolepsy patient (Video 49.11)
Narcolepsy patient with sleep apnea (Video 49.12)
Restless legs syndrome in a male patient (Video 49.13)
Middle-aged female patient with restless legs syndrome (Video 49.14)
REM sleep behavior disorder (Video 49.15)
Parkinson disease with REM sleep behavior disorder and sleep apnea (Video 49.16)
Multiple sclerosis, sleep apnea, and hypnagogic hallucinations (Video 49.17)
Arnold-Chiari malformation (Video 49.18)
Syringomyelia (Video 49.19)
Becker muscular dystrophy (Video 49.20)
Psychiatric disorders (Video 49.21)
50 Gallery of sleep laboratory video findings
Obstructive sleep apnea
Apnea, restlessness in a child
Nasal obstruction and apnea
Arousal threshold to noise in obstructive sleep apnea
Obstructive sleep apnea, violent body movements
Obstructive sleep apnea, violent body movements (×10)
Atypical snoring after uvulopalatopharyngoplasty
Vigorous movements in obstructive sleep apnea (×10)
Obstructive sleep apnea in special populations
Obesity hypoventilation
Obesity hypoventilation, heart failure
Obesity hypoventilation, treated
Obesity hypoventilation, polysomnography with synchronized digital video
Obstructive sleep apnea in pregnancy
Postpartum obstructive sleep apnea
Postpartum obstructive sleep apnea, treated
Apnea in acromegaly
Apnea in acromegaly (×10)
Apnea and down syndrome
Upper airway resistance syndrome
Upper airway resistance syndrome, quiet snoring
Upper airway resistance syndrome, quiet snoring (×7)
Upper airway resistance syndrome, variable snoring
Upper airway resistance syndrome, variable snoring (×5)
Central sleep apnea and cheyne-stokes respiration
Idiopathic central apnea
Retinitis pigmentosa, central apnea
Central apnea, obesity
Obstructive sleep apnea and cheyne-stokes breathing
Pulmonary edema
Respiratory diseases
Asthma
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease, upper airway obstruction
Chronic obstructive pulmonary disease, airway secretions, periodic limb movement disorder
Chronic obstructive pulmonary disease, airway secretions, periodic limb movements during sleep (×10)
Overlap syndrome
Overlap syndrome, treated
Pulmonary fibrosis
Neurologic and other disorders
Restless legs syndrome, insomnia
Restless legs syndrome and periodic limb movements during sleep (×25)
Restless legs syndrome, sleep apnea
Restless legs syndrome, sleep apnea (×10)
Periodic limb movement disorder, apnea (×10)
Periodic limb movement disorder, subtle movements (×10)
Rapid eye movement sleep behavior disorder
Rapid eye movement sleep behavior disorder, loud vocalization
Non–rapid eye movement parasomnia, confusional arousal, loud vocalization
Rapid eye movement sleep behavior disorder, obstructive sleep apnea
Sleep paralysis
Delayed sleep phase syndrome
Epilepsy
Seizure involving the leg
Psychogenic “seizures” (x5)
Psychogenic “seizures,” edge enhanced
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
Y
Z
Inside back cover

Citation preview

Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge.

Elsevier eBooks+ gives you the power to browse, search, and customize your content, make notes and highlights, and have content read aloud.

Unlock your eBook today. 1. Visit http://ebooks.health.elsevier.com/ 2. Log in or Sign up 3. Scratch box below to reveal your code 4. Type your access code into the “Redeem Access Code” box 5. Click “Redeem”

It’s that easy!

Place Peel Off Sticker Here

For technical assistance: email [email protected] call 1-800-545-2522 (inside the US) call +44 1 865 844 640 (outside the US) Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on http://ebooks.health.elsevier.com/. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at http://ebooks.health.elsevier.com/ and may not be transferred to another party by resale, lending, or other means. 2022v1.0

ATLAS OF CLINICAL SLEEP MEDICINE THIRD EDITION

Meir H. Kryger, MD, FRCPC Professor Pulmonary Critical Care and Sleep Medicine Yale University New Haven, Connecticut

Alon Y. Avidan, MD, MPH Director, UCLA Sleep Disorders Center Professor, Department of Neurology University of California, Los Angeles Los Angeles, California

Cathy Goldstein, MD Professor Department of Neurology University of Michigan Ann Arbor, Michigan

Elsevier 3251 Riverport Lane St Louis, Missouri 63043

ATLAS OF CLINICAL SLEEP MEDICINE, THIRD EDITION Copyright © 2024 by Elsevier Inc. All rights reserved.

ISBN: 978-0-323-65403-6

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. Previous editions copyrighted 2014, 2010 by Saunders, an imprint of Elsevier, Inc.

Content Strategist: Mary Hegeler Content Development Specialist: Kevin Travers Content Development Manager: Meghan Andress Publishing Services Manager: Catherine Jackson Senior Project Manager/Specialist: Carrie Stetz Design Direction: Ryan Cook Printed in India Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors Sabra M. Abbott, MD, PhD Assistant Professor Ken and Ruth Davee Department of Neurology Northwestern University Chicago, Illinois Takashi Abe, PhD Division of Sleep and Chronobiology Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Imran I. Ali, MD Clair Martig Endowed Chair and Professor of Neurology Department of Neurology University of Toledo College of Medicine and Life Sciences Toledo, Ohio

Ronald D. Chervin, MD Professor of Neurology Michael S. Aldrich Collegiate Professor of Sleep Medicine Director, University of Michigan Sleep Disorders Center University of Michigan Health System Ann Arbor, Michigan Nancy Collop, MD Professor of Medicine Director, Emory Sleep Center The Emory Clinic Atlanta, Georgia Jennifer Corrigan, MD, MSc, BSc Clinical Lecturer Cumming School of Medicine University of Calgary Calgary, Alberta, Canada

J. Todd Arnedt, PhD Professor of Psychiatry and Neurology Director, Behavioral Sleep Medicine Program University of Michigan Hospital and Health Systems Ann Arbor, Michigan

David F. Dinges, MA, MS, PhD Professor and Chief, Division of Sleep & Chronobiology Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Alon Y. Avidan, MD, MPH Director, UCLA Sleep Disorders Center Professor, Department of Neurology University of California, Los Angeles Los Angeles, California

Emmanuel H. During, MD Associate Professor Department of Psychiatry Stanford University Redwood City, California

Ronny P. Bartsch, PhD Senior Lecturer Department of Physics Bar-Ilan University Ramat Gan, Israel

Mohan Dutt, MD Clinical Assistant Professor Department of Neurology University of Michigan Ann Arbor, Michigan

Ruth M. Benca, MD, PhD Professor and Chair Department of Psychiatry and Human Behavior University of California, Irvine Orange, California

Danny J. Eckert, PhD Director and Professor, Adelaide Institute for Sleep Health Flinders University Bedford Park, SA, Australia; Professor, School of Medical Sciences University of New South Wales Sydney, NSW, Australia

Orfeu M. Buxton, PhD Professor Department of Biobehavioral Health Pennsylvania State University University Park, Pennsylvania Anne-Marie Chang, PhD Associate Professor Department of Biobehavioral Health Department of Nursing Pennsylvania State University University Park, Pennsylvania

Jack D. Edinger, PhD Professor Department of Medicine National Jewish Health Denver, Colorado; Adjunct Professor Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, North Carolina

iii

iv  Contributors E. Devon Eldridge-Smith, PhD Assistant Professor Department of Medicine National Jewish Health Denver, Colorado Chiara Formentin, MD, PhD Department of Medicine University of Padova Padova, Italy Patrick M. Fuller, PhD, MS Professor and Vice Chair of Research Director, Laboratory of Systems Neuroscience Department of Neurological Surgery University of California Davis School of Medicine Sacramento, California Jacqueline Geer, MD Department of Pulmonary, Critical Care, and Sleep Medicine Yale School of Medicine Yale University New Haven, Connecticut Cathy Goldstein, MD Professor Department of Neurology University of Michigan Ann Arbor, Michigan Patrick J. Hanly, MD, FRCPC, DABSM Department of Medicine Cumming School of Medicine University of Calgary Calgary, Alberta, Canada Ronald M. Harper, PhD Distinguished Research Professor Department of Neurobiology Brain Research Institute David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Max Hirshkowitz, PhD Consulting Professor Division of Public Mental Health and Population Sciences Stanford University School of Medicine Stanford, California; Professor Emeritus Department of Medicine Baylor College of Medicine Houston, Texas Michael J. Howell, MD Associate Professor Department of Neurology University of Minnesota Minneapolis, Minnesota Mary S.M. Ip, MD Chair Professor Department of Medicine University of Hong Kong Hong Kong, China

Muna Irfan, MBBS Assistant Professor Department of Neurology University of Minnesota; Medical Director, Sleep Services Minneapolis Veterans Affairs Medical Center Minneapolis, Minnesota Plamen Ch. Ivanov, PhD, DSc Research Professor Department of Physics Boston University; Division of Sleep Medicine Harvard Medical School and Brigham and Women’s Hospital Boston, Massachusetts Shahrokh Javaheri, MD Medical Director, Sleep and Pulmonary Medicine Bethesda North Hospital; Professor Emeritus, Pulmonary Critical Care and Sleep Medicine University of Cincinnati Cincinnati, Ohio; Adjunct Professor, Department of Cardiology The Ohio State University Columbus, Ohio Sogol Javaheri, MD, MPH, MA Department of Sleep Medicine Brigham and Women’s Hospital Boston, Massachusetts Christopher W. Jones, PhD Research Assistant Professor Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Yo-El S. Ju, MD Associate Professor Department of Neurology Washington University in St. Louis St. Louis, Missouri Marc Kaizi-Lutu, BA Research Assistant Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Levente Kapas, MD, PhD Associate Professor WWAMI Medical Education Program Department of Integrative Physiology and Neuroscience Washington State University Spokane, Washington Meir H. Kryger, MD, FRCPC Professor Pulmonary Critical Care and Sleep Medicine Yale University New Haven, Connecticut

  Contributors  v Scott J. Kutscher, MD Associate Professor Department of Sleep Medicine Stanford University Redwood City, California

Wallace Mendelson, MD Professor (Retired) Psychiatry and Clinical Pharmacology The University of Chicago Chicago, Illinois

Won Y. Lee, MD Associate Professor Division of Pulmonary and Critical Care Medicine University of Texas Southwestern Medical Center Dallas, Texas

Sara Montagnese, MD, PhD Professor Department of Medicine University of Padova Padova, Italy

Peter Y. Liu, MBBS, PhD Professor of Internal Medicine Harbor-UCLA Medical Center; Professor of Endocrinology The Lundquist Institute Torrance, California

Pier Luigi Parmeggiani, MD Professor Emeritus Department of Human and General Physiology University of Bologna Bologna, Italy

Macy M.S. Lui, MD, FHKCP, FHKAM Consultant and Honorary Clinical Associate Professor Division of Respiratory Medicine Queen Mary Hospital The University of Hong Kong Hong Kong, China Bethany L. Lussier, MD Assistant Professor Division of Pulmonary, Critical Care, and Neurocritical Care University of Texas Southwestern Medical Center Dallas, Texas Atul Malhotra, MD Professor of Medicine Peter C. Farrell Presidential Chair in Respiratory Medicine Pulmonary, Critical Care and Sleep Medicine Research Chief of Pulmonary, Critical Care, and Sleep Medicine University of California, San Diego School of Medicine La Jolla, California Raman K. Malhotra, MD Professor Department of Neurology Washington University in St. Louis St. Louis, Missouri Catherine A. McCall, MD Sleep Medicine Physician/Psychiatrist Pulmonary, Critical Care, and Sleep Medicine/Psychiatry Veterans Affairs Puget Sound Health Care Center; Assistant Professor Psychiatry and Behavioral Sciences University of Washington School of Medicine Seattle, Washington William V. McCall, MD Case Distinguished Chair Professor of Psychiatry and Health Behavior Medical College of Georgia Georgia Regents University Augusta, Georgia

Aric A. Prather, PhD Associate Professor of Psychiatry University of California, San Francisco San Francisco, California Kathryn J. Reid, PhD Research Professor Department of Neurology Northwestern University Feinberg School of Medicine Chicago, Illinois Thomas Roth, PhD Director, Sleep Disorders Center Henry Ford Hospital Detroit, Michigan Logan Douglas Schneider, BSBA, MD Clinical Lead, Sleep Health Global Affairs Alphabet, Inc. Mountain View, California; Consult Neurologist Stanford/VA Alzheimer’s Center Palo Alto Veterans Affairs Healthcare System Palo Alto, California; Clinical Assistant Professor (Affiliated) Psychiatry and Behavioral Sciences Stanford Sleep Center Redwood City, California Colin M. Shapiro, MD, PhD Sleep on the Bay Toronto, Ontario, Canada Amir Sharafkhaneh, MD, PhD Associate Professor of Medicine Program Director, Sleep Fellowship Program Baylor College of Medicine; Medical Director, Sleep Disorders and Research Center Michael E. DeBakey VA Medical Center Houston, Texas Ajaz A. Sheikh, MD, DABSM Assistant Professor of Neurology and Sleep University of Toledo Toledo, Ohio

vi  Contributors Stephen H. Sheldon, DO Professor of Pediatrics and Neurology Northwestern University Feinberg School of Medicine; Former Director, Sleep Medicine Center Ann and Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois

Christopher D. Turnbull, DPhil, BMBCh Nuffield Department of Medicine University of Oxford Oxford University Hospitals NHS Foundation Trust Oxford Centre for Respiratory Medicine Oxford, United Kingdom

Deena Sherman, BA Toronto, Ontario, Canada

Bradley V. Vaughn, MD Professor of Neurology University of North Carolina Chapel Hill, North Carolina

Jerome M. Siegel, PhD Professor Department of Psychiatry and Biobehavioral Sciences; Chief, Neurobiology Research Veterans Affairs Greater Los Angeles Healthcare System University of California, Los Angeles Los Angeles, California

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

Andrea M. Spaeth, MA Department of Psychology University of Pennsylvania Philadelphia, Pennsylvania

Erin J. Wamsley, PhD Associate Professor of Psychology Furman University Greenville, South Carolina

Robert Stickgold, PhD Professor Department of Psychiatry Harvard Medical School; Professor Department of Psychiatry Beth Israel Deaconess Medical Center Boston, Massachusetts

Sophie D. West, MD, FRCP Newcastle Regional Sleep Service Newcastle Upon Tyne Hospitals NHS Foundation Trust Newcastle, United Kingdom

Keith C. Summa, MD, PhD Fellow Department of Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Leslie Swanson, PhD Associate Professor Department of Psychiatry University of Michigan Medical Center Ann Arbor, Michigan Éva Szentirmai, MD, PhD Associate Professor of Biomedical Sciences Washington State University Spokane, Washington

Daniel Whibley, MA, PhD Kratz Lab Department of Physical Medicine & Rehabilitation University of Michigan Ann Arbor, Michigan John W. Winkelman, MD, PhD Chief, Sleep Disorders Clinical Research Program Departments of Psychiatry and Neurology Massachusetts General Hospital Boston, Massachusetts Brian S. Wojeck, MD, MPH Assistant Professor Department of Medicine Section of Endocrinology Yale University New Haven, Connecticut

Lauren Tobias, MD Assistant Professor Department of Pulmonary, Critical Care, and Sleep Medicine Yale University School of Medicine New Haven, Connecticut

Christine H.J. Won, MD, MS Associate Professor Department of Medicine (Pulmonary) Director, Yale Sleep Center Director, Women’s Sleep Health Program Yale University School of Medicine New Haven, Connecticut

Fred W. Turek, PhD Center for Sleep and Circadian Biology Department of Neurobiology and Physiology Northwestern University Evanston, Illinois

Steven Yao, MD Psychiatry Resident Medical College of Georgia Augusta University Augusta, Georgia

  Contributors  vii Kin M. Yuen, MD, MS Assistant Professor Department of Psychiatry and Behavioral Sciences Stanford University Stanford, California; Associate Physician Diplomate Department of Medicine–Pulmonary University of California, San Francisco San Francisco, California

Phyllis C. Zee, MD, PhD Benjamin and Virginia Boshes Professor of Neurology Director, Center for Circadian and Sleep Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois

This page intentionally left blank

Foreword This third edition of the Atlas of Clinical Sleep Medicine has been updatged with advances in the field of sleep medicine and maintains the synthesis of a broad knowledge base and a sensory representation of that knowledge. During the Renaissance, scientists were often also artists. They had the mental agility to move back and forth easily between the sciences and the arts and, more importantly, integrate them. This led to one influencing the other. Science affected the way art was created, and science was depicted in creative artistic formats. With the evolution of art into new forms and the separate specialization of science, these two important human endeavors drifted far apart. Until the 1950s the history of sleep was encountered more frequently in the world of art than in the world of science. Artists depicted nightmares and night terrors, and authors described, with amazing accuracy, individuals who had various sleep disorders ranging from insomnia to sleep apnea. The description by Charles Dickens of “Joe, the Fat Boy” in The Pickwick Papers describes the signs and symptoms of obstructive sleep apnea syndrome with uncanny accuracy. In the 1950s, Drs. Aserinsky, Dement, and Kleitman ushered in the modern era of sleep research with their discovery of rapid eye movement (REM) sleep and the association of REM sleep and dreaming. This discovery promised to help gain insight into the nature of the mind-body connection. For the first time scientists had a mental event—the dream—and a clear physiologic correlate—REM sleep. Also, the nightly occurrence of REM sleep and its associated visual hallucinations were thought to provide insights into the nature of mental disorders characterized by hallucinations while awake. While neither of these hopes came to fruition, this new discipline shed light on the one-third of our existence that had been virtually unexplored. By analogy to geology, it was as though an additional third of the world’s land mass was discovered. Questions arose such as: What do the brain and body do in sleep? What is the biological basis of dreams and nightmares, and what is their significance? Why do some people have difficulty sleeping whereas others cannot even stay awake during the day? With the observation that the control of many physiologic processes differed as a function of state (awake, REM sleep, and non-REM sleep), the field of sleep medicine was born. Clearly one can have normal physiologic function while awake and serious pathophysiology while asleep. Interestingly, as sleep medicine became a new discipline, artists were still fascinated with this mysterious third of existence. Thus, sleep medicine evolved in a parallel course with the depiction of sleep and dreams by authors and artists. This book aims to meld the science of sleep with the arts. Previous atlases have depicted polysomnograms associated with various aspects of sleep physiology and sleep disorders. Several other edited books have provided the reader with a broad understanding of sleep and its disorders. Here the goal is more integrative: it is to give the reader an intellectual as well as a sensory appreciation of the science of sleep and the practice of sleep disorders medicine. Not only is this book different in its approach, but the content is also broader. Along with an in-depth presentation of sleep physiology and pathophysiology, there are chapters on

the history of sleep research as well as the depiction of sleep in the arts. This book informs how to take a history from a sleep disorder patient as well as educate what other individuals with this disorder look like, what the patient’s sleep study looks and sounds like, and how a patient’s disorder is depicted in the arts. Thus readers gain a familiarity with the disorder as well as comfort in knowing all aspects of the patient’s care management. In terms of standardization of sleep medicine procedures, current scoring rules for polysomnography are presented. The goal of the original scoring system, developed in 1960 by Rechtschaffen and Kales, was to standardize the scoring of sleep stages. As sleep research gave birth to sleep medicine, it became important to standardize the scoring not only of normal sleep, but also of abnormal sleep and abnormal events during sleep. The manual developed by the American Academy of Sleep Medicine has achieved that goal. This volume contains highlights of that continually revised manual. Another important methodologic change is the increased use of home sleep testing for obstructive sleep apnea. This initiative arose from the realization that many, but certainly not all, patients with obstructive sleep apnea can be evaluated in a home setting without the need for a more expensive and intrusive sleep laboratory study. Home testing is an evolving methodology in our field and is discussed as such in this text. More importantly, the knowledge base of sleep medicine continues to evolve. This edition pays special attention to several areas that have seen significant strides. The first is pediatric sleep medicine, particularly the field of sleep breathing disorders. For many years pediatric sleep medicine was focused on parasomnias. Today we recognize that virtually all sleep disorders are present in children, but with different presentations, risk factors, and morbidities. As children go through critical periods in development, a sleep disorder that compromises cognitive function can have irreversible consequences. Clearly, the need to recognize, diagnose, and treat pediatric sleep disorders is a high priority in sleep medicine. Another advance has occurred in our understanding of circadian physiology and disorders of circadian desynchrony, resulting in a better understanding of the pathophysiology of medical conditions such as obesity and disorders such as shift-work disorder as well as the use of light and chronobiotic medications in the treatment of circadian disorders. In 2017 the Nobel Prize in Medicine and Physiology recognized the importance of the research linking genetics and chronobiology. For non-sleep clinicians, this book will orient them to the science of sleep as well as give a sense of what it is like to enter a sleep laboratory, what types of information can be gained from a sleep study, and, most importantly, what their patient will experience during a sleep study. For the sleep researcher/sleep clinician, this book provides in-depth coverage of topics ranging from sleep history to basic sleep neurophysiology to the identification, diagnosis, and management of sleep medicine. For all of us, this book will not only stimulate our intellect, but also our senses. Thomas Roth Detroit, Michigan, 2022 ix

Preface Our understanding of sleep and sleep disorders is fairly recent. Rapid eye movement (REM) sleep was first described in the same year as Watson and Crick published their important findings on the structure of DNA. Most people consider the discovery of REM to be the beginning of sleep science and sleep medicine. Until that time, sleep was seldom mentioned by scientists but had been a topic for philosophers, such as Aristotle; playwrights, such as Shakespeare; novelists, such as Charles Dickens; and many visual artists, such as Vincent van Gogh. The visual artists did not simply portray sleep as a restful phase; at times it recorded the danger that sleep might bring. In the first edition of this text, we tried something new. We added to the knowledge about sleep by not simply focusing on words to transmit that knowledge, but also to use still and moving images and sounds to enhance the understanding of the science of sleep. We asked, “How would a great scientist and artist have tackled this job?” We wondered how Leonardo da Vinci would do such a project. We believed that he would have combined words with engaging visual imagery and whatever else was available in the scientific and communication universe of his day. Sleep medicine is a multidisciplinary field that is so much more than just sleep recordings—it is a perfect specialty in which to use multimedia for learning. Putting together this book was like working on a painting—a giant mural. We had ideas about the information we wanted to convey, and we pondered how to use multimedia to present the knowledge, with a book being the anchor. We thank the authors for the brilliant job they have done in capturing sleep medicine in a visual form. I have always believed that knowledge of a medical field is not simply mastering the clinical facts, but also understanding the interaction of history, the arts, and the scientific base that led to the clinical facts. The anatomic drawings of Leonardo da Vinci remind us of the potential beauty of learning about science. This is not our first attempt at creating a multimedia platform for sleep disorders. Many years ago, Journey into Sleep, a CD-based program linked to Internet sites, was published. At that time, the publishing world was convinced—as we were— that the physical book printed on paper was dead. We were all wrong. About a decade ago, it became apparent that CDs and DVDs as primary sources of content were doomed because the Internet was so much more convenient, and that is where people expect to find certain types of content. Physical books survived and have flourished. This book and its multimedia content were made possible by a flurry of recent technological changes: high-speed Internet, inexpensive mass storage, high-resolution graphics cards and computer displays, digital photography, and sleep data acquisition systems. There are many photographs in the Atlas. Acquiring the images required a high-resolution camera that could fit into a pocket. Patients were delighted that their images would be used for teaching and they gave permission to include them. Previously, sleep medicine atlases displayed data originally collected on paper, which resulted in images that could be changed only with great difficulty, and they could not easily x

emphasize certain teaching points. The examples in this book represent what is actually seen in the modern sleep disorders center, warts and all, using various data acquisition systems. The traces shown are real, and the montages used are those that enhance understanding and clarity. By using digital data acquisition and analysis systems, we are able to emphasize the important teaching points much more easily than when paper was used. We are able to change the time base, compress the data, and split the screen so that the neurophysiologic variables, as well as cardiorespiratory variables, can be shown optimally using different time bases. It is as easy to see 8 hours on the screen as 30 seconds. A sleep medicine clinician uses information from several sources to establish a diagnosis and determine optimal treatment. These sources include interviews with the patient, examination of the patient, evaluation of tests, and integration of these data with a knowledge base that includes understanding of the relevant pathophysiology. In a clinical learning setting, the mentor will transmit information to the trainee about each of these phases in the clinical interaction. In this book, we are attempting to emulate all parts of the process. We learn a great deal from what a patient tells us in his or her own words and from observing and evaluating the data. I hope that what is presented is helpful to the clinician and ultimately the patient. It is the patient who will benefit the most, and it is from the patient we learn the most. We present and explain the current scoring rules and show the reader not just how to score, but also how to understand. We chose not to be constrained by the recommended epoch length and rules but to build from them and use the tools provided by modern systems to display the data as a clinician might in order to understand the signals coming from an ill patient. The purpose of the book is to produce an atlas that would be useful for anyone wanting to learn about sleep. We hope that this work pleases the reader. We know it is not perfect, and as careful as we tried to be we realize that readers will probably find errors. It is our hope that readers will provide us feedback as this book continues to evolve. We learned a great deal from the first two editions. Almost all the media have been technically improved or re-created so that information can be ported to a high-resolution electronic device; we suspect that most readers will explore the content of the book on a smart device or computer. The sleep medicine world around us has also changed. Home sleep testing has taken the sleep world by storm. There is a continuously updated manual for the scoring of sleep, and work continues on the classification of sleep disorders. Emerging treatments for virtually every sleep disorder are emerging. New sophisticated tools not only for diagnosis and monitoring, but also for evaluation of treatment adherence and efficacy, are being introduced at an impressive rate. Artificial intelligence has emerged as a potential method to extract greater nuance, meaning, and value from the physiologic signals collected during the polysomnogram. Our understanding of the relationship of genetics, sleep, metabolic diseases, and the circadian system has exploded. The

  Preface  xi COVID-19 pandemic promoted innovative changes (some irreversible) in the practice of sleep medicine. Collectively, these advances will further effective patient-centered care and incorporate precision medicine in the evaluation and management of sleep disorders. The overall goal of the Atlas, which is to intrigue clinicians, trainees, and scientists with a visually appealing sleep education resource, has not changed. It is to present knowledge about sleep and to use words, images, and video to enhance the presentation and teaching of sleep medicine. We hope that no matter where you read these words, this work will amplify and enrich your knowledge about sleep. Meir H. Kryger, MD Hamden, Connecticut Alon Avidan, MD, MPH Los Angeles, California Cathy Goldstein, MD Ann Arbor, Michigan January 2023 TECHNICAL DETAILS All of the images and videos of patients and sleep traces were obtained digitally in working sleep disorder centers. Most of the photos and patient interviews were taken with small digital cameras that could fit into a pocket. The patient

video interviews were also taken with the same digital camera with a screen size of 640 3 480 pixels at 29 frames per second. The videos of sleeping patients were taken from data captured during the sleep recordings. The images are in black and white (there is no “color” when using an infrared light source in the dark) and were compressed to the MPEG 4 format during acquisition. Most of the videos shown are unedited. When editing was necessary, Adobe Premier Elements, Quicktime, or Microsoft Moviemaker was used. Almost all the sleep recordings were captured using a screen resolution of 1600 3 1200 pixels. The data were stored in the highest resolution without compression, if possible. These are working polysomnographic traces and may not be the perfect configuration as described in scoring manuals, but they represent what is actually seen in the sleep disorders center. We hope that the reader will learn how to best interpret and understand what is seen. That is the purpose of this atlas. The digitized images were then processed by artists at Elsevier to supply a uniform look and feel so that the overall appearance of the records had some visual consistency. These photos and records span many years; thus, there is some variability in the resolution just as there is variability in the resolution of data acquisition systems. The screenshots obtained represent the spectrum of the most widely used data acquisition systems, including Compumedics, Grass, Nihon Kohden, and Respironics.

Polysomnogram Recordings The polysomnograms shown in this book were generated from the most commonly used modern systems and at times from older systems. Most often, the display and montage shown are those that someone interpreting the record might use. Frequently that would involve splitting the display into two windows: an upper window that displays the channels used for the recording and staging of sleep (most often a 30-second

epoch) and a lower window that displays the channels used to best document movements and sleep breathing disorders (the epoch length usually varies from 30 seconds to 10 minutes, depending on the abnormality being observed). Below are examples of the styles used when two windows are shown. The blue arrows point toward where the length of the epoch of the window is indicated.

E2-M1 E1-M2

10s

C4-M1

UPPER WINDOW

C3-M2 CHIN1 ECG

04:42:14

R-R

04:42:24

70

74

72

72

68

65

66

60

68

67

34

RLeg

10s

SNORE PTAF

LOWER WINDOW

THERM THOR ABD

SaO2 (%)

xii

100 92 85

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

  Polysomnogram Recordings  xiii

Cursor: 23:51:38, Epoch: 121 - STAGE 2

EMG1-EMG2

1 min/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1

UPPER WINDOW

128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG3 2.05 mV

5 min/page

LAT-LAT256 V

RAT-RAT128 V

100

SaO2 %

90

THOR EFFORT 4.1 mV

ABD EFFORT 8.19 mV

120

Pulse bpm

40 75

PCO2

mm Hg 0

NASAL PRES 250 mV

LOWER WINDOW

Acknowledgments Hundreds of people were involved in the production of this book. They are located all over the world. Many we have never met. These range from authors and their editorial assistants and secretaries to the staff at Elsevier. It is not possible to name all the people that have played an important role in such a book. I thank them all. We would like to thank the staff at Elsevier. We originally proposed a type of book that had not been produced before: a volume using still images and videos to teach about sleep. Elsevier encouraged the project from the very beginning. In part, because of the COVID-19 pandemic, there were many technical and editorial challenges. We would like to thank Nancy Duffy, and later Melanie Tucker, our editors at Elsevier, for their unwavering support. I would like to thank Kevin Travers, the developmental editor, who displayed never-ending calm and patience at every step.

xiv

We would like to thank the production staff and the design staff for the beautiful work they have done. We would like to thank the technical staff for having developed innovative methods to deal with the technical challenges at every step of the way. We would like to thank Carrie Stetz, who carried the book to the finish line. We would like to thank the authors who have done a magnificent job in visually presenting information that normally would be described in words. It was not an easy task for them, and we thank them for their achievements. We also want to thank Tom Roth and the late Bill Dement, who have always been an inspiration to all of us. The sleep field will never forget their important contributions to the health and safety of people around the world. We would like to thank our families for understanding that we were trying to create something new.

Contents Section 1: Sleep in Visual Arts and Literature Chapter 1 Sleep in Art and Literature  1

Chapter 14

Sleep Restriction  117

Section 2: History of Sleep Medicine and Physiology Chapter 2 History of Sleep Medicine and Physiology  10

Chapter 15

Sleep and Athletic Performance  124

Chapter 16 

Dreaming in Normal and Disrupted Sleep  131

Colin M. Shapiro, Deena Sherman, and Meir H. Kryger

Meir H. Kryger

Section 3: The Biology of Sleep Chapter 3 Sleep Mechanisms  22

Patrick M. Fuller, Phyllis C. Zee, Orfeu M. Buxton, and Alon Y. Avidan

Chapter 4

Localization and Neurochemistry of Sleep-Wake Physiology and Pathophysiology  29

Section 5: Pharmacology Chapter 17 Pharmacology  134 Wallace Mendelson

Section 6: Impact, Presentation, and Diagnosis Chapter 18 Impact, Presentation, and Diagnostic Considerations  147 Mohan Dutt, Leslie Swanson, J. Todd Arnedt, Ronald D. Chervin, and Cathy Goldstein

Chapter 6

Chapter 7

Circadian Rhythms Regulation  36

Kathryn J. Reid, Anne-Marie Chang, Phyllis C. Zee, and Orfeu M. Buxton

Chapter 9

Control of Breathing  56

Central and Autonomic Regulation in Cardiovascular Physiology  64 Interactive Regulation of Sleep and Feeding  68 Éva Szentirmai and Levente Kapàs

Chapter 11

Chapter 20

Section 8: Insomnia Chapter 21 Insomnia  175

E. Devon Eldridge-Smith, Jack D. Edinger, Meir H. Kryger, and Thomas Roth

Section 9: Neurologic Disorders Chapter 22 Central Disorders of Hypersomnolence  185 Emmanuel H. During

Chapter 23

Movement Disorders in Sleep  206

Chapter 24

Sleep and Epilepsy  227

Chapter 25

Cerebrovascular Disease and Sleep  251

Endocrine Physiology  72 Peter Y. Liu

Section 4: Normal Sleep and Its Variants Chapter 12 Sleep in Mammals   78 Jerome M. Siegel

Chapter 13

Normal Sleep in Humans  83 Alon Y. Avidan

Circadian Desynchrony and Health  168

Keith C. Summa and Fred W. Turek

Danny J. Eckert and Atul Malhotra

Richard L. Verrier and Ronald M. Harper Chapter 10

Sabra M. Abbott, Kathryn J. Reid, and Phyllis C. Zee

Cytokines, Host Defense, and Sleep  51 Aric A. Prather

Chapter 8

Section 7: Circadian System Disorders Chapter 19 Circadian Rhythm Disorders  161

Physiologic Regulation in Sleep  39

Plamen Ch. Ivanov, Pier Luigi Parmeggiani and Ronny P. Bartsch

Scott J. Kutscher

Erin J. Wamsley and Robert Stickgold

Logan Douglas Schneider Chapter 5

Andrea M. Spaeth, Christopher W. Jones, Marc Kaizi-Lutu, Takashi Abe, and David F. Dinges

Catherine A. McCall and John W. Winkelman

Ajaz A. Sheikh, Imran I. Ali, and Bradley V. Vaughn

Lauren Tobias and Jacqueline Geer

xv

xvi  Contents Chapter 26

Sleep and Other Neurologic Diseases  258

Chapter 39

Sleep and Psychiatric Disease  396

Sleep and Neuromuscular Disease  271

Chapter 40

Sleep and Ophthalmologic Disorders  405

Raman K. Malhotra and Yo-El S. Ju

Chapter 27

Meir H. Kryger, Alon Y. Avidan, Bethany L. Lussier, and Won Y. Lee

Section 10: Parasomnias Chapter 28 Parasomnias  285

Muna Irfan and Michael J. Howell

Section 11: Sleep Breathing Disorders Chapter 29 Examination of the Patient With Suspected Sleep Breathing Disorders  300

Christopher D. Turnbull and Sophie D. West

Chapter 41

Sleep and Pain  409

Chapter 42

COVID-19 and Sleep  414

Sleep Apnea in the Adolescent and Adult  314 Nancy Collop

Chapter 31

Chapter 32

Section 12: Other Medical and Psychiatric Disorders Chapter 33 Cardiovascular Diseases  357

Sogol Javaheri and Shahrokh Javaheri

Chapter 34

Chapter 44

Pregnancy and Postpartum  426

Chapter 45

Midlife Transition and Menopause  430

Chapter 46

Chapter 35

Diseases of the Pituitary Gland  374

Chapter 36

Gastrointestinal Disorders  379

Chapter 37

Diabetes Mellitus  385

Chapter 38

Sleep Disorders in Chronic Kidney Disease  390

Brian S. Wojeck and Meir H. Kryger

Sara Montagnese and Chiara Formentin

Macy M.S. Lui and Mary S.M. Ip

Jennifer Corrigan and Patrick J. Hanly

Fibromyalgia and Chronic Fatigue Syndrome  433 Lauren Tobias

Section 14: Diagnostic Assessment Methods in Adults Chapter 47 Polysomnography and Home Sleep Test Assessment Methods in Adults  438 Max Hirshkowitz and Amir Sharafkhaneh

Thyroid Disease  369 Meir H. Kryger

Kin M. Yuen

Lauren Tobias

Respiratory Diseases and the Overlap Syndromes  348 Christine H.J. Won

Meir H. Kryger and Cathy Goldstein

Lauren Tobias

Sleep Breathing Disorders in Children  338 Stephen H. Sheldon

Daniel Whibley

Section 13: Women’s Health Chapter 43 The Menstrual Cycle  420

Meir H. Kryger

Chapter 30

Catherine A. McCall, Steven Yao, Ruth M. Benca, and William V. McCall

Section 15: Media Galleries Chapter 48 Gallery of Polysomnographic Recordings  462

Max Hirshkowitz and Meir H. Kryger

Chapter 49

Gallery of Patient Interview Videos  526 Meir H. Kryger

Chapter 50

Gallery of Sleep Laboratory Video Findings  531 Meir H. Kryger

Index  545

Video Contents Videos are available at eBooks.Health.Elsevier.com.

Video 12.1  Waking head and bill movements and REM sleep movements in the platypus

Video 24.3  Nocturnal frontal lobe epilepsy seizure with dystonic and clonic features occurring during sleep Video 24.4  Hyperkinetic nocturnal frontal lobe epilepsy seizures

Chapter 22

Chapter 28

Video 22.1  Cataplexy in Doberman pinschers Video 22.2  Cataplexy in mice Video 22.3  Cataplectic facies in a child watching a cartoon Video 22.4  A cataplectic attack in an adult

Video 28.1  Video 28.2  Video 28.3  Video 28.4  Video 28.5 

Chapter 23

Chapter 49

Video 23.1  Suggested immobilization test

Videos 49.1 to 49.21  Patient interviews

Chapter 24

Chapter 50

Video 24.1  Nocturnal frontal lobe epilepsy seizures with dystonic posturing Video 24.2  Nocturnal frontal lobe epilepsy seizure with dystonic and clonic features occurring at awakening

Videos 50.1 to 50.47  Sleep laboratory findings

Chapter 12

Short confusional arousal Sleep-related eating disorder Original REM sleep behavior disorder (RBD) RBD patient throwing pillow RBD patient with bed alarm intervention

xvii

This page intentionally left blank

Section 1  |  Sleep in Visual Ar ts and Literature Chapter

Sleep in Art and Literature

1

Colin M. Shapiro, Deena Sherman, and Meir H. Kryger

It appears that every man’s insomnia is as different from his neighbor’s as are their daytime hopes and aspirations. —F. Scott Fitzgerald The scientist explores the functions, mechanisms, and pathologies of sleep (Fig. 1.1). The visual artist, on the other hand, is not concerned with these matters; instead, when representing sleep, a number of themes repeatedly emerge. They have intense fascination with mythology, dreams, religious themes, the parallel between sleep and death, reward, abandonment of conscious control, healing, a depiction of innocence and serenity, and the erotic. The subject of sleep is revisited in art time and time again. Why do artists return to this inactive, common, basic human function? Certainly, a sleeping Venus is not as exciting as a dramatization of a bombing on a Spanish town or as uplifting as a starry night. The appeal of sleep lies in the fact that although it is common, it is extremely complex. A sleeping woman takes on the posture of death but is very much alive. She is conscious but not cognizant. She lies physically in reality, but her thoughts run in fantasy. Sleep delights, frightens, regenerates, and may even lead to fatigue. It can overpower us

like a heavy, irrepressible fog or elude us like the sweet thrills of happiness. Furthermore, although sleep is a basic human function, it is a unique experience for everybody. Thus just as every person’s sleeplessness differs from their neighbor’s, so does their sleep. Sleep is a necessity, and every person does it (or hopes to), but the actual experience cannot be shared. When one goes to sleep, one falls alone, and when one enters dreamland, one walks by one’s self. Here lies the appeal for artists. This inactive state contains so many connotations, evokes a large array of emotions, and holds an abundance of internal activity. How does one execute through painting one’s experiences and thoughts on sleep? Artists encounter a great barrier to overcome in trying to convey a multifaceted action whose origins lie in inaction. It is extremely difficult for an artist to separate one sleeping figure who may represent strength in sleep from another who symbolizes vulnerability. This chapter explores the various devices and methods artists use to articulate their explorations and understandings of sleep. Furthermore, it investigates the different themes and ideas that artists have had about this mysterious human experience. MYTHOLOGY

Figure 1.1  Mahla Shapiro, Light to Deep and Dreaming Sleep, 2008.

One way artists explore sleep is through mythology. Artists take advantage of the viewer’s knowledge of and familiarity with the characters, stories, and settings of myth. This allows the artist to convey his or her definition of sleep by immersing it in these visual mythical cues. This is accomplished once the viewer recognizes these cues because it forces the viewer to ask, “What are the implications of sleep in the context of the story?” An example of this is Sandro Botticelli’s Mars and Venus (Fig. 1.2). In this painting, the fully clothed Venus sits at the left, upright and alert, whereas the sleeping Mars on the right lies languidly, incapacitated, exposed, and vulnerable. Venus appears to be in control, while Mars is reduced to being a plaything for the baby satyrs. Thus, this painting likens the state of sleep to weakness. It is a powerful force that can overtake the god of war. Sleep is undesirable because it is capable of lowering the defenses of someone as formidable as the god of war. The god of war becomes subject to humiliation. Furthermore, he has become prey to the outside world. Patients often do not appreciate this power of sleep, even those who suffer from sleep disorders, who may need to be reminded, for example, that sleep deprivation is used as a technique of 1

2  Sleep in Art and Literature

Figure 1.2  Sandro Botticelli, Mars and Venus, ca. 1483. National Gallery of London.

torture. In other words, sleep is so highly necessary that “take those sleeping pills” may be the simplistic mantra. Lorenzo Lotto’s Sleeping Apollo (Fig. 1.3) portrays sleep in a manner similar to that of Botticelli’s Mars and Venus. Once again, the sexes are divided; the naked female Muses are on the left, and the slumbering Apollo sits on the right. Fame, who flies above Apollo, is ready to desert him and join the other Muses. The Muses have taken advantage of the sleeping Apollo to abandon their clothes and arts to frolic about. Like Mars, Apollo is unaware of the activities of the waking world. The effects of sleep in both paintings produce a comic reaction. However, the way Mars and Apollo are portrayed in their sleep produces two decidedly different comic reactions. The sprawled, exposed sleeping Mars, with his own lance held by the baby satyrs, pointing at him, is an object to be ridiculed. The portrayal of sleeping Apollo is less negative. He sits more upright with what appears to be an instrument in his hand. He is depicted more like the dozing professor whose students have gone off to play. Thus, sleep takes on a different meaning. The undignified position of Mars, the god of war, compounded with the connotations of strength, power, and chaos, portrays sleep as a weakening force that places one in a compromising position. On the other hand, in Sleeping Apollo, sleep appears not to take away strength or might, but reason. This is reinforced by the fact that Apollo is linked to reason and foresight. Sleep has removed him of rationality and made him completely

oblivious to what has happened. This is further symbolized by the abandoning of the books and instruments of the Muses in front of him. Also, Apollo sits in the dark, enclosed by the trees; he is alone in the secluded realm of sleep and completely segregated from the outside world. Lack of rationality in sleep has become a key issue in the realm of forensic aspects of sleep, with recent media emphasis on the condition of sexsomnia and the consternation over the lack of mens rea in the sleeping state. Giorgione’s Sleeping Venus (Fig. 1.4), instead of two figures, has one, the female figure, who is sleeping. As in the other two paintings, Venus lies in a pastoral setting; but unlike in Mars and Venus, she is alone, and she is the one who is sleeping and nude. The curves of her body emulate the undulating hills. She has her left hand covering her genitals. This is an extremely erotic picture. Sleep has taken on a different meaning here. Venus has become not someone to laugh at, like Mars or Apollo. Her strength or power or reason has not been taken away from her because of sleep. Rather, sexuality—which Venus is associated with—has become enhanced by sleep. According to Maria Ruvoldt, the conscious placement of her hand over her genitals refers to her procreative powers. Also, she has her right arm up to expose her armpit. This gesture is commonly associated with seduction in certain periods in Western art. Moreover, because the curves of her body imitate the landscape, there is a direct connection between her and nature, thus further associating her with fecundity.

Figure 1.3  Lorenzo Lotto, Sleeping Apollo, ca. 1530. Szepmuveseti Museum, Budapest.

Atlas of Clinical Sleep Medicine   3

Figure 1.4  Giorgione, Sleeping Venus, ca. 1508. Gemäldegalerie Alte Meister, Dresden, Germany.

RELIGION Instead of classical mythology, many artists have turned to the Bible in their representations of sleep. In his oil painting Earthly Paradise (Fig. 1.5), Pierre Bonnard depicts a slumbering Eve and an alert Adam. Bonnard uses the same pictorial language in his rendering of Eve: the exposed armpit and her rounded form alluding to nature. Her rendering and sleeping posture make her look thanatotic. Although the pairing of the two biblical characters reminds us of Botticelli’s Mars and Venus, they are not similar to the two mythical characters. By using the same visual language as Giorgione, Bonnard allows the female sleeper to be the empowered, natural being, as opposed to Botticelli’s weakened male protagonist. One could argue, as the Art Institute of Chicago does, that “the male, seen as essentially intellectual, is able to transcend the earthly.” However, one can interpret this as Eve being given more power because she was given more attention in terms of her physiognomy, rather than the awakened Adam. She is foreshortened and is positioned closest to the viewer. Furthermore, her color is in great contrast with the rest of the painting, so she becomes a focal

Figure 1.5  Pierre Bonnard, Earthly Paradise, 1916 to 1920. The Art Institute of Chicago. (Copyright 2008 Artists Rights Society [ARS], New York/ADAGP, Paris.)

point, and detail is given to her face. On the other hand, Adam is rendered in shadow, and only his profile is shown. Although he is standing—which could insinuate evolution— he is colored like the rest, to the point where he looks like a tree, or is simian-like. In works such as Piero della Francesca’s Dream of Constantine (Fig. 1.6), sleep is depicted as the state in which the divine communicates with humans. This is a common occurrence in mythology and religious stories. Well-known instances are the Bible’s Jacob and his dream of the ladder that reached heaven, as well as the Egyptian Pharaoh’s prophetic dreams that would be interpreted by Joseph. Whatever the story, it is necessary that the protagonist enter the state of sleep to hear God speak to him. In this early Renaissance painting, Constantine is shown reposed in a tent and is flanked by his sentinels. There is—or what appears to be—an angel swooping from the upper-left corner as if to deliver a divine message from God. This image depicts the moment, Laurie Schneider Adams tells us, when Constantine’s dream “revealed the power of the Cross, and led to his legal sanction of Christianity.” As opposed to Botticelli’s Mars and Venus and Giorgione’s Sleeping Venus, Constantine is neither emasculated nor empowered with sexual prowess. Sleep is depicted as a state wherein only the divine becomes revealed and the sleeper can realize higher states of consciousness. This is further exemplified by the contrast between Constantine and his guards. The leader is composed and peaceful in his rest as though receptive to a divine message. (This may be thought of as a foreshadowing of current research that links sleep in a critical way with the consolidation of memory.) The soldiers, on the other hand, appear languid and unaware of the angel that is delivering the message. The artist uses both this event

Figure 1.6  Piero della Francesca, Dream of Constantine, ca. 1452. San Francesco, Arezzo, Italy.

4  Sleep in Art and Literature and sleep as a way to demonstrate the former and to explore the latter. It is interesting to note that the title and content of the painting force the viewer to ask whether he or she is witnessing an event that is occurring in reality, or are we privy to the actual dream of Constantine? Are we the awake sleepers who are also in Constantine’s higher state and are witnessing the delivery of this divine message? The power of sleep is expressed in two biblical images in masterpieces by Caravaggio. In one, Mary and the infant Jesus are sleeping in Rest on the Flight into Egypt (c. 1597) (Fig. 1.7A). In the other, Mary Magdalene, wearing the clothes of a prostitute, is resting (see Fig. 1.7B). Now that she

A

has abandoned her gold, jewelry, and alcohol, she can sleep peacefully. The same model was apparently used for both, and the resting heads are in similar positions. REST John Keats equated sleep with rest. What is more gentle than a wind in summer? What is more soothing than the pretty hummer That stays one moment in an open flower, and buzzes cheerily from bower to bower? What is more tranquil than a musk-rose blowing In a green island, far from all men’s knowing? More healthful than the leafiness of dales? More secret than a nest of nightingales? More serene than Cordelia’s countenance? More full of visions than a high romance? What, but thee Sleep? Soft closer of our eyes! Low murmurer of tender lullabies! Light hoverer around our happy pillows! Wreather of poppy buds, and weeping willows! Silent entangler of a beauty’s tresses! Most happy listener! when the morning blesses Thee for enlivening all the cheerful eyes That glance so brightly at the new sun-rise. —Sleep and Poetry Although it may seem that only the mythical, powerful, and divine are depicted sleeping, there have been many examples of those in other social strata sleeping. Jan Steen’s The Dissolute Household (ca. 1668) (Fig. 1.8) represents what modern times would term a “dysfunctional family.” This family setting is the perfect example of indulgence of many types: gambling, gluttony, and prostitution. All order is lost in this household, where cards and oysters are strewn on the floor. The eye is immediately drawn to the woman at the table in restful sleep. Vernon Hyde Minor states that she is the wife of

B Figure 1.7  A, Michelangelo Merisi da Caravaggio, Rest on the Flight into

Egypt, ca. 1597. Doria Pamphilj Gallery, Rome. B, Michelangelo Merisi da Caravaggio, Penitent Magdalene, ca. 1595. Doria Pamphilj Gallery, Rome.

Figure 1.8  Jan Steen, The Dissolute Household, ca. 1668. Wellington Museum, London.

Atlas of Clinical Sleep Medicine   5 the man who is philandering with the prostitute. It is as though all the bawdiness has worn out the wife. This echoes the themes in Botticelli’s Mars and Lotto’s Apollo. Like Mars and Apollo, the weakened state of sleep/sleepiness/tiredness/ fatigue (overlapping but distinct states) has made the wife vulnerable enough to become both the fool and the cuckold. Amidst all the indulgence and disorder, a monkey in the upper-right corner plays with the clock and essentially “stops time.” It is as though this morally challenged family is perpetually caught in this state of depravity. It insinuates that the only course of escape is to move into another state of being—sleep. That sleep is a wondrous healing state of escape and rest and comfort for all is a common artistic theme, depicted in Laurent Delvaux and Peter Scheemakers’ Cleopatra (Fig. 1.9). Jean-François Millet produced Noonday Rest in 1866 (Fig. 1.10A). In 1875, John Singer Sargent emulated (see the signature) this image in Noon (see Fig. 1.10B). Van Gogh, in turn, emulated the same theme in Noon: Rest from Work in 1890 (see Fig. 1.10C). The luxury of sleep and rest is portrayed in the image in Repose (Nonchaloire) (ca. 1911) of this wealthy woman painted by John Singer Sargent (Fig. 1.11). In Le Berceau (The Cradle), 1872, Berthe Morisot portrays how complex something like sleep can be for the artist. The infant is peacefully asleep. The mother is calm, relaxed, and grateful—but vigilant as she watches over her baby (Fig. 1.12). The child who is peacefully asleep is a theme that recurs repeatedly in the visual arts. John Everett Millais, in L’Enfant du Regiment, shows the healing power of sleep. In the midst of a battle, the injured child is sleeping. In this image, we are confronted by violence, the bleeding bandaged arm, and peace of sleep that has overcome the violence (Fig. 1.13). In all of these examples, a clear contrast is established: sleep and awake, unaware and alert, weakened and empowered. By depicting opposites side by side, artists enabled viewers to define these conscious states by what they were not. This is an extremely effective way to explore sleep beyond the physical signs but difficult from an epistemologic perspective or psychological perspective. The alert poses of Botticelli’s Venus and of Bonnard’s Adam set against Mars and Eve, respectively, remind us of what sleep is not: a state of awareness and strength. For Lotto’s Apollo, Steen’s sleeping wife, and even Giorgione’s Venus, sleep is not being part of the active world. In Giorgione’s Sleeping Venus, one could say that the landscape with the village painted in the right is Venus’s antithesis. It is a reminder that while Venus is asleep, life in the town must and does continue. In Millais’s L’Enfant, sleep offers an escape from a dangerous world. And lastly, for Piero della Francesca’s Constantine, sleep is a demarcation between the blessed and the ignorant.

A

B

C Figure 1.10  A, Jean-François Millet, Noonday Rest, 1866. Museum of Fine Arts, Boston. B, John Singer Sargent, Noon (after Jean-François Millet), ca. 1875. Metropolitan Museum of Art, New York. C, Vincent Van Gogh, Noon: Rest from Work (after Jean-François Millet), 1890. Musée d’Orsay, Paris.

INNOCENCE

Figure 1.9  Laurent Delvaux and Peter Scheemakers, Cleopatra, ca. 1723. Yale Center for British Art, New Haven, CT.

Sleep as a vulnerable state of innocence is frequently portrayed by artists. As an example, the painter Gaspare Traversi in Teasing a Sleeping Girl shows four people watching an innocent girl sleep; one is teasing her with a feather (Fig. 1.14). The detail of Gustave Klimt’s The Three Ages of Woman also displays peace and innocence (Fig. 1.15).

6  Sleep in Art and Literature

Figure 1.13  John Everett Millais, L’Enfant du Regiment, ca. 1855. Yale Center for British Art, New Haven, CT.

Figure 1.11  John Singer Sargent, Repose (Nonchaloire), 1911. National Gallery of Art, Washington, DC.

Figure 1.14  Gaspare Traversi, Teasing a Sleeping Girl, ca. 1760. Bequest of Harry G. Sperling, 1971.

Figure 1.12  Berthe Morisot, Le Berceau (The Cradle), 1872. Musée d’Orsay, Paris.

DREAMS, DANGER, AND DEATH The painting of dreams is an excellent way for artists to explore sleep. It allows them to not only share their unique experiences and move sleep from the external to the internal, but also to combine elements that would not normally share the same space. In The Sleep of Reason Produces Monsters (ca. 1799), Francisco José de Goya clearly shows that dreams can be

disturbing when they are invaded by monsters (Fig. 1.16). Is this what awakens those with posttraumatic stress disorder? Henry Fuseli in The Nightmare (ca. 1781) shows a woman possibly in a state of sleep paralysis (Fig. 1.17). She has visions of a devil-like creature on her abdomen and a horse’s head peering at her from the left, but she cannot move. Another example of dreaming is Henri Rousseau’s The Dream (1910) in which there is a nude female lounging on a Victorian couch in the middle of a jungle (Fig. 1.18A). Among many hidden menacing animals, there is one in the center that draws the viewer’s attention. It is an undefinable creature that appears to be both human and animal and is playing an instrument. The sky is light to indicate day; however, the moon is full and clearly visible. All of these elements would not normally be together, yet the subject of dreaming allows them to be so. The juxtaposition of these things, combined with the realism in which they are rendered, evokes the feelings of eeriness and perplexity so often associated with dreams. Another dreamlike image by Rousseau is that of the

Atlas of Clinical Sleep Medicine   7

Figure 1.17  Henry Fuseli, The Nightmare, 1781. Detroit Institute of the Arts, Detroit, MI.

Figure 1.15  Gustave Klimt, The Three Ages of Woman, 1905. Galleria Nazio-

nale d’Arte Moderna e Contemporanea, Rome, Italy.

A

Figure 1.16  Francisco José de Goya, The Sleep of Reason Produces Monsters, #43, 1799. From Los Caprichos.

B Sleeping Gypsy (1897) (see Fig. 1.18B). This image is a dream about sleep. A lion lurks over the sleeper, but it does not seem to be attacking the sleeper. Is it because the lion is full? Is the lion protecting the sleeper? Are sleep and the dream protecting the sleeper? These works remind one that sleep may be restorative and positive, but there is a lurking danger of sleep as well.

Figure 1.18  A, Henri Rousseau, The Dream, 1910. Museum of Modern Art,

New York. B, Henri Rousseau, The Sleeping Gypsy, 1897. Museum of Modern Art, New York.

8  Sleep in Art and Literature As we have seen, artists throughout time have actualized sleep through myth, religion, class, and dreams. Another recurring theme is death. That sleep may be a reversible form of death and death a form of sleep has always fascinated writers and artists. Even in the 19th century, sleep and death were equated by some physicians. William Shakespeare equated sleep with death: To be, or not to be: that is the question: Whether ‘tis nobler in the mind to suffer The slings and arrows of outrageous fortune, Or to take arms against a sea of troubles, And by opposing end them? To die: to sleep: No more; and by a sleep to say we end The heart-ache and the thousand natural shocks That flesh is heir to, ‘tis a consummation Devoutly to be wish’d. To die, to sleep; To sleep: perchance to dream: ay, there’s the rub; For in that sleep of death what dreams may come —Hamlet, Act 3, Scene 1 Sleep that knits up the ravell’d sleave of care, The death of each day’s life, sore labour’s bath, Balm of hurt minds, great nature’s second course, Chief nourisher in life’s feast. —Macbeth, Act 2, Scene 2 As noted earlier, religion has contributed to views about sleep in general and artistic portraits in particular. For example, a bed made of arrows is not generally counted among the beds one would be happy to rest on. The bed of arrows, as shown in Figure 1.19, belongs to Bhishma, a hero of the Hindus. According to historical record, Bhishma’s bed of arrows was also his deathbed in a war that is said to have occurred around 6000 bce. This emphasizes the perceived link of sleep and death. Bhishma’s body was so covered with arrows shot at him that when he lay down, the arrows made a bed. Only his head was not supported by arrows. So Bhishma asked Arjun, another war hero, to create a pillow of arrows for him. Arjun did this by putting the arrows into the ground for Bhishma’s

head. An interesting aspect of Bhishma’s death is that he could control the exact time of his death. The states of waking, dreaming, and deep sleep are associated with the syllable aum that Hindus chant when they meditate. When the sounds a-u-m that comprise aum are chanted, it is believed that one goes through all three states. Meditation is a means of connecting with one’s innermost self and is an integral part of Hinduism. Urns containing the remains of the deceased have been frequently decorated by images of the dead person sleeping, as in the pre-Roman Etruscan examples from Siena, Italy (Fig. 1.20A). Interestingly, in the upper-right example, the dead person is represented not as sleeping but awake and looking surprised. The death of a child often was also memorialized with a sculpture of a peacefully sleeping child, as in this sculpture in the Hermitage Museum (see Fig. 1.20B). A more modern linking of sleep and death is shown by the painter John William Waterhouse in Sleep and His HalfBrother Death (1874). As one moves from foreground to background, one clearly goes from life to death. There is no mistaking which of the brothers is alive, even though both have similar postures (Fig. 1.21). It is only fairly recently that some behaviors during sleep that are annoying to the bedpartner are understood to be dangerous to the sleeper. One wonders whether the fragment of a longer poem by John V. Kelleher, a 16th century Irish poet, would be considered amusing today. You thunder at my side, Lad of ceaseless hum; There’s not a saint would chide My prayer that you were dumb. The dead start from the tomb With each blare from your nose. I suffer, with less room, Under these bedclothes. With could I better bide Since my head’s already broke— Your pipe-drone at my side, Woodpecker’s drill on oak? ... Farewell, tonight, to sleep. Every gust across the bed Makes hair rise and poor flesh creep. Would that one of us were dead! —The Snoring Bedmate

Figure 1.19  The Death of Bhisma, from Mahabharata, ca. 18th century. Smithsonian Institution, Washington, DC.

As understanding of sleep through science, philosophy, literature, and art changes throughout time, so will the visual renderings related to sleep and dreams. Although one might at first glance think that the more we understand about sleep the less we will be fascinated and that there will be a commensurate decline in involvement of all artists in the subject of sleep and dreams, this does not seem to be the case.

Atlas of Clinical Sleep Medicine   9

A Figure 1.21  John William Waterhouse, Sleep and His Half-Brother Death, 1874. Private collection.

Current artists seem to be engrossed by the subject, just as modern songwriters and poets have continued the compositions of librettists of opera and classical poets (who often wrote about sleep and dreams). Whatever the case, we will continue to dream. B Figure 1.20  A, Etruscan Funerary Urns. Museum Santa Maria della Scala, Siena, Italy. B, Unknown artist, Sleeping Boy. Catherine Palace, Pushkin, Russia.

Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

e1 Bibliography

Adams LS. Art Across Time. Vol 2. Boston: McGraw-Hill; 1999:523, 582, 862. Arnason HH. History of Modern Art. New York: Harry N. Abrams; 1998. Kryger M. Sleep in Art: How Artists Portrayed Sleep and Dreams in the Last 7000 Years. Amazon: 2019. Minor VH. Baroque & Rococo: Art & Culture. Englewood Cliffs, NJ: Prentice Hall; 1999: 261. Ruvoldt M. The Italian Renaissance Imagery of Inspiration: Metaphors of Sex, Sleep and Dreams. Cambridge, UK: Cambridge University; 2004:40, 94.

Shapiro CM, Trajanovic NN, Fedoroff JP. Sexsomnia—a new parasomnia? Can J Psychiatry. 2003;48(5):311–317. Shapiro CM, Vaccarino K. Sleep in art. In: Shapiro CM, ed. Sleep Solutions Manual. Pointe Claire, Canada: Kommunicom Publications; 1995:223–246. The Art Institute of Chicago. Master Paintings in The Art Institute of Chicago. Chicago: The Art Institute of Chicago; 1999:121.

Section 2  |  Histor y of Sleep Medicine and Physiology Chapter

2

History of Sleep Medicine and Physiology Meir H. Kryger

Although the field of medicine is fairly recent, historical, literary, and scientific descriptions have added to our knowledge. Sleep disorders are not new, and it is appropriate to begin a historical timeline of sleep medicine and physiology with Hippocrates, the father of medicine. TIMELINE 400 bce Hippocrates (Fig. 2.1) wrote: I have known many persons in sleep groaning and crying out, some in a state of suffocation, some jumping up and fleeing out of doors, and deprived of their reason until they awaken, and afterward becoming well and rational as before, although they be pale and weak; and this will happen not once but frequently. 360 bce Historical documents describe Dionysius (Fig. 2.2), the tyrant of Heraclea, as immensely obese and record that he died “choking on his own fat.”1 His physicians may have used the first treatment of apnea (i.e., sticking needles through the skin to arouse him from sleep). Now up to a certain point under the flesh, completely callous as it was by fat, the needle caused no sensation; but if the needle

Figure 2.1  ​Peter Paul Rubens, etching of Hippocrates, 1638.

10

went through so as to touch the region which was free of fat, then he would be thoroughly aroused. —Athenaeus, The Deipnosophists, translated by C.B. Gulick 350 bce Aristotle (Fig. 2.3) wrote about sleep and waking, whether they are a function of the body or the soul, and the significance of dreams. He observed that all creatures sleep. Accordingly, almost all other animals are clearly observed to partake in sleep, whether they are aquatic, aerial, or terrestrial, since fishes of all kinds, and mollusks, as well as all others which have eyes, have been seen sleeping. “Hard-eyed” creatures and insects manifestly assume the posture of sleep; but the sleep of all such creatures is of brief duration, so that often it might well baffle ones observation to decide whether they sleep or not. —Aristotle, On Sleep and Sleeplessness, translated by J.I. Beare and G.R.T. Ross2 1603 Shakespeare describes sleepwalking in Macbeth, Act 5, Scene 1 (Fig. 2.4): Since his Majesty went into the field, have seen her rise from her bed, throw her nightgown upon her, unlock her closet, take forth paper, fold it, write upon’t, read it, afterwards seal it, and again return to bed; yet all this while in a most fast sleep... Falstaff, who appears in three Shakespeare plays, was obese, snored, and fell asleep at inappropriate times. These are symptoms of sleep apnea. 1605 Miguel de Cervantes Saavedra (Fig. 2.5), in his novel The Ingenious Hidalgo Don Quixote of La Mancha,3 probably described rapid eye movement (REM) sleep behavior disorder in Part 1, Chapter 35: [A]nd in his right hand he held his unsheathed sword, with which he was slashing about on all sides, uttering exclamations as if he were actually fighting some giant: and the best of it was his eyes were not open, for he was fast asleep, and dreaming that he was doing battle with the giant. 1672 Sir Thomas Willis (of the circle of Willis) describes the features of restless legs syndrome (RLS).4 The condition will not receive a name until 1945 (Fig. 2.6). 1729 The first report of circadian rhythm was that of Jean-Jacques d’Ortous de Mairan,5 who set up an ingenious experiment using a mimosa plant that opened up its leaves at a certain time when it was sunny. He put the plant into a box so there was no exposure to light, and the plant’s leaves still opened at the same time. This plant was able to keep track of time (Fig. 2.7). 1816 William Wadd, Surgeon Extraordinaire to the King of England, writes a monograph titled Cursory Remarks on Corpulence; or Obesity Considered as a Disease, in which he described sleepiness in obesity.6 One of his cases “became at length so lethargic, that he fell asleep in the act of eating, even in company.”

Atlas of Clinical Sleep Medicine   11

Figure 2.2  ​Coin of Dionysius, which did not show him as obese.

Figure 2.4  ​Henry Fuseli, Lady Macbeth Sleepwalking, 1784. Louvre Museum.

Figure 2.3  ​Rembrandt van Rijin, Aristotle with a Bust of Homer, 1653. Metropolitan Museum of Art.

1818 John Cheyne7 describes the breathing pattern named after him in A case of Apoplexy in Which the Fleshy Part of the Heart Was Converted into Fat: For several days his breathing was irregular; it would entirely cease for a quarter of a minute, then it would become perceptible, though very low, then by degrees it became heaving and quick, and then it would gradually cease again: this revolution in the state of his breathing occupied about a minute, during which there were about thirty acts of respiration. 1832 Just after the discovery in 1831 by Samuel Guthrie of chloroform (which was later used as an anesthetic agent), Justus von Liebig discovered chloral hydrate, perhaps the first widely used and abused hypnotic agent. 1836 Charles Dickens (Fig. 2.8) publishes The Posthumous Papers of the Pickwick Club.8 In this story, he describes Joe, the fat boy whose symptoms of snoring and sleepiness form the basis of the first article to describe the Pickwickian syndrome, published in 1956. “And on the box sat a fat and red-faced boy in a state of somnolency” (Fig. 2.9). 1862 Caffé in France is the first to describe a condition of hallucinations associated with sleepiness. It was incorrectly considered a form of epilepsy. 1864 Adolf von Baeyer discovers barbituric acid, the parent compound of the barbiturates.

Figure 2.5  ​Miguel de Cervantes Saavedra described rapid eye movement behavior disorder.

12  History of Sleep Medicine and Physiology

Figure 2.8  ​Charles Dickens.(Courtesy Meir H. Kryger.)

Figure 2.6  ​Sir Thomas Willis.

Figure 2.9  ​Joe, the fat boy, “in a state of somnolency,” The Posthumous Papers of the Pickwick Club.(Courtesy Meir H. Kryger.)

Figure 2.7  ​Jean-Jacques d’Ortous de Mairan.

1869 William Hammond publishes Sleep and Its Derangements.9 He uses the phrase “persistent wakefulness” to describe what would be called insomnia today. He also describes sleep state misperception, blaming the condition on increased blood flow to the brain.

1875 Richard Caton is the first to describe in a single sentence in an abstract that electrical activity was present in the brains of cats, rabbits, and monkeys10: Feeble currents of varying direction pass through the multiplier when the electrodes are placed on two points of the external

Atlas of Clinical Sleep Medicine   13 surface, or one electrode on the gray matter, and one on the surface of the skull. 1877 Karl Westphal is the first to describe sudden bouts of sleeping associated with loss of motor tone.11 1880 Jean Baptiste Edouard Gélineau is the first to use the term narcolepsy to describe a disease with irresistible sleep.12 1890s Ivan Pavlov begins experiments on salivation in dogs in response to food and stimuli (Fig. 2.10). His experiments led to his description of the existence of conditioned reflexes, a concept important in the psychological treatment of insomnia. 1895 Nathaniel Kleitman, the first and most famous sleep researcher, is born. 1898 William Wells makes the association of nasal obstruction and daytime sleepiness13: “[T]he stupid-looking lazy child who frequently suffers some headaches at school, breathes through his mouth instead of his nose, snorts, and is restless at night, and wakes up with a dry mouth in the morning, is well worthy of the selected solicitous attention of the school medical officer.” 1902 Leopold Löwenfeld makes the statement that narcolepsy is associated with cataplexy. 1902 Emil Fischer and Joseph von Mering synthesize barbital, marketed in 1904 by the Bayer Company as Veronal. This became the first widely used barbiturate hypnotic. 1918 William Osler, in Principles and Practice of Medicine, describes sleeplessness and mental symptoms, including drowsiness, in congestive heart failure (Fig. 2.11). 1929 Hans Berger is the first to record an electroencephalogram in humans.14 1934 Luman Daniels points out that in narcolepsy there is sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. 1934 In a brilliant series of papers describing the clinical features of heart failure, W. R. Harrison describes the clinical consequences of Cheyne-Stokes breathing in heart failure. He describes sleep onset and sleep maintenance insomnia as well as paroxysmal nocturnal dyspnea, and he shows how the periodic breathing pattern improves with treatment of the heart failure (Fig. 2.12).15 1935 Alfred Loomis describes the electroencephalogram findings of what was eventually called non–rapid eye movement (NREM) sleep.16

Figure 2.10  ​Ivan Pavlov described conditional reflexes.

Figure 2.11  ​Sir William Osler described drowsiness in heart failure.

1937 Annie Spitz describes three cases of what is clearly obstructive sleep apnea in patients who have right-sided heart failure, Cheyne-Stokes respiration, snoring, and sleepiness.17 Figure 2.13 is the first known published photograph of a sleep apnea patient. 1939 Nathaniel Kleitman publishes Sleep and Wakefulness as Alternating Phases in the Cycle of Existence. In his brilliant career, he trained many of the pioneer researchers in sleep medicine18 (Fig. 2.14). 1945 Karl-Axel Ekbom introduces the term restless legs syndrome and describes the condition.19 SUBJECT RF

Figure 2.12  ​W.R. Harrison showed in 1934 that Cheyne-Stokes respiration in heart failure improves with treatment.

14  History of Sleep Medicine and Physiology

Figure 2.13  ​Photo from article by Annie Spitz in 1937.

1949 Giuseppe Moruzzi and Horace Magoun describe the reticular activating system and the neurologic basis for wakefulness and arousal.20 1953 Nathaniel Kleitman, at the University of Chicago, assigns a graduate student, Eugene Aserinski, to use eye muscle movements as a measure of the depth of sleep. The method used, electro-oculography, documented REM

sleep. The researchers observed that these movements were associated with dream recall.21 1956 Sydney Burwell and others describe the Pickwickian syndrome. The article, which focused on respiratory failure, did not adequately explain the excessive daytime sleepiness that was the presenting complaint (Fig. 2.15).22 1955 William C. Dement’s brilliant career begins with the studies in REM sleep in humans and animals (Fig. 2.16).23,24 1956 Leo Sternbach discovers the benzodiazepine RO6-690, which led to the approval of librium in 1960. Benzodiazepines replaced the barbiturates as hypnotics. 1959 Michel Jouvet describes REM sleep atonia in cats.24 Within several years Allan Rechtschaffen, William C. Dement, and Michel Jouvet were to head research programs exploring the basic science of sleep (Fig. 2.17A). 1960 Allan Rechtschaffen explores the psychophysiology of dreams.25 1960 Gerry Vogel describes sleep-onset REM in narcolepsy.26 1961 The precursor of the Sleep Research Society is formed. It later becomes the Association for the Psychophysiological Study of Sleep (APSS). Ultimately, the sleep scientists formed the Sleep Research Society. 1963 Richard Wurtman’s group reports that melatonin synthesis in the pineal gland is controlled by light. 1964 The APSS is founded. The APSS became the precursor for the Association of Sleep Disorders Centers (1975), the American Sleep Disorders Association (1987), and, ultimately, the American Academy of Sleep Medicine (1999). 1964–1968 Case reports from three centers in Europe (Carl Jung in Weisbaden in 1965; Henri Gastaut in Marseilles in 1965; Elio Lugaresi in Bologna in 1968) describe what we now know to be the sleep apnea syndrome27–29 (they called the condition Pickwick syndrome; see Fig. 2.17B).

Figure 2.15  ​Dickens’s Joe, the fat boy, from an article by Sydney Burwell. Figure 2.14  ​Nathaniel Kleitman. (Courtesy William C. Dement.)

The illustration used by Burwell was not the original illustration from the novel.

Atlas of Clinical Sleep Medicine   15

A

Figure 2.16  ​William C. Dement at the beginning of his career, 1957.

1967 Lawrence Monroe reports physiologic findings between good and poor sleepers. His description is a precursor of the concept of a hyperarousal state.30 1968 Roger Broughton describes the concept of some parasomnias being disorders of arousal and not related to dreaming31 (see Fig 2.17C). 1968 Allan Rechtschaffen and Anthony Kales produce a sleep scoring manual. It formed the basis of sleep staging for most research for the next 40 years32 (Fig. 2.18). 1970 William C. Dement founds the world’s first sleep disorders center at Stanford University (Fig. 2.19). 1971 Ron Konopka and Seymour Benzer discover a mutant fly with a single gene mutation that could lengthen, shorten, or induce circadian arrhythmia, depending on the location of mutation in the gene.33 1972 Robert Moore (Fig. 2.20) shows that destruction of the suprachiasmatic nucleus (SCN) results in loss of a circadian adrenal corticosterone rhythm, thus establishing the importance of the SCN in circadian physiology.34 Simultaneously, Frederick Stephan and Irving Zucker showed that ablation of the SCN abolishes behavioral rhythms.35 1972 The Rimini Symposium on Hypersomnia and Periodic Breathing, held in Italy, is the first major conference in which sleep apnea is the main focus (Fig. 2.21). At this time, the term sleep apnea had not yet been coined. 1974 Meir H. Kryger describes one of the first cases of sleep apnea in North America and documents that control breathing was normal, hypercapnia was not present, and upper airway resistance changed with position. Kryger showed that significant cardiac arrhythmias, such as bradycardia and asystole, are reversed by tracheostomy (Fig. 2.22).36

B

C Figure 2.17  ​A, Allen Rechtschaffen (left), William C. Dement (center), and

Michael Jouvet (right), 1963. B, Henri Gasteaut (with arm outstretched) teaching trainees in Marseilles, France, circa 1964. To his left is Carlo Tassinari (a coauthor in the apnea papers). C, Roger Broughton, circa 1965. (A, Courtesy William C. Dement.)

16  History of Sleep Medicine and Physiology

Figure 2.18  ​Allan Rechtschaffen and Anthony Kales sleep scoring manual. (Courtesy Meir H. Kryger.)

Figure 2.21  ​The first major sleep apnea symposium was in Rimini, Italy.

Figure 2.19  ​William C. Dement, 2008.

Figure 2.20  ​Robert Moore.

1974 Hewlett-Packard introduces the first fiberoptic-based ear oximeter. 1976 The American Sleep Disorders Association is established. The name is later changed to the American Academy of Sleep Medicine. 1976 Fred Turek and Michael Menaker establish that treatment with melatonin can alter the circadian clock of sparrows, laying the foundation for the use of melatonin and melatonin agonists as chronobiotic drugs today (Fig. 2.23).37 1976 The papers presented at the first American symposium on sleep breathing disorders are published as Sleep Apnea Syndromes.38 The term sleep apnea was first introduced by Christian Guilleminault’s team in 1975 (Fig. 2.24). 1976 Charles Czeisler begins his career by describing the 24-hour cortisol secretory patterns in humans,39 then melatonin rhythms,40 and then the effect of light on the circadian rhythm41 (Fig. 2.25). 1978 Mary Carskadon and colleagues report a large difference between subjective and objective measures of sleep in insomniacs and show that arousals increase with age (Fig. 2.26).42 1978 The first issue of the journal Sleep is published (Fig. 2.27). Christian Guilleminault is the editor. 1981 Colin Sullivan describes the use of nasal continuous positive airway pressure in an article in The Lancet. This revolutionized the treatment of sleep apnea, which up to that time was treated surgically, usually with tracheostomy. Other advancements were made by David Rapoport and Mark Sanders (Fig. 2.28).43 1981 Thomas Roth’s team reported on the many disorders associated with insomnia; this was the precursor of the concept of comorbid insomnia (Fig. 2.29).44

Atlas of Clinical Sleep Medicine   17

Figure 2.22  ​Meir H. Kryger described asystole in sleep apnea. A tracheostomy normalized the cardiac rhythm.

Figure 2.23  ​Sparrow from experiments of Fred Turek and Michael Menaker. Figure 2.25  ​Charles Czeisler.

Figure 2.24  ​Christian Guilleminault.

1982 The National Institutes of Health holds the first consensus symposium conference on insomnia. 1984 Jeffrey Hall and Michael Rosbash at Brandeis University45 and Michael Young at Rockefeller University46 described the period gene in fruit flies. Thirty-three years later, they are awarded the Nobel Prize for this discovery. 1986 The sleep group in Minnesota, led by Carlos H. Schenck (Fig. 2.30) and Mark Mahowald (Fig. 2.31),

Figure 2.26  Mary Carskadon.

describes REM sleep behavior disorder, a condition in which people are not paralyzed during their dreams, but react physically to dream content.47 1986 Sonia Arbilla and Salomon Langer describe zolpidem, the first nonbenzodiazepine with preferential affinity for a BZ1 receptor subtype. 1988 Jiang He and colleagues48 and later that year Christian Guilleminault and colleagues49 show that untreated patients

18  History of Sleep Medicine and Physiology

Figure 2.29  ​Thomas Roth.

Figure 2.27  ​First issue of Sleep.

Figure 2.28  ​David Rapoport (left), Colin Sullivan (center), and Mark Sanders (right).

with sleep apnea have a high mortality rate. This was shown to be particularly true for patients younger than 50 years of age. 1989 Meir H. Kryger, Thomas Roth, and William C. Dement edit the first comprehensive sleep medicine textbook, Principles and Practice of Sleep Medicine (Fig. 2.32).50 1990 The National Sleep Foundation is established in the United States. 1991 Michael Thorpy spearheads the creation of the first International Classification of Sleep Disorders51 (Fig. 2.33). 1993 U.S. legislation establishes the Center for Sleep Disorders Research at the National Institutes of Health. 1993 Terry Young, in the first community-based epidemiologic study on sleep apnea, shows that sleep apnea is extremely common among males and has a high prevalence among females. Up to that time, it was thought that sleep apnea was rare among females.52

Figure 2.30  ​Carlos H. Schenck.

1994 David Gozal explored the anatomic basis of central chemosensitivity in the human brain using functional magnetic resonance imaging53 and later in his career reported diagnostic- and morbidity-related biomarkers and genetics in obstructive sleep apnea.54,55 1994 The first circadian-mutant mammal was produced by Martha Vitaterna, Lawrence Pinto, Fred Turek, Joseph Takahashi, and colleagues by inducing mutations using a chemical mutagen and then screening animals for an abnormal circadian phenotype.56 1995 Nathaniel Kleitman gives a lecture at 100 years of age at the APSS (Fig. 2.34). 1997 Modafinil is shown to be effective as a stimulant. Ultimately, it was found to be an efficacious treatment in narcolepsy and later in other clinical conditions of excessive sleepiness.

Atlas of Clinical Sleep Medicine   19

Figure 2.33  ​Michael Thorpy. Figure 2.31  ​Mark Mahowald.

Figure 2.34  ​Nathaniel Kleitman, 100 years of age. (Courtesy Meir H. Kryger.) Figure 2.32  ​Principles and Practice of Sleep Medicine, first edition.

1997 Joseph Takahashi, Lawrence Pinto, and Fred Turek’s team at Northwestern University discover and clone the first mammalian circadian clock gene called Clock.57 Soon many circadian genes were found to be similar in flies, mice, and humans, demonstrating the conservation of function over a prolonged evolutionary period. Figure 2.35 shows the circadian phenotype in wild-type, heterozygous, and homozygous mutant animals. 1999 Eve Van Cauter demonstrates that sleep restriction can induce, in otherwise healthy people, physiologic and endo-

crine changes indicative of early signs of insulin resistance.58 This led to a flood of epidemiologic, clinical, and animal studies for investigating the relationship between chronic partial sleep loss and obesity, diabetes, and cardiovascular disease (Fig. 2.36). 1999 Following a 10-year search, Emmanuel Mignot’s group found that familial narcolepsy in dogs was caused by mutations in the hypocretin receptor 2 (HcrtR2) gene (Fig. 2.37).59 Shortly after, Mashashi Yanagisawa’s group independently found that hypocretin knockout mice also had narcolepsy.60 This was followed by the discovery at Stanford University61 and confirmed by Jerome Siegel’s

20  History of Sleep Medicine and Physiology Time (hour) 0

24

48

Day

1

30

A Time (hour) 0

24

Figure 2.37  ​Narcoleptic puppies.

48

Day

1

30

B Time (hour) 0

24

48

1 Day

f

A

30

C Figure 2.35  ​Activity-rest plots in wild-type and two mutant animals.

f

B Figure 2.38  ​A, Narcolepsy. B, Normal hypocretin gene expression in brain. (Courtesy Emmanuel Mignot.)

Figure 2.36  ​Eve Van Cauter.

group62 at the University of California, Los Angeles, that most cases of human narcolepsy with cataplexy and HLADQB1*0602 positivity are associated with a loss of hypocretin peptide in the cerebrospinal fluid and the brain (Fig. 2.38).

2005 The National Institutes of Health holds a second consensus conference on management of insomnia. 2005 Fred Turek (Fig. 2.39) and his colleagues reported that Clock-mutant mice develop an abnormal feeding rhythm, become hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic dysfunction, hyperglycemia, and hypoinsulinemia, suggesting that the circadian clock gene network is intimately involved in mammalian energy balance.63 2007 Juliane Winkelmann found through a genome-wide association study that single nucleotide polymorphisms in the

Atlas of Clinical Sleep Medicine   21

Figure 2.39  ​Fred Turek.

BTBD9, MEIS1, and MAP2K5/LBXCOR1 regions are associated with RLS.64 Hreinn Stefansson, David Rye, and their colleagues65 also found independently that the BTBD9 polymorphism was associated with low ferritin levels, periodic limb movement (PLM), and to a lesser extent RLS. 2008 The Centers for Disease Control and Prevention establish sleep as one of its areas of interest, thereby placing the topic onto the public health agenda. 2010 Joe Bass’s laboratory reports that Clock genes in pancreatic islet cells regulate insulin secretion.66 2011 Mitchell A. Lazar’s laboratory reports the linkage of the metabolic and clock genes for hepatic lipid metabolism.67 2012 Rachel Edgar and colleagues linked the co-evolution of cellular circadian and metabolic timekeeping with redox homeostatic mechanisms, which began about 2.5 billion years ago.68 2014 Phyllis Zee laid the foundation to the development of treatments for circadian-based disorders, and in 2014 she established and continues to lead the first circadian medicine

Figure 2.40  ​Phyllis Zee.

clinic in the United States. She made numerous invaluable contributions to understanding the mechanisms linking circadian rhythm disturbances with neurologic and cardiometabolic disorders69 (Fig. 2.40). 2017 A Nobel Prize is awarded to Jeffrey Hall, Michael Rosbash, and Michael Young, who described the period gene in fruit flies in 1984. 2019 Since the discovery of the glymphatic system, research has focused on the effect of sleep on clearance of abnormal chemical products in the brain.70, 71 2020 The COVID-19 pandemic affected sleep in the uninfected population and the infected population, with insomnia and fatigue being common in patients with long COVID.72 2026 The 50th anniversary of the American Academy of Sleep Medicine. Visit eBooks.Health.Elsevier.com for the References and Bibliography for this chapter.

e1 References

1. Athenaeus, Gulick CB. The Deipnosophists. London: Heinemann; 1927. 2. Aristotle, Beare JI, Ross GRT. The Parva naturalia: De sensu et sensibili, De memoria et reminiscentia, De somno, De somniis, De divinatione per somnum. Oxford: Clarendon Press; 1908. 3. Cervantes Saavedra Md. El ingenioso hidalgo don Qvixote de la Mancha. Valencia: Impresso en casa de P. P. Mey; 1605. 4. Willis T. De Anima Brutorum Quæ Hominis Vitalis Ac Sensitiva Est, Exercitationes Duæ. Oxon; 1672. 5. Mairan D. Observation botanique. In Histoire de l’Academie Royale des Sciences. Paris; 1729. 6. Wadd W. Cursory Remarks on Corpulence; or Obesity Considered as a Disease. 3rd ed. London; 1816. 7. Lyons JB. John Cheyne’s classic monographs. J Hist Neurosci. 1995;4(1):27–35. 8. Dickens C. The Posthumous Papers of the Pickwick Club, ed. by ‘Boz’. Philadelphia; 1836. 9. Hammond WA. Sleep and its Derangements. n.p.1869. 10. Caton R. The electrical currents of the brain. Br Med J. 1875;2:278. 11. Westphal C. Eigentümliche mit Einschlafen verbundene Anfälle. Archiv für Psychiatrie und Nervenkrankheiten. 1877;7:631–635. 12. Gélineau J. De la narcolepsie. Gazette des Hôpitaux. 1880;53:626–628. 13. Wells W. Some nervous and mental manifestations occuring in connection with mental disease. Am J Med Sci. 1898:677–682. 14. Berger H. Uber das Elektrenkephalogramm des Menschen. Arch F Psychiat. 1929;87:527–570. 15. Harrison WR, King CE, Calhoiun JA. Congestive heart failure. Cheyne-Stokes respiration as the cause of paroxysmal dyspnea at the onset of sleep. Arch Intern Med. 1934;53:891–910. 16. Loomis AL, Harvey EN, Hobart G. Potential rhythms of the cerebral cortex during sleep. Science. 1935;81(2111):597–598. 17. Spitz A. Das klinische syndrome narkolepsie mit fettsucht und polyglobulie in seinen bezichungen zum morbus Cushing. Dtsch Arch Klin Med. 1937;181. 18. Kleitman N. Sleep and Wakefulness as Alternating Phases in the Cycle of Existence. Chicago: Univ. of Chicago Press; 1939. 19. Ekbom K. Restless legs: clinical study of hitherto overlooked disease (Thesis). Acta Medica Scandinavica. 1945;121:1–123. 20. Moruzzi G, Magoun H. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949;1: 455–473. 21. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science. 1953;118(3062):273–274. 22. Bickelmann AG, Burwell CS, Robin ED, Whaley RD. Extreme obesity associated with alveolar hypoventilation; a Pickwickian syndrome. Am J Med. 1956;21(5):811–818. 23. Dement W. Dream recall and eye movements during sleep in schizophrenics and normals. J Nerv Ment Dis. 1955;122(3):263–269. 24. Jouvet M, Michel F, Courjon J. On a stage of rapid cerebral electrical activity in the course of physiological sleep. C R Seances Soc Biol Fil. 1959;153:1024–1028. 25. Trosman H, Rechtschaffen A, Offenkrantz W, Wolpert E. Studies in psychophysiology of dreams. IV. Relations among dreams in sequence. Arch Gen Psychiatry. 1960;3:602–607. 26. Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Arch Gen Psychiatry. 1960;3:421–428. 27. Gastaut H, Tassinari CA, Duron B. Polygraphic study of diurnal and nocturnal (hypnic and respiratory) episodal manifestations of Pickwick syndrome. Rev Neurol (Paris). 1965;112(6):568–579. 28. Junk R, Kuhlo W. Neurophysiological studies of abnormal night sleep and the Pickwickan syndrome. In: Bally C, Stradlé J, eds. Sleep Mechanisms. Amsterdam: Elsevier; 1965. 29. Lugaresi E, Coccagna G, Petrella A, Berti Ceroni G, Pazzaglia P. The disorder of sleep and respiration in the Pickwick syndrome. Sist Nerv. 1968;20(1):38–50. 30. Monroe LJ. Psychological and physiological differences between good and poor sleepers. J Abnorm Psychol. 1967;72(3):255–264. 31. Broughton RJ. Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in “dreaming sleep.” Science. 1968;159(3819):1070–1078. 32. Kales A, Rechtschaffen A, University of California Los Angeles. Brain Information Service., NINDB Neurological Information Network. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Bethesda, MD: U.S. National

Institute of Neurological Diseases and Blindness, Neurological Information Network; 1968. 33. Konopka RJ, Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1971;68(9):2112–2116. 34. Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 1972;42(1):201–206. 35. Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A. 1972;69(6):1583–1586. 36. Kryger M, Quesney LF, Holder D, Gloor P, MacLeod P. The sleep deprivation syndrome of the obese patient. A problem of periodic nocturnal upper airway obstruction. Am J Med. 1974;56(4):530–539. 37. Turek FW, McMillan JP, Menaker M. Melatonin: effects on the circadian locomotor rhythm of sparrows. Science. 1976;194(4272):1441–1443. 38. Guilleminault C, Dement WC, Kroc Foundation. Sleep Apnea Syndromes. New York: A. R. Liss; 1978. 39. Czeisler CA, Ede MC, Regestein QR, Kisch ES, Fang VS, Ehrlich EN. Episodic 24-hour cortisol secretory patterns in patients awaiting elective cardiac surgery. J Clin Endocrinol Metab. 1976;42(2):273–283. 40. Weitzman ED, Weinberg U, D’Eletto R, et al. Studies of the 24 hour rhythm of melatonin in man. J Neural Transm Suppl. 1978(13):325– 337. 41. Czeisler CA, Richardson GS, Zimmerman JC, Moore-Ede MC, Weitzman ED. Entrainment of human circadian rhythms by light-dark cycles: a reassessment. Photochem Photobiol. 1981;34(2):239–247. 42. Richardson GS, Carskadon MA, Flagg W, Van den Hoed J, Dement WC, Mitler MM. Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol. 1978;45(5):621–627. 43. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet. 1981;1(8225):862–865. 44. Zorick FJ, Roth T, Hartze KM, Piccione PM, Stepanski EJ. Evaluation and diagnosis of persistent insomnia. Am J Psychiatry. 1981;138(6): 769–773. 45. Reddy P, Zehring WA, Wheeler DA, et al. Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms. Cell. 1984;38(3):701–710. 46. Bargiello TA, Young MW. Molecular genetics of a biological clock in Drosophila. Proc Natl Acad Sci U S A. 1984;81(7):2142–2146. 47. Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep. 1986;9(2):293–308. 48. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest. 1988;94(1):9–14. 49. Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients. Mortality. Chest. 1988;94(6):1200–1204. 50. Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: Saunders; 1989. 51. Thorpy MJ, American Sleep Disorders Association. Diagnostic Classification Steering Committee. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. Pocket ed. Rochester, MN: ASDA; 1991. 52. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230–1235. 53. Hathout GM, Kirlew KA, So GJ, et al. MR imaging signal response to sustained stimulation in human visual cortex. J Magn Reson Imaging. 1994;4(4):537–543. 54. Kheirandish-Gozal L, Gozal D. Pediatric OSA syndrome morbidity biomarkers: the hunt is finally on! Chest. 2017;151(2):500–506. 55. Xu Z, Gutierrez-Tobal GC, Wu Y, et al. Cloud algorithm-driven oximetry-based diagnosis of obstructive sleep apnoea in symptomatic habitually snoring children. Eur Respir J. 2019;53(2). 56. Vitaterna MH, King DP, Chang AM, et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science. 1994;264(5159):719–725. 57. Antoch MP, Song EJ, Chang AM, et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell. 1997;89(4):655–667. 58. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435–1439.

e2 59. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365–376. 60. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437–451. 61. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39–40. 62. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–474. 63. Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005;308(5724):1043–1045. 64. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39(8):1000–1006. 65. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357(7):639–647. 66. Marcheva B, Ramsey KM, Buhr ED, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466(7306):627–631. 67. Feng D, Liu T, Sun Z, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331(6022):1315–1319. 68. Edgar RS, Green EW, Zhao Y, et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature. 2012;485(7399):459–464. 69. Reid KJ, Santostasi G, Baron KG, Wilson J, Kang J, Zee PC. Timing and intensity of light correlate with body weight in adults. PLoS One. 2014;9(4):e92251.

70. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018;17(11):1016–1024. 71. Carlstrom LP, Eltanahy A, Perry A, et al. A clinical primer for the glymphatic system. Brain. 2022;145(3):843–857. 72. Kumar N, Gupta R. Disrupted sleep during a pandemic. Sleep Med Clin. 2022;17(1):41–52.

Bibliography

Bailey DR, Attanasio R. The history of sleep medicine. Dent Clin North Am. 2012;56(2):313–317. Dement WC. History of sleep medicine. Neurol Clin. 2005;23(4):945–965, v. doi:10.1016/j.ncl.2005.07.001 Huon LA, Guilleminault C. A succinct history of sleep medicine. Adv Otorhinolaryngol. 2017;80:1–6. Kirsch DB. There and back again: a current history of sleep medicine. Chest. 2011;139(4):939–946. Kryger MH. Sleep apnea. From the needles of Dionysius to continuous positive airway pressure. Arch Intern Med. 1983;143(12):2301–2303. Kryger M. Charles Dickens: impact on medicine and society. J Clin Sleep Med. 2012;8(3):333–338. Schulz H. The history of sleep research and sleep medicine in Europe. J Sleep Res. 2022;31(4):e13602. Shepard JW Jr, Buysse DJ, Chesson AL Jr, et al. History of the development of sleep medicine in the United States. J Clin Sleep Med. 2005; 1(1):61–82.

Section 3  |  The Biology of Sleep Chapter

3

Sleep Mechanisms Patrick M. Fuller, Phyllis C. Zee, Orfeu M. Buxton, and Alon Y. Avidan

Sleep is an active process whose timing and length are controlled by discrete structures in the nervous system (Figs. 3.1 and 3.2). Current data suggest that sleep may also be a localized process and that the whole brain is not “asleep” at the same time. When the opportunity for sleep arises, humans transition to sleep via sleep- and wake-promoting groups of cells that exert mutually inhibitory activity. Neurons in the ventrolateral preoptic (VLPO) nucleus are the most important for transitioning into sleep as they inhibit wake-promoting systems. The key neurotransmitters and hormones involved in sleep induction include g-aminobutyric acid (GABA) and melatonin, while serotonin, acetylcholine, and glutamate are predominantly involved in promoting wakefulness. Orexin neurons send output signals to a wide variety of brain regions that regulate wakefulness, rapid eye movement (REM) sleep and non-REM sleep and act via these regions to maintain and stabilize wakefulness. Loss of orexin neurons, as occurs in human narcolepsy, results in debilitating excessive daytime sleepiness, sleep attacks, and wake instability.

AROUSAL SYSTEMS The concept has evolved that sleep control uses centers and processes that cause arousal and those that promote sleep (Figs. 3.3 and 3.4; see Fig 3.2). SLEEP-PROMOTING SYSTEMS The VLPO system and adjacent median preoptic nuclei (MnPO) are sleep-active neurons. Loss of VLPO neurons produces profound insomnia and sleep fragmentation (see Figs. 3.3 and 3.4). Neurotransmitter systems governing sleep and wakefulness are illustrated in Fig. 3.5. Arousal during wakefulness is achieved via the ascending reticular activating system (ARAS) and the dorsal and ventral pathways to the cortex. Promotion of sleep is brought about by GABAergic neurons within the cortex, the brainstem, the ventrolateral preoptic

GABA Ventrolateral preoptic nucleus

Melatonin (regulation) Suprachiasmatic nucleus Melatonin Pineal gland

Glutamate Brain cortex

Melanin-concentrating hormone

Orexin

Locus coeruleus Dorsal raphe

Lateral hypothalamus cortex

Dopamine

Serotonin

Ventral tegmental area Acetylcholine

Raphe nucleus

Pontine reticular formation

Figure 3.1  ​This sagittal section of the brain illustrates discrete areas and corresponding neurotransmitters responsible for sleep (blue) and wake (red) transi-

tion and maintenance. GABA, γ-aminobutyric acid.(From Ballester P, Richdale AL, Baker EK, Peiró AM. Sleep in autism: a biomolecular approach to aetiology and treatment. Sleep Med Rev. 2020;54:101357.)

22

Atlas of Clinical Sleep Medicine   23 Sleep

Wake Cerebral cortex

Thalamus Site of sleep spindle generation Pineal gland

Dorsal raphe

Regulated by the SCN Site of melatonin production Melatonin production increases before sleep

Cells mainly active during wakefulness Serotonin neurons

Medullary GABA neurons

Locus coeruleus

Sleep-active neurons

Cells mainly active during wakefulness Norepinephrine neurons

Lateral hypothalamus Cells mainly active during wakefulness Orexin neurons Stabilize wakefulness Tuberomammillary nucleus

Preoptic area Ventrolateral preoptic nucleus (VLPO) Median preoptic nucleus (MnPO) Cells active during sleep Galanin (Gal) neurons g-aminobutyric acid (GABA) neurons

Cells mainly active during wakefulness Histamine neurons Suprachiasmatic nucleus Controls circadian timing of sleep/wakefulness Inputs via retinohypothalamic tract

Figure 3.2  ​The basic circuitry, including key “nodes,” that underlies the regulation of sleep and wakefulness and the transitions between these states in mam-

mals. Current models of wakefulness and sleep hold that wakefulness is maintained by the combined excitatory influence of forebrain-projecting noradrenergic (locus coeruleus), histaminergic (tuberomammillary nucleus), serotoninergic (dorsal raphe), and cholinergic (not shown) cell groups located at or near the mesopontine junction. Sleep, on the other hand, is initiated and maintained by neurons in the median preoptic (MnPO) and ventrolateral preoptic (VLPO) nuclei via inhibitory projections to the more rostrally situated wakefulness-promoting cell groups. Hypocretin (orexin) neurons located in the lateral hypothalamus reinforce activity in the brainstem arousal pathways and also stabilize both sleep and wakefulness. Disruption of the hypocretin system leads to narcolepsy. The suprachiasmatic nuclei (SCN) determine the timing of the sleep-wake cycle and help “consolidate” these behavioral states. The pineal gland, located in the epithalamus, produces melatonin, a hormone thought to function as a hypnotic signal. The cerebral cortex and medullary brainstem also contain subpopulations of g-aminobutyric acid (GABA)-ergic sleep-active neurons.

nucleus, parts of the lateral hypothalamus, the basal forebrain, and the subthalamus. Switching between sleep states is determined by an oscillatory circuit in the brainstem (Fig. 3.6). Sleeppromoting neuronal networks appear to form mutually inhibitory connections with arousal-promoting neuronal networks. This relationship has been likened to a flip-flop switch that favors rapid transitions and state stability. Cortical arousal, measured via the electroencephalogram, is illustrated in Fig. 3.7. SLEEP DRIVE The cellular determinant of homeostatic sleep drive is promoted by the endogenous somnogen, adenosine. Sleep drive has been conceptualized as a homeostatic pressure that builds during the diurnal waking period and is subsequently dissipated by sleep during the night. This homeostatic process, or “sleep homeostat,” represents the drive or the need for sleep (Fig. 3.8).

CONTROL OF RAPID EYE MOVEMENT SLEEP REM sleep is a distinct state in which the function of the central nervous system and the autonomic nervous system differs from both wakefulness and non-REM sleep (Fig. 3.9). CONTROL OF THE TIMING OF SLEEP In mammals, the circadian clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus is fundamental for establishing the circadian rhythm of sleep-wake cycles. Regulation of sleep and wakefulness by the SCN is evident because the sleepwake cycle continues on an approximately 24-hour basis, even when environmental conditions are constant (i.e., in the absence of environmental time cues), but only if the SCN is intact. In humans, a clear circadian variation in sleep propensity and sleep structure has been demonstrated by uncoupling the rest-activity cycle from the output of the circadian pacemaker (Fig. 3.10). Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

24  Sleep Mechanisms

A

B

A

Cat is comatose

Th Aq

Awake

V3

O

B

Asleep

Hy K.oculomet

V4 Cerebral cortex

Cerebellum Afferent collaterals

Figure 3.3  ​An active role for the brain in sleep-wake behavior was first indi-

cated in 1916, when Baron Constantine von Economo performed a postmortem brain analysis on victims of a viral encephalitis—encephalitis lethargica, or von Economo’s “sleeping sickness”—that profoundly affected sleep-wake regulation. As seen here in the original drawing taken from von Economo’s clinicoanatomic studies, lesions at the junction of the midbrain and posterior hypothalamus (diagonal hatching) produced hypersomnolence. By contrast, lesions of the basal forebrain and anterior hypothalamus (horizontal hatching) produced profound insomnia. Von Economo also observed that lesions between these two sites (arrow), which included the lateral hypothalamic area, caused narcolepsy. O, Optic nerve (second cranial nerve); V3, third ventricle; Hy, hypothalamus; Th, thalamus; V4, fourth ventricle; Aq, cerebral aqueduct; K. oculomet, oculomotor nerve (third cranial nerve). (From Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis. 1930;71[3]:249–259.)

Thalamus Subthalamus and hypothalamus

Midbrain Pons

Bulb Ascending reticular activating system in brainstem Figure 3.4  ​Top, In 1935, Frédéric Bremer uncovered evidence of an ascending arousal system necessary for cortical arousal when he demonstrated that transection of the brainstem at the pontomesencephalic level (cerveau isole, A), but not the spinomedullary junction (encephale isole, B), produced coma in anesthetized cats. Bremer hypothesized that the resulting reduction in “cerebral tone” following the cerveau isole was caused by interruption of ascending sensory inputs, that is, a passive deafferentation theory of sleep. More than a decade after Bremer’s transection experiments, Giovanni Moruzzi, a student of Bremer’s, and Horace Magoun demonstrated that electrical stimulation of the rostral pontine reticular formation produced a desynchronized electroencephalogram, an electrophysiologic correlate of the conscious state, in anesthetized cats. Moruzzi and Magoun interpreted their experimental data as evidence for an active “waking center” in the mesopontine reticular formation, essentially refuting the deafferentation theory of sleep. Moruzzi and Magoun called this brainstem system the ascending reticular activating system. (Top, Modified from Bremer F. Bulletin de l’Académie Royale de Belgique 1937;4.)

Atlas of Clinical Sleep Medicine   25

Thalamus

Thalamus

LHA (ORX. vPAG (DA) MCH)

LHA

BF (ACh TMN Raphe GABA) (His) (5-HT)

Hypothalamus

vPAG

VLPO (Gal, GABA)

LDT (ACh) PPT (ACh)

LDT PPT

TMN Raphe

Cerebellum

LC (NE)

Hypothalamus

Pons

LC

Cerebellum

Pons

Medulla

Medulla

A

B

Figure 3.5  ​In the 1970s and 1980s, the neurochemistry of several brainstem “arousal” centers was elaborated. A, In the contemporary view, the ascending

arousal system consists of noradrenergic (NE) neurons of the ventrolateral medulla and locus coeruleus (LC), cholinergic neurons (ACh) in the pedunculopontine tegmental/laterodorsal tegmental (PPT/LDT) nuclei, serotonergic (5-hydroxytryptamine [5-HT]) neurons in the dorsal raphe nucleus, dopaminergic neurons (DA) of the ventral periaqueductal gray matter (vPAG), and histaminergic neurons (His) of the tuberomammillary nucleus (TMN). Wakefulness-promoting glutamatergic neurons of the parabrachial nucleus also provide direct innervation of the hypothalamus, basal forebrain (BF), and cerebral cortex. These systems collectively produce cortical arousal via two pathways: a dorsal route through the thalamus and a ventral route through the hypothalamus and BF. The latter pathway receives contributions from the hypocretin (orexin, ORX) and melanin-concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) as well as from g-aminobutyric acid (GABA)-ergic or cholinergic neurons of the BF. Note that all of these ascending pathways traverse the region at the midbrain-diencephalic junction, where von Economo observed that lesions caused hypersomnolence. As shown here, several putative brainstem arousal centers were identified and characterized nearly 30 years ago. It nevertheless remained unclear for many years how this arousal system was “turned off” so sleep could be initiated and maintained. B, Although work by Walle J.H. Nauta in 1946 provided support for the concept of sleep-promoting circuitry in the anterior hypothalamus/preoptic area, it was not until the mid-1990s that the identity of this sleep-promoting circuitry was revealed. In these investigations, it was demonstrated that the median preoptic nucleus and ventrolateral preoptic nucleus (VLPO) contain sleep-active cells, the latter of which contains the inhibitory neurotransmitters GABA and galanin (Gal). The VLPO (orange circle) projects to all the main components of the ascending arousal system. Inhibition of the arousal system by the VLPO during sleep is critical for the maintenance and consolidation of sleep. Recent work has revealed a node of GABAergic neurons in the parafacial zone of the rostral medulla that are also sleep active.

Orexin

Sleep VLPOc VLPOex

Homeostatic sleep drive Circadian “hypnotic” signal

TMN LC-raphe

Awake

Orexin TMN LC-raphe VLPOc VLPOex

Circadian “alerting” signal

Figure 3.6  ​The main sleep-promoting pathways from the ventrolateral preoptic nuclei (VLPO) and median preoptic nucleus (MnPO) inhibit the components of

the ascending arousal pathways in both the hypothalamus and the brainstem, including awake-active noradrenergic neurons of the ventrolateral medulla and locus coeruleus (LC), cholinergic neurons in the pedunculopontine tegmental/laterodorsal tegmental nuclei, serotonergic neurons in the dorsal raphe nucleus, dopaminergic neurons of the ventral periaqueductal gray matter, histaminergic neurons of the tuberomammillary nucleus (TMN), and glutamatergic neurons of the parabrachial nucleus. This interaction between the VLPO and MnPO and components of the arousal system is, to a large degree, mutually inhibitory, and as such these pathways function analogously to an electronic “flip” switch/circuit. By virtue of the self-reinforcing nature of these switches—that is, when each side is firing, it reduces its own inhibitory feedback—the flip switch is inherently stable in either end state, but it avoids intermediate states. The flip design thus ensures stability of the behavioral state and facilitates rapid switching between behavioral states. The LH (lateral hypothalamic) orexin (hypocretin) neurons likely play a stabilizing role for the switch. Specifically, it appears that LH orexin neurons actively reinforce monoaminergic arousal tone. The position of the orexin neurons outside the flip switch permits them to stabilize the behavioral state by reducing transitions during both sleep and wakefulness. Narcoleptic humans or animals that lack orexin have increased transitions in both states. VLPOex, extended ventrolateral preoptic nucleus; VLPOc, core ventrolateral preoptic nucleus. (Modified from Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms. 2006;21[6]:482–493.)

26  Sleep Mechanisms

Cx 

 RE

 

TC

Th LDT PPT

LDT/PPT control of thalamocortical circuit

Figure 3.7  ​During cortical arousal, the electroencephalogram directly reflects the collective synaptic potentials of inputs, largely to pyramidal cells within the

neocortex and hippocampus. The thalamocortical (TC) system has been widely considered to be a major source of this activity. In turn, the overall level of activity in the TC system is thought to be regulated by the ascending arousal system. Today, it is generally accepted that a brainstem cholinergic activating system, located in the pedunculopontine tegmental (PPT) and laterodorsal tegmental (LDT) nuclei (green ovals), induces tonic and phasic depolarization effects on TC neurons to produce the low-voltage, mixed-frequency, fast activity of the waking and rapid eye movement (REM) sleep electroencephalogram (EEG). The PPT and LDT cease firing during non-REM (NREM) sleep, which hyperpolarizes the TC neurons to produce two important effects: (1) sensory transmission through the thalamus (Th) to the cortex is blocked; and 2) oscillatory activity between TC neurons, cortical neurons (Cx), and reticular thalamus (RE) neurons (inset) is unmasked to manifest several characteristics of the sleep EEG—slow-wave activity (0.5 to 4 Hz) and spindles. Thus the thalamus appears to be a critical relay for the ascending arousal system for “gating” sensory transmission to the cortex during sleep and wakefulness. In addition to the thalamus, a critical “relay” role for the basal forebrain in maintaining electrocortical and neurobehavioral arousal has also recently been demonstrated.

MnPO BF

VLPO A2A

A

Cholinergic neurons

A1

Adenosine (% of hour 2)

250 200 150 100 50 0

1 2 3 4 5 6 Prolonged waking

1 2 3 (hours) Recovery

B Adenosine Figure 3.8  ​The cellular determinant of homeostatic sleep drive is unknown, although a putative endogenous somnogen, adenosine, is believed to play a critical role. A, Adenosine is a naturally occurring purine nucleoside. It is hypothesized that adenosine accumulates during wakefulness, and upon reaching sufficient concentrations, it inhibits neural activity in wake-promoting circuitry of the basal forebrain (BF) via A1 receptors located on BF cholinergic neurons. It is likely that it activates sleep-promoting ventrolateral preoptic nuclei (VLPO) neurons, via A2A receptors, located adjacent to the BF. A role for adenosine and BF cholinergic neurons in sleep homeostasis has been challenged by Blanco-Centurion and colleagues. B, Mean BF extracellular adenosine values by hour during 6 hours of prolonged wakefulness and in the subsequent 3 hours of spontaneous recovery sleep in cats. Microdialysis values in the six animals are normalized relative to the second hour of wakefulness. MnPO, Median preoptic nucleus.(Data from Porkka-Heiskanen T, Strecker RE, Thakkar M, et al. Adenosine: a mediator of the sleepinducing effects of prolonged wakefulness. Science. 1997;276[5316]:1265–1268.)

Atlas of Clinical Sleep Medicine   27

SLD/PC (REM-on) vIPAG/LPT (REM-off)

A LDT/PPT (REM-on) orexin VLPO LC/DR

Figure 3.9  ​In this contemporary model of rapid eye movement (REM) sleep

and non-REM (NREM) sleep switching, two populations of mutually inhibitory neurons in the upper pons form a switch for controlling transitions between REM and NREM sleep (A). g-Aminobutyric acid (GABA)-ergic ventrolateral periaqueductal gray matter (vlPAG, light green) neurons and laterodorsal tegmental/pedunculopontine (LPT/PPT, light green) neurons fire during non-REM states to inhibit entry into REM sleep, during which these neurons are inhibited by a population of GABAergic REM sleep–active neurons in the sublaterodorsal region (SLD; red). This mutually inhibitory relationship produces an REM-NREM flip switch, promoting rapid and complete transitions between these states. The core REM sleep switch is, in turn, modulated by other neurotransmitter systems (B). Noradrenergic neurons in the locus coeruleus (LC) and serotonergic neurons in the dorsal raphe (DR; dark green) inhibit REM sleep by actions on both sides of the flip switch (exciting REM-off neurons and inhibiting REM-on neurons); during REM sleep, they are silent (dashed lines), whereas cholinergic neurons (blue) promote REM sleep by having opposite actions on the same two neuronal populations. The hypocretin (orexin) neurons inhibit entry into REM sleep by exciting neurons in the REM-off population (and by presynaptic effects that excite monoaminergic terminals), whereas the ventrolateral preoptic nuclei (VLPO) neurons promote entry into REM sleep by inhibiting this same target. During REM sleep (C), a separate population of glutamatergic neurons in the SLD (red) activates a series of inhibitory interneurons in the medulla and spinal cord, which inhibit motor neurons and thereby produce the atonia of REM sleep. Withdrawal of tonic excitatory input from the REM-off regions may also contribute to the loss of muscle tone. At the same time, ascending projections from glutamatergic neurons in the parabrachial (PB) nucleus and precoeruleus (PC) area activate forebrain pathways that drive EEG desynchronization and hippocampal theta rhythms, thus producing the characteristic EEG signs of REM sleep. BF, Basal forebrain; EEG, electroencephalogram. (Modified from Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68[6]:1023–1042.)

SLD/PC (REM-on)

vIPAG/LPT (REM-off)

B REM EEG

BF SLD/PC (REM-on) vIPAG/LPT (REM-off) Medullary interneurons Spinal interneurons

C

REM atonia

 Motor neurons

28  Sleep Mechanisms

Corticosteroid release

Wakefulness, feeding

CRH

Sleep

PVH

GABA

orexin glu

dSPZ

TRH

VLPO

A

MCH

LHA

DMH

vSPZ

SCN

Melatonin Sleep-wake Light state

PVH dSPZ

PACAP

Feeding cues

glu

DMH

vSPZ NPY, GABA

B

SCN

5-HT

IGL, MRN

Locomotor activity

Figure 3.10  ​The circadian rhythm of sleep-wake cycles is likely regulated at multiple levels in the hypothalamus. Top, A coronal section of the brain shows the

location (box) of the rat suprachiasmatic nucleus (SCN). A, The circadian clock in the SCN sends an indirect projection to the dorsomedial hypothalamic nucleus (DMH) via the subparaventricular zone (SPZ), which is critical for the circadian rhythm of sleep-wake cycles. The DMH, in turn, provides rhythmic output to brain regions critical for the regulation of sleep and wakefulness, hormone synthesis and release, and feeding. B, This multistage regulation of circadian behavior in the hypothalamus allows for the integration of multiple time cues from the environment to shape daily patterns of sleep and wakefulness. 5-HT, 5-hydroxytryptamine (serotonin); CRH, corticotrophin-releasing hormone; dSPZ, dorsal subparaventricular zone; GABA, g-amino butyric acid; glu, glutamate; IGL, intergeniculate leaflet; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; MRN, median raphe nucleus; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating polypeptide; PVH, paraventricular hypothalamic nucleus; TRH, thyrotropin-releasing hormone; VLPO, ventrolateral preoptic nucleus; vSPZ, ventral subparaventricular zone. (Modified from Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms. 2006;21[6]:482–493.)

e1 Bibliography

Anaclet C, Lin JS, Vetrivelan R, et al. Identification and characterization of a sleep-active cell group in the rostral medullary brainstem. J Neurosci. 2012;32(50):17970–17976. Ballester PAL, Richdale EK, Peiró AM. Sleep in autism: a biomolecular approach to aetiology and treatment. Sleep Med Rev. 2020;54:101357. Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol. 2004;73(6):379–396. Blanco-Centurion C, Xu M, Murillo-Rodriguez E, et al. Adenosine and sleep homeostasis in the basal forebrain. J Neurosci. 2006;26(31): 8092–8100. Bremer F. Cerveau “isole” et physiologie du sommeil. Comptes Rendus de la Société de Biologie (Paris). 1935;118:1235–1241. Bremer F. Preoptic hypnogenic area and reticular activating system. Arch Ital Biol. 1973;111:85–111. De Luca R, Nardone S, Grace KP, et al. Orexin neurons inhibit sleep to promote arousal. Nat Commun. 2022;13(1):4163. Edgar DM, Dement WC, Fuller CA. Effect on SCN lesions on sleep in squirrel monkeys: processes in sleep-wake regulation. J Neurosci. 1993;13(3): 1065–1079. Fuller PM, Sherman D, Pedersen NP, Saper CB, Lu J. Reassessment of the structural basis of the ascending arousal system. J Comp Neurol. 2011; 519(5):933–956. Gerashchenko D, Wisor JP, Burns D, et al. Identification of a population of sleep-active cerebral cortex neurons. Proc Natl Acad Sci U S A. 2008; 105(29):10227–10232. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature. 2006;441(7093):589–594.

Luppi PH, Fort P. Sleep-wake physiology. Handb Clin Neurol. 2019;160:359–370. Morairty S, Rainnie D, McCarley R, Greene R. Disinhibition of ventrolateral preoptic area sleep-active neurons by adenosine: a new mechanism for sleep promotion. Neuroscience. 2004;123(2):451–457. Moruzzi G, Magoun H. Brainstem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949;1:455–473. Nauta WJH. Hypothalamic regulation of sleep in rats: experimental study. J Neurophysiol. 1946;9:285–316. Peever J, Fuller PM. The biology of REM sleep. Curr Biol. 2017;27(22):R1237–R1248. Scamell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747–765. Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci. 1998;18(12):4705–4721. Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Activation of ventrolateral preoptic neurons during sleep. Science. 1996;271(5246):216–219. Steiner MA, Yanagisawa M, Clozel M, eds. The Orexin System. Basic Science and Role in Sleep Pathology. Frontiers of Neurology and Neuroscience. Vol 45. Basel: Karger; 2021:38–51. Steriade M, McCormick DA, Sejnowski TJ. Thalamocortical oscillations in the sleeping and aroused brain. Science. 1993;262:679–685. Todd WD, Venner A, Anaclet C, et al. Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations. Nat Commun. 2020;11(1):4410. Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis. 1930;71:249–259.

Chapter

Localization and Neurochemistry of Sleep-Wake Physiology and Pathophysiology

4

Logan Douglas Schneider

INTRODUCTION This chapter provides an overview of the main neurocircuitry and neurotransmitters that underly three main states of consciousness: the wake state, non–rapid eye movement (NREM) sleep, and REM sleep. The mechanisms by which the brain can maintain and seamlessly transition between these states are also discussed. Wakefulness appears to be facilitated by fast-acting neurotransmitters (mainly glutamate) that are released by a number of widely distributed neuronal populations from the parabrachial nucleus/precoeruleus (PB/PC) to the basal forebrain (BF) to the supramammillary nucleus (SUM). This wake-promoting backbone is modulated by a number of monoaminergic neurotransmitters, such as dopamine (DA), norepinephrine (NE), histamine (HA), and serotonin (5HT), as well as the sleep-wake stabilizing hormone hypocretin (Hcrt), also known as orexin. Accompanying the ventral flow of cortical arousal is the dorsal flow of cholinergic transmission, which allows for cortical processing of incoming information through depolarization of thalamic neuronal populations while awake and asleep (the result of which is dreaming, in the latter case). Sleep is actively promoted through a different set of fastacting neurotransmitters, predominantly g-aminobutyric acid (GABA), that are primarily secreted from neurons originating in the preoptic area of the hypothalamus with projections to the majority of the aforementioned wake-promoting regions. The mutual inhibition between these wake and sleep systems allows for smooth transitions between wake and sleep states as the balance of activity progressively weighs more heavily on one side or the other of the flip-flop switch. A number of factors influence the likelihood of state transitions, ranging from the time since the system was last active (i.e., a homeostat) to external inputs that adjust sleep to meet the organismal need. REM sleep is coordinated by another flip-flop switch that reflects a balanced antagonism between the REM sleep– promoting sublaterodorsal (SLD) nucleus and the REM sleepinhibiting ventrolateral periaqueductal gray (vlPAG). This process is facilitated, at least in part, by the melanin-concentrating hormone (MCH) cells closely associated with the hypocretinergic populations in the lateral hypothalamic area (LHA). WAKE-PROMOTING NEUROTRANSMITTERS The monoaminergic populations throughout the brainstem ensure redundancy in the promotion of wakefulness, but none of them are, in and of themselves, necessary for wakefulness,

highlighting their complementary roles. The most potent wake-promoting monoamine, dopamine, is still not nearly as fundamental to the wake state as glutamate, as evidenced by the far more striking reductions in wakefulness that occur with experimental elimination of the glutamatergic system. SLEEP-PROMOTING NEUROTRANSMITTERS Underlying the two main sleep states (NREM and REM sleep) are a host of interconnected neuronal populations that ensure smooth transitions between vastly different electrophysiologic states through networks that connect the two flip-flop switches. NREM Sleep The ventrolateral preoptic (VLPO) nucleus appears to be the primary sleep-sustaining neuronal population, with the accompanying median preoptic (MnPO) nucleus serving to initiate the transition to sleep. Their wake-inhibiting activity is mediated through GABA and, to a lesser degree, galanin. REM Sleep REM sleep requires a unique state that ensures that REMactive neurons promote the characteristic REM features (i.e., dream mentation, muscular atonia), while REM-inactive neurons remain quiescent so the brain remains effectively asleep despite the abundant “conscious” activity. EXTERNAL SLEEP-WAKE REGULATION (TWO-PROCESS MODEL) To ensure that the various states of consciousness are triggered and sustained appropriately, the underlying neurocircuitry relies on a variety of inputs that help adapt sleep and wake activity to the needs of the organism. Homeostasis While a number of factors appear to contribute to the homeostatic regulation of sleep, the most well-understood somnogen is adenosine. This breakdown product of the energy-storing molecule adenosine triphosphate (ATP) scales the sleep drive to meet the energetic expenditures of the organism. Circadian Rhythms Various behavioral and environmental cues help entrain the intrinsic biorhythms that help optimally place the sleep and wake periods within the ever-changing biopsychosocial world 29

30  Localization and Neurochemistry of Sleep-Wake Physiology and Pathophysiology of each organism. The strongest timer of the approximately 24-hour (circadian: circa means “about”; diem means “day”) alertness signal is the melatonin-suppressing effect of light, which is transduced by retinal ganglion cells for transmission via the body’s “master clock” in the suprachiasmatic nucleus (SCN) to the dorsal medial hypothalamus (DMH), where it is integrated with other biological time givers (zeitgebers) from dietary/metabolic changes to thermal variations. EXPLANATORY DIAGRAMS The Waking State Figure 4.1 shows the network responsible for the waking state. The backbone of the wake-promoting neurotransmission is the primarily glutamatergic activity of the PB and SUM accompanied by the multiple neurotransmitters of the BF nucleus (predominantly GABA and acetylcholine) and the dopaminergic activity of the ventral periaqueductal gray (vPAG).1 The various monoaminergic populations—histamine from the tuberomammillary nucleus (TMN), serotonin from the dorsal raphe nucleus (DRN), and norepinephrine from the locus coeruleus (LC)—all provide modulatory input to this cortical arousal pathway.2 The dominance of the monoaminergic tone during wakefulness is stabilized by input from the hypocretin (orexin) system.2 Cholinergic projections from the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei depolarize sleep-related thalamic nuclei, allowing various

afferent pathways to transmit their information to the cortex for processing.2 NREM Sleep A less elaborate network, predominately dictated by GABAergic neuronal activity, serves to promote and maintain sleep (Fig. 4.2). Neurons in the VLPO area project extensively to the wake-promoting monoaminergic systems as well as the hypocretin (orexin) neurons in the lateral hypothalamic area. The importance of these neurons in the active promotion of sleep has been demonstrated through the insomnia-inducing consequences of VLPO lesions.3 In addition to the VLPO’s extensive inhibitory projections, the importance of the parafacial zone in sending inhibitory projections to the PB seems to be essential to diminishing cortical activation, allowing for the synchronous oscillations characteristic of slow-wave sleep.1 It has been demonstrated that the wake-promoting neuronal populations (primarily of the monoaminergic system) and the sleep-promoting centers of the preoptic area (the VLPO and MnPO nuclei) are connected in a reciprocal inhibitory circuit akin to a flip-flop switch.4 Norepinephrine and acetylcholine are two of the main neurotransmitters that provide tonic inhibition of the sleep-inducing and sleep-maintaining preoptic area nuclear groups. Withdrawal of monoamineactivating external/environmental stimuli, circadian cues integrated through the dorsomedial hypothalamus, and increased homeostatic pressure temporally align to promote MnPO and VLPO activity to facilitate the onset of sleep. The balanced

Wake-promoting

Primary Modulatory

Sleep-promoting Wake/REM-active

MCH Hcrt VLPO VLPO O BF A

TMN

SUM

REM-active vPAG

Adenosine A1 receptor

DRN LDT PPT PB

Adenosine A2A receptor

LC A

Adenosine

Figure 4.1  ​Networks involved in the waking state. Building on the backbone of fast neurotransmission originating from the parabrachial nucleus, basal

forebrain, and supramammillary nucleus, the widely distributed modulatory neurocircuitry of the monoamines (dopamine, norepinephrine, histamine, and serotonin) help promote and maintain the wake state with the assistance of hypocretin from the lateral hypothalamic area. The dorsal flow of acetylcholine to the thalamus helps facilitate conscious processing throughout the activated cortex. A, Adenosine; BF, basal forebrain; DRN, dorsal raphe nucleus; Hcrt, hypocretin (orexin)-containing neurons; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MCH, melanin-containing neurons; PB, parabrachial nucleus; PPT, pedunculopontine tegmental nucleus; REM, rapid eye movement sleep; SUM, supramammillary nucleus; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; VLPO, ventrolateral preoptic nucleus.

Atlas of Clinical Sleep Medicine   31

A A A

Wake-promoting

Primary Modulatory

Sleep-promoting REM-active

MCH Hcrt A A

A A

BF A

VLPO A

TMN

Adenosine A1 receptor

vPAG

Adenosine A2A receptor

DRN LDT PPT PB

A

Adenosine

LC PZ

Sleep-active

Figure 4.2  ​Networks involved in the promotion of sleep. The GABAergic median and ventrolateral preoptic areas serve to inhibit the wake-promoting areas

distributed throughout the brainstem, while the parafacial zone inhibits the root of the wake-promoting, glutamatergic backbone originating in the parabrachial nucleus. A, Adenosine; BF, basal forebrain; DRN, dorsal raphe nucleus; GABA, g-aminobutyric acid; Hcrt, hypocretin (orexin)-containing neurons; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MCH, melanin-containing neurons; PB, parabrachial nucleus; PPT, pedunculopontine tegmental nucleus; PZ, parafacial zone; REM, rapid eye movement sleep; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; VLPO, ventrolateral preoptic nucleus.

activity of the wake-promoting and sleep-promoting centers allows for a smooth transition between states of consciousness as multiple inputs can modulate the firing rates of either neuronal group to ensure varying degrees of activation. The accumulation of the somnogen adenosine likely plays a pivotal role in tipping the scales of the wake-sleep mutual antagonism in favor of the sleep-promoting VLPO nucleus. The presence of excitatory A2A purinergic receptors in the meninges adjacent to the VLPO nucleus contributes to the homeostatic induction of sleep and promotion of slow-wave activity. Similarly, activation of the inhibitory A1 purinergic receptors in the BF can further suppress the wake-promoting cholinergic projections originating in this brain region. Of note, one of the primary mechanisms by which caffeine promotes wakefulness is through the antagonism of adenosine’s activity at these purinergic receptors.5 REM Sleep REM sleep is generally orchestrated by the activity of the glutamatergic SLD nucleus (Fig. 4.3). The GABAergic projections of the vlPAG serve to inhibit the SLD nucleus, comprising another mutually antagonistic flip-flop switch, this time balancing transitions between NREM and REM sleep.2 A number of excitatory inputs, from both the monoaminergic system and the hypocretinergic (orexinergic) system, prevent the impingement of REM sleep–related phenomena into the waking state. However, inhibitory inputs from the VLPO and lateral hypothalamic area’s MCH neurons render the SLD-inhibiting functions of the vlPAG inactive during REM sleep. The VLPO neurons also help maintain the sleeping

state during REM sleep through the persistent inhibition of cortically arousing brain regions (such as the monoaminergic cellular populations). The MCH neurons appear to be relatively important to the process of transitioning from NREM to REM sleep.6 In particular, their activity seems to be influenced by ambient temperatures, such that they are less likely to promote REM (a state in which muscle atonia would limit heat generation) when thermally disadvantageous for the organism.7 With the SLD nucleus disinhibited, a number of other REM-active neuronal populations coordinate the hallmark characteristics of REM sleep. First, ascending projections from the SLD nucleus are accompanied by the cholinergic LDT/PPT neurons to again depolarize the thalamic nuclei, facilitating cortical processing transmitted via the thalamocortical network. The LDT/PPT neurons appear to be reactivated as a result of the near-total silence of the monoaminergic systems, notably the noradrenergic locus coeruleus and the serotonergic dorsal raphe.8 The descending glutamatergic projections of the SLD nucleus activate the glycinergic spinal inhibitory interneurons as well as the GABAergic/ glycinergic gigantocellular neurons located in the ventral medulla. Both of these neuronal groups aid in maintenance of atonia during REM sleep through their inhibition of a-motoneurons in the spinal cord, while the ventral medullary centers also send rostral projections to the vlPAG to assist in the REM state stability. The termination of REM sleep usually occurs as a transition into a state of wakefulness (usually brief), which may be explained by the persistence of cholinergic activity from the

32  Localization and Neurochemistry of Sleep-Wake Physiology and Pathophysiology

A

A

REM-inactive Sleep-promoting Sleep-active

Hcrt CH MCH

A

A BF A

REM-active

VLPO O TMN N

vPA AG vPAG

A

Adenosine A1 receptor

vIPAG vvIP IPAG PA P AG G DR RN N DRN LDT L P PPT PB

Adenosine A2A receptor A

Adenosine

LC S SLD

REM-active pathways REM-inactive pathways

M vM S SII

excitatory inhibitory excitatory inhibitory



Figure 4.3  ​Networks involved in the promotion of rapid eye movement (REM) sleep. While the ventrolateral preoptic (VLPO) nucleus maintains the brain in a

sleep state, its projections to the ventrolateral periaqueductal gray (vlPAG) shift the balance in favor of REM sleep through inhibiting the vlPAG’s suppression of the sublaterodorsal (SLD) nucleus. The caudal SLD projections provide polysynaptic inhibition of spinal motoneurons via indirect activation of the inhibitory ventral medulla and spinal inhibitory interneurons. The ventral medulla provides complementary inhibition of the vlPAG, further suppressing its activity and preventing awakening as a result of withdrawal of its excitation of the parabrachial nucleus. a, a-Motoneuron; A, adenosine; BF, basal forebrain; DRN, dorsal raphe nucleus; Hcrt, hypocretin (orexin)-containing neurons; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MCH, melanin-concentrating hormone; PB, parabrachial nucleus; PPT, pedunculopontine tegmental nucleus; SII, spinal inhibitory interneuron; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; vM, ventral medulla.

LDT/PPT as the system transitions from REM to NREM sleep. Recall that the wake systems inhibit all GABAergic REM-active neurons, thereby allowing the cortical activity of dream mentation to persist unabated, despite the withdrawal of sleep-promoting activity, resulting in vivid dream recall. Because the duration of REM sleep is negatively coupled with the corporeal metabolic rate, it is likely that this process involves reduced activity of the thermally responsive MCH neurons.7 Sleep-Wake Regulation The coupled flip-flop switches that regulate state transitions are regulated through various external inputs that are transduced primarily by the hypothalamus (Fig. 4.4). These time-giving cues range from the environmental influence of light-dark cycles and temperature variations to activity levels, caloric balance, and even the degree of social interaction. This ensures that the sleep-wake circuits that regulate the primary backbone of glutamatergic excitatory signals originating from the PB and BF are suited to the unique needs of the organism. Sleep-Wake Dysregulation in Pathologic States REM Behavior Disorder Most cases of REM behavior disorder (RBD) are associated with or eventually develop an a-synucleinopathy, such as Parkinson disease, Lewy body dementia, or multiple system

atrophy. It seems that the rostral spread of toxic a-synuclein aggregates9 plays a role in the pathophysiology of this biomarker of incipient neurodegenerative disease. As a result of damage to the caudally projecting excitatory pathways of the SLD nucleus and the inhibitory projections from the ventral medulla, somatic muscle atonia during sleep diminishes (Fig. 4.5).10 Additionally, it has been repeatedly demonstrated that serotonergic medications tend to precipitate RBD events in individuals with and without evidence of neurodegeneration. Although the REM-suppressing activity of serotonin has been explored at great length, the exact pathways that mediate the loss of REM atonia in RBD remain to be elucidated.11,12 Moreover, it is unclear what actually causes RBD events to occur, be it a dream-based elaboration on activity caused by central motor pattern generators or a physical manifestation of violent dream content. Narcolepsy Type 1 Compared with the neurodegeneration commonly implicated in RBD, the lack of excitatory hypocretinergic/orexinergic inputs to the REM-active SLD neurons causes disinhibition of the spinal a-motoneurons in individuals with narcolepsy type 1 (NT1), (Fig. 4.6).13 As a result of the loss of SLDfacilitated inhibition, breakthrough phasic motor activity during REM sleep is often present, but seldom to the same degree as in individuals who have lost the primary inhibitory neurocircuitry to neurodegeneration.

Atlas of Clinical Sleep Medicine   33

Figure 4.4  ​General mechanism by which environmental and organismal inputs influence the sleep-wake flip-flop switches to promote the different states of

consciousness. A variety of environmental and behavioral inputs—from daily light level and temperature variations to metabolic feeding signals, timing and intensity of activity, and even socialization—are integrated via various hypothalamic nuclei to regulate the fundamental sleep-wake circuitry that feeds forward into an awake and/or consciously processing cortex. DMN, Dorsomedial nucleus; LHA, lateral hypothalamic area; MAs, monoamines; NREM, non–rapid eye movement sleep; REM, rapid eye movement sleep; SCN, suprachiasmatic nucleus; SLD, sublaterodorsal nucleus; vlPAG/LPT, ventrolateral periaqueductal gray/lateral pontine tegmentum; (e)VLPO, (extended) ventrolateral preoptic area.

On the other hand, the hypocretin-deficient state in individuals with NT1 is also characterized by the impingement of REM atonia into the waking state in a nearly pathognomonic phenomenon termed cataplexy. The relatively rapid onset of REM atonia in individuals with NT1 is usually induced by strong emotional stimuli (e.g., laughing, telling or hearing a joke).14 Processing of strong emotions likely originates in the medial prefrontal cortex, with subsequent projection down to the amygdala. It is believed that stimulation of the emotional centers in the amygdala activates the descending glutamatergic projections of the SLD nucleus, which results in a similar inhibition of a-motoneurons as would occur during REM sleep, despite maintenance of consciousness through the persistent activity of wake-promoting neurocircuitry.13 Additional inhibitory signals from the amygdala to the vlPAG and LC result in withdrawal of their suppression of the SLD nucleus.15 Comparatively, in individuals with retained hypocretinergic

(orexinergic) function, projections to REM-inactive populations in the vlPAG and brainstem monoaminergic centers usually help preserve wake-state muscle tone in the face of emotional stimuli.13 Acknowledgment This research is supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the Veterans Affairs Palo Alto Health Care System, and the Department of Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC). Visit eBooks.Health.Elsevier.com for the References and Bibliography for this chapter.

34  Localization and Neurochemistry of Sleep-Wake Physiology and Pathophysiology

Hcrt

Hcrt

MCH CH

CH MCH O VLPO

VLPO BF

N TMN

BF

vPA AG vPAG

vPA AG vPAG

N TMN

vIPAG vvIP PA AG A G

vIPAG vvIP PA P AG G

DR RN N DRN

DR RN N DRN LDT L P PPT PB

L LDT P PPT PB

LC

LC

S SLD

M vM S SII

A

B



REM-inactive

Sleep-promoting

Sleep-active



REM-active

Normally active pathways

Impaired REM-active pathways REM-inactive pathways

excitatory Lewy body inhibitory excitatory

Disinhibited

Activity-impaired pathways Disinhibited pathways

inhibitory Figure 4.5  ​Hypothesized network dysfunction in the setting of REM sleep behavior disorder (RBD) caused by a-synuclein pathology. Compared with the normally functioning REM-promoting neurocircuitry (A), note the progressive rostral spread of Lewy bodies (a-synuclein aggregates) that causes degeneration of the brainstem neurocircuitry necessary for the production of REM-sleep atonia well before it affects other sleep-wake neurocircuitry (B). As a result of the degeneration of gigantocellular neurons in the ventral medulla and neuronal populations in the sublaterodorsal nucleus, the two main motoneuron-inhibiting pathways that project caudally are lost, allowing for breakthrough of motor activity during REM sleep in association with dreaming content. a, a-motoneuron; BF, basal forebrain; DRN, dorsal raphe nucleus; Hcrt, hypocretin (orexin)-containing neurons; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MCH, melanin-concentrating hormone; PB, parabrachial nucleus; PPT, pedunculopontine tegmental nucleus; REM, rapid eye movement sleep; SLD, sublaterodorsal nucleus; SII, spinal inhibitory interneuron; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; vlPAG, ventrolateral periaqueductal gray; VLPO, ventrolateral preoptic nucleus; vM, ventral medulla.

Atlas of Clinical Sleep Medicine   35

Primary

Wake-promoting

Modulatory

Sleep-promoting Wake/REM-active

MCH Hcrt VLPO

REM-active

BF A

Amy

Destroyed neurons/pathways

G vIPAG LDT PPT

Adenosine A1 receptor

L LC

Adenosine A2A receptor

SLD

A

vM

REM-inactive

Hypothesized pathways active during cataplexy Adenosine

SII a

Figure 4.6  ​Hypothesized mechanism that allows for cataplexy (the onset of REM sleep atonia while awake) in the setting of hypocretin neuron loss, as seen in

individuals with narcolepsy type 1. Emotional stimulation, originating in the medial prefrontal cortex and activating the amygdala, likely inhibits the locus coeruleus and the ventrolateral periaqueductal gray without the wake-sustaining hypocretinergic input. These disinhibited regions along with additional excitation of the sublaterodorsal nucleus result in activation of the REM atonia circuitry despite the maintenance of waking consciousness. a, a-Motoneuron; A, adenosine; Amy, amygdala; BF, basal forebrain; Hcrt, hypocretin (orexin)-containing neurons; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MCH, melanin-concentrating hormone; PPT, pedunculopontine tegmental nucleus; REM, rapid eye movement sleep; SLD, sublaterodorsal nucleus; SII, spinal inhibitory interneuron; SUM, supramammillary nucleus; VLPO, ventrolateral preoptic nucleus; vM, ventral medulla.

e1 References

1. Saper CB, Fuller PM. Wake-sleep circuitry: an overview. Curr Opin Neurobiol. 2017;44:186–192. 2. Schneider LD. Anatomy and physiology of normal sleep. In: Miglis MG, ed. Sleep Neurol Dis. 1st ed. Elsevier Science; 2017:1–28. 3. Lu J, Greco MA, Shiromani P, Saper CB. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J Neurosci. 2000;20:3830. 4. Gallopin T, Fort P, Eggermann E, et al. Identification of sleep-promoting neurons in vitro. Nature. 2000;404:992–995. 5. Fredholm BB, Chen JF, Masino SA, Vaugeois JM. Actions of adenosine at its receptors in the CNS: Insights from Knockouts and Drugs. Annu Rev Pharmacol Toxicol. 2005;45:385–412. 6. Weber F, Dan Y. Circuit-based interrogation of sleep control. Nature. 2016;538:51–59. 7. Komagata N, Latifi B, Rusterholz T, Bassetti CLA, Adamantidis A, Schmidt MH. Dynamic REM sleep modulation by ambient temperature and the critical role of the melanin-concentrating hormone system. Curr Biol. 2019;29:1976–1987.e4. 8. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747–765.

9. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211. 10. Valencia Garcia S, Brischoux F, Clément O, et al. Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder. Nat Commun. 2018;9:504. 11. Arnaldi D, Famà F, De Carli F, et al. The role of the serotonergic system in rem sleep behavior disorder. Sleep. 2015;38:1505. 12. Monti JM, Jantos H. Mechanisms involved in the inhibition of REM sleep by serotonin. In: Serotonin and Sleep: Molecular, Functional and Clinical Aspects. Basel: Birkhäuser Basel; 2008:371–385. 13. Luppi P-H, Clément O, Sapin E, et al. The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev. 2011;15:153–163. 14. Schneider L, Mignot E. Diagnosis and management of narcolepsy. Semin Neurol. 2017;37:446–460. 15. Szabo ST, Thorpy MJ, Mayer G, Peever JH, Kilduff TS. Neurobiological and immunogenetic aspects of narcolepsy: implications for pharmacotherapy. Sleep Med Rev. 2019;43:23–36.

Chapter

5

Circadian Rhythms Regulation Kathryn J. Reid, Anne-Marie Chang, Phyllis C. Zee, and Orfeu M. Buxton

All living creatures exhibit self-sustaining circadian (,24-hour) rhythms in physiology and behavior that are regulated by a central “clock” or pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. This timing system is involved in the regulation of many physiologic functions that include core body temperature (CBT), sleep, and the timing of hormone production; essentially all physiologic systems in the body are modulated by circadian rhythmicity. The molecular mechanism of the circadian system at the cellular level consists of multiple feedback loops regulating the transcription of genes (Fig. 5.1). The central circadian pacemaker, the SCN, also controls the timing of peripheral clocks in individual cells and organs throughout the body, including the liver, heart, and adrenal glands, and in turn these peripheral rhythms may feed back to the SCN (Fig. 5.2). Although the circadian clock functions independently of external influences, synchronizing agents such as light exposure, physical activity, and melatonin from the pineal gland can influence the circadian clock. In humans, light is the strongest time cue for the circadian clock. The sleep-wake cycle is the most apparent circadian rhythm in humans. Circadian rhythm sleep-wake phase

Genetic core components of mammalian circadian system Nucleus

Cytoplasm Degradation

BMAL1 CLOCK

p

PER 1 E-box

PERs

p

PER 2 PER 3

CRYs CRY1 CRY2

Figure 5.1  ​Core components of the mammalian circadian clock. In the core feedback loop, the transcription factors BMAL1 (dark purple square) and CLOCK (light purple square) bind to E-box domains on gene promoters, including the genes for Period (Per) and Cryptochrome (Cry). PERs (blue diamonds) and CRYs (gray circles) dimerize and translocate to the nucleus after binding with casein kinase 1d (CK1d) or CK1 (green triangle) , where they repress their own transcription.

36

disorders (see Chapter 19) develop when the circadian clock or its entraining pathways are disrupted or when the external environment is misaligned with the timing of the circadian clock (Figs. 5.3 and 5.4). Optimal sleep-wake and physiologic function occurs when the timing of socially or work-imposed sleep and wake schedules align appropriately with the external physical environment and internal circadian rhythms. As a result of their influence on the circadian clock, light exposure, exercise, and exogenous melatonin administration can be used to shift the timing of the circadian clock. Phaseresponse curves to light and other synchronizing agents such as melatonin characterize the phase-shifting effects that vary by circadian time of day (Fig. 5.5). Light exposure in the late evening, before the CBT reaches a minimum (CBTmin), delays circadian rhythms; light in the morning, after CBTmin has been reached, advances circadian rhythms. Exercise elicits phase advances in the early evening and phase delays in the late evening and mid-nighttime hours. The response to melatonin is the opposite of the response to light; melatonin given in the evening will advance the circadian clock, whereas melatonin in the morning will delay it. Circadian phase markers, such as the dim light melatonin onset (DLMO) or CBTmin, can be used to confirm the diagnosis of circadian rhythm sleep-wake disorders and to correctly time treatment with light and/or melatonin (see Chapter 19). CBT can be determined using a rectal thermistor or other temperature sensor system worn for 24 to 28 hours (see Fig. 19.2). The CBTmin usually occurs about 2 to 3 hours before wake time, and it is generally easier to fall asleep on the declining part of the CBT rhythm and to wake on the rising portion. DLMO can be determined from plasma or saliva sampled at regular intervals (every 30 minutes) under dim light conditions (see Fig. 19.3). DLMO usually occurs about 2 to 3 hours before habitual sleep time in individuals with a conventional regular sleep-wake schedule and in those with a delayed sleep-wake phase disorder. Although DLMO is currently considered the gold standard for estimating circadian phase, techniques are being developed that can estimate circadian phase from one or two blood samples by evaluating the levels of multiple metabolites, proteins, and/or transcripts that exhibit a unique pattern at that circadian time, with close to the temporal precision of DLMO. Further work is needed to completely validate and refine the temporal precision of these methods, particularly for clinical or field-based application. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

Atlas of Clinical Sleep Medicine   37

SCN

SCN

Peripheral clocks

Systemic rhythms

Leptin ng/mL

15

Peripheral clocks

Behavioral rhythms

10 5 0 0

4

8 12 16 20 24 ZT (hours)

Peripheral transcriptional rhythms

Peripheral transcriptional rhythms

Physiologic rhythms

Physiologic rhythms

A

B

Figure 5.2  ​Communication routes of the mammalian circadian timing system. A, The suprachiasmatic nucleus (SCN) pacemaker entrains peripheral clocks. Via

transcriptional regulation of clock-controlled genes in target tissues, peripheral physiologic functions are reset and synchronized to the light-dark cycle. B, Pathways of interaction between central and peripheral clocks. The SCN resets physiologic rhythms via the entrainment of peripheral tissue clocks, but at the same time regulates behavioral and systemic (e.g., endocrine) functions in a more direct manner. Peripheral rhythms may, in turn, directly or indirectly feed back to the SCN. This interlocked balance system creates plasticity in the entrainment of the circadian timing system and promotes adaptation to complex changes in environmental parameters. TZ, Time zero. (From Barclay J, Tsang A, Oster H: Interaction of central and peripheral clocks in physiological regulation. Prog Brain Res. 2012;199:163–181.)

Circadian rhythms regulation

Pineal gland

Light

Melatonin RHT

RGC

SCN

Hypothalamic and brainstem Sleep-wake regulating centers

SCG

Figure 5.3  ​The basic components of the circadian

system. Photic information that reaches the suprachiasmatic nucleus (SCN) is transmitted from the retina via the retinohypothalamic tract (RHT). The retinal ganglion cells (RGCs) of the eye, melanopsin-containing photoreceptors, provide the primary photic input to the circadian clock, transmitting the signal to the neurons of the SCN. Melatonin is released from the pineal gland at night, and its output is regulated by the SCN via the superior cervical ganglion (SCG). In addition to its ability to synchronize circadian rhythms, melatonin can also promote sleep. Integrated timing information from the SCN is transmitted to sleep-wake centers in the brain. Thus, the sleep-wake cycle is generated by a complex interaction of endogenous circadian and sleep processes as well as by social and environmental factors.

38  Circadian Rhythms Regulation Sleep-wake cycle: two-process model Homeostatic sleep drive

Melatonin Circadian alerting signal (SCN)

9 am

3 pm

9 pm

Awake

3 am

9 am

Asleep

Figure 5.4  ​At least two variables seem to play a role in the regulation of the timing of sleep. First is the homeostatic sleep drive, which increases the longer a

1.0

Melatonin PRC

Light PRC

3 2

0.5 1 0

0.0

1 0.5 2 3

1.0

12

Phase shift with light (hr)

Phase shift with melatonin (hr) Delay Advance

person is awake. The second is timing information from the suprachiasmatic nucleus (SCN). In this two-process model, the SCN promotes wakefulness by stimulating arousal networks. SCN activity appears to oppose the homeostatic sleep drive, thus the alerting mediated by the SCN increases during the day. The propensity to be awake or asleep at any time is related to the homeostatic sleep drive and the opposing SCN alerting signal. At normal bedtime, both the alerting drive and the sleep drive are at their highest level. The SCN has at least two types of melatonin receptors, MT1 and MT2, involved in the regulation of sleep. Stimulation of MT1 receptors is believed to decrease the alerting signal from the SCN, whereas MT2 stimulation is thought to be involved in synchronizing the circadian system. (Data from Dijk DJ, Edgar DM. Circadian and homeostatic control of wakefulness and sleep. In: Turek FW, Zee PC, eds. Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker, 1999;111–147.)

15

18

21 0 3 Clock time

6

9

12

9 12 15 3 0 3 6 Hours before and after DLMO Time of melatonin or bright light Figure 5.5  Human phase-response curves to bright light and melatonin. The light phase-response curve (PRC) was generated from seven subjects who were exposed to approximately 3 days (73.5 h) of an ultradian light-dark cycle (2.5 hours awake in dim light [,100 lux] alternating with 1.5 hours of sleep in darkness). Subjects lived on the ultradian schedule on two different occasions, once with bright-light pulses of about 3500 lux for 2 hours at the same time each day, and once without bright-light pulses, counterbalanced. Phase shifts of the midpoint of the melatonin rhythm collected in dim light (,5 lux) before and after the 3 days were plotted against the time of the light pulse relative to each subject’s baseline dim light melatonin onset (DLMO) and were corrected for the free run, when the bright light was not applied. The average baseline DLMO (upward arrow), average baseline sleep schedule (rectangle), and estimated time of body temperature minimum (DLMO 1 7 hours; triangle) are shown. The solid line is a smoothed curve fit to the seven points. Subjects (n 5 6), living at home, took 0.5 mg melatonin at the same time each day for 4 days. Phase shifts of the DLMO were plotted against the time of melatonin administration relative to each subject’s baseline DLMO. A smoothed curve was fit to the data after averaging the 70 data points into 3-hour “bins.” (Melatonin PRC calculated from data of Lewy AJ, Bauer VK, Ahmed S, et al: The human phase-response curve [PRC] to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int. 1998;15[1]:71–83. Courtesy Eastman and Burgess, unpublished data; and Revell VL, Eastman CI. How to trick mother nature into letting you fly around or stay up all night. J Biol Rhythms. 2005;20[4]:353–365.) 9

6

e1 Bibliography

Barclay J, Tsang A, Oster H. Interaction of central and peripheral clocks in physiological regulation. Prog Brain Res. 2012;199:163–181. Braun R, Kath WL, Iwanaszko M, et al. Universal method for robust detection of circadian state from gene expression. Proc Natl Acad Sci U S A. 2018;115(39):E9247–E9256. Buxton OM, Lee CW, L’Hermite-Balériaux M, Turek FW, Van Cauter E. Exercise elicits phase shifts and acute alterations of melatonin levels that vary with circadian phase. Am J Physiol. 2003;284(3):R714–R724. Czeisler CA, Allan JS, Strogatz SH, et al. Bright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle. Science. 1986;233(4764):667–671. Czeisler CA, Weitzman E, Moore-Ede MC, et al. Human sleep: its duration and organization depend on its circadian phase. Science. 1980;210(4475):1264–1267. Lewy AJ, Bauer VK, Ahmed S, et al. The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int. 1998;15(1):71–83.

Moore RY. A clock for the ages. Science. 1999;284(5423):2102–2103. Murphy PJ, Campbell SS. Physiology of the circadian system in animals and humans. J Clin Neurophysiol. 1996;13(1):2–16. Rollag MD, Berson DM, Provencio I. Melanopsin, ganglion-cell photoreceptors, and mammalian photoentrainment. J Biol Rhythms. 2003;18(3):227–234. Saper CB, Lu J, Chou TC, et al. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 2005;28(3):152–157. Van Cauter E, Sturis J, Byrne MM, et al. Demonstration of rapid light– induced advances and delays of the human circadian clock using hormonal phase markers. Am J Physiol. 1994;266(6 Pt 1):E953–E963. Wittenbrink N, Ananthasubramaniam B, Munch M, et al. High accuracy determination of internal circadian time from a single blood sample. J Clin Invest. 2018;128(9):3826–3839.

Chapter

Physiologic Regulation in Sleep

6

Plamen Ch. Ivanov, Pier Luigi Parmeggiani, and Ronny P. Bartsch

DYNAMICS OF INDIVIDUAL SYSTEMS AND FUNCTIONAL CHANGES IN SLEEP AND WAKE STATES AND ACROSS SLEEP STAGES Physiologic regulation in mammals varies with the state of the brain and is affected by arousal and the stage of sleep. This is the result of the functional dominance of phylogenetically different structures of the brain in different behavioral states. Figure 6.1 summarizes some of the functional changes that occur during sleep. Physiologic events during non–rapid eye movement (NREM) sleep are functionally similar in different species. During rapid eye movement (REM) sleep, such events vary within and among species. Nervous system processes specific to REM sleep result in this autonomic variability and are not related to mental content or homeostatic control. The basic features of NREM sleep are active thermoregulation and a decrease in the activity of antigravity muscles. The basic features of REM sleep are muscle atonia, rapid eye PHYSIOLOGIC REGULATION IN SLEEP NREM GH early secretion PRL early secretion ACTH late secretion T late secretion TSH inhibition Regular decrease Effective Effective Active Tone maintained Eurhythmic decrease Regular decrease Regular decrease Effective Effective Decreased function Decreased urine flow

HOMEOSTATIC

FUNCTIONS

REM

ENDOCRINE

BREATHING

Ventilation Reflexes proprioceptive Chemoreceptive Intercostal muscles Upper airways muscles

CIRCULATION

Heart rate Blood pressure Cardiac output Reflexes proprioceptive Chemoreceptive

GASTROINTESTINAL RENAL

Variable amplitude Overridden Overridden Inactive Tone reduced Variably arrhythmic Irregular oscillations Irregular oscillations Overridden Overridden Decreased function Decreased urine flow

SEXUAL

Penile erection

REGULATION

POIKILOSTATIC

Figure 6.1  ​Overview of functional changes during sleep. Comprehensive investigations on the influence of sleep regulation on interactions among diverse physiologic systems from the cellular to the organism level require an integrative framework and network physiology approach. ACTH, Adrenocorticotropic hormone; GH, growth hormone; NREM, non–rapid eye movement; PRL, prolactin; REM, rapid eye movement; T, testosterone; TSH, thyroid-stimulating hormone.

movements, and myoclonic twitches. The basic autonomic feature of NREM sleep is the functional prevalence of parasympathetic influences associated with quiescence of sympathetic activity. The basic autonomic feature of REM sleep is the great variability in sympathetic activity associated with phasic changes in tonic parasympathetic discharge. During NREM sleep, mammals maintain homeostasis at a lower level of energy expenditure compared with quiet wakefulness. In contrast, REM sleep in all species is characterized by impaired homeostatic activity of physiologic functions (poikilostasis). The impairment of homeostatic control in REM sleep is more dramatic and evident in a function that depends on mechanisms strictly controlled by structures in the diencephalon (preoptic-hypothalamic area), such as temperature regulation in furred animals (Table 6.1 and Figs. 6.2 to 6.5). In functions characterized by more widely distributed control mechanisms, such as respiration (Figs. 6.6 and 6.7) and circulation (Figs. 6.8 and 6.9), the features of functional impairment are rather more complex as a result of the persistence of more or less efficient reflex regulation or peripheral autoregulation. The functional changes in REM sleep depend essentially on the suppression of a highly integrated homeostatic regulation operative in NREM sleep. Compared with REM sleep, volitional and instinctive drives during active wakefulness may also impose a load on, or interfere with, homeostatic mechanisms at central and/or effector levels to overwhelm their regulatory power. However, such homeostatic mechanisms are still operative and are capable of reestablishing the functional equilibrium that so well characterizes quiet wakefulness and NREM sleep. Integrated physiologic systems under neural regulation, such as the cardiac and respiratory system, exhibit complex dynamics characterized by continuous fluctuations. These fluctuations are not simply noise caused by external perturbations, but they carry important information related to the underlying mechanisms of physiologic control and how these mechanisms are modulated during sleep. Different levels of activation of sympathetic and parasympathetic branches of the central nervous system during sleep and wake states, changes in sympathovagal balance with sleep-stage transitions, and circadian rhythms affect the regulation of physiologic systems and their output signals. Counterintuitively, the amplitude of heartbeat fluctuations is significantly higher during the sleep state compared with the wake state as a result of reduced sympathetic and dominant parasympathetic tone during sleep (Fig. 6.10), leading to broader tails in the distribution of physiologic fluctuations (Fig. 6.11). One measure of the variability is the standard deviation, which exhibits a clear sleep-stage stratification pattern (Fig. 6.12). 39

40  Physiologic Regulation in Sleep Table 6.1  Thermoregulatory Responses in Wakefulness and Sleep Responses Specific Behavioral Autonomic

Nonspecific

Wake

NREM

REM

Locomotion Posture Vasomotion Piloerection Shivering Tg Nonshivering Tg Thermal Tp Sweating Vigilance

No locomotion Posture Vasomotion Piloerection Shivering Tg (1) Nonshivering Tg Thermal Tp (1) Sweating (1) Arousal

No locomotion Postural atonia Inconsistent vasomotion No piloerection No shivering Tg Depressed nonshivering Tg No thermal Tp Sweating (0,–) Arousal

1, strong; –, weak; 0, absent; NREM, non–rapid eye movement; REM, rapid eye movement; Tg, thermogenesis; Tp, tachypnea.

Ta, 6 C

NREM

REM

Hp

EMG

2 sec

Ta, 36 C

NREM

500 V

P

REM

O

EMG

2 sec

500 V

Hp

RM

Figure 6.2  ​Shivering and thermal tachypnea are absent during rapid eye movement (REM) sleep in the cat but are present during non–rapid eye movement (NREM) sleep. EMG, Electromyogram (neck muscles); Hp, hippocampus; O, occipital cortex; P, parietal cortex; RM, respiratory movements; Ta, ambient temperature. (From Parmeggiani PL, Rabini C. Sleep and environmental temperature. Arch Ital Biol. 1970;108[2]:369–387.)

Although physiologic fluctuations such as heart rate may appear erratic, mathematical analyses yield robust self-similar patterns across a broad range of time scales that change with sleep and under pathologic conditions (Fig. 6.13). This robust temporal organization across time scales from seconds to hours is characterized by power-law correlations in physiologic dynamics—scale-invariant structures that undergo transitions from wake to sleep (Fig. 6.14)—across sleepstages (Figs. 6.15 and 6.16) and circadian phases (Fig. 6.17). Measures of physiologic variability provide insights into key aspects of sleep regulation and the dynamics of diverse physiologic systems during sleep and wake states and can serve as diagnostic markers of aging and disease.

0.30 Ta = 30 C

MR (cal/g/min)

0.26

= Awake = SWS = PS

0.22 0.18 0.14 0.10 0.06 32

33

34

35 36 Thy (C)

37

38

39

Figure 6.3  ​Metabolic rate (MR) versus hypothalamic temperature (Thy) dur-

ing wakefulness, non–rapid eye movement (NREM) sleep (slow-wave sleep [SWS]), and rapid eye movement (REM) sleep (paradoxical sleep [PS]) at 30°C ambient temperature (Ta) in a kangaroo rat. The effect of the thermal stimulus decreases during NREM sleep and disappears during REM sleep. (Modified from Glotzbach SF, Heller HC. Central nervous regulation of body temperature during sleep. Science. 1976;194[4264]:537–539.)

COUPLING AND NETWORK INTERACTIONS AMONG PHYSIOLOGIC SYSTEMS DURING SLEEP AND WAKE STATES The human organism is an integrated network in which complex physiologic systems, each with its own regulatory mechanisms, continuously interact. These interactions are mediated through intrinsic feedback coupling mechanisms that are affected by sleep. A prime example of physiologic interactions

Atlas of Clinical Sleep Medicine   41 NREM

EEG

REM

mW 83

mW 80

EMG

39.12 39.09 39.06

HT

RM 20 sec

Figure 6.4  ​Preoptic-anterior hypothalamic diathermic warming (in a cat) elicits tachypnea during non–rapid eye movement (NREM) sleep and is ineffective

40

40 Phase 2

35 30

30

25 P

20

I

Vl (L/min)

Chest sweating (mg · min1cm2)  102

during rapid eye movement (REM) sleep at neutral ambient temperature. Tachypnea disappears immediately at REM sleep onset (arrow), when hypothalamic temperature is still above threshold. EEG, Electroencephalogram; EMG, electromyogram (neck muscle); HT, hypothalamic temperature (5 mm behind the warming electrode); RM, respiratory movements; mW, milliwatt. (From Parmeggiani PL, Franzini C, Lenzi P, Zamboni G. Threshold of respiratory responses to preoptic heating during sleep in freely moving cats. Brain Res. 1973;52:189–201.)

II

15 10

20

5 0

L+D SWS

PS 0

5 10 15 20 25 30 35 40 Time (min) Figure 6.5  ​Chest sweating in humans drops (P) just before the onset of rapid eye movement (REM) sleep, is fully abolished during the initial part of REM sleep (I), and slowly and irregularly increases during the remainder of the REM episode (II). L1D, light and deep; PS, paradoxical sleep; SWS, slow-wave sleep. (Modified from Dewasmes G, Bothorel B, Candas V, Libert JP. A shortterm poikilothermic period occurs just after paradoxical sleep onset in humans: characterization changes in sweating effector activity. J Sleep Res. 1997;6[4]:252–258.) 20 15 10 5

NREM

10 100

90 Sao2 (%)

80

40

50 PACO2 (mm Hg)

60

F.igure 6.6  ​Breath-by-breath response of minute inspired volume ventilation

(VI) to decreasing arterial O2 saturation (Sao2) and to increasing alveolar partial pressure of CO2 (Paco2) in a sleeping dog. During rapid eye movement (REM) sleep, note the scatter of data points around calculated linear regression lines and the marked decrease of the ventilatory response to hypercapnia. Red circles, REM sleep; blue circles, non-REM sleep. (Modified from Phillipson EA. Regulation of breathing during sleep. Am Rev Resp Dis. 1977;115[6 Pt 2]: 217–224.) REM

LOC ROC HP NM D

3 sec

400 V

IE RM

Figure 6.7  ​Respiratory muscle activity during sleep at ambient thermal neutrality in a cat. Postural activity of neck and intercostal muscles disappears during

the transition from non–rapid eye movement (NREM) sleep to rapid eye movement (REM) sleep. Respiratory activity of intercostal muscles also disappears, whereas that of the diaphragm persists. D, Diaphragm; IE, intercostalis externus muscle; HP, hippocampus; LOC, left occipital cortex; NM, neck muscles; RM, respiratory movements; ROC, right occipital cortex. (From Parmeggiani PL, Sabattini L. Electromyographic aspects of postural, respiratory and thermoregulatory mechanisms in sleeping cats. Electroencephalogr Clin Neurophysiol. 1972;33[1]:1–13.)

is the coupling between the systems that control the breathing pattern and those that control the heart rate. Cardiorespiratory coupling is strongly influenced by sleep regulation and exhibits phase transitions across sleep stages. In normal control subjects, there is a continuous periodic modulation in the heart rate within each breathing cycle, and the amplitude of this modulation depends nonlinearly on the breathing

frequency, a mechanism known as respiratory sinus arrhythmia (RSA). Another example is that central apnea may be associated with bradycardia and asystole, and obstructive apnea may be associated with severe bradycardia at the end of apneas and with tachycardia when breathing resumes. Recent studies have discovered an alternative form of cardiorespiratory coupling, called phase synchronization, that is characterized by the

42  Physiologic Regulation in Sleep CA

Sleep-Wake Transition in Heart Rate Variability

CAO 1.6

Wake

114/min

Awake

1.4

132/min

1.2

NREM 105/min

123/min

REM 87/min

111/min

Figure 6.8  ​Spontaneous heart rate shown by electrocardiogram across

Heartbeat Interval (sec)

1.0

wake and sleep states with and without bilateral common carotid artery occlusion (CAO) in a cat. During rapid eye movement (REM) sleep, note the bradyarrhythmia and the baroreceptor reflex response that barely exceeds the spontaneous heart rate during non–rapid eye movement (NREM) sleep. CA, Carotid artery. (Data from Azzaroni A, Parmeggiani PL. Mechanisms underlying hypothalamic temperature changes during sleep in mammals. Brain Res. 1993;632[1-2]:136–142.) NREM

REM

EEG

EMG 150 mL• min1

PBF 0 80 mL• min1

0.8 0.6 0.4

A

0

1.6

10000

5000

15000

20000

25000

Asleep

1.4 1.2 1.0 0.8 0.6 0.4

0

10000

5000

15000

B

Beat number Figure 6.10  ​Changes in the degree of sympathetic and parasympathetic activation during wake and sleep states lead to transitions in physiologic variability. In cardiac dynamics, the transition from the wake to sleep state is typically associated with decrease in the average heart rate (increased average interbeat interval). However, other key aspects of heart rate variability also change with sleep-wake transitions. A, Higher sympathetic tone during the wake state is reflected in a smaller amplitude of beat-to-beat increments and pronounced trends embedded in heartbeat variability. B, In contrast, dominant parasympathetic tone during sleep leads to a significantly higher amplitude of heartbeat interval increments and reduced trends. (Modified from Ivanov PCh, Bunde A, Amaral LAN, et al. Sleep-wake differences in scaling behavior of the human heartbeat: analysis of terrestrial and long-term space flight data. Europhys Lett. 1999;48[5]:594–600.)

MBF 0

2s

100

by bradyarrhythmia and a decreased peak and mean blood flow in the common carotid artery (in a rabbit). EEG, Electroencephalogram; EMG, electromyelogram; MBF, mean blood flow; NREM, non–rapid eye movement; PBF, peak blood flow. (Data from Calasso M, Parmeggiani PL. Carotid blood flow during REM sleep. Sleep. 2008;31[5]:701–707.)

consistent occurrence of heartbeats at the same relative phases within consecutive breathing cycles (Fig. 6.18). Cardiorespiratory coupling is strongly influenced by sleep regulation and is affected by age and pathology. The deeper the sleep, the greater the synchronization between the heart rate and breathing rhythm (Figs. 6.19 and 6.20), despite the significant increase in heartbeat and respiratory fluctuations during sleep (see Figs. 6.10 and 6.11). Significant reduction with aging in heart rate and respiratory variability during both wake and sleep states (see Fig. 6.12) is paralleled counterintuitively by a reduction in both RSA and cardiorespiratory synchronization with aging (see Figs. 6.19 and 6.20). In patients with neuropathy, such as from diabetes, loss of synchronization may be evident. The two coexisting forms of cardiorespiratory coupling, RSA and phase synchronization (Fig. 6.21), change with transition across sleep stages, however, with markedly different responses (Fig. 6.22), indicating differentiated impact of sleep regulation on different forms of physiologic coupling.

Normalized histogram

Figure 6.9  ​An episode of rapid eye movement (REM) sleep is characterized

10–1

Asleep 10–2 Awake

10–3

0

1

2

3

4

5

Amplitude of heartbeat fluctuations

Figure 6.11  ​Dominant parasympathetic tone during sleep leads to larger

physiologic fluctuations. In contrast with the belief that heart rate variability is higher during daily activity compared with a more metronome-like regular heartbeat during sleep, normalized histograms of the amplitudes of heartbeat interval increments under healthy conditions show significantly higher probability (more than one decade on the vertical axis) for large amplitudes of heartbeat fluctuations during sleep, as indicated by the higher tail of the histogram during the sleep state compared with the wake state. (Modified from Ivanov PCh, Rosenblum MG, Peng C-K, et al. Scaling behaviour of heartbeat intervals obtained by wavelet-based time-series analysis. Nature. 1996;383:323–327.)

0.08 0.02 0.06

0.04

A

Wake REM Light Deep

Heartbeat Interval (sec)

0.1

Self-similarity in healthy heart rate variability

0.06

0.05

0.04 0.02 0.03

0.02

B

Wake REM Light Deep

Figure 6.12  ​Sleep stage transitions lead to stratification in basic measures

of physiologic variability. A, A well-pronounced chair-like stratification pattern in the standard deviation of heartbeat intervals reflects a gradual decrease of sympathetic tone with transitions from the wake state to rapid eye movement (REM) sleep and from light sleep to deep sleep in both healthy young adults and older adults. B, In contrast, the standard deviation of heartbeat interval increments does not significantly change (within error bars) with transitions across sleep stages. Both measures in A and B exhibit the same vertical shift as a result of suppressed parasympathetic (vagal) tone in older adult subjects, indicating that the standard deviation of heartbeat increments is a measure of parasympathetic tone during sleep, while the standard deviation of heartbeat intervals is a measure of both sympathetic and parasympathetic tone during different sleep stages. (Modified from Schmitt DT, Stein PK, Ivanov PCh. Stratification pattern of static and scale-invariant dynamic measures of heartbeat fluctuations across sleep stages in young and elderly. IEEE Trans Biomed Eng. 2009;56[5]:1564–1573.)

Further, sleep affects the entire network of interactions among diverse physiologic systems (Fig. 6.23) in which different sleep stages are characterized by specific physiologic network connectivity and topology (Fig. 6.24). Physiologic network reorganization with transitions from wake to sleep and across sleep stages occurs globally at the level of the entire network as well as at each network node (physiologic system) (Fig. 6.25), indicating a hierarchical structure of physiologic network interactions that is modulated by changes in autonomic function during sleep stages. This demonstrates the robust interplay between network structure and physiologic function as well as the necessity to measure not only the dynamics of individual physiologic systems (e.g., cardiac, respiratory, brain, temperature, muscle tone), but also their coupling and network interactions to comprehensively study and quantify the impact of sleep regulation on physiologic function in health and disease. The principles presented here are clinically significant. Compensatory responses, such as those that occur in obstructive sleep apnea, require the functions present in wakefulness that are lost in sleep. Automatic reflexive control of somatic and autonomic functions allows homeostatic behavior in NREM sleep without awareness, whereas the impaired homeostasis of REM sleep elicits physiologic disturbances and can impede compensatory reactions to these disturbances. Figure 6.1 summarizes some of the functional changes during sleep. The modern advances in understanding physiologic regulation presented here underlie the necessity to channel future efforts in basic research and clinical practice within the new conceptual framework and interdisciplinary field of network physiology.

Scale of observation

Young Elderly

Standard deviation of heartbeat increments (sec)

Standard deviation of heartbeat intervals (sec)

Atlas of Clinical Sleep Medicine   43

A

B

Breakdown of self-similarity with sleep apnea

Time

Figure 6.13  ​ Complex temporal organization of physiologic variability.

A, Seemingly random heartbeat interval fluctuations derived from a 30-minute electrocardiogram recording (horizontal axis,  1700 heartbeats) of a healthy subject during sleep (top panel). Mathematical analysis of the heartbeat signal at different time scales reveals a hierarchical organization across scales characterized by arches (middle panel) that bifurcate in a self-similar manner from larger to smaller scales. Brighter colors correspond to large heartbeat interval fluctuations, and white tracks (arches) show the evolution of the fluctuations in time (horizontal axis,  1700 heartbeats) and across different scales of observation (vertical axis, from  5 seconds to 10 minutes, with large scales at the top of the panel). The plot shows a hierarchical self-similar structure formed by the white arches. A magnification (red box) of the central portion of the middle panel in A (with 200 heartbeats on the horizontal axis and smaller scales of observation from  5 seconds to 1.5 minutes on the vertical axis) shows similar branching patterns. Such complex cascades with self-similar organization in heartbeat variability result from nonlinear feedback interactions between multiple sympathetic and parasympathetic inputs that underlie cardiac control during sleep and operate over a broad range of time scales. B, For sleep disorders such as sleep apnea, this self-similarity breaks down to a repetitive pattern at small and intermediate scales of observation, indicating that variability can provide important insights into the mechanisms of physiologic regulation during sleep. (Modified from Ivanov PCh, Amaral LAN, Goldberger AL, et al. From 1/f noise to multifractal cascades in heartbeat dynamics. Chaos 2001;11[3]:641–652.)

44  Physiologic Regulation in Sleep Healthy

wake1.0

Correlation exponent α of heartbeat intervals

102 10 Fluctuation function F (n)

1

sleep0.8

100 10–1

Awake

A

Asleep Heart failure

wake1.2

101 100

sleep1.0

10–1 10–2

B

10

100

1000

Young Elderly 1

0.8

0.6

10000

Time scale (heartbeat number n)

Acknowledgments We acknowledge support from the W.M. Keck Foundation, National Institutes of Health (NIH Grant 1R01-HL098437), and the US-Israel Binational Science Foundation (BSF Grant 2020020). Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

REM

Light

Deep

logic dynamics. With transitions from the wake state to rapid eye movement (REM), light, and deep sleep, the correlation exponent a of heartbeat intervals (see Fig. 6.14) significantly decreases for both healthy young adult and older adult subjects. Dominant sympathetic tone during the wake state and REM is associated with stronger heartbeat correlations and higher a values, while dominant parasympathetic tone during light and deep sleep leads to weaker correlations with a lower exponent a. Such sleep-stage stratification in the correlation of heartbeat fluctuations indicates a strong coupling between cardiac function and sleep regulation. Uncorrelated white noise behavior (i.e., absence of long-term memory) is characterized by a 5 0.5 (horizontal dashed line). A similar sleep-stage stratification pattern is observed also for respiratory dynamics. (Modified from Schmitt DT, Stein PK, Ivanov PCh: Stratification pattern of static and scale-invariant dynamic measures of heartbeat fluctuations across sleep stages in young and elderly. IEEE Trans Biomed Eng. 2009; 56[5]:1564–1573.)

1.8 mag

scales from a few seconds to many hours. Competing sympathetic and parasympathetic inputs lead to complex self-similar organization in heartbeat fluctuations (see Fig. 6.13) that is quantified by temporal autocorrelations represented by the fluctuation function F(n) (shown on the vertical axis) over a broad range of time scales n (horizontal axis). The level of these autocorrelations is determined characterized by the correlation exponent a (slope of the curve) – a long-term memory mechanism, characterized by a power law that correlates a heartbeat interval at a given moment in time with intervals thousands of heartbeats later. With transition from wake to sleep states, dominant parasympathetic tone leads to a complete reorganization of this memory process across time scales and to a lower value for the correlation exponent a. This effect of sleep regulation is observed also under pathologic conditions such as heart failure, however with much higher values for the correlation exponent a during both wake and sleep because of suppressed vagal tone (increased level of sympathetic tone) in heart failure. Sleep-wake transitions in long-term correlations are also present in other physiologic systems (e.g., respiration). (Modified from Ivanov PCh, Bunde A, Amaral LAN, et al. Sleepwake differences in scaling behavior of the human heartbeat: analysis of terrestrial and long-term space flight data. Europhysics Lett. 1999;48[4]:594– 600; Ivanov PCh. Scale-invariant aspects of cardiac dynamics. Observing sleep stages and circadian phases. IEEE Eng Med Biol Mag. 2007;26[6]:33–37; and Schmitt DT, Ivanov PCh. Fractal scale-invariant and nonlinear properties of cardiac dynamics remain stable with advanced age: a new mechanistic picture of cardiac control in healthy elderly. Am J Physiol Reg Int Comp Physiol. 2007;293:R1923–R1937.)

Wake

Figure 6.15  ​Sleep-stage stratification in temporal correlations of physio-

1.6 1.4 1.2

sign

Figure 6.14  ​Sleep-wake transitions modulate physiologic dynamics on

1.0 0.8 Wake

REM

Light

Deep

Figure 6.16  ​Linear and nonlinear characteristics of physiologic dynamics

change with sleep and wake states and across sleep stages. Correlations in the magnitude of heartbeat increments characterized by the scaling parameter amag reflect changes in the degree of nonlinearity. These changes are caused by a transition in physiologic regulation during wake and sleep states, with a minimal degree of nonlinearity during deep sleep (amag 5 1.55), a higher degree of nonlinearity during light sleep and rapid eye movement (REM) sleep, and the highest degree during the wake state (amag 5 1.7). The sign series of the increments of consecutive heartbeat intervals are highly anticorrelated (alternating positive and negative increments) and reflect linear properties of physiologic dynamics characterized by the scaling parameter asign, which gradually increases from deep sleep to light sleep, REM sleep, and the waking state in response to changes in cardiac autonomic regelation across sleep stages. (From Ivanov PCh. Scale-invariant aspects of cardiac dynamics. Observing sleep stages and circadian phases. IEEE Eng Med Biol Mag. 2007;26[6]:33–37.)

Atlas of Clinical Sleep Medicine   45

Circadian Rhythm in Heartbeat Correlations

Heartbeat Correlations 8

100

α = 1.2

2AM 0AM 5PM

10–1

α = 0.8

10

% deviation from mean α

Fluctuation function F(n)

Awake at different circadian phases

101

A

102

Time scale (heartbeat number n)

4

0

–4

–8

–2

Awake at all circadian phases

usual sleep period 0

B

Circadian phase (degrees) Circadian Rhythm in Mean Heartbeat RR Intervals

Circadian Rhythms in Heartbeat Correlations (c)

4 0 –4 usual sleep period

–8 0

C

Asleep at all circadian phases

60 120 180 240 300 360 60 120 180 240 300 360

8 % deviation from mean RR

% deviation from mean α

8

60 120 180 240 300 360 60 120 180 240 300 360

Awake Asleep

4

0

-4

-8

Usual sleep period 0

60 120 180 240 300 360 60 120 180 240 300 360

D Circadian phase (degrees) Circadian phase (degrees) Figure 6.17  ​Circadian influence on physiologic dynamics. A, Reorganization of temporal correlations in heartbeat intervals (vertical axis) over a broad range of time scales (horizontal axis) at different circadian phases. The correlation exponent a gradually changes from a 5 1.2 in the morning hours (elevated sympathetic tone) to a 5 1.0 during daytime and a 5 0.8 during the habitual sleep period (decreased sympathetic tone). Because the subject was awake across all circadian phases while controlling for the daily behavior pattern, this change in the temporal organization of heartbeat fluctuations across time scales indicates strong endogenous circadian influence on cardiac dynamics that is mediated through the suprachiasmatic nucleus in the brain and the sympathetic innervation of the heart. B and C, Circadian rhythms in the exponent a obtained from healthy subjects during a 7-day forced desynchrony protocol in which sleep/wake behavior cycles were adjusted to 28 hours and subjects were (B) awake or (C) asleep across all circadian phases. Peaks at 60 degrees to 90 degrees circadian phase (9:00 to 11:00 am) indicate strong heartbeat correlations regardless of whether or not the subjects were awake or asleep. The decrease in a during the usual sleep period (shaded regions) is accompanied by an increase in the mean heartbeat (RR) interval (decreased heart rate). Decreased heart rate and decreased a during the usual sleep period are consistent with a relative increase of parasympathetic tone in cardiac neuroautonomic regulation. However, this is not a simple relationship across the entire circadian cycle because the circadian peaks in a at 60 degrees to 90 degrees during both sleep and waking states are not accompanied by a peak in heart rate (D). This important dissociation between mean heart rate and the correlation exponent a is notable because a provides a unique insight into cardiac dynamic regulation by quantifying self-similar structures in the non-equilibrium heartbeat fluctuations (see Fig. 6.13) beyond the traditional concept of homeostatic equilibrium. ( A–B, Modified from Hu K, Ivanov PCh, Chen Z, et al. Endogenous circadian rhythm in an index of cardiac vulnerability independent of changes in behavior. Proc Natl Acad Sci U S A. 2004;101[52]:18223–18227. C–D, From Ivanov PCh, Hu K, Hilton MF, et al. Endogenous circadian rhythm in human motor activity uncoupled from circadian influences on cardiac dynamics. Proc Natl Acad Sci U S A. 2007;104[52]:20702–20707.)

Respiration

46  Physiologic Regulation in Sleep 6

A

3

IBIi 3

3 0

1

2

2

2

RRi

2 ECG

3

3 1

1

1 0 –1 t0

16218

16216

16220 Time (sec)

Trajectory of respiratory cycles

3 : 1 synchronization

φr1 0

t0

φr

2

222

3

φr3 –5

16224

3

3

2

2 1

–5

C

360

111

5

16222

φr(deg)

B

2

1

φr3

φr2

1

φr1

90 333

0

5

D

16216

16220 16224 Time (sec)

Figure 6.18  ​Synchronization between the cardiac and respiratory rhythms during sleep. Coupling feedback mechanisms between the cardiac system and the

respiratory system lead to continuous adjustment of the (A) interbreath interval (IBI) and (B) heartbeat (RR) interval. Heartbeats occur at the same relative phase (marked by symbols) within consecutive breathing cycles (shown in a different color), that is, their respective frequencies and phases “lock” at a particular ratio. C, 3:1 synchronization between breathing and heartbeat intervals, where for each breathing cycle (represented by a close-to-circular trajectory) there are 3 heartbeats that occur at the same relative phases fr(t) within consecutive breathing cycles (symbols collapse). D, Phase synchrogram. Segments of horizontal lines indicate cardiorespiratory synchronization. Different symbols represent heartbeats in different breathing cycles as in A and C; vertical dashed lines show the beginning of each breathing cycle. ECG, Electrocardiogram. (Modified from Bartsch RP, Schumann AY, Kantelhardt JW, Penzel T, Ivanov PCh. Phase transitions in physiologic coupling. Proc Natl Acad Sci U S A. 2012;109[26]:10181–10186.)

4

3.5

3.5

3

3

D 1.2

1.2

1

1

0.8

0.8 15840

B

15960 Time (sec)

No synchronization

16080

E

Synchronization 720

360

360

15960 Time (sec)

1800

1920 Time (sec)

2040

No synchronization

720

15840

C

Elderly subject during light sleep

4

A RRi (sec)

chronization in the presence of continuous fluctuations in both the interbreath interval (IBI) and heartbeat (RR) intervals in both young adults (A and B) and older adults (D and E) is a manifestation of the temporal organization and adjustment of the cardiac and respiratory rhythms as a result of their nonlinear coupling. Segments in red (C and F) correspond to periods of cardiorespiratory synchronization. An episode of 3:1 synchronization is shown for the young subject, that is, 6 heartbeats within 2 breathing cycles (6 horizontal lines in a 720-degree interval) are consistently placed at the same respiratory phases fr over many consecutive breathing cycles; a segment of 7:2 synchronization (i.e., 7 heartbeats) are synchronized with each 2 breathing cycles for the older adult subject. Notably, the young adult subject exhibits a longer period of cardiorespiratory synchronization despite a significantly higher IBI and RR interval compared with the older adult subject, indicating stronger coupling.  (Modified from Bartsch RP, Schumann AY, Kantelhardt JW, Penzel T, Ivanov PCh. Phase transitions in physiologic coupling. Proc Natl Acad Sci U S A. 2012;109[26]: 10181–10186.)

φr (deg)

Figure 6.19  ​Cardiorespiratory phase syn-

IBIi (sec)

Young subject during light sleep

16080

1800

F

1920 Time (sec)

Sync

2040

Atlas of Clinical Sleep Medicine   47

Cardiorespiratory synchronization Sleep-stage dependence

Synchronization strength (%)

14 12 10 8 6 4 2

A

REM

Wake

Light

Deep

Cardiorespiratory synchronization Sleep-stage dependence across age groups 18 REM Wake Light sleep Deep sleep

Synchronization strength (%)

16 14 12 10 8 6 4 2 0 B

20–34

35–49

50–64

65–79

≥80

Age (years)

Figure 6.20  ​Phase transition in physiologic coupling in response to changes in sleep regulation. A, Significant increase in cardiorespiratory phase synchroniza-

tion during deep sleep and light sleep compared with rapid eye movement (REM) sleep and the wake state, indicates modulation in cardiorespiratory coupling as a result of sleep. With increase of parasympathetic tone during light sleep and deep sleep, the strength of cardiorespiratory coupling, as represented by the degree of synchronization, also increases despite higher amplitude in heartbeat and respiratory variability (see Figs. 6.10 to 6.11). Statistical significance of the results for each sleep stage is demonstrated by a comparison to a surrogate test (red bars) in which breathing cycles and heartbeat intervals were randomized, thus eliminating their coupling. B, The sleep-stage stratification pattern in cardiorespiratory synchronization is stable across all age groups. Suppression of parasympathetic tone in older adult subjects and increased sympathetic tone lead to a reduction in synchronization across the entire sleep period that is most pronounced during light sleep and deep sleep. (Modified from Bartsch RP, Schumann AY, Kantelhardt JW, Penzel T, Ivanov PCh. Phase transitions in physiologic coupling. Proc Natl Acad Sci U S A. 2012;109[26]:10181–10186.)

48  Physiologic Regulation in Sleep Respiratory sinus arrhythmia and phase synchronization 0.1

Deviation from mean heartbeat interval

0

–0.1 0

A

90

180

270

360

450

540

630

720

630

720

Respiratory sinus arrhythmia and no phase synchronization 0.1

0

–0.1

B

0

90

180

270

360

450

540

Phase of breathing cycle (deg)

Figure 6.21  ​Respiratory sinus arrhythmia (RSA) and cardiorespiratory phase synchronization represent different coexisting forms of cardiorespiratory coupling.

Figure 6.22  ​Transitions in cardiorespiratory phase synchronization, respira-

tory sinus arrhythmia (RSA) and average breathing frequency across sleep stages. Average values obtained from a group of healthy subjects for each sleep stage are normalized on the corresponding values during REM sleep. Although the average breathing frequency decreases by 10% to 15% with transition from the wake state and rapid eye movement (REM) sleep to light sleep and deep sleep, the two forms of cardiorespiratory coupling (RSA and phase synchronization) increase. The response of cardiorespiratory synchronization to the relative decrease in sympathetic tone during light sleep and deep sleep, however, is by a factor of 10 higher than the response in RSA, indicating that sleep regulation affects very differently these two coexisting forms of cardiorespiratory coupling. (Modified from Bartsch RP, Liu KKL, Ma QDY, Ivanov PCh. Three independent forms of cardiorespiratory coupling: transitions across sleep stages. Comp Cardiol (2010). 2014;41:781–784.)

Relative % change in REM units

A, Whereas RSA leads to periodic modulation of the heart rate within each breathing cycle (highlighted by a sinusoid line fitted to the data points) associated with increase in heart rate during inspiration and decrease during expiration, phase synchronization leads to clustering of heartbeats at certain phases fr of the breathing cycle (highlighted by red ovals). Shown are consecutive heartbeats over a period of 200 seconds. The horizontal axis indicates the phases fr of the breathing cycle where heartbeats occur, and the vertical axis indicates the deviation of each heartbeat interval from the mean RR interval. Heartbeats are plotted over pairs of consecutive breathing cycles (0 to 720 degrees) to better visualize rhythmicity. Data are selected from a subject during deep sleep. B, For the same subject as in A, heartbeats from another period of 200 seconds also during deep sleep are plotted over pairs of consecutive breathing cycles. Data show well-pronounced RSA with a similar amplitude as in A; however, heartbeats are homogeneously distributed across all phases of the respiratory cycles, indicating absence of synchronization and reduced cardiorespiratory coupling. deg, Degrees. (Modified from Bartsch RP, Schumann AY, Kantelhardt JW, Penzel T, Ivanov PCh. Phase transitions in physiologic coupling. Proc Natl Acad Sci U S A. 2012;109[26]:10181–10186; Bartsch RP, Ivanov PCh. Coexisting forms of coupling and phase-transitions in physiological networks. Comm Comput Inform Sci. 2014;438:270–287; and Bartsch RP, Liu KKL, Ma QDY, Ivanov PCh. Three independent forms of cardiorespiratory coupling: transitions across sleep stages. Comp Cardiol (2010). 2014;41:781–784.)

Cardiorespiratory synchronization

400

Respiratory sinus arrhythmia 300

Breathing frequency

>400%

200

≈40%

100 REM

Wake

Light

Deep

Atlas of Clinical Sleep Medicine   49 Leg

Chin

δ

Time delay

Resp

Eye

HR β

θ α

A

Light sleep

Deep sleep

σ

25 sec Time

B

4 min

Network transition in 4 min period

Network Connectivity [%]

C

Deep sleep

Light sleep

40

W REM LS DS

20 0 1

D

2 Time [hours]

3

4

Figure 6.23  ​Influence of sleep and sleep-stage transitions on the network of interactions between physiologic systems. A, Dynamic network of physiologic

interactions in which ten network nodes represent six physiologic systems: brain activity (electroencephalographic waves: d, , a, s, and b), cardiac (HR), respiratory (Resp), chin muscle tone, leg movements, and eye movements. B, Transitions in physiologic interactions across sleep stages. The time delay between two pairs of signals. a-brain waves and chin muscle tone (top) and HR and eye movement (bottom) quantifies their physiologic interaction: highly irregular behavior (blue dots) during deep sleep is followed by a period of stable (almost constant) time delay during light sleep, indicating an onset of stable physiologic interaction (marked by red dots for the HR-eye and yellow dots for the a-chin interaction). C, Sleep-stage transitions are associated with changes in network structure: network snapshots over 30-second windows during a 4-minute period at the transition from deep sleep (dark gray segment) to light sleep (light gray segment) shown in B. During deep sleep, the network consists mainly of brain-brain links. With the transition to light sleep, links between other physiologic systems (network nodes) emerge, and the network becomes highly connected. The stable a-chin and HR-eye interactions during light sleep in B are shown in C by a yellow and a red network link, respectively. D, Physiologic network connectivity for one subject during 4 hours of sleep calculated in 30-second windows as the fraction (%) of present links out of all possible network links. The red line marks the sleep stages. Low connectivity is consistently observed during deep sleep (0:30 to 1:15 hours and 1:50 to 2:20 hours) and REM sleep (1:30 to 1:45 hours and 2:50 to 3:10 hours), while transitions to light sleep and the wake state are associated with a significant increase in physiologic network connectivity. (Modified from Bashan A, Bartsch RP, Kantelhardt JW, et al. Network physiology reveals relations between network topology and physiological function. Nat Commun. 2012;3:702.)

A

Average strength (%) of network links

Number of network links

Network characteristics of interactions between physiological systems

30 20 10 0

Wake

REM

Light

Deep

B

15 10 5 0

Wake REM Light Deep Figure 6.24  ​Transitions in neuroautonomic regulation associated with different sleep stages lead to transitions in structural and dynamic characteristics of the

network of interactions between physiologic systems. A, Network connectivity (number of network links) and B, network link strength (average strength of interactions between all systems in the network) exhibit a pronounced sleep-stage stratification pattern with less and weaker links during deep sleep and rapid eye movement (REM) sleep compared with the wake state and light sleep. Data are averaged from a group of healthy subjects. Network connectivity and link strength are obtained from the interactions between six physiologic systems: brain electroencephalographic activity, heart rate, respiration, chin muscle tone, leg movement, and eye movement. (Data from Ivanov PCh, Bartsch RP. Network physiology: mapping interactions between networks of physiologic networks. In: D’Agostino G, Scala A, eds. Networks of Networks: The Last Frontier of Complexity. Springer: 2014:203–222.)

50  Physiologic Regulation in Sleep

Wake chin

leg

HR

eye

resp eye hr α

α

LS

chin

leg

δ θ

A

REM

α

α

β

hr

δ θ

chin

leg resp eye

resp eye hr

θ

β

chin

leg

δ

DS

α

α

β

resp hr

δ θ α

α

β

Network links to heart rate

Average strength (%) of network links

15

10

5

0 REM Deep B Wake Light Figure 6.25  ​Sleep-stage transitions lead to hierarchical reorganization in the structure and dynamics of the network of physiologic interactions. Transitions in connectivity and average link strength in the entire network (shown in Fig. 6.24) are associated with a corresponding increase or reduction in the number of links and link strength for each network node. A, the number of links to a specific network node (heart) and B, the average strength of the links connecting the heart to the rest of the network exhibit a sleep-stage stratification pattern with lower connectivity and weaker links during deep sleep and REM sleep, and much higher connectivity with stronger links during light sleep and the waking state. Data are averaged from a group of healthy subjects. Network links represent interactions above a threshold. Network connectivity and link strength are obtained from the interactions between the heart and five other physiologic systems (brain electroencephalographic d, , a, s, and b activity, respiration, chin muscle tone, leg movement, and eye movement). DS, Deep sleep; LS, light sleep; HR, heart rate; REM, rapid eye movement. (Modified from Ivanov PCh, Bartsch RP. Network physiology: mapping interactions between networks of physiologic networks. In: D’Agostino G, Scala A, eds. Networks of Networks: The Last Frontier of Complexity. Springer: 2014:203–222.)

e1 Bibliography

Bartsch RP, Liu KKL, Ivanov PCh. Network Physiology: how organ systems dynamically interact. Plos One. 2015;10(11):e0142143. Calasso M, Zantedeschi E, Parmeggiani PL. Cold-defense function of brown adipose tissue during sleep. Am J Physiol. 1993;265:R1060–R1064. Ivanov PCh, Rosenblum MG, Amaral LAN, Struzik ZR, Havlin S, Goldberger AL, Stanley HE. Multifractality in human heartbeat dynamics. Nature. 1999;399:461–465. Ivanov PCh, Amaral LAN, Goldberger AL, Stanley HE. Stochastic feedback and the regulation of biological rhythms. Europhys Lett. 1998;43:363–368. Ivanov PCh, Liu KKL, Bartsch RP. Focus on the emerging new fields of Network Physiology and Network Medicine. New J Phys. 2016;18(10): 100201. Ivanov PCh, Liu KKL, Lin A, Bartsch RP. Network physiology: from neural plasticity to organ network interactions. In “Emergent Complexity from Nonlinearity, in Physics, Engineering and the Life Sciences”, ed. Mantica G, Stoop R, Stramaglia S. Springer Proceedings in Physics 191;2017.

Kantelhardt JW, Ashkenazy Y, Ivanov PCh, et al. Characterization of sleep stages by correlations in the magnitude and sign of heartbeat increments. Phys Rev E. 2002;65(5):051908(6). Kantelhardt JW, Havlin S, Ivanov PCh. Modeling transient correlations in heartbeat dynamics during sleep. Europhys Lett. 2003;62(2):147–153. Lin A, Liu KKL, Bartsch RP, Ivanov PCh. Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions. Philos Trans A Math Phys Eng Sci. 2016;374(2067):20150182 Parmeggiani PL, Calasso M, Cianci T. Respiratory effects of preopticanterior hypothalamic electrical stimulation during sleep in cats. Sleep. 1981;4:71–82. Parmeggiani PL, Rabini C. Sleep and environmental temperature. Arch Ital Biol. 1970;108:369–387. Parmeggiani PL. Systemic Homeostasis and Poikilostasis in Sleep: Is REM Sleep a Physiological Paradox? London: Imperial College Press; 2011. Schumann AY, Bartsch RP, Penzel T, Ivanov PCh, Kantelhardt JW. Aging effects on cardiac and respiratory dynamics in healthy subjects across sleep stages. Sleep. 2010;33:943–955.

Chapter

Cytokines, Host Defense, and Sleep

7

Aric A. Prather

The immune system and sleep are reciprocally regulated, meaning that alterations in sleep can have a robust impact on immunity and that immune activation has a direct effect on sleep in the brain. OVERVIEW OF THE IMMUNE SYSTEM The immune system is complex and multifaceted. It is composed of cells and soluble molecules that work in an orchestrated and tightly regulated fashion to protect the body from foreign antigens such as viruses and bacteria. The immune system is typically divided into two arms: the innate immune system and the adaptive immune system. Cells in the innate arm of the immune system include granulocytes (e.g., basophils, neutrophils, and eosinophils), monocytes (which develop into macrophages), dendritic cells, and natural killer (NK) cells. Cells of the adaptive arm include B cells (CD191) and T cells (CD41 and CD81), which express unique receptors that recognize specific antigenic peptides. EFFECT OF SLEEP DEPRIVATION Experimental studies using total or partial sleep deprivation (e.g., 4 hours of sleep opportunity per night) show robust changes in immune cell distribution and functioning, with potential implications for host resistance to infectious agents. Indeed, compared with a normal sleep condition, those with sleep loss show an increase in total leukocytes (white blood cells) in the peripheral circulation as well as an increase and/or decrease in specific cell subsets. For example, it has been shown that sleep is associated with a decreased number of circulating T cells, while sleep loss is associated with an increased number of circulating monocytes. During sleep, antigen-presenting cells (APCs) and T cells migrate from the periphery to accumulate in lymphoid tissue. With regard to immune function, sleep promotes activation of T cells, facilitating T-cell division if challenged, and the production of cytokines, interleukin (IL)-2, and interferon-g (IFN-g), which play important roles in promoting a T-helper cell type 1 response. In contrast, under experimental sleep loss, there is a decrease in T-cell proliferative capacity and in T-cell production of IL-2, leading to a shift toward a T-helper cell type 2 response. These sleep-related changes are largely independent of an already pronounced circadian rhythm, which drives much of the redistribution of immune cells moving between tissues and organs via the blood and lymphatic system.

Although it remains unclear whether these changes in immune parameters brought on by sleep and sleep loss are clinically meaningful, there is accruing evidence that insufficient sleep is associated with increased risk to susceptibility to infectious illness. Indeed, cross-sectional and prospective studies support associations between self-reported short (#5 hours) to relatively long (9 hours) sleep and reports of sleep disorders, with increased reports of infections and physician-diagnosed pneumonia. These observational findings were confirmed using experimental data. In a study of healthy participants experimentally treated with live rhinovirus, those who habitually slept an average of fewer than 6 hours per night measured by wrist actigraphy were more than 4 times more likely to develop a biologically verified cold compared with those sleeping more than 7 hours per night (Fig. 7.1A). Habitual short sleep and experimental sleep loss have also been shown to impair vaccination efficacy, including antibody responses to hepatitis A, hepatitis B, and influenza vaccines (see Fig. 7.1B); some of these findings were mixed, and the effects of experimental sleep loss are short lived in many cases. Mechanisms through which sleep influences antibody generation are not well delineated, though some data suggest that a percentage of slow-wave sleep (SWS) following vaccination is positively associated with greater generation of antibody levels in the future. In related work, greater postimmunization SWS was associated with more antigen-specific CD41 T cells in the peripheral circulation. T cells are essential for facilitating adaptive immunity, and although the molecular mechanisms through which sleep promote T-cell migration are not completely understood, several hormones released during sleep, including growth hormone, aldosterone, and prolactin, are believed to play a role in facilitating the extravasation of CD41 T cells from the blood into secondary lymphoid tissues. Sleep is also posited to modulate qualitative aspects of cellular immunity, such as promoting more robust T-cell and B-cell receptor repertoires (Fig. 7.2). SLEEP, IMMUNE FUNCTION, AND DISEASE Normal sleep regulates immune cell distribution and function, including the cellular production of inflammatory cytokines. Inflammation is proposed as a key immunologic pathway involved in the development and progression of a cadre of chronic medical conditions observed at greater frequency among individuals with insufficient or disturbed sleep, including cardiovascular disease, autoimmune conditions, and neurodegenerative diseases such as Alzheimer disease. Studies using serial sampling across the night under conditions of 51

52  Cytokines, Host Defense, and Sleep 50 45 % developing colds

40 35 30 25 20 15 10 5 0

7

Hours 4.0

Antibody response to vaccine

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

7 Sleep duration (hours) Figure 7.1  Shorter sleep duration is associated with increased risk of upper respiratory infection and impaired antibody responses to vaccination. A, Shorter sleep duration, as measured by wrist actigraphy over the course of 1 week, was associated with increased rates of developing a biologically verified cold following experimental inoculation with rhinovirus in a sample of healthy adults. The percentage of colds is based on predicted values and statistically adjusted for age and viral-specific antibodies before rhinovirus challenge. B, Shorter sleep duration, measured by wrist actigraphy over the course of 1 week, predicted fewer hepatitis B–specific antibodies in response to their second hepatitis B immunization, statistically adjusting for age, sex, body mass index, and response to the initial immunization.

normal sleep show that inflammatory cytokines, such as IL-6, increase during the night and are reduced under conditions of sleep loss. Similar alterations are observed in the production of tumor necrosis factor-a (TNF-a) in stimulated monocytes. Interestingly, the data linking sleep loss and alterations in circulating levels of inflammation are not clear-cut. Indeed, meta-analytic review of the literature indicated that partial, total, and prolonged sleep deprivation failed to reliably increase circulating levels of proinflammatory mediators (IL-6, TNF, C-reactive protein [CRP]); this is in contrast with data that support the activation of upstream inflammatory signaling pathways (nuclear factor [NF]-kB, STAT, AP-1) in response to sleep loss. Sleep disturbances, which are thought to be more chronic in nature, were associated with elevated levels of IL-6 and CRP. Habitual short sleep duration was similarly linked to elevated levels of systemic inflammation, though the effect sizes were smaller than for sleep disturbance (Table 7.1).

Sleep regulates immunity through several effector systems of the central nervous system (CNS), namely the hypothalamicpituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) (Fig. 7.3). Cortisol, which is a glucocorticoid released from the adrenal gland, shows a reliable circadian rhythm marked by a peak upon awakening, known as the cortisol awakening response, and a nadir in the evening. The increase in inflammatory activity early during sleep correlates with this reduction in HPA axis activity. Sleep disturbance is associated with repeated or prolonged activation of the HPA axis, which may lead to glucocorticoid receptor insensitivity on activated immune cells. This can render inflammationproducing cells unchecked, resulting in excess production of inflammatory proteins. In normal sleep, there is a shift from sympathetic to parasympathetic (vagal-mediated) activity at the onset of non–rapid eye movement (NREM) sleep; however, rapid eye movement (REM) sleep is marked by an increase in SNS activity. Sympathetic outflow has been shown to modulate inflammatory activity via b-adrenergic signaling, which in turn activates NF-kB and consequent cellular production of inflammatory proteins. Sleep disturbance, including in those with insomnia, is often marked by elevated nocturnal SNS activation. Inflammatory cytokines are not only a consequence of poor sleep but also play an integral role in regulating sleep in the brain, particularly following infection (Fig. 7.4, Table 7.2). Mice infected with the influenza virus show a significant increase in NREM sleep and an inhibition of REM sleep that lasts several days postinfection, which appears to be largely driven by macrophages and the proinflammatory mediators they produce. IL-1 and TNF mRNA show circadian variation in the brain, with their highest levels observed during periods of maximal sleep. Furthermore, administration of IL-1 or TNF promotes NREM sleep. Mouse models that are knockouts for the IL-1 (type 1) and/or TNF receptors sleep less than wild-type mice, underscoring the role of these cytokines in sleep regulation. Indeed, TNF is proposed to be one of the immune mediators that contributes to the sleep homeostat. In humans, there is some evidence that inflammatory activity tracks with sleep propensity. For example, in a study of healthy individuals, greater production of inflammatory cytokines following toll-like receptor 4 stimulation before sleep predicted greater sleep continuity and SWS. Lipopolysaccharide (LPS), which is a cell wall component of gram-negative bacteria, has been used in humans to examine the effects inflammatory processes on sleep. In this regard, low doses of endotoxin produce enhanced NREM and SWS, along with the other expected sickness behaviors, such as fatigue and anhedonia. Pharmacologic administration with IL-6 or IFN-g can suppress early NREM sleep and reduce REM sleep. Conversely, there is some evidence that cytokine antagonists, such as those that block TNF or IL-6, can improve sleep, including increasing SWS, increasing sleep efficiency, and reducing sleep complaints. It is important to note that human studies using inflammatory antagonists have largely been carried out in patients with inflammatory disorders (e.g., rheumatoid arthritis); it is unclear whether the observed effects would transfer to healthy sleepers. There are several pathways through which the peripheral immune system communicates with the brain. Direct neural innervation occurs via cytokines that interact with the vagus nerve that projects to brainstem nuclei, including the nucleus

Atlas of Clinical Sleep Medicine   53 Qualitative effects

Qualitative effects

l

More efficient APC-T cell synapses

se

es dv

o

Enhanced extravasation of APCs and T cells

Blo

Recruitment of broader TCR repertoire

Sleep

More tailored effector functions

Facilitated production of proinflammatory cytokines by APCs

More antigen-specific effector and persisting CD4+ T cells

Higher antibody titers

Recruitment of broader BCR repertoire

Affinity maturation, suitable glycosylation, and sialylation

Figure 7.2  The quantitative and qualitative influences of sleep on CD41 T-cell memory.Sleep increases the trafficking of antigen-presenting cells (APCs) and CD41 T cells out of the bloodstream and into secondary lymphoid organs and promotes the production of proinflammatory cytokines by APCs. Sleep also promotes an increase in the number of antigen-specific CD41 T cells and antibodies following vaccination. Qualitative changes in immunity are also observed with more sleep, including better efficiency in which APCs and CD41 T cells interact, more specific T-cell effector functions, and more specific B-cell subsets, which lead to the production of antibodies with higher affinity. BCR, B-cell receptor; TCR, T-cell receptor. (From Lange T, Born J, Westermann J. Sleep matters: CD41 T cell memory formation and the central nervous system. Trends Immunol. 2019;40:674-686.)

Table 7.1  Overall Effect Sizes for Associations Between Sleep Duration and Sleep Disturbances With Markers of Systemic Inflammation

CRP IL-6 TNF-a

Sleep Duration Effect Size (95% CI)

Sleep Disturbance Effect Size (95% CI)

0.09 (0.01 to 0.17) 0.11 (–0.01 to 0.23) 0.29 (–0.27 to 0.84)

0.12 (0.05 to 0.19) 0.20 (0.08 to 0.31) 0.07 (–0.13 to 0.28)

Based on meta-analytic data derived from Irwin et al. (2016). Overall effect sizes with a 95% confidence CI are displayed. In analyses that combined subjective and objective measures of sleep duration, shorter duration was associated with elevated CRP (16 samples, n 5 5040) but not IL-6 (18 samples, n 5 2573) or TNF-a (4 samples, n 5 157). In analyses that combined different measures of sleep disturbance (i.e., symptoms, questionnaires, and insomnia diagnosis), greater sleep disturbance was associated with higher CRP (31 samples, n 5 34,943) and IL-6 (29 samples, n 5 3339) but not TNF-a (8 samples, n 5 672). CI, Confidence interval; CRP, C-reactive protein; IL-6, interleukin-6; TNF-a; tumor necrosis factor-a.

tractus solitarii and ventrolateral medulla, as well as nuclei in the hypothalamus and the amygdala. Additionally, macrophage-like cells reside within the circumventricular organs and choroid plexus of the brain and, when activated, produce cytokines such as IL-1, which can enter the brain via volume diffusion. Finally, active transport across the blood-brain barrier (BBB)

can facilitate the movement of proteins; notably, there is some evidence that sleep patterns may modulate BBB permeability. The links between sleep and cytokines have led to the hypothesis that inflammation may serve as a key mechanism linking sleep disturbance and neurodegenerative diseases, such as Alzheimer disease (Fig. 7.5). Indeed, neuroinflammation via primed microglial cells in the brain is associated with a reduction in amyloid clearance, which in turn is associated with poor sleep and neurodegenerative disease. Additionally, sleep disturbance is associated with alterations in aging pathways within immune cells (Fig. 7.6), providing yet another pathway through which insufficient or disturbed sleep may accelerate aging, both in the body and in the brain. The links between sleep and the immune system are bidirectional. In animals and humans, sleep appears to play a critical role in regulating the immune system and modulating host defense against infectious agents, a process mediated by cytokines. Conversely, cytokines act directly on the CNS to aid in sleep regulation. Although the many functions of sleep continue to be debated, the accruing evidence demonstrates that regulation of immunity is on the list. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

54  Cytokines, Host Defense, and Sleep EEG NREM sleep

Awake

NREM sleep REM sleep

70

Stage 3 and 4

Precent recording time

Stage 1 Stage 2

SNS nerve fibers

Proinflammatory cytokines

IL-6, TNF

Circulation Adrenal gland

ADRB2

TLR4

NF-kB

Expression of proinflammatory immuno response genes

mRNA

60

55

50

Baseline

Proinflammatory cytokines

IL-6, TNF

Cancer

Day 2

Day 4

Day 8

Table 7.2  Effects of Cytokines on the Brain Cytokine

Cardiovascular disease

Day 1

Postinfection Figure 7.4  Influenza virus infection increases non–rapid eye movement (NREM) sleep.By day 2 after intranasal inoculation of mice with influenza virus, NREM sleep increases. This increase persists for 1 week or more. The mice recover from the infection after about 2 weeks, and sleep returns to normal values at that time. The inset shows the detection of viral antigen within the olfactory bulb after inoculation. The cell shown has characteristics of microglia and appears to be activated. Microglia are responsible, in part, for cellular host defenses in the brain. Such cells likely produce cytokines, which in turn are involved in sleep regulation.

Epinephrine

Norepinephrine

65

Major depressive disorder

IL-1b

IL-6 TNF-a

Figure 7.3  Sleep and inflammation.Acute sleep loss and periods of sleep

disturbance can result in activation of the sympathetic nervous system and release of the neurotransmitter norepinephrine into lymphoid organs as well as the release of epinephrine into the systemic circulation via the adrenal glands. Epinephrine and norepinephrine bind to adrenergic receptors on immune cells, leading activation of nuclear factor (NF)-kB–mediated inflammatory processes. Activation of this pathway can similarly occur via toll-like receptor 4 (TLR4). Activation of this transcriptional pathway results in upregulation in the expression of proinflammatory genes. In turn, the cell produces proinflammatory cytokines, including interleukin (IL)-6, IL-1b, and tumor necrosis factor (TNF)-a. These proinflammatory mediators feed back on the brain via the vagus nerve, active transport, and other mechanisms, potentially creating a feedforward loop. EEG, Electroencephalogram; NREM, non-REM sleep; REM, rapid eye movement; SNS, sympathetic nervous system. (From Irwin MR, Opp MR. Sleep health: reciprocal regulation of sleep and innate immunity. Neuropsychopharmacology. 2017;42:129-155.)

Nerve growth factor Brain-derived neurotrophic factor Growth hormone– releasing hormone

Brain Stimuli That Promote Production/Release

Sleep Effects: Promotes

IL-1, TNF, NF-kB, sleep loss, pathogens, neuronal activity, stress, feeding IL-1, TNF, NF-kB, sleep loss, pathogens, stress TNF, IL-1, NF-kB, sleep loss, pathogens, neuronal activity, stress, ambient temperature IL-1, TNF, NF-kB, sleep loss, neuronal activity, pathogens, stress Neuronal activity, stress, pathogens, sleep loss

NREM/EEG SWA

IL-1, sleep loss, microbes

NREM/EEG SWA

NREM NREM/EEG SWA NREM/REM

NREM/REM

EEG, Electroencephalogram; IL, interleukin; NF-kB, nuclear factor k-B; NREM, non–rapid eye movement sleep; REM, rapid eye movement sleep; SWA, electroencephalogram slow-wave (0.50 to 4 Hz) activity; TNF-a, tumor necrosis factor-a.

Atlas of Clinical Sleep Medicine   55 Insomnia Sleep disturbance Short sleep duration

Systemic inflammation

Sleep EEG Awake

NREM sleep

REM

Proinflammatory cytokines

Stage 1 Stage 2 Stage 3 and 4

C-reactive protein

CNS pathology Amyloid pathology

Neuronal damage

Microglial cell Primed microglial cell

Local inflammation

Astrocyte

Cognitive aging Alzheimer disease

Figure 7.5  Potential mechanism linking sleep, inflammation, and alzheimer disease.Sleep disturbance is associated with elevated systemic inflammation, which

can lead to interaction with the brain via vagus afferents. Inflammation may promote changes in the morphology of microglial cells in the brain, leading them to be inflammatory and resulting in reduced amyloid clearance within the brain. Accumulation of amyloid, which is considered a piece of the process that leads to the occurrence of Alzheimer disease, promotes further neuroinflammation resulting in a feedforward loop. CNS, Central nervous system; EEG, electroencephalogram; NREM, non-REM sleep; REM, rapid eye movement sleep. (From Irwin MR, Vitiello MV. Implications of sleep disturbance and inflammation for Alzheimer’s disease dementia. Lancet Neurol. 2019;18[3]:296-306.)

Sleep disturbance

Insomnia

Short sleep duration

1 Telomere shortening 2 7

DNA damage

Inflammatory gene expression

NF-kB 10 3 4

6 5

Proinflammatory cytokines

9 INC4s

senescent p16 signal marker

C-reactive protein

Figure 7.6  Sleep and immune aging. There is accruing evidence that insufficient sleep and insomnia symptoms are associated with alterations in markers of

immune aging, beyond age-related increases in proinflammatory cytokine activity. These include shortening of telomeres, an increase in DNA damage responses, and expression of the cell surface senescent marker p16INK4a. Cellular aging promotes further inflammatory activity, resulting in accelerated transition of a cell to the senescence-associated secretory phenotype. (From Irwin MR, Vitiello MV. Implications of sleep disturbance and inflammation for Alzheimer’s disease dementia. Lancet Neurol. 2019;18[3]:296-306.)

e1 Bibliography

Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiol Rev. 2019;99:1325–1380. Davis CJ, Krueger JM. Sleep and cytokines. Sleep Med Clin. 2012;7: 517–527. Irwin MR. Why sleep is important for health: a psychoneuroimmunology perspective. Annu Rev Psychol. 2015;66:143–172. Irwin MR. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 2019;19:702–715. Irwin MR, Olmstead R, Carroll JE. Sleep disturbance, sleep duration, and inflammation; a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2016;80:40–52.

Irwin MR, Opp MR. Sleep health: reciprocal regulation of sleep and innate immunity. Neuropsychopharmacology. 2017;42:129–155. Prather AA, Hall M, Fury JM, et al. Sleep and antibody response to hepatitis B vaccination. Sleep. 2012;35:1063–1069. Prather AA, Janicki-Deverts D, Hall MH, Cohen S. Behaviorally assessed sleep and susceptibility to the common cold. Sleep. 2015;38:1353–1359. Rockstrom MD, Chen L, Taishi P, et al. Tumor necrosis factor alpha in sleep regulation. Sleep Med Rev. 2018;40:69–78. Taylor-Gjevre RM, Gjevre JA, Nair BV, Skomro RP, Lim HJ. Improved sleep efficiency after anti-tumor necrosis factor a therapy in rheumatoid arthritis patients. Ther Adv Musculoskelet Dis. 2011;3:227–233.

Chapter

8

Control of Breathing Danny J. Eckert and Atul Malhotra

NORMAL SLEEP The goal of the respiratory system is to supply oxygen, remove carbon dioxide, and maintain acid-base balance. Breathing is controlled via feedforward and feedback mechanisms that include three key components: (1) central control, (2) effectors, and (3) sensors (Fig. 8.1). The primary centers for central respiratory control are in the pons and medulla (Fig. 8.2). During the wake state, these centers receive input from a variety of sources to modulate breathing (Fig. 8.3). Oxygen and carbon dioxide levels are two of the main chemical signals that modulate breathing (Fig. 8.4). Sleep decreases the ventilatory response to hypoxia and hypercarbia. This effect varies with the stage of sleep (Fig. 8.5). Sleep also modifies muscle activation. This is most notable in the upper airway (Fig. 8.6). The genioglossus is the largest and most studied of the upper respiratory dilator muscles. It is controlled by the motor nucleus via the hypoglossal nerve, which receives input from a variety of central sites as well as feedback from upper airway mechanoreceptors (Fig. 8.7).

This reduction in upper airway patency is the result of a combination of factors, including anatomy, dilator muscle activity, arousal threshold, and the response of the respiratory control system to perturbations (Fig. 8.9). Central sleep apnea is defined as absence of airflow without respiratory effort. There are several manifestations of central sleep apnea, including high-altitude–induced periodic breathing, narcotic-induced central sleep apnea, cardiovascular disease resulting in Cheyne-Stokes breathing, and sleep-wake transition breathing instability (Fig. 8.10). There are multiple physiologic mechanisms that can contribute to central apneas (Fig. 8.11).

NPBM & KF Pons

SLEEP APNEA Sleep is associated with several respiratory disorders (see Chapters 28 to 31). Obstructive sleep apnea and central sleep apnea are two of the most common. Obstructive sleep apnea occurs when upper airway patency is compromised (Fig. 8.8).

vI-NTS

G

Central control

VR

G DR

DR

G VR

NA

G

BOT Medulla

NRA

Spinal cord

Figure 8.2  Central control of breathing.The central respiratory control cenEffectors Sensors

Figure 8.1  Control of breathing overview. Breathing is controlled via feedfor-

ward and feedback mechanisms involving central control, effectors, and sensors. (Modified from Eckert DJ. Respiratory physiology: understanding the control of ventilation. In: Kryger MH, Roth T, Dement WC, Goldstein C, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022:246.)

56

ters are in the pons and medulla. The medulla is the location of the primary respiratory control center. Transections below the medulla cease respiration. The dorsal respiratory group (DRG) contains the ventrolateral nucleus of the tractus solitaries (vl-NTS). This region is thought to be involved in inspiration. The ventral respiratory group (VRG) contains the pre-Botzinger complex (BOT), the nucleus ambiguous (NA), and the nucleus retroambigualis (NRA). These cells fire rhythmically in vitro and respond to hypoxia. They provide neural input to the phrenic nerve and the hypoglossal nucleus. Some controversy exists regarding the role of the parafacial respiratory group (PRG) and retrotrapezoid nucleus (RTN), including the possibility of more than one oscillator that can drive breathing. (The PRG and RTN are not included in the figure for simplicity.) The pneumotaxic center (which inhibits breathing during inspiration) is located in the nucleus parabrachialis medialis (NPBM) and Kolliker-Fuse (KF) nuclei of the dorsolateral pons. When this area is damaged, bradypnea and larger tidal volumes result.

Atlas of Clinical Sleep Medicine   57

Higher brain centers (cerebral cortex–voluntary control over breathing)

Emotional stimuli acting through the limbic system Respiratory centers (medulla and pons)

Peripheral chemoreceptors O2 , CO2 , H Stretch receptors in lungs

Central chemoreceptors CO2 , H Pons

C

Pyramid

C

Receptors for touch, temperature, and pain stimuli

C

C

Wakefulness drive to breathe

Receptors in muscles and joints

Figure 8.3  Modulators of breathing. The intrinsic central nervous system respiratory control is modulated by cells responsive to blood chemistry, specifically

35

35

30

30

25 20 15 10 5 0

A

Minute ventilation, L/min

Minute ventilation, L/min

Pco2 (and/or H1 concentration) and Po2. The primary central chemoreceptors (C) are located near the ventral surface of the medulla. The ventral medullary surface and the retrotrapezoid nucleus are two neuronal groups that are extremely sensitive to changes in H1 concentration. CO2 is lipid soluble and quickly crosses the blood-brain barrier. The CO2 that enters the central nervous system is rapidly hydrated, and the H1 concentration increases. This activates these chemoreceptors, and ventilation increases. The primary peripheral chemoreceptors are the carotid and aortic bodies. The carotid bodies are located at the bifurcation of the common carotid arteries. The aortic bodies are located near the arch of the aorta (but are mainly relevant in nonhuman species). Both sets of chemoreceptors are sensitive to Po2 and to a lesser extent Pco2. Secondary modulators: The cerebral cortex is responsible for voluntary control of breathing. It sends signals through the corticospinal and corticobulbar tracts. Receptors in the lung are responsible for reacting to lung volume and irritants. They send feedback through the vagus nerve. Proprioceptors in muscles and tendons stimulate breathing, as evidenced by passive movements increasing respiratory rate. There is also an independent input to breathe known as the wakefulness drive to breathe. Note: Some modulators can either increase or decrease breathing depending on the prevailing conditions. 1, Excitatory input; –, inhibitory input.

20 30 40 50 Arterial PCO2 (mm Hg)

25 20 15 10 5 0

B

120 100 40 1.0 .10 Arterial PO2 (mm Hg)

Figure 8.4  Response to hypercapnia and hypoxia.A, The increase in ventilation in response to increases in Pco2 is linear, approximately 2.5 L/min for each

increase in Pco2. B, Ventilation increases as Po2 decreases below 75 mm Hg. The response is more dramatic when the Po2 decreases below 55 mm Hg. Ventilation increases greater than threefold when the Po2 has reached 40 mm Hg (75% saturation). As evident in the curves, there is a rapid response to changes in Pco2. In comparison, the response to hypoxia is blunted until there is a large decrease in Po2.

58  Control of Breathing 30

AWAKE

STAGE N2

STAGE N3

REM

20 20

e ag

St

10

*P < .05

N3

2

eN

g Sta

*P < .05

VE (L/min)

Ventilation (L/min)

Aw ak e

10

0 30

EM

R

20

0

A

30

40

10

50

End-tidal PCO2 (mm Hg)

B

0 100

90

80 100 SAO2 (%)

90

80

Figure 8.5  The response to hypercapnia and hypoxia is reduced during sleep. A, Hypercapnia was induced in 12 healthy individuals using a modified rebreath-

ing technique while recording electroencephalogram (EEG) to assess the participants’ stage of sleep. The graph represents the mean minute ventilation for all 12 subjects. The mean minute ventilation at baseline is indicated. Although not clearly displayed in the figure, in reality baseline breathing is typically reduced during sleep versus wake with further potential sleep stage–related reductions depending on the prevailing conditions. The hypercapnic ventilatory response is reduced in stage N2 and the slow-wave sleep state compared with the wake state and is further decreased during rapid eye movement (REM) sleep. The blunting of chemoresponsiveness during REM sleep may be a major mechanism whereby many forms of central apnea resolve during REM sleep. Cheyne-Stokes breathing and high-altitude periodic breathing tend to resolve during REM sleep. This may be secondary to the decrease in chemoresponsiveness associated with REM sleep. B, Isocapnic hypoxia was induced in 10 male subjects while recording EEGs to assess the participants’ stage of sleep. The graphs represent data from one individual. The response to hypoxia was blunted . in stage 2 and stage 3/4 and further decreased during REM sleep. *P , .05, REM different from stages 2 and slow-wave sleep. SaO2, Hemoglobin saturation; V    E, expired minute ventilation. (From Douglas NJ, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults. Am Rev Resp Dis. 1982;126[5]:758–762.)

Promotion of airway collapse

Promotion of airway patency

Negative pressure on inspiration

Pharyngeal dilator muscle contraction (genioglossus)

Extraluminal positive pressure Fat deposition Retrognathia or micrognathia mandible

Lung volume (longitudinal traction)

Figure 8.6  The upper airway is vulnerable to collapse.The pharynx comprises predominantly muscle, fat, and connective tissue. This relatively soft structure is

vulnerable to collapse as it is devoid of bony support. The supine position exacerbates this tendency to close. Pharyngeal dilator muscle activity is increased in individuals with sleep apnea during wakefulness. This may be caused, at least in part, by compensation for anatomic deficiency. During sleep onset, drive to the pharyngeal muscles is reduced. Inspiration yields a negative airway pressure that creates a collapsing influence on the upper airway. All of these factors tend to compromise the pharynx. As a result, patency requires activation of several muscles including the genioglossus, tensor palatini, and stylopharyngeus. As the lung expands, it helps open the pharynx by longitudinal traction. This balance of forces can be weighted toward collapse by obesity and anatomy (e.g., a small mandible) to result in greater instability and sleep-disordered breathing.

Atlas of Clinical Sleep Medicine   59

Cortex

Orexin



PPT/LDT



LC raphe





XII Genioglossus

Nucleus of the solitary tract



Local Ventrolateral upper medulla airway receptors

Cardiovascular and respiratory reflexes

Figure 8.7  The hypoglossal motor system.The hypoglossal nerve controls the genioglossus muscle (tongue). It is involved in many activities including speech

and swallowing and is the most-studied pharyngeal dilator muscle. The activity of the hypoglossal nerve is affected by many factors, including cortical and brainstem stimulation, breathing pattern, chemoreceptor activation, and input from mechanoreceptors in the pharynx. Several neurochemical systems, such as the cholinergic (from the pedunculopontine and laterodorsal tegmental [PPT/LDT] nucleus), adrenergic (from the locus coeruleus [LC] and subcoeruleus), serotonergic (from the raphe), and orexinergic (from the hypothalamus), modulate sleep and probably have significant roles in modulating genioglossal activity.

60  Control of Breathing

5.0

EMGgg (Volts)

2.5 0.0 2.5 5.0

EMGsub (V)

50 0 50 50

EEG (V)

25 0 25 50

Pepi (cm H2O)

0

50 2

Flow (L/sec)

0 2 100

SaO2 (%)

95 90 85

2 min

80

5.0

EMGgg (Volts)

2.5 0.0 2.5 5.0

EMGsub (V)

50 0 50

AROUSAL

50

EEG (V)

25 0 25 50 0

Pepi (cm H2O) 50

Snoring

2

Flow (L/sec)

Arousal threshold

Snoring

0

APNEA

2 100

SaO2 (%)

95 90 85 80

20 sec

Oxygen desaturation

Figure 8.8  Upper airway muscles and arousal threshold. The tracing shows an experimental recording from a patient with obstructive sleep apnea. The cessa-

tion of airflow (apnea) leads to both oxygen desaturation and electroencephalogram (EEG) arousal from sleep. Note the progressive increases in genioglossal muscle activity (electromyographic activity [EMGgg]) that occur with increasing respiratory efforts. Obstructive apnea is characterized by ongoing respiratory efforts in contrast to central apnea, in which respiratory effort ceases during attenuated airflow. Respiratory effort leads to swings in intrathoracic pressure that can be estimated with an epiglottic catheter (Pepi). Negative intrathoracic pressure is thought to be the primary stimulus for respiratory arousal from sleep. Respiratory efforts (as sensed by mechanoreceptors in the chest wall) are thought to be an important contributor to respiratory-related arousal from sleep. If arousal occurs prematurely (low arousal threshold), then insufficient respiratory stimuli accumulate to activate the genioglossus muscle. On the other hand, if arousal is markedly delayed (high arousal threshold), then profound hypoxemia may develop. Ideally, increases in EMGgg are sufficient to restore airway patency before arousal from sleep. EMGsub, Submental electromyography. (Modified from Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008;5[2]:144–153.)

Atlas of Clinical Sleep Medicine   61 OBSTRUCTIVE HYPOPNEA-APNEA Surface forces

UA narrowing/ collapse

Breathing effort/ PO2, PCO2

UA dilator muscle activity

Hypoventilation

Arousal

Chemosensitivity UA dilator muscle activity/ responsiveness UA resistance Lung volume Rapid PO2 PCO2 Return to

sleep

UA dilator muscle activity/ responsiveness Rapid UA reopening

Hyperventilation

Figure 8.9  Potential cycle of ventilatory instability. Obstructive sleep apnea leads to increases in breathing effort in association with hypoxemia and hypercapnia.

Respiratory effort can trigger arousal from sleep with resulting physiologic changes that can restore airway patency and yield hyperventilation. Upon return to sleep, the upper airway (UA) can again collapse, leading to repetitive apnea. Mechanisms listed outside of the circle are associated with restoration of pharyngeal airway patency, whereas those on the inside tend to promote upper airway collapse. Many of these factors can clearly be interrelated. (Modified from Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008;5[2]:144–153.)

100

EEG (mV) 100 55

Tone (dB) 0 20

PMASK (cm H2O) 10 20

PEPI (cm H2O) 10 45

PETCO2 (mm Hg) 0 2

VT (L) 0

Flow (L/s)

1

1

A

10s

Figure 8.10  Various forms of central apnea. A, Experimentally induced arousal from sleep can yield hyperventilation based on a robust ventilatory response to arousal.

The electroencephalogram (EEG) shows an increase in frequency (underscored portion) that is typical of arousal. The hyperventilation leads to hypocapnia that can result in apnea if the Pco2 falls below the CO2 apnea threshold. The absence of respiratory effort (as seen in the epiglottic pressure channel [Pepi]) defines central apnea.   Continued

62  Control of Breathing

EEG SaO2

Chest Abdomen

EEG SaO2 Chest Abdomen

B

1 min

Arousal

Arousal

Arousal

Arousal

Arousal

EEG SaO2

Airflow

Chest

Abdomen

C

1 min

Figure 8.10, cont’d  B, Narcotic-induced central apneas occur in up to 50% of patients on chronic narcotic therapy. Intermittent pauses are observed in the chest and abdominal respiratory belts that occur in central apnea (top). With dose reduction of the narcotic agent (bottom), the breathing pattern is normalized. These graphs illustrate the dose dependence of narcotic-induced central apnea. This breathing pattern is sometimes associated with low respiratory rates (bradypnea). C, A crescendo-decrescendo (Cheyne-Stokes) pattern in association with central apneas whereby an absence of respiratory effort is seen in association with cessations in airflow. The arousal from sleep typically occurs at the peak of the hyperpnea that corresponds with paroxysmal nocturnal dyspnea complaints in patients. This breathing pattern is seen in one-third to one-half of congestive heart failure patients with left ventricular dysfunction. Note that the intermittent desaturations that occur are delayed in time as a result of the slow circulation in congestive heart failure. Pmask, Mask pressure. (Modified from Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: pathophysiology and treatment. Chest. 2007;131[2]:595–607.)

Atlas of Clinical Sleep Medicine   63

“Can’t breathe” factors ( Respiratory motor output) “Won’t breathe” factors (CNS depression & CCHS)

Loss of wakefulness stimulus

Chemosensitivity

 between eupnea CO2 and apnea threshold

Loss of behavioral inputs

Drive Hypocapnia

Inhibitory reflexes Central apnea/hypopnea

Hyperventilation

Obstructive apnea/hypopnea UA anatomy

Chemosensitivity

Hypercapnia

Ventilatory response to arousal

Metabolic production

Arousal Arousal threshold

Figure 8.11  Complex Relationship Between Obstructive and Central Sleep Apnea. There is considerable overlap in the pathogenesis and clinical expression of

these two entities. As seen in the green shaded components of the diagram, central apnea leads to hypercapnia, which then yields hyperventilation. In turn, the CO2 levels decrease with hypocapnia, leading to reduced respiratory drive and again yielding central apnea. Several factors can contribute to central apnea based on lack of central drive (will not breathe) or inability of the respiratory system to adequately translate neural drive to the respiratory muscles (cannot breathe). Obstructive sleep apnea can also lead to arousal from sleep, which can yield a robust ventilatory response to arousal and subsequent central apnea. Obstructive or central apnea can occur during reduced central respiratory drive, depending on the prevailing upper airway mechanics. As a further example of the complex interaction between obstructive and central sleep apnea, the terms complex sleep apnea or treatment-emergent central sleep apnea have been used to describe patients diagnosed with obstructive sleep apnea who develop central sleep apnea on the first night of continuous positive airway pressure (CPAP) therapy. Although the underlying mechanisms are poorly understood and these central apneas commonly recede over time, approximately 10% of patients may experience complex apnea on their first night of CPAP therapy. CNS, Central nervous system; CCHS, congenital central hypoventilation syndrome; UA, upper airway. (Modified from Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: Pathophysiology and treatment. Chest. 2007;131[2]:595–607.)

Chapter

9

Central and Autonomic Regulation in Cardiovascular Physiology Richard L. Verrier and Ronald M. Harper

OVERVIEW Circulatory homeostasis during sleep requires coordination of two physiologic systems: the respiratory system, which is essential for oxygen and carbon dioxide exchange, and the cardiovascular system, which provides blood transport. The initial stage, non–rapid eye movement (NREM) sleep, is characterized by relative autonomic stability with vagus nerve dominance and heightened baroreceptor gain. There is near sinusoidal modulation of heart rate variations, termed normal respiratory sinus arrhythmia, caused by coupling with respiratory activity and cardiorespiratory centers in the brain (Fig. 9.1). Rapid eye movement (REM) sleep is initiated at 90-minute intervals and exhibits a more irregular pattern with periodic surges in heart rate, arterial blood pressure, and other cardiovascular parameters. The challenge to homeostatic regulation is even greater in individuals who have diseased respiratory or cardiovascular systems, particularly in those with apnea or heart failure, or in infants, whose cardiorespiratory control systems may be underdeveloped.

Wakefulness

REM sleep induces a near paralysis of accessory respiratory muscles and diminishes descending forebrain influences on brainstem control regions (see Chapters 6 and 8). Those reorganizations of control during REM sleep have the potential to interfere substantially with compensatory breathing mechanisms that assist arterial blood pressure management and to remove protective forebrain influences on hypotension or hypertension. The significant interaction between breathing and arterial blood pressure is evident in normalization of blood pressure by continuous positive airway pressure in patients with apnea-induced hypertension. Patients with heart failure exhibit severe insular cortex, cerebellar, and other brain gray matter loss, particularly on the right side (Fig. 9.2), and impaired functional magnetic resonance signal responses to cold pressor challenges and to Valsalva maneuvers. The cerebellar and insular injuries exert a significant impact on coordination of breathing and circulation time, contributing to extreme periodic breathing and impaired dynamic blood pressure responses and loss of synchronization of breathing effort with cardiovascular action. These injuries lead to an inability to mount appropriate blood pressure and heart rate responses; the damage appears to stem from disordered breathing and accompanying neural circulatory changes during sleep. HEART RATE SURGES

Quiet sleep

ms

500

REM

400 300 200

0

400 Successive intervals

Figure 9.1  ​The x-axis represents successive heartbeats and the intervals between heartbeats from a healthy 4-month-old infant during quiet sleep, rapid eye movement (REM) sleep, and wakefulness. The y-axis represents time (in milliseconds [ms]) between those heartbeats. Note the rapid modulation of intervals during quiet sleep contributed by respiratory variation. Note also the lower frequency modulation during REM sleep and the epochs of sustained rapid rate during wakefulness.

64

REM-induced accelerations in heart rate, consisting of an abrupt (though transitory) 35% to 37% increase concentrated during phasic REM, were observed in canines (Fig. 9.3). These marked heart rate surges were accompanied by an increase in arterial blood pressure and were abolished by cardiac sympathectomy. Nerve recordings of sympathetic pathways in human subjects further support the potential involvement of sympathetic activation in REM-associated accelerations in heart rate (Fig. 9.4). Because central sympathetic outflow is heavily dependent on integrity of the insular cortex, damage to this structure from sleep-disordered breathing can exacerbate the outflow. In the normal heart, the REM-related increases in heart rate are accompanied by increases in coronary blood flow, which are appropriate to the corresponding increase in cardiac metabolic demand. However, during severe coronary artery stenosis (with baseline flow reduced by 60%), there were phasic decreases—rather than increases—in coronary arterial blood flow during REM sleep coincident with these heart rate surges (Fig. 9.5). Consequently, the flow changes may not match the metabolic requirements of the heart and can result in myocardial ischemia. This phenomenon could underlie the clinical entity known as nocturnal angina.

Hippocampus

Cerebellum

Cerebellum

A

B

Heart failure

Sleep apnea

Figure 9.2  ​Areas of gray matter loss (arrows). Yellow and red areas represent areas

of great loss within the insular cortex in patients with heart failure (n = 9) and in the hippocampal region and cerebellum of patients with obstructive sleep apnea (n = 21). Gray matter loss was calculated from structural magnetic resonance imaging scans relative to controls. (Modified from Woo MA, Macey PM, Fonarow GC, et al. Regional brain matter loss in heart failure. J Appl Physiol. 2003;95:677-684; and Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Resp Crit Care Med. 2002;166:1382-1387.)

Slow-wave sleep

REM sleep

Awake

40

*

30 20

*

10 0

Awake

1

2

3

*

4

REM

*

250 200 150 100 50 0

Awake

1

2

*

*

3

4

REM

Figure 9.4  ​Sympathetic burst frequency and amplitude during wakeful-

ness, non–rapid eye movement (NREM) sleep (eight subjects), and REM sleep (six subjects). Sympathetic activity was significantly lower during NREM stages 3 and 4 (*P , .001). During REM sleep, sympathetic activity increased significantly (P , .001). Values are means 6 standard error of the mean. (Modified from Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med. 1993;328[5]:303–307.)

HEART RHYTHM PAUSES Abrupt decelerations in heart rhythm occur predominantly during tonic REM sleep and are not associated with any preceding or subsequent change in heart rate or arterial blood pressure (Fig. 9.6). In some individuals afflicted with a genetically based long QT3 syndrome, the pause can trigger cycle-length–dependent arrhythmias such as torsades de pointes.

200

Heart rate (bpm) 100 0

Mean arterial 200 pressure 100 (mm Hg) 0 Arterial 200 pressure 100 (mm Hg) 0

PHYSIOLOGIC MECHANISMS UNDERLYING NOCTURNAL CARDIAC EVENTS

Circumflex 60 coronary artery 30 flow (mL/min) 0 Mean circumflex 60 coronary artery 30 flow (mL/min) 0 EEG

Burst amplitude (%)

Insular cortex

Burst frequency (bursts/min)

Atlas of Clinical Sleep Medicine   65

The physiologic mechanisms described provide a conceptual framework for understanding a number of cardiac syndromes that have increased prevalence during sleep (Table 9.1). Surge

Surge

50 V

EOG 100 V

1 min

Figure 9.3  ​Effects of slow-wave sleep, rapid eye movement (REM) sleep, and

quiet wakefulness on heart rate, phasic and mean arterial blood pressure, phasic and mean left circumflex coronary flow, electroencephalogram (EEG), and electrooculogram (EOG) in the dog. Sleep spindles are evident during slow-wave sleep, eye movements during REM sleep, and gross eye movements on awakening. Surges in heart rate and coronary flow occur during REM sleep.(From Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function. Am J Physiol. 256[5 Pt 2]:H1378–H1383.)

SUMMARY Sleep states exert a major impact on cardiorespiratory function, a direct consequence of the significant variations in brain states that occur in the normal cycling between NREM and REM sleep. Dynamic fluctuations in central nervous system variables influence heart rhythm, arterial blood pressure, coronary artery blood flow, and ventilation. Whereas REM-induced surges in sympathetic and parasympathetic nerve activity with accompanying significant surges and pauses in heart rhythm are well tolerated in normal individuals, patients with heart disease may be at heightened risk for life-threatening arrhythmias and myocardial ischemia and infarction. During NREM sleep, in the severely compromised heart, there is the potential for hypotension that can impair blood flow through stenotic coronary

66  Central and Autonomic Regulation in Cardiovascular Physiology Slow-wave sleep

REM sleep

Slow-wave Awake sleep

200 Heart rate (bpm) 100 0 Mean arterial 200 pressure 100 (mm Hg) 0 Arterial 200 pressure 100 (mm Hg) 0 60 Circumflex coronary artery 30 flow (mL/min) 0 Mean circumflex 60 coronary artery 30 flow (mL/min) 0 Surge EEG

Surge

50 V

EOG 100 V

1 min

Figure 9.5  ​Effects of sleep stage on heart rate, mean and phasic arterial blood pressure, and mean and phasic left circumflex coronary artery blood flow in a

typical dog during stenosis. Note the phasic decreases in coronary flow occurring during heart rate surges while the dog is in rapid eye movement sleep. EEG, Electroencephalogram; EOG, electrooculogram; REM, rapid eye movement.(From Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function during stenosis. Physiol Behav. 1989;45:1017–1020.)

50 V

ECG 150

105

150

EMG

1 mV

CA 1

50 V

LGN DIA

5 V Phasic

Tonic

5 sec

Figure 9.6  ​Representative polygraphic recording of a primary heart rate

deceleration during tonic rapid eye movement (REM) sleep. During this deceleration, the heart rate decreased from 150 to 105 beats/min, or 30%. The deceleration occurred during a period devoid of ponto-geniculo-occipital (PGO) spikes in the lateral geniculate nucleus (LGN) or theta rhythm in the hippocampal leads (CA 1). The deceleration is not a respiratory arrhythmia, as it is independent of diaphragmatic movement (DIA). The abrupt decrease in amplitude of hippocampal theta (CA 1), PGO waves (LGN), and respiratory amplitude and rate (DIA) are typical of transitions from phasic to tonic REM. ECG, Electrocardiogram; EMG, electromyogram.(From Verrier RL, Lau RT, Wallooppillai U, et al. Primary vagally mediated decelerations in heart rate during tonic rapid eye movement sleep in cats. Am J Physiol. 1998;274[4]:R1136–R1141.)

vessels to trigger myocardial ischemia or infarction. Damage from sleep-disturbed breathing or stroke to central brain areas that regulate autonomic activity and coordinate upper airway and diaphragmatic action can lead to enhanced sympathetic outflow, increasing risk of heart failure and contributing to hypertension in obstructive sleep apnea. Coordination of cardiorespiratory control is especially pivotal in infancy, when central undeveloped descending influences or other immature sensory processes can compromise function and pose special risks. Throughout sleep, the coexistence of coronary disease and apnea is associated with a heightened risk of cardiovascular events because of the challenge of dual control of the respiratory and cardiovascular systems. Sleep apnea is an important risk factor for atrial fibrillation. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

Atlas of Clinical Sleep Medicine   67 Table 9.1  Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events Indication (U.S. Patients per Year) Angina, MI, arrhythmias, ischemia, or cardiac arrest at night; 20% of MIs (220,000 cases/year) and 15% of sudden deaths (55,000 cases/year) occur between midnight and 6:00 am. Unstable angina, Prinzmetal angina Acute MI (1.1 million)

Heart failure (6.5 million) Atrial fibrillation (.6 million) Sleep apnea in patients with coronary disease (5 to 10 million patients with sleep apnea) Long QT syndrome (1 case per 2000 live births) SIDS (2000–2500 cases or 8% of infant deaths) Brugada syndrome in Western populations; Asians with warning signs of SUNDS Patients with epilepsy (3.4 million) Patients taking cardiac medications (16.5 million patients with cardiovascular disease)

Possible Mechanism The nocturnal pattern suggests a sleep state–dependent autonomic trigger or respiratory distress. Nondemand ischemia and angina peak between midnight and 6:00 am. 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 for congestive heart failure. Sleep-related breathing disorders are pronounced in the setting of heart failure and may contribute to its progression and to mortality risk. 29% of episodes occur between midnight and 6:00 am. Respiratory and autonomic mechanisms are suspected. Patients with hypertension or atrial or ventricular arrhythmias should be screened for the presence of sleep apnea. The profound cycle length changes associated with sleep may trigger pause-dependent torsades de pointes in these patients. SIDS commonly occurs during sleep with characteristic cardiorespiratory symptoms. SUNDS is a sleep-related phenomenon in which night terrors may play a role. Brugada syndrome is genetically related to the long QT syndrome. SUDEP occurs primarily at night and in patients with a history of nocturnal seizures. Annual toll is 3600 deaths. b-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 contribute to pause-dependent torsades de pointes during the profound cycle length changes of sleep. Because arterial blood pressure is decreased during NREM sleep, additional lowering by antihypertensive agents may introduce a risk for ischemia and infarction due to lowered coronary perfusion.

MI, Myocardial infarction; NREM, non–rapid eye movement; SIDS, sudden infant death syndrome; SUDEP, sudden unexplained death in epilepsy; SUNDS, sudden unexplained nocturnal death syndrome. From Mehra R Mittleman MA, Verrier RL. Sleep-related cardiac risk. In: Kryger MH, Roth T, Dement WC, Goldstein C, editors. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022.

e1 Bibliography

Harper RM, Henderson LA, Verrier RL. Central and autonomic mechanisms regulating cardiovascular function. In: Kryger MH, Roth T, Dement WC, Goldstein C, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022. Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function. Am J Physiol. 1989;256:H1378–H1383. Kwon Y, Gharib SA, Biggs ML, et al. Association of sleep characteristics with atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis. Thorax. 2015;70:873–879. 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. Mehra R, Mittleman MA, Verrier RL. Sleep-related cardiac risk. In: Kryger MH, Roth T, Dement WC, Goldstein C, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022.

Mehra R, Verrier RL. Cardiac arrhythmogenesis during sleep: mechanisms, diagnosis, and therapy. In: Kryger MH, Roth T, Dement WC, Goldstein C, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022. Rowe K, Moreno R, Lau RT, et al. Heart rate surges during REM sleep are associated with theta rhythm and PGO activity in cats. Am J Physiol. 1999;277:R843–R849. Sakamoto M, Jin K, Kitazawa Y, Kakisaka Y, Nakasato N. Abnormal heart rate variability during non-REM sleep and postictal generalized EEG suppression in focal epilepsy. Clin Neurophysiol. 2022;140:40–44. Woo MA, Macey PM, Fonarow GC, et al. Regional brain gray matter loss in heart failure. J Appl Physiol. 2003;95:677–684.

Chapter

10

Interactive Regulation of Sleep and Feeding Éva Szentirmai and Levente Kapás

Sleep and feeding are complex behaviors regulated by core circuits in the brain. The activity of these circuits is influenced by multiple sets of signals arising from within the brain (e.g., the influence of suprachiasmatic nucleus) from the external environment, such as light-dark cycles and ambient temperature, and also by somatic and visceral signals arising from the body outside the brain, mainly from metabolic organs. There are significant overlaps between components of the sleep and feeding circuits in the brain and among the signals that modulate their activities. Considering that one of the main functions of wakefulness that is shared across a broad spectrum of animal taxa, if not among all animals, is feeding, it is not surprising that the regulation of feeding and sleep-wake activity is intertwined. In general, most metabolic signals of positive energy states suppress feeding and facilitate sleep, while hunger signals that trigger eating have potent wakepromoting activities; that is, they facilitate active engagement with the environment. SHARED BRAIN CIRCUITS OF SLEEP AND FEEDING REGULATION The activity of several brain structures changes with sleepwake cycles, and the stimulation or inhibition of these brain regions affects sleep and/or feeding behavior. The general emerging view is that core components of both the sleep and feeding circuitry are mainly located in the hypothalamus and the brainstem (Fig. 10.1). In the hypothalamus, there are significant overlaps between sleep- and feeding-related circuits in the preoptic area, lateral hypothalamus, paraventricular nucleus, and the dorsal and medial hypothalamic regions (Fig. 10.2). In the brainstem, the nucleus of the solitary tract (nucleus tractus solitarii [NTS]) is a major target for metabolic signals carried by the vagus nerve and is also accessible to circulating macromolecules because of its poorly developed blood-brain barrier. The activity of neurons of the NTS is modulated by the arousal and feeding state of the organism, and the stimulation of the NTS elicits both increased sleep and suppressed feeding responses.

Ghrelin is a hormone produced by the stomach under fasting conditions, and it stimulates both wakefulness and food intake in rodents. In rats, plasma and hypothalamic ghrelin levels increase in response to sleep deprivation. Ghrelin receptor– deficient transgenic mice show impaired arousal responses to novel environment or food restriction. In ghrelin receptor– deficient mice, the integration of thermoregulatory and sleep responses to metabolic challenges is severely deteriorated. The wake-promoting effect of ghrelin involves the activation of hypothalamic orexinergic and neuropeptide Y (NPY)-ergic mechanisms. Ghrelin also stimulates the hypothalamicpituitary-adrenal axis by stimulating corticotropin-releasing hormone (CRH) secretion in the paraventricular nucleus. NPY, orexin, and CRH all promote wakefulness. The hypothalamic NPY-orexin-ghrelin network plays an important role in integrating circadian, visual, and metabolic signals (Fig. 10.3). The ghrelin gene also codes for another biologically active peptide, obestatin; it has the opposite effects on both food intake and sleep as ghrelin. In humans, the effects of ghrelin on sleep are less clear. Systemic repeated bolus injections of ghrelin during the night enhance stage 4 sleep and suppress rapid eye movement (REM) sleep in male healthy subjects, although ghrelin is ineffective in female subjects. Epidemiologic studies suggest a

SHARED SOMATIC SIGNALING BETWEEN SLEEP AND FEEDING REGULATION Output from the core sleep and feeding circuits determines the feeding and activity behavior of the animal. This output, the final decision about these behaviors, is shaped by afferent hormonal and neural influences from the body. Hormones of the gastrointestinal tract, adipose tissues, and immune cells play a central role in the shared signaling for sleep and feeding (Table 10.1). 68

Figure 10.1  ​Mounting evidence supports the idea that mechanisms responsible for feeding behavior and the control of sleep are coordinated by partly overlapping hypothalamic and brainstem neuronal systems. These systems receive information about the energy status of the body through hunger, adiposity, and satiety signals.

Atlas of Clinical Sleep Medicine   69 Nitric oxide Dorsomedial hypothalamus Ventromedial Medial preoptic area hypothalamus

CRH

Incr ea feed sed ing r ula tric en s rav leu Pa nuc

sed rea ing c n I d fee

Orexin

Orexin CRH

Ghrelin

us

lam

yp

lh

ra ate

a oth

L



NPY



Arcuate nucleus

Ghrelin

Leptin

Figure 10.2  ​Hypothalamic ghrelin-, orexin- and neuropeptide Y (NPY)-ergic neurons form a well-characterized circuit that is implicated in the regulation of food

intake and sleep. Circulating ghrelin and leptin can modulate the activity of the circuit through NPY in the arcuate nucleus. Ghrelin promotes wakefulness when injected to the lateral hypothalamus (LH), paraventricular nucleus (PVN), or medial preoptic area (MPA). Ghrelin administration and ghrelinergic neurons activate orexinergic cells in the LH and NPY-containing cells in the arcuate nucleus. In the PVN, ghrelin facilitates corticotropin-releasing hormone (CRH) release indirectly through the stimulation of NPY-ergic neurons. Ghrelin microinjection into the LH may promote wakefulness through the stimulation of orexin release. In the PVN, ghrelin indirectly facilitates CRH release that leads to increased wakefulness. In the MPA, ghrelin’s wakefulness-promoting effect might be mediated by nitric oxide (NO). Several actions of ghrelin are NO dependent, and NO-ergic mechanisms are implicated in sleep regulation.

Table 10.1  Relationship Between Sleep and Ghrelin, Leptin, and Cholecystokinin Plasma and Hypothalamic Levels Ghrelin Effect of acute sleep deprivation Relation to chronic short sleep duration in humans Effects on sleep

Sleep in KO animals

Plasma levels in sleep disorders

Leptin

Cholecystokinin

Elevated plasma and hypothalamic levels

Reduced diurnal amplitude

NA

Elevated plasma levels

Reduced plasma levels

NA

Humans: no effect or increased sleep Rodents: central administration induces wakefulness Normal diurnal rhythm, fragmented sleep in ghrelin and ghrelin receptor KO mice

Increases NREM sleep, decreases REM sleep

Peripheral administration increases NREM sleep, central injection has no effect CCK-1 receptor–deficient rats have normal sleep-wake activity

Enhanced nocturnal ghrelin levels in night eating syndrome

Attenuated diurnal rhythm of sleep, increased and fragmented NREM sleep Reduced levels in narcolepsy and in night eating syndrome

NA

CCK, Cholecystokinin; KO, knockout; NA, not available; NREM, non–rapid eye movement; REM, rapid eye movement.

relationship between sleep duration and plasma ghrelin levels. Habitual short sleep duration and sleep restriction to 4 hours per night are associated with elevated ghrelin plasma levels and increased hunger, suggesting that chronic sleep curtailment is a risk factor for obesity. Cholecystokinin (CCK) is released from the small intestine after eating a fat- or protein-rich meal. Systemic administration of CCK elicits the complete behavioral sequence of the satiety syndrome, including the cessation of feeding, increased sleep, decreased motor activity, and social withdrawal. These actions are mediated by peripheral targets because central injections of CCK do not suppress feeding or promote sleep, and antagonists of the peripheral CCK receptors abolish the effects. Although the feeding-suppressive effects of CCK are mediated by the vagus nerve, sleep induction appears to be independent of the vagus and pancreatic insulin.

Animals that lack CCK-1 receptors do not show any gross alteration in their baseline sleep pattern, suggesting that, in the absence of CCK signaling through the peripheral receptor subtype, normal sleep-wake activity can be maintained. Adipokines are adipose tissue–derived hormones that play a role in the regulation of sleep and feeding. Two of the best characterized adipokines are leptin and tumor necrosis factor (TNF). Both hormones suppress feeding and stimulate metabolism. Circulating leptin enters the brain via saturable transport mechanisms. Leptin receptors are expressed in various hypothalamic nuclei and in the brainstem. Via these receptors, leptin stimulates melanocyte-stimulating hormone secretion and suppresses NPY-producing cells, two of the main effects that underlie leptin’s satiety effects. The effects of leptin itself on sleep are less understood. Leptin plasma levels peak at night in humans; this diurnal rhythm appears to be

70  Interactive Regulation of Sleep and Feeding Circadian signals NPY

Wake Visual signals

Orexin Eating

Ghrelin Metabolic signals Figure 10.3  ​The hypothalamic ghrelin-orexin–neuropeptide Y (NPY) circuit receives and integrates metabolic, circadian, and visual signals. The activation of the circuit has two main parallel outputs in rodents: increased wakefulness and increased feeding activity.

entrained by eating. Sleep deprivation suppresses the nocturnal increase in leptin. In rats, plasma leptin levels peak following dark onset–elicited eating activity. Obese, leptin-deficient mice have increased amounts of non–rapid eye movement (NREM) sleep, but sleep appears to be more fragmented. Injection of leptin to rats stimulates NREM sleep and suppresses REM sleep, while in mice it only stimulates NREM sleep. The most important source of circulating TNF in healthy subjects is the adipose tissue. Its somnogenic effects have been demonstrated in multiple species, including rats, mice, and humans. Proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNF-a, are produced by activated macrophages and other cells of the immune system. Their increased production during clinically manifest systemic infections and in other systemic proinflammatory conditions underlies the development of “sickness syndrome.” Leading signs and symptoms of sickness syndrome include loss of appetite, increased sleep, fatigue, fever, and social withdrawal. The extent to which these cytokines contribute to the regulation of sleep and appetite under healthy conditions is a subject of current research. The integration of sleep and feeding signals is already manifest at the level of neuronal afferents to the core brain circuits. The cranial vagus nerve provides the main neuronal afferent connection between visceral organs and the brain, and it carries both satiety and sleep-promoting signals from the viscera. For example, vagotomy attenuates or completely abolishes the satiety actions of several gastrointestinal hormones, such as CCK, glucagon, and enterostatin, and the sleep-inducing effects of IL-1 and TNF-a. METABOLIC ORGANS MODULATE SLEEPWAKE ACTIVITY AND FEEDING The recognition that adult humans have significant amounts of active brown adipose tissue (BAT) opened new directions in our understanding of the integration of sleep and metabolism. The function of brown adipocytes in metabolic processes is fundamentally different from that of white counterparts. White adipose tissue is responsible for storing excess energy in the form of fat, while BAT dissipates excess energy in the form of heat. The tightly regulated balance in

the activities of the two fat tissues is critical in maintaining metabolic homeostasis. The ability of BAT to produce heat is a result of the unique presence of the uncoupling protein 1 (UCP-1) in the mitochondria of brown adipocytes. Recent evidence revealed that the active BAT is a source of somnogenic signals. Pharmacologic stimulation of BAT enhances sleep, while UCP-1–deficient mutant mice have significantly less spontaneous sleep. BAT-derived signals also appear to be important for generating optimal metabolic milieu for normal homeostatic sleep responses after sleep loss. Furthermore, sleep increases in response to proinflammatory stimuli are completely abolished in UCP-1–deficient animals, suggesting a key role for BAT in integrating metabolic, inflammatory, and sleep responses. Although traditionally not considered an organ, from several perspectives the microbiota functions as a separate organ in the mammalian body. The host and microbiota constitute a complex ecosystem, forming a holobiont whose parts live in symbiosis with a high capacity to adapt to changing environmental conditions. New evidence indicates that depletion of intestinal microbiota leads to decreased sleep, which suggests that the microbiota is a source of sleep-promoting signals. The intestinal microbiota is a rich source of bacterial molecules, including metabolites produced by live bacteria, such as short-chain fatty acids, and cell wall components of dividing or disintegrating bacteria, such as lipopolysaccharide and peptidoglycan fragments. These bacterial products translocate from the intestinal lumen into the venous outflow of the guts and enter the internal environment of the host under healthy physiologic conditions. The translocation of microbial products is further facilitated by increased fat in the diet, alcohol, and mild stressors. These bacterial products may underly the sleep-promoting influences arising from the microbiota (Fig. 10.4). Translocation of bacterial products can be mimicked by their direct injection into the portal vein, the venous outflow of the intestinal system. Intraportal injections of short-chain fatty acids and bacterial cell wall fragments suppress feeding and induce robust sleep increases. The sleep responses are mediated by the activation of viscerosensors, located in the hepatoportal region. BIDIRECTIONAL RELATIONSHIP BETWEEN FEEDING/METABOLIC STATUS AND SLEEP-WAKE ACTIVITY In rats and mice, ingestion of a protein- and fat-rich meal is followed by the satiety syndrome, which encompasses the cessation of eating, decreased locomotion, social withdrawal, and the appearance of prolonged sleep episodes. Sleep and feeding responses are abolished by a lesion of the vagus nerve or by blocking peripheral CCK receptors, which indicates the importance of gastrointestinal signals in the development of satiety syndrome. The effects of fasting on sleep depends on the energy reserves of the subject and on the relative contribution of regular feeding bouts to maintaining basal metabolic rate. Mice rely on regular feeding to maintain normal metabolism, and overnight fasting greatly suppresses energy expenditure. Food deprivation almost completely abolishes nocturnal sleep episodes in mice. This response is greatly attenuated in ghrelindeficient animals, which suggests that ghrelin is required for the coordinated arousal-feeding response in negative energy states.

Atlas of Clinical Sleep Medicine   71

Figure 10.4  Intestinal microbiota affects the function of the brain. M  icrobial molecules derived from the intestinal microbiota may directly stimulate sensory nerve endings in the intestinal wall or may enter the circulation by translocating through the intestinal wall to the portal blood. All portal blood is drained to the liver, where microbial molecules, such as lipopolysaccharide and short-chain fatty acids (SCFAs) interact with hepatic cells, including resident macrophages. Bioactive signal molecules produced by the macrophages stimulate local hepatic sensory afferents and/or enter the systemic circulation and reach the brain.

Not only does feeding status affect sleep, but changes in sleep-wake activity also profoundly modulate metabolism and eating behavior. There is a strong correlation between habitual short sleep and the incidence of metabolic diseases in humans. There is considerable evidence that people eat more and prefer high-fat food when they are sleep deprived or working

night shifts; thus it is possible that sleep loss impairs metabolic homeostasis by having a negative impact on eating behavior. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

e1 Bibliography

Cryan JF, O’Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99:1877–2013. Esposito M, Pellinen J, Kapás L, Szentirmai É. Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice. Eur J Neurosci. 2012; 35:233–243. Kapás L, Obál Jr F, Alföldi P, et al. Effects of nocturnal intraperitoneal administration of cholecystokinin in rats: simultaneous increase in sleep, increase in EEG slow-wave activity, reduction of motor activity, suppression of eating, and decrease in brain temperature. Brain Res. 1988;438:155–164. Szentirmai É, Kapás L. Ghrelin regulation of sleep, circadian clock and body temperature. In: Ghrelin in Health and Disease, Thorner M, Smith RG, eds. Springer Science and Business Media. 2012:149–180.

Szentirmai É, Kapás L, Krueger JM. Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2007;292:R575–R585. Szentirmai É, Kapás L, Sun Y, Smith RG, Krueger JM. The preproghrelin gene is required for normal integration of thermoregulation and sleep in mice. Proc Natl Acad Sci U S A. 2009;106(33):14069–14074. Szentirmai É, Kapás L. Intact brown adipose tissue thermogenesis is required for restorative sleep responses after sleep loss. Eur J Neurosci. 2014;39:984–998. Szentirmai É, Millican NS, Massie AR, Kapás L. Butyrate, a metabolite of intestinal bacteria, enhances sleep. Sci Rep. 2019;9:7035. Tizard I. Sickness behavior, its mechanisms and significance. Anim Health Res Rev. 2008;9:87–99.

Chapter

11

Endocrine Physiology Peter Y. Liu

OVERVIEW OF ENDOCRINE PHYSIOLOGY Ultradian and Circadian Mechanisms That Control Hormone Secretion Across the 24-Hour Day Neuroendocrine networks exist to orchestrate important physiologic processes such as metabolism, growth, and reproduction by maintaining target hormones in homeostasis through stimulatory (positive) feedforward and inhibitory (negative) feedback (Fig. 11.1). The multiple control sites constituting the neuroendocrine network are linked by bloodborne signals called hormones. These hormones are secreted in an episodic fashion, creating pulses, which are typified by abrupt variations in circulating hormone concentrations. The size (mass per pulse), frequency, and regularity of these pulses as well the basal (nonpulsatile) secretory component contain information that is critical for signaling between control sites and for generating these pulses. The control sites for classical neuroendocrine networks consist of specific neurons in the hypothalamus and secretory cells in the pituitary gland and a target gland (Table 11.1). These neuroendocrine networks are controlled by endogenous (biological) processes in response to external environmental factors that should ultimately synchronize the biological rhythm to the environmental rhythm. Every cell, tissue, and organ in the body contains a molecular clock. These peripheral clocks are aligned by the master circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalami through

*

(-) (-)

S(t)

2. Feedforward (+) signaling

(+)

S(t)

Effector 3. Feedback (-) regulation

H(t)

Effector 4. Diffusion/advection/elimination

S(t)

Time 5. Pulsatile secretion

Time

Figure 11.1  ​Schematic representation of the hallmarks of neuroendocrine

axes. (1), Positive feedforward signaling; (–), negative feedback signaling; S(t), time-dependent hormone secretion; H(t), time-dependent hormone concentrations.

72

Temporal Variations of Plasma Levels of Hormones Levels of hormones can be related to the time of day, whether the person is asleep, and whether sleep deprivation is present. Figure 11.2 shows data from a carefully controlled fixed-order in-laboratory study in which male subjects were studied for 53 hours including 8 hours of nocturnal sleep from 11:00 pm to 7:00 am; 28 hours of continuous wakefulness (including a night of total sleep deprivation); and daytime recovery sleep from 11:00 am to 7:00 pm, beginning 12 hours out of phase with the usual bedtime. These studies strongly suggest that (1) growth hormone (GH) secretion is primarily controlled by sleep-wake homeostasis and is maximal during slow-wave sleep (SWS); (2) cortisol secretion is almost entirely related to clock time (circadian rhythm), and its level is minimally affected by sleep or sleep deprivation; (3) secretion of thyroidstimulating hormone is controlled by both sleep homeostasis and circadian rhythmicity; and (4) sleep onset, no matter when it occurs, has a stimulatory effect on the release of prolactin. Table 11.1  Hormonal Signals of Classical Neuroendocrine Networks

Hallmarks of neuroendocrine axes

1. Multiple control sites

hormonal (mainly melatonin, but also cortisol for metabolically active organs) and autonomic signals that ensure that every clock is correctly timed. Neuroendocrine networks are subject to these same circadian rhythms, which can be modeled as Process C (Table 11.2). In addition, hormone secretion is regulated by the sleep homeostat, which is modeled as Process S (see Table 11.2).

Network

Hypothalamus

Pituitary Gland

Target Gland

Target Hormone

Gonadal Gonadal Adrenal Thyroidal

GnRH GnRH CRH TRH

LH LH ACTH TSH

Testis Ovary Adrenal Thyroid

Testosterone Estradiol Cortisol Thyroxine

ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone.

Table 11.2  Regulation of Hormone Secretion Process C

Circadian rhythmicity

Process S

Sleep homeostat

Modulating factors

Can synchronize or desynchronize systems

Effects depend on time of day, irrespective of the presence of sleep or wakefulness Effects depend on the amount of prior wakefulness Light, body position, temperature, stress, food intake

Atlas of Clinical Sleep Medicine   73 20

Growth hormone (g/L)

15

120

10

110

90

0 20

80

Cortisol (g/dL) 160

15

120

5

100

0 TSH (U/mL)

3 2

250

Insulin secretion rate (% of mean)

140

10

4

Plasma glucose (% of mean)

100

5

Plasma levels

130

Prolactin (% of mean)

200 150 100

80 60

Nocturnal sleep Daytime Nocturnal deprivation sleep sleep 18 22 02 06 10 14 18 22 02 06 10 14 18 22 Clock time Figure 11.3  ​Mean (1SEM) profiles of glucose and insulin secretion in a group of normal young male subjects. Subjects were studied over a 53-hour period that included 8 hours of usual nocturnal sleep, 28 hours of continuous wakefulness (including one night of sleep deprivation), and a daytime recovery sleep period. SEM, Standard error of the mean. (Modified from Van Cauter E, Blackman JD, Roland D, et al. Modulation of glucose regulation by circadian rhythmicity and sleep. J Clin Invest. 1991;88[3]:934–942.)

50

Nocturnal Nocturnal sleep Daytime sleep deprivation sleep 18 22 02 06 10 14 18 22 02 06 10 14 18 22 Clock time Figure 11.2  ​Mean (1SEM) hormonal profiles obtained in a protocol designed to delineate the respective contributions of the circadian rhythmicity and the sleep-wake homeostasis. The effects of the circadian modulation can be observed in the absence of sleep, and the effects of sleep can be observed at an abnormal circadian time. SEM, Standard error of the mean; TSH, thyroid-stimulating hormone. (Modified from Van Cauter E, Spiegel K. Circadian and sleep control of hormonal secretions. In: Zee PC, Turek FW, editors. Regulation of Sleep and Circadian Rhythms, vol 133 of Lung Biology in Health and Disease [Lenfant C, series ed]. New York: Marcel Dekker; 1999:397–426.)

Glucose Regulation and Hunger In the study illustrated in Figures 11.2 and 11.3, the subjects were fasting, and caloric intake was fixed through an intravenous glucose infusion set at a constant rate. Despite the fact that exogenous glucose input was constant, the levels of glucose and insulin secretion rate increased during sleep, returned to baseline in the morning, and then gradually increased during the day; the latter suggests a circadian effect. During daytime sleep, glucose and insulin also increased. Thus there is likely both a sleep and a circadian effect on glucose regulation and insulin secretion. Leptin, a satiety hormone produced by fat cells, and ghrelin, a hunger hormone produced by gastric cells, demonstrate diurnal variation. However, the 24-hour variation in leptin levels also depends on when meals are taken; levels are low in the morning, increase gradually during the day, and are highest at night. Ghrelin is also high at night. During the daytime, ghrelin levels decrease after eating and then increase in anticipation of the next meal (Fig. 11.4).

CONDITIONS THAT AFFECT HORMONES AND METABOLISM Aging Aging is associated with a marked reduction in the proportion of SWS, particularly in men, and a smaller reduction in the proportion of rapid eye movement (REM) sleep. Because GH secretion is maximal in SWS, a reduction in GH levels during sleep is apparent, particularly in older men. In contrast, the overall wave shape of the 24-hour cortisol profile remains relatively unchanged with aging, although the minimum cortisol values in the evening are higher in older individuals (Fig. 11.5). Other hormones, such as testosterone, are lower in older men compared with younger men. Disease States That Reduce Slow-Wave Sleep In untreated obstructive sleep apnea (OSA) (see Chapter 30), sleep is fragmented and SWS is reduced. Nocturnal GH levels are also reduced in untreated OSA but are increased by continuous positive airway pressure (CPAP) treatment (Fig. 11.6). A 2014 randomized sham-controlled trial in middle-age men assessed pulse characteristics of GH secretion through high-frequency assessment of blood GH concentrations every 10 minutes (Fig. 11.7). In this study, 12 weeks of CPAP, compared with sham, increased mean GH secretion but also increased pulsatile secretion, mass per pulse, and pulse frequency, but not basal secretion.1 Sleep Deprivation Many reviews as well as meta-analyses of cross-sectional and prospective studies now establish an association between short sleep duration and obesity, type 2 diabetes mellitus, and other cardiometabolic disorders.

74  Endocrine Physiology 9 Meal

Meal

Meal

Leptin produce (ng/mL) 6 suppresses

Fat cells Appetite

3 increases 1200 Ghrelin (pg/mL) produce 800

Gastric cells

400

21

1

5

9

13

17

21

Clock time

Figure 11.4  ​Individual 24-hour profiles of leptin and ghrelin. Black bars represent bedtimes. Identical meals were presented at 5-hour intervals (unpublished data).

17-24 years old

Plasma GH (g/L)

12

8

8

4

4

Plasma cortisol (nmol/L)

0

08

12

16

20

00

04

08

0

500

500

400

400

300

300

200

200

100

100

0

08

12

16

20

00

70-83 years old

12

04

08

0

08

12

16

20

00

04

08

08

12

16

20

00

04

08

Clock time Clock time Figure 11.5  ​Mean (1SEM) profiles of growth hormone (GH) and cortisol in young and older male subjects with a similar body mass index (24.1 6 0.6 kg/m2 and 24.1 6 0.8 kg/m2, respectively). SEM, Standard error of the mean. (Modified from Van Cauter E, Leproult R, Plat L. Age-related changes in slow-wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA. 2000;284[7]:861–868.)

Atlas of Clinical Sleep Medicine   75 Multiple well-controlled laboratory studies have investigated the metabolic consequences of up to 14 nights of moderate sleep restriction and have indicated an increased risk for type 2 diabetes after sleep loss. The results of three representative studies are shown in Figure 11.8. Recurrent sleep restriction also affects other endocrine axes. For example, after 1 week of sleep restriction to 5 hours per night, daytime testosterone levels decreased in young healthy male subjects (Fig. 11.9), an effect that could be translated into 15 to 20 years of aging. A recent randomized controlled trial of sleep deprivation extends these findings by showing that sleep loss also reduces testosterone levels in older male subjects.2 At the end of 1 week of sleep restriction versus sleep extension, marked differences are evident in 24-hour levels of leptin, which could result in an increase in appetite (Fig. 11.10). In the epidemiologic study shown in Figure 11.11, a linear relationship between duration of sleep and leptin levels (see Fig. 11.11A) and an inverse relationship between duration of sleep and ghrelin levels (see Fig. 11.11B) were found. These findings should result in increased appetite.

Untreated sleep apnea

8

Plasma GH (g/L)

4

0 12

On CPAP

8

4

0

22

23

0

2

1

3

4

5

Acknowledgments This chapter has been updated from the previous edition, which was coauthored by Rachel Leproult, PhD, and Eve Van Cauter, PhD. Their contribution to the prior work and to the field of sleep endocrinology is gratefully acknowledged.

6

Clock time

Figure 11.6  ​Nocturnal profiles (mean 1SEM) of growth hormone (GH)

before and after continuous positive airway pressure (CPAP) treatment. SEM, Standard error of the mean. (Modified from Saini J, Krieger J, Brandenberger G, et al. Continuous positive airway pressure treatment: effects on growth hormone, insulin and glucose profiles in obstructive sleep apnea patients. Horm Metab Res. 1993;25[7]:375–381.)

P = .001

P = .18 Basal GH secretion (mU/L/8h)

25

0 A

4

2

0

B

CPAP

Sham

20

0 P = .004

12 Mass per pulse (mU/L)

Mean GH concentration (mU/L)

0

40

P = .01

P = .002 2

1

P = .002

C 20 Pulse frequency (per 24h)

Total GH secretion (mU/L)

50

Visit eBooks.Health.Elsevier.com for the References and Bibliography for this chapter.

Pulsatile GH secretion (mU/L/8h)

12

8

4

0

CPAP

Sham

10

0

CPAP Sham E D F Figure 11.7  ​Mean (6SEM) levels in a group of 11 men treated with CPAP and another group of 7 men treated with sham showing (A) total growth hormone (GH) secretion, (B) basal GH secretion, (C) pulsatile GH secretion, (D) mean GH concentration, (E) mass per pulse, and (F) pulse frequency. P values denote between-group differences determined by Student t-test. SEM, Standard error of the mean. (Modified from Hoyos CM, Killick R, Keenan DM, et al. Continuous positive airway pressure (CPAP) increases pulsatile growth hormone secretion and circulating IGF-1 in a time-dependent manner in men with obstructive sleep apnea (OSA): a randomised sham-controlled study. Sleep. 2014;37[4]:733–741.)

76  Endocrine Physiology Short sleep duration and diabetes risk (estimated by intravenous glucose tolerance test) 10 Insulin sensitivity [(mU/L)1 × min1]

5 0 800

Acute insulin response (mU × L1 × min1)

600 400 200 0 4000 3000

Disposition index

2000 1000 0

Rested

After 6 nights 4 h TIB

n = 10

Rested

After 14 nights 5.5 h TIB

n = 11

Rested

After 6 nights 5 h TIB

n = 20

Figure 11.8  ​Results from the intravenous glucose tolerance test obtained in three laboratory studies that investigated diabetes risk under rested conditions (blue bars) and after sleep restriction (red bars). TIB, Time in bed. (Data from Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354[9188]:1435–1439; Leproult R, Van Cauter E. Role of sleep and sleep loss in hormonal release and metabolism. Endocr Dev. 2010;17:11–21; Nedeltcheva AV, Kessler L, Imperial J, et al. Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab. 2009;94[9]:3242–3250; and Buxton OM, Pavlova M, Reid EW, et al. Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes. 2010;59[9]:2126–2133.)

Serum testosterone (nmol/L) 30

Rested condition

25

Partial sleep restriction condition

20 15 10

14 18 14 22 02 06 10 Figure 11.9  ​Mean (6SEM) testosterone levels after resting condition (time in bed from 22:00 to 8:00 for three nights, in blue) and after sleep restriction (time in bed from 00:30 to 05:30 for seven nights, in red). SEM, Standard error of the mean. (Modified from Leproult R, Van Cauter E. Effect of 1 week of sleep restriction on testosterone levels in young healthy men. JAMA. 2011;305[21]:2173–2174.)

24-Hour Plasma Leptin Levels (ng/mL) 4 hours in bed 12 hours in bed 3 h 49 min ± 5 of sleep 9 h 3 min ± 15 of sleep 6.5 5.5 4.5 3.5 2.5 1.5

9 9 17 21 1 5 9 13 17 21 1 5 Clock time Clock time Figure 11.10  ​Mean (6SEM) leptin profiles at the end of 1 week of sleep restriction (4 hours in bed per night, red) and at the end of 1 week of sleep extension (12 hours in bed per night, blue). (Data from Spiegel K, Leproult R, L’Hermite–Balériaux M, et al. Impact of sleep duration on the 24-hour leptin profile: relationships with sympatho-vagal balance, cortisol and TSH. J Clin Endocrinol Metab. 2004;89[11]:5762–5771.) 9

13

Atlas of Clinical Sleep Medicine   77

A

(57)

(59) (147)

(167)

(158)

(76) (54)

6.0

6.5

7.0 7.5 8.0 Average nightly sleep (h)

8.5

9.0

Association between sleep duration and serum ghrelin levels Adjusted ghrelin (ng/mL) (square root scale)

Adjusted ghrelin (pg/mL) (square root scale) 729 784 841 900 961 1024 1089

Adjusted leptin (ng/mL) (square root scale) 13.0 14.4 16.0 17.6 19.4

Association between sleep duration and serum leptin levels Adjusted leptin (ng/mL) (square root scale)

(69) (172)

(67) (115)

(144)

(89) (150)

(50)

4.5

5.0

5.5

B

6.0 6.5 7.0 Total sleep time (h)

7.5

8.0

Figure 11.11  ​Relationship between sleep duration and serum leptin (A) and ghrelin (B) levels. (Modified from Taheri S, Lin L, Austin D. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1[3]:e62.)

  e1 References

1. Hoyos CM, Killick R, Keenan DM, Baxter RC, Veldhuis JD, Liu PY. Continuous Positive Airway Pressure (CPAP) increases pulsatile growth hormone secretion and circulating IGF-1 in a time-dependent manner in men with Obstructive Sleep Apnea (OSA): a randomised sham-controlled study. Sleep. 2014;37(4):733–741. 2. Liu PY, Takahashi PY, Yang RJ, Iranmanesh A, Veldhuis JD. Age and time-of-day differences in the hypothalamo-pituitary-testicular, and adrenal, response to total overnight sleep deprivation. Sleep. 2020; 43(7):zsaa008.

Bibliography

Brubaker PL, Martchenko A. Metabolic homeostasis: it’s all in the timing. Endocrinology. 2022;163(1):bqab199. Copinschi G, Challet E. Endocrine rhythms, the sleep-wake cycle, and biological clocks. In: Jameson JL, Degroot LJ, eds. Endocrinology. 7th ed. Vol 1. Philadelphia: Elsevier; 2016:147–173.

Killick R, Banks S, Liu PY. Implications of sleep restriction and recovery on metabolic outcomes. J Clin Endocrinol Metab. 2012; 97(11):3876–3890. Lightman SL, Birnie MT, Conway-Campbell BL. Dynamics of ACTH and cortisol secretion and implications for disease. Endocr Rev. 2020; 41(3):470–490. Liu PY. A clinical perspective of sleep and andrological health: assessment, treatment considerations and future research. J Clin Endocrinol Metab. 2019;104(10):4398–4417. Van Cauter E, Tasali E. Endocrine physiology in relation to sleep and s leep disturbances. In: Kryger M, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia: Elsevier; 2017: 202–219. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA. 2000;284:861–868. Zavala E. Misaligned hormonal rhythmicity: mechanisms of origin and their clinical significance. J Neuroendocrinol. 2022;34(6):e13144.

Section 4  |  Normal Sleep and I ts Variants Chapter

12

Sleep in Mammals Jerome M. Siegel

The amount of sleep required by animals varies greatly. The horse and elephant sleep about 2 to 4 hours a day, and the big brown bat sleeps 20 hours a day. Rapid eye movement (REM) sleep amounts have even greater variation across species (Fig. 12.1). The platypus has the most REM sleep of any

10

5

Long-nosed armadillo

European polecat

20 Giant armadillo Tiger

Tenerec Lion

Platypus Phalanger R = –0.3, n.s. Cat Arctic Star-nosed Cheetah Desert hedgehog fox mole Dog Jaguar Redfox European Lesser hedgehog Short-nosed echidna short-tailed Eastern American mole shrew

Hours of sleep per day

Hours of sleep per day

15

Greater short-tailed shrew

Herbivores

Carnivores

Little brown bat Big brown bat

20

animal, approximately 8 hours a day (Video 12.1, Fig. 12.2). Dolphins and other cetaceans do not appear to have any REM sleep, birds have very little, and conclusive evidence for the presence of REM sleep in reptiles is lacking. Fur seals (Fig. 12.3) average 80 minutes of REM sleep per 24 hours

15

Mongolian gerbil

Golden Mountain hamster beaver

Vole

10

African striped mouse

Guinea pig Degu

0

0

0.001

0.01

0.1

1

10

100

1000 10,000

0.001

Rabbit

Tree hyrax

5

0.01

0.1

Weight (kg)

Three-toed sloth

Chinchilla

1

Asiatic elephant Rock Goat Tapir Giraffe African Sheep hyrax elephant Cow Roe deer Horse Donkey R = –0.8, P < .001

Gray hyrax

10

10

5

Thick-tailed opossum Virginia opossum Owl monkey Arctic ground squirrel Eastern American chipmunk Northern grasshopper mouse Thirteen-lined ground squirrel House Norway rat mouse Cotton Patas monkey rat Deer Chimpanzee mouse Mole rat Potto R = –0.3, n.s. Tree shrew Baboon Pig Human Slow loris Genet Macaque Galago Squirrel monkey Grivet

0 0.001

Carnivores Omnivores Herbivores

20 Hours of sleep per day

Hours of sleep per day

15

15 R = –0.3, n.s. R = –0.3, n.s.

10

R = –0.5

5 R = –0.8, P < .001

0 0.01

0.1

1

10

Weight (kg)

1000 10,000

Weight (kg)

Omnivores 20

100

100

1000 10,000

0.001

0.01

0.1

1

10

100

1000 10,000

Weight (kg)

Figure 12.1  Sleep time in mammals. Carnivores are shown in dark red, herbivores in green, and omnivores in blue. Sleep times in each of these differ significantly, but carnivores sleep significantly more than herbivores. Sleep amount is an inverse function of body mass over all terrestrial mammals (black line). This function accounts for approximately 25% of the interspecies variance (bottom right) in reported sleep amounts. Herbivores are responsible for this relation because body mass and sleep time were significantly and inversely correlated in herbivores but were not correlated in carnivores or omnivores. (From Siegel JM. Clues to the functions of mammalian sleep. Nature. 2005;437[7063]:1264–1271.)

78

Atlas of Clinical Sleep Medicine   79 Fur seals, bilateral sleep on land, unihemispheric sleep in water

Wake – Pool

50

EEG EOG EMG Wake – Burrow EEG

2 50

6 10 14

2

6 10 14

2

6 10 14

2

6 10 14

2

6 10 14

EOG EMG Quiet sleep – Moderate voltage

50

EEG EOG EMG Quiet sleep – High voltage

50

EEG EOG EMG REM sleep – Moderate voltage

50

EEG

REM sleep – High voltage EEG EOG EMG

2 sec

Figure 12.3  Fur seals have bilateral sleep on land, but unihemispheric sleep

in water. (From Lyamin OI, Kosenko PO, Korneva SM, et al. Fur seals suppress REM sleep for very long periods without subsequent rebound. Curr Biol. 2018;28[12]:2000–2005.)

50

Power uV

EMG

100 uV

EOG

2

6 10 14 Hz

Figure 12.2  Brainstem rapid eye movement (REM) sleep state in the platy-

pus. REM and twitches can occur while the forebrain is showing a slow-wave activity pattern. Electroencephalogram (EEG), electrooculogram (EOG), electromyogram (EMG), and EEG power spectra of samples show sleep-wake states in the platypus. ( From Siegel JM, Manger PR, Nienhuis R, et al. Sleep and the platypus. Neuroscience. 1999;91[1]:391–400.)

when they are on land, an amount of sleep similar to that in humans, but have little or no REM sleep when they are in water, where they spend about 7 months of the year. They have no “rebound” of REM sleep when they return to land. Recent findings undermine the idea that sleep has a vital universal neural or physiologic function across species. Dolphins and other cetaceans never have high-voltage slow waves in both sides of the brain, in contrast to all terrestrial mammals (Fig. 12.4). Instead, they have unihemispheric slow waves with closure of the eye contralateral to the hemisphere with slow waves. Furthermore, orca and dolphin mothers and their calves are continuously active, and calves keep both eyes open for 2 months or longer after birth. No rebound of inactive behavior

follows. During this period, the calf ’s brain and body grow to their prodigious size and capacity without any apparent need for sleep. An equally remarkable observation is that adult dolphins working for reward can discriminate between visual stimuli presented at 30-second intervals on their left or right sides, 24 hours a day, for as long as 15 days. During this time their performance shows no progressive decline, and no rebound of inactivity follows the continuous vigilance task. In contrast, humans whose sleep is interrupted on a similar schedule are dramatically impaired, demonstrating the variability of sleep need across species. Migrating birds experience greatly reduced sleep time with intact learning abilities, high rates of performance, and no subsequent sleep rebound. The polygynous pectoral sandpiper was shown to greatly reduce its sleep time during a 3-week mating period without signs of performance decrement or sleep rebound. Such variation in sleep time may well be typical under natural conditions. In contrast, animal (or human) studies done under safe laboratory conditions of controlled temperature and ad libitum food availability may lead to the incorrect conclusion that sleep durations are fixed.

80  Sleep in Mammals

1 cm

100 V L

R 1 min

Beluga Right EEG

Left EEG

Rat Right EEG

Left EEG

Figure 12.4  Cetacean sleep: unihemispheric slow waves in cetaceans. Top, Immature beluga, adult dolphin, and section of adult dolphin brain. Electroen-

cephalographic (EEG) readings of adult cetaceans, represented here by the beluga, are shown during sleep. All species of cetacean so far recorded have unihemispheric slow-wave activity. Top traces show left and right EEG activity. The spectral plots show 1 to 3 Hz power in the two hemispheres over a 12-hour period. The pattern in the cetaceans contrasts with the bilateral pattern of slow waves seen under normal conditions in all terrestrial mammals, represented here by the rat (bottom traces). (From Siegel JM. Clues to the functions of mammalian sleep. Nature. 2005;437[7063]:1264–1271.)

People of similar intelligence, age, sex, and body build can have very different sleep times. They also vary in their response to sleep loss; some are highly impaired and some are unable to resist sleep, whereas others show high levels of functioning despite sleep loss. The effect of sleep deprivation on performance is not strongly related to baseline sleep duration.

Furthermore, human sleep duration is not linearly related to health; both high and low values are linked to shortened life span. Some evidence suggests that individuals (without preexisting conditions such as sleep apnea) with longer than normal spontaneous sleep durations are at greater risk for a shortened lifespan than are those with less than average sleep

Atlas of Clinical Sleep Medicine   81 time compared to individuals sleeping 7 hours, the optimal duration. A report that sleep deprivation by the “disk over water” technique leads to death in rats may be related to the stress of frequent awakenings rather than sleep loss. Sleep deprivation has not been reported to cause death in mice or rats deprived by other techniques. Fatal familial insomnia and sleeping sickness can cause death in humans, but sleep loss or excess sleep does not appear to be responsible; these diseases affect many body organs. Numerous attempts have been made to correlate the variation in sleep time across species with physiologic variables such as body mass, life span, brain size, brain/body weight ratio, and litter size. However, such studies have not identified correlations that account for a significant amount of the cross-species variance (Figs. 12.5 and 12.6). The few weak and inconsistent correlations that have been reported appear to be largely a function of the way the data are handled and which animals are excluded from the dataset. The definitive study of the phylogeny of REM and non-REM (NREM) sleep times in birds concluded that none of the physiologic parameters typically studied in mammals showed even a weak relationship with sleep time. However, one relation does appear to be consistent across both birds and mammals: species such as herbivores, which eat food with low caloric density, sleep significantly less than those that eat more nutritionally dense foods (carnivores; see Fig. 12.6). In other words, if a species needs to eat more than 12 hours a day, it cannot sleep more than 12 hours; animals have evolved to adjust sleep time appropriately to such waking needs. Most species, including humans, can reduce sleep to acquire food, avoid predation, mate, be available to their young during critical periods, and deal with other needs. It does not appear that sleep intensity—as measured by electroencephalogram (EEG) synchrony, REM sleep time, or lack of responsiveness—is negatively correlated with sleep time. In other words, the horse and giraffe, which sleep 2 to 4 hours a day, do not sleep more deeply than the lion, which

sleeps 12 to 14 hours a day. In the same way, elderly humans, who sleep 6 to 7 hours a day, do not sleep more deeply than teenagers, who sleep more than 10 hours a day. To the contrary, both developmentally and phylogenetically, the general tendency is for short sleepers to sleep less deeply than long sleepers. So why do most of us feel so poorly when we reduce sleep? Natural selection has imposed a certain amount of sleep on us to restrict activity to appropriate times of day and to reduce long-term nonvital energy expenditure. The pressure to sleep operates by reducing brain activity. Although individuals with naturally short sleep are not at elevated risk of death compared with those who have naturally long sleep times, repeated sleep deprivation below the body’s programmed level is stressful and is likely to have significant health consequences. Certain hormonal processes are linked to sleep; but these are species specific, not universal. It has been argued that quiet waking could serve the energy conservation functions attributed to sleep without the risks associated with the sleep state. However, the brain consumes as much as 25% of the body’s energy at rest. This amount does not greatly differ between active and quiet waking, but it is greatly reduced in sleep. Animals with safe sleeping sites will achieve a selective advantage in reducing brain energy consumption by sleep. Animals with unsafe sleep sites do not sleep deeply. Species whose environment has a severe seasonal variation in food availability have evolved to increase sleep during periods of food shortage and decrease sleep when food is available. Others who have safe sites hibernate during periods of greatly reduced availability, achieving even more reduction in energy expenditure. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

BUSHTAIL POSSUM Trichosurus vulpecula

1 cm

ELEPHANT Loxodonta africana

5 cm 18 hours of sleep, 6.6 hours of REM

3.6 hours of sleep, 1.8 hours of REM

Figure 12.5  ​Sleep amount is not proportional to the relative size of the cerebral cortex or to the degree of encephalization, as illustrated by a comparison between the bushtail possum and the elephant. REM, Rapid eye movement [sleep]. (From Siegel JM. Clues to the functions of mammalian sleep. Nature. 2005;437[7063]:1264–1271.)

82  Sleep in Mammals High Sleep

Low Sleep Rodentia Degu Octodon degu

Golden mantled ground squirrel Spermophilus lateralis

Total sleep REM sleep Body weight Brain weight Brain/body weight ratio Life span Caloric density of food

15.9 3.0 0.193 0.003 0.016 7 ++

7.7 0.9 0.240 0.0025 0.010 11 +

Carnivora Genet Genetta genetta

Cat Felis catus

Total sleep REM sleep Body weight (kg) Brain weight (kg) Brain/body weight ratio Life span Caloric density of food

12.5 3.2 3.3 0.030 0.009 13 +++

6.3 1.3 1.3 0.016 0.012 13 ++ Chiroptera Greater short-nosed fruit bat Cynopterus sphinx

Big brown bat Eptesicus fuscus

Total sleep REM sleep Body weight (kg) Brain weight (mg) Brain/body weight ratio Life span Caloric density of food

15.0 1.15 0.0424 1.061 0.025 10 +

20 3.9 0.0136 0.238 0.0175 20 +++

Aves Burrowing owl Athene cunicularia

Total sleep REM sleep Body weight (kg) Brain weight (kg) Brain/body weight ratio Life span Caloric density of food

14.3 0.7 0.120 0.003 0.025 8 +++

Greylag goose Anser anser

6.4 0.7 3.3 0.011 0.003 8 +

Figure 12.6  Sleep, brain, and life span parameters across mammalian orders and the avian class.  The strongest correlate of sleep time across species is diet.

Animals that eat food with high caloric density do not need to spend as much time ingesting food as animals that eat food with low caloric density. In zoos and laboratories, where most sleep studies have been done and animals are well fed, carnivores sleep more than omnivores, who sleep more than herbivores. However, food deprivation increases waking and decreases sleep in carnivores and omnivores. Flexibility in sleep time increases the likelihood that energy input and output will be equalized and that there will be time for other essential tasks, such as mating and care of young. 111, Carnivores; 11, omnivores; 1, herbivores. Sleep durations in hours/24-hour period; life span in years. (Owl data from http://Birdsflight.com; photos of other animals courtesy of Wikipedia Commons site.)

  e1 Bibliography

Jones SG, Paletz EM, Obermeyer WH, Hannan CT, Benca RM. Seasonal influences on sleep and executive function in the migratory white-crowned sparrow (Zonotrichia leucophrys gambelii). BMC Neurosci. 2010;11:87. Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry. 2002; 59:131–136. Lyamin O, Pryaslova J, Lance V, Siegel J. Animal behaviour: continuous activity in cetaceans after birth. Nature. 2005;435:1177. Lyamin OI, Kosenko PO, Korneva SM, Vyssotski AL, Mukhametov LM, Siegel JM. Fur seals suppress REM sleep for very long periods without subsequent rebound. Curr Biol. 2018;28(12):2000–2005.

Ridgway S, Keogh M, Carder D, et al. Dolphins maintain cognitive performance during 72 to 120 hours of continuous auditory vigilance. J Exp Biol. 2009;212:1519–1527. Siegel JM. Clues to the functions of mammalian sleep. Nature. 2005; 437:1264–1271. Siegel JM. Do all animals sleep? Trends Neurosci. 2008;31:208–213. Siegel JM. Sleep in animals: a state of adaptive inactivity. In: Kryger MK, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 6th ed. Elsevier; 2017:103–114. Zitser J, Anaturk M, Zsoldos E, et al. Sleep duration over 28 years, cognition, gray matter volume, and white matter microstructure: a prospective cohort study. Sleep. 2020;43(5):zsz290.

Chapter

Normal Sleep in Humans

13

Alon Y. Avidan

All organisms have periods of activity and inactivity. This is true from viruses to the most complex of mammals. Two fundamental questions—What is sleep? Why do we sleep?—have been raised since antiquity and remain perplexing to this day. WHAT IS SLEEP? The three key basic physiologic processes of life consist of wakefulness, non–rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Figure 13.1 highlights the universal features of sleep among all animals: quiescence, sensory detachment, and attenuated metabolic function but preserved homeostasis/circadian regulation characterized by wakelike encephalographic (EEG) activity in the forebrain, accompanied by eye movements, muscle twitches, and cardiorespiratory fluctuations. Neural signature hallmarks of sleep have been identified in animals ranging from nematodes to humans. Sleep results from a combination of passive withdrawal of afferent stimuli to the brain and activation of certain neurons in selective brain areas. • Sleep has been defined behaviorally as a reversible state of perceptual disengagement from and unresponsiveness to the environment. • Sleep is a complex state in which changes occur in physiologic and behavioral processes compared with wakefulness. • Sleep is physiologic, necessary, temporary, reversible, and cyclic. Scientific progress in elucidating the function and structure of sleep has been substantial in recent years, particularly in gaining an appreciation of the glymphatic system, control of the circadian system, and recognition of the consequences of poor or restricted sleep. WHAT IS THE FUNCTION OF SLEEP? The function of sleep remains a physiologic enigma, with several theories about its function and purpose—yet not all are satisfactory or sufficient. Experimental sleep deprivation in animals has demonstrated that sleep is necessary for survival. Sleep deprivation in humans causes sleepiness and decreased performance, reduced vigilance, poor concentration, impaired memory, attention-impaired cellular immunity, impaired glucose tolerance, increased body mass index, and hypertension. CURRENT THEORIES ABOUT WHY WE SLEEP Current theories about why we sleep include restorative theory, energy conservation theory, adaptation theory, memory

consolidation theory, thermoregulatory function theory, synaptic homeostasis theory, and glymphatic theory. Restorative Theory Restorative theory is supported by the observed increase in the synthesis of macromolecules such as nucleic acids and proteins in the brain during sleep. Energy Conservation Theory Animals with a high metabolic rate that sleep longer than those with slower metabolism have been cited in favor of this theory. However, in humans, the theory is weakened as only 120 calories are conserved during an 8-hour period of sleep duration. Adaptation Theory Adaptation theory suggests that sleep is an instinct that allows creatures to survive under a variety of environmental conditions. Memory Consolidation Theory Sleep is essential for memory consolidation. Data support that new memory processing is strengthened by sleep. Sleep can rescue memories that are lost during wakefulness. Thermoregulatory Function Theory Thermoregulatory function theory is supported by the observation that normal thermoregulatory homeostasis is maintained and promoted during sleep, while significant thermoregulatory abnormalities occur following total sleep deprivation. Thermoregulation is promoted during NREM sleep but is suspended during REM sleep, which is often associated with shivering, piloerection, and sweating. Synaptic Homeostasis Theory Synaptic homeostasis theory hypothesizes that the cardinal function of sleep is the restoration of synaptic homeostasis, which is countered by synaptic strengthening triggered by learning during wakefulness. Sleep is viewed as “the price we pay for plasticity,” suggesting that an increased synaptic strength has various costs, including greater demand for trafficking of cellular supplies to synapses, which contributes to cellular stress, changes in support cells such as glia, and higher energy consumption. Sleep improves the signal-to-noise ratio and allows for renormalizing of synaptic strength, reduction in the burden of plasticity on neurons, and restoration of neuronal selectivity, which enhances the capacity to learn and contributes to the consolidation and integration of new memories (Figs. 13.2 to 13.4). Glymphatic Theory This relatively new theory proposes a sleep state–dependent system that enhanced brain flushing supported by enhanced 83

84  Normal Sleep in Humans

Nematodes

Drosophila

Pogona

Taeniopygia

Mus

Homo

Danio

Octopus

Giardia

Hydra

Homogenous state of quiescence Sensory detachment

Metabolic reduction

Energy saving

Circadian/homeostatic regulation

Behavioral sleep

A

Paradoxical Oscillations Silencing

Silencing

Paradoxical activity Synaptic potentiation

Paradoxical Oscillations Silencing

Paradoxical Oscillations Silencing

Paradoxical Oscillations Silencing

Paradoxical Oscillations Silencing

Oscillating activity

Silencing

Synaptic homeostasis

Core signature found with REM and NREM

Neural plasticity

Metabolic clearance

Cell repair

Learning

DNA or tissue repair

Synaptic downscaling

Neural sleep signatures

B

Neural tissue

Epithelial tissue

Muscle tissue

Sleep signatures

REM/PS, NREM/SWS, Silencing, local sleep

Lower temperature, reduced respiration

Muscle atonia during NREM/SWS. Eye movements & myoclonic twitches in REM/PS

Sleep cells & genes

Many

Brown fat, fat body, epidermis: BMP-1/NAS-38, AMPs, ADE2, NFkappaB, UCP-1

BMAL1, FOXO

Waste clearance, endocytosis, DNA repair, synaptic remodeling

Immune response, sleep deprivation, ROS protection

Sleep-dependent tissue repair

Sleep-related processes

Tissue physiology of sleep

C Figure 13.1  What is sleep? A, Sleep is universal among all animals and has preserved common characteristics of quiescence, sensory detachment, and attenu-

ated metabolic function, but preserved homeostasis/circadian regulation. B, Neural signature hallmarks of sleep have been identified in animals ranging from nematodes to humans. Three different sleep signatures are known, including rapid eye movement (REM)/paradoxical sleep (PS), characterized by wakelike electroencephalographic (EEG) activity in the forebrain, accompanied by eye movements, muscle twitches, and cardiorespiratory fluctuations. Non-REM (NREM) slow-wave sleep (SWS) is identified by high-voltage slow EEG bursts in the forebrain, with progressive muscle atonia and reduced cardiorespiratory rate. Silencing is perhaps the core biomarker of neural sleep physiology, as it accompanies both REM/paradoxical sleep and NREM/SWS in prominent areas of the brain outside the cortex. C, Sleep physiology in tissues across the body. Sleep can be divided into tissue/cellular signatures strongly coupled with sleep that have been identified in neurons and muscles. Sleep can be examined by the tissue, cellular, and molecular processes that are dependent on proper sleep regulation, which has been found in all major tissue types. Yet it remains to be seen whether sleep is present in animals that lack a nervous system, including porifera sponges or simple multicellular organisms in which alteration of behavioral states in a circadian-dependent manner can be identified. Sleep may need to be viewed as a biologic event relevant to the entire body, beyond the brain and nervous system, as future attempts about what sleep actually is take place. ROS, Reactive oxygen species. (From Jaggard JB, Wang GX, Mourrain P. Non-REM and REM/paradoxical sleep dynamics across phylogeny. Curr Opin Neurobiol. 2021;71:44–51.)

Atlas of Clinical Sleep Medicine   85

S

Synaptic strength

Wake Net synaptic potentiation

Sleep Synaptic re-normalization

th eng str c ti ap yn

Energy costs Supplies costs Saturation

A

Structural

Time

Energy costs Supplies costs Saturation

Wake

Sleep

Synapse number/size

Measured parameters

Molecular Synaptic receptors (AMPARs) Electrophysiological Minis

Evoked responses

S y n a p t i c s t r e n g t h

Neuromodulatory tone Neuronal excitability Excitation/ inhibition

Unit firing

B Figure 13.2  Synaptic homeostasis theory. The synaptic homeostasis theory notes that wakefulness is associated with a net overall increase in synaptic strength in

brain circuits that needs to be modulated to normalcy by sleep. A, The key basis of this hypothesis is that an increase in synaptic strength occurs during wakefulness, when key neuronal circuits in the brain are potentiated (synaptic strength). This culminates in cellular and system costs, which are proceeded by synaptic “renormalization” occurring during sleep and synaptic downselection of circuits (dotted blue lines). B, The color gradient in the synaptic strength curve reflects synaptic strength, exemplified by electrophysiologic measures such as firing rates and neuronal excitability, the degree of neuromodulators, and the excitation/inhibition balance. Excitatory glutamatergic receptors (AMPARs) are shown as squared boxes close to the ASI. During sleep, the brain is essentially disconnected from the environment, promoting sleep-dependent renormalization. At the synaptic level, the accumulation of proteins likely controls the endocytosis of excitatory neurotransmitters, promoting synaptic weakening. The slope used to measure cortical evoked responses is indicated (steeper slope corresponds to a greater response) Minis, Miniature excitatory synaptic currents.

cerebrospinal fluid (CSF) flow through a relatively newly discovered drainage system, the glymphatic system (Fig. 13.5). This system promotes CSF circulation and fluid exchange, which enhances the clearance of interstitial metabolic waste products across the blood-brain barrier and serves as the “garbage truck” of the brain. Clearance is particularly specific during NREM, N3, or slow-wave sleep (SWS; Fig. 13.6). By inference, when the glymphatic fluid flow and interstitial fluid clearance system fail in this essential physiologic role, one

would presume a high likelihood of apolipoprotein E deposition, highlighting its role in mediating between poor sleep and neurodegenerative conditions. HOW MUCH SLEEP IS ENOUGH? To sustain life, 3 to 5 hours of sleep per night are required. However, achieving only this amount of sleep (often called

86  Normal Sleep in Humans

Circadian rhythms and brain state differentially influence synaptic markers in flies. Flight motor neuron synaptic bouton number reach a maximum in the sleep phase. Mushroom body gamma neurons have smaller axonal processes after sleep.

Sleep decreases or increases synaptic efficacy in adult rodents depending on brain region and stimulus. Sleep enhances stimulus response plasticity in occipital (visual) cortex: a form of in vivo long-term synaptic potentiation. Transcallosal evoked potentials in frontal cortex are smaller when measured after sleep.

Sleep increases synaptic efficacy in cats. Developing cats: Sleep promotes cortical potentiation in non-deprived eye circuits in the visual cortex following monocular deprivation. Adult cats: Evoked electrophysiologic potentials in somatosensory cortex are larger when measured after sleep.

Sleep increases synaptic efficacy in developing chicks.

Sleep enhances visual imprinting, a process that involves a neuronal gain of response to the imprinting stimulus and increases in post-synaptic proteins and glutamate receptors.

Figure 13.3  Synaptic plasticity and sleep. Sleep and circadian rhythms strongly influence synaptic plasticity. This figure highlights the effects of sleep and its

dependence and variation on the waking experience of the organism that precedes sleep, the specific animal species examined, developmental age, the type of synapse being reviewed, and the presence of or absence and prominence of circadian rhythms. (From Frank MG, Cantera R. Sleep, clocks, and synaptic plasticity. Trends Neurosci. 2014;37[9]:491–501.)

Active phase

re tu

ra

pe tem

HP A

Br

ain

Inactive phase

ac tiv

ity

Figure 13.4  State-clock model of synaptic plasticity highlighting the variation

of synaptic activity across the circadian clock that drives 24-hour rhythms in synaptic plasticity. These form the framework by which experience-dependent changes are promoted during wakefulness and further consolidated during sleep (green and red arrows). The direction that the latter changes, however, is not fixed and depends on the type of experience that precedes sleep and the type of circuit. The active/inactive phase in mammals is characterized by prominent circadian rhythm fluctuations with corresponding oscillations in brain temperature and hypothalamic-pituitary axis (HPA) activity. The active phase is identified by increased cortical synaptic efficacy (high glutamate receptor signaling, trafficking to existing synapses) and morphology (more synapses forming), while the opposite occurs during sleep (the inactive phase), which is characterized by a decrement in brain temperature and HPA activity. (From Frank MG, Cantera R. Sleep, clocks, and synaptic plasticity. Trends Neurosci. 2014;37[9]:491–501.)

Atlas of Clinical Sleep Medicine   87 Skull

Subarachnoid space Para-arterial CSF influx Neuron Paraarterial space Artery

AQP4

Vein

Astrocyte vascular endfeet

Paravenous efflux

ISF

Figure 13.5  Role of the glymphatic system, a pathway that removes cellular waste from the brain during sleep. The flow of cerebrospinal fluid (CSF) as it passes

through the para-arterial space surrounding the cerebral arteries is shown (top). This space is demarcated by the nonluminal surface of the blood vessel and the apical processes of the astrocyte. A unique water channel, aquaporin-4 (AQP4), facilitates convective flow out of the para-arterial space into the interstitial space and subsequent clearance away from the brain during sleep. The CSF exchanges with interstitial fluid (ISF) and generates a convective flow that clears the waste using a paravenous route that is most active during sleep. (Modified from Nishino S, editor. Basic sleep concepts, science, deprivation, and mechanisms of neurotransmitters and neuropharmacology of sleep/wake regulations. Encyclopedia of Sleep. Palo Alto, CA: Stanford University School of Medicine; 2013:395-406.)

CSF Influx

Sleep

Superior Sagittal sinus

AQP4 2 3

Fluid dispersion

Choroid plexus 1

Dural sinus

Capillaries

Perivenous ISF 4

Periarterial CSF

Prominent Clearance During N3 Sleep

B Awake

A

Meningeal and cervical lymphatics

Nerves Bone Parenchyma CSF Periarterial space 5

Perivenous space Lymphatics

Efflux

C

Figure 13.6  Model of the glymphatic system in the brain and its regulation by the sleep-wake cycle. The glymphatic system is illustrated by the following com-

ponents: A, A fluid transport pathway composed of five distinct segments: (1) cerebrospinal fluid (CSF), which is derived from the choroid plexus; (2) arterial wall pulsatility, which preferentially drives CSF deeper into the brain along perivascular spaces; (3) access into the brain parenchyma by the CSF, which is supported by aquaporin-4 (AQP4) water channels and disperses within the neuropil, a space identified by densely packed forest of cellular processes and extracellular matrix; (4) interstitial fluid (ISF), which combines with CSF and accumulates in the perivenous space; and (5) subsequent CSF drainage out of the brain through meningeal and cervical lymphatic vessels. B–C, Two models represent dominant paths of CSF flow during sleep. CSF accesses the brain via glymphatic transport (B), but CSF is shunted away during wakefulness (C) and remains mostly excluded via lymphatic vessels. This paradigm is supported by magnetic resonance imaging studies suggesting that up to 20% of contrast agents injected into the cisterna magna are taken up by the brain in anesthetized animals.

88  Normal Sleep in Humans Box 13.1  Sleep Need and Duration During the Life Cycle Newborns (0–3 months) need between 14 and 17 hours of sleep. This includes daytime naps because newborns rarely sleep through the night. Older infants (4–12 months) should sleep 12 to 16 hours per 24 hours (including naps) on a regular basis to promote optimal health. Toddlers (1–2 years) should sleep 11 to 14 hours per 24 hours (including naps) on a regular basis to promote optimal health. Preschool children (3–5 years) should sleep 10 to 13 hours per 24 hours (including naps) on a regular basis to promote optimal health. School-age children (6–13 years) should sleep 9 to 12 hours per 24 hours on a regular basis to promote optimal health. Teenagers (13–18 years) should sleep 8 to 10 hours per 24 hours on a regular basis to promote optimal health. Adults (18–64 years) should aim for 7 to 9 hours of nightly sleep. Older adults (.65 years) should aim for 7 to 8 hours of nightly sleep.

core sleep) leads to sleepiness, impaired performance, and reduced executive functions. To sustain optimal alertness throughout the day, the sleep requirement varies across age groups (Box 13.1), and sleep-wake staging changes considerably with age (Table 13.1; Figures 13.7 and 13.8). For optimal health, adults should aim to obtain 7 or more hours per night on a regular basis. Consistent sleep duration of less than 7 hours per night is associated with adverse health outcomes, including obesity, insulin resistance, hypertension, impaired immune function, lower pain threshold, cardiovascular and cerebrovascular events, mood disorders, impaired cognition, and predisposition toward increased mortality. Sleep duration of more than 9 hours per night may be appropriate for young adults and during recovery from sleep deprivation and illness, but it remains speculative whether a duration of more than 9 hours per night is associated with health consequences. NEUROPHYSIOLOGY OF SLEEP AND WAKEFULNESS Figure 13.9 illustrates the physiologic correlates of brain function fluctuation and state changes across the sleep-wake cycle, and Figure 13.10 highlights the key factors that influence sleep, including prior sleep duration, regularity, and quality. The presumed function of REM, NREM, and awake states is shown in Fig. 13.11. Table 13.2 outlines the anatomic structures and neurotransmitters involved in wakefulness-generating neural networks, which include glutamate, acetylcholine, norepinephrine, dopamine, histamine, hypocretin, and serotonin. Figures 13.12 and 13.13 provide a detailed review of the key neuronal groups and their organizational interactions for generating the brain states of wakefulness and NREM sleep (see Fig. 13.12) and REM sleep (see Fig. 13.13). The interaction of the neuromodulators and mediators of sleep on brainstem structures responsible for arousal and sleep is described in Figures 13.14 and 13.15. Transition from wakefulness into sleep is highlighted in Figure 13.16.

Table 13.1  Sleep Stage Maturation During Aging Age In utero Newborns

1 year

2 years 3 to 5 years 5 to 12 years Teenage years Second to seventh decade Older adults (.65 years)

Findings At 30 weeks’ gestation, 80% “active sleep” Sleep 16 to 18 hours every 24 hours Sleep 5 to 10 hours during daytime Active sleep: 50% Quiet sleep Indeterminate sleep Establishment of major nocturnal sleep period by 3 to 4 months Sleep 13 to 15 hours every 24 hours; 2 to 3 hours during daytime naps Rapid eye movement sleep: 30% 12 to 14 hours; 1.5 to 2.5 hours during daytime naps 25% REM sleep (fixed) 11 to 13 hours sleep every 24 hours Sleep 0 to 2.5 hours during daytime naps Sleep 9 to 12 hours every 24 hours; usually no naps Sleep 8 to 9 hours every 24 hours; usually no naps Marked decline in amplitude of slow-wave sleep Gradual decline in amount of slow-wave sleep Other stages remain relatively fixed Decreased nocturnal sleep Increased napping Increased difficulty falling asleep Increased difficulty staying asleep Lighter sleep Increased awakening Changes in sleep timing and depth, melatonin secretion

WAKEFULNESS Wakefulness is promoted by the ascending brain arousal systems; inhibition of these systems promotes sleep (Fig. 13.17). The brainstem reticular activating system (RAS) contains neurons that inhibit sleep-generating neurons and activate cortical neurons through ascending projections via the thalamus, hypothalamus, and basal forebrain. Descending projections from the reticular formation to the spinal cord are important for maintaining postural control and muscle tone. TRANSITION BETWEEN WAKEFULNESS AND SLEEP Key physiologic changes that occur during the transition from wakefulness to sleep are shown in Figures 13.18 to 13.20. Brain control of the passage from the sleep to wake states may be modeled as a “flip” switch. According to this model, sleep- and wakefulness-generating neural networks are mutually inhibitory, such that when sleep networks are active, they inhibit wakefulness networks, and when wakefulness networks are active, they inhibit sleep networks. The “sleep switch” is modulated by the internal circadian timekeeping system and by hypocretin cells in the hypothalamus, both of which are believed to be important for stabilizing the switch to promote consolidated sleep and wakefulness.

Atlas of Clinical Sleep Medicine   89

Hours

Sleep duration recommendations across the life span 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Recommended May be appropriate Not recommended

Newborns

Infants

Toddlers

Preschoolers School-aged children

Teenagers

Young adults

Adults

Older adults

Age group

Figure 13.7  Updated practical recommendations for daily sleep duration across the life span from the National Sleep Foundation multidisciplinary expert panel.

Sleep duration ranges are depicted as hours of sleep per day, designated as recommended, may be appropriate, or not recommended. Recommended sleep durations are as follows: 14 to 17 hours for newborns, 12 to 15 hours for infants, 11 to 14 hours for toddlers, 10 to 13 hours for preschoolers, 9 to 11 hours for school-age children, 8 to 10 hours for teenagers, 7 to 9 hours for young adults and adults, and 7 to 8 hours for older adults. (From Hirshkowitz M, Whiton K, Albert SM, et al. National Sleep Foundation’s sleep time duration recommendations: methodology and results summary. Sleep Health. 2015;1[1]:40–43.)

Sleep duration recommendations

Infants 4–12 mo

Children 3–5 yr

Children 6–12 yr

Teens 13–18 yr

Adults 19–65 yr

Older adults 65 yr+

12–16 (including naps)

10–13 (including naps)

9–12

8–10

7–8

7–8

Hours a day

The 2015 Joint Consensus Statement from the American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) Figure 13.8  Sleep duration recommendations consensus from the American Academy of Sleep Medicine and Sleep Research Society for the proper amount of sleep needed to promote optimal health in adults. (Modified from Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38[6]:843–844.)

90  Normal Sleep in Humans

Wake

Sleep

Electroencephalographic Asynchronous Low-amplitude high-frequency

Synchronous High-amplitude low-frequency

↑ Neuronal firing rate

↓ Neuronal firing rate (–10% to –30%)

↑ [K+]e ↓ [Mg2+]e ↓ [Ca2+]e

Ionostatic

4.25 mM 0.7 mM 1.2 mM

↓ [K+]e ↑ [Mg2+]e ↑ [Ca2+]e

3.75 mM 0.8 mM 1.3 mM

Glymphatic

↑ Perivascular-lymphatic flux ↑ Extracellular volume 22–24%

↓ Perivascular-lymphatic flux ↓ Extracellular volume: 13–15%

Metabolic

Cerebral metabolic rates Glucose Oxygen

A

Cerebral metabolic rates Glucose Oxygen

–30% to –50% –5% to –25%

↓ Oxygen-glucose index 4.5–5.5 (high aerobic glycolysis)

↑ Oxygen-glucose index 5.5–6.5 (low aerobic glycolysis)

↓ [Glucose] ↑ [Lactate]

↑ [Glucose] ↓ [Lactate]

1.2 mM 1 mM

Cellular signaling

↑ Noradrenergic activity Lactate

1.5 mM 0.8 mM

↓ Noradrenergic activity

Glymphatic flux

Norepinephrine Lactate K+ R

AMPA

Presynaptic neuron

Na+ Plasticity-related Gene expression

Glutamate NMDAR

Lactate K

K+

AMPAR

D-serine + EA K+ K AT Lactate

NMDAR

Postsynaptic neuron

Na

Mg2+ Block

+

K+

Na+

Astrocyte

Lactate Glutamate

K+

K+ Clearance

Glycogen

B

Postsynaptic neuron

Na+ Na+

NKA

Lactate

Na+

Glutamate

Ca2+

K+

+

Ca2+ Presynaptic neuron

Astrocyte

Figure 13.9  Physiologic correlates associated with brain state changes across the sleep-wake cycle. This model illustrates the variation across the circadian clock

of synaptic activity that ultimately drives 24-hour rhythms in synaptic plasticity and forms the framework by which physiologic changes are supported during wakefulness and further promoted and consolidated during sleep (green and red arrows). In mammals, the active/inactive phase is characterized by discrete circadian rhythm fluctuations with corresponding oscillations in hypothalamic-pituitary axis (HPA) activity and brain temperature. Increased cortical synaptic efficacy gives rise to the active phase identified by high glutamate receptor signaling and synaptic formation. Sleep, on the other hand, promotes the inactive phase, characterized by attenuation in HPA axis activity and a reduction in brain temperature. (A) Electroencephalographic, ionostatic, glymphatic, and metabolic features of wakefulness and sleep states. Sleep is identified by the appearance of synchronous high-amplitude slow-wave activity and reduction in neuronal firing rate. One observes attenuation in neuronal excitability, a process promoted by alterations in interstitial fluid ion composition as well as increased glymphatic clearance of neuroactive compounds. Metabolic shifts transitioning from the wake state are characterized by elevated aerobic glycolysis to more oxidative metabolism, which characterizes sleep. Approximate values of main cerebral ions and metabolites are shown. Noradrenergic tone dictates and promotes state transitions and maintains brain state by acting at different targets, including ionostatic and glymphatic control systems. (B) Schematics of state-dependent astrocyte-neuron interactions. During wakefulness, neuronal and astrocytic metabolism is demarcated by an increase in rates of aerobic glycolysis, glycogen metabolism, and lactate production in a norepinephrine-dependent manner. Lactate gives rise to norepinephrine release by noradrenergic terminals, and it is involved in NMDAR-mediated synaptic plasticity mechanisms and expression of plasticity-related genes. During sleep, one observes suppression of noradrenergic activity, but rather prominent glymphatic clearance of lactate, glutamate, and K1 (potassium). Clearance is facilitated by increased extracellular space volume and decreased synaptic coverage by astrocytic processes. K1 is also sequestrated by astrocytic a2-Na1/K1 adenosine triphosphatase (a2-NKA), which contributes to the decreased extracellular K1 and associated with neuronal excitability with processes that promote sleep. During sleep, increased levels of extracellular calcium (Ca21) and magnesium (Mg21) enhance release probability of vesicles (possibly with reduced quantal content) while blocking NMDAR activation, thereby modifying synaptic plasticity rules. AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; EAAT, excitatory amino acid transporter; NKA, Na1/K1-activated adenosine triphosphatase; NMDAR, N-methyl-d-aspartate receptor.

Atlas of Clinical Sleep Medicine   91

CRH

Clock genes

Glucocorticoids Reproductive (e.g., prolactin, estrogen)

Circ ad rhyt ian hm

Ho rm

Melatonin

Age

s hic ap gr tyle mo es De & lif

on es

Stress

xis

a HPA

Sex

Occupation

Adenosine GABA

Glutamate Serotonin

CCK

Die ta hun ry int ger ake /sa tiet & y

Histamine

put t in muli ren ti Affe tory s ita exc

NO

Determinants of sleep

Orexin

NPY

Leptin/ghrelin Insulin

ATP Acetylcholine

Mineralocorticoids

Sleep loss

Noradrenaline

GRHR VIP

PGD2 oleamide

Cytokines Adenosine

Figure 13.10  Determinants of sleep. Sleep quality, duration, and need are often driven by underlying sleep loss and disturbances, sleep duration, afferent input,

sleep-wake phase duration and regularity, activation of the hypothalamic-pituitary axis (HPA), individual demographics and lifestyle, and food intake habits. ATP, Adenosine triphosphate; CCK, cholecystokinin; CRH, corticotropin-releasing hormone; GABA, gamma-aminobutyric acid; GRHR, gonadotropin-releasing hormone receptor; NO, nitric oxide; NPY, neuropeptide Y; PGD2, prostaglandin D2; VIP, vasoactive intestinal peptide.

SLEEP MECHANISMS: FROM WAKEFULNESS TO SLEEP Normal sleep physiology can be divided into NREM and REM sleep stages. Sleep-generating networks vary between these stages (see Figs. 13.18 and 13.19). The origin and localization of the key attributes of what contributes to NREM and REM sleep is illustrated in Figure 13.20. TRANSITION FROM WAKEFULNESS TO NON– RAPID EYE MOVEMENT SLEEP The transition from wakefulness to NREM sleep is associated with inhibition of the renin-angiotensin system and thalamocortical disassociation mediated through the inhibitory neurotransmitter g-aminobutyric acid (GABA). NREM sleep in healthy adult humans is demarcated by an electroencephalographic (EEG) pattern that changes from a fast, low-amplitude, desynchronized waveform pattern to a higher-amplitude,

synchronized waveform pattern. NREM sleep is divided into stages, referred to as N1, N2, and SWS. (Stages 3 and 4 are combined by the American Academy of Sleep Medicine [AASM] and are referred to as N3.) Stage N1 is a transitional stage typically observed at sleep onset. Stage N2 sleep consists of a dominant theta pattern with the presence of sleep spindles and K-complexes. N3, or deep NREM sleep (SWS), is defined by a slow, high-amplitude, synchronized EEG waveform quantified by the amount of delta activity (0.5 to 2.5 Hz). Stage N3 sleep occurs mostly during the first half of the night. In healthy adult humans, NREM and REM sleep alternate throughout the night approximately every 80 to 120 minutes. The duration of REM episodes increases across the night. REM sleep is primarily a cholinergic (acetylcholine) state during which neurons in the reticular formation are active, primarily those located in the pontine tegmentum, leading to cortical activation (see Fig. 13.20). REM sleep (see Fig. 13.18; Fig. 13.21) is defined by a fast, low-amplitude, desynchronized theta EEG waveform, with

92  Normal Sleep in Humans

AWAKE

NREM SLEEP

REM SLEEP

Sleep-on neurons are inactive

Forebrain sleep-on neurons fire

Brainstem REM-on neurons fire

Rapid eye movements

Abs

enc

e of

vivid

drea

ms

Vivi d

Free radicals can damage cell membranes when neurons are active as during the awake state

drea

NREM sleep may allow cells to repair membranes damaged by free radicals

ms

occ

ur

Some receptors are inactive during REM sleep, which may be necessary for their proper functioning during wakefulness

Figure 13.11  Function of the two types of sleep. One hypothesis is that non–rapid eye movement (NREM) sleep may allow brain cells a chance to undergo

repair. A second hypothesis is that the interrupted release of monoamines during rapid eye movement (REM) sleep may allow the brain’s receptors for these neurotransmitters to recover and regain full sensitivity, which may help with regulation of learning and mood. A third hypothesis is that the potent neuronal activity of REM sleep in early life may allow the brain to develop properly. (Modified from Siegel JM. Why we sleep. Sci Am. 2003;289[5]:92–97.)

Table 13.2  Neurotransmitters of Sleep Neurotransmitter

Localization and Function

Noradrenergic (norepinephrine) Dopaminergic

Found in the locus coeruleus, project to the forebrain and cerebral cortex, and are involved in attention and maintaining and enhancing cortical activation. Activities of locus coeruleus neurons are higher during wakefulness than during sleep. Localized to the substantia nigra and ventral tegmental areas. These neurons project to the striatum and frontal cortex, which when activated are important for behavioral arousal and movement. Although dopamine neurons are reported to show similar firing rates across sleep-wake states, inputs to dopamine neurons from other arousal systems may influence sleep and wakefulness. Found in the brainstem, they excite thalamocortical cells, which result in arousal and information transfer to the cerebral cortex. Cholinergic cells, located in neurons in the basal forebrain, promote behavioral and cortical arousal. Localized in the tuberomammillary nucleus of the caudal hypothalamus and provide excitatory input to the cerebral cortex; antihistamines that cross the blood-brain barrier produce drowsiness. Excitatory amino acids found within many neurons projecting to the cerebral cortex, the forebrain, and brainstem. Released in the largest amounts during wakefulness; their antagonists produce sleep. Localized in the lateral hypothalamus and project to widespread areas of the brainstem, thalamus, hypothalamus, and cerebral cortex; reported to have a role in brain arousal.

Cholinergic Histaminergic Glutamate and aspartate Orexin/hypocretin

Atlas of Clinical Sleep Medicine   93

Non-REM sleep

Awake

A

B Thalamus O/H Ach

His

GABA

DA Glu

Reticular formation

Basal forebrain

5HT Ach NA

Pons Cerebellum

GABA

5HT

Medulla

Serotonin (5HT) Noradrenaline (NA) Histamine (His) Dopamine (DA) Orexin/hypocretin (O/H) C1–C8

T1–T12

Glutamate (Glu) (reticular formation)

L1–L5 S1–S5

Wake-active orexin/ hypocretin neurons: high relative activity

C1

C1–C8

Acetylcholine (Ach)

T1–T12

L1–L5 S1–S5

Wake-active orexin/ hypocretin neurons: low relative activity

C2

Strong excitation

Weak excitation Weak inhibition in sleep

Strong inhibition in waking

Sleep-active GABA neurons: low relative activity

Wake-active monoaminergic neurons: high relative activity

Sleep-active GABA neurons: high relative activity

Weak inhibition in waking

Strong inhibition in sleep

Position of sleep switch

Non-REM sleep

Wake

D1

A

Wake-active monoaminergic neurons: low relative activity

D2

Wake

Off

On

B

Non-REM sleep

Figure 13.12  Sleep-wake neurophysiology of wakefulness and non–rapid eye movement (NREM) sleep. The key neuronal groups that help generate the brain

states of wakefulness (A, left) and NREM sleep (B, right). A, The key neuronal clusters whose ascending projections are responsible for producing the electrophysiologic basis for wakefulness and whose descending projections influence brainstem autonomic networks and spinal motor activity. B, NREM sleep is promoted when wakefulness-generating systems are inhibited by clusters of neuronal groups containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). C, The organizational structure for the maintenance of wakefulness (C1) and NREM sleep (C2) and the switch between the two states are also shown. D, Wakefulness during the day (D1) and consolidated periods of sleep at night (D2) are brought about via mutual inhibitory interactions between wakefulness and sleep-promoting neuronal groups that lead to the “switch” being stable in either position. The transition to sleep at night and wakefulness during the day is linked to the circadian-mediated decrease and increase in core body temperature; the decrease in body temperature activates GABA sleep-promoting neuronal systems, whereas the increase in body temperature deactivates them. The NREM sleep-active GABA neuronal groups include those in the ventrolateral preoptic region of the thalamus as well as those in the basal forebrain and anterior hypothalamus. Relatively high levels of neuronal activity are represented by large symbols and solid lines, whereas relatively low levels of neuronal activity are represented by small symbols and dashed lines. Inhibitory neuronal projections from cell groups are indicated by squares and excitatory projections are indicated by arrowheads. (Modified from Horner RL. Emerging principles and neural substrates underlying tonic sleep-state-dependent influences on respiratory motor activity. Philos Trans R Soc Lond B Biol Sci. 2009;364[1529]:2553–2564; Horner RL. Central neural control of respiratory neurons and motoneurons during sleep. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 5th ed. St Louis: Elsevier; 2011:237–249; Horner RL. Respiratory physiology. In: Kushida C, ed. Encyclopedia of Sleep, vol. 1. Waltham, MA: Academic Press; 2013:517–524; Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437[7063]:1257–1263; and Horner RL, Malhotra A. Control of breathing and upper airways during sleep. In: Broaddus CB, et al, eds. Murray & Nadel’s Textbook of Respiratory Medicine. Philadelphia: Elsevier; 2022.)

94  Normal Sleep in Humans REM sleep generation and motor suppression Cholinergic-aminergic interactions

Glutamate-GABA interactions

GABA Glycine and GABA

Serotonin C1–C8 T1–T12 L1–L5 S1–S5

Noradrenaline Acetylcholine Glutamate Motor pools

Glycine and GABA C1–C8 T1–T12 L1–L5 S1–S5

Excitation

Figure 13.13  Sleep-wake neurophysiology of rapid eye movement (REM) sleep. There are two explanations for REM sleep generation: one involves the

interactions of cholinergic and aminergic cell clusters (left), and the second involves interactions of glutamatergic and gamma-aminobutyric acid (GABA)-ergic cell clusters (right). The cardinal features of REM sleep are explained by ascending cortical activation and descending spinal motor inhibition. Muscle atonia during REM sleep is mediated via inhibition of spinal motor activity, which involves descending projections to the medial and ventral horn of the spinal cord via the inhibitory activity of glycine and GABA onto spinal motoneurons. (Modified from Horner RL. Emerging principles and neural substrates underlying tonic sleepstate-dependent influences on respiratory motor activity. Philos Trans R Soc Lond B Biol Sci. 2009;364[1529]:2553–2564; Horner RL. Central neural control of respiratory neurons and motoneurons during sleep. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 5th ed. St Louis: Elsevier; 2011:237–249; Horner RL. Respiratory physiology. In: Kushida C, ed. Encyclopedia of Sleep, vol. 1. Waltham, MA: Academic Press; 2013:517–524; Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437[7063]:1257–1263; and Horner RL, Malhotra A. Control of breathing and upper airways during sleep. In: Murray & Nadel’s Textbook of Respiratory Medicine. Philadelphia: Elsevier; 2022.)

characteristic sawtooth waves, and inhibition of skeletal muscle activity referred to as muscle atonia. REM sleep is divided into phasic and tonic REM sleep, each with its own corresponding unique physiologic and electrographic properties (Fig. 13.22). STAGING OF SLEEP All animals sleep. When they do, they generally assume a posture that is instantly recognizable as one of sleeping or resting (Fig. 13.23). However, upon inspection, we cannot really tell if the animal is asleep; in addition, there are different “depths” of sleep. By using techniques that record the electrical activity of the nervous system, we can now categorize by stage the depth of sleep in humans and other species. Sleep staging uses the frequency, amplitude, and pattern of data obtained by EEG (brain wave activity), electrooculography (EOG, eye movements), and electromyography (EMG, muscle tone), which together score the record as stage W, N1, N2, N3, or R. Representative 30-second fragments are shown in Figures 13.24 to 13.29. Tables 13.3 through 13.5 summarizes sleep-wake staging according to the traditional Rechtschaffen and Kales (R&K) system as well as the current system developed by the AASM.

Specific features of sleep-stage EEG frequencies are shown in Figures 13.30 and 13.31. NORMAL CIRCADIAN FUNCTION The human circadian rhythm is composed of endogenous autonomous oscillators generated by the suprachiasmatic nucleus (SCN) in the hypothalamus. The circadian clock helps coordinate internal time and discrete physiologic processes with the external environment in a 24-hour daily cycle. The circadian clock system in humans subserves the key regulatory signal for nearly all physiologic activities. Disorders of circadian sleep-wake patterns contribute to severe consequences on human health. For example, jet lag and shift work have revealed that sleep-wake circadian disorders can culminate in substantial psychiatric illness, metabolic syndrome, cognitive impairment, dysplasia, and cancer. NORMAL SLEEP Figure 13.32 show the proportion of the night spent in the various sleep stages in adults; predictable physiologic and endocrine changes are shown in Figure 13.33.

Atlas of Clinical Sleep Medicine   95 EEG

EOG

Wake

NREM1

NREM sleep NREM2 Sleep K-complex spindle

NREM3

REM sleep

Slow waves

EMG

75V 1s

Thalamus

Cortex Delta sleep – ½ to 2 cps-delta waves  75V

REM OFF

LC

NE

SWS

 NE

Awake – low voltage-random, fast Reticular activating system (RAS)

DRN



1 sec

h

PPT



50 V

AWAKE

Ac

 REM ON

5HT

LDT

Ach

REM sleep – low voltage-random, fast with sawtooth waves Sawtooth waves

REM

Sawtooth waves

C3-A2

GLY

Atonia

C4-A3 LOC ROC EMG

Figure 13.14  Brainstem-mediated arousal and sleep induction. The reticular activating system (RAS) oversees the wake state through activity of four subnuclei:

(1) the locus coeruleus (LC), which releases norepinephrine (NE); (2) the dorsal raphe nuclei (DRN), which release serotonin (5HT); (3) the pedunculopontine (PPT) nuclei; and (4) the laterodorsal tegmentum (LDT), which is associated with acetylcholine (Ach). The PPT-LDT neurons are active in wakefulness as well as rapid eye movement (REM) sleep and are believed to be the REM “on” switch. Lesions in the PPT-LDT area do not affect wakefulness but lead to loss of REM sleep. Slow-wave sleep (SWS) is modulated through the LC and DRN by decreasing the release of NE. Wakefulness is achieved through the combined activity of the PPT, LC, and DRN nuclei releasing Ach, NE, and 5HT, respectively. The primary neurotransmitter of REM is Ach. SWS is achieved through suppression of the wakefulness neurotransmitters NE and 5HT and release of Ach. EEG, Electroencephalogram; EOG, electro-oculogram; EMG, electromyogram; GLY, glycine; NREM, non-REM sleep. (Modified from Webster HH, Jones BE. Neurotoxic lesions of the dorsolateral pontomesencephalic tegmentum-cholinergic cell area in the cat. II. Effects upon sleep-waking states. Brain Res. 1988;458[2]:285–302; top panel from Canto CB, Onuki Y, Bruinsma B, van der Werf YD, De Zeeuw CI. The sleeping cerebellum. Trends Neurosci. 2017;40[5]:309–323.)

Sleep histograms summarize sleep laboratory recordings and demonstrate the progression of stages during the night. The typical hypnogram shows how a night of sleep for a patient is organized (Fig. 13.34). The y-axis corresponds to the various stages of NREM sleep, alternating with REM sleep. Most SWS occurs in the first part of the night, and most REM sleep occurs in the last part. The sleep architectural changes typically seen across the life span are depicted by the sleep histograms shown in Figure 13.35. In normal individuals, sleep is entered by way of NREM sleep, with the first NREM episode occurring at about 90 minutes. Thereafter, NREM and REM alternate about every 90 minutes. Figure 13.36 shows that the slow waves in stage N3 in a child often have a very high amplitude; the other stages more closely resemble those of an adult. Figure 13.37 shows REM sleep in the same patient.

FACTORS THAT AFFECT SLEEP Many diseases, medications, lifestyle choices, and habits can adversely affect sleep (Table 13.6). Figure 13.38 shows the changes in the quantity of the sleep stages throughout the life span. Figure 13.39 and Figure 13.40 outline the age-specific changes in specific sleep stages as a function of time (in years). Figures 13.41 and 13.42 highlight the changes in sleep, confirming the observed trend in reduction in SWS and reduced sleep efficiency. SLEEP CHANGES IN CHILDREN From conception to adolescence, sleep undergoes some dramatic changes. Major alterations in sleep organization across infancy,

96  Normal Sleep in Humans Wakefulness

Non-REM sleep

REM sleep

Hypocretin BF

TMN

Hypocretin

SN VTA Raphe

PPT LDT LC

A

VLPO

TMN

SN VTA Raphe

PPT LDT LC

B

Thalamus

TMN Raphe

C

Wakefulness

BF: Acetylcholine

++++

+

++++

LDT: Acetylcholine

++++

+++ → 0

++++

Dorsal and median raphe: Serotonin

++++

++

0

Locus coeruleus: (NE)

++++

++

0

TMN: (Histamine)

++++

++

0

Posterior/lateral hypothalamus (hypocretin/orexin)

++++

+

+

+

+++

++++

Neurophysiology

Wakefulness

Nonrapid eye movement (non-REM) sleep

Motor neurons

Neurochemistry

Ventrolateral preoptic area (GABA)

PPT REM-on LDT neurons LC

Rapid eye movement (REM) sleep

Rapid eye movement (REM) sleep

Nonrapid eye movement (non-REM) sleep

Posture

Erect sitting, or recumbent

Recumbent

Recumbent

Mobility

Normal

Slightly reduced or immobile; postural shifts

Moderately reduced or immobile; myoclonic jerks

Response to stimulation

Normal

Mildly to moderately reduced

Moderately reduced to no response

Level of alertness

Alert

Unconscious but reversible

Unconscious but reversible

Eyelids

Open

Closed

Closed

Eye movements

Waking eye movements

Slow-rolling eye movements

Rapid eye movements

EEG

Alpha waves; desynchronized

Synchronized

Theta or sawtooth; desynchronized

EMG (muscle tone)

Normal

Mildly reduced

Moderately to severely reduced or absent

EOG

Waking eye movements

Slow-rolling eye movements

Rapid eye movements

Figure 13.15  Neurochemistry of sleep and wakefulness. The midsagittal view is shown with superimposed schematic representation of circuits most relevant for

wakefulness (A), non–rapid eye movement (NREM) sleep (B), and rapid eye movement (REM) sleep (C). A, Mechanism of wakefulness (arousal). Hypocretin/orexin neurons project toward and excite the other wake-promoting brainstem nuclei as well as the basal forebrain, and widely throughout the cortex (red arrows). Cholinergic input (orange) from the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei projects through the thalamus and facilitates thalamocortical transmission of arousal signals. A second pathway projects through the hypothalamus to cortical centers and facilitates the processing of thalamocortical inputs that arise from midbrain centers, including the noradrenergic (blue) locus coeruleus (LC); the serotonergic (purple) dorsal raphe (Raphe); the histaminergic (pink) tuberomammillary nucleus (TMN); and the dopaminergic (yellow) ventral periaqueductal gray matter (VPAG). This pathway also receives input from the cholinergic (orange) basal forebrain (BF) and the peptidergic neurons of the lateral hypothalamus (LH) and perifornical neurons (PeF), which contain hypocretin or melaninconcentrating hormone (light green). The melatonergic (red) neural network affects arousal and sleep through regulation of circadian rhythms. This internal biologic clock originates in the suprachiasmatic nucleus (SCN), projects through the dorsomedial hypothalamus (DMH), and sends inhibitory signals to the g-aminobutyric acid (GABA)-ergic (gray) ventrolateral preoptic nucleus (VLPO) of the hypothalamus. B, During NREM sleep, the VLPO projects toward and inhibits the wakepromoting nuclei (green lines). C, During REM sleep, the LDT and PPT cholinergic neurons lack the wake inhibition (from hypocretin/orexin, TMN, raphe, and LC) and excite the thalamus (yellow). Medullary interneurons inhibit motor neurons, causing atonia in REM. EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram; GABA, γ-aminobutyric acid; NE, norepinephrine; SN, substantia nigra; VTA, ventral tegmental area. (From Avidan AY. Sleep and its disorders. In: Daroff RB, et al. Bradley and Daroff’s Neurology in Clinical Practice. Philadelphia: Elsevier; 2021.)

childhood, and adolescence are depicted in Figures 13.43 to 13.49. Maturation of the neonatal EEG is shown (see Fig. 13.44), depicting the appearance of key electrographic findings that start to differentiate the unique components of NREM sleep. Although infants spend a significant amount of time sleeping throughout the day, with multiple nighttime awakenings (see Fig. 13.45), sleep begins to consolidate into one to two naps by 1 year of age, to one nap in the preschool period, and eventually to all nighttime sleep by school age (see Fig. 13.48). Over time, sleep architecture exhibits developmental changes with decreases in total sleep time (see Fig. 13.39) and SWS and increases in stage N2 sleep from childhood through adolescence (see Fig. 13.40). By adolescence, the total sleep obtained falls short of what is recommended for healthy daytime functioning

because of a variety of factors (see Fig. 13.49), including the tendency toward a delayed sleep-phase pattern (Fig. 13.50). Although the development of sleep is a dramatic and relatively rapid process during the first decades of life, changes in sleep continue across the life span. SLEEP CHANGES WITH AGING Sleep in older adults tends be characterized by some advancement of the circadian rhythm (see Fig. 13.50), increased frequency if awakening, reduced SWS, and more time awake in bed, while sleep need continues to be at 7 to 8 hours per night. Sleep is affected by underlying medical conditions, changes

Atlas of Clinical Sleep Medicine   97

Thalamus

VLPO

Thalamus SCN VLPO SCN BF

Pin

PeF DMH

VPAG LDT

PeF DMH LH

BF VPAG

Raphe

LDT TMN

TMN

LC PC/PB

PPT

Raphe

Pons LC

PPT

SLD Cerebellum

Pons

r cula Reti ating v acti tem sys S) (RA

Wakefulness

A

Cerebellum

B

Sleep

Figure 13.16  The transition of the brain from the awake state to the sleep state requires the orchestration of some important arousal and sleep centers and

pathways of neurotransmission. A, During wakefulness, cholinergic input (orange) from the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei project through the thalamus and facilitate thalamocortical transmission of arousal signals. A second pathway projects through the hypothalamus to cortical centers and facilitates the processing of thalamocortical inputs that arise from midbrain centers, including the noradrenergic (blue) locus coeruleus (LC); the serotonergic (purple) dorsal raphe (Raphe); the histaminergic (pink) tuberomammillary nucleus (TMN); and the dopaminergic (yellow) ventral periaqueductal gray matter (VPAG). This pathway also receives input from the cholinergic (orange) basal forebrain (BF) and the peptidergic neurons of the lateral hypothalamus (LH) and perifornical neurons (PeF), which contain hypocretin or melanin-concentrating hormone (light green). The melatonergic (red) neural network affects arousal and sleep through regulation of circadian rhythms. This internal biologic clock originates in the suprachiasmatic nucleus (SCN), projects through the dorsomedial hypothalamus (DMH), and sends inhibitory signals to the g-aminobutyric acid (GABA)-ergic (gray) ventrolateral preoptic nucleus (VLPO) of the hypothalamus. B, This rendering of the human brain illustrates important sleep and arousal centers and pathways of neurotransmission that occur during the sleep state. The VLPO of the hypothalamus sends descending GABAergic inhibitory signals to the midbrain arousal centers that include the PeF, TMN, VPAG, raphe, LDT and PPT, and LC. During the early hours of dark periods, the pineal gland (Pin) releases melatonin (red), which has inhibitory effects on the SCN and DMH of the melatonergic system. Nuclei that control neural activity during rapid eye movement (REM) sleep have been identified in the pontine midbrain. The pericoeruleus (PC) and parabrachial (PB) nuclei send glutaminergic (green) projections through the BF to affect cortical activity during REM sleep, and projections from the sublaterodorsal nucleus (SLD) send glutamatergic signals through the spinal cord to induce the atonia characteristic of REM sleep. (From Wafford KA, Ebert B. Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time. Nat Rev Drug Discov. 2008;7[6]:530–540.)

Hypocretin BF

TMN SN Raphe VTA

VLPO

PPT LDT LC

TMN SN Raphe VTA

PPT LDT LC

ular Retic ting activa m syste ) (RAS

A

B

Figure 13.17  Hypothalamic mechanisms in sleep-wake control. These systems innervate the ascending arousal systems and excite and inhibit the system,

respectively, to mediate the effects. A, Hypocretin neurons in the lateral hypothalamic area innervate all ascending arousal systems as well as the cerebral cortex. B, Neurons of the ventrolateral preoptic (VLPO) area produce g-aminobutyric acid and galanin, which inhibit all arousal systems during non–rapid eye movement sleep. BF, basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmental nuclei; PPT, pedunculopontine; SN, substantia nigra; TMN, tuberomammillary nucleus; VTA, ventral tegmental area. (From Nishino S, ed. Basic sleep concepts, science, deprivation, and mechanisms of neurotransmitters and neuropharmacology of sleep/wake regulations. In: Encyclopedia of Sleep. Palo Alto, CA: Stanford University School of Medicine; 2013:395–406.)

98  Normal Sleep in Humans

NREM sleep

Wake

NREM1

NREM2 Sleep spindle

REM sleep

NREM3

K-complex

Slow waves

75V 1s

A Awake Stage 1 Stage 2 Stage 3

B

Time (n) 5 0 Awake Stage 1 Stage 2 Stage 3 110 100 90 10 5 30 25 20 4 2

Eye movements (per min) EEG sleep stage Systolic blood pressure (torr)

Breaths (per min) Pulse (beats/min)

Body movements (number)

0

200

C

220

240

260

280

300

Time (min)

Figure 13.18  In mammals, the two types of sleep are rapid eye movement (REM) sleep and non–rapid eye movement (NREM) sleep. These sleep types are

defined in terms of electrophysiologic signs detected with a combination of electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG), the measurement of which in humans is collectively termed polysomnography. REM sleep—also known as paradoxical, active, or desynchronized sleep—is characterized by awake-like and “activated” (high-frequency, low-amplitude, or “desynchronized”) signals in the EEG; singlets and clusters of REMs in the EOG; and very low muscle tone (atonia) in the EMG. Note that the term desynchronized for the activated states of waking and REM has been rendered obsolete by the discovery of highly synchronized g-frequency (30 to 80 Hz) activity in these states. NREM sleep is divided into four stages that correspond to increasing depth of sleep, as indicated by progressive dominance of the EEG by high-voltage, low-frequency “synchronized” wave activity. Such low-frequency waves dominate the deepest stages of NREM (stage N3, also termed slow-wave sleep). Stage 2 NREM is characterized by distinctive sleep spindles, K-complex waveforms, and a slow (,1 Hz) oscillation, which influences their timing. The characteristic waveforms of the different sleep stages are shown in A, and changes in peripheral physiology associated with the sleep stages are shown in C. NREM and REM sleep alternate in each of the four or five cycles that occur in each night of adult human sleep. Early in the night, NREM sleep is deeper and occupies a disproportionately large amount of time, especially in the first cycle, when the REM epoch may be short or aborted. Later in the night, NREM sleep is shallow, and more of each cycle is devoted to REM (red bars). B depicts these changes over the course of a night’s sleep. A depicts, in detail, features of an early-night sleep cycle in which NREM reaches its greatest depth at stage 3 (delta-sleep). C depicts a late-night cycle in which NREM descends only to stage 3. The constant period length of the NREM-REM cycle indicates that it is timed by a reliable oscillator, the amplitude of which varies according to extrinsic factors. The cyclic organization of sleep varies within and among species. The period length of each REM-NREM epoch increases with brain size across species, and the depth and proportion of the NREM phase in each cycle increases with brain maturation within species. NREM sleep complexity is a function of brain systems, such as the thalamocortical circuitry, that reach their maximum development in mature humans only to decline in postmature age. It can therefore be concluded that the differentiation of sleep is a function of brain differentiation, a rule that indicates both mechanistic and functional links between sleep and other brain functions. (From Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci. 2002;3[8]:591–605; top panel from Canto CB, Onuki Y, Bruinsma B, van der Werf YD, De Zeeuw CI. The sleeping cerebellum. Trends Neurosci. 2017;40[5]:309–323.)

Atlas of Clinical Sleep Medicine   99 Awake Stage W

NREM sleep Stage N1

Stage N2

REM sleep Stage N3

Stage R

EEG

High Level of consciousness

Low Light

Type of sleep

Intermediate

Slow-wave

Tonic REM with periods of phasic activity

90-minute cycles throughout the night

Figure 13.19  The relationship between human sleep, level of consciousness, and electroencephalogram patterns. Stages of sleep are characterized by differ-

ences in the frequency and amplitude of electroencephalogram (EEG) waves. N1 is composed of light sleep with low-amplitude waveforms. N2 is characterized by sleep spindles (the higher-frequency waves) and K-complexes (not shown). N3 is composed of slow-wave sleep (SWS) with high-amplitude waves and a deeper level of unconsciousness. These stages comprise non–rapid eye movement (NREM) sleep. The final stage is rapid eye movement (REM) sleep, which is associated with mixed EEG frequency (all waves shown) and, in some individuals, with low-amplitude sawtooth waves (not shown) and a higher level of consciousness. (From Bryant PA, Trinder J, Curtis N. Sick and tired: Does sleep have a vital role in the immune system? Nat Rev Immunol. 2004;4[6]:457–467.)

Forebrain areas key to the neuropsychology of dreaming Prefrontal cortex: Ventromedial Dorsolateral

Anterior limbic structures: Amygdala, anterior cingulate, ventral striatum

Posterior cortices: Inferior parietal Visual association

Thalamocortical control of NREM sleep rhythms; EEG activation and deactivation

Hippocampal-cortical control of memory consolidation

Origin and expression of circadian rhythms

Diencephalic control of sleep onset

Pontine control of the REM-NREM cycle

Hypothalamic nuclei: • Suprachiasmatic • Subparaventricular • Dorsomedial

Hypothalamic nuclei: • Ventrolateral preoptic • Lateral • Tuberomammillary • Basal forebrain

Mesopontine nuclei: • Laterodorsal tegmental • Pedunculopontine • Dorsal raphe • Locus coeruleus

Figure 13.20  Brain regions playing a role in

the neurobiology of sleep.  The bottom tier of subcortical regions (blue boxes) control sleep-wake transitions and, within sleep, REM-NREM sleep alternation. The top tier includes areas that are key to the generation of the electroencephalographic (EEG) rhythms of sleep, the subjective experience of sleep mentation or dreaming, and sleep’s effects on cognition (considered in schematic representations of the regulatory circuits that control sleep-wake and REM-NREM transitions along with their key inputs and outputs). NREM, non–rapid eye movement; REM, rapid eye movement. (From Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci. 2002;3[8]:591–605.)

100  Normal Sleep in Humans Rapid eye movement (REM) sleep

REM sleep atonia pathways

RPT REM-gating neurons Hypocretin

Thalamus

PPT/LDT LC

TMN

PPT REM-on LDT neurons Raphe

Pons REM-on neurons

LC Medullary interneurons

Motor neurons

A

Motor neurons

B

Figure 13.21  Rapid eye movement (REM) sleep and REM sleep atonia pathways.  A, REM sleep is driven by a distinct population of brainstem cholinergic

pedunculopontine and laterodorsal tegmental (PPT/LDT) neurons. During wakefulness and non–rapid eye movement (NREM) sleep, these cells are inhibited by norepinephrine (NE), serotonin (5HT), and histamine; during REM sleep, the aminergic neurons fall silent, thus disinhibiting the PPT/LDT REM-generating neurons. These PPT/LDT cholinergic neurons produce the atonia of REM sleep by activating the medial medulla, which inhibits motor neurons. The medial medulla also reduces excitatory signals from the locus coeruleus (LC) that normally increase motor tone. In vitro experiments suggest that hypocretin neurons excite cholinergic neurons, although recent in vivo experiments have shown that hypocretin neurons likely inhibit REM-on cholinergic neurons through activation of inhibitory GABAergic interneurons. B, Early work showed that motor neuron hyperpolarization during REM sleep was accompanied by the release of glycine onto motor neurons, and NE and 5HT release onto motor neurons is decreased during atonia. Stimulation of cholinoceptive neurons in the pontine reticular formation ventral to the LC and LDT elicit REM sleep with muscle atonia. Some of these GABAergic REM sleep–gating neurons are located in the more rostral pontomesencephalic tegmentum (RPT) by what appears to be a disinhibition of the REM sleep effector neurons. The effector neurons would use glutamate as a neurotransmitter and give rise, in part, to descending projections into the medullary reticular formation and/or spinal cord. GABA, g-aminobutyric acid; TMN, tuberomammillary nucleus. (From Nishino S, ed. Neurotransmitters and neuropharmacology of sleep/wake regulations. In: Encyclopedia of Sleep. Palo Alto, CA: Stanford University School of Medicine; 2013:395–406.)

REM sleep - phasic components

Ponto-geniculo-occipital waves Rapid eye movements Middle ear muscle activity Tongue movements Muscle twitches Cardiovascular variability Dreaming

REM sleep - tonic components

EEG desynchronization EMG atonia High arousal threshold Elevated brain temperature Hippocampal theta rhythm Poikilothermia Olfactory bulb activity Increased penile tumescence/vaginal engorgement Dreaming

Figure 13.22  ​Rapid eye movement (REM) sleep. Tonic versus phasic REM sleep. EEG, electroencephalography; EMG, electromyography.

Atlas of Clinical Sleep Medicine   101

A

Atonia

Hypotonia Figure 13.23  ​Animals assume a recognizable posture when sleeping

(top). Posture-dependent regulation of muscle tone during rapid eye movement (REM) sleep in geese (bottom), which like other birds can experience REM sleep while balancing on one foot with the head facing backward (A) or forward and unsupported (B). When the head is supported, it usually remains still, and the neck electromyogram (EMG) shows atonia. By contrast, when the head is unsupported, it drops in a controlled manner, and the neck EMG shows hypotonia. Birds only occasionally show behavioral signs of reduced tone in the muscles involved in holding the wings against the body and balancing on one foot. (B, Illustration courtesy Damond Kyllo, PhD.)

B

E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.24  Stage W (wakefulness). This fragment is a 30-second epoch. The two top channels represent the channels that monitor eye movements. The next

six channels are used to record the electroencephalogram (EEG). The first three of these (F4-M1, C4-M1, O2-M1) are recommended for scoring sleep. The others are backups in case electrodes malfunction. The bottom channel is the chin electromyogram. The key finding that indicates this is wakefulness is the presence of alpha rhythm over the occipital region (monitored by the O leads) occupying more than 30 seconds of the epoch.

102  Normal Sleep in Humans E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.25  Stage N1. A mixed-frequency, low-amplitude pattern has replaced the alpha rhythm for .50% of the epoch.

E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.26  Stage N2. A train of sleep spindles (open triangle) toward the beginning of the epoch is followed shortly by a K-complex (red solid triangle).

E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.27  Stage N3. More than 20% of the epoch consists of slow-wave activity.

Atlas of Clinical Sleep Medicine   103 E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.28  Stage R. Rapid eye movements (open triangle) and a mixed-frequency, low-amplitude electroencephalogram are shown; muscle tone (chin electromyogram) is absent (red solid triangles). Note that some of the activity of the eyes has spilled over into the two frontal (F) leads (open squares).

Awake: low voltage − random, test 50V 1 sec Drowsy: 8 to 12 cps − alpha waves

N1: 3 to 7 cps − theta waves

Theta waves

N2: 12 to 14 cps − sleep spindles and K complexes K complex Sleep spindle

Delta sleep: (N3) 1/2 to 2 cps − delta waves 75 V

REM sleep: low voltage − random, test with sawtooth waves

Sawtooth waves

Sawtooth waves

Figure 13.29  ​Features of sleep-stage electroencephalogram frequencies. cps, Cycles per second; REM, rapid eye movement.

Table 13.3  Sleep Stage Systems: Rechtschaffen and Kales vs. American Academy of Sleep Medicine Terms Used to Describe Type of Sleep NREM

Classic Stage R & K Sleep Stage Definitions

Updated AASM Sleep Stage Definitions

1 2 3 4 REM

N1 N2 N3

“Light sleep” “Deep sleep” or slow-wave sleep

REM

REM sleep, dreaming sleep, paradoxical sleep

R

AASM, American Academy of Sleep Medicine; NREM, non–rapid eye movement; R & K, Rechtschaffen and Kales; REM, rapid eye movement.

Table 13.4  Sleep-Stage Electroencephalographic Rhythms and Characteristics: Rechtschaffen and Kales vs. American Academy of Sleep Medicinea

EEG electrodes Major body movements Slow-wave sleep Terminology of stages Reference electrode Scoring stage 2 (or N2) sleep

R & K Manual

AASM Scoring Manual

Score sleep stages using central (C3, C4) leads Movement time can be scored if more than half the epoch is obscured Consists of both stage 3 and stage 4 sleep with delta wave amplitude measured using central leads Stage 1, stage 2, stage 3, stage 4, and stage REM sleep Left and right ear or mastoid, termed A1 or A2 3-minute rule that states if greater than 3 minutes pass in between spindles or K complexes, then score stage 1 sleep

Score using frontal, central, and occipital leads No movement time staging exists Only recognizes stage N3 sleep with delta wave amplitude measured using frontal leads Stage N1, stage N2, stage N3, and stage R sleep Left and right mastoid, termed M1 or M2 No 3-minute rule exists

a

Sleep-stage scoring rules are summarized according to the traditional Rechtschaffen and Kales (R & K) system as well as the current system developed by the American Academy of Sleep Medicine (AASM). AASM, American Academy of Sleep Medicine; EEG, electroencephalogram; NREM, non–rapid eye movement; R & K, Rechtschaffen and Kales; REM, rapid eye movement.

Table 13.5  Sleep-Stage Electroencephalographic Rhythms and Characteristics: Rechtschaffen and Kales vs. American Academy of Sleep Medicinea Stage Wake (W) EEG

•

Low voltage, mixed frequency; at least one K complex/sleep spindle

•

• •

Occasional SREM Tonic activity, low EMG activity

Duration

• SREM • Tonic activity, high-medium EMG activity • 10 minutes

•

20 minutes

Arousal threshold Physiologic changes

• Lowest • Lower • Highest • Progressive reduction of physiologic activity, blood pressure, heart rate slow down

EOG EMG

• •

a

N3 (Stages 3 and 4)

•

•

Tonic activity, high EMG activity Under voluntary control

•

N2 (Stage 2)

Low voltage, mixed frequency; theta activity; vertex sharp waves

•

Eyes open: low voltage, mixed frequency; alpha attenuates Eyes closed: low voltage, high frequency; more than 50% alpha activity Eye blinks, voluntary control, SREM when drowsy

N1 (Stage 1)

Stage 3: 20%–50% high-amplitude delta activity Stage 4: .50% high-amplitude delta activity

•

• •

Mirrors EEG Tonic activity, low EMG activity

• • •

•

30–45 minutes

•

%TST Dreaming

• 2%–5%

• 44%–55%

• 3.8%

• 10%–15% • Diffuse dreams

Parasomnias and movement disorders

•

•

• Confusional arousals, somniloquy

• Sleepwalking, night terrors

Hypnic jerks in transition to N1

Hypnic jerks

REM Sleep Low voltage, mixed frequency; presence of sawtooth waves; desynchronized EEG (EEG is synchronized in all other stages)

Phasic REM TREM: relatively reduced PREM: episodic EMG twitching • The first REM period is very short, lasting about 5 minutes; the second is about 10 minutes; the third is roughly 15 minutes. The final REM period usually lasts for 30 minutes, but sometimes lasts for 1 hour • Low • TREM: muscle paralysis; increased cerebral blood flow • PREM: irregular breathing, variable heart rate, REM, phasic muscle twitching • 20%–25% • Vivid, bizarre, and detailed dreams • REM sleep behavior disorder, REM nightmares

Sleep-stage scoring rules are summarized according to the traditional Rechtschaffen and Kales (R & K) system as well as the current system developed by the American Academy of Sleep Medicine (AASM). EEG, Electroencephalography; EOG, electrooculography; EMG, electromyography; MT, movement time; REM, rapid eye movement; PREM, phasic rapid eye movement; SREM, slow-rolling eye movement; TREM, tonic rapid eye movement; TST, total sleep time.

Atlas of Clinical Sleep Medicine   105 EEG rhythm

Characteristics

Best seen

Slow waves

0.5–2 Hz; amplitude  75 V

Frontal

1s

Examples LOC-A1 ROC-A1 F4-A1 C4-A1 O2-A1

Spindle

8–12 Hz

Central

LOC-A1 ROC-A1 F4-A1 C4-A1 O2-A1

K-complex

Diphasic; large amplitude, duration  0.5 s

Frontal

LOC-A1 ROC-A1 F4-A1 C4-A1 O2-A1

Figure 13.30  Sleep rhythms encountered on an electroencephalogram (EEG). Note that although all slow waves are in the delta frequency range, not all delta waves are slow waves. (Modified from Vaughn BV, Giallanza P. Technical review of polysomnography. Chest. 2008;134[6]:1310–1319.)

Inh

ibit

Melatonin synthesis

Light/dark cycle

Pineal gland

Serum melatonin level

SCN

ion

tion ula Stim

Time duration (24 h)

Sleep regulation 16:00

20:00

00:00

Clock time 04:00 08:00

AANAT & HIOMT - Light regulation of two key enzymes involved in the biosynthetic pathway of melatonin Room light (< 200 lux) Constant light (< 3 lux) Light at night Light pollution

12:00

16:00

Circadian regulation

Normal entrained rhythm ASPS DSPS

Suppresses melatonin

Sleep disturbances

Non-24-hour sleep wake disorder (N24SWD) Jet lag disorder (JLD)

Traveling to a different Time zone

Circadian dysregulation

Shift work disorder

AANAT - Aralkylamine N-acetyltransferase HIOMT - Hydroxyindole-O-methyl transferase

Irregular sleep-wake rhythm disorder (ISWRD)

Figure 13.31  The circadian rhythm of melatonin secretion and its involvement in sleep regulation. Light exposure promotes wakefulness by stimulating the

suprachiasmatic nucleus (SCN), while darkness promotes melatonin synthesis in the pineal gland. Generally, indoor room light (,500 lux) leads to melatonin suppression and phase-shift responses. Various types of circadian rhythm sleep disorders are shown in the actigraphy recordings and are highlighted in purple. ASPS, Advanced sleep phase syndrome; DSPS, delayed sleep phase syndrome. (From Pandi-Perumal SR, Cardinali DP, Zaki NFW, et al. Timing is everything: circadian rhythms and their role in the control of sleep. Front Neuroendocrinol. 2022;66:100978.)

106  Normal Sleep in Humans

R 25% N1 5%

N3 15%

R N1 N2 W N3

W 5% N2 45–55%

Figure 13.32  Proportion of the night spent in the various sleep stages in adults. Wakefulness (W) in sleep usually makes up less than 5% of the night. Stage N1

A

EEG slow-wave activity (%)

sleep generally makes up 2% to 5% of sleep; stage N2 makes up 45% to 55%; and stage N3 makes up 3% to 15%. Non–rapid eye movement sleep is therefore usually 75% to 80% of sleep. Stage R sleep is usually 20% to 25% of sleep and occurs in three to six discrete episodes.

150

6

14 Wakefulness

Corresponding time of day 22 6 14 Sleep

22

6

Wakefulness

100 50

Homeostatic sleep pressure

Sleep latency (min)

20.0

3.0 Circadian drive for wakefulness

C

Wakefulness in sleep (%)

B 20

0

E

0 1

Body temperature (C)

D

Plasma melatonin (z-scores)

1

37.0

36.5 0

120

240 0 120 240 0 Circadian phase (degrees) Figure 13.33  Circadian and homeostatic regulation of sleep and wakefulness in humans. A, Increase of homeostatic sleep pressure during wakefulness and its dissipation during sleep as reflected in electroencephalographic (EEG) slow-wave activity during daytime naps and nocturnal sleep. Circadian variation in wake-sleep propensity as reflected in B, the latency to sleep onset after 18 hours, 40 minutes of wakefulness. C, Wakefulness in sleep opportunities, measured during forced desynchrony of the sleep-wake cycle. D, Endogenous circadian rhythms of melatonin. E, core body temperature. (A, Data from Dijk DJ, Beersma DGM, Daan S. EEG power density during nap sleep: reflection of an hourglass measuring the duration of prior wakefulness. J Biol Rhythms. 1987;2[3]:207–219. B–E, Data from Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol. 1999;516[Pt 2]:611–627.)

Atlas of Clinical Sleep Medicine   107

Figure 13.34  Normal sleep hypnogram. REM, rapid eye movement; NREM, non–rapid eye movement. (From Stores G. Aspects of parasomnias in childhood and adolescence. Arch Dis Child. 2009;94[1]:63–69.)

Stage

Stage

W

W

R

R

N1

N1

N2

N2

N3

N3 Slow-wave sleep most common first third of night

A

0

1

2

3

4 5 Hours in bed

Adults have less slow-wave sleep than children

6

7

8

B

0

1

2

3

4 5 Hours in bed

6

7

8

Stage W R N1 N2 N3 Older adults have little slow-wave sleep and many awakenings

4 5 6 7 8 Hours in bed Figure 13.35  Histograms showing the changes in sleep with aging. Shown are hypnogram recordings from a child (A), a young to middle-age adult (B), and an older adult (C). Slow-wave sleep is maximal in children and decreases with aging. It is minimal or absent in older adults. The same holds true for rapid eye movement sleep, which diminishes to a lesser extent and becomes more fragmented with aging. Older adults also have prolonged sleep latency compared with younger subjects; in addition, arousals are more frequent, and sleep efficiency is reduced ([total sleep time/total recording time] 3 100).

C

0

1

2

3

108  Normal Sleep in Humans E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.36  Stage N3 in a child. This epoch is obtained from the record of a 10-year-old boy. Notice the very high amplitude of the slow waves.

E2-M1 E1-M2 F4-M1

30s

C4-M1 02-M1

F3-M2 C3-M2 01-M2 Chin1

Figure 13.37  Stage R in the same patient in Figure 13.36. The overall pattern is similar to this stage in an adult.

Table 13.6  Factors that Affect Sleep Factor Medical diseases Neurologic diseases Psychiatric diseases Sleep disorders Medications Habits Lifestyle

Examples Heart failure, chronic obstructive pulmonary disease, endocrine disorders, diabetes Stroke, epilepsy Depression, schizophrenia Sleep apnea, narcolepsy, restless leg syndrome Antidepressants Alcohol, caffeine Voluntary sleep restriction, shift work

Minutes 600 500

Sleep latency

400

WASO REM

300

Stage N3

200 Stage N2 100

Stage N1

0 35 45 85 55 65 75 Age (y) Figure 13.38  ​Changes in sleep stages with age. REM, Rapid eye movement; WASO, wake after sleep onset. (Modified from Ohayon M, Carskadon MA, Guilleminault C, Vitiello MV. 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[7]:1255–1273.) 5

10

15

25

Atlas of Clinical Sleep Medicine   109

Figure 13.39  Representation of sleep architecture changes across age and sex. Top row, Sleep efficiency, sleep latency. Bottom row, Minutes in each stage. The graphs depict the uncertainty in predictions. Regression parameters are randomly sampled 100 times from each model’s joint parameter distribution, and each is used to plot a regression line. REM, Rapid eye movement sleep; SWS, slow-wave sleep; WASO, wake after sleep onset. (From Yelton BD, McDevitt EA, Cellini N, et al. Quantifying sleep architecture dynamics and individual differences using big data and Bayesian networks. PLOS One. 2018;13[4]:e0194604.)

110  Normal Sleep in Humans Sleep changes with aging

NON-REM AWAKE

NON-REM AWAKE

NON-REM

AWAKE

REM REM

REM

Old age

Adulthood Infancy

Figure 13.40  Sleep changes with aging. As we age, our brain waves change, and we tend to experience less deep sleep. Less time is spent in stage N3, but periods of N1 and N2 sleep may be longer. In fact, N1 sleep can increase as much as 8% to 15%. Most studies also demonstrate an overall decline in rapid eye movement (REM) sleep. The change in sleep architecture that occurs is associated with aging, but the disruptions in sleep are likely a result of the impact of medical or psychiatric conditions. In infants, REM sleep represents a larger percentage of total sleep at the expense of stage N3. Newborns transition from wakefulness into REM sleep until they are 3 or 4 months of age, after which time wakefulness begins to transition directly into non–rapid eye movement (NREM) sleep. In mature adults, sleeping 8 to 8.4 hours is considered fully restorative. In some cultures, total sleep may be divided into an overnight period of 6 to 7 hours and a midafternoon nap of 1 to 2 hours. N1 sleep usually accounts for 5% to 10% of total sleep time, whereas N2 sleep represents 40% to 50% of total sleep time. N3 occurs mostly in the first third of the night and represents up to 20% of total sleep time. REM represents 20% to 25% of total sleep time. In old age, there is an overall decrease in total sleep time compared with young adults. Stage N3 sleep decreases by 10% to 15% or more, and N2 sleep increases by 5%. Sleep latency and the number and duration of overnight arousal periods also increase. (Data from National Sleep Foundation; 2003.)

HUMAN SLEEP AND AGE 24 Hours in day

Awake

Younger

Older Awake

16

REM sleep

REM sleep

Deep sleep

8

700

NREM sleep

11 PM to 6 AM

11 PM to 6 AM

1 Conception

0 Birth

1 Age (y)

10

20

100 Death

Figure 13.41  Human sleep and age. The marked preponderance of rapid

eye movement (REM) sleep in the last trimester of pregnancy and the first year of life decreases progressively as waking time increases. Note that non–rapid eye movement (NREM) sleep time, such as waking time, increases after birth. Despite its early decline, REM sleep continues to occupy approximately 1.5 hours per day throughout life. This suggests that its strongest developmental contribution is to early brain-mind development, but that it subsequently plays an equally indispensable part in brain-mind maintenance. (From Roffwarg HP, Muzio JN, Dement WC. Ontogenetic development of the human sleep-dream cycle. Science. 1966;152[3722]:604–619.).

Total sleep (min)

600

0

500

Total time in bed

400

NREM stage N1 REM

300 200

NREM stage N2

100

NREM—SWS 10

20

30

40 50 Age (y)

60

70

80

Figure 13.42  Age-related changes in sleep architecture. The most dramatic

changes include a reduction in slow-wave sleep (delta sleep) and rapid eye movement (REM) sleep and an increase in stage N1 and N2 sleep. Sleep efficiency and sleep continuity also decrease (evidence level C). NREM, non–rapid eye movement sleep; SWS, slow-wave sleep. (Modified from Timby BK. Fundamental Nursing Skills and Concepts. 8th ed. Philadelphia, 2001, Lippincott Williams & Wilkins; 2001; Williams RL, Karacan I, Hursch CJ. EEG of Human Sleep: Clinical Applications. New York: Wiley & Sons; 1974.)

Atlas of Clinical Sleep Medicine   111 0

50

100

Age [days]

150

200

250

300

350

Figure 13.43  Actigram data demonstrating rest/activity in representative

400

5

11

17

22

5

Time of day [h]

infants.  Dark bars represent activity; the same activity scale is used in each plot. In infants exposed to dim lighting, day/night differences in rest/activity patterns in synchrony with the light/dark cycle are generally not apparent until about 20 days after discharge from the hospital. ( From Jenni OG, Carskadon MA. Sleep behavior and sleep regulation from infancy through adolescence: normative aspects. Sleep Med Clin. 2007; 2[3]:321–329.)

Tracé alternant

Frontal sharp wave transients Occipital dominant alpha rhythm

Temporal alpha bursts Temporal theta bursts

Vertex transients

Beta delta complexes

26

28

30

32

34

Sleep spindles

36

38 40 42 44 Conceptional age (weeks)

46

48

50

52

54

Figure 13.44  Maturation of the electroencephalogram. Development, appearance, and disappearance of electroencephalographic landmarks from prematurity to 3 months postterm. Sleep spindles and vertex transients generally appear at around 48 weeks of conception. (From Hrachovy RA. Development of normal EEG. In: Levin KH, Luders HO, eds. Comprehensive Clinical Neurophysiology. Philadelphia: WB Saunders; 2000:387–413.)

112  Normal Sleep in Humans Asynchronous

Synchronous

REM Awake NREM 27-28

29-30 31-33 34-35 36-37 38-40 Conceptional age (weeks) Figure 13.45  ​Maturation and consolidation of neonatal sleep. NREM, Non-REM sleep; REM, rapid eye movement [sleep]. (From Hrachovy RA. Development of normal EEG. In: Levin KH, Luders HO, eds. Comprehensive Clinical Neurophysiology. Philadelphia: WB Saunders; 2000:387–413.) Sleep duration from age 0 to 12 24 22 20 18 16 14

10

0

Infant

Toddler

12 years

11 years

10 years

9 years

8 years

7 years

6 years

4–5 years

2–3 years

1–2 years

12 months

2

9 months

4

6 months

6

3 months

8 0–2 months

Hours

12

Child

Figure 13.46  Sleep duration during the first 12 years of life. Plot of sleep duration data from age 0 to 12 years. Data are presented as the mean 6 1.96 standard

deviation. (From Galland BC, Taylor BJ, Elder DE, Herbinson P. Normal sleep patterns in infants and children: a systematic review of observational studies. Sleep Med Rev. 2012;16[3]:213–222.)

A

B

Figure 13.47  Total and nighttime sleep duration during the first 15 years of life. Data from percentiles of total (A) and nighttime (B) sleep duration (time in

bed) per 24 hours in 493 healthy children studied longitudinally from 1 month to 16 years of age (Zurich Longitudinal Studies). Nighttime sleep duration is relatively stable across the early childhood years, as total sleep falls when children drop their daytime naps. After the first year, the dropping of naps from two to one per day and then no routine napping by about 4 years of age is a common feature of sleep development for Western children. Racial/cultural differences in this pattern, with naps sustained further into childhood in African Americans, have been reported (Crosby et al., 2005). (Modified from Iglowstein I, Jenni OG, Molinari L, Largo RH. Sleep duration from infancy to adolescence: reference values and generational trends. Pediatrics. 2003;11[2]:302–307.)

Atlas of Clinical Sleep Medicine   113 Sleepy– go to bed

Sleep

Wake up

Newborn infant

Standard phase

1 year old Not sleepy– stay up late

4 years old 10 years old

Delayed sleep phase

Adult 6 PM

6 PM

Wake up

Midnight

6 AM Noon 6 PM Time of day Figure 13.48  Maturation of sleep from infancy to adulthood. Polyphasic sleep following birth changes first to biphasic sleep among preschool children and then later to monophasic sleep. Among older adults, periods of sleep during the day become more frequent again. As a child develops, sleep gradually becomes more consolidated and restricted to take place at nighttime. The newborn sleeps about 16 to 18 hours per day, and sleep is widely distributed around the 24-hour day. By 16 weeks of age, the total amount of sleep drops to about 14 to 15 hours per day, and a clear diurnal pattern emerges. A further gradual decline to about 10 to 12 hours occurs between 3 and 5 years of age. By 10 years of age, sleep amounts of 10 hours or less are reported; sleep duration continues to decrease across adolescence until the adult pattern is reached. (From the Sleep Society Sleep Syllabus. Available at: http://www.sleephomepages.org/sleepsyllabus/fr-c.html and http://www. sleepsources.org/uploads/sleepsyllabus/a.html. Copyright 1997 WebSciences International and Sleep Research Society [United States].)

9 PM

12 AM

3 AM 6 AM 9 AM Noon Time of day Figure 13.50  ​Delayed sleep-phase pattern in adolescents. (Modified from Ancoli-Israel, S. All I Want Is a Good Night’s Sleep. St Louis: Mosby–Year Book; 1996.)

related to vision, and environmental changes, as shown in Figure 13.51. Figure 13.52 shows the changes in sleep that are frequently seen in older adults. The corresponding changes in sleep structure that occur with healthy aging are depicted in Table 13.7 and are independent of medical conditions or medications. General observations reveal curtailment in deep NREM sleep, more frequent awakenings from sleep, and increased time spent awake in bed (Fig. 13.53; see Figs. 13.41 to 13.43). Such sleep disturbances may be exacerbated by agerelated comorbidities such as pain, cardiovascular disease,

Adolescent development and sleep: the perfect storm Sleep timing

Preadolescence Circadian phase delay

A d o l e s c e n c e

Slowed rise of sleep pressure

Bioregulatory pressure  delay Psychosocial pressure  delay Bedtime autonomy

Academic pressure

Screen time & social networking

Societal pressure  early rise School start time Late to bed, early to rise ≥ short sleep

Figure 13.49  Sleep in adolescence. Sleep timing from preadolescence through adolescent development, depicting the key factors that affect sleep in adolescence.

Sleep timing is long and timed at an early hour for preadolescents. Maturational changes as a result of the circadian phase delay that arise from the circadian timing system along with the slowed rise of sleep pressure originating from sleep-wake homeostasis force a delay of the timing of sleep. In addition, psychosocial factors such as self-selected bedtimes, the impact of academic pressures on sleep, and the proliferation of use of technology and social networking in the evening also contribute to and push for a delay in the timing of sleep even further. Unfortunately, societal pressures that require for an even earlier rise time—specifically, pushing for an early start to the school day—are the forces that influence the curtailment of time available for sleep. As a result, adolescents whose sleep time is too short are asked to be awake at an inappropriate circadian phase, worsening the total sleep deprivation. (From Carskadon MA. Sleep in adolescents: the perfect storm. Pediatr Clin North Am. 2011;58[3]:637–647.)

114  Normal Sleep in Humans Changes with age: sleep efficiency

Table 13.7  Variables That Increase or Decrease Sleep with Age

100

Increase

Percent

90

Sleep latency Arousals, awakenings, stage shifts Stages N1, N2 Napping Resistance to sleepiness, sleep deprivation Phase advancement

80 70 60

Men Women

70 40 50 60 Age Figure 13.51  Sleep efficiency with aging. As a result of physiologic, hormonal, and environmental changes, older adults tend to sleep less efficiently. Although they may be in bed 8 hours, at 55 years of age and older, both men and women may be in actual sleep for just 7 hours or less. Frequent disruptions and poor sleep rob the older person of the continuous sleep necessary to experience the deeper stages of sleep and reap their benefits. (Modified from Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. 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[7]:1255–1273.) 10

20

Decrease

30

psychiatric conditions, nocturia (especially in the setting of prostate disease or Parkinson disease), and sleep disorders such as sleep apnea and movement disorders of sleep. Estimates reveal that between 40% and 70% of older adults have chronic sleep problems, and up to 50% of the cases are undiagnosed or untreated by primary care physicians. Unfortunately, these sleep problems become more significant in geriatric patients

Rapid eye movement sleep Sleep efficiency Slow-wave sleep (worse in men) Slow-wave sleep amplitude

with dementia. Aging is also associated with some predictable changes in circadian physiology. Aging is accompanied by a reduction in the amount of time spent in SWS and an increase in lighter levels of sleep at the expense of reduced sleep efficiency (Fig. 13.54). The proportion of REM sleep is generally preserved, but the latency to the first REM period decreases, and the overall amount of REM sleep may decrease as a result of an overall reduction in nocturnal sleep time. Older adults also take longer to initiate sleep and have a reduced total sleep time, frequent awakenings, and early morning awakenings, and they are more likely to nap. The prevalence of napping in older adults ranges from 25% to 80%. Studies that have used the multiple sleep latency test to assess the extent of daytime sleepiness in older adults have shown that, given the opportunity, older adults tend to fall asleep during the day faster than younger patients. This daytime sleepiness suggests that older adults may not be getting sufficient sleep at night. This is interpreted to mean that

Suprachiasmatic nucleus

Pineal gland

Sun/ambient light exposure Retina-macula Lens

Retino-hypothalamic tract SCN

Excessive noise Inappropriate light exposure Cataracts

Macular degeneration

Melatonin level

Decreased light exposure Underlying Sleep Disorders: OSA, RLS, PLMD and Psychiatric Disorders

Figure 13.52  Sleep in older adults. Older adults are affected by underlying problems. Medical, psychiatric, and sleep disorders can cause arousal and disrupt

sleep. In addition, changes in the visual system (green boxes) and changes in light exposure and other environmental factors can result in circadian rhythm changes (purple boxes). OSA, Obstructive sleep apnea; PLMD, periodic leg movement disorder; RLS, restless legs syndrome. (From Avidan AY. Sleep in dementia and other neurodegenerative disorders. In: Culebras A, ed. Sleep Disorders and Neurologic Diseases, 2nd ed. New York: Taylor & Francis Group; 2007.)

Atlas of Clinical Sleep Medicine   115

More likely to develop sleep disorders

May take longer to initiate sleep

Circadian rhythm may advance, leading to early sleep and early awakening

Overall reduction in nocturnal sleep time

Increased need to nap during the day

ALTERATIONS IN SLEEP WITH AGING

Amount of REM sleep may also decrease

Latency to the first REM period tends to decrease

Sleep fragmentation

Decreased sleep efficiency

Reduction in the amount of SWS

More time in the lighter stages of sleep

Decrement in the amplitude of the low-frequency waves in SWS

Figure 13.53  Aging and sleep. A variety of medical, sleep-related, and psychosocial factors cause older adults to experience sleep disruption. REM, rapid eye movement; SWS, slow-wave sleep.

the need for sleep in older adults is not reduced, but rather that the ability to sleep is changed. When assessing the sex differences in the sleep of healthy older adult patients, data reveal that women fall asleep more easily and maintain sleep better than men. Recent studies to evaluate the effects of menopause on sleep have found associated subjective reports of insomnia. Menopause, when assessed objectively, was found to prolong sleep latency, reduce REM sleep, and reduce total sleep time.

• Women show relatively stable levels of SWS until the time of menopause, at which time an age-related decline is reported. • SWS in men is reported to be significantly lower than that of women throughout the life span. • The percentage of stage N2 sleep is reported to be increased in older adults. • The frequency and duration of nocturnal awakenings are increased in older adults. • REM sleep changes with age are less consistent.

SLEEP CHARACTERISTICS THAT CHANGE WITH AGE AND THEIR POSSIBLE NEUROPHYSIOLOGIC MECHANISMS

CIRCADIAN CHARACTERISTICS THAT CHANGE WITH AGE

Age-associated changes in sleep EEG include the following findings: • SWS and total sleep time are reduced (see Fig. 13.39). • Wake after sleep onset increases. • The number and duration of arousals increase. • Time spent in SWS declines. • Sleep efficiency declines. • Men show larger reductions in SWS across all ages.

Age-related changes in the circadian system have been reported to include an advance in circadian timing (see Fig. 13.54) and a reduction in circadian amplitude (Fig. 13.55). These changes may be related to changes in the master circadian clock in the SCN and/or to changes in input and output pathways of the SCN. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

116  Normal Sleep in Humans

Sleepy– go to bed

Wake up Standard phase

Sleepy–go to bed early

Wake up Advanced phase

6 PM

9 PM

12 AM

3 AM 6 AM Time of day

9 AM

Noon

Figure 13.54  ​Advanced sleep-phase syndrome. (Modified from Ancoli-Israel, S. All I Want Is a Good Night’s Sleep. St Louis: Mosby–Year Book; 1996.)

Sleeptiming, Circadian Changes, & Melatonin Rhythm in Older Adults and Young Adults Reduced circadian amplitude Awakening at an earlier circadian time closer to melatonin midpoint

Earlier clock hour for circadian melatonin phase

Advanced sleep onset and wake time. Shorter sleep duration. Figure 13.55  Sleep timing and circadian changes in older adults.  Part of the explanation of the tendency toward advancement of the circadian rhythms in

older adults is a result of underlying changes in circadian physiology. Circadian melatonin rhythm and sleep timing for young adults (black solid line, box) and older adults (red line, open box) are shown. Older adults generally show reduced circadian amplitude and earlier timing of sleep and circadian phase compared with young adults. Older adults also awaken at an earlier biologic time such that waking time occurs closer to the melatonin maximum. (From Wright KP, Frey DJ. Age-related changes in sleep and circadian physiology: from brain mechanisms to sleep behavior. In: Avidan AY, Alessi C, eds. Geriatric Sleep Medicine. New York: Informa Healthcare; 2008.)

  e1 Bibliography

Berry RB, Quan SF, Abreu AR, et al. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Ver. 2.6. Darien, IL: American Academy of Sleep Medicine; 2020. Blumberg MS, Dooley JC, Tiriac A. Sleep, plasticity, and sensory neurodevelopment. Neuron. 2022;110(20):3230–3242. Frank MG, Cantera R. Sleep, clocks, and synaptic plasticity. Trends Neurosci. 2014;37(9):491–501. Hirshkowitz MK, Whiton SM, Albert C, et al. National Sleep Foundation’s updated sleep duration recommendations: final report. Sleep Health. 2015; 1(4):233–243. Holst SC, Landolt HP. Sleep-Wake Neurochemistry. Sleep Med Clin. 2022;17(2):151–160. Jacobson LH, Hoyer D, de Lecea L. Hypocretins (orexins): the ultimate translational neuropeptides. J Intern Med. 2022;291(5):533–556.

Jaggard JB, Wang GX, Mourrain P. Non-REM and REM/paradoxical sleep dynamics across phylogeny. Curr Opin Neurobiol. 2021;71:44–51. Pizza F, Barateau L, Dauvilliers Y, Plazzi G. The orexin story, sleep and sleep disturbances. J Sleep Res. 2022;31(4):e13665. Rasmussen MK, Mestre H, Nedergaard M. Fluid transport in the brain. Physiol Rev. 2022;102(2):1025–1151. Saelee R, Haardörfer R, Johnson DA, Gazmararian JA, Suglia SF. Racial/ ethnic and sex/gender differences in sleep duration trajectories from adolescence to adulthood in a US national sample. Am J Epidemiol. 2022;kwac156. Siegel JM. Sleep function: an evolutionary perspective. Lancet Neurol. 2022;21(10):937–946. Tekieh T, Robinson PA, Postnova S. Cortical waste clearance in normal and restricted sleep with potential runaway tau buildup in Alzheimer’s disease. Sci Rep. 2022;12(1):13740.

Chapter

14

Sleep Restriction Andrea M. Spaeth, Christopher W. Jones, Marc Kaizi-Lutu, Takashi Abe, and David F. Dinges

SLEEP RESTRICTION

the workplace and accidents (Fig. 14.5). Sleep loss resulting from chronic sleep restriction also impairs memory function (i.e., working memory, encoding and consolidation), disturbs mood, increases anxiety, and heightens physiologic reactivity to stressful situations (Fig 14.6).

A

50 0 50 100 45 cm H2O

FVC < 50%

MIP < –60 cm H2O

Overnight oximetry < 88% for 5 minutes or longer

Step 3 - Initiate NIV based on Steps 1 and 2

Option1: PAP titration in the sleep laboratory using NIV

Option 2: Volume-assured pressure support (VAPS) initiation

Step 4 - Prescribe NIV and monitor longitudinally in clinic; download data analysis to meet the physiologic needs of the patient Patient-triggered breaths percentage is high (indicates high work of breathing • Systematically address if set tidal volumes or respiratory rates are set inadequately to meet patient’s needs

Hours of compliance are low • Systematically address mask interface, sialorrhea, synchrony with backup support, and assessment of pressure delivered

Figure 27.12  ​Initiation and longitudinal management of noninvasive ventilation for neuromuscular disease. FVC, Forced vital capacity; MIP, maximal inspiratory pressure; PAP, positive airway pressure.

any of the following four guidelines: (1) FVC less than 50% of predicted, (2) MIP of 60 cm H2O or less, (3) Paco2 45 mm Hg, or (4) overnight oxygen desaturation less than 88% for at least 5 minutes. Importantly, there are no sleep apnea diagnosis codes or thresholds for including the AHI to qualify for initiation of NIV, which is often confusing to many sleep-trained clinicians (Fig. 27.12). NONINVASIVE VENTILATION BENEFITS IN NEUROMUSCULAR DISEASE: PHYSIOLOGY AND SLEEP Proper initiation of NIV is essential to provide ventilatory support to patients with NMD and has been proven to improve quality of life, reduce morbidity from unnecessary

tracheostomy, and reduce mortality. NIV effectively provides respiratory muscle rest to reduce work of breathing, relieves dyspnea symptoms exacerbated during sleep, and improves sleep quality. Ideally, utilizing a respiratory assist device such as bilevel PAP with a backup rate (BPAP-ST) or volumeassured pressure support (VAPS) is ideal to optimize pressure settings. According to the American Academy of Sleep Medicine (AASM) Task Force on Best Clinical Practices, NIV titration is preferentially performed in a sleep laboratory to allow for observation of airflow, mask leakage, tidal volume, and respiratory rate along with exhaled or transcutaneous carbon dioxide monitoring. In addition, successful NIV titration requires experienced technologists who can be attentive to patient comfort, including claustrophobia, optimal interface/mask fitting, need for addition of supplemental oxygen, and balancing patient-device synchrony to consolidate sleep

Atlas of Clinical Sleep Medicine   281 Box 27.3  Goals in NIV Titration for Patients With Neuromuscular Disease • Monitoring of tidal volume, respiratory rate, and minute ventilation • Monitoring of oxygenation and carbon dioxide values • Use of EMG: monitor accessory muscle usage and work of breathing • Goals of increasing tidal volumes (8 mL/kg), decreasing respiratory rate, and decreasing EMG muscle tone • Ideally, use settings of a high IPAP, low EPAP, and backup rate that matches the patient’s respiratory rate. The following is an example prescription: • IPAP 5 16 cm H2O • EPAP 5 4 cm H2O • Backup rate 5 14 breaths/min • Inspiratory time 5 1.5 seconds • Patient comfort, attention to mask comfort EMG, Electromyography; EPAP, expiratory positive airway pressure; IPAP, inspiratory positive airway pressure; NIV, noninvasive ventilation.

architecture and work of breathing. There is no “cookbook” manner; technologists and clinicians should combine their experience and judgment with the application of these recommendations to attain the best possible titration for any given patient (Box 27.3). In addition, recording respiratory muscle EMG activity is recommended in titration of NIV in patients with NMD. Bipolar electrodes placed over the seventh to eighth intercostal space, 2 cm apart horizontally in the right anterior axillary line (to reduce electrocardiogram artifact), function as surface diaphragm electrodes. Alternatively, sternocleidomastoid

electrodes and right parasternal intercostal muscle electrodes placed in the second and third intercostal spaces in the midclavicular line can monitor accessory muscle EMG activity. EMG activity in the intercostal muscles during NREM sleep may increase as the respiratory rate decreases, suggesting increased upper airway resistance or obstruction, which may lead to arousals, hypopneas, or apneas. In NMD patients, hypoxemia can be particularly prolonged. Respiratory muscle compromise can cause sleep apnea or sleep-related hypoventilation/hypoxemia, which usually worsens during REM sleep if it is achieved. According to the AASM Best Clinical Practice guidelines mentioned earlier, this allows titration to adequate noninvasive positive pressure ventilation support for muscle rest and ensures reduction in inspiratory EMG activity of the respiratory muscles during NREM sleep. Most studies initiate patients on low pressure settings of 8/4 cm H2O with a backup rate of 12 cm H2O and gradually increase inspiratory PAP to augment ventilation to achieve reduction in accessory muscle work, then increase the backup rate to match the patient’s respiratory needs (Fig. 27.13). Proper PSG also allows detection of poor thoracic movement during machine-delivered breaths, a pattern that may be important for titration in patients with glottic closure to prevent excessive ventilation (Fig. 27.14). PSG should ideally occur in an AASM-accredited sleep center or laboratory with a trained registered technologist or sleep-trained respiratory therapist. Consistency in laboratory protocols is essential to successfully titrating a patient in the sleep center. Clinical staff should focus on goals of optimizing ventilatory support, augmenting tidal volume to address hypoxia, reducing work of breathing, and optimizing patient/ ventilation synchrony. To facilitate comfort and therefore successful titration, the following accommodations could be made available: hospital bed, Hoyer lift, suction, call system

Figure 27.13  ​A patient with neuromuscular disease on noninvasive ventilation during a positive airway pressure (PAP) titration study in the sleep laboratory

utilizing sternocleidomastoid electromyography (EMG) to optimize settings. Suboptimal bilevel PAP settings of inspiratory PAP 8, expiratory PAP 4, and pressure support of 4 cm H2O are shown (left). Although the PAP flow signal and oxygenation appear adequate, the increased sternocleidomastoid EMG (blue box) muscle tone in this 30-second epoch indicates inadequate ventilatory support. In addition, respiratory rate is elevated at 16 breaths/min along with shallow breathing. Optimal bilevel PAP spontaneous timed pressures of inspiratory PAP 15, expiratory PAP 5, and pressure support of 10 cm H2O are shown (right), as indicated by reduced EMG muscle tone (red box). The sternocleidomastoid (STER) EMG tone is markedly reduced, indicating optimal rest of accessory muscles of breathing. The respiratory rate is reduced to 10 breaths/min, indicating improved minute ventilation.

282  Sleep and Neuromuscular Disease

Figure 27.14  ​Patient with bulbar-predominant amyotrophic lateral sclerosis demonstrating glottic closure, indicated by an absent thorax and abdomen excursion during device-delivered breaths (red box). Glottic closure is associated with hyperventilation and low carbon dioxide levels and may be ameliorated by lowering either pressure support or backup rate or by increasing expiratory positive airway pressure.

Box 27.4  Essential Accommodations and Supplies for a Successful Noninvasive Ventilation Sleep Study Accommodations for caregiver Access to a suction device Call button for patient to notify the technologist Emergency cardiorespiratory policies Hospital bed Hoyer lift Protocolized care focused on optimizing ventilatory support Technical expertise (experienced technologists)

for the patient, accommodations for a caregiver, emergency cardiorespiratory procedures, and technical expertise (Box 27.4). LONGITUDINAL MANAGEMENT OF NONINVASIVE VENTILATION IN NEUROMUSCULAR DISEASE Optimizing management of the underlying neuromuscular condition often requires multidisciplinary support. Follow-up of ventilation use, particularly in progressive NMD, can be

difficult and retitration is rarely feasible, particularly in rapidly progressive disease. Therefore, meticulous review of available download data from the NIV may be useful in making adjustments to address utilization patterns, address barriers to NIV use, and evaluate ventilatory parameters relevant to goals of reducing the patient’s work of breathing (Table 27.2; Fig. 27.15). VAPS devices allow for programming target tidal volumes based on patient height and can deliver a variety of inspiratory pressures to achieve the volume goal. In NMD patients, this strategy allows for efficient initiation of NIV without reliance on a sleep laboratory to identify optimal pressure needs. Careful attention to the following variables on the download confirms optimal settings to ensure adequate rest of respiratory muscles: average exhaled tidal volumes, average breath rate, percent of patient-triggered breaths (ideally should be low, indicating less need for respiratory drive to initiate breaths), and average hours of usage (Fig. 27.16). CONCLUSION Understanding pathophysiologic respiratory dysfunction in NMD allows for an appreciation of the benefits of respiratory support with NIV to optimize morbidity and mortality in

Atlas of Clinical Sleep Medicine   283 Table 27.2  Data Obtained From a PAP Download, Potential Problems, and Potential Solutions Data AHI is elevated

Leak is elevated

Usage is increased

Potential Problem • • • • • • • • •

% Patient triggered breaths is increased Tidal volumes are low

• • • •

Pressure averages (usually on VAPS settings)

• •

Potential Solutions

Central apneas Apneas caused by glottis closures from high pressures Central hypopneas from insufficient pressure support Ineffective trigger/trigger dyssynchrony Neck extensor weakness obstructing upper airway Daytime use Variable interface use Progressive bulbar weakness Progressive disability and weakness, needing more respiratory support in daytime Inadequate ventilatory support Increasing disability Increasing disability Decreasing chest wall compliance (consider infection, pleural effusion, pneumothorax, or abdominal pathology) Increasing disability Decreasing chest wall compliance (consider infection, pleural effusion, pneumothorax, or abdominal pathology)

• • • • • • •

Increase backup rate Reduce pressures Increase pressure support Change trigger sensitivity Obtain a neck stability brace Mask/interface adjustments Chin strap

•

Patient may require daytime ventilation

•

Consider increasing backup rate, inspiratory pressure, or inspiratory time Consider increasing backup rate, inspiratory pressure, or inspiratory time Further clinical evaluation Increase lower limit of pressure support range, increase inspiratory time, or increase upper limit of pressure

• • •

AHI, Apnea-hypopnea index; PAP, positive airway pressure; VAPS, volume-assured pressure support.

IPAP

EPAP Breaths per minute Patient-triggered breaths Peak flow Leak Vte Ti/Ttot

Minute ventilation

Max Min Avg Max Min Avg Max Min Avg Max Min Avg Max Min Avg Max Min Avg Max Min Avg Max Min Avg Max Min Avg

04/07 2020

Apnea count

05/07 2020

24.33 20.74 23.52 9.12 8.27 8.99 22 9 13.11 100 0 7.2 75.6 11.4 36.77 63.2 32.9 40.32 1131 105 518.03 48 17 22.54 18.5 2 6.78 0

24.6 20.6 23.53 9.09 8.1 8.98 39 11 13.17 100 0 9.23 91.5 12.2 36.25 66.5 31.7 40.71 1465 115 512.51 50 18 22.95 30.6 1.7 6.75 0

06/06 2020 24.76 20.46 23.54 10.15 8.44 8.98 35 10 13.22 100 0 10.58 103 12.7 36.76 71.8 28.2 38.71 1392 143 522.65 52 19 23.2 29.5 2.2 6.92 0

07/06 2020 24.02 20.67 23.51 9.05 8.22 8.98 23 10 13.13 100 0 8.49 60.7 15 34.14 40.6 29.7 32.76 927 205 488.41 44 19 22.75 15 3.3 6.43 0

Figure 27.15  ​Case example of effective noninvasive ventilation in a 40-year-old man with amyotrophic lateral sclerosis with preserved bulbar muscle function.

The patient was on nocturnal noninvasive ventilation for 7 years with the following settings: inspiratory positive airway pressure (IPAP) of 24 cm H2O, expiratory PAP (EPAP) of 9 cm H2O, and backup rate 13 breaths/min. On these settings, the patient percent trigger is very low at a range of 7.2% to 10.58% (blue arrow), indicating favorable reduction in work of breathing to initiate breaths.

patients with NMD. We believe that sleep medicine–trained clinicians have expertise to favorably improve the quality and quantity of life for patients with NMD by leveraging knowledge in sleep architecture, PSG, NIV, and mask interfaces. Additionally, they can download compliance monitoring in a

unified effort to synchronize breathing and optimize sleep and quality of life in a comfortable and effective manner. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

Max Avg Min

Breath rate

Max Avg Min

Exhaled tidal volume

Max Avg Min

Total leak

Max Avg Min

Percent patienttriggered breaths

Max

Minute ventilation

Max

Avg Min Avg

12/1/2019

Min Attained IPAP pressure

11/1/2019

Avg

10/1/2019

Min Attained EPAP pressure Max

9/1/2019

Avg

8/1/2019

Max

7/1/2019

Min AHI

6/1/2019

284  Sleep and Neuromuscular Disease

0.2 3.5 1.9

0.3 7.3 1.8

0 5.5 1.2

0.1 5.7 1.6

0 4.8 1.5

0.2 3.8 1.4

0.1 3.8 1.4

5 5 5

5 5 5

5 5 5

5 5 5

5 5 5

4.9 5 5

5 5 5

16.6 17 17

16.9 17 17

16.9 17 17

17 17 17

16.9 17 17

16.6 17 17

17 17 17

13 15.5 13.5

13 13.8 13.2

13 14 13.3

13 14 13.4

13 14 13.1

13 14.3 13.3

13 13.6 13.3

466.3 675 555.3

453.7 685.7 549.7

466.2 698.8 574.9

513.8 465.1 691.7 734.3 587.2 582.3

437.8 663.8 570.4

437.1 624.7 546

21.8 38.3 28.2

25.4 37.4 29.8

26.8 37.7 31.1

24 40.7 31.4

22.6 46.4 31.8

21.4 40.3 28.9

25.5 37.8 29.7

2.7 56.7 11.4

2.2 16.2 6.7

2.8 23.6 9.1

3.8 21.5 9.2

3 18.4 5.9

3.1 32.6 9.6

3.4 16.2 9.3

7 9.8 8

6.3 10 7.8

6.6 10 8.2

7 10 8.3

6.5 10.6 8.2

6.3 9.3 8.1

6.4 8.5 7.7

Compliance summary Date range Percent days with device usage Average usage (all days) Average usage (Days used) Percent of days with usage >= 4 hours

6/19/2019 – 12/9/2019 (174 days) 99.4% 7 hrs. 20 mins. 54 secs. 7 hrs. 23 mins. 27 secs. 97.7%

Figure 27.16  ​Case example of favorable data obtained from a volume-assured pressure support download device (Respironics Trilogy ventilator; Philips Healthcare) for a patient with postpolio syndrome with restrictive lung disease and diaphragm muscle weakness. The patient was on noninvasive ventilation with the following settings: inspiratory positive airway pressure (IPAP) of 17 cm H2O, expiratory PAP (EPAP) of 5 cm H2O, and a backup rate set at 14 breaths/min. Favorable findings of muscle rest include (1) average exhaled tidal volumes of 546 to 587 mL; (2) average respiration rate of 13 breaths/min; (3) range of patient-triggered breaths of 6.7% to 11.4%, and more recently 9.3%, indicating adequate reduction in patient-triggered breaths; and (4) average usage of 7 hours and 20 minutes.

  e1 Bibliography

Aboussouan LS. Sleep-disordered breathing in neuromuscular disease. Am J Respir Crit Care Med. 2015;191(9):979–989. Aboussouan LS, Mireles-Cabodevila E. Sleep-disordered breathing in neuromuscular disease: diagnostic and therapeutic challenges. Chest. 2017;152(4):880–892. Benditt JO. Pathophysiology of neuromuscular respiratory diseases. Clin Chest Med. 2018;39(2):297–308. Benditt JO. Respiratory care of patients with neuromuscular disease. Respir Care. 2019;64(6):679–688. Berry RB, Chediak A, Brown LK, et al. Best clinical practices for the sleep center adjustment of noninvasive positive pressure ventilation (NPPV) in stable chronic alveolar hypoventilation syndromes. J Clin Sleep Med. 2010;6(5):491–509.

Bourke SC. Respiratory involvement in neuromuscular disease. Clin Med (Lond). 2014;14(1):72–75. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J. 2002;19(6):1194–1201. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006;5(2):140–147. McKim DA, Road J, Avendano M, et al. Home mechanical ventilation: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2011; 18(4):197–215. Selim BJ, Wolfe L, Coleman JM III, Dewan NA. Initiation of noninvasive ventilation for sleep related hypoventilation disorders: advanced modes and devices. Chest. 2018;153(1):251–265.

Section 10  | Parasomnias Chapter

28

Parasomnias Muna Irfan and Michael J. Howell

OVERVIEW Parasomnias are abnormal physical and experiential phenomena that arise from sleep. They can occur in various stages of sleep, such as rapid eye movement (REM) sleep, non-REM (NREM) sleep, or both. NREM parasomnias, which are manifested mainly as disorders of arousal such as sleepwalking, result from an incomplete dissociation of wakefulness from NREM sleep. Sleep-related eating disorder (SRED) is characterized by a disruption of the nocturnal fast with episodes of feeding after an arousal from sleep. NREM parasomnias are often associated with the use of sedative hypnotic medications, in particular the widely prescribed benzodiazepine receptor agonists (BRAs). Rapid eye movement sleep behavior disorder (RBD) is characterized by a loss of skeletal muscle paralysis during REM sleep that leads to potentially injurious dream enactment. The loss of REM atonia in RBD is often a cardinal finding in the development of a-synuclein neurodegenerative disorders such as Parkinson disease. Certain epilepsy syndromes may have motor seizures limited to the nocturnal period and thus can be confused with disorders of arousal and RBD. Other parasomnias include experiential phenomena, such as exploding head syndrome and sleeprelated hallucinations (Table 28.1; Box 28.1). PATHOPHYSIOLOGY OF PARASOMNIAS The underlying pathophysiology of parasomnias is based on the understanding that sleep and wakefulness are not

mutually exclusive states of being. As one falls asleep and advances through the various sleep stages, the stage shifts are not completely “on or off,” but rather involve interplay through complex neuronal pathways for an equivocal stage to declare itself. It is during this period of sleep-wake dissociation that a person can encounter an admixture of different states of being. They may overlap or intrude into one another and result in complex behaviors (Fig. 28.1). Another hypothesis is that central pattern generators (CPGs), as illustrated in Figure 28.2, lead to deafferentation of the locomotor centers from the generators of the different sleep states. Locomotor centers are present at both spinal and supraspinal levels, and this dissociation can explain motor activity or ambulation, especially in patients with disorders of arousal. DISORDERS OF AROUSAL: NREM PARASOMNIAS The NREM parasomnias include confusional arousals, sleepwalking, and sleep terrors and represent dissociated states of being. Brain regions that coordinate motor and visual function are wakeful, but those areas of the cortex that lead to executive function and memory linger in sleep. These disorders of arousal are common in children and occur 1% to 4% of adults, with most adults describing parasomnias persisting from childhood. The disorders of arousal vary across a spectrum of duration, autonomic activity, and arousal threshold. Confusional arousals are characterized by disoriented behavior limited to the sleeping

Table 28.1  Clinical Features Characteristics Age of onset Frequency Behaviors Time of sleep period Postevent confusion Associations

Disorders of Arousal (CA/SW/ST/SREDa) Usually childhood in CA, SW, ST; occurs in adulthood in SRED Range from nightly to less than once per year Confused, disoriented Usually in the first half of sleep Yes RLS (SW and SRED)

RBD Bimodal: toxic (young adult), idiopathic (middle-age or older adult) REM without atonia nightly; DEB most often nightly to monthly Dream enactment Usually in the second half of sleep Rare α-Synuclein disorders (Parkinson disease, multiplesystem atrophy, dementia with Lewy bodies)

Nocturnal Seizure Any Nightly with some cases of .20 per night Stereotyped, repetitive Any Yes Daytime epilepsy

a

SRED can be a disorder of arousal or a separate parasomnia. CA, Confusional arousal; DEB, dream-enactment behavior; RBD, rapid eye movement sleep behavior disorder; RLS, restless legs syndrome; SRED, sleep-related eating disorder; ST, sleep terrors; SW, sleepwalking.

285

286  Parasomnias Box 28.1  International Classification of Sleep Disorders III (ICSD-3) Parasomnia Classification NREM Parasomnias • Disorders of arousal • Confusional arousals • Sleep-related sexual behaviors • Sleepwalking • Sleep terrors • Sleep-related eating disorder REM Parasomnias • RBD • Recurrent isolated sleep paralysis • Nightmare disorder Other Parasomnias • Exploding head syndrome • Sleep-related hallucinations • Sleep enuresis • Parasomnia caused by a medical disorder • Parasomnia caused by a medication/substance • Parasomnia unspecified Normal Variants • Sleep talking RBD, Rapid eye movement sleep behavior disorder; REM, rapid eye movement; NREM, non–rapid eye movement.

Nocturnal spells: overlapping states • RBD • Hypnagogic hallucinations • Sleep paralysis

• Confusional arousals • Sleepwalking • Sleep terrors Sleep phenomena Wake REM

Seizures

NFLE

NREM Psychogenic spells

• Dissociative disorders • PTS

Figure 28.1  Overlapping states of being, as described by Mahowald and

Schenck. Parasomnias are explainable by the basic notion that sleep and wakefulness are not mutually exclusive states; these may dissociate and oscillate rapidly. The abnormal admixture of the three states of being—non–rapid eye movement (NREM) sleep, REM sleep, and wakefulness—may overlap and give rise to parasomnias. REM parasomnias occur as a result of the abnormal intrusion of wakefulness into REM sleep; likewise, NREM parasomnias, such as sleepwalking, occur because of abnormal intrusions of wakefulness into NREM sleep. Other nocturnal spells that may be confused with parasomnias include nocturnal frontal lobe epilepsy (NFLE) and psychogenic spells such as those associated with posttraumatic stress (PTS) and dissociated disorders. RBD, Rapid eye movement sleep behavior disorder. ( Modified from Mahowald MW, Schenck CH. Non–rapid eye movement sleep parasomnias. Neurol Clin. 2005;23[4]:1077–1106; and Avidan AY, Kaplish N. The parasomnias: epidemiology, clinical features, and diagnostic approach. Clin Chest Med. 2010;31[2]: 353–370.)

area with subsequent impaired recall of events (Figs. 28.3 and 28.4; Video 28.1). In adults, they can sometimes be triggered by a comorbid sleep disorder such as obstructive sleep apnea (OSA; Fig. 28.5). Sleepwalking is a combination of ambulation and impaired consciousness (Figs. 28.6 and 28.7). Sleep terrors usually occur in preadolescent children, involve episodes of intense fear initiated by a sudden loud vocalization, and are accompanied by precipitously increased autonomic nervous system activity (Figs. 28.8 to 28.10). Patients with sleep terrors are typically inconsolable. The major differences between sleep terrors and REM nightmares are shown in Table 28.2. Sexsomnia is also a subtype of disorder of arousal in which sexual behaviors occurs in partial arousal from NREM slowwave sleep. NREM parasomnia patients are often difficult to awaken during an event; if awakened, they are usually confused and disoriented and have amnesia for any mental activity preceding the arousal. Comorbid conditions that promote sleep inertia or fragmented sleep lead to incomplete cortical arousal. Phenomena that deepen sleep, such as sleep deprivation and sedative medications, promote NREM parasomnias by impairing arousal mechanisms (Clinical Case 28.1). Conditions that cause repeated cortical arousals, such as sleep-disordered breathing (see Fig. 28.5) or noise, lead to parasomnias through increased sleep fragmentation. The isolated activation of functional groups of motor neurons with a relative paucity of activity in brain regions that control executive function and memory account for the poor judgment and amnesia that characterize NREM parasomnias. NREM parasomnias are associated with the normal, alternating arousal microstructure of NREM sleep, the cyclic alternating pattern (CAP; Fig. 28.11). An increase in CAP rate, a biomarker for arousal instability, has been noted among sleepwalking patients (Fig. 28.12). Another parasomnia, SRED, is characterized by nocturnal episodes of dysfunctional eating after an arousal from sleep. SRED is similar in many respects to other disorders of arousal. Like sleepwalking, prolonged ambulation is common, and complications include weight gain and eating potentially dangerous substances. Polysomnography (PSG) in cases of SRED often demonstrates frequent periodic limb movements (PLMs) and rhythmic masticatory movements (i.e., chewing) during sleep and drowsy wakefulness (Fig. 28.13). Amnestic nocturnal eating can occasionally be documented during PSG when patients have readily available food at the bedside during their sleep study (Video 28.2). Prolonged disorders of arousal and SRED frequently emerge in the setting of the commonly prescribed BRAs, most notably zolpidem. Furthermore, the rise in prolonged complex amnestic behaviors in the previous 2 decades parallels the widespread use of BRAs. Intriguingly, many cases of BRA-induced parasomnias are noted to have comorbid restless legs syndrome (RLS), which can be easily misdiagnosed and treated as insomnia. RLS is characterized by an intrinsic motor restlessness that often interferes with sleep onset and is associated with other nocturnal urges, such as the urge to eat. Because BRAs disinhibit frontal and hippocampal function, it is not surprising that these agents unleash amnestic episodes of ambulation and binge eating (SRED) when prescribed to RLS patients with subconscious urges to ambulate and eat (Clinical Case 28.2).

Atlas of Clinical Sleep Medicine   287 Alimentary: bruxism, oral automatism

Epilepsy

Defensive/predatory: biting Emerging behavior

Emotional: facial expression, fear

Parasomnia

Locomotive: pedaling, fugue, cyclic leg movement Central pattern generators (CPGs)

Cerebral cortex Speech Leg/hand movement

Cerebellum

Basal ganglia

Spinal cord

Eating Protective reflexes Swallowing CPG Respiratory CPG Locomotor CPG Postural networks Chewing CPG Expression of emotions Saccadic motor map Reaching

Brainstem

Locomotion Selection sequence timing

Breathing Chewing Swallowing Eye movement

Figure 28.2  ​Along all levels of the neuraxis that stem from the brain to the upper brainstem and spinal cord, several neuronal networks exist that produce

different types of behavior (top) when activated. The networks are collectively referred to as central pattern generators (CPGs), depicted as the tan regions (bottom). The spectrum of resulting behaviors may be simple and stereotyped, such as rhythmic lip smacking and swallowing, to the more polymorphic and complex, such as those generating locomotion and search behaviors. The CPGs are thought to lead to monomorphic spells, which are stereotyped behaviors (automatisms) in which the possible etiology could be related to nocturnal seizures or highly complex (locomotive) polymorphic behavior, in which the cause may be a parasomnia. (Modified from Grillner S. The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci. 2003;4[7]:573–586; and Tassinari CA, Cantalupo G, Högl B, et al. Neuroethological approach to frontolimbic epileptic seizures and parasomnias: the same central pattern generators for the same behaviours. Rev Neurol [Paris]. 2009;165[10]:762–768.)

LOC-A2 ROC-A2 F3-A2 F4-A1 C3-A2 C4-A1 O1-A2 O2-A1 CHIN1-CHIN2 CHIN1-Fp1 LLeg-LAT2 RLeg-RAT2 INT-F8 Sca-T4 LArm-Cz RArm-Fp2 ECGL-ECGR SNORE PTAF FLOW breaths/min CHEST ABD TCM-TCM OSAT 98.3%

Epoch 85: Wake

04/24/2010 00:13:15

[*] SUDDEN AROUSAL WITH CONFUSION

98.1 98.1 98.1 98.1 98.1 98.1 98.1 98.1 98.1 98.1 98.2 98.3 98.3 98.3 98.4 98.4 98.3 98.3 98.3 98.3 98.3 98.4 98.3 98.4 98.3 98.3

Figure 28.3  ​Spontaneous confusional arousal. This 30-second polysomnograph demonstrates a sudden arousal in a 39-year-old woman with a history of non–rapid eye movement parasomnias unprecipitated by a respiratory event. She subsequently sat up, verbally berated her husband (who was not present), and attempted to remove her electroencephalogram wires.

288  Parasomnias 1

27

53

79

W

105 131 157

CA

CA

183 209

235 261 287 313 339

365 391

417 443 469

CA

495 521

547 573 599 625 651

677 703

729 755

781 807

833 859 885

911 937 963

CA

F 1 2 3

Figure 28.4  ​Hypnogram with multiple confusional arousals (CAs). Note that several CAs emanated from slow-wave sleep during the first half of the night.

E2-M1 E1-M2 CHIN1-CHIN2 F4-M1 F3-M2 ARC RE

C4-M1 C3-M2 O2-M1 O1-M2 ECG1-ECG2 ECG2-ECG3 LAT1-LAT2 RAT1-RAT2

W

1

W

SNORE 500 V

W

1

W

NPRE 187.5 V

RERA

N/O 200 V

RERA

THOR 100 V

RERA

ABD 3.2 V

RERA

SpO2 % Pleth 2V

100.0

1

W

1

W

SpO2 Art 94

80.0

W

91

1

89

W

93

92

1

93

93

91

W

Figure 28.5  ​Polysomnogram (120-second epoch) from a 54-year-old man conducted to evaluate for arousals with confusion and singing behavior. The figure illustrates one of the patient’s representative events, an arousal from slow-wave sleep, as demarcated by the star, with the patient’s arms abducted (flapping his arms and described by the technicians to be “quacking like a duck”). (Modified from Avidan AY, Kaplish N. The parasomnias: epidemiology, clinical features, and diagnostic approach. Clin Chest Med. 2010;31[2]:353–370.)

Elimination of sedating agents and reversing comorbid conditions often dramatically diminish nocturnal behaviors. In mild cases, reassurance that these behaviors are normal and unrelated to psychiatric disease is often sufficient. Medications are occasionally prescribed (Tables 28.3 and 28.4). RAPID EYE MOVEMENT SLEEP PARASOMNIAS Rapid Eye Movement Sleep Behavior Disorder REM sleep is characterized by an activated brain state in combination with skeletal muscle paralysis to prevent dream

enactment (Fig. 28.14). The suppression of motor activity during REM sleep is the cumulative result of multiple complex pathways that terminate at spinal motor neurons, most notably via the magnocellular reticular formation in the medulla. In RBD, this normal atonia is lost, and patients come to medical attention with dream-enactment behavior that varies from small hand movements to violent activities such as punching, kicking, or leaping out of bed (Figs. 28.15 to 28.18; Video 28.3). RBD can be a heralding symptomatology associated with future phenoconversion into synuclein neurodegeneration. It can also be noted in hypocretin

Atlas of Clinical Sleep Medicine   289

Epoch 731

Epoch 730

Epoch 729

Epoch 728 LOC-M2

ROC-M2 F3-M2 37.5 V

F4-M1 37.5 V

C3-M2 O1-M2 O2-M1

CHIN2-Fpz

M

PLM

PLM

Arousal with attempted sleepwalking

PLM

PLM

LAT1-LAT2

Figure 28.6  ​Sleepwalking with restless legs syndrome (RLS) and periodic limb movement disorder. This 2-minute polysomnogram demonstrates an arousal

with attempted sleepwalking preceded by frequent periodic limb movements. The 28-year-old woman also described wakeful motor restlessness consistent with RLS. Dopaminergic therapy resolved the RLS symptoms and sleepwalking episodes.

: Stage 2

Epoch 311: Stage 2

Epoch 312: Wake

LOC-M2 ROC-M1 F3-M2 F4-M1 C3-M2 C4-M1 O1-M2 O2-M1 CHIN1 CHIN2 SNORE

OBSTRUCTIVE APNEA

Ptaf2

AROUSAL WITH ATTEMPTED SLEEPWALKING EPISODE

Flow breaths/min CHEST ABD Effort Sum OSAT 98.6 %

98.6

100.0

98.9

97.7

96.9

97.8

96.6

97.0

Figure 28.7  ​Sleepwalking with obstructive sleep apnea. This 90-second polysomnogram demonstrates an arousal with an attempted sleepwalking episode after an obstructive apnea in a 40-year-old man.

290  Parasomnias Characteristic pattern of sleep terrors Events typically last 3–5 minutes Slow-wave sleep Amnesia for the event Attempts to wake increase confusion

Sudden arousal

Sits up and screams

Mumbled speech

Panic

No response to parents

Tremendous autonomic discharges

Confusion/disorientation

Figure 28.8  ​Characteristic pattern of sleep terror. Sleep terrors are characterized by a sudden arousal associated with a scream, agitation, panic, and heighted autonomic activity. Inconsolability is almost universal. The child is incoherent and has altered perception of the environment, appearing confused. This behavior may be potentially dangerous and could result in injury. (Modified from Avidan AY, Kaplish N. The parasomnias: epidemiology, clinical features, and diagnostic approach. Clin Chest Med. 2010;31[2]:353–370.)

E2-M1 125 V E1-M2 125 V CHIN1-CHIN2 533.3 V F4-M1 166.7 V

pt sat up quickly - screaming - see video

ARC SF

C4-M1 166.7 V O2-M1 166.7 V ECG1-ECG2 2.67 mV ECG2-ECG3 2.67 mV LAT1-LAT2 166.7 V RAT1-RAT2 166.7 V

3

3

W

SNORE 500 V

3

3

W

Position

W W

Right Supine Left Prone

NPRE 187.5 mV

THOR 400 V ABD 400 V SpO2 % Pleth 2V

100.0

99.0

99.0

99.0

99.0

80.0

3

3

W

sat up quickly - screaming - see video

N/O 400 V

SpO2 Art

99.0

98.0

W

Figure 28.9  ​Two-minute epoch of a diagnostic polysomnogram from a 9-year-old boy performed to evaluate for arousals associated with screaming and inconsolable crying. The figure illustrates one of the patient’s representative spells, illustrating an arousal with screaming arising out of slow-wave sleep with the patient’s arms flexed and held close to the chest, as if afraid and protecting himself. (Modified from Avidan AY, Kaplish N. The parasomnias: epidemiology, clinical features, and diagnostic approach. Clin Chest Med. 2010;31[2]:353–370; polysomnogram courtesy Timothy Hoban, MD, University of Michigan, Ann Arbor.)

Atlas of Clinical Sleep Medicine   291 Cursor: 02:53:00, Epoch: 398 - AWAKE

LOC-A2 128 V

ROC-A1 128 V

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 CHIN1-CHIN2 102.4 V

Leg/L-LEG/R 21.8 mV

ECG1-ECG2 2.05 mV

MIC

1.02 mV

AIRFLOW 1.02 mV

THOR 512 V

ABD

1.02 mV

HR

BPM

255.0

0.0

78.1

73.1

75.1

3

79.1

77.1

2

79.1

78.1

75.1

W

PT SAT UP LEANING FORWARD, OPENED HIS EYES, TALKING AND CHEWING

128 V

86.1

121.1

W

Figure 28.10  ​Sleep terror. This 90-second polysomnogram shows an arousal from non–rapid eye movement sleep in a patient with sleep terrors. Such arousals typically arise from slow-wave sleep, as in this case. Note the precipitous nature of the arousal and the increase in heart rate.

Table 28.2  Differences Between Sleep Terrors and Nightmares Characteristic Timing during the night Severity Autonomic discharge Recollection State on waking Injuries Violence Displacement from bed REM, Rapid eye movement.

Sleep Terror First third (deep slowwave sleep) Severe Severe and intense Absent Confused, disoriented Common Common Common

Nightmare Last third (REM sleep) Mild Mild Present usually Lucid Rare Rare Very rare

Clinical Case 28.1  Jumping Out a Window A 19-year-old man arrived at the sleep center 4 days after a near-fatal parasomnia. The patient described several weeks of sleep restriction as a result of college academic responsibilities and social commitments and said he went to bed at 3 am. Approximately 45 minutes later, his roommate was startled awake to see the patient silhouetted in the frame of an open window. Without warning, the patient leaped out and fell 6 m (nearly 20 feet) before fortunately landing in a pile of sand. His only sequela from the event was a broken wrist. Besides one episode of sleepwalking 2 years prior, the patient’s history and examination were unremarkable. He had no history of seizures or psychiatric disease and no prescription medication or recreational drug use. A detailed neurologic examination was normal. Formal sleep studies were remarkable: total sleep time was 16 hours on polysomnography, and actigraphy was consistent with circadian misalignment and behaviorally induced insufficient sleep syndrome. There was no evidence of sleepdisordered breathing, and the patient’s rapid eye movement muscle atonia was normal. The patient did well with an increase in sleep intake and morning light therapy.

292  Parasomnias

Epoch 298: Stage 2

Epoch 297: Stage 2

Epoch 296: Stage 2

Epo

LOC-A2 ROC-A1 F3-A2 F4-A1 C3-A2 C4-A1 O1-A2 O2-A1 CHIN1 CHIN2

PERIODIC AROUSAL

PERIODIC AROUSAL

PERIODIC AROUSAL

PERIODIC AROUSAL

ECGLECGR SNORE PTAF Flow breaths/min CHEST ABD OSAT 98.0 %

97.4

97.6

97.5

97.4

97.0

97.8

97.9

97.7

97.5

97.4

97.6

97.6

97.5

97.4

97.2

97.0

97.6

97.9

97.6

97.2

97.6

97.2

Figure 28.11  ​Cyclic alternating pattern. This 2-minute polysomnogram demonstrates a normal cyclic alternating pattern during non–rapid eye movement sleep. Notice the oscillation between high-amplitude synchronized cortical electroencephalographic activity (A phase) with low-amplitude desynchronized activity (B phase) approximately every 30 seconds.

Epoch 796

Epoch 798

Epoch 797

LOC-M2 ROC-M2 F3-M2 F4-M1

37.5 V

37.5 V

37.5 V

37.5 V

C3-M2

C4-M1 O1-M2 O2-M1

CHIN2-Fpz Periodic arousal ECGLECGR

Periodic arousal

Periodic arousal

Periodic arousal

Confusional arousal Patient woke and subsequently attempted to climb out of bed.

Figure 28.12  Rapid cyclic alternating pattern (CAP) with confusional arousal. This 90-second polysomnogram demonstrates a confusional arousal that emanates from the A phase (high-amplitude, synchronized cortical electroencephalographic activity) of a more rapid CAP compared with Figure 28.11. An increased CAP rate, suggestive of non–rapid eye movement instability, has been associated with sleepwalking and confusional arousals.

Atlas of Clinical Sleep Medicine   293

Cursor: 10:45:00, Epoch: 205 - AWAKE

E1-M2 125 V

E2-M2 125 V

C3-M2 125 V

C4-M1 125 V

O1-M2 125 V

O2-M1 125 V

F4-M1 125 V

CHIN1-CHIN2 200 V

Leg/L-LEG/R 16 mV

ECG1-ECG2 1 mV

RIGHT IC1 - RIGHT IC2 2 mV

THOR 4 mV

ABD 4 mV

GOING FOR THE GUMMY BEARS JF

250 V

FLOW

Figure 28.13  ​Rhythmic masticatory muscle activity in sleep-related eating disorder (SRED). This 60-second polysomnogram is from a 56-year-old woman with

a history of amnestic nocturnal eating. The rhythmic muscle artifacts in the electroencephalogram and electrooculogram leads are chewing movements frequently seen in SRED.

Clinical Case 28.2  Zolpidem-Induced Sleep-Related Eating Disorder in a Patient With Restless Legs Syndrome A 49-year-old woman came to medical attention with a 6-month history of weight gain (10 kg) as a result of amnestic nocturnal eating after starting zolpidem for sleep initiation difficulties. The patient stated that before starting zolpidem, she had trouble initiating sleep related to an intrinsic motor restlessness. Furthermore, conscious nocturnal eating, typically a small snack, would often help her fall asleep. Upon starting zolpidem, she no longer had trouble falling asleep but would note abdominal distention on waking in the morning. Her family described middle-of-the-night binges on peanut butter, breads, ice cream, and candy; the patient was amnestic for these events. Polysomnography with zolpidem demonstrated amnestic nocturnal eating after an arousal from non–rapid eye movement sleep (see Video 28.2) and frequent periodic limb movements. Clinical evaluation suggested that the patient had restless legs syndrome with nonmotor (eating) features. Zolpidem was discontinued, pramipexole was started, and subsequently both sleep initiation difficulties and parasomnia behaviors resolved.

Table 28.3  Parasomnia Treatments DOA

SRED

RBD

SP

Strong All patients with parasomnias appear to benefit from evidencebeing treated for comorbid sleep disorders, eliminating based provoking agents, and modifying the bedroom treatments environment to prevent sleep-related injury. Clonazepam Pramipexole Clonazepam, None Moderate melatonin evidencebased treatmentsa Paroxetine Topiramate Customized Clomipramine Weak for STsa bed alarm evidencebased treatmentsb a

Large case series or small controlled trial without conflicting results. Case series without conflicting results. DOA, Disorder of arousal; RBD, rapid eye movement sleep behavior disorder; SP, sleep paralysis; SRED, sleep-related eating disorder; STs, sleep terrors.

a

294  Parasomnias Table 28.4  Treatment for Most Common Non–Rapid Eye Movement Parasomnias Parasomnia Confusional arousal

Somnambulism (sleepwalking)

Sleep-related eating Sleep terrors

Treatment • •

Reassurance of the benign nature of the event Avoid precipitants: sleep deprivation, alcohol, central nervous system depressants • Escitalopram (10 mg) for sexsomnia • Safeguard the sleep environment, and protect the patient • Avoid precipitants: sleep deprivation, lithium, nonbenzodiazepine receptor agonists • Benzodiazepines • Clonazepam (0.5 to 1 mg) • Diazepam (10 mg) • Triazolam (0.25 mg) • Imipramine (50 to 300 mg) • Trazodone • Paroxetine • Pramipexole • Topiramate • Reassurance of the benign nature of the event • Anticipatory awakenings • Cognitive behavioral therapy • Paroxetine (20 to 40 mg) • Clonazepam (0.5 to 1 mg)

From Zak R, Mallea J, Aurora RN. Management of parasomnias. In: Avidan AY, Zee PC, eds. Handbook of Sleep Medicine. 12th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

(orexin) dysfunction, toxic etiologies, and direct central nervous system (CNS) lesions (Clinical Cases 28.3 and 28.4). Because of its association with REM sleep, dream-enactment behavior predominantly appears during the second half of the sleep period. Unlike patients with disorders of arousal, RBD patients are alert and oriented immediately upon awakening, and they report dream mentation that often correlates with the observed behaviors (Video 28.4). RBD appears to have an age- and etiology-related bimodal distribution. Among younger adults, RBD is most frequently noted with antidepressant medications or in the setting of

LOC-M2

Epoch 949

48

narcolepsy. Among older adults, RBD is most commonly indicative of an impending synucleinopathy. An evidence-based review suggests that both low-dose clonazepam and/or high-dose melatonin can be effective therapies for the treatment of RBD (Table 28.5). It is also recommended that the patient’s sleeping environment be modified to prevent sleep-related injuries. Medically resistant patients may respond to a customized bed alarm that redirects them after they arise from bed (Video 28.5). SLEEP PARALYSIS Sleep paralysis is the preservation of atonia after an arousal from REM sleep. Dream mentation, often terrifying, may coexist with wakeful cognition. Sleep paralysis is often perceived as a sense of dyspnea, from the lack of accessory muscles of respiration, with frightening dream mentation, such as a demonic presence. Various cultures have paranormal or religious interpretations for these experiences because patients with no history of thought disorder will describe in vivid detail such things as alien abduction, sexual assault by animals, or demonic possession (Fig. 28.19; Clinical Case 28.5). The events usually last less than 1 minute and either spontaneously resolve or are halted by external auditory or tactile stimulation from a bed partner. Because sleep paralysis occurs with an impaired dissociation from REM sleep, it is considered a REM parasomnia. Other abnormalities in sleep-wake state transitions include experiential parasomnias and enuresis. These phenomena include experiential parasomnias either leading into (hypnagogic) or out of (hypnopompic) sleep. EXPERIENTIAL PARASOMNIAS Sleep-onset experiences include exploding head syndrome and sleep-related hallucinations (hypnogogic hallucinations). Sleep-wake transitional phenomena include sleep-related hallucinations (hypnopompic hallucinations) and sleep paralysis.

Epoch 950

Epoch 951

ROC-M2 F3-M2 F4-M1 C3-M2

37.5 V

37.5 V

37.5 V

37.5 V

C4-M1 O1-M2 O2-M1 CHIN1CHIN2 Rarm1Rarm2

Figure 28.14  ​Normal rapid eye movement (REM) atonia. This 2-minute polysomnogram demonstrates the normal lack of muscle tone seen in REM sleep.

Atlas of Clinical Sleep Medicine   295

Epoch 976

Epoch 975 LOC-M2

ROC-M2

F3-M2 37.5 V

37.5 V

37.5 V

37.5 V

F4-M1

C3-M2

C4-M1

O1-M2

O2-M1

CHIN1CHIN2 Rarm1Rarm2

Figure 28.15  ​Rapid eye movement (REM) without atonia (tonic). This 60-second polysomnogram demonstrates a tonic elevation of REM motor activity in rapid eye movement sleep behavior disorder.

h 598

Epoch 599

LOC-M2

ROC-M2 F3-M2 37.5 V

37.5 V

37.5 V

37.5 V

F4-M1

C3-M2 C4-M1 O1-M2

O2-M1

CHIN1CHIN2

Rarm1Rarm2

Figure 28.16  ​Rapid eye movement (REM) without atonia (phasic). This 60-second polysomnogram demonstrates a phasic elevation of REM motor activity in rapid eye movement sleep behavior disorder. Notice that the motor activity is temporally associated with the phasic eye movements of REM sleep.

296  Parasomnias

R

R

R

R

R

R

Cursor: 04:29:00, Epoch: 787 - REM

R

R

R

R

2 min/page

LOC-A2 204.8 V

ROC-A1 204.8 V

C3-A2

102.4 V

C4-A1

102.4 V

O1-A2

102.4 V

O2-A1

102.4 V

CHIN1-CHIN2

PT VERBALIZED IN REM ON BK

51.2 V

Leg/L-LEG/R 409.6 V

ECG1-ECG2 1.02 mV

Figure 28.17  ​Rapid eye movement (REM) without atonia (tonic and phasic). This 2-minute polysomnogram demonstrates a combined tonic and phasic elevation of REM motor activity.

RR

R

RR

R

Cursor: 04:29:14, Epoch: 1089 - REM

R

R

R

R

2 min/page

LOC-A2 512 V

ROC-A1 512 V

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

CHIN1-CHIN2 128 V

ECG1-ECG2 1.02 mV

Leg/L-LEG/R

THOR 64 V

ABD

512 V

PT MOVING LEGS IN REM

2.05 mV

Figure 28.18  ​Rapid eye movement (REM) without atonia (phasic) in extremities only. Note the prominent extremity, but not chin, phasic muscle activity in this

2-minute polysomnogram. Chin electromyography alone can miss REM without atonia, as in this case of a 35-year-old woman with rapid eye movement sleep behavior disorder associated with narcolepsy.

Atlas of Clinical Sleep Medicine   297 Clinical Case 28.3  Medication-Induced Rapid Eye Movement Sleep Behavior Disorder

Clinical Case 28.4  Injurious Rapid Eye Movement Sleep Behavior Disorder and Bed Alarm Therapy

A 49-year-old man was referred for a 6-month history of violent dream-enactment behaviors. These events started soon after initiating venlafaxine for a mood disorder. His wife describes near-nightly episodes of punching and kicking that has necessitated her sleeping in a separate bedroom. Before taking venlafaxine, the patient had no history of parasomnias or other sleep disorders. The patient noticed no difficulties with smell, constipation, or other symptoms suggestive of early a-synuclein disease. A detailed neurologic examination revealed no evidence of extrapyramidal disease. Polysomnography demonstrated phasic rapid eye movement without atonia (see Fig. 28.16) and without other significant findings. The patient was hesitant to switch antidepressant medications, so he was started on high-dose melatonin— ultimately reaching 9 mg at bedtime—which he tolerated without difficulty. His dream-enactment behavior effectively resolved.

A 70-year-old man with a 15-year history of injurious dreamenactment behavior and a 5-year history of Parkinson disease was evaluated after recently fracturing three lumbar vertebrae as a result of leaping out of bed. Polysomnography demonstrated rapid eye movement without atonia along with elaborate dream-enactment behavior (see Video 28.4). High-dose melatonin was only partially effective, and low-dose clonazepam was poorly tolerated because of morning gait impairment. Based on the history that his wife could verbally calm him during dream enactment, a bed alarm was customized with his wife’s voice to redirect him once he arose from bed (see Video 28.5). After 2 years of follow-up, the patient had not left the bed and reported no subsequent sleep-related injury.

Table 28.5  Treatment for Rapid Eye Movement Sleep Behavior Disorder Based on Suggested Level of Evidence

Environmental modification Clonazepam Melatonin Pramipexole, acetyl cholinesterase inhibitors, zopiclone, desipramine, clozapine, carbamazepine, sodium oxybate

Dose

Level of Recommendation

0.5–2 mg qh 3–12 mg qh

A B B C

From Zak R, Mallea J, Aurora RN. Management of parasomnias. In: Avidan AY, Zee PC, eds. Handbook of Sleep Medicine. 12th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

Epoch 1171

Epoch 1172

Epoch 1173

Epoch 1174

LOC-M2

ROC-M2

F3-M2 37.5 V

37.5 V

37.5 V

37.5 V

F4-M1

C3-M2

C4-M1

O1-M2

O2-M1

CHIN1CHIN2 Rarm1Rarm2

Figure 28.19  ​Sleep paralysis. This 2-minute polysomnogram demonstrates sleep paralysis (see Clinical Case 28.5). The patient’s electroencephalogram becomes wakeful during the second half of epoch 1172; however, the patient’s rapid eye movement atonia persists throughout epoch 1173 and into 1174.

298  Parasomnias Clinical Case 28.5  Sleep Paralysis

Clinical Case 28.6  Nocturnal Frontal Lobe Epilepsy

A 42-year-old woman with a lifelong history of sleep paralysis described feeling “frozen” and unable to move or scream on a near-nightly basis. These events were described as terrifying and often associated with frightening dream mentation, including physical and sexual assault. Episodes were more severe during times of stress and sleep deprivation. These events led to sleep anxiety and avoidance, which had compounded the problem on numerous occasions. She was not hypersomnolent and did not experience cataplexy. Polysomnography demonstrated a persistence of rapid eye movement (REM) sleep atonia into wakefulness for 2 minutes (see Fig. 28.19). No other sleep or circadian rhythm disturbance was discovered. The patient did only modestly well with sleep extension and a bedtime REM-suppressing agent, clomipramine. Unfortunately, side effects limited the use of this agent, and the patient was lost to follow-up.

A 29-year-old developmentally disabled man was noted by family to have screaming and thrashing episodes up to 20 times per night. The patient was unaware of these events. Previous investigations included prolonged epilepsy monitoring, which concluded that the events were nonepileptic because seizure activity was never seen on electroencephalography (EEG). A previous polysomnogram (PSG) suggested mild obstructive sleep apnea. Continuous positive airway pressure was tried, poorly tolerated, and did not alter the frequency or severity of these events. Repeat PSG demonstrated behavioral events arising out of light non–rapid eye movement sleep and, as with events seen in previous investigations, these were not epileptiform on EEG. However, because the events were stereotyped, abnormal, and repetitive, nocturnal frontal lobe epilepsy (NFLE) was considered likely. NFLE often is without EEG correlation because seizures can emanate from deep cortical structures not well characterized by surface electrodes. Carbamazepine at bedtime immediately resolved the nocturnal behaviors.

The theatrically named exploding head syndrome describes a startling auditory hallucination at the initiation of sleep. Patients claim they are awoken by a sudden loud noise and may describe the feeling as “an exploding head.” The character of auditory hallucination varies from simple (“a church bell”) to complex (“the sound of someone pounding on several piano keys”). Myoclonic jerks often co-occur with the auditory phenomena. Sleep-related hallucinations, either hypnogogic or hypnopompic, are typically visual and appear in human or other animal form. They are often associated with anxiety and a foreboding sense of terror. This feeling is heightened if hallucinations are combined with sleep paralysis. Of note, the painting by Henry Fuseli, The Nightmare (1781), illustrates REM sleep-wake transition experiential phenomena (see Fig. 1.17). The woman in the painting clearly demonstrates the atonia of sleep paralysis combined with frightening visual hallucinations. These experiential parasomnias most often occur in the setting of either sleep deprivation or comorbid sleep pathology. Sleep paralysis and sleep-related hallucinations are part of the classical pentad of narcolepsy along with hypersomnolence and cataplexy. These conditions lead to experiential parasomnias by impairing a sharp transition between sleep and wakefulness. Treating underlying sleep disorders and optimizing the duration and circadian timing of sleep will successfully treat the vast majority of cases. REM-suppressing agents, such as antidepressants, can sometimes be useful for challenging cases of sleep paralysis and sleep-related hallucinations. SLEEP ENURESIS Sleep enuresis is defined by recurrent (at least twice a week) involuntary urination during sleep. By 6 years of age, 90% of children have developed 24-hour control of micturition. Sleep enuresis is either primary, in a patient who has never developed nocturnal continence, or secondary, in a patient who had previously been continent but subsequently lost bladder control at night. Primary sleep enuresis is often either a failure of the brain to arouse from sleep in response to bladder expansion or the result of inappropriate bladder contraction during sleep.

Familial cases are common, and boys are more commonly affected than girls. The vast majority of primary sleep enuresis cases resolve spontaneously. Secondary sleep enuresis is most commonly caused by other sleep disorders, such as OSA. A collapsing airway in combination with increased respiratory effort decreases intrathoracic pressure, and atrial natriuretic peptide is subsequently secreted from the heart, leading to increased urinary output. In addition, OSA also leads to enuresis by impairing cortical arousal through increased homeostatic sleep drive combined with increased autonomic activity. Other etiologies of secondary sleep enuresis include urinary tract disorders, nocturnal seizures, and disorders that lead to increased urine production. NOCTURNAL SEIZURES The motor behavior of epileptic activity can mimic parasomnias, and seizures may occur exclusively during sleep. Sleeprelated synchronized brain activity promotes the spread of seizure activity; thus NREM sleep is the most epileptogenic state. The behaviors from nocturnal seizure activity are often bizarre, stereotyped, and recurrent. A 32-lead seizure montage can often be helpful because an electroencephalogram (EEG) may demonstrate epileptic activity. However, because many nocturnal seizures emanate from deep, most often frontal lobe structures, nocturnal seizures should be considered even in the absence of any EEG abnormality, especially if behavior is stereotyped and recurrently arises from NREM sleep (Clinical Case 28.6; Fig. 28.20). Treatment of nocturnal seizures warrants use of antiepileptic agents. For a more thorough review of epilepsy and sleep, see Chapter 24. Table 28.6 summarizes the different types of nocturnal events based on semiology, timing during the night, duration, EEG activation, and other key features. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

Atlas of Clinical Sleep Medicine   299

LOC-A2 ROC-A1

2

2

2

2

30 sec/page

Cursor: 03:11:39, Epoch: 531 - STAGE 2

C3-A2 O2-A1 CH1-CH2 LEGS L/R Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp1-F7 F7-T3

Fp2-F8 F8-T4 T4-T6 T6-O2 FZ-CZ ECG AIRFLOW SOUND

SOUND FROM THROAT BEFORE EEG AROUSAL

T3-T5 T5-O1

Figure 28.20  ​This epoch reveals a run of electrical seizure activity without clinical manifestations. The presence of such activity in this patient suggested the diagnosis of nocturnal seizures.

Table 28.6  Key Similarities and Differentiating Features of NREM and REM Parasomnias and Nocturnal Seizures Confusional Arousals Time in sleep cycle Sleep stage EEG discharges Scream CNS activation Motor activity Awakenings Duration (in minutes) Postevent confusion Age Genetics Organic CNS lesion

Early SWS 2 2 1 2 2 0.5210 1 Child 1 2

Sleep Terrors Early SWS 2 1111 1111 1 2 1210 1 Child 1 2

Sleepwalking Early, middle SWS 2 2 1 111 2 2230 1 Child 1 2

Nightmares Late REM 2 11 1 1 1 3220 2 Child, adult 2 2

REM Sleep Behavior Disorder Late REM 2 1 1 1111 1 1210 2 Older adult 2 11

CNS, Central nervous system; EEG, electroencephalogram; REM, rapid eye movement; NREM, non2rapid eye movement; SWS, slow-wave sleep. Modified from Avidan AY, Kaplish N. The parasomnias: epidemiology, clinical features, and diagnostic approach. Clin Chest Med. 2010;31(2):3532370.

Nocturnal Seizures Any Any 1 1 1 1111 1 5215 1 Young adult 6 1111

  e1 Bibliography

American Academy of Sleep Medicine (AASM). International Classification of Sleep Disorders. 3rd ed. Darien, IL: AASM; 2014. Antelmi E, Lippolis M, Biscarini F, Tinazzi M, Plazzi G. REM sleep behavior disorder: mimics and variants. Sleep Med Rev. 2021;60:101515. Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain. 2007;130:2770–2788. Dauvilliers Y, Schenck CH, Postuma RB, et al. REM sleep behaviour disorder. Nat Rev Dis Primers. 2018;4(1):19. Drakatos P, Marples L, Muza R, et al. NREM parasomnias: a treatment approach based upon a retrospective case series of 512 patients. Sleep Med. 2019;53:181–188. Holoyda BJ, Sorrentino RM, Mohebbi A, Fernando AT, Friedman SH. Forensic evaluation of sexsomnia. J Am Acad Psychiatry Law. 2021; 49(2):202–210. Hoque R, Jaisani Z. Evaluation of paroxysmal sleep related complex motor behaviors with stereo-EEG. Sleep Med. 2021;84:73–75.

Howell MJ, Schenck CH. Restless nocturnal eating: a common feature of Willis-Ekbom syndrome (RLS). J Clin Sleep Med. 2012;8:413–419. Irfan M, Schenck CH, Howell MJ. NonREM disorders of arousal and related parasomnias: an updated review. Neurotherapeutics. 2021;18(1): 124–139. McCarter SJ, Tabatabai GM, Jong HY, et al. REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment. Neurology. 2020;94(1):e15–e29. Pressman MR. Factors that predispose, prime, and precipitate NREM parasomnias in adults: clinical and forensic implications. Sleep Med Rev. 2007;11:5–30. Provini F, Antelmi E, Vignatelli L, et al. Association of restless legs syndrome with nocturnal eating: a case-control study. Mov Disord. 2009;24:871–877. Tassinari CA, Cantalupo G, Högl B, et al. Neuroethological approach to frontolimbic epileptic seizures and parasomnias: the same central pattern generators for the same behaviours. Rev Neurol (Paris). 2009;165(10): 762–768.

Section 11  |  Sleep Breathing Disorders Chapter

29

Examination of the Patient With Suspected Sleep Breathing Disorders Meir H. Kryger

Many patients with sleep breathing disorders have anatomic abnormalities that cause obstruction of the upper airway or may suggest specific diseases. Because findings may lead to specific treatment decisions, a thorough physical examination is performed in all patients suspected of having a sleep breathing disorder. In some patients, abnormal findings in the upper airway or elsewhere may lead to suspicion of sleep apnea. All patients whose findings are shown in this chapter had documented sleep apnea. OVERALL INSPECTION OF THE PATIENT Sleep apnea can occur in any age group, in both sexes, and in all ethnic groups. It often runs in families. Many patients do not fit the stereotype of the obese middle-age man. The child shown in Figure 29.1 had sleep apnea caused by enlarged tonsils. The mother and her son in Figure 29.2A both had sleep apnea; she had hypothyroidism (see Chapter 34), and her son was obese. The two brothers shown in Figure 29.2B had sleep apnea, as did both of their parents.

on the pharyngeal airway. This can occur directly as well as indirectly because some structures are attached to the mandible, such as the tongue. The physical examination includes an intraoral examination and offers many clues as to the cause of sleep apnea. Inspection of the Face In some patients, inspection of the face can reveal the disease that may be causing sleep apnea, such as thyroid disease (see Chapter 34) or acromegaly (see Chapter 35). Inspection can also give insight into physiologic abnormalities. Hyperpigmentation on the forehead, resembling acanthosis nigricans, may be present in the patient with sleep apnea (child or adult) who sleeps sitting up with the forearm resting on a

FACIAL AND JAW STRUCTURES Many anatomic abnormalities can lead to sleep apnea. For example, either an upper jaw (maxilla) or lower jaw (mandible) that is too far posterior can lead to sleep apnea by encroaching

A

B Figure 29.1  ​Enlarged tonsils in a child.

300

Figure 29.2  ​Sleep apnea runs in families. A, Mother and son with sleep apnea. B, These brothers had sleep apnea, as did both of their parents.

Atlas of Clinical Sleep Medicine   301

Figure 29.3  ​Hyperpigmentation of the forehead in a patient who sleeps sitting up with his forearm on a table and the forehead resting on the forearm.

A

Figure 29.5  ​Floppy eyelids in a middle-age female patient. Notice her arched eyebrows.

Figure 29.6  ​Bloodshot eyes in a male patient with overlap syndrome.

B Figure 29.4  ​A, Drooping eyelids in a young male patient with sleep apnea. B, Drooping eyelids in middle-aged male patient.

table and the forehead resting on the forearm (Fig. 29.3). This is often found in patients with very severe apnea because it is the only position in which they can sleep. In many instances, sleep apnea is apparent at the first meeting with the patient. For example, drooping eyelids suggest sleepiness (Fig. 29.4). Floppy eyelids have also been associated with sleep apnea (Fig. 29.5). Arched eyebrows can be a sign that the patient is trying to open the eyelids (also see Chapter 40). The patient shown in Figure 29.6 is obese, is cyanotic, and has bloodshot eyes. The latter finding was related to polycythemia. Obesity hypoventilation syndrome or overlap syndrome should be suspected when a patient has these findings. All patients with Down syndrome should be suspected of having sleep apnea (Fig. 29.7).

Figure 29.7  ​Patient with Down syndrome.

Bony Structures Abnormalities in the skeletal structures of the face can lead to an abnormal position of the adjacent structures or attached soft tissues. Such abnormalities can obstruct the nasal or pharyngeal airways (Figs. 29.8 and 29.9). Pervasive Facial Abnormalities Congenital facial abnormalities may be pervasive and may affect the development of the maxilla, mandible, and other structures that include those involved in the auditory system (Fig. 29.10). Such patients may also be born with a cleft palate and/or missing or extra (supernumerary) teeth.

302  Examination of the Patient With Suspected Sleep Breathing Disorders

Frontal

Nasion Nasal

Temporal Zygomatic

Anterior nasal spine Maxilla

Mandible

Mental protuberance

Figure 29.8  ​Landmarks (orange) and bones (blue) of the human skull.

Nasion Hard palate

Soft palate

Anterior nasal spine

Tongue

Airway

Mental protuberance

Figure 29.9  ​Facial structure and sleep apnea. Shown are the landmarks (orange), anatomy (blue), and the sagittal section.

Maxillary and Mandibular Insufficiency The patient shown in Figure 29.11 appeared on initial inspection to have a prognathic mandible; note the concave facial profile. In fact, he has a large fat pad over his chin that gives the appearance of a prognathic mandible. More detailed examination of his facial features indicated that he has maxillary insufficiency (note his flat face and small cheekbone, or zygomatic

bone); crowding of the mandibular anterior teeth may be indicative of an undersized mandible (Fig. 29.12). Terms used to describe dental bite abnormalities are provided in Table 29.1. Small Lower Jaw The 8-year-old child shown in Figure 29.13A was referred because of sleepiness, poor school performance, high blood

Atlas of Clinical Sleep Medicine   303

Figure 29.10  ​Pervasive congenital abnormality of the face may affect the

Figure 29.12  ​Crowded teeth indicate a small mandible.

auditory system.

Figure 29.11  ​Maxillary insufficiency.

pressure, and a family history of sleep apnea. He responded to continuous positive airway pressure treatment. He has a small lower jaw (mandibular retrognathia) that was only apparent when his bite was examined. Note the convex facial profile, which is a feature of a child with an underdeveloped mandible. Men with a retrognathic jaw often grow a beard in an attempt to improve their appearance (Fig. 29.13B). Retrognathia causes the patient’s tongue to rest in a more posterior and superior position, thus impinging on the pharyngeal airway. A receding chin is a sign of mandibular insufficiency. Such patients usually have an overjet with mandibular anterior teeth excessively lingual (or posterior) to the maxillary anterior teeth. Figures 29.14 and 29.15 demonstrate the overjet during a lateral examination. Figure 29.16 shows a patient with complete overlap of the maxillary over the mandibular anterior teeth (excessive overbite) when fully in occlusion on the posterior teeth.

Table 29.1  Terms Used to Describe Dental Bite Abnormalities Finding

Description

Malocclusion

Upper and lower teeth that are misaligned. Slight protrusion of upper teeth is called class I malocclusion. Upper front teeth excessively overlap the bottom front teeth when back teeth are closed. Also called class II malocclusion. The lower front teeth or jaw sit ahead of the upper front teeth or jaw. Also called class III malocclusion. Protruding upper front teeth creating a horizontal overlap.

Overbite

Underbite

Overjet

Crossbite

Openbite

When the maxillary teeth occlude the palatal to the mandibular teeth. In posterior, classified as unilateral or bilateral. In anterior, from the edge of the mandibular incisors to the facial surface of the maxillary incisors. Anterior openbite: the front teeth do not touch when the front teeth are closed together. Posterior openbite: the back teeth do not touch when the front teeth are closed together.

Measurement (mm)

Significance

Various aspects can be identified and quantified.

If significant, can affect dental and medical health, function, and esthetics.

Vertically from the edge of the maxillary incisors to the edge of the mandibular incisors. Horizontally from the edge of the facial surface of the mandibular incisors to the facial surface of the maxillary incisors. Horizontally from the edge of the facial surface of the maxillary incisors to the facial surface of the mandible incisors. Horizontally in deviation from ideal occlusion.

If excessive, can affect function, speech, dental health and attrition, and esthetics.

Vertically from the edge of the maxillary affected teeth to the edge of the lower effected teeth.

Can affect function, speech, dental attrition, and esthetics. If excessive, can affect function, speech, lip incompetence, susceptibility to trauma, and esthetics. Can affect function, speech, health of temporomandibular joint, and esthetics. Can be associated with mouth breathing and tongue posture.

Can affect function, speech, health of temporomandibular joint, and esthetics. Can be associated with mouth breathing and tongue posture.

304  Examination of the Patient With Suspected Sleep Breathing Disorders

A

B

Figure 29.13  ​A, Child with retrognathia and sleep apnea. B, Male adults with retrognathic mandibles often grow beards.

Figure 29.14  ​Receding chin and overjet.

Figure 29.15  ​Receding chin and overjet.

Figure 29.16  ​Retrognathia. The upper teeth overlap the lower teeth.

Atlas of Clinical Sleep Medicine   305

Figure 29.17  ​Examples of protrusive maxillary anterior teeth.

Figure 29.18  ​Abnormal mandibular arch. Figure 29.19  ​Asymmetric mandibular arch.

Patients with protrusive maxillary anterior teeth frequently have retrognathic mandibles (Fig. 29.17). Some patients have an anterior open bite that may be the result of a severe tongue thrust or even a consequence of severe thumb sucking, or airway irregularities such as adenoid hypertrophy. The lowering of the resting tongue position is associated with a narrowing of the maxillary arch and dental crossbite. Patients with abnormal maxillary and mandibular arches and with asymmetry or crowding may have a micrognathic (small) mandible and may be at risk for sleep apnea. The crowding of the lower arch causes inadequate space for the anterior portion of the tongue to move anteriorly. This in turn may cause the posterior part of the tongue to “bunch up.” Such patients may develop a scalloped tongue from the tongue constantly pressing anteriorly (Figs. 29.18 to 29.21). NASAL AIRWAY Examination of the nasal airway should include inspection of nasal symmetry and a search for anatomic abnormalities that could lead to nasal obstruction.

Figure 29.20  ​Scalloped tongue.

306  Examination of the Patient With Suspected Sleep Breathing Disorders

Figure 29.21  ​Small mandible, crease in tongue, bruxism.

Figure 29.23  ​Enlarged nasal turbinates.

that may be found include a deviated nasal septum, which in some patients can be associated with a high-arched palate. Trauma to the Nose and Nares The patient shown in Figure 29.24 had severe trauma from a gunshot wound to his face that required extensive reconstructive surgery. His nose was entirely reconstructed. It does not have an airway leading to the nasopharyngeal airway, so he breathes exclusively via his oral airway, which has also had reconstructive surgery. Traumatic Injury to the Nose Inspection can reveal asymmetry of the nose. These patients may have been told they have a deviated septum. In the following examples, the patients are not overweight. The patient shown in Figure 29.25A had a broken nose; note the asymmetry. The patient shown in Figure 29.25B had been a boxer. The region below the nasal bone is wide and was hard to palpation; note the cyanosis of the lips. Figure 29.26A shows examination of the nares from below in a patient with a previous nasal fracture. Bulging of the septum in the left nostril is apparent. Note the size of the left nasal airway after application of an external nasal strip (Fig. 29.26B). EXAMINATION OF THE PALATE

Figure 29.22  ​Severe rosacea and rhinophyma.

Diseases of the Nose and Nares The patient shown in Figure 29.22 has severe rosacea. This disease can lead to nasal obstruction and sleep apnea. Diseases that affect the nasal turbinates, such as allergic rhinitis, can also lead to nasal obstruction (Fig. 29.23). Other abnormalities

A high-arched palate is frequently present in patients with a narrow dental arch (Fig. 29.27). It must be kept in mind that the nasal airway sits above the arch of the palate, and a high arch may impinge on the size of the nasal airway and cause a deviation of the nasal septum. Children with such anatomy may benefit from rapid maxillary expansion. EXAMINATION OF THE PHARYNX Mallampati Classification The Mallampati classification describes the relationship between the tongue and the size of the pharynx and was first described as a method for anesthesiologists to predict difficult

Atlas of Clinical Sleep Medicine   307

Figure 29.24  ​Facial reconstruction after a gunshot wound. Nasal reconstruction led to total obstruction.

A

B Figure 29.25  ​Examples of a broken nose.

A

B Figure 29.26  ​Broken nose. A, Without nasal strip; note the bulge. B, With nasal strip.

308  Examination of the Patient With Suspected Sleep Breathing Disorders tracheal intubation. The patient, in the sitting position, is asked to open his or her mouth as far as possible and to protrude the tongue. The Mallampati classification is as follows: Class I: Soft palate, fauces, uvula, and posterior and anterior pillars are visible (Fig. 29.28). Class II: Soft palate, fauces, and uvula are visible (Fig. 29.29). Class III: Soft palate, fauces, and only the base of the uvula are visible (Fig. 29.30). Class IV: Soft palate is not visible (Fig. 29.31).

Figure 29.27  ​High-arched palate. (Courtesy Dr. Paola Pirelli.)

Examination of the Tonsils Enlarged tonsils and adenoids can lead to sleep apnea by obstructing the upper airway during sleep. Adenoids cannot be visualized in a routine physical examination. Enlarged tonsils and adenoids are the most common cause of sleep

Figure 29.28  ​Mallampati class I. All structures visible.

A

B Figure 29.29  ​Mallampati class II. A, Posterior pillars and much of the uvula are not visible. B, Tip of the uvula is not visible.

Atlas of Clinical Sleep Medicine   309

A

B

Figure 29.30  ​Mallampati class III. A, Only the base of the uvula is visible. B, The base of the uvula is barely visible.

Figure 29.32  ​Grade 0 tonsils.

Figure 29.31  ​Mallampati class IV. The soft palate is not visible.

apnea in the pediatric population. Examination of the tonsils may or may not require use of a tongue blade. Tonsil size is graded on a scale from 0 (no tonsils) to 4 (“kissing tonsils” that touch at midline): Grade 0: Tonsils are absent. The uvula is abnormally wide and almost bifid. This is a variant of normal (Fig. 29.32). Grade 1: Tonsils are hidden behind tonsillar pillars. Grade 2: Tonsils extend to the pillars. In Figure 29.33, the right tonsil is grade 1, and the left is grade 2. Grade 3: Tonsils are visible beyond the pillars (Fig. 29.34). Grade 4: Tonsils are enlarged to the midline (Fig. 29.35). Variants and Abnormal Airway Pharyngeal Findings In Figure 29.35D, the right tonsil is much larger than the left and extends beyond the midline. It was initially difficult to

Figure 29.33  ​Grade 1 tonsil (right side) and grade 2 tonsil (left side).

310  Examination of the Patient With Suspected Sleep Breathing Disorders visualize because it extended behind the uvula. This would be classified as equivalent to grade 4 enlarged tonsils. In Figure 29.36, a nubbin of left tonsillar tissue can be seen. This patient frequently awakened with a sore throat, and the pharyngeal tissues show evidence of trauma (redness) as a result of snoring. Figure 29.37 shows an unexpected finding in a sleep apnea patient: a tiny neoplastic lesion just to the left of the uvula. The most common surgical procedure involving the upper airway is uvulopalatopharyngoplasty, which usually involves removal of the uvula and variable amounts of the soft palate (depending on the surgeon), tonsils, adenoids, and redundant tissue in the pharynx. In the cases shown in Figures 29.38 and 29.39, uvulopalatopharyngoplasty was unsuccessful in treating the apnea. Note the differences in anatomic outcome in these examples.

Figure 29.34  ​Grade 3 tonsils.

A

C

B

D Figure 29.35  Grade 4 tonsils.

Atlas of Clinical Sleep Medicine   311

A

Figure 29.36  ​Trauma (redness) as a result of snoring.

B

Figure 29.37  ​Soft palate tumor.

C Figure 29.39  ​Uvulopalatopharyngoplasty with a small pharyngeal opening

(A), a triangular pharyngeal opening (B), and a large pharyngeal opening (C).

EXAMINATION OF THE NECK

Figure 29.38  ​Outcome of uvulopalatopharyngoplasty.

A large neck collar size is a robust statistical predictor of obstructive apnea, although more so in men than in women. The patient shown in Figure 29.40 has a neck collar size of 49 cm, or 19.3 inches. Most obese patients with apnea have a neck collar size of at least 43 cm, or 17 inches. Congenital abnormalities that involve the neck can also lead to sleep apnea. The patient shown in Figure 29.41 had

312  Examination of the Patient With Suspected Sleep Breathing Disorders

Figure 29.40  ​Measuring neck collar size. Neck collar size in excess of 43 cm is associated with sleep apnea.

Figure 29.41  ​Sleep apnea can be due to Klippel-Feil syndrome. Patients with this syndrome have a low hairline and a short, webbed neck.

severe sleep apnea as a result of Klippel-Feil syndrome. She also had polycystic ovary syndrome (see Chapter 43); note the acne on the face. Findings in the neck are also seen in diseases of the thyroid gland (see Chapter 34). EXAMINATION OF THE ABDOMEN Central obesity is a very common finding in sleep apnea patients. Note the striae in Figure 29.42. Bariatric surgery is commonly done to treat morbid obesity and may result in resolution of sleep apnea. The patient shown in Figure 29.43 continued to have sleep apnea after having lost more than 100 kg. Note his abdominal scar and redundant tissue. EXAMINATION OF THE EXTREMITIES Peripheral Edema In very obese patients who spend most of their time in bed, edema might not always be maximal in the ankles and feet

Figure 29.42  ​Central obesity.

(Fig. 29.44). When edema is very severe in a patient with a sleep breathing disorder, it is almost always in the context of a hypoventilation syndrome (Fig. 29.45). Chronic edema results in discoloration and may result in infections that are difficult to treat (Figs. 29.46 and 29.47).

Atlas of Clinical Sleep Medicine   313

Figure 29.43  ​Bariatric surgery results in weight loss, often leaving excess skin.

Figure 29.45  ​Edema in a patient with hypoventilation syndrome.

A Figure 29.46  ​Chronic edema, even when resolved, may result in discoloration.

B Figure 29.44  ​Edema. A, Edema is not always present in the ankles and feet. B, Pitting edema.

Figure 29.47  ​Chronic edema may result in infections.

Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

  e1 Bibliography

Avidan A, Kryger M. Physical examination in sleep medicine. In: Kryger M, Roth T, Goldstein CA, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022.

Chapter

30

Sleep Apnea in the Adolescent and Adult Nancy Collop

OVERVIEW

DEFINITIONS

Sleep-related breathing disorders encompass a wide variety of respiratory problems that appear exclusively in sleep, affect sleep, or are exacerbated by sleep. The American Academy of Sleep Medicine (AASM) has published a nosology of sleep disorders, the International Classification of Sleep Disorders, which is in its third edition (ICSD-3). All of the sleep-related breathing disorders are listed in Table 30.1 along with the associated International Classification of Diseases, 10th edition (ICD-10) classification. This chapter reviews these breathing disorders in patients older than 10 years.

The term sleep-disordered breathing (SDB) refers to a spectrum of breathing disorders. Obstructive breathing events occur when the upper airway is partially or completely occluded, and central breathing events occur when effort to breathe is reduced or lacking. Obstructive breathing events range from simple snoring to obstructive sleep apnea (OSA). Central breathing events have a variety of causes, and management varies depending on the underlying condition. Both central and obstructive breathing events may occur in the same patient.

Table 30.1  Sleep-Related Breathing Disorders ICD-10 Classification OSA Disorders OSA, adult OSA, pediatric CSA Disorders Primary CSA CSA with Cheyne-Stokes breathing CSA caused by high-altitude periodic breathing CSA caused by a medical or neurologic condition without Cheyne-Stokes breathing CSA caused by a medication or substance Treatment-emergent CSA Primary CSA of infancy Primary CSA of prematurity Sleep-Related Hypoventilation Disorders Obesity hypoventilation syndrome Congenital central alveolar hypoventilation Late-onset central hypoventilation with hypothalamic abnormalities Idiopathic central alveolar hypoventilation Sleep-related hypoventilation caused by a medication or substance Sleep-related hypoventilation caused by a medical condition Sleep-Related Hypoxemia Disorders Sleep-related hypoxemia Isolated Symptoms and Normal Variants Snoring Catathrenia

G47.33 G47.33 G47.31 R06.3 G47.32 G47.37 G47.39 G47.39 P28.3 P28.4 E66.2 G47.35 G47.36 G47.34 G47.36 G47.36

G47.36 R06.33 G47.8

CSA, Central sleep apnea; ICD-10, International Classification of Diseases, 10th edition; OSA, obstructive sleep apnea.

314

RISK FACTORS Obstructive Sleep Apnea Risk factors for OSA include conditions that reduce the upper airway size or worsen the upper airway collapsibility. Obesity is a common risk factor for OSA; the risk increases with increasing body mass index (BMI). OSA is more common in men than women before age 50 years, but it may be equally prevalent in older men and perimenopausal/ postmenopausal women. A high prevalence of OSA is seen in patients with metabolic syndrome, atrial fibrillation, acromegaly, resistant/refractory hypertension, and transient ischemic attack/stroke. The prevalence of SDB increases with age, although the severity seems to be less in older populations. In addition, there appear to be genetic risk factors for OSA. First-degree relatives of patients with OSA are more likely to snore and have observed apneas, even after controlling for age, sex, and obesity. Genetic studies suggest the ventilatory responsiveness, obesity, and craniofacial morphology may in part explain the inheritance of OSA. Other risk factors include syndromes that affect airway caliber or craniofacial anatomy, including retrognathia and tonsillar hypertrophy, and syndromes such as trisomy 21 and Pierre Robin, Apert, Treacher Collins, and Marfan syndromes. Use of alcohol or sedatives before bedtime may affect the severity. Central Sleep Apnea Central sleep apnea (CSA) has a variety of etiologies. The Cheyne-Stokes breathing pattern is most commonly found in patients with heart failure or stroke. Use of respiratory depressants such as long-acting opioids may cause CSA, and there is also an idiopathic form.

Atlas of Clinical Sleep Medicine   315 CLINICAL ASSESSMENT Symptoms Patients with OSA are most likely to present to medical care because bed partners or others have observed loud snoring and/or breath stoppages during sleep. The patient may note excessive daytime sleepiness, frequent awakening, nocturia, unrefreshing sleep, or fatigue. Box 30.1 outlines some of the more common symptoms of OSA. Patients with CSA may also notice poor and/or disrupted sleep, fatigue, and unrefreshing sleep. Examination The physical examination (see Chapter 29) of the patient with OSA is nonspecific and relates to identifying characteristics that narrow the airway, including a large neck circumference, overweight or obesity, micrognathia/retrognathia, enlarged tonsils, and constricted nasal passages. For patients with CSA, examination of the heart may reveal signs of heart disease (e.g., murmur, S3 heart sound) or heart failure (e.g., edema, rales). Laboratory Evaluation The comprehensive overnight polysomnogram (PSG) is the gold standard diagnostic test to document all forms of sleep

Box 30.1  Symptoms of Obstructive SleepDisordered Breathing Snoring Witnessed apnea Excessive daytime sleepiness Morning headache Morning dry throat Depression symptoms Erectile dysfunction Insomnia Impaired vigilance and memory

apnea. Home sleep apnea testing (HSAT) is now the more common modality for diagnosing uncomplicated OSA in patients without significant comorbid conditions; however, it should not be used to diagnose CSA. Data Obtained in Polysomnography The current AASM scoring manual specifies what types of sensors are considered satisfactory for the measurement of breathing disorders during sleep. The manual recommends the use of both an oronasal thermal sensor or polyvinylidene fluoride (PVDF) sensors to assess airflow for apnea and a nasal cannula pressure transducer (NCPT) to assess airflow for hypopnea. Effort belts can be either respiratory-inductive plethysmography or PVDF. Measuring end-tidal CO2 or transcutaneous CO2 may provide additional dimensions of helpful information. Scoring of Respiratory Events With Polysomnography Apneas and hypopneas must last at least 10 seconds. Apnea occurs when oronasal airflow measured by thermal signal or positive airway pressure (PAP) flow or PVDF is reduced by 90% or more from baseline; hypopnea occurs when the nasal pressure transducer signal is reduced by 30% or more from baseline with a 3% or greater drop in arterial oxygen saturation (SaO2). An alternative rule for hypopnea requires a 50% or more reduction in nasal pressure transducer signal with a 4% or greater decrease in SaO2 associated with an arousal. Figure 30.1 demonstrates a respiratory event that meets criteria for a hypopnea, with a marked reduction in the pressure transducer signal and a decrease in SaO2 from 94% to 90%; snoring is also noted. In children younger than 13 years, the length of the event changes from 10 seconds to two missed breaths as determined by the baseline respiratory rate (see Chapter 31). The scoring rules are flexible for ages 13 to 18 years and allow scoring either by adult or pediatric criteria. Figure 30.2 demonstrates the somewhat arbitrary nature of these definitions as well as the difference in thermal and

SNORE NCPT Therm Thor ABD SpO2

Figure 30.1  ​Hypopnea. This 60-second epoch demonstrates the features of a standard hypopnea, lasting approximately 23 seconds (green shading). Note more reduction on the nasal cannula pressure transducer (NCPT) channel than on the thermistor (Therm) channel. The amount of oxygen desaturation amounted to 4% (purple shading). This hypopnea was also associated with an arousal from sleep (blue shading).

316  Sleep Apnea in the Adolescent and Adult L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

SaO2

90

FLOW PRESS

94

94

92

97

93

98

97

98

97

96

96

94

95

92

92

95

92

94

94

92

91

128

0

*MICRO 128 *ECG ABD BODY STAGE

0

128

SR

S3

SR

S3

SR

S3

SR

SR

MV

SR

SR

MV

120”

SR WK

S WK

S WK

S

S WK

S

S1 240”

S

S

S2

S

S2

S

S2

S

S

S2

S

S2 360”

S

S2

S

S

S2

S

S2

S

S

S2

S

S2

S

S2

S

S

S2

480”

Figure 30.2  ​Apneas and possible hypopnea. In this 10-minute compressed epoch, the FLOW channel represents the thermocouple signal, and the PRESS

channel represents nasal pressure. The event marked with the rectangle meets the criteria for an apnea because the flow signal is reduced by more than 90% of baseline for more than 10 seconds (,15 seconds). The oval marks an event that does not qualify as either an apnea or a hypopnea; the oxygen saturation decreases by only 1% (from 95% to 94%), which precludes designating it as a hypopnea. The thermocouple signal is reduced by about 80% of baseline, and by standard criterion, a decrease by 90% or more on the thermocouple (not flow transducer) channel is required for an apnea.

pressure signals. The term respiratory effort-related arousal was coined to capture respiratory events that do not qualify as apneas or hypopneas (Fig. 30.3). As can be seen, there is flattening of the NCPT signal with increasing ventilatory effort, ending in an arousal. These events became much easier to recognize with the use of the NCPT, which has a higher sensitivity to minor changes in airflow. The presence and severity of SDB can depend both on sleep stage and on position. Many patients—particularly younger patients, women, and those with milder disease— experience events only during rapid eye movement (REM) sleep (Fig. 30.4) or when supine. OSAs will show continued effort throughout the event (Fig. 30.5). Central apneic events occur in the absence of respiratory effort. They are commonly seen in heart failure and neurologic disorders, in the presence of respiratory depressants, and in infants. They also occur frequently in nonapneic individuals after arousal (Fig. 30.6). Opioid-induced CSAs are typically short in duration and have two to four irregular breaths in between. This breathing pattern has also been termed Biot’s respirations (Fig. 30.7). Cheyne-Stokes respirations involve a pattern of at least three consecutive cycles of waxing and waning of breathing with either five or more CSAs or hypopneas per hour of sleep or a cyclic crescendo-decrescendo change in breathing amplitude that lasts at least 10 consecutive minutes. In adults, it is one of the most prevalent forms of CSA (Fig. 30.8). Visualization of this type of breathing pattern is probably more readily

apparent in compressed epochs (3 to 5 minutes) than in 30- or 60-second epochs (Fig. 30.9). Mixed sleep apneas share characteristics of both OSA and CSA but typically respond well to treatment for OSA (Figs. 30.10 and 30.11). Both central and obstructive events can be seen in the same individual under a variety of circumstances and can even be induced by treatment with PAP known as treatmentemergent central sleep apnea (TECSA). TECSA can be seen during PAP titrations or may even develop after the patient has been on PAP. Figure 30.12 shows a patient who had both obstructive and mixed apneas at baseline and as PAP was titrated to as high as 16 cm H2O, mixed apneas persisted. In many patients, it appears to resolve after continued PAP use; however, some may need more sophisticated PAP devices (see later). Home Sleep Apnea Testing In 2008, the Centers for Medicare and Medicaid Services (CMS) began allowing remote testing for OSA. The use of HSAT began growing exponentially and currently is widely used to diagnosis patients suspected of having OSA. In 2011, the AASM published a technology review in which the authors described a system for identifying the sensors used in HSAT devices. The SCOPER criteria breaks down the sensors into the following categories: sleep, cardiovascular, oximetry, position, effort (breathing), and respiration (Fig. 30.13). Many HSAT devices measure the same PSG signals for respiratory events, and there are some unique

Atlas of Clinical Sleep Medicine   317

SNORE NCPT Therm Thor ABD

SpO2

Figure 30.3  ​Respiratory effort–related arousal (RERA). The difference in the sensitivity of pressure transducers (NCPT) and thermistors (Therm) is demonstrated in this figure in which reduction of the pressure transducer signal is evident, but reduction in the thermistor channel is minimal. According to the scoring rules of the American Academy of Sleep Medicine, this event does not qualify as either an apnea or a hypopnea because assessment of flow for apneas is supposed to be done by a thermal sensor. This cannot be a hypopnea by the scoring rules because there is only a 1% oxygen desaturation. However, there is an arousal (blue shading), and it does meet the scoring criteria for RERA. The current rules define RERA 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.” Increasing effort is clearly noted in the abdominal channel (ABD), which reduces after the arousal.

devices with alternate signals. The standard HSAT has an airflow signal, usually an NCPT with a respiratory effort measure and pulse oximeter. The oximeter also derives pulse. The device that receives and stores the signals will usually contain a body position detection element (Fig. 30.14). As noted, there are other HSAT devices with unique signals. The WatchPAT (Itamar Medical) collects data on peripheral arterial tonometry, a signal generated from the first finger’s vascular tone that rises and falls with changes in the sympathetic nervous system. This signal, along with pulse oxygen saturation, actigraphy, a sensor with a snore microphone, and body position sensor, utilize a proprietary software algorithm that generates a breathing disturbance index. The device is worn like a wristwatch. The signals can be viewed, but manual scoring is challenging because of the algorithm (Figs. 30.15 and 30.16). HSAT devices are only recommended for diagnosis of OSA in adult patients. The ideal patient for HSAT use has a high index of suspicion for OSA, no comorbid conditions that would alter the results of the test such as heart failure or severe chronic obstructive pulmonary disease, and the ability to follow instructions and wear the device properly. Nonapneic Respiratory Events Oxygen saturation decreases during sleep in humans and typically reaches a nadir in the early morning hours. For those with underlying lung diseases, this nocturnal desaturation can be exaggerated, as shown in Figure 30.17, in which oxygen saturation hovers in the mid-80s even though airflow appears to be continually present. This pattern is commonly seen in patients with underlying lung disease. Another oximetric pattern that is often noted on sleep studies is seen in patients with hypoventilation disorders, such as neuromuscular disease,

restrictive lung disease caused by kyphoscoliosis, or other disorders that limit lung expansion. In Figure 30.18, the typical pattern is seen in a patient with kyphoscoliosis demonstrating marked oxygen desaturation during REM sleep caused by lack of accessory respiratory muscle use. In obesity hypoventilation syndrome, a similar pattern can be seen with the overlay of repetitive obstructive events but progressively lower oxygen saturations during REM sleep (Fig. 30.19). Adolescent Sleep-Disordered Breathing As with obese adults, obese adolescents are also at increased risk for sleep apnea (Fig. 30.20). Other risk factors include tonsillar and adenoidal hypertrophy (Fig. 30.21), late-onset laryngomalacia (Fig. 30.22), craniofacial abnormalities (Fig. 30.23), and Down syndrome (Fig. 30.24) (see also Chapter 31). Neuromuscular disorders such as cerebral palsy, spinal muscle atrophy, and severe kyphoscoliosis can also result in SDB in adolescents and young adults (Fig. 30.25). Prematurity is the most important risk factor for CSAs and periodic breathing during early childhood, but this form of SDB can also occur in adolescents and adults (Fig. 30.26). In both adolescents and adults, sleep apnea is not the only sleep disorder that may interfere with sleep or alertness (Fig. 30.27). TREATMENT General Measures In obese patients, weight loss may be extremely helpful. Bariatric surgery is available to assist with weight loss in the morbidly obese patient. It should be noted, however, that many patients will continue to have OSA even after weight loss, so long-term

318  Sleep Apnea in the Adolescent and Adult 23:00

00:00

01:00

02:00

03:00

04:00

05:00

23:00

00:00

01:00

02:00

03:00

04:00

05:00

Arousal U W R N1 N2 N3 Supine Left Prone Right Upright LM/RRLM PLM Desat

SpO2 [%]

100 90 80 70 60 57

TCCO2 [mmHg]

43 29 125

Heart rate 100 [bpm] 75 50 high Snore

RMI

low 135 90 45

Central Obstructive 90 Apnea 60 [seconds] 30

90 Hypopnea 60 [seconds] 30 90 Autonomic 60 [seconds] 30

Figure 30.4  ​Hypnogram depicting rapid eye movement (REM)-related events with the boxes highlighting REM periods noting frequent oxygen desaturations (Spo2) and hypopneas. REM-related apneas are more common in females and children.

follow-up is needed. Patients with OSA should avoid medications that may affect the drive to breathe, including opiates, and those that reduce upper airway muscle tone, such as alcohol and some sedatives and hypnotics. Patients should be instructed not to drive when sleepy. Continuous Positive Airway Pressure The most commonly prescribed treatment for OSA is continuous positive airway pressure (CPAP), which is created by

a flow generator with air pressure delivered via a tube that is connected to a patient interface that either delivers air through the nose or through the nose and mouth (Fig. 30.28). The types of interfaces include nasal masks that cover the nose (Fig. 30.29), nasal pillows with small inserts that seal the nostrils, and under-the-nose nasal masks with a small hole that is seated under the nostrils (Fig. 30.30). There are also full-face masks that cover the mouth in addition to the nose, including triangular designs that enclose the nose and mouth

Atlas of Clinical Sleep Medicine   319

SNORE NCPT Therm Thor ABD SpO2

Figure 30.5  ​This 60-second epoch shows obstructive sleep apneas (red line) in which there is absent flow in both the nasal cannula pressure transducer signal

(NCPT) and the thermistor signal (Therm) but continued respiratory effort (THOR and ABD). Although not required to score an apnea, these events are also associated with a decrease in oxygen saturation (Spo2, purple shading) and arousal (blue shading).

100

L-EOG 0 V -100

100

R-EOG 0 V -100

50

C3-A2 0 V -50 50

C4-A1 0 V -50 50

O1-A2 0 V -50 50

O2-A1 0 V -50 CHIN

100 0 -100

FLOW 128 SaO2

90

97

97

97

97

97

97

93

96

93

96

96

97

96

97

97

97

97

97

97

97

97

MICRO

128

CHEST

128

ABD

128

SR

SR

SR

SR

SR

SR

SR

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

BODY

Figure 30.6  ​Central sleep apneas. Two examples of compressed 10-minute epochs showing isolated central apneas following arousals. The lack of airflow in the pressure or flow channel coupled with markedly reduced movement/effort in the abdomen/chest channel marks these events as central.

Continued

320  Sleep Apnea in the Adolescent and Adult L-EOG

0

R-EOG

0

50

C3-A2

0 50

C4-A1

0 50

O1-A2

0 50

O2-A1

0

CHIN

0

FLOW128 MICRO128 RR CHEST

128

ABD

128

S

BODY SaO2

90

97

S

S 97

S 97

S 97

S

S 97

S 97

S

S

S 96

S

S

95

S 97

S

S

97

S 97

S 97

S

S 97

S 96

S

S 96

S 97

S 97

S

S 97

SR 97

SR

93

Figure 30.6, cont’d

CURSOR: 23:57:18. EPOCH: 210 • STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

LEG(L)

5 min/page

125 V

LEG(R) 125 V 100

SaO2 % 80

THOR RES x1

ABD RES x1 120

PULSE bpm

40 50

PCO2

mm Hg

0

AIRFLOW 62.5 V

Figure 30.7  ​Central sleep apnea shown in a 5-minute epoch. These are repetitive episodes of central apnea in a 44-year-old patient using opiates for pain in an injured ankle. Notice the small number of breaths in each cycle. Cardiogenic oscillations are evident in the CO2 trace and are best seen in the third apneic episode from the right. This type of breathing pattern is also known as Biot’s respirations.

Atlas of Clinical Sleep Medicine   321 Cursor: 22:17:07. Epoch: 24 • AWAKE

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

LEG(L)

5 min/page

125 V

LEG(R)

125 V 100

SaO2 % 90

THOR RES x1

ABD RES x1 120

PULSE bpm 40 40

PCO2 mm Hg -4

AIRFLOW 41.7 V

Figure 30.8  ​Cheyne-Stokes respirations (CSRs). The compressed 5-minute epoch in the bottom window is from a polysomnogram of a patient with congestive

heart failure and atrial fibrillation. It demonstrates classic central apneas separated by crescendo-decrescendo breathing, with absence or reduction of abdominal and chest movement during the apneas. Oronasal CO2 is being recorded, and the nasal pressure (AIRFLOW) shows little activity because the patient is mouth breathing. CSRs can be seen in patients with poorly controlled heart failure when they are awake, as in this example, and when they are sleeping; its presence is a negative prognostic sign. CSRs can be predicted if the patient has paroxysmal nocturnal dyspnea.

SNORE NCPT Therm Thor ABD SpO2

Figure 30.9  ​Cheyne-Stokes respirations shown in a 5-minute epoch. Note crescendo and decrescendo pattern in all ventilation channels: the nasal cannula

pressure transducer (NCPT), thermistor (Therm), thoracic (Thor), and abdominal (ABD) belts. The arousal is shaded in blue. Note that it typically occurs during the hyperpneic phase and not at the end of the apnea as is commonly seen in obstructive events.

322  Sleep Apnea in the Adolescent and Adult WK MVT REM S1 S2 S3 S4

L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

PFLOW

128

FLOW

128

CFLOW

0

MICRO

128

ECG

0

RR CHEST

128

ABD

128

BODY LeftLeg

0

RightLeg SpO2

0 90

EPAP

0

IPAP

0

EtCO2

0

STAGE

98

95

95

88 0

0

0

0

0

0

123 S2

123 S2

94

93

0

0

0

0

123 M

S2

123 S2

93

0

0

0

0

0

123 S2

94

98

93

0

S2

123 S2

94 0 0

123 S2

REM

90

81 0

0 123

S2

88 0

0 123 REM

0

0

0

123 REM

93

0

REM

81

81 0 0

123 REM

REM

0

0 123 REM

96

84

0

0 123 REM

93

64

0

0

0

0

0

123 REM

83

0

REM

123 REM

123 REM

REM

1 132132133133134134135135136136137137138138139139140140141141142142143143144144 145145146146147147148148149149150150 15115 120”

360”

240”

480”

60

Figure 30.10  ​Mixed sleep apnea in a compressed 10-minute epoch from a 50-year-old male patient with congestive heart failure. The apnea-hypopnea index

was elevated at 92.1 events per hour of sleep, with significant hypoxemia. This patient had evidence of all three main categories of sleep apnea: obstructive sleep apnea is caused by upper airway obstruction, central sleep apnea is caused by lack of inspiratory muscle effort, and mixed sleep apnea is caused by a combination of these factors.

Cursor: 11:35:18, Epoch: 116 • STAGE 2

EMG1-EMG2

30 sec/page

1.02 mVz

C3-A1 128 V

C4-A1 128 V

F4-A1 128 V

O1-A2 128 V

02-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 1.02 mV

LAT-LAT-

5 min/page

512 V

RAT-RAT-

512 V 100

SaO2 %

99 9 9 999 9 9 99 999999 9 967 7 69 99 99 99 9 9 9 9 99 666 6 6 99 9 9 9 999 9 996666559 6 55 4 9 9 9 9 56 5 5 5 9 9 54 49 9 599 5 9 9 6 6 654 3 9 9 94 6 9 45 4 99 8 99 32 8 329 329 88 8 8 8 92 34 8 998 811 4 83 2 88 8 2 11 8 8 1 0 98 8 1 19 8 8 0 99 8 0 8 8 8 91 1 0 9 8 08 8 0 888 888 90 80 89 9 8 8 88 888 9 8 8 8 8 8 8 8 8 78 8 76 8 6 7 7 8 86 75 8 8 7 76 55 88 6 88 8 8 8 4 6548 8 5 888 8 8 8 8 8 5 5 5 54 8 8 8 4 4 5 88 8 4 8 4 8 8 8 8 3 32 7 333 4 3 2 7 8 3 2 8888 3 3 22 1 7 77 32 2 1 7 7 1 75 2 8 8 77 8 1 01 10 1 1 1 0000 1 00 0 08 0 99 9 9 8 99 7

THOR EFFORT 4.1 mV

ABD EFFORT

4.1 mV 120

PULSE bpm

40 75

EtCO2

mm Hg

CPAP Pres

0 20

cm H2O 0

NASAL PRES 500 mV

Figure 30.11  ​Mixed sleep apnea usually begins with central sleep apnea and ends with obstructive sleep apnea. In this example, vigorous leg movements occurred at the end of the apneic episodes. Continuous positive airway pressure abolished the apneas, but the leg movements persisted.

Atlas of Clinical Sleep Medicine   323

Pressure CFlow Thor ABD

SpO2

Figure 30.12  ​This example of a treatment-emergent central sleep apnea with a 2-minute epoch shows persistent mixed apneas in a patient who had both

obstructive and mixed apneas at baseline, and positive airway pressure (PAP) was initiated. This epoch was at a pressure of 13.5 cm H2O, and the PAP was titrated to as high as 16 cm H2O, with mixed apneas persisting.

Sleep

Cardiovascular

Oximetry

Position

Effort (Breathing)

Respiration

S1 ≥ 3 channels including EEG, EMG, EOG

C1 > 1 ECG lead

O1 Oximetry with recommended sampling rate

P1 Visualized position

E1 2 RIP Belts

R1 NCPT + thermal sensor

S2 < 3 channels of EEG ± EOG ± EMG

C2 Peripheral arterial tonometry

O1x Oximetry w/o recommended sampling rate or not described

P2 Other position measure

E2 1 RIP Belt

R2 NCPT

S3 Sleep surrogate (e.g., actigraphy)

C3 1 ECG lead

O2 Oximetry not from digit or ear

E3 Derived effort (e.g., FVP)

R3 Thermal sensor

S4 Other sleep measure

C4 Derived pulse from oximetry

O3 Other oximetry

E4 Other effort (including piezo belts)

C5 Other sleep measure

R4 EtCO2 sensor

R5 Other respiratory sensor

Figure 30.13  ​The SCOPER table depicts the criteria used to categorize home sleep apnea test devices. The complexity is highest at the top levels and decreases

going down the table, allowing determination of a device’s channels. For example, a standard home sleep apnea testing device would be an S3C4O1xP2E2R2 that uses an oximeter and also provides heart rate, a position sensor with a nasal cannula pressure transducer, and one effort belt.

324  Sleep Apnea in the Adolescent and Adult

NCPT

Thor

ABD

SpO2

Pulse

Figure 30.14  ​This 120-second epoch is from a home sleep apnea testing device that measures airflow (NCPT), effort via two belts (Thor and ABD), oximetry

(Spo2), heart rate (Pulse) and body position. In this epoch, the patient is having an obstructive sleep apnea (red shading) with a 22% oxygen desaturation (purple shading). NCPT, Nasal cannula pressure transducer.

WP Stages

PAT PAT amplitude Pulse rate (BPM) SaO2 (%)

Actigraph WP Stages Body Position Snore (dB) 01:25:20

01:26:00

01:26:40

01:27:20

01:28:00

01:28:40

Figure 30.15  ​Another type of home sleep apnea testing device (WatchPAT) utilizes peripheral arterial tonometry (PAT). The top panel is a summary of all events

that were tagged during the study. The PAT signal shows beat-to-beat tone of the vessel with the reductions coinciding with arousals from sleep. The PAT amplitude shows the moving average of the PAT signal. The Pulse rate depicts the patient’s heart rate and is typically out of sync with the PAT signal, consistent with an increase in heart rate associated with an arousal. The Spo2 signal shows a drop in oxygen saturation noted during a breathing event, and the actigraphy shows movement of the wrist, which may also occur with an arousal. The device also has a Body Position/Snore (dB) sensor (bottom 2 panels) that is placed on the patient’s sternum. These signals are integrated to score breathing events and estimate sleep depth.

Atlas of Clinical Sleep Medicine   325 PAT Respiratory Events

Excluded periods

Snore /Body Position

SaO2 (%)

100

70 64 58 dB 52 46 40

Oxygen Saturation/ Pulse Rate (BPM)

210

90

165

80

120

70

75

60

30

Pulse Rate (BPM)

Sit Prone Left Right Supine N/A

Wake/Sleep stages

5 :5

5

06

:2

5

06

5

:5 05

:2

5

05

:5

5

04

:2

5

04

:5

5

03

:2

5

03

5

:5 02

02

:2

55 01 :

25

5

01 :

:5

5

00

:2

5

00

:5

5

23

5

:2 23

22

:5

5 :2 22

21

:5

5

Wake REM L Sleep D Sleep

Figure 30.16  ​Summary of a WatchPAT study with the top panel showing the number of scored respiratory events utilizing the PAT signal; the second panel

depicting snoring (in decibels) and body position (black line); the third panel showing oxygen saturation (black lines) and heart rate (red lines); and the bottom panel showing sleep depth divided into Wake, REM, L Sleep (light sleep), and D Sleep (deep sleep).

L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

FLOW

128

PRESS

0

MICRO 128 SaO2

90

ECG

0

86

87

87

86

86

86

86

86

86

86

84

86

86

86

86

86

86

86

84

86

84

RR CHEST

128

ABD

128

SL

BODY LeftLeg RightLeg STAGE

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

SL

0

LeftLeg Gain 7

S3

S3

S3

S3

S3 120”

S3

S3

S3

S3

S3

S3

240”

S3

S3

S3

S3 360”

S3

S3

S3

S3

S3

S3

S3

480”

Figure 30.17  ​Nonapneic hypoxemia. This 10-minute compressed epoch demonstrates oxygen saturations consistently in the mid-80s despite excellent flow. This patient had chronic obstructive pulmonary disease with mild diurnal hypoxemia.

326  Sleep Apnea in the Adolescent and Adult

100 90

70

Patient goes to bathroom

80

Oximetry

60 85 80 75 70 65 60 55 50 45 40

Transcutaneous CO2

Figure 30.18  ​Overnight summary graph of a patient with kyphoscoliosis. The top panel is the hypnogram depicting stage of sleep; the second panel is oximetry, and the bottom panel is from a transcutaneous CO2 sensor. The patient had an elevated CO2 to start (.65 mm Hg) with it worsening during REM periods as oxygen saturation decreases precipitously as a result of lack of accessory respiratory muscle usage.

23:00

00:00

01:00

02:00

03:00

04:00

05:00

Arousal U W R N1 N2 N3 Supine Left Prone Right Upright LM/RRLM PLM Desat 100 90 SpO2 80 [%] 70 60

Figure 30.19  ​Hypnogram from a patient with obesity hypoventilation syndrome. The baseline portion of the study (before the orange arrow) shows repetitive oxygen desaturations that continue during rapid eye movement (REM) sleep but also shows an overall decrease in the level as a result of REM-related hypoventilation (blue arrows). After the orange arrow, positive airway pressure is initiated, and oxygen saturation is maintained .90% with adequate pressure levels, even during REM sleep (box).

and those seated under the nostrils with a separate section that covers the mouth (Fig. 30.31). Fitting the mask is a critical step (see Chapter 49, Video 49.8). CPAP can be “titrated” in the sleep laboratory to determine the setting required to eliminate respiratory events. Figure 30.32 shows a compressed 20-minute epoch that demonstrates an acceptable CPAP titration. Figure 30.33 is an all-night hypnogram that shows normalization of oxygenation overnight during a CPAP titration. With the acceptance of HSATs, many patients never undergo a laboratory study and are prescribed an autotitrating PAP device. These devices have a minimum and maximum pressure, and the device senses flow changes and makes real-time changes (Fig. 30.34).

Some patients may require more sophisticated pressure delivery. Bilevel positive airway pressure (Bi-PAP) delivers a different pressure during inhalation and exhalation and is used for patients with hypoventilatory syndromes or OSA patients who require very high pressures or have pressure intolerance. Patients who have CSA, mixed OSA and CSA, or TECSA may require Bi-PAP with a backup rate or, alternatively, adaptive servoventilation (ASV). ASV, also called anticyclical ventilation (to the patient’s own respiratory drive), aims to stabilize respiratory drive by varying the amount of pressure support. The device continuously tracks the patient’s airflow in a 3- to 4-minute window, calculates the average weighted minute ventilation (MV) or peak flow, and then

Atlas of Clinical Sleep Medicine   327 CHIN(1) 250 V

Digital video

CURSOR: 01:43:16. EPOCH: 352 • STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x8 ABD RES x1 120

PULSE bpm

40 70

PCO2

mm Hg -4

POSITION CPAP

30

cm H20

2

AIRFLOW 62.5 V

Figure 30.20  ​Obstructive sleep apnea (OSA) is shown in this 5-minute epoch of a 13-year-old obese patient who weighed 225 pounds and had tonsillar

hypertrophy. At presentation, the patient complained of snoring and daytime hypersomnolence. His apnea-hypopnea index (AHI) was 42 respiratory events per hour with lowest measured oxygen saturation of 62%. Forgoing adenotonsillectomy for treatment, the patient underwent nasal continuous positive airway pressure titration with resolution of OSA. AHI scores are higher in obese children compared with normal-weight children with OSA. Obese children are also less responsive to adenotonsillectomy treatment compared with normal-weight children.

Figure 30.21  ​Tonsillar hypertrophy. This 14-year-old was diagnosed with obstructive sleep apnea (OSA) by polysomnography (PSG), with an apnea-hypopnea

index of 6.5 respiratory events per hour. The primary cause of sleep-disordered breathing in preschool and early school-age children is enlarged adenoids and tonsils; this is also often present in adolescents with OSA and needs further evaluation by PSG. (See Chapter 29 for a description of classification of tonsil enlargement.) (Courtesy Meredith Merz, MD.)

328  Sleep Apnea in the Adolescent and Adult

A

B

Figure 30.22  ​Late-onset laryngomalacia can be a risk factor for sleep-disordered breathing in adolescents. These bronchoscopic images demonstrate laryngo-

malacia before (A) and after (B) supraglottoplasty in an 11-year-old patient. Significant improvement was seen in the airway obstruction after surgical therapy. (Courtesy Kris Jatana, MD.)

A

B

C Figure 30.23  ​Craniofacial abnormalities. A, A 16-year-old male patient with a history of multiple craniofacial anomalies as the result of an unidentifiable genetic

disorder. To assess daytime hypersomnia and snoring, a polysomnogram was performed that identified mild obstructive sleep apnea with an apnea-hypopnea index of 7.5 respiratory events per hour. The family opted for nasal continuous positive airway pressure therapy with a custom-fitted nasal mask, which resulted in resolution of the snoring and hypersomnia. B and C, Relatives (an aunt and nephew) with sleep-disordered breathing and congenital craniofacial and musculoskeletal abnormalities of the head and neck. The 26-year-old female patient (B) has severe scoliosis and Klippel-Feil syndrome (KFS), an autosomal-dominant congenital disorder characterized by a defect in the formation or segmentation of the cervical vertebrae during the early weeks of fetal development, resulting in a fused appearance. The clinical triad for KFS consists of a short neck, low posterior hairline, and limited neck movement; fewer than 50% of patients demonstrate all three clinical features. C, The 10-year-old male patient has frontofacionasal dysostosis, a congenital disorder that appears to be inherited as an autosomal recessive trait. Physical traits commonly seen include brachycephaly, cleft lip or palate, hypoplasia of the nose with malformation of the nostrils, narrowing of the palpebral fissures, blepharophimosis, ocular hypertelorism, coloboma, lagophthalmos, and other eye abnormalities. This patient’s complicated medical history also included surgical repair of tetralogy of Fallot and DiGeorge syndrome.

Atlas of Clinical Sleep Medicine   329 L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

PRESS FLOW CFLOW MICRO ECG

0 128 0 128 0

RR CHEST

128

ABD

128

S

BODY LeftLeg RightLeg SaO2

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

0 0 90

EPAP

0

IPAP

0

EtCO2

0

74

75 0 0

0

-1

STAGE

77 0

421

0

-1

S2

S2

82

81 0

0

-1

S2

77 0

-1 S2

0

80 0

81 0

0

0

0

-1 S2

421 422

-1

S2

S2

90

80 76 79 87 83 0 0 0 0

0 0 -1

S2

422 423

0 -1

S2

0 -1

S2

S2

423 424

0

0

-1

-1

S2

S2

83

0

0

0

0

83

S2

S2

0

0

-1 S2

86

80 0

0

-1

424 425

60”

92

0

0

-1 S2

425 426

78 0

-1 S2

0

0

-1

S2

0

-1

S2

426 427

120”

76 76 78 80 78 76 0 0 0 0 0

S2

0

0

-1 S2

S2

427 428

0

-1

-1

S2

S2

S2

428 429

180”

76 0

76 0

76 0

0

0

0

-1

-1

S2

76

-1

S2

S2

429 430

S2

430

240”

30

Figure 30.24  ​Severe obstructive sleep apnea (OSA) in a 25-year-old male patient with Down syndrome who came to the clinic with complaints of daytime

sleepiness with snoring. Physical examination identified midface hypoplasia, macroglossia, and a body mass index of 32. The polysomnogram (PSG) identified an apnea-hypopnea index of 48.2 respiratory events per hour with lowest measured oxygen saturation of 65%. Facial dysmorphisms and upper airway abnormalities place patients with Down syndrome at risk for upper airway obstruction and OSA. The prevalence of sleep-disordered breathing in children with Down syndrome is very high. Obesity, adenoid hyperplasia, previous tonsillectomy or adenoidectomy, congenital heart disease, malocclusion, and macroglossia do not affect the prevalence. PSG should be a routine investigation for children with Down syndrome regardless of body habitus.

L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

PRESS FLOW CFLOW MICRO ECG

0 128 0 128 0

RR CHEST

128

ABD

128

S

BODY LeftLeg RightLeg SaO2

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

0

97

90

97

96

EPAP

0

0

0

0

IPAP

0

0

0

0

EtCO2

0

0

STAGE

S

0

0

93

84 0

0 0 0

80 0

0 0

0 0

76 0

76 0

0

0

0

0

85

82

0 0

93

83 0

0

0 0

0 0

88

88

0

0

0 0

0 0

84 0

84 0

86

88

0

0

0

0

0

0

0

82 0

0 0

82 0

0 0

0 0

94

88

91

89

87

0

0

0

0

82 0

77 0

75 0

82 0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

90

0

REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM

311

311 312

312 313 60”

313 314

314 315 120”

315 316

316 317 180”

317 318

318 319 240”

319 320

320 30

Figure 30.25  ​Sleep-disordered breathing (SDB) in neuromuscular disease. This graph demonstrates a 5-minute epoch of a 12-year-old female patient with type

II spinal muscle atrophy and severe kyphoscoliosis. The apnea-hypopnea index was 30 events per hour of sleep with severe hypoxemia. This graph illustrates respiratory instability during rapid eye movement sleep, and the patient underwent successful bilevel pressure titration. In children with spinal muscular atrophy, SDB leads to relevant impairment of sleep and well-being. Improvement in both sleep and well-being is possible with nocturnal noninvasive ventilation.

330  Sleep Apnea in the Adolescent and Adult LOC-M2 ROC-M1 F3-M2 F4-M1 C3-M2 C4-M1 O1-M1 O2-M2 CZ-O1 CHIN1CHIN2 RATE Snore ECGECG2 SpO2

94

95

95

96

94

95

94

96

95

95

95

95

95

94

96

94

96

94

96

95

96

94

95

94

96

EtCO2

46

45

46

45

46

46

47

47

47

46

46

45

45

46

45

47

46

47

47

47

45

47

46

47

47

47

Capno

30

15

26

7

31

7

31

7

31

7

31

10

22

17

18

23

17

23

18

22

9

30

10

29

14

27

94

PTAF Airflow THOR ABD LAT-RAT

Figure 30.26  ​Central sleep apnea with mild desaturations to 92% in a 13-year-old adolescent who was 6 weeks premature at birth. Magnetic resonance imaging

of the brain was normal and showed no evidence of an abnormality and no signs of an Arnold-Chiari malformation. The young teen had normal growth and development while doing well in school. The lack of symptoms and normal Sao2 led to the decision not to treat this finding.

L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

PRESS FLOW CFLOW MICRO ECG

0 128 0 128 0

RR CHEST

128

ABD

128

LeftLeg RightLeg

S

S

BODY

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

0 0

99

99

98

99

99

99

99

99

99

98

99

99

EPAP

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

IPAP

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

S2

S2

S2

S2

S2

S2

S2

S2

S2

S2

SaO2

STAGE

90

99

98

S2

281

S2

99

S2

99

S2

281 282

99

S2

99

S2

282 283 60”

283 284

98

98

S2

S2

284 285 120”

99

S2

99

S2

99

S2

285 286

99

S2

S2

286 287 180”

287 288

98

99

98

S2

S2

288 289 240”

98

S2

99

S2

99

S2

289 290

S2

S2

290 30

Figure 30.27  ​Periodic limb movements (PLMs) in a 14-year-old male patient evaluated for sleep-disordered breathing (SDB) based on a history of attention-

deficit/hyperactivity disorder with aggressive behavior related to nonrestorative sleep. The parents reported no history of snoring and no witnessed apneas during sleep. Further history elicited long-standing growing pains that were more prevalent in the right leg and sporadic sleep-maintenance insomnia, along with the nonrestorative sleep. The patient occasionally had a morning headache. Family history identified two grandparents who may have had restless legs syndrome (RLS). Polysomnography did not identify SDB but did reveal PLMs, primarily involving the right leg, as illustrated. With a diagnosis of RLS and PLM disorder, laboratory analysis identified an iron deficiency anemia with a ferritin level of 5 ng/mL, so ferrous sulfate therapy was started. Follow-up 3 months later revealed resolution of growing pains along with more consolidated sleep. Further follow-up 6 months later revealed correction of anemia with a ferritin level of 50 ng/mL. Some children who are diagnosed with growing pains meet the diagnostic criteria for RLS, and a positive family history is common for these children.

Atlas of Clinical Sleep Medicine   331

Display

Humidifier

Tubing

Figure 30.28  ​Two different positive airway pressure machines with humidifiers and tubing. The devices have a blower with a display that allows the provider

and patient to see data from the usage along with a humidifier either on the side (left device) or behind it (right device). Tubing may be noninsulated or insulated (right device), in which the tubing plugs into the humidifier section and has a wire through the tube that helps maintain the temperature as the air transits through the tubes. Both devices can use either insulated or noninsulated tubing.

Figure 30.29  ​Different types of nasal positive airway pressure interfaces. These fit completely over the nose but do not cover the mouth. The tubing may come out of the front of the mask (two devices at right) or the top of the unit with soft tubes on the sides of the face to deliver the airflow.

Figure 30.30  ​Different types of under-the-nose positive airway pressure interfaces. The tubing may come from the bottom of the nose or the top of the circuit, with soft tubes on the sides of the face to deliver the airflow. The portion that contacts the nares may have small inserts (pillows) that fit snugly into the nose (two devices at left) or just an opening that fits snugly under the nose (two devices at right).

332  Sleep Apnea in the Adolescent and Adult

Figure 30.31  ​Different full-face mask styles. As can be seen, most masks are triangular and cover the nose and mouth completely, but newer models (far left) are seated below the nostrils and eliminate the weight of the mask on the nasal bridge. The full-face mask is useful for “mouth breathers”—that is, those with nasal obstruction—and for those who have had palatal surgery.

L-EOG

0

R-EOG

0

C3-A2

0

C4-A1

0

O1-A2

0

O2-A1

0

CHIN

0

CFLOW 0 MICRO128 ECG

0

RR CHEST128 ABD

128

S

BODY SaO2

90

95

S

S

95

S

95

S

S

95

S

S

95

96

S

S

S

S

96

96

96

S

S 96

S 95

S

S

95

S

S

96

S

96

S

S

96

S

95

S

S

S

S

S

95

95

95

95

S

S

95

EPAP

0

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

IPAP

0

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

8

STAGE

REM

REM

REM

REM

REM

REM

120”

REM

REM

REM

REM

240”

REM

REM

REM

REM

REM

360”

REM

REM

REM

REM

REM

REM

REM

480”

Figure 30.32  ​Adequate continuous positive airway pressure (CPAP) titration. This 10-minute compressed epoch demonstrates a positive outcome of CPAP titra-

tion. The patient is in rapid eye movement sleep, indicated by the stage scoring at the bottom of the montage and also by the eye jerks in the electrooculogram and low chin tone. The patient is supine, indicated by the S in the BODY channel. The flow channel (CFLOW) is stable, as is saturation (SaO2) at 95% to 96%, and the microphone (MICRO) is silent. This patient should do well on 8 cm H2O CPAP.

adjusts the respiratory parameters to maintain 90% of the calculated MV or peak flow (Fig. 30.35). However, ASV must be used with caution, as it has been shown to result in increased mortality (,45%) in one study of patients with heart failure with low ejection fraction. Patients can be treated for many years, often with dramatic results. However, CPAP may have a variety of complications, such as nasal obstruction or stuffiness, pressure ulcers, and rashes

(Fig. 30.36). Persistent daytime sleepiness after appropriate CPAP therapy in a compliant patient with OSA may require treatment with stimulant medications. CPAP may be effective in adolescents, but as with adults, adherence can be a problem. Oral Appliance Therapy An alternative to CPAP is the use of an oral appliance or dental device. Such devices can be effective in patients with

Atlas of Clinical Sleep Medicine   333 21:49

22:49

23:49

00:49

01:49

02:49

03:49

04:49

05:37

W R 1 2 3 4

Sleep Stages B R F L

Position

HYP

APN

Apneas and Hypopneas 100 90 80 70 60 50 Des

SaO2 20

AHI4.0

16 12

AHI11.7

AHI9.5

8

AHI108

4 0

CPAP Hours

1

2

3

4

5

6

7

8

Figure 30.33  ​Adequate continuous positive airway pressure (CPAP) titration. Top to bottom: This all-night hypnogram consists of sleep stages, position, pres-

ence of apneas and hypopneas, SaO2 desaturations, and CPAP pressure over almost 8 hours of a split-night study. Notice that before CPAP, sleep is unstable with no rapid eye movement (REM) sleep and many apneas and hypopneas with large oscillations in SaO2. On the final CPAP pressure, the apnea-hypopnea index is normal, and the patient has REM sleep. AHI, apnea/hypopnea index.

mild to moderate OSA, especially if the patient is not morbidly obese. Patients with retrognathia (Fig. 30.37) who sleep with their mouths open or those with positional OSA are good candidates for such treatment. The most widely used type of oral appliance is the mandibular advancement device (Fig. 30.38). Dozens of different models are available, generally through a dentist. In teens, rapid maxillary expansion may be beneficial in some situations (Fig. 30.39). Surgery In most patients, surgery is considered only after the lessinvasive treatments have been tried. Surgery can be directed toward anatomic lesions that obstruct the upper airway, such as enlarged tonsils and adenoids, or it may target skeletal

abnormalities that involve facial structures. In 2014, hypoglossal nerve stimulation was shown in a trial to be effective in select patients to adequately treat OSA. The device is implanted under the skin, usually on the right upper thorax, and has a sensing lead that is placed in the intercostal region as well as a stimulation lead that is tunneled under the skin and wraps around the hypoglossal nerve. The patient uses a remote control to turn the device on at night. The device stimulates based on the respiratory cycle (Fig. 30.40) and hence moves the tongue forward to open the upper airway (Fig. 30.41B). Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

334  Sleep Apnea in the Adolescent and Adult Mode: Auto CPAP with A-Flex

Pressure cm H2O Auto CPAP

Min. CPAP Setting

Max. CPAP Setting

20 15 10 5 0 0

1

2

3

4

5

6

7

8

Sleep Therapy Flags PB CA OA H FL VS RE 0 1 2 3 4 5 6 7 8 FL - Flow Limitation, VS - Vibratory Snore, PB - Periodic Breathing, CA - Clear Airway Apnea, RE - RERA, H - Hypopnea, OA - Obstructive Sleep Apnea Total Leak (LPM) Normal mask fit LL 120 100 80 60 40 20 0

0

1

Breathing not detected

2

3

Total leak

Large leak (LL)

4

5

6

7

8

Figure 30.34  ​Download from a patient’s autotitrating positive airway pressure device. The top panel shows the lower and upper pressure limits (lower identified

by the pink bar 5 10 cm H2O, and upper identified by the yellow bar 5 20 cm H2O) with the moving line demonstrating the pressure going up and down in response to the events noted in the second panel. The device senses flow and marks them as the various categories. The bottom panel shows if a leak is present, which may also affect efficacy of the device. On this night, no significant leak was present. CPAP, Continuous positive airway pressure; RERA, respiratory effort– related arousal; LPM, liters per minute.

ECG

PAP

CFlow

Thor

ABD

SpO2

Figure 30.35  ​Polysomnogram of a patient undergoing an adaptive servoventilation titration. Note the pressure levels (PAP) are differing between breaths as the device adapts to the patient’s ventilation. As the airflow (CFlow) goes down, the pressure goes up in response.

Atlas of Clinical Sleep Medicine   335

A

B

Figure 30.36  ​Pressure from the mask can cause tissue breakdown and infection. A, This patient developed a weepy pustule on the bridge of her nose. She had been overtightening her mask. Educating the patient and switching masks solved her problem. B, The local reaction to a full-face mask in this patient was perioral bacterial dermatitis, which required oral amoxicillin and topical 1% metronidazole gel.

Figure 30.37  ​The patient with retrognathia is a good candidate for an oral appliance. Note that although this patient’s mandible is retrognathic, as evidenced

by the overjet, the lower jaw appears normal because of a pad of soft tissue on the chin. In fitting for an oral appliance, an impression of the maxilla and the mandible is taken with the mandible advanced to or beyond normal occlusion. When in place, oral devices then advance the lower jaw, which opens the posterior airway.

A

B

Figure 30.38  ​Mandibular advancement device. A, frontal view of a Herbst appliance with an upper and lower acrylic mouthpiece covering the maxillary and

mandibular teeth held together by a telescoping metal bar that can be either shortened or extended as needed to retrude or protrude the mandible. Rubber bands are placed around the upper and lower biteplates to prevent extended mouth opening. B, Side view showing the telescoping rod. (Courtesy Andrew Soulimiotis.)

336  Sleep Apnea in the Adolescent and Adult

Figure 30.39  ​Rapid maxillary expansion. A rapid maxillary palate expander in a 13-year-old female patient with a body mass index (BMI) of 75% predicted. The

patient had a history of snoring and restless sleep and was referred to an orthodontist for dental occlusion. At the same time, she was referred for polysomnogram, which identified obstructive sleep apnea with an apnea-hypopnea index (AHI) of 5.8 respiratory events per hour. The rapid maxillary expander was placed, and a repeat polysomnogram 6 months after completion of maxillary expansion revealed an AHI of 0.6 respiratory events per hour.

Chin EMG

Snore NCPT Therm Thor ABD SpO2

Figure 30.40  ​Polysomnography of a patient with hypoglossal nerve stimulator on. The lead marked chin EMG shows the electrical stimulation with the increased muscle contraction timed with inspiration; see thoracic effort (Thor) and abdominal effort (ABD) belts. Note that some snoring (Snore) persists.

Atlas of Clinical Sleep Medicine   337

Soft palate Vacuum source

Mouthpiece

A 3. Pacing lead

Submandibular gland

1. Pacing device Surgery to expose structures

CN XII

Digastric m. Mylohyoid m.

Pectoralis major Intercostal muscles Neurovascular bundle Sensing lead Rib Lung

Cuff electrode

Medial branch of CN XII Mylohyoid m.

2. Sensing lead 4. Implanted lead Digastric m.

B Figure 30.41  ​Hypoglossal nerve stimulation. A, Stimulation of branches of the hypoglossal nerve (cranial nerve [CN] XII) can push the tongue forward and

increase the size of the retroglossal airway. B, The Inspire system is composed of a pacing device (1); a lead that senses respiration, which is placed in the rib cage (2); and a pacing lead (3) that is implanted on a branch of the hypoglossal nerve (4). (Modified from Van de Heyning PH, Badr MS, Baskin JZ, et al. Implanted upper airway stimulation device for obstructive sleep apnea. Laryngoscope. 2012;122[7]:1626–1633.)

  e1 Bibliography

American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the scoring of sleep and associated events. J Clin Sleep Med. 2012:8(5):597–619. Berry RB, Quan SF, Abreu AR, et al., for the American Academy of Sleep Medicine (AASM). The AASM Manual for the Scoring of Sleep and Associated Events: Terminology and Technical Specifications. Version 2.6. Darien, IL: AASM; 2020. Chang JL, Goldberg AN, Alt JA, et al. International consensus statement on obstructive sleep apnea [published online ahead of print, 2022 Sep 6]. Int Forum Allergy Rhinol. 2022. doi:10.1002/alr.23079. Collop N, Tracy S, Kapur V, et al. Obstructive sleep apnea devices for out of center (OOC) testing: technology evaluation. J Clin Sleep Med. 2011;7(5):531–548. Fitzgerald DA, Paul A, Richmond C. Severity of obstructive apnoea in children with Down syndrome who snore. Arch Dis Child. 2007;92(5):423–425. Hnin K, Mukherjee S, Antic NA, et al. The impact of ethnicity on the prevalence and severity of obstructive sleep apnea. Sleep Med Rev. 2018; 41:78–86. Kapur VK, Auckley DH, Chowdhuri S, et al. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American

Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(3):479–504. Linz D, McEvoy RD, Cowie MR, et al. Associations of obstructive sleep apnea with atrial fibrillation and continuous positive airway pressure treatment: a review. JAMA Cardiol. 2018;3(6):532–540. McNicholas WT, Pevernagie D. Obstructive sleep apnea: transition from pathophysiology to an integrative disease model. J Sleep Res. 2022; 31(4):e13616. Mitchell RB, Kelly J. Outcome of adenotonsillectomy for obstructive sleep apnea in obese and normal-weight children. Otolaryngol Head Neck Surg. 2007;137(1):43–48. Mukherjee S, Saxena R, Palmer L. The genetics of obstructive sleep apnea. Respirology. 2018;23(1):18–27. Ramar K, Dort LC, Katz SG, et al. Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015. J Clin Sleep Med. 2015;11(7):773–827. 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. Zinchuk AV, Gentry MJ, Concato J, Yaggi HK. Phenotypes in obstructive sleep apnea: a definition, examples and evolution of approaches. Sleep Med Rev. 2017;35:113–123.

Chapter

31

Sleep Breathing Disorders in Children Stephen H. Sheldon

CONGENITAL CENTRAL HYPOVENTILATION SYNDROME Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system typically identified in newborns who have alveolar hypoventilation usually during non–rapid eye movement (NREM) sleep. More severely affected patients hypoventilate while both awake and asleep.1 Although CCHS is typically diagnosed in the newborn period, patients may be diagnosed later in childhood and in adulthood.2 About 90% of CCHS patients are heterozygous for the PHOX2B polyalanine repeat expansion mutation.3 However, if screening for the PHOX2B gene mutation is negative but suspicion is high, sequencing tests should be performed to adequately rule out CCHS as the underlying cause for hypoventilation. Clinical findings suggesting CCHS in the neonate include very shallow respiratory efforts associated with alveolar hypoventilation, cyanosis, and hypercapnia. Symptoms often occur only during sleep (nocturnal and diurnal/naps). During the wake state, the infant is alert and appears to breathe normally. Respiratory distress and increased work of breathing are notably absent. Because underlying pathophysiology involves autonomic nervous system dysregulation and maldevelopment of neural crest–derived cells, other features of CCHS involve physiologically associated abnormalities and findings. Hirschsprung disease is a common feature4 as is dysregulation of glucose homeostasis.5 Neural crest tumors, particularly neuroblastomas, ganglioneuromas, and ganglioneuroblastomas, can be present. Patients with CCHS do not respond normally to hypercapnia or hypoxemia. There is limited ventilatory response to high carbon dioxide levels or low oxygen tension. Late-onset CCHS should be considered in patients who hypoventilate or develop seizures following general anesthesia, in the presence of central nervous system depressants, in the presence of severe pulmonary infections, or when hypoventilation occurs after effective treatment for obstructive sleep apnea (OSA). Cardiac abnormalities include transient sudden asystole and decreased beat-to-beat variability. Pulmonary hypertension, cor pulmonale, and poor school performance may also be associated with CCHS. Ocular findings involve abnormal pupillary function. As with any rare disease with profound morbidity and mortality without therapeutic intervention, multidisciplinary care is needed, including pediatricians, cardiologists, otolaryngologists, ophthalmologists, psychiatrists, psychologists, nurses, social workers, respiratory therapists, teachers, and others. Treatment is focused on maintaining ventilation. This 338

is best accomplished with tracheostomy and mechanical ventilation or with diaphragm pacing. The latter treatment may result in OSA. OBSTRUCTIVE SLEEP APNEA IN CHILDREN OSA in children is common and can result in severe sequelae if unrecognized and untreated. Pediatric OSA is a disorder of breathing characterized by intermittent partial or complete obstruction of the upper airway that disrupts normal respiration and ventilation during sleep and disrupts normal sleep patterns.6 Pediatric OSA is most often caused by enlarged tonsils and adenoids, abnormalities in skeletal structures that involve the jaw, or obesity (Fig. 31.1). Obstruction may also consist of prolonged periods of partial upper airway obstruction accompanied by symptoms or signs of habitual snoring (.3 nights per week); increased work of breathing during sleep; and gasping, snorting, or choking during sleep. Associated symptoms and signs may include sleep-related enuresis, sleeping with neck hyperextension, hyperactivity, attention problems, daytime sleepiness, learning difficulties, hypertrophied tonsils and/or adenoids, failure to thrive, overweight, and hypertension. Neurocognitive impairment and behavioral problems may also occur. Obesity, adenotonsillar hypertrophy, neuromuscular disorders, and craniofacial abnormalities may also contribute to the presence and/or severity of pediatric OSA. The prevalence of pediatric OSA has been reported to range from 1.2% to 5.7% of the pediatric population.7–9 Sequelae from OSA are not uncommon. These range from cognitive deficits to problems in neuropsychologic function,9,10 but there does not seem to be a correlation between the severity of pediatric OSA and neurocognitive morbidity. Objective measurement of sleepiness using multiple sleep latency testing (MSLT) has revealed increased sleepiness in children with pediatric OSA.7,8,11 Cardiovascular effects can range from ventricular remodeling to persistently elevated blood pressure.12 A relationship has also been found between pediatric OSA, polycystic ovarian syndrome, and metabolic syndrome.13 Diagnosis cannot be based on history and physical examination alone.14 Comprehensive nocturnal polysomnography remains the gold standard for diagnosis. Alternative methods have ranged from home pulse oximetry to home audio/video recording. Although home and alternative testing have fairly good sensitivity and are evolving (especially when used in older children),15 the specificity may be quite poor and results in a very poor negative predictive value.16

Atlas of Clinical Sleep Medicine   339

A

B

C Figure 31.1  ​The most common causes of obstructive sleep apnea (OSA) in the child include enlarged tonsils and adenoids (A), obesity (B), and abnormal jaw structure (C). Many diseases that cause craniofacial abnormalities can result in abnormal jaw structure and predispose the patient to develop OSA.

HISTORY AND PHYSICAL EXAMINATION Although the history and physical examination have poor sensitivity and specificity in the diagnosis of pediatric OSA, they are an essential starting point. Symptoms and signs include those listed in the following sections.

Historical Symptoms of Obstructive Sleep Apnea in Children Symptoms of OSA in children include the following: • Habitual snoring (.3 nights per week) • Reported observed apneas • Gasping, snorting, or choking during sleep • Increased work of breathing • Inability to sleep in a flat position • Chronic mouth breathing • Sleeping with the neck hyperextended • Sleeping in a sitting position • Morning headaches • Secondary sleep-related enuresis • Reported observed cyanosis • Daytime sleepiness • Hyperactivity • Daytime attention problems • Learning difficulties Common Physical Examination Findings Common physical examination findings in children include the following: • Enlarged tonsils • Enlarged adenoids with adenoidal facial features • Micrognathia • Retrognathia • High-arched palate • Elongated palate • Crowded oropharynx • Failure to thrive • Elevated blood pressure • Obesity Technical Considerations Polysomnographic diagnosis of pediatric OSA is quite different from that proposed for adult OSA, and the technical considerations differ considerably.17 The sensor recommended for determination of absence of airflow is a thermal sensor, whereas a pressure without square root transformation is recommended for identification of hypopnea. Effort sensors recommended are inductance plethysmography or polyvinylidene fluoride (PVDF) effort belts. Pulse oximetry is used for monitoring oxygen saturation, and continuous monitoring of end-tidal carbon dioxide (Etco2) can be used for evaluation of both airflow and the presence of hypoventilation. Unlike pressure or temperature recordings, the Etco2 wave possesses particular characteristics. As shown in Figure 31.2, the recording between points A and B occurs at the beginning of exhalation and represents dead space air from the nose and nasopharynx. Exhaled air between points B and C represents dead space air from larger and smaller airways (trachea, bronchi, and bronchioles). The recording between points C and E is representative of alveolar air and is termed the alveolar plateau. Point E is the point at which the expiratory portion of a tidal breath occurs and is the point of Etco2. Measurement of exhaled CO2 and breath-to-breath variability of exhaled CO2 is continuous. It is very helpful to measure breath-to-breath variability of exhaled carbon dioxide, rather than simply evaluating a running average of Etco2. Because the Etco2 waveform as described earlier provides accurate documentation of exhaled carbon dioxide, flow limitation and exhalation of dead-space

340  Sleep Breathing Disorders in Children

E C

EtCO2 wave D

B A

Pressure

Figure 31.2  ​A comparison of the end-tidal carbon dioxide (Etco2) waveform

and the pressure waveform. Points A and B, The beginning of exhalation with dead space air from the nose and nasopharynx. B and C, The second phase of exhalation, with CO2 again from dead space air but from larger airways, including the trachea, bronchi, and bronchioles. C to E, The alveolar plateau is CO2 exhaled from the alveoli; it ends with the maximal exhalation of CO2 at the end of a tidal breath. Point E is the point of Etco2. Continuous CO2 is measured and recorded, and breath-to-breath variability is also noted. Elevation of an individual breath’s CO2 is seen during recovery breathing after an apnea or hypopnea. During obstructive hypoventilation, CO2 is elevated more than 50 mm Hg for more than 25% of the total sleep time.

air result in change in shape of the tracing. Alveolar plateau narrows and disappears, leaving a narrow and peaked signal. As flow limitation continues, the peak then decreases in amplitude along with a decrease in pressure and thermal signals (Fig. 31.3). In many cases, because of the difficulty in maintaining sensors because of a child’s tactile defensiveness, redundancy in recording is required, and alternate sensors may be used to determine absence of airflow and/or absence of effort. For example, if the thermal signal is unreliable, the pressure signal may be used to determine apnea; if the pressure signal is unreliable, the thermal signal may be used to determine hypopnea. The Etco2 signal and/or the sum of the respiratory inductive plethysmography belt signal may also be used, if needed. Definitions Obstructive Sleep Apnea Obstructive sleep apnea is defined as two or more respiratory efforts with obstructed airflow with at least a 90% decrease in

a

the flow signal for 90% or more of the event. Duration of the apnea is determined from the end of the last normal breath to the beginning of the first breath to prebaseline for effort (Figs. 31.4 and 31.5). Mixed Sleep Apnea Mixed sleep apnea is defined as two or more obstructed respiratory efforts without airflow, associated with a 90% decrease in the flow signal for at least 90% of the respiratory event. In addition, mixed apnea requires absent inspiratory effort at the beginning of the event and resumption of effort at the end of the event (Fig. 31.6). Central Sleep Apnea Central sleep apnea is identified when absence of airflow is associated with absence of respiratory effort throughout the entire duration of the event. In addition, the event must last at least 20 seconds, or there must be the equivalent of two missed breaths associated with an arousal, awakening, or 3% or more desaturation from the oxygen saturation baseline. Hypopnea A hypopnea (Fig. 31.7) must meet all of the following criteria: • The decrease in the pressure signal (or alternate airflow signal) must be more than 50%. • The event must last for at least two respiratory efforts. • The decrease in pressure must last for 90% of the event or longer. • An arousal, an awakening, or at least a 3% decrease in oxygen saturation occurs. Respiratory Effort–Related Arousal A respiratory effort–related arousal (RERA) may be present if a decrease in airflow is measured by pressure at the nose and mouth, but it is less than 50% from baseline. Flattening of the nasal pressure waveform occurs with continued (but decreased) airflow measured by other sensors, snoring is present, breathing is noisy, Etco2 is elevated on recovery breaths, CO2 is elevated on transcutaneous monitoring, and work of breathing is notably increased. Duration of the event should be more than two respiratory efforts.

b

CO2 Pressure PTAF Airflow Chest Intercostal EMG Abdomen

Figure 31.3  ​An end-tidal CO2 waveform can provide other significant information when assessing occlusive and/or partially occlusive respiratory events

(apneas, hypopneas). When flow limitation occurs, there is a change in the shape of the curve with first loss of alveolar plateau because there is increasing measurement of dead space carbon dioxide levels. This is followed by a decrease in the amplitude of the waveform. Waveforms under (a) represent breaths with alveolar plateaus. Waveforms under (b) represent breaths with airflow limitation and dead-space air. EMG, Electromyography; PTAF, pressure transducer airflow.

Atlas of Clinical Sleep Medicine   341

Figure 31.4  ​Obstructive apnea in a 3-year-old patient. Note the absence of airflow in all flow channels—thermal, pressure, and end-tidal carbon dioxide

(Etco2)—for two continued respiratory efforts; arousal following the event, as noted by increased respiratory effort and airflow; increased chin muscle tone; and a mild decrease in R-R interval on electrocardiogram, indicating a brief elevation in heart rate. A 4% decrease in oxygen saturation from the baseline is evident before the onset of the event. Airflow signal has decreased greater than 90% from baseline, and it persists for more than 90% of the obstructive event.

Figure 31.5  ​Obstructive apneas occur commonly in rapid eye movement sleep. Obstructive respiratory events are frequent in this 2-minute epoch and last about 10 to 20 seconds, fulfill all criteria for obstructive apneas, and are associated with arousal and sleep fragmentation. In addition, periodic oxygen desaturation greater than 3% from baseline is associated with most events.

342  Sleep Breathing Disorders in Children

Figure 31.6  ​Mixed apneas are characterized by respiratory events associated with what appears to be absent respiratory effort during the beginning of the event (point A), with resumption of inspiratory and expiratory respiratory effort without return of airflow (point B). The initial portion of the event, in which rhythmic inspiration and exhalation cannot be identified by respiratory inductive plethysmography or other effort belts, appears “central” when monitoring only airflow by a thermal or pressure sensor. However, the initial portion of a mixed apnea may still be partially obstructive in character, as identified by the prolonged alveolar plateau noted at point C. This represents somewhat prolonged exhalation of carbon dioxide against a partially occluded upper airway.

Figure 31.7  ​Hypopneas are discrete respiratory events in which airflow decreases 50% or more, as measured by the pressure channel, with continued respira-

tory effort as noted in the respiratory inductive plethysmography channels and intercostal electromyogram (EMG). The shape of the end-tidal carbon dioxide (Etco2) waveform changes considerably because alveolar air cannot be exhaled, and there is loss of the alveolar plateau with remaining CO2 coming from airway dead space. Some exaggeration of the normal respiratory sinus variation is apparent on the electrocardiogram; vibratory snore artifact is noted in the chin muscle EMG, and snores are noted in the sonography (Snore) channel.

Atlas of Clinical Sleep Medicine   343 Obstructive Hypoventilation Obstructive hypoventilation is present when either Etco2 or transcutaneous CO2 (TcPco2) is greater than 50 mm Hg for more than 25% of the total sleep time. Expiratory Apnea/Hypopnea Expiratory apneas15,16 are common events that have questionable clinical significance.18 They are difficult to identify when only pressure and thermal methods are used for identification of airflow. Expiratory apneas typically consist of an initial augmented breath (sigh) followed by a respiratory pause of varying length, associated with either rapid or slow return to the normal end-expiratory lung volume. These events can be identified by prolongation of the alveolar plateau as measured by Etco2 waveform (Fig. 31.8).

can result in identical findings (Figs. 31.9 to 31.11). Nevertheless, on occasion there may be paradoxical narrowing of the airway with neck hyperextension (Fig. 31.12). Decision making regarding the method of therapeutic intervention can sometimes be difficult when the tonsils are not significantly hypertrophic on clinical examination. When flexible drug-induced sleep endoscopy was used in 196 children, tonsillar obstruction was present in 45.2% without significant tonsillar enlargement (70 11 enlarged; 126 21 enlarged).20 This procedure-directed tonsillectomy was performed on 57 children, and there was significant improvement in the respiratory disturbance index and nadir oxygen saturation both at 6 months and 1 year following the procedure when compared with controls.

DIAGNOSTIC CONSIDERATIONS

TREATMENT OPTIONS FOR CHILDHOOD OBSTRUCTIVE SLEEP APNEA

The location of the area of obstruction can help direct appropriate management of the patient. Narrowing of the upper airway can occur at any location, from the region of the anterior nasal valve to the level of the glottis and below. At times, subglottic narrowing may also result in upper airway obstruction. Glottic and/or tracheal narrowing may also be involved, particularly in younger children. Laryngomalacia, tracheomalacia, and subglottic stenosis may contribute to or underlie obstructive upper airway disorders.19 Although in otherwise normal children hypertrophy of the tonsils and adenoids is the most common cause, other locations, such as the level of the lingual tonsils or the hypopharynx secondary to micrognathia or retrognathia,

Although the first successful treatment of OSA in childhood was through placement of a tracheostomy, this invasive procedure is rarely required today. Other forms of management are currently recommended and are successful, and new treatment options are on the horizon. Once pediatric OSA has been diagnosed, the approach to treatment depends on patient age, severity of sleep-disordered breathing (SDB), chronicity of SDB, underlying etiology, comorbid states, and patient/parent preference. If the child has symptoms of OSA, is 4 years of age or older, and has physical findings of adenotonsillar hypertrophy, the first-line treatment is adenotonsillectomy. For younger children, an

Figure 31.8  ​This event appears following an augmented breath associated with an arousal during rapid eye movement sleep. There appears to be a central

respiratory pause following the arousal characterized by absence of airflow, as measured by pressure at the nose and mouth, and absence of respiratory effort of the chest or abdomen. Absence of intercostal muscle electromyogram activity is noted. However, end-tidal carbon dioxide recording reveals an extended and prolonged alveolar plateau with persistent exhalation of CO2 throughout the extent of the respiratory pauses. These events are either post-sigh pauses associated with prolonged exhalation, or they may be partially obstructive in character (expiratory apnea/hypopnea).

344  Sleep Breathing Disorders in Children

B

C A

Figure 31.9  ​Hypertrophied adenoids in a 2-year-old patient. Note the narrowing of the posterior nasopharynx (arrows).

Figure 31.10  ​Hypopharyngeal airway narrowing as a result of hypertrophy of lingual tonsils (arrow).

adenoidectomy without tonsillectomy might be considered and, in some cases, a subcapsular tonsillectomy might be recommended. However, adenoidectomy or tonsillectomy alone might not be sufficient because residual tissue may remain and can result in continued obstructive SDB. Unless otherwise contraindicated, an adenotonsillectomy is the treatment of choice for most young children with adenotonsillar hypertrophy. Postoperative polysomnography typically reveals considerable improvement of the SDB, although some residual breathing problems may continue. Risks and benefits must be weighed regardless of treatment choice. Clinical judgment is required in assessment of benefits of adenotonsillectomy compared with the risks and benefits of other forms of treatment.

Figure 31.11  ​Hypopharyngeal airway narrowing as a result of retrognathia.

Narrowing is noted at point A. Note the posterior position of the mandible (point C). A maxillary expander appliance is in place (point B). Interestingly, rapid maxillary expansion will likely do little in the management of this patient’s obstructive sleep apnea because the nasopharynx is adequately sized and the obstruction is located somewhat distal to the nasopharynx.

Although adenotonsillectomy has been the first-line treatment of pediatric OSA for several decades, a study of over 1.2 million children of whom 17,460 had adenoidectomy, 11,830 had tonsillectomy, and 31,377 had adenotonsillectomy yielded unexpected results. The incidence of disease in patients who underwent tonsillectomy and/or adenoidectomy before age 9 years was monitored from 10 years following surgery up to age 30 years. Surgical removal of the tonsils and/or adenoids was associated with a twofold to threefold increased risk of respiratory, infectious, and allergic diseases. It therefore seems important to reassess primary methods of treatment for pediatric obstructive SDB because long-term consequences of a relatively minor surgical procedure may result in sequelae as significant or more significant than those resulting from untreated pediatric OSA.21 Although adenotonsillectomy is a relatively safe surgical procedure, complications can occur.22 Few guidelines exist for anesthesia practice for children with pediatric OSA.23 Of 110 anesthesiologists surveyed, only 27.3% reported that their institution had standardized guidelines for perioperative management of children with OSA following adenotonsillectomy. Of the respondents, 70.9% denied having any hospitalwide guidance regarding management of children with OSA or were unsure if guidelines exist. Management among anesthesiologists and institutions varied considerably. The authors suggested that best practice guidelines for management of these pediatric patients are needed. Similar to adults, nasal continuous positive airway pressure (CPAP) can also be successful in the treatment of children, particularly those with special needs, obese children, and those

Atlas of Clinical Sleep Medicine   345

A

B

Figure 31.12  ​A, The nasopharyngeal airway is widely patent when this 4-year old patient’s neck is evaluated in the neutral position. B, With neck hyperextension, the soft palate and posterior pharyngeal wall approximate and profoundly narrow the nasopharyngeal airway.

in whom adenotonsillectomy may be contraindicated. Adenotonsillectomy may result in less-than-optimal resolution of SDB in the obese patient. Desensitization to the nasal mask is an important interdisciplinary task because it can improve compliance. Appropriate fitting and gradual introduction to the mask and airflow are as important as arriving at a proper pressure. After desensitization, pressure titration can be much more successful. Length of positive airway pressure (PAP) desensitization varies depending on the child’s tolerance and the parents’ consistency, participation, and determination. In the obese patient, optimal therapy includes weight loss, but concomitant therapy with PAP is often required (Figs. 31.13 and 31.14). Some children with bony defects that are either generalized and/or affect skull and facial bones can experience severe OSA requiring interdisciplinary management and PAP therapy. Comprehensive screening for obstructive SDB and appropriate management with PAP therapy can be successful in improving respiration and ventilation during sleep and treating OSA.24 Although bilevel PAP (BiPAP) is commonly thought to improve compliance, little evidence supports that this is true in children. Indeed, compelling anecdotal evidence suggests that CPAP, when appropriately titrated to optimal pressure, is more effective and better tolerated than BiPAP treatment because of needed expiratory load. PAP therapy should be regularly monitored in the sleep clinic because children continue to grow and mature, their needs change, and pressure increase or decrease is common. Adverse effects of PAP therapy are rare but include skin irritation and breakdown, scarring in the mask region, poor compliance with resultant continued symptoms and sequelae, and/or dryness and irritation of the eyes from a mask leak. In very young children, when the membranous bone of the maxilla has not yet completely developed, there is a risk of midface deformities and limited or asymmetrical maxillary growth secondary to pressure from a snugly fitting mask. Topical intranasal corticosteroids have been recommended for children with mild OSA, when adenotonsillectomy is contraindicated, and for children with mild residual OSA following adenotonsillectomy. Individual response to treatment

Figure 31.13  ​In this 5-year-old girl with Crouzon syndrome, severe pediatric obstructive sleep apnea continued after multiple craniofacial surgeries that required nasal continuous positive airway pressure.

is variable, and longitudinal studies have not been conducted to determine the degree and duration of improvement of mild OSA. Intranasal corticosteroids can be augmented by montelukast and/or antihistamines. Again, evidence is unclear as to the degree and duration of improvement of SDB with this adjuvant therapy. In patients with mild to moderate OSA and high-arched elongated palates, rapid maxillary expansion might be considered.

346  Sleep Breathing Disorders in Children

Figure 31.14  ​A 7-year-old girl with Down syndrome. This child was desensitized to her continuous positive airway pressure mask, which was well tolerated. She would place the mask on herself to communicate to her family when it was bedtime. Compliance was excellent.

As with medical treatments, a paucity of evidence supports longterm resolution of OSA using this technique. New pediatric dental techniques may be possible to slowly advance the midface region with both active and passive mandibular advancement. Biobloc orthotropic therapy (BBO) was developed by Dr. John Mew and was first published in the early 1940s. This noninvasive orthodontic technique can significantly increase the size of the hypopharyngeal airway in children, thus decreasing upper airway resistance below the critical closing pressure of the airway. Although described in the literature for more than 50 years, little

A

systematic data exist, other than anecdotally, to document that BBO improves obstructive SDB. Nevertheless, a rapid palatal expansion and twin block mandibular advance device has been shown to improve pharyngeal airway space.25 In addition, other treatment may be required while the child is undergoing maxillary expansion and/or prognathic orthodontia intervention, including adenotonsillectomy and/or PAP therapy (Fig. 31.15). Visit eBooks.Health.Elsevier.com for the References for this chapter.

B

Figure 31.15  ​Active and passive mandibular advancement. A, Biobloc orthotropic maxillary and mandibular appliance (Orthotropics-NA.org). B, Note the rubber bands that extend from the face mask to the maxillary appliance.

Atlas of Clinical Sleep Medicine   347

C

D

Figure 31.15, cont’d ​ C, These bands provide force to pull the alveolar ridge forward. This effect is opposite from traditional orthodontic headgear traction,

which pushes posteriorly. D, Because the orthotropic procedure is slow, when mild to moderate pediatric obstructive sleep apnea persists despite adenotonsillectomy, positive airway pressure (PAP) therapy is sometimes required. The patient showed excellent compliance with both PAP therapy and orthotropic treatment.

  e1 References

1. Ceccherini I, Kurek KC, Weese-Mayer DE. Developmental disorders affecting the respiratory system: CCHS and ROHHAD. Handb Clin Neurol. 2022;189:53–91. 2. Kasi AS, Kun SS, Keens TG, Perez IA. Adult with PHOX2B mutation and late-onset congenital central hypoventilation syndrome. J Clin Sleep Med. 2018;14:2079–2081. 3. Weese-Mayer DE, Rand CM, Zhou A, Carroll MS, Hunt CE. Congenital central hypoventilation syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life. Pediatr Res. 2017;81:192–201. 4. Broch A, Trang H, Montalva L, Berrebi D, Dauger S, Bonnard A. Congenital central hypoventilation syndrome and Hirschsprung disease: a retrospective review of the French National Registry Center on 33 cases. J Pediatr Surg. 2019;54:2325–2330. 5. Musthaffa YM, Goyal V, Harris MA, Kapur N, Leger J, Harris M. Dysregulated glucose homeostasis in congenital central hypoventilation syndrome. J Pediatr Endocrinol Metab. 2018;31:1325–1333. 6. Bitners AC, Arens R. Evaluation and management of children with obstructive sleep apnea syndrome. Lung. 2020;198(2):257–270. 7. Bixler EO, Vgontzas AN, Lin HM, et al. Sleep disordered breathing in children in a general population sample: prevalence and risk factors. Sleep. 2009;32:731–736. 8. Li AM, So HK, Au CT, et al. Epidemiology of obstructive sleep apnoea syndrome in Chinese children: a two-phase community study. Thorax. 2010;65:991–997. 9. O’Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity disorder. Pediatrics. 2003;111:554–563. 10. Spruyt K, Gozal D. A mediation model linking body weight, cognition, and sleep-disordered breathing. Am J Respir Crit Care Med. 2012; 185:199–205. 11. Chervin RD, Weatherly RA, Ruzicka DL, et al. Subjective sleepiness and polysomnographic correlates in children scheduled for adenotonsillectomy vs other surgical care. Sleep. 2006;29:495–503. 12. Brooks DM, Kelly A, Sorkin JD, et al. The relationship between sleep disordered breathing, blood pressure, and urinary cortisol and catecholamines in children. J Clin Sleep Med. 2020;16(6):907–916.

13. Underland LJ, Kenigsberg Fechter L, Agarwal C, et al. Insulin sensitivity and obstructive sleep apnea in adolescents with polycystic ovary syndrome. Minerva Endocrinol (Torino). 2022. doi:10.23736/S2724-6507.22.03619-3. 14. Chervin RD, Weatherly RA, Garetz SL, et al. Pediatric sleep questionnaire: prediction of sleep apnea and outcomes. Arch Otolaryngol Head Neck Surg. 2007;133:216–222. 15. Ioan I, Weick D, Schweitzer C, Guyon A, Coutier L, Franco P. Feasibility of parent-attended ambulatory polysomnography in children with suspected obstructive sleep apnea. J Clin Sleep Med. 2020;16(17): 1013–1019. 16. Marcus CL, Brooks LJ, Draper KA, et al. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012; 130:e714–e755. 17. Berry RB QS, Abreu AR, et al. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Version 2.6. Darien, IL: AASM; 2020. 18. Haupt ME, Goodman DM, Sheldon SH. Sleep related expiratory obstructive apnea in children. J Clin Sleep Med. 2012;8:673–679. 19. Katz ES, Mitchell RB, D’Ambrosio CM. Obstructive sleep apnea in infants. Am J Respir Crit Care Med. 2012;185:805–816. 20. Chen J, He S. Drug-induced sleep endoscopy-directed adenotonsillectomy in pediatric obstructive sleep apnea with small tonsils. PLoS One. 2019; 14:e0212317. 21. Byars SG, Stearns SC, Boomsma JJ. Association of long-term risk of respiratory, allergic, and infectious diseases with removal of adenoids and tonsils in childhood. JAMA Otolaryngol Head Neck Surg. 2018; 144:594–603. 22. Thongyam A, Marcus CL, Lockman JL, et al. Predictors of perioperative complications in higher risk children after adenotonsillectomy for obstructive sleep apnea: a prospective study. Otolaryngol Head Neck Surg. 2014;151:1046–1054. 23. Roberts C, Al Sayegh R, Ellison PR, Sedeek K, Carr MM. How pediatric anesthesiologists manage children with OSA undergoing tonsillectomy. Ann Otol Rhinol Laryngol. 2020;129:55–62. 24. Khirani S, Amaddeo A, Baujat G, et al. Sleep-disordered breathing in children with pycnodysostosis. Am J Med Genet A. 2020;182:122–129. 25. Radescu OD, Colosi HA, Albu S. Effects of rapid palatal expansion (RPE) and twin block mandibular advancement device (MAD) on pharyngeal structures in Class II pediatric patients from Cluj-Napoca, Romania. Cranio. 2020;38:22–29.

Chapter

32

Respiratory Diseases and the Overlap Syndromes Christine H.J. Won

The term overlap syndrome was originally introduced to categorize patients who had sleep apnea and chronic obstructive pulmonary disease (COPD). The notion was that these patients would demonstrate the clinical and laboratory features of their underlying respiratory disease and those of their sleep breathing disorder. In reality, there are overlaps between sleep-disordered breathing and many other respiratory diseases (Box 32.1). This chapter considers the respiratory overlap syndromes. OBSTRUCTIVE PULMONARY DISEASES Obstructive lung diseases are caused by airway inflammation and obstruction and include disorders such as COPD, asthma, and cystic fibrosis. Furthermore, COPD can be considered a spectrum of disorders that ranges from chronic bronchitis, which includes the pathophysiologic abnormalities of airway inflammation, mucus secretion, and bronchial muscle constriction, to emphysema, which is exhibited by alveolar destruction. Many COPD patients have elements of both. In most cases, the likeliest cause is cigarette smoking. Patients with COPD often have unstable sleep because of excessive secretion, coughing, and dyspnea (Box 32.2). Sleep disturbances are common in COPD. Patients with COPD are at increased risk of several types of sleep-breathing disorders, including sleep-related hypoxemia, alveolar hypoventilation, and sleep apnea. In COPD without sleep apnea, significant hypoxemia may occur, primarily during rapid eye movement (REM) sleep. During REM sleep, there is loss of

Box 32.1  Impact of Sleep State on Breathing Mechanics • Blunted ventilatory responses to hypoxemia and hypercapnia (REM . NREM) leading to exaggerated hypoxemia and hypercapnia compared with the wake state • Decreased tonic drive to pharyngeal muscles leading to reduction in airway muscle tone and increased airway resistance • Supine positioning leading to reduced functional residual capacity by 20%–50% or greater during REM sleep • Drop in minute ventilation caused by decreased metabolism and decreased chemosensitivity to oxygen and carbon dioxide • Irregular breathing pattern and hypoventilation during REM sleep NREM, Non–rapid eye movement; REM, rapid eye movement.

348

muscle tone in the accessory muscles of respiration, leaving the diaphragm as the only working muscle (Box 32.3). However, there is often diaphragmatic dysfunction caused by hyperinflation and chronic systemic inflammation in COPD. This leads to alveolar hypoventilation, dependent atelectasis, and poor gas exchange, manifesting as hypoxemia and hypercapnia during REM sleep (Figs. 32.1 to 32.3). When COPD is severe, hypoxemia may persist in all sleep stages (Fig. 32.4). This may be related to significant lung parenchymal disease or to hypoventilation with chronic carbon dioxide (CO2) retention (Figs. 32.5 and 32.6). CO2 monitoring during sleep is important to differentiate the primary cause of sleep-related hypoxemia in COPD patients because one benefits from supplemental oxygen therapy, while the other benefits from noninvasive ventilation. When the COPD patient has comorbid obstructive sleep apnea (OSA), oxygen desaturations may be severe and superimposed on low baseline hypoxemia. CPAP may improve the cyclical oxygen desaturations related to OSA, but addition of oxygen may be necessary in some patients because of intrinsic lung disease (Fig. 32.7). Oxygen should be applied judiciously

Box 32.2  Abnormal Sleep Physiology in Chronic Obstructive Pulmonary Disease • Increased airway resistance n dyspnea • Pooling of secretions n cough • Accessory muscle atonia in REM sleep n hypoventilation/ hypercapnia • Ventilation/perfusion mismatch in lung n hypoxemia • Decreased ventilatory drive n hypercapnia and hypoxemia REM, Rapid eye movement.

Box 32.3  Sleep Disturbance in Chronic Obstructive Pulmonary Disease • Difficulty initiating and maintaining sleep (.50% of patients) • Reduced sleep efficiency • Increased awakenings, sometimes to smoke • Multiple arousals and stage changes • Daytime fatigue, frequent naps • Predicted by daytime hypoxemia and pulmonary function abnormality • Paroxysmal nocturnal dyspnea because of pulmonary hypertension and cor pulmonale

Atlas of Clinical Sleep Medicine   349 100% 90% SaO2

80% 70%

Wake REM Stage

N1 N2 N3 21:47:55

23

00

01

02

03

04

05

06:04:59

Figure 32.1  ​This all-night oximetry tracing shows three prolonged episodes of desaturation in a typical patient with chronic obstructive pulmonary disease. The desaturations occurred in rapid eye movement sleep. Also note the low baseline oxygen saturation (Sao2) level.

100 50 0 130 110 90 70 50 30 100

MIC sec

HR, 8PM

Spo2, x

90 80 70 30 15 0 30 15 0 30 15 0 50 25 0 L p pL S SL R SR PR

CA sec

OA sec

MA sec

HYPO sec

Pos S

S

.

9:26:53 PR 10PM 11PM

12AM

1AM

2AM

3AM

4AM

Figure 32.2  ​This home sleep apnea test shows discrete periods of low oxygen saturation. It is presumed that these are related to rapid eye movement sleep given the duration and the approximately 90-minute periodicity. Positional hypoxemia can be ruled out because the patient remained supine for the entire recording.

350  Respiratory Diseases and the Overlap Syndromes 22:54 W R N1 N2 N3 Hours E poch stage 22:54 100 90 80 70 60 50 Des IDX: 0.0s

00:16

01:16

02:16

3

4

5

00:16

01:16

02:16

3

4

5

03:16

04:16

05:16

7

8

03:16

04:16

05:16

6

7

8

6

05:44

05:44

IDX: 14.5

Figure 32.3  ​This polysomnography recording show rapid eye movement (REM) sleep–related hypoventilation superimposed on chronic baseline hypoxemia

90 80 6:00

5:30

5:00

4:30

4:00

3:30

3:00

2:30

20

100 180 260 70 Pulse

Sp02

100

with mean Spo2 ,90% during non-REM sleep.

Figure 32.4  ​Nocturnal oximetry on a patient with chronic obstructive pulmonary disease shows low baseline oxygen saturation that is independent of

apneas. The etiology of the hypoxemia is uncertain based on oximetry only, and capnography is important to determine whether this patient would benefit from supplemental oxygen via nasal cannula versus noninvasive positive pressure therapy.

Sleep stage 20:54 W R N1 N2 N3

21:54

22:54

23:54

01:18

02:18

03:17

04:17

1

2

3

4

5

6

7

20:54 100 90 80 70 60 50 Des IDX: 0.0 Hours

21:54

22:54

23:54

01:18

02:18

03:17

04:17

1

2

3

4

5

6

7

20:54 80 70 60 50 40 30 20 Hours

21:54

22:54

23:54

01:18

02:18

03:17

04:17

1

2

3

4

5

6

7

Hours E poch: 11 Stage: awake

E poch: 11 Max: 93% Min: 89%

E poch: 11 Max: 54mmHg Min: 53 mmHg

Oxygen saturation

CO2 (end tidal)

04:53

04:53

IDX: 0.0 04:53

Figure 32.5  ​Capnography helped determine that the low oxygen saturation in this patient with chronic obstructive pulmonary disease is from hypoventilation, and a trial of bilevel positive airway pressure therapy was indicated.

Atlas of Clinical Sleep Medicine   351

Figure 32.6  ​In this patient with chronic obstructive pulmonary disease, the airflow is normal, but Spo2 is low and transcutaneous CO2 is high, suggesting that this patient is experiencing hypoventilation likely related to low tidal volumes and ineffective gas exchange.

Sleep stage 21:57 W R N1 N2 N3 Hours E poch: 9 Stage: Awake

21:57 100 90 80 70 60 50 Des

IDX: 0.0Hours

E poch: 9 Max: 97% Min: 89%

20 15

21:57

10 5 0 Hours

22:58

23:58

00:58

01:58

02:58

03:58

04:58

1

2

3

4

5

6

7

02:58

03:58

04:58

5

6

7

22:58

23:58

1

2

Oxygen saturation 00:58 01:58

3

4

05:26

05:26

IDX: 0.0

Airway pressure (IPAP/EPAP)

22:58

23:58

00:58

01:58

02:58

03:58

04:58

1

2

3

4

5

6

7

E poch: 9 IPAP: 0.0/0.0 | EPAP:0.0/0.0 | Backup rate: 0.0 | Humidity: 0.0 | Session AHI: 95.2

05:26

Total AHI: 29.6

Figure 32.7  ​Continuous positive airway pressure (CPAP) therapy is effective in eliminating obstructive sleep apnea as observed by the resolution of cyclical

desaturations. However, CPAP alone is not able to normalize oxygenation in this patient with chronic obstructive pulmonary disease (COPD). In certain patients with overlap (obstructive sleep apnea and COPD), supplemental oxygen with CPAP may be required. Aiming for an Spo2 of 88% to 90% is sufficient for COPD. Hyperoxygenation risks worsening hypoventilation and carbon dioxide retention.

because overoxygenation may blunt ventilatory drive and worsen CO2 retention in patients with obstructive lung disease. Up to one-third of patients with stable COPD report symptoms of restless legs syndrome (RLS), with most reporting moderate to severe symptoms. The occurrence increases during acute exacerbations of COPD. Predictors of RLS include low creatinine levels (a marker of reduced muscle mass) and low ferritin (a marker of iron stores known to correlate with RLS severity in the general population as well) (Fig. 32.8). Patients with other types of obstructive pulmonary disease, such as asthma or cystic fibrosis, may have findings similar to those described earlier. The prevalence of OSA is increased in patients with asthma, which has led the Global Initiative for Asthma to recommend consideration of OSA when evaluating patients with asthma. OSA may be common

in children with cystic fibrosis as a result of comorbid nasal and sinus disease. However, OSA is not common in adults with cystic fibrosis because of their often malnourished state. RESTRICTIVE LUNG DISEASES Intrapulmonary lung restriction includes a variety of lung diseases, including the interstitial lung diseases. These patients often have a rapid, shallow breathing pattern and a chronic sense of dyspnea resulting from stimulation of the lung vagal receptors (Fig. 32.9). Sleep-related hypoxemia is common in interstitial lung diseases. In severe pulmonary disease, REMrelated hypoventilation and hypoxemia may also be observed (Fig. 32.10). OSA in these patients may be generally mild and

352  Respiratory Diseases and the Overlap Syndromes Cursor: 01:50:11, Epoch: 455 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

2 min/page

LEG(L) 125 V

LEG(R)

125 V 100

SaO2 %

85

THOR RES x1

ABD RES x1

50

PCO2

mm Hg 0 15

CPAP

cm H2O 0

AIRFLOW 62.5 V

Figure 32.8  ​Periodic limb movements are observed in this patient with hypoxemia and chronic obstructive pulmonary disease.

Cursor: 00:17:28, Epoch: 006 - STAGE 4

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

02-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

40 THOR EFFORT 3.21 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 50

EtCO2

mm Hg

0

CPAP 20 PRESS cm H2O 10

Figure 32.9  ​Rapid shallow breathing during sleep and wake cycles is characteristic of intraparenchymal restrictive lung disorders.

Atlas of Clinical Sleep Medicine   353 LOC ROC C3-A2 C4-A1 O1-A2

2m

O2-A1 CHIN ECG

SNORE RIGHT LEG LEFT LEG C-FLOW CHEST ABD SpO2 (%)

100 87 75

93

92

93

93

93

92

92

91

91

91

89

89

90

91

91

91

91

91

92

92

92

92

93

93

93

93

93

93

93

Figure 32.10  ​Mild rapid eye movement sleep–related hypoxemia is observed in a patient with interstitial lung disease.

20:34 W R N1 N2 N3

21:34

22:34

23:34

1

2

3

Hours E poch: 16 Stage: Awake

21:34 100 90 80 70 60 50 Des Hours

22:34

1 IDX: 0.0E poch: 16 Max: 98% Min: 97%

23:34

2

00:34

3

Sleep stage 00:34

4 Oxygen saturation 01:34

4

01:34

02:34

03:34

04:34

5

6

7

8

02:34

03:34

04:34

5

6

7

05:14

9

05:36

8

IDX: 0.0 9

Figure 32.11  ​This hypnogram shows rapid eye movement (REM) sleep–related obstructive sleep apnea. Mild sleep apnea, usually REM related, is observed in interstitial lung disease.

predominantly REM related; however, apneic episodes are associated with significant oxygen desaturations (Fig. 32.11). Gastroesophageal reflex disease is also common in interstitial lung diseases and may exacerbate or be exacerbated by OSA. The overlap of OSA with restrictive lung disease confers increased risk for pulmonary hypertension, much like OSA does for COPD. EXTRAPULMONARY LUNG RESTRICTION Extrapulmonary lung restriction results from neuromuscular and musculoskeletal disorders such as kyphoscoliosis, postpolio syndrome, and amyotrophic lateral sclerosis. These disorders

result in ineffective respiratory muscle mechanics, leading to increased work of breathing and easy fatigability. In contrast with patients with intrathoracic restriction, these patients develop blunted chemoresponsiveness and hypoventilate during wake and sleep states. They may come to medical attention with hypercapnic respiratory failure and require bilevel positive airway pressure or noninvasive positive-pressure ventilation (Fig. 32.12). Capnography is a useful addition in the monitoring of these patients (Fig. 32.13). A variety of abnormal breathing patterns during sleep have been reported in extrathoracic restrictive processes, including periodic breathing, central apneas, and obstructive apneas (Fig. 32.14). Neuromuscular disorders are reviewed in Chapter 27.

354  Respiratory Diseases and the Overlap Syndromes 21:34 W R N1 N2 N3

22:34

23:34

00:34

1

2

3

21:34 100 90 80 70 60 50 Des Hours

22:34

23:34

00:34

2

3

21:34 20 15 10 5 0 Hours

22:34

23:34

1

2

Hours E poch: 14 Stage: Awake

1 IDX: 0.0E poch: 14 Max: 89% Min: 86%

Sleep stage 01:34

4 Oxygen saturation 01:34

02:34

03:34

04:34

5

6

7

8

02:34

03:34

04:34

05:36

4 5 Airway pressure (IPAP/EPAP) 02:34 00:34 01:34

6

7

03:34

04:34

4

6

7

3

E poch: 14 IPAP: 0.0/0.0 | EPAP:0.0/0.0 | Backup rate: 0.0 | Humidity: 0.0 | Session AHI: 95.0

5

05:36

8 IDX: 25.1 05:36

8 Total AHI: 12.9

Figure 32.12  ​Patients with extrapulmonary restrictive disease caused by musculoskeletal disorders, neuromuscular disorders, or obesity can present with severe hypoxemia and hypercapnia as a result of altered chemoresponsiveness and poor ventilatory mechanics. These patients are at risk for acute respiratory failure. They benefit from chronic nocturnal noninvasive ventilation.

22:17 W R N1 N2 N3

23:18

00:18

1

2

22:17 100 90 80 70 60 50 Des

23:18

00:18

22:17 20 15 10 5 0

23:18

Hours E poch: 15 Stage: Awake

IDX: 0.0Hours 1 E poch: 15 Max: 96% Min: 95%

2 00:18

01:18

3

4 Oxygen saturation 01:18 02:18

22:17

23:18

Hours 1 E poch: 15 Max: 66mmHg % Min: 65mmHg

00:18

2

03:18

5

01:18

3

4 CO2 (end tidal) 02:18

4

04:18

6

03:18

3 4 5 Airway pressure (IPAP/EPAP) 03:18 01:18 02:18

Hours 1 2 3 E poch: 15 IPAP: 0.0/0.0 | EPAP:0.0/0.0 | Backup rate: 0.0 | Humidity: 0.0 | Session AHI: 95.0

80 70 60 50 40 30 20

Sleep stage 02:18

5

05:18

7

05:57

8

04:18

05:18

6

7

04:18

05:18

6

7

05:57

8 IDX: 25.1 05:57

8 Total AHI: 12.9

03:18

04:18

05:18

05:57

5

6

7

8

Figure 32.13  ​Capnography during a bilevel positive airway pressure titration study shows effective reduction in CO2 by the end of the night.

Atlas of Clinical Sleep Medicine   355 LOC ROC C3-A2 C4-A1 O1-A2

2m

O2-A1 CHIN ECG

SNORE RIGHT LEG LEFT LEG C-FLOW CHEST ABD SpO2 (%)

100 87 75

90

93

93

91

89

90

92

93

91

88

89

93

94

94

91

88

90

94

93

91

90

87

87

89

91

93

92

89

85

Figure 32.14  ​Graph showing a 2-minute epoch in a patient with kyphoscoliosis. The patient was being treated with methadone 40 mg twice a day, had a body

mass index of 40 kg/m2, and was on noninvasive ventilation (inspiratory pressure 12 cm H2O, expiratory pressure 6 cm H2O) with a backup rate of 12 beats/min and an oxygen bleed into the circuit. Findings were those of persistent central apneas in which the apneas occurred in the face of a backup rate, suggesting upper airway closure during the central events. (Courtesy Dr. Lisa Wolfe, Northwestern University.)

EXTRATHORACIC UPPER AIRWAY OBSTRUCTION Extrathoracic upper airway obstruction may result from head, neck, nasal, oropharyngeal, laryngeal, or tracheal tumors. Obstruction may also occur from upper airway stenosis or tracheomalacia (Figs. 32.15 and 32.16). In most cases, significant anatomic obstruction precedes the development of daytime symptoms such as dyspnea, hoarseness, or stridor. However, because upper airway obstruction often worsens during sleep as a result of supine positioning and laxity of upper airway dilatory muscles, the patient may initially be seen with symptoms of sleep-disordered breathing such as snoring, gasping, apnea, and daytime somnolence. Upper airway obstruction should be suspected and investigated by imaging or laryngoscopy in patients with acute onset of sleep apnea not otherwise explained by recent weight gain, medications, or stroke (Figs. 32.17 and 32.18). Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

Figure 32.15  ​Squamous cell carcinoma of the vocal cords causing acute presentation of obstructive sleep apnea.

356  Respiratory Diseases and the Overlap Syndromes

Figure 32.16  ​Laryngomalacia causes upper airway obstruction. It occurs in infants and is rare in adults. In adults, it may be caused by trauma, surgery, or degenerative diseases such as Parkinson disease or amyotrophic lateral sclerosis.

W R N1 N2 N3

22:54

Hours E poch: 27 Stage: Awake

100 90 80 70 60 50 Des

22:54

IDX: 0.0 Hours

E poch: 27 Max: 90% Min: 86%

23:55

00:55

01:55

02:55

03:55

1

2

3

4

5

23:55

00:55

1

2

23:55

00:55

Oxygen saturation 01:55 02:55

3

4

03:55

5

04:58

6

7

04:58

6

IDX: 55.0

7

Airway pressure (IPAP/EPAP)

20

22:54

01:55

02:55

15 10 5 0

0.0

32.2

03:55

04:58

AHI: 3.8

0.0

AHI: 88.4 Hours 1 2 E poch: 27 IPAP: 0.0 / 0.0 | EPAP: 0.0 / 0.0 | Backup Rate: 0.0 | Humidity: 0.0 | Session AHI: 88.4

3

4

5

6

Total AHI: 36.4

7

Continuous heart rate

200 160 120 80 40 0

22:54

23:55

00:55

01:55

02:55

03:55

Hours

1

2

3

4

5

04:58

6

7

Figure 32.17  ​Obstructive sleep apnea responds to continuous positive airway pressure (CPAP) therapy, even in overlap syndromes. The cyclical desaturations

resulting from apneas are resolved with appropriate CPAP. When obstructive sleep apnea is difficult to resolve even at the highest pressures, one should consider fixed upper airway obstruction and screen for tumors or other pathology.

  e1 Bibliography

Aras G, Kadakal F, Purisa S, Kanmaz D, Aynaci A, Isik E. Are we aware of restless legs syndrome in COPD patients who are in an exacerbation period? Frequency and probable factors related to underlying mechanism. COPD. 2011;8(6):437–443. Jaoude P, El-Solh AA. Survival benefit of CPAP favors hypercapnic patients with the overlap syndrome. Lung. 2014;192(5):633–634. Khan WH, Mohsenin V, D’Ambrosio CM. Sleep in asthma. Clin Chest Med. 2014;35(3):483–493. McSharry DG, Ryan S, Calverley P, Edwards JC, McNicholas WT. Sleep quality in chronic obstructive pulmonary disease. Respirology. 2012; 17(7):1119–1124. Mermigkis C, Chapman J, Golish J, et al. Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis. Lung. 2007;185(3):173–178. O’Neill E, Ryan S, McNicholas WT. Chronic obstructive pulmonary disease and obstructive sleep apnoea overlap: co-existence, co-morbidity, or causality? Curr Opin Pulm Med. 2022;28(6):543–551.

Ozsancak A, D’Ambrosio C, Hill NS. Nocturnal noninvasive ventilation. Chest. 2008;133(5):1275–1286. Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med. 2003;167(1):7–14. Shiina K, Tomiyama H, Takata Y, et al. Overlap syndrome: additive effects of COPD on the cardiovascular damages in patients with OSA. Respir Med. 2012;106(9):1335–1341. Sowho M, Amatoury J, Kirkness JP, Patil SP. Sleep and respiratory physiology in adults. Clin Chest Med. 2014;35(3):469–481. Teodorescu M, Barnet JH, Hagen EW, Palta M, Young TB, Peppard PE. Association between asthma and risk of developing obstructive sleep apnea. JAMA. 2015;313(2):156–164. Tobias L, Won C. Lung diseases. In: Savard J, Ouellet MC, eds. Handbook of Sleep Disorders in Medical Conditions. Philadelphia: Elsevier; 2019: 122–144.

Section 12  |  Other Medical and Psychiatric Disorders Chapter

Cardiovascular Diseases

33

Sogol Javaheri and Shahrokh Javaheri

This chapter reviews cardiovascular diseases encountered among patients with sleep disorders. Both obstructive sleep apnea (OSA) and central sleep apnea (CSA) may be comorbid with a variety of cardiovascular diseases (CVDs) and are associated with excess morbidity and mortality and huge economic costs.1 See Chapter 9 for a review of the regulation of cardiovascular physiology in sleep. IMPACT OF CARDIOVASCULAR DISEASES Since 1900, with the exception of the 1918 influenza pandemic, CVD has been the leading cause of death in the United States. According to the 2022 American Heart Association update,1 the prevalence of CVD (comprising coronary artery disease [CAD], heart failure [HF], stroke, and hypertension) in adults 20 years of age is 49% and increases with age in both males and females. In 2018, the estimated mortality of cardiovascular death was 874,613 individuals, with a staggering economic impact of $378 billion.

EFFECT OF SLEEP DISORDERS ON CARDIOVASCULAR PHYSIOLOGY OSA may either cause or contribute to the progression, morbidity, and mortality of various CVDs. OSA is characterized by recurrent upper airway occlusion that is either complete (apnea) or partial (hypopnea). The acute overnight consequences of OSA include recurrent episodes of hypoxemia/reoxygenation; increases and decreases in Pco2; increased sympathetic activity; and large, negative swings in intrathoracic pressure. Figure 33.1 shows an example of OSA resulting in desaturation followed by reoxygenation with resumption of breathing. An arousal occurs at the termination of the apnea. In this patient, an esophageal balloon was inserted to measure intrathoracic pressure. Note the progressively increasing negative swings in intrathoracic pressure as a result of diaphragmatic contraction against the closed upper airway. The negative pressure swings are also reflected in the surrounding cardiac chambers, pulmonary vascular bed and interstitium, and the intrathoracic aorta. This OSA-related negative pressure increases the transmural

CHIN EMG EEG C3A2 EEG O1A2

ECG THERMOCOUPLE

50 mV

PETCO2

RC ABD SaO2 20 10 PES (cm H2O) 0 10 20

Figure 33.1  ​Three immediate nocturnal consequences of obstructive sleep apnea. These include altered blood gas chemistry characterized by hypoxemia/ deoxygenation and hypercapnia/hypocapnia, arousals, and large negative swings in intrathoracic pressure.

357

358  Cardiovascular Diseases pressure of the cardiac chambers and intrathoracic blood vessels. Increased transmural pressure of the atria activates mechanoreceptors and may contribute to atrial premature excitation and other arrhythmias such as atrial fibrillation. Increased left ventricular transmural pressure increases afterload and oxygen consumption. Increased aortic transmural pressure increases the propensity for aortic dilation and dissection, whereas increased negative interstitial pressure increases the propensity for developing pulmonary edema. Increasing evidence suggests that through these acute mechanisms, OSA leads to activation of redox-sensitive genes, oxidative stress, inflammatory processes, sympathetic overactivity, and hypercoagulability. All of these can contribute to endothelial dysfunction (Fig. 33.2), which is the underlying pathophysiologic mechanism that mediates a variety of cardiovascular disorders, including hypertension, atherosclerosis (CAD as well as cerebrovascular disease), pulmonary hypertension, right and left ventricular systolic and diastolic dysfunction, stroke, and even sudden death (Fig. 33.3). At times apneas can be very prolonged, resulting in severe desaturation, as depicted in Figure 33.4. Therefore, because the apnea-hypopnea index (AHI) does not account for length of apneas, severity of oxygen desaturation, presence or absence of arousals, or whether or not they are rapid eye movement (REM)-related, it may not be the best marker of disease severity, particularly in patients with HF.

OBSTRUCTIVE SLEEP APNEA AS A CAUSE OF CARDIAC ARRHYTHMIAS Dysrhythmias commonly comorbid with OSA may include bradycardia, sinus pause (Fig. 33.5), heart block, ventricular ectopy and tachycardia (Fig. 33.6), and atrial fibrillation. Arrhythmias are apt to occur in patients with severe OSA and comorbid cardiac disease. The mechanisms that mediate these dysrhythmias relate to the three major consequences of OSA: (1) altered blood gases that result in hypoxemia, hypercapnic acidosis, and hypocapnic alkalosis; (2) changes in autonomic tone; and (3) negative swings in intrathoracic pressure that may distend the atria and ventricles. Particularly in the presence of CAD, the threshold for developing arrhythmias may be low. In patients with OSA, nocturnal arrhythmias may contribute to the higher nighttime prevalence of sudden death. In the general population, sudden cardiac death, presumably in part caused by ventricular arrhythmias and myocardial infarction, shows a day-night variation with preponderance in the early morning hours, from 6 am to noon. In contrast, in patients with sleep apnea, the peak in sudden death occurs during sleeping hours between midnight and 6 am, and the severity of sleep apnea correlates with the risk of nocturnal sudden death. The clinical implication is that the recognition and treatment of OSA may eliminate or reduce arrhythmias and improve morbidity and mortality in this population.

O2 delivery Redux gene attraction, oxidation stress, inflammation, hypercoagulability PO2 PCO2

Sleep apnea/ hypopnea

Hypoxic and hypercapnic pulmonary vasoconstriction Sympathetic activation

Arousals Parasympathetic withdrawal

Ppl

Transmural pressure of cardiac chambers, aorta, and pulmonary microvascular bed

Cardiac dysfunction Endothelial dysfunction syndrome

RV afterload, RVH BP and LV afterload: • MVO2, myocardial toxicity, arrythmias Heart rate • MVO2 Changes in RV and LV • afterload, MVO2, arrythmias Aortic dilation Lung H2O

Figure 33.2  ​Consequences of recurrent sleep apneas and hypopneas include hypoxemia/reoxygenation in association with hypercapnia and hypocapnia,

respectively, during apnea followed by hyperpnea. Other consequences are arousals and negative flows in pleural pressure, which in conjunction could eventually result in significant cardiovascular dysfunction. Hypoxemia may result in diminished oxygen delivery to the myocardium, which could result in arrhythmias and systolic and diastolic dysfunction. Hypoxemia/reoxygenation could result in activation of redox-sensitive genes, oxidative stress inflammation, and hypercoagulability, leading to endothelial dysfunction syndrome. Both alveolar hypoxia and hypercapnia (as a result of sleep apnea/hypopnea) result in  ). This eventually hypoxic and hypercapnic pulmonary vasoconstriction that increases right ventricular afterload and its myocardial oxygen consumption (MVO 2 could result in right ventricular hypertrophy (RVH) and cor pulmonale. Hypoxemia and hypercapnia, along with arousals, could also lead to sympathetic activation  , and arrhythmias. In addition, this increase in that would increase blood pressure (BP). This would result in increased left ventricular afterload, increased MVO 2 sympathetic activation and release of myocardial norepinephrine could result in myocardial toxicity and apoptosis. Arousals also result in parasympathetic  withdrawal, which increases the heart rate and MVO2. Finally, negative swings in pleural pressure (Ppl) increase the transmural pressure of the left ventricle (LV)  . In addition, increasing the transmural pressure and right ventricle (RV), both of which increase the wall tension of the ventricles, leading to an increase in MVO 2 also affects the intrathoracic aorta and predisposes to aortic dilation and potential dissection. Furthermore, increased pleural pressure of the atria predisposes to development of atrial fibrillation. Finally, a negative interstitial pressure increases transcapillary fluid flow, which facilitates the development of pulmonary edema. Overall, therefore, the consequences of sleep apnea and hypopnea in conjunction could result in cardiovascular dysfunction. Pco2, Partial pressure of carbon dioxide; PO2, partial pressure of oxygen.

Atlas of Clinical Sleep Medicine   359

Reoxygenation/hypocapnia

pnia erca hyp

etic overactivity Sympath

al hyper tension diurn d n la rna CBF ctu ations in Alter

⇓ and ⇓ and

Consequences ⇓D O2 ;

⇑w all te

⇑

⇓a

nd

Endothelial dysfunction ⇑

C

Systemic HTN Pulmonary HTN

ns ion

No

y

m xe po

ia/

Intermediary mechanisms

BF

H

Primary events

Systolic HF Diastolic HF

Sleep apnea and hypopnea

Adhes ion Trans cri Pla tele t ag

molecules

a Inflamm

ption factors

m Inflam

Oxidat ive s

grega tio

Me t abol ic

ti o

Arrhythmias

n

atio

Atherosclerosis

n

CAD

ROS

tress

n/coagulopathy

dysregulation

Stroke

sis mbo Thro

e nc ista s e r ptin in/le Insul

Sudden death

Figure 33.3  ​Proposed pathophysiologic pathways in the development of cardiovascular disease in obstructive sleep apnea. CAD, Coronary artery disease; CBF, cerebral/coronary blood flow; DO2, dissolved oxygen; HF, heart failure; HTN, hypertension; ROS, reactive oxygen species.

L-EOG

R-EOG

CHIN

C4-A1

O1-A2

ECG

FLOW

CHEST

ABD

SaO2

84

94 77

75

74

86

60"

94 79

77

77

87

120"

82

77

73

70

68

180"

64

61

63

88

81

240"

83

84

79 30

Figure 33.4  ​Example of a prolonged obstructive apnea almost 2 minutes in duration in rapid eye movement sleep, resulting in significant oxygen desaturation.

360  Cardiovascular Diseases L-EOG

R-EOG

*C4-A1

*O2-A1

CHIN

*L-EMG

Sinus Pause ECG

*PFLOW

CHEST

ABD

SaO2

67 67 66 66 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 STAGE REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM

726 5"

10"

15"

20"

25"

3

Figure 33.5  ​Example of sinus arrest in a patient with obstructive sleep apnea. (From Kapa S, Javaheri S. Constructive sleep apnea and arrhythmias. In: Lee Chiong T, Javaheri S, eds. Sleep Medicine Clinics: Sleep and Cardiovascular Disease. Philadelphia: Elsevier; 2007:575–581.)

OBSTRUCTIVE SLEEP APNEA AS A CAUSE OF CORONARY ARTERY DISEASE Through the mechanisms of endothelial dysfunction, which were discussed earlier (see Figs. 33.2 and 33.3), OSA may either be a cause of or may contribute to CAD or its progression. Evidence is mounting, from both population and sleep clinic cohort studies, that OSA causes or contributes to the progression of CAD and eventually to elevated cardiovascular death and all-cause mortality. OSA has been implicated as a cause of nocturnal ST-segment depression and angina pectoris. These conditions may be more prevalent in patients with established CAD. We recommend polysomnography for the diagnosis of OSA and continuous positive airway pressure (CPAP) titration, if appropriate, for all patients with nocturnal angina, which should be eliminated with therapy. In a retrospective sleep laboratory cohort study, Peker and colleagues2 reported incident CAD in almost 25% of untreated OSA patients during a 7-year follow-up. The corresponding numbers in treated OSA patients and nonapneic snorers were 4% and 6%, respectively. In an observational

sleep laboratory cohort study of 1300 OSA patients and healthy study participants from Spain, Marin and colleagues3 observed that during a mean follow-up period of approximately 10 years, a 3 to 4 times higher incidence of fatal and nonfatal cardiovascular events was observed in the patients with severe OSA, defined as an AHI of 30 or more per hour, compared with simple snorers. Furthermore, in 372 patients with severe OSA who were compliant with CPAP, cardiovascular event rates were similar to those in nonapneic snorers. The Wisconsin Sleep Cohort Study4 is an 18-year mortality follow-up study (mean observation, approximately 14 years) conducted on a cohort sample of 1522 participants 30 to 60 years of age at baseline. The adjusted hazard ratio (HR) for all-cause mortality with severe sleep-disordered breathing (SDB) versus no SDB was 3 (95% confidence interval [CI], 1.4 to 6.3; Fig. 33.7). Importantly, after excluding the 126 participants who had used CPAP therapy, the association for all-cause mortality with severe SDB versus no SDB became stronger, and the adjusted heart HR increased to 3.8 (CI, 1.6 to 9) for all-cause mortality and to 5.2 (CI, 1.4 to 19.2) for cardiovascular mortality (see Fig. 33.7).

Atlas of Clinical Sleep Medicine   361

L-EOG

R-EOG

*C4-A1

*O2-A1

CHIN

*L-EMG

ECG

*FLOW

CHEST

ABD

SaO2

85

84

84

83

82 81 5"

81

80 79

79 78

78

77

10"

77 75

75 15"

75 75 75 75

74

73

73 72

20"

71

71 71

70 7

25"

Figure 33.6  ​Example of supraventricular tachycardia in a patient with obstructive sleep apnea.

All-cause mortality with untreated SDB

OBSTRUCTIVE SLEEP APNEA AS A CAUSE OF SYSTEMIC HYPERTENSION

100 AHI 5 AHI 5-15

Percent surviving

90

AHI 15-30 80 70 HR  3.8 (CI  1.6-9) P  .001 n  1396

60 50

AHI 30

15 20 10 Years of follow-up Figure 33.7  ​Probability of survival in patients with untreated obstructive sleep apnea. AHI, Apnea-hypopnea index; CI, confidence interval; HR, hazard ratio; SDB, sleep-disordered breathing. (Modified from 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[8]:1071–1078.) 0

5

OSA is an independent risk factor for systemic arterial hypertension. Based on biologic plausibility (see Figs. 33.2 and 33.3), animal studies, longitudinal epidemiologic human studies that account for confounding factors, and therapeutic trials, evidence has evolved that indicates OSA is an important cause of hypertension. In the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, OSA is recognized as the first identifiable cause of hypertension. In a longitudinal study, Peppard and associates5 reported that the incidence of newly diagnosed arterial hypertension in a 4-year follow-up period increased as the AHI increased—a dose-dependent relationship. The increase in the risk for developing hypertension was doubled in those with an AHI of 5 to 15 events per hour, and a threefold increase in risk was seen in those with an AHI greater than 15 events per hour compared with study participants without a sleep disorder at baseline.

362  Cardiovascular Diseases From a clinical point of view, it is important to recognize that approximately one-half of the 70 million Americans who have systemic hypertension may have OSA. Furthermore, it is important to note that effective treatment of OSA has been shown to decrease systemic blood pressure. Multiple randomized controlled trials (RCTs) using ambulatory blood pressure monitoring have

demonstrated that blood pressure decreases significantly with the use of CPAP (Fig. 33.8A); this reduction in blood pressure is most pronounced in individuals with resistant hypertension (see Fig. 33.8), those with the most severe sleep apnea and desaturation index, and those who used CPAP the most. (For further details, see Artz, 2007 in the Bibliography.)

Effect of CPAP on Simple Hypertension 5

Net reduction in blood pressure (mm Hg) mean (95% Cl)

*16 (818) 4

*8 (968) *10 (587)

*28 (1,948)

*7 (471) *12 (572)

3

*31 (1,820)

2

*†4 (1,206)

1 0 −1 −2

Bazzano

Aljami

A

Mo

Heantjens Montesi

24h-SBP (mm Hg)

Fava

Bakker

Bratton

24h-DBP (mm Hg)

Effect of CPAP on Resistant Hypertension Meta-analyses

Randomized controlled trials 12

(n=41)

(n=35)

†

(n=40)

11 Net reduction in blood pressure (mm Hg) mean (95% Cl)

10

*4 (n=329)

9

(n=196)

*5 (n=446)

8 7 6

(n=117)

5 4 3 2 1 0 −1 −2 −3 −4

Lozano

Pedrosa

Martinez-Garcia De Oliveira Muxfeldt

lftikhar

Liu

B Figure 33.8  A, Summary of different meta-analyses of randomized controlled trials. Positive figures mean improvement in BP level with CPAP (net changes)

*Number of studies included (number of patients included). †Patients without daytime hypersomnia. B, Summary of five randomized controlled trials and two meta-analyses. The differences between the two meta-analyses depend on the most updated references included in the 2015 meta-analysis. Positive figures mean improvement in BP level with CPAP (net changes). *Number of studies included (number of patients included). †Daytime BP values. BP, Blood pressure; CI, confidence interval; CPAP, continuous positive airway pressure; DBP, diastolic blood pressure; RCT, randomized controlled trial; SBP, systolic blood pressure. (Modified from Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol. 2017;69[7]:841–858.)

Atlas of Clinical Sleep Medicine   363 It is important to note that in spite of all of the aforementioned studies showing the adverse consequences of OSA on the cardiovascular system and associated mortality, several recent RCTs have failed to show any benefit of CPAP in improving CVD and mortality. The major pitfalls of these studies have been reviewed, and poor adherence is one of the leading factors accounting for negative results. Other issues relate to the phenotype of the enrolled subjects; the power and duration of the trials; and composite, rather than a single organ (brain vs. heart) outcome, specifically stroke, which is the most common consequence of OSA. In a per-protocol analysis of five RCTs, use of more than 4 hours of CPAP was associated with improved cerebrovascular outcomes, but not cardiac outcomes (Fig. 33.9). In summary, the results of the aforementioned studies indicate that both adequate control of OSA and adherence to CPAP are required elements for improvement of OSA-induced hypertension. Improvement in hypertension plays a key role in decreasing the incidence of stroke and myocardial infarction, and this contributes to increased survival. HEART FAILURE Clinical Features Congestive HF is a risk factor for sleep apnea, and patients with HF may come to medical attention with insomnia (sleep onset and sleep maintenance). These phenotypes of insomnia may be linked to periodic breathing and limb movements and related arousals while nodding off or during non-REM

(NREM) sleep, when these events are prevalent. Other potential causes include paroxysmal nocturnal dyspnea—awakening with the sensation of intense dyspnea, orthopnea, and cough. Some b-blockers impair synthesis of melatonin in the pineal gland and may contribute to insomnia. EPIDEMIOLOGY The American Heart Association has estimated that about 6 million Americans age 20 years and older have HF. Furthermore, it is projected that the prevalence will increase 46% from 2012 to 2030, resulting in more than 8 million people age 18 years and older with HF.1 The prevalence of sleep apnea, both central and obstructive, remains high in the era of b-blockers. Several studies have shown a high prevalence of both OSA and CSA in the presence of left ventricular dysfunction and in subjects with HF with reduced ejection fraction (HFrEF) and those with HF with preserved ejection fraction (HFpEF) (Fig. 33.10). The hallmark of OSA in patients with HF is similar to that in patients with OSA in the general population in that such patients are obese and have habitual snoring. In contrast, patients with CSA are normally thinner than patients with OSA, and the prevalence of habitual snoring is much less. For these reasons, the suspicion for the presence of CSA in cardiology and in primary care clinics is low, so these patients often go undiagnosed. The risk factors for CSA in patients with HFrEF include a high New York Heart Association class, the presence of atrial fibrillation, more than

CPAP improves cerebrovascular outcomes RR (95%CI) Stroke TIA

0 0.2 MACCE 1° 0.4 * CCVE * 0.6 0.8

*

*

Fatal + nonfatal event

*

Non All CV CV cause Favors CPAP

AMI + Fatal + HF angina nonfatal event Angina

AMI

1 1.2 1.4 Favors control

1.6 1.8 2

Main outcomes

Cardiac outcomes Controls, n = 1141

Cerebrovascular outcomes

Mortality

CPAP use ≥ 4 hr/day, n = 943

Figure 33.9  Effective use of continuous positive airway pressure (CPAP) improves cerebrovascular outcomes. Summary of the main results regarding the effects

of CPAP treatment on single or composite cardiovascular or cerebrovascular events. Risk ratios (RR) with 95% confidence intervals (CI) are shown on the y-axis. The x-axis shows the different individual and composite cardiovascular events (CCVEs) divided into groups corresponding to the main outcomes, cardiac outcomes, cerebrovascular (CV) outcomes, and mortality. 1°, primary; AMI, acute myocardial infarction; HF, heart failure; MACCE, major adverse cardio-cerebrovascular events; TIA, transient ischemic attack. (Modified from Javaheri S, Martinez-Garcia MA, Campos-Rodriguez F, Muriel A, Peker Y. Continuous positive airway pressure adherence for prevention of major adverse cerebrovascular and cardiovascular events in obstructive sleep apnea. Am J Respir Crit Care Med. 2020;201[5]:607–610. Copyright 2022 the American Thoracic Society.)

364  Cardiovascular Diseases Prevalence (%) of sleep apnea in left ventricular dysfunction 100% AHI > 15/h OSA 80%

CSA

60%

40%

20%

0% LVSD asymptomatic

LVDD asymptomatic

HFrEF

HFpEF

ADHF

Figure 33.10  ​Prevalence of moderate to severe sleep apnea (AHI 15/h) in asymptomatic left ventricular systolic dysfunction (LVSD) or left ventricular diastolic

dysfunction (LVDD), heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF), and acutely decompensated heart failure (ADHF). AHI, Apnea-hypopnea index; CSA, central sleep apnea; OSA, obstructive sleep apnea. (From Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol. 2017;69[7]:841–858.)

P = .01

% With central sleep apnea

100

ABNORMAL BREATHING PATTERNS IN HEART FAILURE

90 P = .007

80 70 60

P = .003 P = .04

P = .03

P = .002 P = .04

50 40 30 20 10 0

I & II III NYHA

NSR A.fib rhythm

5

0.5 0.4

Peri- and postmenopause

0.3 0.2 0.1 Premenopause 0

30

35

40

45 50 Age (years)

55

60

65

Figure 45.4  ​Prevalence of sleep-disordered breathing indicated by apnea-hypopnea index (AHI) . 5 for premenopausal women and perimenopausal/postmenopausal

women by age. (Modified from Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Resp Crit Care Med. 2003;167[9]:1181–1185. Copyright 2022 American Thoracic Society.)

Large epidemiologic cohort studies have shown that the prevalence of sleep-disordered breathing in women increases during the menopausal transition (Fig. 45.4). This may be caused in part by the loss of protective effects of female reproductive hormones, but changes in body habitus and aging likely contribute as well. Studies evaluating whether hormone

replacement therapy reduces the risk of obstructive sleep apnea in postmenopausal women are inconclusive. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

  e1 Bibliography

Baker FC, de Zambotti, Rahman S, Joffe H. Sleep and menopause. In: Kryger M, Roth T, Dement WC, Goldstein C, eds. Principles and Practice of Sleep Medicine. 7th ed. Philadelphia: Elsevier; 2022. Baker FC, Lampio L, Saaresranta T, Polo-Kantola P. Sleep and sleep disorders in the menopausal transition. Sleep Med Clin. 2018;13(3):443–456. Brown AMC, Gervais NJ. Role of ovarian hormones in the modulation of sleep in females across the adult lifespan. Endocrinology. 2020;161(9):bqaa128. Correction in Endocrinology. 2022;163(1).

Cheng YS, Sun CK, Yeh PY, Wu MK, Hung KC, Chiu HJ. Serotonergic antidepressants for sleep disturbances in perimenopausal and postmenopausal women: a systematic review and meta-analysis. Menopause. 2020;28(2): 207–216. Lindberg E, Bonsignore MR, Polo-Kantola P. Role of menopause and hormone replacement therapy in sleep-disordered breathing. Sleep Med Rev. 2020;49:101225. Tobias L, Thapa S, Won CHJ. Impact of sex on sleep disorders across the lifespan. Clin Chest Med. 2021;42(3):427–442.

Chapter

46

Fibromyalgia and Chronic Fatigue Syndrome Lauren Tobias

INTRODUCTION Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are prevalent chronic conditions associated with impaired quality of life and whose etiologies are unexplained. Diagnosis and management of these disorders can be challenging for both patients and health care professionals. A majority of patients with these overlapping syndromes describe sleep disturbances. The relationship between poor sleep and pain is complex and likely multidirectional. Figure 46.1 illustrates potential pathways linking pain and poor sleep in patients with FM and other chronic pain syndromes. FM is characterized by chronic generalized pain with specific sites of musculoskeletal tenderness for which no alternative cause may be identified. Patients commonly report associated somatic symptoms of fatigue, nonrestorative sleep, cognitive dysfunction, and mood disturbances. If fatigue rather than pain is the predominant symptom, patients may be diagnosed instead with ME/CFS. Patients with ME/CFS describe debilitating periods of exhaustion that interfere with normal activities. Both FM and CFS are more common in women, with a female-to-male ratio of 2:1, similar to other chronic pain conditions. FM is more common and is prevalent in 2% of the general population compared with less than 1% who meet formal criteria for ME/CFS. There are considerable clinical similarities between the two conditions, as displayed in Box 46.1. Patients with both disorders are also likely to have comorbid conditions, including irritable bowel syndrome, dysmenorrhea, multiple chemical sensitivities, temporomandibular joint disorder, tension headaches, and chronic sinusitis (Box 46.2). FIBROMYALGIA Clinical Presentation and Diagnosis Diagnosis of FM is based on clinical history alone; no specific laboratory or imaging tests can distinguish the pain of FM

• Chronic painful illness • Genetic variations in pain processing

Pain

Box 46.1  Similarities Between Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome More common in women Associated common symptoms • Sleep disturbances • Neurocognitive and mood disturbances • Fatigue • Chronic pain No identifiable cause Testing (laboratory, radiologic) is normal Chronic symptoms, may wax/wane No highly effective treatment available

Box 46.2  Comorbid Symptoms and Conditions Commonly Present in Patients With Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Headaches Dysmenorrhea Temporomandibular joint disorder Chronic fatigue Irritable bowel syndrome Interstitial cystitis Painful bladder syndrome Endometriosis Back and neck pain Noncardiac chest pain Multiple chemical sensitivities

from that of other chronic pain conditions. The newest diagnostic criteria for FM place a greater emphasis on the presence of somatic symptoms such as sleep disturbances and fatigue than the original diagnostic criteria put forth in 1990. Clinicians are no longer recommended to palpate specific “tender point” locations on physical examination but rather to estimate

Poor sleep

• Disorders impacting sleep quality • Environmental stress • Genetic variation affecting sleep quality

Figure 46.1  Potential factors influencing the bidirectional relationship between poor sleep and chronic pain.

433

434  Fibromyalgia and Chronic Fatigue Syndrome Box 46.3  Diagnostic Criteria for Fibromyalgia 1. Multisite pain defined as six or more pain sites from a total of nine possible sites 2. Moderate to severe sleep problems or fatigue 3. Multisite pain plus fatigue or sleep problems must have been present for at least 3 months The presence of another pain disorder or related symptoms does not rule out a diagnosis of fibromyalgia. However, a clinical assessment is recommended to evaluate for any condition that could fully account for the patient’s symptoms or contribute to the severity of the symptoms. From Arnold LM, Bennett RM, Crofford LJ, et al. AAPT diagnostic criteria for fibromyalgia. J Pain. 2019;20(6):611–628.

widespread or multisite soft tissue tenderness (Box 46.3). Complicating the diagnosis is the fact that up to 25% of patients with generalized inflammatory disorders such as rheumatoid arthritis also fulfill the criteria for FM. Pathogenesis Emerging research suggests that dysregulation of the nociceptive system may play a role in the development and persistence of FM. Affected individuals may process painful stimuli differently at the level of the central nervous system, resulting in lower pain thresholds. The centralized pain of FM is thereby distinguished from both nociceptive pain (associated with inflammation or tissue damage) and neuropathic pain (associated with nerve damage). Functional magnetic resonance imaging studies have demonstrated that in response to nonpainful stimuli (e.g., light, pressure, or heat), patients with FM may exhibit brain activation patterns characteristically seen in response to pain. Studies have not yet clearly identified distinct genetic factors associated with FM. Some evidence supports the role of environmental triggers such as certain viral infections, physical trauma such as motor vehicle accidents, drugs, and psychological stress. Sleep Sleep disturbance is reported by over 90% of patients with FM and is related to the severity of underlying pain. Patients may describe nonrestorative sleep, nocturnal awakenings, restlessness, a perception that sleep is light, and stiffness on awakening (Box 46.4). It is important to carefully evaluate patients for comorbid sleep disorders that could contribute to sleep disruption, such as sleep-disordered breathing or restless legs syndrome. A hypnogram from a patient with FM is shown in Figure 46.2. Studies evaluating the impact of FM on sleep have described variable impacts on traditional sleep parameters as measured by polysomnography. Notably, research has been limited by differing definitions of the disorder itself as well as in the medication status of patients being studied (e.g., use of rapid eye movement [REM]-suppressive medications such as antidepressants). In general, overnight polysomnography in patients with FM shows lower sleep efficiency, longer sleeponset latency, and reduced slow-wave sleep. Patients may also exhibit alpha-delta sleep, also called alpha intrusion, characterized by the abnormal intrusion of alpha activity (8- to 13-Hz oscillations) into delta activity (1- to 4-Hz oscillations) during slow-wave sleep. An example of the alpha-delta sleep pattern is shown in Figure 46.3. The alpha intrusion pattern appears

Box 46.4  Symptoms of Sleep Disturbance Reported by Patients With Fibromyalgia Nonrestorative, light sleep Frequent nighttime awakenings Fatigue and stiffness on awakening Restless sleep Involuntary leg movements

especially prevalent in those with FM, and some have suggested that such sleep-related irregularities may contribute to, or even cause, the musculoskeletal pain at the core of this condition. The finding of alpha-delta sleep is not unique to FM, however. Treatment Treatment options for FM are shown in Box 46.5. Nonpharmacologic treatment is considered first-line therapy, and pharmacologic agents should only be considered when nonpharmacologic treatment is ineffective. Nonpharmacologic treatment is ideally multimodal, including patient education, exercise therapy, and cognitive behavioral therapy for insomnia (CBTI). Aerobic and strengthening exercises improve pain and physical function, and most studies demonstrate a modest favorable effect on sleep (Figure 46.4). CBTI is a multicomponent therapy including sleep hygiene, education about circadian rhythms and synchronization, relaxation techniques, stimulus control, managing worry before sleep, cognitive restructuring, and sleep restriction. CBT has been found helpful for insomnia symptoms in patients with FM, independent of an effect on pain or mood. Pharmacologic agents include serotonin-norepinephrine reuptake inhibitors (duloxetine and milnacipran are approved by the US Food and Drug Administration [FDA] for this indication), low-dose tricyclic antidepressants (the earliest studied agents), and anticonvulsants such as pregabalin. Sodium oxybate has been shown to alleviate symptoms of FM, improve sleep, and reduce the amount of alpha-delta sleep, but it is not FDA approved for this population because of safety concerns. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME Clinical Presentation and Diagnosis ME/CFS is a multisystem debilitating disorder in which patients experience persistent, unexplained exhaustion not relieved by rest that is accompanied by cognitive impairment, autonomic dysfunction, and chronic pain. The definition of ME/CFS is shown in Box 46.6 and requires that symptoms have been present for at least 6 months. Patients experience a substantial reduction in quality of life. Unrefreshing, nonrestorative sleep is a hallmark of the condition. Patients are characteristically previously active and healthy. They may describe diffuse aching and muscle fatigue, but strength and objective testing such as electromyography and biopsies are normal. Pathogenesis As with FM, the etiology of ME/CFS is poorly understood. As with FM, several potential physical and environmental

Atlas of Clinical Sleep Medicine   435 1 AM

2 AM

3 AM

4 AM

5 AM

6 AM

7 AM

Sleep stage

12 AM

12 AM

1 AM

2 AM

3 AM

4 AM

5 AM

6 AM

7 AM

8 AM

Sleep stage

A

B Figure 46.2  Hypnograms for a healthy control participant (A) and a patient with fibromyalgia (B). The hypnogram for the patient with fibromyalgia shows a

disturbed sleep pattern, with long time in bed and sleep latency as well as fragmented and lighter sleep. (From Diaz-Piedra C, Catena A, Sánchez AI, Miró E, Martínez MP, Buela-Casal G. Sleep disturbances in fibromyalgia syndrome: the role of clinical and polysomnographic variables explaining poor sleep quality in patients. Sleep Med. 2015;16[8]:917–925.)

Figure 46.3  Alpha-delta sleep pattern (also called alpha intrusions) in a patient with fibromyalgia (30-second epoch). Note the alpha waves superimposed on

delta waves during non–rapid eye movement sleep during polysomnography. The patient also reported symptoms of temporomandibular joint pain and chronic daily headaches.

Box 46.5  Recommended Nonpharmacologic and Pharmacologic Therapy for Fibromyalgia From the European League Against Rheumatism Overarching Principles Optimal management requires prompt diagnosis. Full understanding of fibromyalgia requires comprehensive assessment of pain, function, and psychosocial context. It should be recognised as a complex and heterogeneous condition where there is abnormal pain processing and other secondary features. In general, the management of fibromyalgia should take the form of a graduated approach. Management of fibromyalgia should aim at improving health-related quality of life balancing benefit and risk of treatment that often requires a multidisciplinary approach with a combination of nonpharmacological and pharmacological treatment modalities tailored according to pain intensity, function, associated features (such as depression), fatigue, sleep disturbance and patient preferences and comorbidities by shared decision-making with the patient.

Initial management should focus on nonpharmacological therapies. Specific Recommendations Nonpharmacological management • Aerobic and strengthening exercise • Cognitive behavioural therapies • Multicomponent therapies • Defined physical therapies: acupuncture or hydrotherapy • Meditative movement therapies (qigong, yoga, tai chi) and mindfulness-based stress reduction Pharmacological management • Amitriptyline (at low dose) • Duloxetine or milnacipran • Tramadol • Pregabalin • Cyclobenzaprine

From Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis. 2017;76(2):318–328.

436  Fibromyalgia and Chronic Fatigue Syndrome Study or subgroup Da Silva et al., 2017 (A & F; L–B; Co-photo) Lynch et al., 2012 (M–QG; L–B) Da Silva et al., 2017 (A & F; L–B) Carson et al., 2010 (M–Y; L–B) Hakkinen et al., 2001 (R; L–B) McBeth et al., 2012 (A; L–B; Co–CBT) Valkeinen et al., 2008 (A & R; L–B) Wong et al., 2018 (M–TC; L–B) McBeth et al., 2012 (A; L–B) Tomas–Carus et al., 2007 (A; W–B) Haak et al., 2007 (M–QG; L–B) Gianotti et al., 2014 (A, F & R; L–B; Co–edu) Sañudo et a., 2015 (A; L–B) Wigers et al., 1996 (A; L–B)

Exercise (experimental) Mean SD Total –1.2 1.13 20 –3.04 3.75 44 –0.6 1.46 20 22 –1.44 3.89 28.66 11 –10 –1.3 7.94 94 –4.23 22.25 13 –0.2 2 17 6.07 92 0.4 0.43 1.57 17 0.43 1.18 29 –0.5 4.07 20 16 0.2 3.24 10 44.37 16

Total (95% Cl) Heterogeneity. Tau2 = 0.00; Chi2 = 13.68, df = 13 (P = 0.40); l2 = 5% Test for overall effect: Z = 2.09 (P = 0.04)

Usual care (control) Std. mean difference IV, Random, 95% CI Mean SD Total Weight –0.86 [–1.65, –0.07] 10 3.8% –0.1 1.46 –0.71 [–1.13, –0.28] –0.62 3.02 45 12.2% 4.1% –0.32 [–1.08, 0.45] 0 2.46 10 7.1% –0.29 [–0.86, 0.28] 0.28 7.08 26 10 3.2% –0.20 [–1.06, 0.66] –3 39.02 –0.19 [–0.55, 0.17] 9.4 44 16.8% 0.3 3.7% –0.13 [–0.94, 0.67] –1.18 22.25 11 14 4.7% 0.00 [–0.71, 0.71] –0.2 2.1 44 16.7% 0.01 [–0.34, 0.37] 0.3 7.75 0.06 [–0.62, 0.73] 1.57 17 5.2% 0.34 8.5% 0.06 [–0.45, 0.58] 0.34 1.54 28 4.6% 0.08 [–0.64, 0.79] –0.84 4.6 12 12 4.2% 0.13 [–0.62, 0.88] –0.3 4.21 17 5.0% 0.16 [–0.52, 0.85] 2 50

431

300 100.0%

Std. mean difference IV, Random, 95% CI

–0.17 [–0.32, –0.01] –1

–0.5 0 0.5 Favours (exercise) Favours (usual care)

1

Figure 46.4  Randomized controlled trials analyzing the effectiveness of exercise in enhancing sleep quality in people with fibromyalgia have demonstrated

benefit. CI, Confidence interval; SD, standard deviation. (From Estévez-López F, Maestre-Cascales C, Russell D, et al. Effectiveness of exercise on fatigue and sleep quality in fibromyalgia: a systematic review and meta-analysis of randomized trials. Arch Phys Med Rehabil. 2021;102[4]:752–761.)

Box 46.6  Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis requires that the patient have the following three symptoms: 1. A substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest 2 . Postexertional malaise 3 . Unrefreshing sleep At least one of the following two manifestations is also required: • Cognitive impairment • Orthostatic intolerance Frequency and severity of symptoms should be assessed. The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity. From Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Press; 2015.

stressors have been put forth as possible disease triggers, but none are proven. Emerging research suggests that autoimmune mechanisms may play a role in at least a subset of patients. Figure 46.5 displays the overlap between ME/CFS and other conditions postulated to have an autoimmune etiology. Sleep Nearly all patients with ME/CFS exhibit subjective sleep complaints, but studies have yielded mixed results regarding objective differences on polysomnography when compared with controls. Sleep architecture in several studies has been notable for slower sleep onset, more frequent awakenings, and a larger proportion of time spent in slow-wave sleep. Some studies have reported reductions in REM sleep in ME/CFS patients, but others have not. In a study comparing monozygotic twins discordant for ME/CFS who were subject to a phase delay in sleep onset, the ME/CFS twin showed less

POTS 0.17%

Hashimoto thyroiditis 0.8% 11–40%

17–20%

ME/CFS 0.2–0.3% 30–77% Fibromyalgia 5.4%

18–41% Family history of autoimmune diseases

Figure 46.5  Autoimmune-associated comorbid conditions in myalgic

encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overall prevalence of diseases and prevalence for comorbidity with ME/CFS are indicated. POTS, Postural orthostatic tachycardia syndrome. (From Sotzny F, Blanco J, Capelli E, et al. Myalgic encephalomyelitis/chronic fatigue syndrome—evidence for an autoimmune disease. Autoimmun Rev. 2018;17[6]:601–609.)

slow-wave activity during a period of recovery sleep. As in FM, patients with CFS have been described as having alpha intrusion into sleep. Dysfunction of the autonomic nervous system during sleep may also contribute to the unrefreshing sleep experienced by many patients with ME/CFS. ME/CFS patients have exhibited less heart rate variability during slow-wave sleep in several studies, suggesting lower parasympathetic activity during this recuperative stage of sleep. Such autonomic hypervigilance may contribute to patients’ poorer sleep quality. A related technique to examine sleep in ME/CFS is cardiopulmonary coupling, which evaluates the alignment between heart rate and respiration dynamics to determine sleep stability. Preliminary evidence has demonstrated poor cardiopulmonary coupling in ME/CFS patients, consistent with more unstable sleep.

Atlas of Clinical Sleep Medicine   437 A number of studies have shown that ME/CFS patients do not have pathologic sleepiness as measured by a multiple sleep latency test, highlighting the importance of attempting to distinguish sleepiness from fatigue. As with FM, it is important to assess patients for the presence of comorbid sleep disorders such as sleep apnea or limb movement disorders, which in one study were present in over one-half of patients. Treatment Although many potential treatment modalities have been evaluated, the available evidence supports only CBTI and

graded exercise therapy. Although many patients experience symptom exacerbation with exercise, a careful goal-oriented exercise prescription that prevents patients from “overdoing it” has been shown to be beneficial for various outcomes, including sleep quality. Patients should be counseled to avoid unproven therapies that may be potentially harmful. Even with treatment, the disease tends to wax and wane over time and resolves in only a minority of patients. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

  e1 Bibliography

Arnold LM, Bennett RM, Crofford LJ, et al. AAPT diagnostic criteria for fibromyalgia. J Pain. 2019;20(6):611–628. Choy EHS. The role of sleep in pain and fibromyalgia. Nat Rev Rheumatol. 2015;11(9):513–520. Clauw DJ. Fibromyalgia. JAMA. 2014;311(15):1547. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Press; 2015. Gota CE. Fibromyalgia: Recognition and management in the primary care office. Rheum Dis Clin North Am. 2022;48(2):467–478.

Hernando-Garijo I, Jiménez-Del-Barrio S, Mingo-Gómez T, Medrano-dela-Fuente R, Ceballos-Laita L. Effectiveness of non-pharmacological conservative therapies in adults with fibromyalgia: a systematic review of high-quality clinical trials. J Back Musculoskelet Rehabil. 2022;35(1):3–20. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis. 2017;76(2):318–328. Sarzi-Puttini P, Giorgi V, Marotto D, Atzeni F. Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat Rev Rheumatol. 2020;16(11):645–660. Thieme K, Mathys M, Turk DC. Evidenced-based guidelines on the treatment of fibromyalgia patients: are they consistent and if not, why not? Have effective psychological treatments been overlooked? J Pain. 2017;18(7):747–756.

Section 14  |  Diagnostic Assessment Methods in Adults Chapter

47

Polysomnography and Home Sleep Test Assessment Methods in Adults Max Hirshkowitz and Amir Sharafkhaneh

OVERVIEW A little more than a half century ago, sleep medicine evolved from mainly a research endeavor to a clinical specialty. The tools for the scientific study of sleep were borrowed and adapted for clinical application. The principal tool was polysomnography (PSG), an unusual concatenation of Greek and Latin terms. A polysomnographic recording, more commonly known as a sleep study, involves collecting electrophysiologic data concerning brain activity, breathing, oxygenation, movement, and cardiac rhythm. Concurrent video recording was subsequently added. Sleep studies were mainly performed in hospitals and freestanding sleep disorder centers. The vast majority of sleep studies are conducted to diagnose sleep-related breathing disorders and determine their type and severity. A small percentage are used to diagnose narcolepsy, nocturnal seizures, parasomnias, and other sleep disorders. This disproportionate use of PSG to assess breathing during sleep led to further methodologic development and spawned an abbreviated version of the sleep study specifically designed for use in the patient’s home. Such studies acquired the moniker home sleep test (HST). Initially, clinical sleep study methodology, composition, and data reduction procedures (scoring) varied substantially among testing facilities. Later, standardization largely stemmed from the American Academy of Sleep Medicine (AASM) developing a clinical polysomnography manual and third-party insurance carriers (including government programs) requiring procedure adherence for reimbursement. Further codification evolved from the AASM Standards of Practice guidelines, which use an evidence-based medicine approach. Research methods, by necessity, are more diverse because their purpose is to chart new frontiers in knowledge. Furthermore, researchers continually modify these methods to increase sensitivity, incorporate new technology, and widen the scope of inquiry. Nevertheless, as clinical utility for PSG grew, some de facto standards gained acceptance and were endorsed by expert panels. The AASM clinical manual was largely based on existing techniques, and its content represents the efforts of many individuals. Previous guidelines adapted include the following: • A manual of standardized terminology, techniques, and scoring system for sleep stages in human subjects (discussed below) 438

• Guidelines developed by the American Sleep Disorders Association (ASDA) task forces for arousal scoring and periodic leg movement scoring • Work by “the Chicago Group” on sleep-related breathing The AASM manual provided a single information source describing how to record, score, and distill human sleep data for clinical purposes. This chapter primarily addresses PSG and HST assessment. SLEEP STAGING In 1937, Loomis and colleagues recorded the first known, continuous, all-night electrophysiologic sleep study. It became immediately obvious that a procedure was needed to reduce this massive dataset into a manageable form. Over the following three decades, an assortment of sleep stage classification schemes emerged, culminating in the standardized technique described in A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages in Human Subjects. Doctors Allan Rechtschaffen and Anthony Kales chaired this project, leading to its nickname, “The R and K Manual.” It focused on normal sleep and established sleep stage scoring for adults. As pointed out in the first AASM scoring manual preface, “the rapidly emerging field of sleep medicine requires a more comprehensive system of standardized metrics that considers events occurring outside of normal brain activity.” Recording Current clinical PSG practice uses three types of electrophysiologic activity to categorize sleep into four different stages and differentiate it from wakefulness. The three electrophysiologic activities are brain activity, eye movements, and skeletal muscle tone. Electroencephalogram for Brain Activity For classifying sleep stages, the AASM manual recommends recording frontal, central, and occipital electroencephalograms (EEGs)—specifically monopolar derivations from F4, C4, and O2 linked to the contralateral mastoid (M). Backup electrodes are placed at homologous sites at left scalp loci. An alternative recording montage allows substitution of midline bipolar recordings from frontal and occipital derivations (Table 47.1; Figs. 47.1 to 47.3).

Atlas of Clinical Sleep Medicine   439 Table 47.1  Recording Montage for Sleep Staging and Respiratory Monitoring Sampling Rate (Hz) Recorded Activity

Standard Site

Alternate Site

C4–M1 O4–M1 F4–M1 E1a–M2 E2b–M2 Submental EMG Lead II Nares and mouth Earlobe or finger Nose Inserted Various Microphone Rib cage and abdominal movement

Central EEG Occipital EEG Frontal EEG Left EOG Right EOG Muscle tone ECG Airflow thermistor Oximetry Nasal pressure Esophageal pressure Body position Snoring sounds Respiratory effort

Cz-Oz Fz–Cz E1a–Fp E2a–Fp

Intercostal EMG

Filter Setting (Hz)

Preferred

Minimal

Low f

High f

500 500 500 500 500 500 500 100 25 100 100 1 500 100 500

200 200 200 200 200 200 200 25 10 25 25 1 200 25 200

0.3 0.3 0.3 0.3 0.3 10 0.3 0.1 0.1 0.1 0.1 — 10 0.1 10

35 35 35 35 35 100 70 15 15 15 15 — 100 15 100

a

Place electrode 1 cm below the eye’s outer canthus. Place electrode 1 cm above the eye’s outer canthus. Cz, Central zero (midline); E1, left eye; E2, right eye; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram; f, frequency; Fp, frontal pole; Hz, Hertz; M1, left mastoid; M2, right mastoid; Oz, occipital zero (midline). b

Classic derivations

Updated recommended derivations

Nasion

Nasion

Fp1

Preauricular point

F7

F3

Fpz

Fz

Fp2

F4

Fp1

F8

Preauricular point

F7

Fpz

Fp2

F3

Fz

F4

C3

Cz

C4

P3

Pz

P4

F8

A2

A1 T3

T5

C3

Cz

C4

P3

Pz

P4

O1

Oz

T4

T6

O2

T3 Mastoid M1

T5

O1

Oz

T4

T6

Mastoid M2

O2

Inion

Inion

Figure 47.1  ​Classic Rechtschaffen and Kales derivations for recording the

Figure 47.2  ​Updated American Academy of Sleep Medicine recommended

Eye Movements To detect eye movements, electrodes are placed near the right and left outer canthi of the eyes (E2 and E1, respectively). The manual recommends a monopolar electrooculographic (EOG) montage, with E2 placed 1 cm above and E1 placed 1 cm below the outer canthus. When a lateral eye movement occurs, the positive corneal potential moves toward one electrode and away from the other. As a result, this electrode arrangement produces robust right-versus-left EOG out-of-phase activity when horizontal eye movements occur. This allows eye movements to be easily differentiated from frontal EEG activity picked up by EOG electrodes, which appears as in-phase activity. Staggering the electrode placements slightly above and slightly below each

eye’s horizontal plane allows some limited appreciation of vertical eye movements recorded polysomnographically. An alternative recording montage allowing for better visualization of vertical eye movements (albeit sacrificing the in-phase/outof-phase frontal EEG activity differentiation) has both EOG placements 1 cm below the outer canthi and referenced to the middle of the forehead (see Table 47.1).

electroencephalogram. Electrode locations as recommended in 1969. Electrode pairs are indicated by the same colors.

derivations for recording the electroencephalogram. Electrode pairs are indicated by the same colors. Electrode locations as recommended in 2007.

Electromyogram for Skeletal Muscle Tone Finally, to record a submentalis electromyogram (EMG), one electrode is placed 1 cm above the inferior edge of the mandible (on the midline); the other two are placed 2 cm below and 2 cm to the right and left of the midline, respectively. Recordings

440  Polysomnography and Home Sleep Test Assessment Methods in Adults scored when alpha activity occupies 15 or more seconds of an epoch (Fig. 47.4). By contrast, when clear alpha activity is absent, differentiating wakefulness from sleep can, at times, be difficult.

Updated alternative derivations Nasion

Fp1

F7

T3 Mastoid M1

T5

Fpz

Fp2

F3

Fz

F4

C3

Cz

C4

P3

Pz

P4

O1

Oz

F8

T4

T6

Mastoid M2

O2

Inion

Figure 47.3  ​Updated American Academy of Sleep Medicine alternative

derivations for recording the electroencephalogram. Alternative electrode locations as recommended in 2007. Backup electrode substitutions: O1 for Oz, Fpz for Fz, and C3 for Cz. Electrode pairs are indicated by the same colors.

should reference one of the two electrodes below the mandible to the one above, with the remaining electrode reserved for backup. Submentalis EMG is commonly referred to as chin EMG because of the location of the electrodes. Staging Classification Sleep-stage classification involves characterizing the predominant electrocortical activity over a set length of time. This time-domain interval is called an epoch. The AASM manual standardizes epoch length at 30 seconds. The 30-second epoch harkens back to when PSGs were recorded on fan-fold paper. One page was 30 seconds in duration when the chart drive was set to 10 mm/sec. Overall, the sleep process is classified into three distinct conceptual organizational states of the central nervous system (CNS): wakefulness, rapid eye movement (REM) sleep, and non–rapid eye movement (NREM) sleep. On the basis of EEG, EOG, and EMG activity, each recorded epoch is classified as either stage N1 (NREM 1), N2 (NREM 2), N3 (NREM 3), R (REM), or W (wakefulness).* Waves Six EEG waveforms are commonly used to differentiate states and classify sleep stages: alpha activity, theta activity, vertex sharp waves, sleep spindles, K-complexes, and slow-wave activity (Table 47.2). Stages Stage W. In patients with well-defined alpha activity, wakefulness and sleep are easily differentiated. Stage W (wakefulness) is

*This terminology has become so familiar that its intrinsic irony is seldom appreciated. REM sleep represents only 20% to 25% of sleep in normal adults, yet we label the majority of sleep as non-REM. That would be akin to referring to wakefulness as nonsleep, even though it represents the predominant state of CNS activity each day. The overemphasis and preoccupation with REM-related activity (to the neglect and detriment of NREM phenomena research) likely arose from two factors. First, the discovery of REM sleep and its relationship to dreaming created tremendous excitement, energized sleep research, and captivated our imagination. Second, the dramatically distinctive feature, the rapid eye movement, provided an easily applied term that highlighted the intriguing and paradoxical nature of this type of sleep.

Stage N1. Vertex sharp waves often herald sleep onset and thereby provide a valuable landmark for recognizing stage N1 sleep. Wakefulness usually transitions to either stage N1 or N2. Stage N1 is marked by a general slowing of background EEG activity with the appearance of theta and vertex sharp waves. N1 may also be marked by the cessation of blinking and saccadic eye movements and by the appearance of slow eye movements (Fig. 47.5). Although not required, N1 can be discerned by its low-voltage, mixed-frequency background EEG containing theta activity in the absence of slow waves, sleep spindles, K-complexes, prominent alpha activity, or REM. Sleep stage scoring reliability for stage N1 is substantially lower than for any other stage; this holds true for both interscoring and intrascoring agreement. This problem arises from stage N1 being largely defined by rules of exclusion rather than by clearly recognizable electrophysiologic events. Luckily, stage N1 is transitory and accounts for only a small percentage of the night’s sleep complement. Stage N2. Stage N2 is easily recognized by sleep spindles or K-complexes (Fig. 47.6) that occur on a low-voltage, mixedfrequency background EEG in the absence of significant slow-wave activity (i.e., less than 6 seconds of 75 µV or more). Stage N3. When 6 seconds or more of slow-wave activity are present in an epoch, they are scored as stage N3 (Fig. 47.7). The designation N3 generally conforms to activity previously designated as slow-wave sleep, named for the highly synchronized low-frequency activity. Slow-wave activity scoring requires 75 µV or greater peak-to-peak amplitude from a frontal derivation. However, it is important to realize that the recording montage dramatically affects EEG amplitude. Thus, if a frontal EEG is recorded using the AASM alternate bipolar montage (Fz–Cz), amplitudes will be lower and N3 sleep will be reduced. The AASM manual does not provide a guideline for amplitude adjustment; therefore stage N3 scoring is best derived from the monopolar central lead included in the alternate montage. Stage R. Criteria for scoring stage R sleep (REM sleep) remains essentially unchanged. Stage R sleep is characterized by low-voltage, mixed-frequency EEG, very low chin EMG levels, and REM (Fig. 47.8). Sawtooth activity represents a unique variant of theta activity, containing waveforms with a notched or sawtooth-shaped appearance, frequently observed during stage R (Table 47.3). Smoothing Rules When an epoch contains characteristic features of more than one sleep stage, it is scored according to the characteristics comprising its majority. One source of scoring difficulty arises when epochs without actual eye movements are contiguous with REM sleep. The AASM manual does not address the concept of differentiation between phasic and tonic REM sleep (see Fig. 47.8). Nevertheless, this concept is widely used in research and can provide useful instruction. The term phasic REM sleep refers to epochs scored as stage R clearly

Atlas of Clinical Sleep Medicine   441 Table 47.2  Sleep Electroencephalogram Waveforms Sample

Label

Definition

Alpha activity

8- to 13-Hz rhythm, usually most prominent in occipital leads. Thought to be generated by cortex, possibly via dipole located in layers 4 and 5. Used as a marker for relaxed wakefulness and central nervous system arousals.

Theta activity

4- to 8-Hz waves, typically prominent in central and temporal leads. Sawtooth activity (shown in figure) is a unique variant of theta activity (containing waveforms with a notched or sawtooth-shaped appearance) frequently seen during rapid eye movement sleep.

Vertex sharp waves

Sharply contoured, negative-going bursts that stand out from the background activity and appear most often in central leads placed near the midline.

Sleep spindle

A phasic burst of 11- to 16-Hz activity, prominent in central scalp leads; typically last for 0.5 to 1.5 seconds. Spindles are a scalp representation of thalamocortical discharges; the name derives from their shape (which is spindle-like).

K-complex

Recently redefined in the AASM manual as an EEG event consisting of a well-delineated negative sharp wave immediately followed by a positive component standing out from the background EEG with total duration 0.5 seconds, usually maximal in amplitude over the frontal regions.

Slow waves

High-amplitude (75 µV) and low-frequency (#2 Hz) variants of delta (1- to 4-Hz) activity. Slow waves are the defining characteristics of stage N3 sleep.

REM

Rapid eye movements are conjugate saccades occurring during REM sleep correlated with the dreamer’s attempt to look at the dream sensorium. They are sharply peaked with an initial deflection usually ,0.5 second in duration.

SEM

Slow eye movements are conjugate, usually rhythmic, rolling eye movements with an initial deflection usually 0.5 second in duration.

AASM, American Academy of Sleep Medicine; EEG, electroencephalogram; SEM, slow eye movement.

F3-M2 C3-M2 O3-M2

E1-M2 E2-M2

EMGSM

Figure 47.4  ​Epoch of stage W. This figure depicts 30 seconds of polysomnographic activity characterizing stage W (wakefulness) according to American

Academy of Sleep Medicine scoring criteria. C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; M2, right mastoid electrode location; O3, left occipital scalp derivation.

442  Polysomnography and Home Sleep Test Assessment Methods in Adults F3-M2 C3-M2 O3-M2

E1-M2

E2-M2

EMGSM

Figure 47.5  ​Epoch of stage N1. This figure depicts 30 seconds of polysomnographic activity characterizing stage N1 sleep according to American Academy of Sleep Medicine scoring criteria. C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; M2, right mastoid electrode location; O3, left occipital scalp derivation.

F3-M2 C3-M2 O3-M2

E1-M2

E2-M2

EMGSM

Figure 47.6  ​Epoch of stage N2. This figure depicts 30 seconds of polysomnographic activity characterizing stage N2 sleep according to American Academy of Sleep Medicine scoring criteria. C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; M2, right mastoid electrode location; O3, left occipital scalp derivation.

F3-M2 C3-M2 O3-M2

E1-M2 E2-M2 EMGSM

Figure 47.7  ​Epoch of stage N3. This figure depicts 30 seconds of polysomnographic activity characterizing stage N3 sleep according to American Academy of Sleep Medicine scoring criteria. C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; M2, right mastoid electrode location; O3, left occipital scalp derivation.

Atlas of Clinical Sleep Medicine   443 F3-M2

C3-M2

O3-M2

E1-M2

E2-M2 EMGSM

A

B

Figure 47.8  ​Phasic and tonic rapid eye movement (REM) sleep. This figure depicts polysomnographic activity characterizing stage R (REM) sleep according to

American Academy of Sleep Medicine scoring criteria. A, Stage R, with phasic bursts of REM (phasic REM). B, Quiescent period of stage R sleep (tonic REM). C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; M2, right mastoid electrode location; O3, left occipital scalp derivation.

Table 47.3  Electrophysiologic Characteristics of Each Sleep Stage Sleep Stage Electrophysiologic Activity Low-voltage, mixedfrequency EEG Vertex sharp waves Sleep spindles K-complexes EEG beta bandwidth activity EEG alpha bandwidth activity EEG gamma bandwidth activity EEG delta bandwidth activity Slow-wave activityc Eye movement activity EMG activity level

Wa

N1

N2







  

N3 

 

 15 s

Slow and rapid Variable

R

 ,15 s

,15 s

,15 s













,6 s Slow

,6 s

6 s Rapid

,6 s

Low

Low

Low

Atonic

b

a

With eyes closed. Special form of theta wave called sawtooth owing to its appearance. For purposes of sleep staging, monopolar slow-wave activity from frontal or central derivations must be 75 µV. EEG, electroencephalogram; EMG, electromyogram; s, seconds. b c

accompanied by eye movements and sometimes by other phasic events. By contrast, an epoch designated as tonic REM sleep has the same background EEG activity, nearly completely diminished chin EMG, but lacks eye movements. If such an epoch occurs in isolation, it is typically scored as N1; however, when surrounded by epochs of phasic REM sleep, it is considered stage R. In fact, N1-like epochs without eye movement contiguous with REM sleep continue to be scored as stage R until

some indication occurs that another sleep process has emerged. Indicators can be a spindle, a K-complex, a CNS arousal, an increase in chin EMG, a body movement followed by slow eye movements, or the appearance of another scorable sleep stage in the first half of the epoch. The AASM manual provides examples to guide scoring decisions at stage transitions. AROUSAL SCORING Electroencephalogram Speeding and Central Nervous System Arousals Sleep staging forms what may be called the building blocks of sleep macroarchitecture. Staging provides information that is useful for forming a general impression of sleep’s overall continuity and integrity. Staging also serves as a biomarker for detecting gross disturbances and for correlating pathophysiology with the organizational state of the CNS (i.e., REM, NREM, or wakefulness). Staging parameters, however, fail to capture transient sleep disturbances, which last less than 15 seconds. Therefore techniques are needed to identify brief CNS arousals that fail to meet the epoch scoring criteria for wakefulness. CNS arousals involve an abrupt shift during sleep to faster EEG activities—including theta, alpha, and beta but not sleep spindles—for 3 seconds or longer. CNS arousal scoring rules largely derive from a previous concept called EEG speeding. Usually, the frequency shift manifests as alpha activity and is best visualized in occipital leads. For the shift to qualify as an arousal, the person must have been asleep for at least 10 seconds. Finally, during REM sleep, the EEG shift must be accompanied by at least 1 second of increased chin EMG tone (Fig. 47.9) because alpha bursts routinely appear during REM sleep and do not intrinsically represent pathophysiology. The 3-second duration was not arbitrary; it was the minimum arousal duration reliably scored by hand among the task force members. Undoubtedly, digital systems could reliably score shorter arousals, but the clinical significance of such events is not known.

444  Polysomnography and Home Sleep Test Assessment Methods in Adults F3-M2 C3-M2 O3-M2 E1-M2 E2-M2

A

EMGSM F3-M2 C3-M2 O3-M2 E1-M2 E2-M2

B

EMGSM

Figure 47.9  ​Central nervous system arousals from non–rapid eye movement (NREM) (A) and REM sleep (B). C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; M2, right mastoid electrode location; O3, left occipital scalp derivation.

A

B

A

B

A

B

A

B

A

F3-M2 C3-M2 O3-M2 E1-M2 E2-M2 EMGSM EMGLeg Flow RCMvmt ABMvmt

Figure 47.10  ​Cyclic alternating pattern (CAP). This figure depicts polysomnographic activity characterizing phase A (burst) and phase B (quiescent) activity. This

period of CAP activity appears not to be associated with either periodic leg movements or breathing abnormalities. ABMvmt, Abdominal movement measured with inductive plethysmography; C3, Left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGLeg, surface electrode electromyogram recorded from left and right anterior tibialis; EMGSM, surface electrode electromyogram from submentalis muscle; F3, left frontal scalp derivation; Flow, airflow measured with nasal-oral thermistor; M2, right mastoid electrode location; O3, left occipital scalp derivation; RCMvmt, rib cage movement measured with inductive plethysmography.

Cyclic Alternating Pattern The cyclic alternating pattern (CAP) refers to an EEG pattern seen during sleep (Fig. 47.10) in which EEG activity bursts— usually a high-amplitude slow, sharp, or polymorphic wave burst—alternate with periods of quiescence. The burst constitutes the A phase, and the quiescence is labeled the B phase. The Parma Groups, led by Terzano and Parrino, organized an international workshop during which recording and scoring techniques were codified. In essence, the A phase was subcategorized into three types based on the presence and duration

of intermixed or intermingled EEG alpha activity. Type A1 contains little or no alpha EEG activity and consequently does not meet AASM arousal scoring criteria. Type A2 often meets AASM arousal criteria, and A3 meets AASM criteria 95% of the time. Sleep associated with A1 bursts is conceptualized as unstable but is preserved by a descending cortical response that helps reinforce a sleep-protective thalamic gating mechanism. By contrast, if the attempt to reinforce this gate fails, an arousal or awakening occurs and an A3 burst is observed. A2 responses fall somewhere in between (Fig. 47.11).

Atlas of Clinical Sleep Medicine   445 Type 1

Type 2

Type 3

E1-M2 E2-M2 EMGSM F3-M2

C3-M2

O3-M2

Figure 47.11  ​Examples of cyclic alternating pattern A phase types 1, 2, and 3 activity. Type 1 does not appear to have electroencephalographic activity suggestive of central nervous system arousal. By contrast, type 2 activity suggests possible arousal, whereas type 3 meets American Academy of Sleep Medicine criteria for central nervous system arousal from non–rapid eye movement sleep. E1, Left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyogram from submentalis muscle; M2, right mastoid electrode location.

SLEEP-RELATED BREATHING DISORDERS It took many years and substantial educational efforts to convince the medical community that sleep-related breathing disorders do not exclusively afflict hypoventilating, morbidly obese men. An estimated 90% or more of all PSG studies performed on any given night are conducted to diagnose or assess treatment for sleep-disordered breathing (SDB). Ironically, recording and scoring techniques for evaluating SDB were among the last to be standardized. Recording Technique Key features needed to assess SDB include airflow, respiratory effort, blood oxygenation, and sleep disturbance. The AASM manual recommends recording all four data channels when clinically evaluating adult patients with overnight PSG (see Table 47.1 for sampling rates and filter settings). This is done with (1) a thermal sensor at the nose and mouth to detect apnea; (2) a nasal pressure transducer to detect hypopnea; (3) either an esophageal manometer or chest/abdominal inductance plethysmograph—or, alternatively, intercostal EMG—to detect respiratory effort; and (4) a pulse oximeter with its signal averaged over 3 seconds or less to detect oxyhemoglobin desaturations. Although end-tidal CO2 measurement is not recommended for adults by the AASM manual, it can be useful for quantifying hypoventilation. Other sections in this atlas contain illustrations of end-tidal CO2 recordings. Snoring sounds can help differentiate different types of SDB events; however, methods for using such data are not specified in the manual. SDB scoring is event based, not time-domain based. Consequently, the 30-second fixed epoch length is somewhat irrelevant. Scoring mainly involves identifying, counting, and characterizing discrete SDB event sequences. Sleep-related respiratory signals are considerably slower than variations in EEG-EOG-EMG activity; therefore, viewing tracings over longer time frames can facilitate breathing pattern and event recognition. The viewing flexibility provided by digital PSG reflects a great advantage when scoring and interpreting

sleep-related respiratory impairments. Nonetheless, the 30-second fixed epoch length specified by the AASM manual applied to sleep staging does affect SDB scoring. Sleep onset can occur during an epoch scored as stage W if it begins in the latter portion of an epoch. When apnea occurs in such a case, some tabulation programs do not count it because it is not recognized as sleep related. Similarly, when a sleep-related respiratory event occurs early enough during an epoch to provoke an awakening that renders the epoch to be staged as wakeful, again, some software fails to count the episode. Clinicians must determine how their digital systems handle such disconnects so they can adjust summaries accordingly. Definitions and Scoring Rules Sleep Apnea Conceptually, a cessation of airflow for two or more respiratory cycles during sleep constitutes an episode of sleep apnea. This works out to be, on average, a 10-second or longer halt in ventilation. Episodes can be classified as central, obstructive, or mixed. The cessation of breathing during central sleep apnea results from an absence of inspiratory effort. By contrast, obstructive sleep apnea results from airway occlusion notwithstanding continued and even increasing inspiratory effort. Finally, a mixed sleep apnea episode usually begins with no inspiratory effort and is followed by an unsuccessful attempt to breathe against a collapsed airway. The AASM manual defines apnea as a 10-second or longer, 90% or greater, drop in the nasal/oral airflow channel’s peak-to-trough amplitude compared with the pre-event baseline (Fig. 47.12). Obstructive sleep apneas are far more commonly observed in most sleep laboratories than are central sleep apneas. However, central sleep apnea can take several forms, arising from different etiologies that include heart failure, brain damage, metabolic disorders, toxic exposure, and CNS depressants. Figure 47.13 illustrates an example of Cheyne-Stokes respiration presenting as recurrent central sleep apnea episodes as typically observed in patients with heart failure.

446  Polysomnography and Home Sleep Test Assessment Methods in Adults F3-M2 C3-M2 O3-M2 E1-M2 E2-M2 EMGSM Flow RCMvmt ABMvmt

A

B

C

Figure 47.12  ​Sleep apnea episodes. Obstructive (A), central (B), and mixed (C) apneas are shown. Note the presence of respiratory effort (rib cage and

abdominal movement), notwithstanding cessation of airflow, throughout the obstructive apnea and during the latter portion of the mixed apnea. By contrast, respiratory effort is absent during the flow cessation throughout the central apnea and during the early portion of the mixed apnea. ABMvmt, Abdominal movement measured with inductive plethysmography; C3, left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyography from submentalis muscle; F3, left frontal scalp derivation; Flow, airflow measured with nasal-oral thermistor; M2, right mastoid electrode location; O3, left occipital scalp derivation; RCMvmt, rib cage movement measured with inductive plethysmography.

10m 0s AM

10m 0s 5:44:00 AM

5:45:00 AM

5:46:00 AM

5:47:00 AM

5:48:00 AM

5:49:00 AM

5:50:00 AM

5:51:00 AM

5:52:00 AM

5:53:00

Neck_PDS 0.5 V Snore_PDS 0 bar FLOW 0 mL/s Thermistor 0 V Nasal pr -0.25 mbar XSum 0 mV THOR 0 V ABD 0

SpO2 - %

Pulse - bpm

V 100

85 85 84 82 82 81 82 83 84 85 85 84 82 82 83 82 83 83 84 83 82 81 81 82 83 84 85 85 85 84 83 82 82 83 84 84 84 83 81 81 81 82 82 84 85 86 85 84 83 82 83 84 84 85 84 83 82 81 82 82 84 85 85 85 83 82 82 82 83 84 84 85

75 50

90

Figure 47.13  ​Cheyne-Stokes respiration pattern. Note the waxing and waning of respiratory effort, manifested as flattening in the thoracic and abdominal movement channels, with corresponding cessation of airflow.

Atlas of Clinical Sleep Medicine   447 Hypopnea In the strictest sense, a hypopnea is merely a shallow breath and is not intrinsically pathophysiologic. However, during sleep, reduced ventilation that produces significant oxygen desaturations can adversely affect sleep, wakefulness, and health. Also, flow limitations that provoke CNS arousals, awakenings, and sleep fragmentation can undermine the sleep process. Thus the pathophysiology lies not with the hypopnea but rather with its consequence. The previous AASM manual operationalized hypopnea scoring based on two different sets of rules, the first designated “recommended” criteria, the other “alternative” criteria. Fortunately, a single definition evolved and was adopted by the AASM defining hypopnea as a 10-second or longer, 30% or greater, drop in nasal pressure signal amplitude or other airflow measure compared with the pre-event amplitude that either provokes a 3% or more drop in oxygen saturation or a CNS arousal (Fig. 47.14). Unfortunately, this AASM definition was at variance with the one required by Centers for Medicare and Medicaid Services (CMS) to justify treatment with positive airway pressure (PAP) therapy.* Having different definitions and revising definitions without changing terminology create ambiguity and confusion by impeding accurate communication. It is preferable that when a term is newly defined, it be given a unique identifier, such as hypopnea 2007 for events scored using the previously recommended AASM criteria,

*The previous AASM manual had two definitions for hypopnea and recommended using the one that closely approximated what was compulsory for billing CMS (which required a 4% drop in oxyhemoglobin saturation). If a medical practice includes any CMS-covered patients, CMS scoring must be performed for all patients to avoid committing Medicare fraud (Medicare patients must be treated identically to private-pay patients to avoid creating a two-tiered medical system).

hypopnea 2012 for those meeting later AASM criteria, and hypopnea CMS for those scored using Medicare criteria. Indeed, any unambiguous set of terms would be an improvement for communicating without having to stop and review which criteria were being applied (see Fig. 47.14). Respiratory Effort–Related Arousals The PSG activity designated respiratory effort–related arousals (RERAs) identify SDB events that do not meet apnea or hypopnea scoring criteria based on airflow measures. RERAs emphasize the sleep disturbance (CNS arousal) produced by increasing effort to breathe during a partially obstructive respiratory event. Originally the RERA designation helped quantify more subtle breathing events that would otherwise be missed. However, with the original AASM manual, RERA scoring evolved into serving as a surrogate for “alternative” hypopnea when the required oxyhemoglobin desaturation criteria for “recommended” hypopnea scoring was not met. It appears that RERAs have now mostly returned to their original definition, with the modification that they are identified by inspiratory flattening of nasal pressure or a PAP machine’s flow channel rather than by measuring respiratory effort with an esophageal pressure transducer. RERA scoring requires a 10-second or longer increased respiratory effort that manifests as “flattening” in the nasal pressure channel that provokes a CNS arousal but does not meet apnea or hypopnea amplitude or oxygen saturation criteria. Nasal pressure recordings can alert the clinician to much more subtle respiratory events than the traditional nasal-oral thermistors. However, notwithstanding their greater sensitivity to SDB events, nasal pressure recordings are compromised when sleepers “mouth breathe” because of nasal congestion, their anatomy, or both.

F3-M2 C3-M2 O3-M2 E1-M2 E2-M2 EMGSM Flow RCMvmt ABMvmt SaO2

100 96 92 88

100 96 92 88

A

B

Figure 47.14  ​Desaturating and traditional hypopnea episodes. A, Sleep hypopnea associated with a greater than 4% oxygen desaturation (meeting Medicare

criteria). B, Sleep hypopnea terminated by central nervous system arousal (meeting current American Academy of Sleep Medicine criteria). Many sleep laboratories differentiate the respiratory event in part A as a desaturating hypopnea, distinct from the traditional hypopnea, by labeling the latter as a respiratory effort–related arousal. ABMvmt, Abdominal movement measured with inductive plethysmography; C3, left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGSM, surface electrode electromyography from submentalis muscle; F3, left frontal scalp derivation; Flow, airflow measured with nasal-oral thermistor; M2, right mastoid electrode location; O3, left occipital scalp derivation; RCMvmt, rib cage movement measured with inductive plethysmography; Sao2, oxygen saturation with percent indicated on grid.

448  Polysomnography and Home Sleep Test Assessment Methods in Adults MOVEMENTS Leg Movement Recording Technique To record leg movements, a pair of surface electrodes is placed longitudinally at homologous sites (2 to 3 cm apart) on the belly of the anterior tibialis muscle of each leg. Both left and right legs should be recorded either on separate channels (greatly preferred) or combined on a single channel (see Table 47.3 for sampling rates and filter settings). The actual movement associated with periodic limb movement disorder (PLMD) can be merely a Babinski-like extension of the great toe. However, movements may be more dramatic and may involve the ankle, knee, hip, and/or upper extremities. Periodic Leg Movement Scoring Rules Overall, the general approach for scoring periodic leg movements has changed little since Coleman’s original description. However, specific criteria for detecting and segmenting leg movements were updated with an eye toward digital PSG capabilities. The AASM manual reaffirmed most of the scoring rules developed by the International Restless Legs Syndrome Study Group (IRLSSG) chaired by Zucconi. Criteria require the duration of each anterior tibialis EMG burst to range from 0.5 second to 10 seconds (inclusive) beginning when the EMG amplitude increases to 8 µV (minimally) above the resting level and ending when the amplitude decreases to within 2 µV of the resting level. These criteria come with the caveat that because surface electrode–recorded EMGs cannot be calibrated, the empirically determined amplitude criteria serve to facilitate automation and do not represent any biologic watershed demarcation. To constitute a periodic leg movement episode, there must be a sequence of four or more movements with the intermovement interval ranging from 5 to 90 seconds (inclusive). Leg movements can be unilateral or bilateral, or they may alternate. Leg movements that occur during sleep may be associated with CNS arousals (Fig. 47.15). Periodic leg movements that occur during wakefulness sometimes serve as a biomarker for restless legs syndrome (RLS, Fig. 47.16).

Other Movements Descriptions and criteria for other types of sleep-related movements are described in the AASM manual. These types include hypnagogic foot tremor, excessive fragmentary myoclonus, sleep bruxism, REM sleep behavior disorder (RBD), and rhythmic movement disorder. A discussion of the recording and scoring techniques for these movements is beyond the scope of this chapter. For details, see the AASM manual. ELECTROCARDIOGRAM The AASM manual recommends recording cardiac rhythm concurrently during PSG. A single modified electrocardiographic (ECG) lead placed on the torso and aligned parallel to the right shoulder and the left hip provides the necessary tracing. Adult sinus tachycardia during sleep involves a sustained rate of 90 beats/min or higher, whereas bradycardia is a sustained rate below 40 beats/min. Three consecutive beats with a rate above 100 beats/min and a 120-ms QRS duration or greater constitute sleep-related wide complex tachycardia. Sleep-related narrow-complex tachycardia is similar, except that the QRS duration must be less than 120 ms in duration. Cardiac pauses with a duration of 3 seconds or more are reported as asystoles. The manual also recommends reporting other arrhythmias and ectopic beats if they are judged to be clinically significant. HOME SLEEP TESTING Most clinical sleep assessments are performed to diagnose SDB, titrate PAP therapy, or both. The appropriateness of HST depends on clinical factors, and its overall accuracy remains somewhat controversial. Nevertheless, the CMS approved HST to diagnose sleep apnea, and local coverage determination (LCD) contractors and private third-party insurance carriers have largely ruled HST as “reasonable and necessary.” The COVID-19 pandemic greatly accelerated

C3-M2 O3-M2 E1-M2 E2-M2 EMGSM EMGLeg EMGLeg Flow RCMvmt ABMvmt

Figure 47.15  ​Periodic leg movements during sleep. This figure illustrates polysomnographic activity commonly observed on recordings from individuals with

periodic limb movement disorder. ABMvmt, Abdominal movement measured with inductive plethysmography; C3,, left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; EMGLeg, surface electrode electromyography recorded from left and right anterior tibialis—on separate channels; EMGSM, surface electrode EMG from submentalis muscle; Flow, airflow measured with nasal-oral thermistor; M2, right mastoid electrode location; O3, left occipital scalp derivation; RCMvmt, rib cage movement measured with inductive plethysmography.

Atlas of Clinical Sleep Medicine   449 LOC-A2

A

E1-M2

B

ROC-A2

E2-M2

Chin EMG

EMGSM

C3-A2

C3-M2

O1-A2

O3-M2

ECG

ECG

L. Anterior Tibialis EMG

EMGLeg

R. Anterior Tibialis EMG

EMGLeg

Snoring

Flow RCMvmt

Thoracic Effort

ABMvmt

Abdominal Effort

Figure 47.16  ​Restless legs type I and II activity. This figure illustrates polysomnographic activity commonly observed on recordings from individuals with rest-

less legs syndrome. A, Very brief electromyography discharges on anterior tibialis channels lead up to movements. B, Periodic leg movements during wakefulness. A2, Right ear; ABMvmt, abdominal movement measured with inductive plethysmography; C3, left central scalp derivation; E1, left outer canthus eye electrode location; E2, right outer canthus eye electrode location; ECG, electrocardiogram; EMGLeg, surface electrode electromyography recorded from left and right anterior tibialis; Flow, airflow measured with nasal-oral thermistor; LOC, left oculogram; M2, right mastoid electrode location; O3, left occipital scalp derivation; RCMvmt, rib cage movement measured with inductive plethysmography; ROC, right oculogram.

Pretest clinical assessment

Is SRBD suspicion high?

no

yes

Narcolepsy suspicion high?

yes

Schedule for a laboratory PSG with a MSLT on the following day

yes

Schedule laboratory PSG with extended montage & video monitoring

no

Schedule Pt for a home level II or level III study

Suspicion for parasomnia or seizure? no

Is test positive for SRBD?

no

yes Is PAP titration needed?

Schedule laboratory PSG

Possible APAP candidate

Treat sleep disorder & follow clinically

no

yes

Does Pt have HD, LD, ND, yes MO, UP3?

Laboratory titration needed

no

Figure 47.17  ​Home sleep testing algorithm and recording sample. This figure shows an algorithm used to perform home sleep testing with cardiopulmonary

(type III) recorders. APAP, Automatic positive airway pressure; HD, heart disease; LD, lung disease; MO, morbid obesity; MSLT, multiple sleep latency test; ND, neurologic disease; PAP, positive airway pressure; PSG, polysomnography; Pt, patient; SRBD, sleep-related breathing disorder; UP3, uvulopalatopharyngoplasty.

HST acceptance as part of the effort to minimize face-to-face contact and reduce all except essential services. HST represents a limited test that may facilitate SDB diagnosis and reduce costs if used properly. However, the success of a home sleep test depends on (1) proper patient selection, (2) appropriate portable recorder application, (3) study interpretation by a qualified sleep specialist, (4) readily available access to laboratory PSG when

needed after a negative test or for continuing problems notwithstanding treatment, and (5) systematic follow-up (Fig. 47.17). Proper patient selection is easily accomplished. HST is often appropriate in individuals with increased risk of moderate to severe OSA indicated by the presence of excessive daytime sleepiness and at least two of the following criteria: habitual loud snoring; witnessed apnea, gasping, or choking;

450  Polysomnography and Home Sleep Test Assessment Methods in Adults or diagnosed hypertension. One popular instrument is called the STOP-BANG questionnaire. This questionnaire has eight yes-or-no items that address snoring, tiredness, observed cessation of breathing, presence or history of hypertension, obesity (body mass index . 35), age (.50 years), neck circumference (.15.75 inches), and sex (being male). A score of 5 or above constitutes a high pretest probability for SDB that can be confirmed with HST. Because HST lacks the sensitivity of PSG, it can rule in, but not rule out, SDB. HST recorders are classified as levels II, III, and IV. Most recording devices fall into the level III category and acquire three or more respiratory channels and heart rate. Sometimes referred to as cardiopulmonary recorders, these devices are worn at home during sleep. The data are transferred from the recorder to a computer for review and analysis. Systems with only one or two channels, usually including oximetry, fall into the level IV category. Like cardiac Holter monitors, sleep cardiopulmonary recorders are appropriate when a high clinical suspicion for disease exists. The most common HST devices are level III devices and do not record brain activity. Consequently, they do not detect CNS arousals. As such, they cannot identify SDB events that lead to sleep disturbance unless an oxyhemoglobin desaturation occurs concurrently. More importantly, if the patient has a disorder other than easily verified sleep apnea, it will likely remain undiagnosed. If symptom presentation is mixed, the patient is not sleepy, or pretest probability is low, the patient should be referred for full laboratory assessment. Patients with symptoms suggesting other or comorbid sleep disorders (sleepwalking, cataplexy, dream enactment with injury) should likewise be referred for laboratory evaluation. The HST recording should be reviewed and interpreted by an experienced sleep medicine practitioner (Fig. 47.18). When the portable study is positive for obstructive sleep apnea and is severe enough to warrant PAP therapy, the patient is referred for either laboratory titration or home-based automatic

11:35:42 PM Desat

SpO2

Desat

self-adjusting PAP titration. During treatment follow-up, patients with residual sleep-related symptoms (e.g., sleepiness, insomnia, fatigue) should be referred for further assessment. Although not addressed in the AASM manual, to ensure good patient care, HST works best when embedded within an overall sleep disorders program rather than being used as an isolated test. Patients with negative HST results should be referred for attended PSG, and patients with positive HST results may need attended PAP titration. Cardiopulmonary recorders are prone to recording problems. Signal failures are not ameliorated because the test proceeds unattended, and data loss lowers the sensitivity of the test.* Furthermore, partial data loss is very common (Figs. 47.19 and 47.20). HST recorders are merely tools, and they can be used either skillfully or poorly. As the Czech novelist Milan Kundera wrote, “A tool knows exactly how it is meant to be handled, while the user of the tool can only have an approximate idea.” OVERALL ASSESSMENT PSG is an important part of the overall patient assessment in sleep medicine practice. The AASM manual focuses on PSG recording and scoring techniques and sets clinical standards for laboratory sleep studies. The rules and definitions form the backbone for scoring and summarizing sleep-related physiologic activity. However, this technical component is only a part of patient evaluation. Sleep continuity, integrity, and architecture must be considered within the context of age, sex, concordance with the usual sleep-wake schedule, comorbid conditions, and medication. Finally, the type, frequency, *For example, if the oximetry probe detaches, no hypopnea can be scored because level III recorders do not include the EEG signals necessary to score CNS arousals. Thus, in such a case, if the patient’s SDB is not severe enough to meet criteria based on apnea alone, the HST is negative.

2 min

11:37:42 PM Desat

Desat

%

80

Abdo

Ob.Ap

Ob.Ap

Ob.Ap

Ob.Ap

Ob.Ap

Ob.Ap

62.5 mV 1.5

Airflow cm H20 1.5 80

HR 8PM 40

Figure 47.18  ​Home sleep testing recording sample. This figure shows a sample tracing of data obtained during a home sleep test using home sleep-testing

equipment on a patient with high clinical suspicion for having sleep-disordered breathing. This is from a level III study that shows 2 minutes of data and was taken from an obese patient with classic obstructive sleep apnea syndrome by history; thus the pretest probability of sleep apnea was high. A low sampling rate is evident in the oxygen saturation (SpO2) trace as steps in the data. Notice that the airflow signal (inspiration goes up) from the measurement of nasal pressure shows highfrequency noises that are particularly apparent at the beginning of this epoch. These represent the vibration of snoring. The patient had these types of findings, as shown here, during four periods of the night spaced with 60- to 120-minute intervals. Presumably, these occurred during rapid eye movement sleep. Because it is not clear whether the patient was awake or asleep during periods of normal breathing, interpretation of such a study can be difficult. Indices in such home studies are calculated on recording time. This patient’s calculated apnea index was 14.8. In this case, the patient had symptoms; therefore he would meet criteria for treatment with positive airway pressure (PAP). If he did not have symptoms, the Centers for Medicare and Medicaid Services (CMS) and carriers using CMS criteria would not approve PAP therapy, and restudy with overnight polysomnography would be needed. Abdo, Abdominal movement; HR, heart rate; ObAp, obstructive apnea.

SpO2 %

100 92.5 85 77.5 70

SpO2 %

30

CA, sec

0

30

30

OA, sec

15

0

0

30

30

MA, sec

15

HYPO, sec

15

0 15

MA, sec

30

CA, sec

15

OA, sec

100 92.5 85 77.5 70

15

0

0

50

50

HYPO, sec

25

Pos

N

N

Pos

S

S 9:53:38 PM

SpO2 %

CA, sec

11 PM

12 AM

1 AM

2 AM

3 AM

4 AM

100 92.5 85 77.5 70

6:32:19 PM

SpO2 %

CA, sec

0 OA, sec

0

11 PM

12 AM

1 AM

2 AM

3 AM

30 15 30 15 30 15 0

HYPO, sec 50 25

HYPO, sec

0

50 25 0

N

Pos

S

N S

11 PM

12 AM

1 AM

2 AM

3 AM

4 AM

5 AM

11:35:55 PM

1 PM

2 PM

3 PM

4 PM

5 PM

Figure 47.19  ​Home sleep test histograms. This four-panel illustration shows summary histograms from four different patients. The histogram in the top left panel shows very severe sleep apnea with both obstructive

and central components. The histogram in the top right panel shows sleep-disordered breathing (SDB) that may be related to rapid eye movement (given the increasing severity every 80 to 100 minutes); however, the oxyhemoglobin desaturations also coincide with the patient shifting to the supine position. By contrast, the histogram in the bottom left panel also shows recurrent oxyhemoglobin desaturation, but spaced further apart (120 to 180 minutes) during sustained lateral recumbence (nonsupine). Finally, the histogram in the bottom right panel shows milder SDB, even though the patient slept supine the entire night. Recording channels displayed (top to bottom) include Spo2 (oxygen saturation), CA (central apnea), OA (obstructive apnea), MA (mixed apnea), HYPO (hypopnea), and Pos (position, N, nonsupine or S, supine). Note that hypopnea in this figure was scored according to reduced ventilation and not oxyhemoglobin desaturation criteria.

Atlas of Clinical Sleep Medicine   451

MA, sec

15

9:25:11 PM

10 PM

0

30 0

Pos

9 PM

0

30 15

MA, sec

8 PM

100 92.5 85 77.5 70

30 15

OA, sec

25 0

0

94 90 88 87 89 86 86

94

92

93

93 89

85 84 84

85

87 87

84 84

94

92 86

85 85

94

92

94 94 91 91

94 91

88 87 87

85 84 85

88 88 88

SaO2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

HR

HR 84 80 82 85 85 83 88 88 88 80 79 84 78 75 78 83 83 77 84 85 85 82 82 83 74 76 73 71 71 71 73 86 86 86 80 79 92 93 93 90 82 86

AIRFLOW

AIRFLOW

RESP EFFORT

RESP EFFORT

SNORE

SaO2

SN

95

SN

SN

SN

99 98 99 99 97 97 98 98 97 97 97 97 96 96 96

SN

94 93 95

99 98 97

SN

SN

99 98 95 94 94

96

SN

95 94

97

99

97

SN

95 95

97

SN

99 98 98 97 96 95

HR 76 76 67 60 59 59 61 62 62 59 61 64 64 64 61 60 63 64 60 61 60 61 61 60 63 63 61 57 60 62 65 59 62 62 60 60 62 64 64 60 61 61

AIRFLOW

SNORE

SaO2

92 92

SN

94 95

96

SN

SN

SN

SN SN

SN SN

95 94 94 93 93 93 94 94 93 93 94

92 92

93

94 94

SN SN

SN

SN

SN SN

SN SN

92 92 91 92 91 92 92 92 91 92 91 91 91 90 91 90 90 91

94 93 93

HR 62 63 63 63 62 62 63 63 64 63 63 63 63 63 63 63 63 63 63 62 62 63 63 63 64 64 64 64 65 65 65 66 65 66 66 66 66 67 67 67 67 68

AIRFLOW

RESP EFFORT

RESP EFFORT

SNORE

SNORE

SN

SN SN SN SN

SN SN SN SN SN

SN SN

SN SN

SN SN SN

SN SN SN SN SN SN

SN

SN SN SN SN

SN SN SN

SN SN

Figure 47.20  ​Home sleep test tracings. This four-panel illustration shows 5-minute tracings from four different patients. The top left panel shows a patient with severe obstructive sleep apnea accompanied by prominent oxyhemoglobin desaturation events. The top right panel also shows a patient with severe sleep-disordered breathing (SDB); however, the oximetry channel is not functioning. Without oximetry, hypopnea cannot be scored according to Centers for Medicare and Medicaid Services criteria. In this case, the SDB manifests as apnea events, making diagnosis possible. The bottom left panel shows a tracing that is missing both airflow and snoring sounds. Although the oximetry channel suggests that sleep apnea is present, diagnosis cannot definitively be made. The bottom right panel shows a pattern indicating snoring and some hypopnea events. HR, Heart rate; RESP, respiratory; Sao2, oxyhemoglobin saturation; SNORE, snore sound.

452  Polysomnography and Home Sleep Test Assessment Methods in Adults

SaO2

Atlas of Clinical Sleep Medicine   453 W R N1 N2 N3 0

1

2

3

4 5 6 7 8 9 Time in bed (hours) Figure 47.21  ​Normal sleep macroarchitecture. This figure illustrates normal sleep-stage progression for a healthy young adult. N1, Sleep stage NREM 1; N2, sleep stage NREM 2; N3, sleep stages NREM 3 and 4; R, rapid eye movement sleep; W, wakefulness.

magnitude, duration, and severity of pathophysiology detected during sleep must be correlated with the patient’s symptoms, signs, somatic condition, and psychological status. Sleep evaluations can be particularly sensitive to underlying conditions inhibited by volitional or waking-stage processes. Sleep Stage Changes Across the Night In normal young adults, the macroarchitectural sleep stage pattern across the night is fairly consistent (Fig. 47.21). Stage N2 occupies approximately one-half of the total sleep time, stage N3 may account for one-eighth to one-fifth of the total sleep time (12.5% to 20%), and the remaining NREM stage (N1), which occurs at sleep onset and during wakefulness transitions, usually totals less than 5% of sleep. REM sleep (stage R) appears every 90 to 100 minutes in distinct episodes that elongate as the night progresses, thereby loading the second half of the sleep session with the majority of time spent in this CNS organization state. In total, approximately one-fifth to one-fourth of sleep is spent in stage R. Under normal circumstances, the transition from wakefulness to sleep is rapid (5 to 15 minutes) and is marked by the appearance of stage N1 or N2 sleep. A healthy young adult sleeps 85% to 95% of the typical 7 to 8 hours spent in bed. Stage R typically first occurs after an hour and a half of sleep. Slow-wave activity, and therefore stage N3, predominates in the first third of the night and becomes rarer as the sleep period progresses toward morning. Men and women differ little in sleep macroarchitecture; however, women may have slightly better-preserved stage N3 with advancing age. The aforementioned descriptions of normal sleep in the healthy young adult derive from electrophysiologic data that universally exclude results obtained during the first night sleeping in a laboratory. Sleep disturbances associated with the initial experience of sleeping in a laboratory are so well known they are called first night effects. First-night data are excluded by researchers interested in the commonalities of normal sleep, who rightfully believe these are artifacts created by procedure (analogous to the uncertainty in quantum mechanics postulated by the Heisenberg principle). Ironically, first-night data are more appropriate for comparison in clinical practice because diagnostic PSGs most often are made on the first night a patient has ever slept overnight in a laboratory. Consequently, results should be compared with normative values collected from normal healthy adults sleeping in the laboratory for the first time (Table 47.4).

Sleep Stage Changes as a Function of Age Sleep microarchitecture and macroarchitecture change over the life span. For this reason, judging sleep integrity, continuity, or composition should be done against age-specific normative values. During infancy, multiple-feeding REM-NREM cycles consolidate to one major and several minor sleep episodes by the end of the first year. This further reduces to a major and a single minor sleep episode by 4 years of age and to the adult single major sleep period at around 10 years of age. At some time between the two milestones of 6 months and 1 year of age, the prevailing sleep-onset REM, or, more precisely, active sleep, switches to the adult pattern in which the transition from wakefulness to sleep is through an NREM stage. Overall, across childhood and into adulthood, total sleep time gradually decreases. Part of this is the decreasing stage N3 after adolescence; however, other stages also decrease, and wakefulness within the sleep period increases. This trend continues as a function of age, with N3 reducing to low levels or even disappearing altogether in older adults. By contrast, active sleep, the infant’s equivalent of stage R sleep, decreases spectacularly from greater than 50% at birth to 20% to 25% by adolescence. Then, after remaining stable for perhaps five decades, the stage R percentage decreases slightly further. Decreasing sleep duration and consolidation are often associated with sleep disturbances related to the accumulated pathologies that invariably accompany aging. However, some total sleep decrease is nonspecific or of unknown etiology. Some researchers argue that age-related deterioration of underlying physiologic sleep mechanisms is responsible. The fact remains that as we enter our senior years, we spend more time in bed but less time sleeping. Parameters, Pathophysiology, and Interpretation For summarizing a sleep study, the AASM manual provides a list of parameters for calculating, tabulating, and reporting. Some parameters are recommended, and some are optional (Table 47.5). This provides an objective technique for assessing sleep disturbances and instability. Time-indexed measures (i.e., rates per hour or percentage time) are useful to control for differences in recording, sleep duration that occurs across nights, or, more importantly, comparisons among individuals. For example, the number of leg movement–related arousals per hour better characterizes activity level than does the overall number of leg movement–related arousals.

454  Polysomnography and Home Sleep Test Assessment Methods in Adults Table 47.4  Normal Value Ranges for “First Night” Laboratory Polysomnographya Age (Years) 20–29 (n 5 44) General, Sleep Continuity, and Integrity Measures Time in bed (min) 361–449 Sleep latency (min) 0–25 Total sleep time (min) 285–410 72–100 Sleep efficiency index† Latency to arising (min) 0–10 Number of awakenings 1–18 Awakenings per hour 0–3 Number of REM sleep episodes 2–4 NREM Sleep Stage Percentages N1 percentage of time in bed 1–7 N2 percentage of time in bed 40–58 N3 percentage of time in bed 12–19 Stage R percentage of time in bed 11–25

30–39 (n 5 23)

40–49 (n 5 49)

50–59 (n 5 41)

.60 (n 5 29)

335–451 3–24 269–411 75–98 0–32 4–12 1–2 2–4

355–454 0–28 275–384 71–93 0–29 6–17 1–3 3–5

342–444 0–20 268–395 73–95 0–15 7–16 1–3 3–5

353–439 0–30 237–360 62–89 0–14 7–21 1–3 2–5

1–6 40–60 11–19 10–25

2–9 40–64 4–13 9–24

3–9 44–64 3–11 12–24

3–10 42–60 2–8 8–19

a

Normal value range lower and upper bounds are calculated as the parameter mean minus 1 standard deviation (SD) to the parameter mean plus 1 SD, respectively, with negative values replaced by zero. † Sleep efficiency index is the total sleep time as a percentage of time in bed.

Table 47.5  Recommended Polysomnographic Parameters Category Sleep stage

Arousals Respiration

a

Classa

Description

R R R R R R I R I R R R R R O O O I

Clock times that polysomnogram began and finished Total duration of the recording and amount of time spent actually sleeping Latencies to sleep (from lights out) and stage R (from sleep onset) Time and percent (of total sleep time) spent in each sleep stage Percent time of total recording spent asleep (sleep efficiency index) Time spent awake after initial sleep onset (wake after sleep onset) Latency to persistent sleep Number and index (number per hour of sleep) Number and duration of cyclic alternating pattern episodes Number of each type of apnea (i.e., central, mixed, obstructive) and hypopnea Number of all apneas and hypopneas combined Apnea, hypopnea, and apnea-hypopnea indices (number per hour of sleep) Mean and minimum oxygen saturation percentages Indication of whether Cheyne-Stokes breathing pattern occurred Indication of whether hypoventilation was observed Number and index (number per hour of sleep) of RERAs Number and index of 3% (or more) or 4% (or more) oxygen desaturations During positive airway pressure titration; optimal pressure; time at optimal pressure; whether stage R occurred during time at optimal pressure; indexes for apnea, apnea/hypopnea, and apnea/hypopnea/RERA at optimal pressure Mean and maximum heart rate during sleep and maximum during recording Indication of whether bradycardia, asystole, sinus tachycardia, narrow complex tachycardia, wide complex tachycardia, atrial fibrillation, or other arrhythmias occurred (and provide pause lengths or rates where appropriate) Number and index (number per hour of sleep) of periodic limb movements during sleep Number and index of periodic limb movements during sleep that were associated with central nervous system arousal Number and index of periodic limb movements during wakefulness Indication of whether bruxism, restless legs activity, rhythmic movement, rapid eye movement–related movements, fragmentary myoclonus, or other types of movements occurred during sleep or wakefulness Clinical correlates of pathophysiology and diagnosis Other EEG abnormalities (e.g., spikes, sharps, excessive or diminished waveform activity, hypersynchronous delta or alpha-delta sleep) Heart rhythm abnormalities Behavioral observations Sleep histogram

Heart rhythm

R R

Movement

R R I I

Other

R R R R O

Classification by the American Academy of Sleep Medicine as recommended (R), optional (O), or not mentioned but considered important and recommended in other guidelines (I). EEG, Electroencephalogram; RERA, respiratory effort–related arousal.

Atlas of Clinical Sleep Medicine   455 PSG interpretation must proceed from context. Important contexts include (1) sleep schedule and napping pattern, (2) symptoms, (3) comorbid illnesses and conditions, and (4) medications, alcohol, and recreational substances. Sample forms useful for such assessments are provided in Figures 47.22 to 47.25. The screening questionnaire includes a checkbox version of the Epworth Sleepiness Scale, whose validation study was presented at the Helsinki World Sleep Apnea Congress in

2003. It also inquires about overall sleep disturbances and collects information concerning sleep schedule and napping from which one can deduce (1) whether the sleep schedule is adequate, (2) whether the patient is “fasting” and “bingeing” on sleep, and (3) whether the patient phase delays, phase advances, or remains regular. The symptom checklist is straightforward, and patients can affirm any sleep problems they may be experiencing. Some of the symptoms are strong markers for particular

Sleep Center Screening Questionnaire Patient name

Date

EPWORTH SLEEPINESS SCALE How LIKELY are you to DOZE off or FALL ASLEEP in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Please check one box per line. ---CHANCE OF DOZING OFF--never

slight moderate

high

sitting and reading watching TV sitting, inactive in a public place (example, a theater or a meeting) as a passenger in a car for an hour without a break lying down to rest in the afternoon when circumstances permit sitting and talking to someone sitting quietly after lunch without alcohol in a car, while stopped for a few minutes in traffic BRIEF SLEEP SYMPTOM CHECKLIST (please check the boxes that best describe you) never

rarely frequently always

I snore loudly I awaken gasping or choking for breath I awaken in the morning unrefreshed I have problems falling asleep or staying asleep (insomnia) My sleep is very restless My sleep is disturbed by unusual behaviors (for example: nightmares, sleepwalking, dream enactments, tongue biting, bedwetting... etc.) I fall asleep while driving I’ve been told that I stop breathing in my sleep (told by ) SLEEP SCHEDULE (please provide the following information) What time do you go to bed on WEEKDAYS? AM or PM Do you nap? [yes] [no] What time do you get up on WEEKDAYS? AM or PM How often do you nap? times per week What time do you go to bed on WEEKENDS? AM or PM How long are the naps? minutes What time do you get up on WEEKENDS? AM or PM Do you awaken refreshed? [yes] [no] Are you a shift worker? [yes] [no] If yes, what kind of shift do you work?

Figure 47.22  ​Sleep clinic screening questionnaire. Sample self-administered questionnaire form used in the sleep medicine clinic to assess sleepiness (using the Epworth Sleepiness Scale developed by Dr. Murray Johns), sleep schedule, napping, and general symptoms of sleep disorders.

456  Polysomnography and Home Sleep Test Assessment Methods in Adults

SLEEP PROBLEMS CHECKLIST Patient Name

Date

What problem causes you to seek our help, and how does it affect your life?

CHECK the box for each problem you CURRENTLY HAVE. Loud snoring with frequent awakenings Crawling feelings in legs when trying to sleep Leg-kicking during sleep Leg cramps in sleep Trouble falling asleep at night Trouble staying asleep at night Racing thoughts when trying to sleep Increased muscle tension when trying to sleep Fear of being unable to sleep Laying in bed worrying when trying to sleep Waking too early in the morning Sleep talking Sweating a lot at night Waking up with reflux (and/or heartburn) Waking up to urinate 2 or more times nightly Nightmares

Teeth grinding during sleep Morning headaches Morning dry mouth Sleepwalking Tongue biting in sleep Bedwetting Acting out dreams with injury Acting out dreams without injury Uncontrollable daytime sleep attacks Falling asleep unexpectedly Falling asleep at work Falling asleep at school I use sleeping pills to help me sleep I use alcohol to help me sleep Pain interfering with sleep Where is the pain?

For each symptom, please CHECK the boxes that BEST DESCRIBE YOU: Never

Rarely Sometimes

Usually

Always

When falling asleep, I feel paralyzed (unable to move) I feel unable to move (paralyzed) after a nap I have dream-like images (hallucinations) when I awaken in the morning even though I know I am not asleep I see vivid dream-like images (hallucinations) either just before or just after a daytime nap, yet I am sure I am awake when they happen I am often unable to move (paralyzed) when I am waking up in the morning I get “weak knees” when I laugh I get sudden muscular weakness (or even brief periods of paralysis, being unable to move) when laughing, angry, or in situations of strong emotion

Developed by Max Hirshkowitz @ Flatland Logic Group

Figure 47.23  ​Sleep problems checklist. Sample self-administered questionnaire form used in the sleep medicine clinic to determine chief complaints, presence or absence of common symptoms associated with sleep disorders, and severity of complaints constituting narcolepsy’s symptom triad other than sleepiness (i.e., cataplexy, sleep paralysis, and hypnagogia).

sleep disorders, whereas others are nonspecific. Furthermore, some symptoms serve to alert the sleep specialist reviewing the PSG to be alert for distinct electrophysiologic phenomena. If a patient bites their tongue during sleep, careful scrutiny of the tracing for spikes, phantom spikes, and sharp waves would be prudent. If a patient reports dream enactment with injury, focus

should be put on REM-related movements and REM without atonia as correlates of possible RBD. The bottom section of the questionnaire specifically addresses the triad of symptoms associated with narcolepsy (i.e., sleep paralysis, hypnagogia, and cataplexy). Sleep-relevant comorbid conditions are listed on the sleep clinic health problems checklist so patients can easily

Atlas of Clinical Sleep Medicine   457

Sleep Center Health and Family Questionnaire Patient name

Date

1. How would you rate your current general health? very poor

poor

average

good

very good

2. Check () if you now have or in the past had the following: Diabetes

now

past

Anemia

now

past

High blood pressure

now

past

Peptic ulcers

now

past

Stroke

now

past

Acid reflux (heartburn)

now

past

Heart disease or CHF

now

past

Kidney disease

now

past

Heart attack

now

past

Thyroid disease

now

past

Angina

now

past

Arthritis

now

past

Emphysema or COPD

now

past

Back pain

now

past

Asthma

now

past

Head trauma

now

past

Tuberculosis

now

past

Severe headaches

now

past

Other lung disease

now

past

Epilepsy (seizures)

now

past

Nasal allergies

now

past

Passing-out spells (fainting)

now

past

Runny or blocked nose

now

past

Depression

now

past

Hormonal problem

now

past

Anxiety disorder

now

past

Urological problem Prostate disease

now now

past past

Problems with alcohol Problems with drugs

now now

past past

3. Please list hospitalizations. Please give the reasons for each hospitalization and the dates (as best you can remember). REASONS FOR HOSPITALIZATION

DATE

4. Please give important details about your medical conditions.

Figure 47.24  ​Sleep center health and family questionnaire. Sample self-administered questionnaire form used in the sleep medicine clinic to collect information

about an individual’s comorbid health conditions; hospitalizations; caffeine, alcohol, and nicotine use; marital status; occupation; and general family health status. CHF, Congestive heart failure; COPD, chronic obstructive pulmonary disease. Continued

458  Polysomnography and Home Sleep Test Assessment Methods in Adults

5. List your current average for each category below. hours worked per day days worked per week days of vacation per year number of cigarettes smoked per day other tobacco used per day (pipefuls or cigars) cups of regular coffee per day cups of tea per day glasses of cola or other caffeinated beverages per day cans of beer per day (12 oz.) glasses of wine per day (3-4 oz.) alcoholic drinks per day (1-2 oz. straight or mixed) 6. If you smoke or used to smoke... If you quit, how long ago did you quit?

What is the most you ever smoked? 7. What is your current relationship status? single

married

divorced

widowed

separated

living with someone

8. How many times have you been married? 9. What is your occupation? FAMILY INFORMATION 1. Is your father living?

yes

no

If no, at what age did he die?

If yes, how old is he? What caused his death?

What was your father’s major occupation? 2. Is your mother living?

yes

If no, at what age did she die?

no

If yes, how old is she? What caused her death?

What was your mother’s major occupation? 3. Do any of your brothers and sisters (if applicable) have any major diseases or sleep disorders? If yes, please describe:

Figure 47.24, cont’d

affirm active or past history of each infirmity. In addition to the instruments used here as examples, many sleep clinics administer a depression screening test and the International Restless Legs Study Group screening test. In sleep medicine, few diagnostic criteria are quantitatively codified. Pathophysiologies are mainly correlates. The disease process can be an upstream or downstream factor, or it can be only indirectly related. In the case of sleep apnea, however, criteria have been established. To qualify a patient for PAP therapy using CMS criteria, the apnea-hypopnea index (AHI) must be 5 or more for patients with symptoms or relevant comorbidities. (For CMS, hypopneas are defined as partial airway restriction events with a 4% or more oxyhemoglobin

desaturation.) However, for patients who are neither sleepy nor have any significant, potentially related comorbid medical conditions, the AHI must reach 15 or more. AASM criteria are similar but use the respiratory disturbance index (RDI),* rather than the AHI, in the decision paradigm.

*The acronym RDI has unfortunately been used to index several different but associated sleep-related respiratory impairments. RDI was originally used to index desaturation events but subsequently became virtually synonymous with apneahypopnea index (AHI). The CMS attempted to resolve the erroneous use of AHI for cardiorespiratory home sleep tests (because the denominator is total recording time rather than total sleep time) by renaming the HST analog as RDI, thus adding to the confusion rather than resolving it.

Atlas of Clinical Sleep Medicine   459

Sleep Center Medication Questionnaire Patient name

Date

We need to know what drugs, vitamins, and herbal substances you have taken in the past 6 months. Please complete the form below. Check your medicine cabinet and your medical records for drugs. Think back about the health problems you have had and the medicines you took for them. Name of drug, vitamin, or herbal substance used

Dose

# of pills

Taken for Taken for what how long? problem?

Still taking? Yes

No

Figure 47.25  ​Sleep center medication questionnaire. Sample self-administered questionnaire form used in the sleep medicine clinic to collect information about medication and substance use.

OTHER ASSESSMENTS AND INTERPRETATION Multiple Sleep Latency Test The multiple sleep latency test (MSLT) is used to document sleepiness and provides supporting information to diagnose narcolepsy. When performed correctly in adults, a series of four or five nap opportunities (test sessions) are provided at 2-hour intervals, commencing approximately 2 hours after arising from the previous night’s PSG recording. Subjects being tested lie down in bed and are allowed to get comfortable; they are then instructed to let themselves fall asleep, try to fall asleep, or not to resist falling asleep. Between test sessions, the patient must get out of bed but is not permitted to drink caffeinated beverages. If an individual does not fall asleep (based on PSG criteria according to concurrently recorded

tracings), the nap opportunity is terminated after 20 minutes. However, if sleep onset occurs, the test session is extended 15 additional minutes. Extending the test session allows for assessment of the REM pressure that characterizes narcolepsy. If two REM onsets or no REM sleep occurs during the first four nap opportunities, the test may conclude. By contrast, if REM sleep occurs on only one test session, a fifth nap opportunity is conducted. The mean sleep latency is calculated, and the naps during which REM sleep occurs are determined. A mean sleep latency less than 5 minutes is considered pathologic sleepiness, and values greater than 10 are considered normal; values in between represent a gray zone. A diagnosis of narcolepsy is supported when two (or more) naps contain REM sleep or one (or more) nap and the immediately prior overnight PSG reveal stage R at sleep onset (Fig. 47.26).

460  Polysomnography and Home Sleep Test Assessment Methods in Adults for a duration of 1 hour. Standard PSG recordings are made as the individual sits in bed at a 45-degree angle, with eyes open and legs outstretched in front, while attempting to stay awake and not move. Leg movements are scored (anterior tibialis EMG 0.5- to 10.0-second bursts, separated by 4 or more seconds); 40 movements per hour confer an 81% sensitivity and 81% specificity for RLS.

W R N1 N2 N3 Nap 1

Nap 2

Nap 3

Nap 4 15 minutes

Figure 47.26  ​Summary sleep stage histograms from a multiple sleep latency

test. Note that rapid eye movement sleep occurred on all four nap opportunities, thereby supporting the diagnosis of narcolepsy in a sleepy patient in whom other causes of sleepiness have been ruled out (chronic sleep deprivation, another untreated hypersomnolence-producing sleep disorder, withdrawal from stimulants, or use of central nervous system depressants). These patients may also have ancillary symptoms associated with narcolepsy, such as cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Sleep onset occurred on all nap opportunities with the longest during test session 3. Also, the final nap was extended slightly longer than it should have been. N1, Sleep stage NREM 1; N2, sleep stage NREM 2; N3, sleep stages NREM 3 and 4; R, REM sleep; W, wakefulness.

An AASM clinical practice committee recently published recommended protocols for conducting the MSLT and maintenance of wakefulness test (MWT). The article’s abstract states the following: Although no evidence-based changes to the protocols were warranted, the task force made several changes based on consensus. These changes included guidance on patient preparation, medication and substance use, sleep prior to testing, test scheduling, optimum test conditions, and documentation. This paper provides guidance to providers who order and administer the MSLT and MWT. The recommendations provide answers to clinical questions often raised by providers. These guidelines should improve the test reliability and validity. (For details, see Kran et al., 2021.) Maintenance of Wakefulness Test The MWT has supplanted the MSLT for assessing sleepiness in regulatory situations. Although not a diagnostic test, the MWT is included here because it has become an objective standard in sleep medicine for establishing “fitness for duty.” As mentioned earlier, a recent protocol guideline for conducting the MWT (and MSLT) has been published and is recommended reading for anyone using these procedures. In MWT, four test sessions are scheduled at 2-hour intervals, with the first commencing approximately 2 to 3 hours after a person’s usual morning rising time. The individual being tested wears street clothes, reclines on the bed with a bolster pillow, and is instructed to attempt to remain awake. The room is dimly lit, not totally dark. If unequivocal sleep onset occurs (i.e., one epoch of stage N2, N3, or R or three consecutive epochs of N1), the test session is terminated. If no unequivocal sleep onset occurs, the test session terminates after 40 minutes. Recordings involve collecting PSG parameters used to score sleep stages. A sleep latency of less than 8 minutes is considered abnormal. Suggested Immobilization Test The suggested immobilization test (SIT) is a PSG procedure used to support diagnosis in patients with suspected RLS. The SIT is performed 1.5 to 2.0 hours before overnight PSG

Actigraphy Actigraphy involves having an individual wear a wristwatch-like device that contains accelerometers, a clock, and internal memory. The device usually also records concomitant light levels with a photo sensor. The device can record for several days, weeks, or months, depending on the memory size and sampling resolution. Data are transferred to a computer for display and analysis. These devices provide information about an individual’s restactivity cycle, which may serve as a surrogate for the sleep-wake cycle. For clinical purposes, actigraphic data are interpreted in conjunction with a sleep diary. Actigraphy supplies potentially useful information concerning sleep habits, circadian rhythm disorders, insomnia, and parasomnia. Misalignments between sleep diary and rest-activity cycle, progressive phase delay or advance, and chaotic sleep-wake schedules are easily visualized with actigraphy (Fig. 47.27). Actigraphic data can also help document the sleep-wake cycle leading to scheduled MSLT procedures, assess sleep duration in suspected insufficient sleep syndrome, and estimate sleep parameters in insomnia and circadian rhythm sleep-wake disorders. Consumer actigraphic devices are now widely available. Most purport to distinguish between sleep and wakefulness, and peer-reviewed published data support some manufacturers’ claims. Some of these sleep trackers claim the ability to identify REM sleep. The Consumer Technology Association (CTA), in conjunction with the American National Standards Institute and the National Sleep Foundation, have developed and published performance standards for sleep-tracking device evaluation. The inclusion of optical photoplethysmography allows for pulse and oximetry measurement; therefore, consumer-available devices may one day play a role in the clinical evaluation and management of sleep disorders. However, increased transparency in the function and performance of these devices is required. SUMMARY The AASM manual helps establish recording and scoring criteria for nearly the full range of PSG parameters, including sleep stages, arousal scoring, respiratory events, cardiac events, and movement activity. This chapter summarizes and illustrates the critical features and essence of the manual’s content, which represents a crucial step toward standardizing the field. However, although useful, our current method of labeling and quantifying the physiologic signal recorded during PSG may deplete it of complexity, nuance, and potential meaning and value. The use of machine learning to analyze PSG signals may allow the ability to subtype and endotype sleep disorders and predict impact, sequelae, and response to treatment, particularly when combined with other health parameters. Precision sleep medicine is visible on the horizon. Visit eBooks.Health.Elsevier.com for the Bibliography for this chapter.

Atlas of Clinical Sleep Medicine   461

12:00 PM

8:00 PM

12:00 AM

6:00 AM

12:00 PM

12:00 AM

6:00 AM

12:00 PM

Sunday 10/30/2011 (DAY 8)

Monday 10/31/2011 (DAY 9)

Tuesday 11/1/2011 (DAY 10)

Wednesday 11/2/2011 (DAY 11)

Thursday 11/3/2011 (DAY 12)

Friday 11/4/2011 (DAY 13)

Saturday 11/5/2011 (DAY 14) 12:00 PM

6:00 PM

Legend: Activity

White light

Red light

Green light

Blue light

Rest

Sleep

Excluded

Custom

Sleep/wake

Off wrist

Marker

Figure 47.27  ​One-week actigraphy histogram. This histogram shows an erratic sleep-wake cycle. The subject begins the week on Sunday with a fairly conven-

tional night of sleep (approximately 11 pm to 6:30 am) only to shorten it slightly the next night by delaying bedtime to midnight. The following night, the subject appears to “sleep in,” extending rest time to more than 12 hours (which agreed with the sleep diary). The following night, sleep is contracted to less than 6 hours with an earlier than usual bedtime the following night. Friday night, the patient does not retire until after 2 am and sleeps until 11 am. This chaotic week was capped off by a 9 pm bedtime followed by a 9.5-hour sleep period on Saturday night.

  e1 Bibliography

Berry RB, QS, Abreu AR, et al, for the American Academy of Sleep Medicine (AASM). The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.6. Darien, IL: AASM; 2020. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8(5):597–619. Bonnet M, Carley D, Carskadon M, et al. ASDA Report. EEG arousals: scoring rules and examples. Sleep. 1992;15:173–184. Coleman RM. Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In: Guilleminault C, ed. Sleeping and Waking Disorders: Indications and Techniques. Menlo Park, CA: Addison-Wesley; 1982:267–295. 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(7):737–747. Definitions and Characteristics for Wearable Sleep Monitors; ANSI/CTA2052.1; 2016. https://shop.cta.tech/products/performance-criteria-andtesting-protocols-for-features-in-sleep-tracking-consumer-technologydevices-and-applications. Goldstein C. Current and future roles of consumer sleep technologies in sleep medicine. Sleep Med Clin. 2020;15(3):391–408. Hirshkowitz M. Polysomnography: understanding this technology’s past might guide future developments. IEEE Pulse. 2014;5(5):26–28. Hirshkowitz M, Moore CA, Hamilton CR, et al. Polysomnography of adults and elderly: sleep architecture, respiration, and leg movements. J Clin Neurophysiol. 1992;9:56–62. Iber C, Ancoli-Israel S, Chesson A, Quan SF, for the American Academy of Sleep Medicine (AASM). The AASM Manual for the Scoring of Sleep

and Associated Events: Rules, Terminology and Technical Specifications. Westchester, IL: AASM; 2007. Kran LE, Arand DL, Avidon AY, et al. Recommended protocols for the multiple sleep latency test and maintenance of wakefulness test in adults: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 2021;17(12):2489–2498. Loomis AL, Harvey N, Hobart GA. Cerebral states during sleep, as studied by human brain potentials. J Exp Psychol. 1937;21:127–144. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home: potential pitfalls and practical guidance. Ann Am Thorac Soc. 2020;17(9):1040–1046. Methodology of Measurements for Features in Sleep Tracking Consumer Technology Devices and Applications; ANSI/CTA/NSF-2052.2, 2017. https://shop.cta.tech/products/methodology-of-measurement s-for-features-in-sleep-tracking-consumer-technology-devices-andapplications. Performance Criteria and Testing Protocols for Features in Sleep Tracking Consumer Technology Devices and Applications; ANSI/CTA/NSF2052.3, April 2019. https://shop.cta.tech/products/definitions-andcharacteristics-for-wearable-sleep-monitors-ansi-cta-nsf-2052-1-a. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages in Human Subjects. NIH Publication No. 204. Washington, DC: U.S. Government Printing Office; 1968. Terzano MG, Parrino L, Smerieri A, et al. Atlas, rules, and recording technique for scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med. 2002;3:187–199. Zucconi M, Ferri R, Allen R, et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW). Developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 2006;7:175–183.

Section 15  |  Media Galleries Chapter

48

Gallery of Polysomnographic Recordings Max Hirshkowitz and Meir H. Kryger

This chapter presents a wide variety of polysomnographic recordings organized by disorder or disease. OBSTRUCTIVE SLEEP APNEA (OSA)

E2-M1 Microarousal [Aon] [Snr(I)]

Microarousal [HYP] [Snr(I)]

2m

E1-M2 C4-M1 C3-M2 CHIN1 ECG

23:17:58

98 99

99 100

100 101

23:19:58

RLeg LLeg Snore

2m

PTAF

THERM THOR ABD SaO2 (%)

100 75 50

96

95

92

95 91

91

89

91

99

98

97

96

96

95

95

96

95

93

92

91

91

94

97

97

96

94

93

92

91

Figure 48.1  ​Obstructive sleep apnea. In OSA, despite thoracic and abdominal efforts, there is a cessation of airflow. In this example, airflow is being monitored

by the use of the thermocouple (THERM) and nasal pressure (PTAF, for nasal pressure airflow). The American Academy of Sleep Medicine (AASM) scoring manual recommends that apnea be scored when there is a 90% or more reduction in the peak thermal sensor excursion (or excursion of the alternate sensor, nasal air pressure) for more than 10 seconds. The same manual suggests that hypopnea be scored when nasal pressure signal excursions—or their alternates, calibrated or uncalibrated inductance plethysmography—decrease by more than 30%. In this example, the scoring technician has labeled the first event a hypopnea and the next two events apneas. In reality, there is little physiologic difference between hypopneas and apneas, and indeed, more hypoxemia was present with the hypopneic episode. All of the data should be examined: in this example, the snoring channels; the chin electromyogram (EMG), which is also detecting snoring; and the electroencephalogram (EEG) channels, which show the arousals linked to the abnormal respiratory events. Epoch lengths should be used that best enhance the interpretation and understanding of the patient (i.e., not always the recommended 30-second epoch). The top and bottom windows are 2-minute epochs.

462

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mv

0:56:12

0:57:02

0:57:12

0:57:02

0:58:12

0:59:02

0:59:12

1:00:02

1:00:12

1:01:02

0:56:12

0:57:02

0:57:12

0:57:02

0:58:12

0:59:02

0:59:12

1:00:02

1:00:12

1:01:02

LEG(L) 125 V

SaO2 % THOR RES x1 PULSE bpm

PCO2 mm Hg SOUND 20 mv

Blood pressure 20 v

Hvw 20 v

Figure 48.2  ​Obstructive sleep apnea. Understanding cardiorespiratory sensors is important. The American Academy of Sleep Medicine manual recommends a

thermal sensor for detecting apneas and nasal pressure to detect hypopneas. Both of these sensors have significant potential limitations. Nasal pressure results in absent or decreased airflow in patients who are mouth breathers and may result in overestimation of the number of apneas and the length of individual events. In this figure, oronasal end-tidal Pco2, nasal pressure, and nasal airflow are being monitored. Note that many more unobstructed breaths are detected using oronasal Pco2 and that it lags pressure by 5 to 10 seconds because of the technology of the capnometer. Thermal sensors are dependent on where they are placed in the airstream; they are nonlinear with airflow and are uncalibrated, and it is suggested that a square root transformation be made on the signal to prevent reporting hypopneas that are not present. It is recommended that pulse oximetry be collected with signal averaging of 3 seconds. In this example, the oxygen saturation (Sao2) starts to increase rapidly within 5 to 10 seconds of the onset of breathing, whereas in Figure 48.1 the Sao2 lagged by about 30 seconds. There a finger probe was used, whereas in this case and in many others in this text, a rapidly responding ear oximeter was used. Note that this patient has a classic tachycardia/bradycardia pattern, which corresponds very closely to the episodes of obstructive apnea. The pulse rate is usually derived directly from the calculation of the R-R interval of the electrocardiogram and is a fast-responding, accurate signal. Thus it is important to understand phase differences between channels. The top and bottom windows are 5-minute epochs.

Cursor: 22:29:40, Epoch: 3 - STAGE3

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mv

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

THOR RES x1

ABD RES x2

120

PULSE bpm

40 50

PCO2

mm Hg 0 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.3  ​Obstructive sleep apnea. This 47-year-old former boxer had his nose broken multiple times, with resultant severe sleep apnea. The minimal channels

required to differentiate obstructive from central apnea are Sao2, breathing effort (thoracic and/or abdominal), and oronasal airflow. A calibrated, rapidly responding end-tidal CO2 (Etco2) analyzer to monitor oral and nasal airflow and detect the presence of hypoventilation is superior to a thermistor or thermocouple, which merely detect the presence or absence of airflow. Note that the Etco2 has detected more breaths than the pressure transducer (labeled AIRFLOW) in this patient, who does a great deal of mouth breathing. For examining sleep, the ideal epoch length is 30 seconds; for examining breathing during sleep, the ideal epoch length is 2 to 5 minutes, although this may vary from patient to patient. In this example, the top window is a 30-second epoch, and the bottom window is a 5-minute epoch.

464  Gallery of Polysomnographic Recordings CHIN(1) 250 V

Digital video

Cursor: 01:43:16, Epoch: 352 - STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 V

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x8

ABD RES x1

120

PULSE bpm

40 76

PCO2 mm Hg -4

POSITION 30

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.4  ​Sleep apnea in a child. This 12-year-old boy had been snoring since birth. He was modestly overweight, had headaches and a history of awakening with shortness of breath, and was a restless sleeper. His preferred sleeping position was on his stomach. Here he is sleeping on his back and demonstrates obstructive sleep apnea. Children with sleep apnea commonly assume positions that minimize airway obstruction.

Digital video

CHIN(1) 250 V

Cursor: 01:43:16, Epoch: 352 - STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 V

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x8

ABD RES x1

120

PULSE bpm

40 76

PCO2

mm Hg -4

POSITION 30

CPAP

cm H2O 2

AIRFLOW 62.5 V

Figure 48.5  ​Sleep apnea (the same patient shown in Fig. 48.4). Here the patient is sleeping mostly on his stomach. The apnea has resolved entirely. This child had enlarged tonsils and adenoids that were surgically removed, resulting in resolution of the sleep apnea.

Atlas of Clinical Sleep Medicine   465 E2-M1 E1-M2

30s

F4-M1 F3-M2

C3-M2 CHIN2 ECG 02:01:19

631 632

632 633

633 634

02:03:19

Snore

2m

THERM PTAF

THOR ABD SaO2 (%)

100 92

98

98

97

97

97

98

97

97

97

96

94

96

98

98

97

96

95

98 94

93

92

90

99

99

98

98

98

93 88

85

Figure 48.6  ​Sleep apnea in a retrognathic child. This 7-year-old female patient had a history of snoring loudly since birth, and apnea and restless sleep were observed. She was thin, with a body mass index of 21. During sleep, the patient thrust her lower jaw forward and arched her neck in an unconscious attempt to enlarge the pharyngeal airway. In rapid eye movement sleep, the patient had quite long episodes of apnea, shown in this figure. Note the thoracic/abdominal paradox when the apnea “breaks.”

Figure 48.7  ​Retrognathic child with sleep apnea. This 5-year-old boy slept with his lower jaw thrust forward in an attempt to enlarge the pharyngeal airway.

He had a history of snoring, waking up gasping, and shortness of breath, and observed apnea was reported. The boy snored 62% of the night and had an apneahypopnea index of 2.4, which is above the threshold of 1 required for the diagnosis of pediatric sleep apnea.

466  Gallery of Polysomnographic Recordings Cursor: 02:06:10, Epoch: 326 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page LEG(R) 83.3 V 100

80

THOR RES x4

ABD RES x4

120

PULSE bpm

40 76

PCO2

mm Hg -4

POSITION

20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.8  ​Obstructive sleep apnea with leg electromyographic activity. Here, leg movements are detected with every apneic episode. The movements occur

at the time of the greatest respiratory efforts. Are these periodic limb movements, or are they merely movements linked to respiratory effort? Does this patient have one or two diagnoses? The scoring manual notes that “A leg movement should not be scored if it occurs during a period from 0.5 seconds preceding an apnea or hypopnea to 0.5 seconds following an apnea or hypopnea.”

Cursor: 03:20:10, Epoch: 474 - STAGE 3

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page LEG(R) 83.3 V

100

SaO2 %

80

THOR RES x4

ABD RES x4

120

PULSE bpm

40 76

PCO2 mm Hg -4

POSITION 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.9  ​Obstructive sleep apnea with activity in the leg channels on continuous positive airway pressure (CPAP). These data are from the same patient shown in Figure 48.8 but occurred later in the night. On CPAP, the leg movements have resolved entirely; thus the movements were linked to the abnormal breathing pattern. This patient does not have periodic leg movements during sleep.

Atlas of Clinical Sleep Medicine   467 Cursor: 10:52:29, Epoch: 23 - REM

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

20 min/page

LEG(L) 125 mV

LEG(R) 125 mV

100

SaO2 %

50

THOR RES x1

ABD RES x1

80

PULSE bpm

40 50

PCO2

mm Hg 0 5

CPAP cm H2O

0

AIRFLOW 62.5 V

Figure 48.10  ​Mixed sleep apnea with leg activity. Shown is another patient with leg movements and severe sleep apnea. The leg movements are not as periodic or as regular as those in Figure 48.9. Are the movements simply a reflection of the breathing efforts? One clue is that the heart rate, measured by the pulse, shows oscillations that are not always linked to the abnormal breathing patterns.

Cursor: 12:41:15, Epoch: 240 REM

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

20 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

50

THOR RES x2

ABD RES x1

80

PULSE bpm

40 50

PCO2 mm Hg 0 15

CPAP

1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 1 11 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 11 1 1 1 1 11 1 1 1 1 1 1 1 11 1 11 1 1 1 1 11 1 1 1 1 1 1 1 11 1 11 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 2 2 2 2 2 22 1 1 2 2 2 1 1 2 2 1 1 2 2 2 21 22 2 22 2 2 2 2 22 1 2 2 2 2 2 2 2 11 2 2 2 2 2 12 2 2 2 2 2 2 2 1 2 2 2 2 2 21 1 2 2 2 2 2 2 1 2 22 2 21 2 2 2 2 22 2 2 2 2 2 2 2 1 2 2 2 2 2 2 1 1 2 2 2 1 2 2 22 2 2 1 2 2 22 22 2 2 1 2 2 2 2 2 2 2 2 2 22 2 2 12 11 2 2 2 2 22 2 2 21 2 2 2 2 1 2 2 2 1 22 1 22 2 2 22

cm H2O

0

AIRFLOW 62.5 V

Figure 48.11  ​Mixed sleep apnea with activity in the leg channels on continuous positive airway pressure. This is the same patient shown in Figure 48.10. The apnea has resolved, but the leg movements continue at a very high rate. Note the improvement in Sao2. This patient has both sleep apnea and periodic leg movements during sleep.

468  Gallery of Polysomnographic Recordings Digital Video

CHIN(1) 250 V

Cursor: 00:53:01, Epoch: 150 - STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

80

THOR RES x1

ABD RES x1

120

PULSE bpm

40 76

PCO2

mm Hg -4

POSITION

30

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.12  ​Obstructive sleep apnea with acromegaly. Synchronized digital video is extremely helpful in explaining the physiologic abnormalities in this patient. She slept with her mouth wide open and moved her jaw forward to reestablish breathing.

Cursor: 02:09:59, Epoch: 396 - REM

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 LOC-A2 ECG 2.5 mV

2 min/page

LEG(R) 125 V 100

SaO2 %

80

THOR RES x1

ABD RES x4

120

PULSE bpm 40 60

PCO2 mm Hg 0

AIRFLOW 125 V

Figure 48.13  ​Obstructive sleep apnea. or hypoventilation? This 31-year-old male patient had a history of snoring, awakening with severe nocturnal headaches,

and morbid obesity (body mass index of 49). Rapid eye movement sleep is detected, even though all electroencephalographic channels show a great deal of electrocardiographic artifact. The nasal pressure channel suggests that the events are simply episodes of obstructive sleep apnea. The Pco2 channel shows breaths throughout the 2-minute epoch in the bottom window. Hypoventilation is suggested by the high end-tidal Pco2 being recorded. Using current data acquisition systems, the clinician can drill down and examine individual breaths in great detail (see Fig. 48.14).

Atlas of Clinical Sleep Medicine   469 Cursor: 02:09:59, Epoch: 396 - REM

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 LOC-A2 ECG 2.5 mV

15 sec/page

LEG(R) 125 V 100

SaO2 %

80

THOR RES x1

ABD RES x4

120

PULSE bpm 40 60

5555 5 555 555 5 4 4 44 44 555 4 44 4 554 4 44 44 4444 44 44 44 44 4 44 00 11 1 2 0 4 44 4 4 89 1 22 44 43 2 8 4 00 44 4 44 4 44 78 7 3 57 8 9 8 5 3 3 78 3 56 8 888 9996 33 3 344 41 3 3 3 15 3 2 4 5 66 33 3 13 38 3 371 4 382 3 0 9 3 83 25 7 2 25 0 2 5 2 5 2 2 22 4 21 6 22 22 1 2 0 21 21 22 7 2 02 2 2 8 2 8 7 1 8 1 1 6 6 1 1 5 15 41 1 4 11 13 12 1 1 35 40 1 1 10 1 11 1 1 1 1 0 1 9 1 9 1 8 8 0 96 6 9 86 5 6 8 4 6 86 5 85 4 5 8 54 52 8 66 8 2 6 4 8 6 5 4 4 46 9 5 4 3 32 212 4 8 4 4 0 2 2 22 1111 125 2 1 2 4 3 2 12 5 22 1112 3 3 0 0

PCO2 mm Hg

AIRFLOW 125 V

Figure 48.14  ​Obstructive sleep apnea or hypoventilation? The bottom window shows a 15-second epoch. CO2 is being detected with each of the small

breaths; breathing frequency is about 26 breaths/min. The digital system can include data points collected throughout on the CO2 channel. The highest end-tidal Pco2 noted here is 54 mm Hg. This number underestimates the true Pco2 for two reasons: (1) oronasal sampling will entrain some air, thereby diluting the airstream; and (2) the patient has a rapid, shallow breathing pattern, which will not result in a true measurement of alveolar Pco2. Thus interpreting all the data leads to the conclusion that the main problem is hypoventilation. Some health care systems require such documentation to provide the patient with a mechanical ventilator or a bilevel positive airway pressure device.

Cursor: 23:50:40, Epoch: 253 - REM

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 uV

LEG(R) 125 V

100

SaO2 %

70

THOR RES x2

ABD RES x2 120

PULSE bpm 40 50

PCO2

mm Hg 0

POSITION

20

CPAP cm H2O

2

AIRFLOW 15.6 V

Figure 48.15  ​Obstructive sleep apnea and the importance of sleep-stage recording. In this example, the patient has five episodes of oxygen desaturation followed

by a much longer episode of apnea, and oxygen desaturation is much greater. The top window is a 30-second epoch, and the bottom window is a 5-minute epoch; the top and bottom windows are synchronized by the vertical orange lines. In the middle of the top window, the patient has gone into rapid eye movement (REM) sleep, with sawtooth waves immediately followed by REM sleep. Sleep apnea is generally more severe in REM sleep.

470  Gallery of Polysomnographic Recordings Cursor: 11:14:45, Epoch: 19 - STAGE 1

EMG1-EMG2

30 sec/page

1.02 mV

C3-A1 128 V

C4-A1 128 V

Fr3-A1 128 V

Fr4-A1 128 V

O1-A1 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A1 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

85

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

Figure 48.16  ​Awake and asleep: obstructive sleep apnea. Sleep laboratories often ignore data obtained during wakefulness. These data are from a 49-year-old female patient who for 3 years had the perception that her breathing stopped during wakefulness. In addition, she had a history of snoring and severe sleepiness (Epworth sleepiness score of 24). Here the patient is awake but drowsy; note the slow eye movements.

Cursor: 11:52:16, Epoch: 95 - STAGE 3

EMG1-EMG2

30 sec/page

1.02 mV

C3-A1 128 V

C4-A1 128 V

Fr3-A1 128 V

Fr4-A1 128 V

O1-A1 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A1 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

85

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

Figure 48.17  ​Awake and asleep: obstructive sleep apnea. Here the same patient shown in Figure 48.16 is in non–rapid eye movement sleep. The abnormal breathing pattern continues.

Atlas of Clinical Sleep Medicine   471 Cursor: 11:04:16, Epoch: 41 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O21

125 V

ROC-A1 125 V

LOC-A3 125 V

ECG 2.5 mV

10 min/page

LEG(L) 625 V

LEG(R) 625 V

100

SaO2 %

85

THOR RES x1.5

ABD RES x1

120

PULSE bpm

40 76

PCO2

mm Hg -4 30

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.18  Awake and asleep: obstructive sleep apnea. This is the same patient shown in Figures 48.16 and 48.17. Continuous positive airway pressure (CPAP)

treatment was ineffective; the patient was then treated with bilevel pressure in a spontaneous mode. Note in the channel labeled CPAP that clusters of four to five square waves represent the pressure generated by the bilevel machine in response to patient effort, but the apnea episodes continue. In fact, the patient now has central apneas. At the vertical orange line in the middle of the bottom window, the backup rate is added to the bilevel system. By the end of the epoch, both the breathing pattern and Sao2 have normalized.

Cursor: 00:40:39, Epoch: 241 - STAGE 2

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT 512 V

RAT-RAT 512 V

100

SaO2 %

80

THOR RES 2.05 mV

ABD EFFORT 4.1 mV

80

Pulse bpm

40 50

ETCO2 mm Hg

0

NASAL PRES 2.50 mV

Figure 48.19  ​Mixed sleep apnea. Mixed apnea usually begins with central apnea (absent thoracic and abdominal effort) followed by obstructive apnea, as

documented by efforts to breathe in the absence of airflow. Physiologic changes with mixed apnea are very similar to the changes in obstructive sleep apnea: oxygen desaturations, increases in heart rate, and arousals. Consequently, most clinicians regard mixed apnea as obstructive events. Patients may respond extremely well to continuous positive airway pressure (CPAP), or they may develop PAP-emergent central sleep apnea. Whether the PAP-emergent episodes resolve over time (as CO2 receptors recover from blunting) or persist (due to underling cardiac, metabolic, or drug-related factors) depends on the patient’s comorbid conditions and status. These data are from a 50-year-old male patient who began to snore at 16 years of age after sustaining a broken nose playing hockey. The nasal obstruction related to the fracture was never treated, but he responded well to CPAP.

472  Gallery of Polysomnographic Recordings Cursor: 11:32:46, Epoch: 82 - STAGE 4

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT 512 V

RAT-RAT 512 V

100

SaO2 %

90

THOR EFFORT 2.05 mV

ABD EFFORT 8.19 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

CPAP PRES

0 20

cm H2O

0

NASAL PRES 500 mV

Figure 48.20  ​Obstructive sleep apnea in a patient with Down syndrome. Physical examination showed an enlarged tongue. In this 5-minute recording sample, the range of Sao2 is between 90% and 100%. Thus the decreases in Sao2 are quite small. Even though oxygenation pathophysiology was only mild to moderate, the patient had severe sleepiness associated with his abnormal breathing pattern.

EMG1-EMG2 1.02 mV

Digital Video

Cursor: 22:37:38, Epoch: 65 - STAGE 2

30 sec/page

Close

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

O2-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

10 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 8.19 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

60 50

ETCO2 mm Hg

0 12

CPAP PRES cm H2O

0

NASAL PRES 250 mV

Figure 48.21  ​Obstructive sleep apnea and periodic limb movements (PLMs). This female patient had both severe apnea and severe PLMs. Examining the

synchronized digital video is very useful with such patients because the clinician can see and hear episodes of obstruction and the often vigorous movements. This patient moved a great deal during sleep, and she sweated and kicked off her bedclothes. Note the very large-amplitude, low-frequency oscillation in the three channels referenced to the A1 electrode, representing sweat artifact.

Atlas of Clinical Sleep Medicine   473 EMG1-EMG2 1.02 mV

Digital Video

Cursor: 03:03:27, Epoch: 597 - STAGE 2

30 sec/page

Close

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

O2-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

10 min/page

LAT-LAT1.02 mV

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 8.19 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

60 50

ETCO2 mm Hg

0 12

CPAP PRES cm H2O

0

NASAL PRES 250 mV

Figure 48.22  ​Obstructive sleep apnea and periodic limb movements. This is the same patient shown in Figure 48.21, now on continuous positive airway pressure. Her breathing has become entirely normal, the leg movements have ceased, and the sweat artifact is gone.

Cursor: 23:47:51, Epoch: 161 - STAGE 3

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

1 hr/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

50

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

Figure 48.23  ​Upper airway resistance syndrome. A clue to a sleep breathing abnormality becomes evident when examining the breathing variables in time

compression; the bottom window is 1 hour. The Sao2 signal is “ragged,” tiny deflections are associated with sudden increased excursion in thoracic and abdominal effort, and an arousal is noted in the electroencephalogram (synchronized orange vertical lines). Figures 48.24 and 48.25 show additional information when drilling down on the data.

474  Gallery of Polysomnographic Recordings EMG1-EMG2 1.02 mV

Digital Video

30 sec/page

Close

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

90

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 250 mV

Figure 48.24  ​Upper airway resistance syndrome, drilling down on the previous polysomnographic fragment (see Fig. 48.23). The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch. The gain of the Sao2 signal has been increased, and the scale is 90% to 100%. The synchronized digital video shows that the mouth is open and the patient is snoring quietly. The synchronizing orange vertical lines indicate the patient is one breath away from an event. The drop in Sao2 is only 2%, the nasal pressure changes are small, and the oronasal Etco2 measurement shows continuous breathing. Figure 48.25 shows a moment one breath later.

EMG1-EMG2 1.02 mV

Digital Video

30 sec/page

Close

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

90

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 250 mV

Figure 48.25  ​Upper airway resistance syndrome. This is the same patient shown in Fig. 48.24, one breath later. The patient has closed her mouth and is now

breathing through her nose (see the nasal pressure change). This is followed by an increase in Sao2. On the video, she snorts and then turns her head. The orange vertical lines, which synchronize the top and bottom windows, show that this is associated with an arousal on electroencephalogram. This is a respiratory effort– related arousal, although the nasal pressure transducer was not giving the information needed to properly characterize the event. Whereas some experts claim that the nasal pressure transducer is adequate for scoring hypopneas because, in part, they believe mouth breathing is a rare event, it has been our experience that mouth breathing is a very common finding.

Atlas of Clinical Sleep Medicine   475 Cursor: 00:41:27, Epoch: 237 - STAGE 2

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V C4-A1 128 V Fr3-A2 128 V Fr4-A1 128 V O1-A2 128 V O2-A1 128 V ROC-A1 128 V LOC-A2 128 V ECG1-ECG2 2.05 mV

5 min/page

LAT-LATRAT-RAT100

SaO2 %

50

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 200 mV

Figure 48.26  ​Upper airway resistance syndrome. The bottom window shows a 5-minute epoch. Reductions in Sao2 are small and reverse with increases in the nasal pressure signal. Here the synchronizing orange vertical lines precede a K-complex and a speeding up of the electroencephalogram. This is a respiratory effort–related arousal.

Cursor: 02:49:56, Epoch: 494 - STAGE 2

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LATRAT-RAT-

100

SaO2 %

90

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

90

Pulse bpm

50 60

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 200 mV

Figure 48.27  ​Upper airway resistance syndrome (the same patient shown in Fig. 48.26). The Sao2 is steady, as is the breathing pattern. Massive rapid eye movement sleep rebound occurred in the second part of the night, when the patient was on continuous positive airway pressure (not shown).

476  Gallery of Polysomnographic Recordings 30 sec/page

Cursor: 10:57:20, Epoch: 74 - STAGE 3

EMG1-EMG2 1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

2192

2195

2197

2200

2202

2205

2207

2210

2212

2215

2217

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

90

THOR EFFORT 8.19 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

ETCO2

40 75

mm Hg

POSITION

0

20

CPAP PRES 0 cm H2O

NASAL PRES 200 mV

2155

2180

2205

2230

2255

2280

2305

2330

2355

2390

2405

Figure 48.28  ​Prolonged obstructive hypoventilation. In some continuous heavy snorers, a slow but progressive reduction is sometimes seen in Sao2, associated

with a progressive increase in effort, followed by a snort and then an increase in Sao2. In this example, the change in Sao2 is only about 3%. The patient is breathing entirely through the mouth, and the nasal pressure trace is completely flat and not helpful. This would be scored as a respiratory effort–related arousal.

E2-M1 E1-M2

60s

Microarousal [snr(l)]

C4-M1 C3-M2

CHIN1

RERA (3.0s)

ECG

485 486

02:24:14

R-R

72

80 88 88 93 94 94 94 88 79

68 33

33

33

33

32

33

94

94

33

72

36

35

36

68

68

68

71 71

68

02:25:14 68

62

34

67

66

34

70

72

74

76 76

72 71

71

71

69

64

65

68

68

68

68

69

71

72

72

73

72

70

72 75

RLeg

60s

Snore PTAF

THERM THOR ABD Sum SaO2 (%)

100 92 85

94

94

94

95

94

93

93

93

94

95

96

97

97

96

95

96

96

96

96

95

95

96

97

96

95

94

94

Figure 48.29  ​Upper airway resistance syndrome causing cardiac arrhythmia. The top and bottom windows are 1-minute epochs. Note that in the beginning

of the epoch, a very low heart rate (,33 beats/min) is recorded in the R-R channel. The patient is in rapid eye movement sleep, as indicated in the eye channels. About one-fourth of the way into the epoch, a microarousal occurred in response to abnormal breathing. This is a respiratory effort–related arousal. There has been an increase in the snoring channel and, following the arousal, the heart rate increased abruptly to about 94 beats/min. When the heart rate was low, the electrocardiogram indicated a 2:1 Mobitz second-degree atrioventricular block, and there were two P waves for each conducted beat. This was presumably caused by increased parasympathetic activity, which in turn was caused by the increase in the patient’s respiratory effort when the upper airway was obstructed. See Figures 48.70 to 48.73 for more details about heart blocks.

Atlas of Clinical Sleep Medicine   477 30 sec/page

Cursor: 11:15:30, Epoch: 101 - STAGE 4

EMG1EMG2 C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2 ECG1ECG2

3002

3005

3007

3010

3012

3015

3017

3020

3022

3025

3027 10 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

Ob.Hyp Ob.Hyp

Ob.Hyp

Ob.Hyp Ob.Hyp

Ob.Hyp

Ob.Hyp

Ob.Hyp

Ob.Hyp

O

Ob.Hyp Ob.Hyp

Ob.Hyp

Ob.Hyp Ob.Hyp

Ob.Hyp

Ob.Hyp

Ob.Hyp

Ob.Hyp

O

Ob.Hyp Ob.Hyp

Ob.Hyp

Ob.Hyp Ob.Hyp

Ob.Hyp

Ob.Hyp

Ob.Hyp

Ob.Hyp

O

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0

POSITION 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

2750

2800

2850

2900

2950

3000

3050

3100

3150

3200

3250

Figure 48.30  ​Upper airway resistance syndrome or obstructive hypopneas? The bottom window shows a 10-minute epoch. Small oscillations in Sao2 are

associated with changes in nasal pressure, but note that little change occurs in the oronasal Pco2 trace. This suggests that the patient is mouth breathing during each event, thereby causing the reduction in Sao2. The clinician could infer that these are hypopneas. This 54-year-old male patient had a body mass index of 31 and a 20-year history of snoring, recently observed apnea, and sleepiness. His apnea-hypopnea index was 52.3, but on continuous positive airway pressure it decreased to 7.9. Interpretation of a study should include consideration of all available data; the final diagnosis was severe obstructive sleep apnea syndrome.

CENTRAL SLEEP APNEA

Cursor: 00:25:44, Epoch: 241 - AWAKE

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.67 mV

LEG(L)

2 min/page

250 V

LEG(R) 250 V

100

SaO2 %

90

THOR RES x1

ABD RES x1 120

Pulse bpm

30 50

PCO2

mm Hg 0

AIRFLOW 62.5

Figure 48.31  ​Idiopathic central sleep apnea. The term central apnea refers to a cessation of breathing in excess of 10 seconds with markedly reduced or absent effort

to breathe. Central apnea may occur during wakefulness, as in this example. This is a 71-year-old patient who had central apnea of unknown etiology recorded during both wakefulness and sleep. Note the absence of effort in both the thoracic and abdominal effort channels. The longest episode of apnea is almost 30 seconds. Note the cardiogenic oscillations in the CO2 trace. Although the patient is awake throughout, fluctuating levels of alpha-wave activity appear in the electroencephalographic channels. In this example, the patient’s overall breathing rate is only 7 breaths/min. The top window shows a 30-second epoch, and the bottom window shows a 2-minute epoch. Similar findings occur in some patients who use opioid medications. This patient responded well to low-flow continuous positive airway pressure.

478  Gallery of Polysomnographic Recordings Cursor: 25:57:18, Epoch: 210 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

5 min/page

LEG(L) 250 V

LEG(R)

250 V 100

SaO2 %

90

THOR RES x1

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg 0

AIRFLOW 62.5 V

Figure 48.32  ​Central apnea related to opiates. These data are from a 44-year-old soldier treated for severe nerve pain related to an ankle injury. The patient had

had snoring, severe sleepiness, and witnessed apnea for 2 to 3 years. His pain was treated with morphine. He had a breathing frequency of only four or five breaths/min and repetitive cycles of two to three breaths, followed by central apneic episodes. The bottom window shows a 5-minute epoch. It is likely that this pattern is related to the morphine. The patient also had central apnea during wakefulness.

Cursor: 23:59:35, Epoch: 215 - STAGE 2

CHIN(1)

30 min/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

30 min/page

LEG(L) 250 V

LEG(R)

250 V 100

SaO2 %

80

THOR RES x1

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg 0

AIRFLOW 62.5 V

Figure 48.33  ​Central apnea related to opiates. The top and bottom windows are 30-minute epochs. Rapid eye movement (REM) sleep occurs when there are

large, dense deflections in the two electrooculogram channels. Note that the patient’s breathing pattern actually changes during REM, and much less periodicity is evident in the breathing pattern and the SaO2. When the patient emerges from REM sleep at the end of this epoch, the abnormal breathing pattern seen in Figure 48.32 returns. The central apneic episodes in non-REM sleep are likely being maintained by the ventilatory chemical control system, which is depressed by morphine. When the patient goes into REM sleep, REM processes override the ventilatory control system.

Atlas of Clinical Sleep Medicine   479 Digital Video

CHIN(1)

Cursor: 11:04:53, Epoch: 51 - STAGE 3

30 sec/page

Close

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x1

ABD RES x1 120

PULSE bpm

40 50

PCO2 mm Hg 0 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.34  ​Idiopathic central sleep apnea. This 30-year-old male patient came to medical attention with severe daytime sleepiness, snoring, and nocturnal headaches. Episodes of central apnea (reduced or absent thoracic and abdominal efforts) and oxygen desaturations are apparent. Note that each cluster of breaths is made up of only four to five breaths, and the apnea episodes are about 20 seconds long. The top window is a 30-second epoch, and the bottom window is a 5-minute epoch. Because of his snoring history, this patient was first tested on continuous positive airway pressure (see Fig. 48.35).

Digital Video

CHIN(1) 250 V

Cursor: 12:33:35, Epoch: 229 - STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x1

ABD RES x1 120

PULSE bpm

40 50

PCO2

mm Hg 0 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.35  ​Idiopathic central sleep apnea on continuous positive airway pressure (CPAP; the same patient shown in Fig. 48.34). While on CPAP, worsening of the patient’s apneic episodes was marked, to about 40 seconds in length. Complex sleep apnea is a term recently introduced that implies that ventilatory instability in some patients leads to episodes of central apnea. Operationally, this is defined as patients who develop central sleep apnea with PAP therapy. By that definition, some might conclude that this patient had a variant of complex sleep apnea. However, defining a disease based on the response to treatment is problematic, and many do not believe that this is an independent entity. The most accurate description of his diagnosis would be “central apnea worsened by positive airway pressure.” Thus, although his history suggested obstructive sleep apnea, simply initiating CPAP without monitoring or without first determining apnea type would have placed this patient at increased risk. In the sleep laboratory setting, the clinician could proceed to the next step, testing on bilevel PAP, shown in Figure 48.36.

480  Gallery of Polysomnographic Recordings Digital Video

CHIN(1) 250 V

Cursor: 13:00:30, Epoch: 204 - STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

Sao2 %

85

THOR RES x2

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg 0 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.36  ​Idiopathic central sleep apnea on bilevel positive airway pressure (BiPAP; the same patient shown in Fig. 48.35). There was a further marked lengthening of this patient’s apneic episodes to about 100 seconds. Clearly this approach was not going to be effective. Rather than proceeding to BiPAP with a timed backup, this patient was started on adaptive servoventilation, shown in Figure 48.37.

Digital Video

CHIN(1) 250 V

Cursor: 14:33:35, Epoch: 469 - STAGE 4

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x4

ABD RES x4

120

PULSE bpm

40 50

PCO2 mm Hg 0 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.37  ​Idiopathic central sleep apnea on adaptive servoventilation (the same patient shown in Figs. 48.35 and 48.36). This type of airway pressure sup-

port calculates the patient’s minute ventilation and takes into account the breathing pattern. It compensates by adding additional support during episodes of apnea and less support during hyperpnea. The patient’s episodes of central sleep apnea were resolved by this treatment.

Atlas of Clinical Sleep Medicine   481 30 sec/page

Cursor: 11:52:40, Epoch: 165 - AWAKE

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

4922

2.5 mV

4925

4927

4930

4932

4935

4937

4940

4942

4945

4947 10 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x4

ABD RES x0.7 120

PULSE bpm

40 60

PCO2

mm Hg -4 20

CPAP cm H2O

2

4970

5020

5070

5120

5170

5220

5270

5320

5370

5420

5470

Figure 48.38  ​Idiopathic central sleep apnea: treatment with adaptive servoventilation (ASV). This 55-year-old male patient came to medical attention with cogni-

tive impairment and sleepiness but no snoring. He was found to have episodes of central apnea and had worsening episodes on continuous positive airway pressure (CPAP); he had no response to oxygen and was then tested on ASV. The top window shows a 30-second epoch, and the bottom window shows a 10-minute epoch, each starting at the same time. The channel labeled CPAP shows the pressure output of the ASV device. Note that when the patient is apneic, the device produces the most pressure. By the end of the epoch, the patient’s breathing pattern is normalizing, as is his Sao2. Figure 48.39 shows a more prolonged response.

30 sec/page

Cursor: 12:53:10, Epoch: 286 - AWAKE

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

8552

2.5 mV

8555

8557

8560

8562

8565

8567

8570

8572

8575

8577 30 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x1

ABD RES x0.5

120

PULSE bpm

40 60

PCO2 mm Hg -4 20

CPAP cm H2O

2

8700

8850

9000

9150

9300

9450

9600

9750

9900

10050

10200

Figure 48.39  ​Idiopathic central apnea: treatment with adaptive servoventilation (the same patient shown in Fig. 48.38). The bottom window shows a 30-minute

epoch. Note that after about 7 minutes, all data show signs of normalizing, except that the adaptive servoventilation (ASV) is still showing periodic changes in pressure support. By the end of the epoch, everything has normalized, including the output of the ASV, which is now steady. Thus the pressure support delivered by the ASV device has changed based on changes in the patient’s breathing pattern.

482  Gallery of Polysomnographic Recordings MIXED AND COMPLEX SLEEP APNEA Cursor: 01:09:47, Epoch: 351 - STAGE 2

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

O2-A1 125 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

20 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

Figure 48.40  ​Mixed apnea becoming complex sleep apnea. This 63-year-old male patient had a history of a recent coronary artery bypass graft, daytime

sleepiness, snoring, and observed sleep apnea. The top window is a 30-second epoch, and the bottom window is a 20-minute epoch. Examination of the thoracic and abdominal respiratory effort channels reveals that several of the more than 20 apnea episodes shown here had evidence of a central component (absent or decreased effort) followed by efforts. These are episodes of mixed apnea. Figure 48.41 shows the response to treatment.

Cursor: 02:19:48, Epoch: 491 - STAGE 2

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

O2-A1 125 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

30 min/page LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

Figure 48.41  ​Mixed apnea becoming complex sleep apnea (the same patient shown in Fig. 48.40). The first treatment that was tried was continuous positive

airway pressure (CPAP), which caused the mixed apneas to become central apneas. The patient even had episodes of central apnea while he was awake. At about the vertical orange line in the bottom window, oxygen was added to the CPAP system, and the episodes of central apnea resolved.

00:35 M1 W R 1 2 3 4

01:35

02:35

03:35

1

2

3

00:35 Cen Mix Obs HYP Cen Mix Obs APN Hours

01:35

02:35

03:35

1

2

00:35 100 90 80 70 60 50 Des Hours

01:35

02:35

1

2

3

23:52

00:52

01:52

1

2

3

22:51 Cen Mix Obs HYP Cen Mix Obs APN Hours

23:52

00:52

1

2

22:51 100 90 80 70 60 50 Des Hours

23:52

00:52

1

2

3

22:51 20 15 12 8 4 0 Hours

23:52

00:52

01:52

Hours

Sleep Stage 04:35

05:35 06:02

4

Apnea/Hypopnea 04:35

5

6

7

05:35 06:02 HDI:20

Note the very large numbers of central apneas ADI: 19.6

3

4

Oxygen saturation 03:35 04:35

5

AHI:21.6

7

05:35 06:02

4

5

6

7

A 22:51 MT W R 1 2 3 4 Hours

Sleep Stage 02:52

4

Apnea/Hypopnea 01:52 02:52

03:52

04:52

05:35

5

6

7

03:52

04:52

05:35 HDI: 16.6

ADI: 42.9

3

4

Oxygen saturation 01:52 02:52

4

CPAP

02:52

5

6

03:52

04:52

5

6

03:52 AHI: 38.5 04:52

AHI: 59.6

05:35

7

05:35

21.8 64.3

43.1 Total AHI: 44.7

1

2

3

4

5

6

7

B

Figure 48.42  ​Sleep apnea that worsens with treatment; another variant of complex apnea is shown here and in Fig. 48.43. A, Hypnogram of a patient being

treated with opiates for pain. This diagnostic study shows that he had central sleep apnea with an apnea-hypopnea index of 19. The next figure shows what happened when he was titrated with continuous positive airway pressure (CPAP). B, Hypnogram of the patient while he was being titrated, first on CPAP then on bilevel PAP (BiPAP), ending with BiPAP and a backup rate. The bottom panel shows PAP settings. The treatments worsened this patient’s sleep breathing findings and sleep structure. It is worth noting that increasing ventilatory support worsens, rather than solves, the problem.

484  Gallery of Polysomnographic Recordings Cursor: 23:46:41, Epoch: 162 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C3-A2 128 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

50

THOR EFFORT x0.5

ABD RES x0.5

120

PULSE bpm

40 50

PCO2 mm Hg -4

AIRFLOW 31.3 V

Figure 48.43  ​Mixed apnea in a patient with idiopathic pulmonary fibrosis. This patient had very rapid and severe oxygen desaturations likely related to low lung volumes. Note that the Sao2 range is 50% to 100%.

HEART FAILURE

Cursor: 22:17:07, Epoch: 24 - AWAKE

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

50

THOR RES x1

ABD RES x4

120

PULSE bpm

40 40

PCO2

mm Hg

-4

AIRFLOW 41.7 V

Figure 48.44  ​Congestive heart failure (CHF) with awake Cheyne-Stokes breathing. Sleep-onset insomnia and paroxysmal nocturnal dyspnea are common in

CHF and were present in this patient. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch. The patient was wide awake. Note the classic periodic breathing (Cheyne-Stokes), with a waxing and waning of ventilation and a large number of breaths in each cycle. In other forms of Cheyne-Stokes breathing, such as at high altitude, the number of breaths in each periodic breathing cycle is much smaller. As the patient begins to doze off, the episodes of apnea or hypopnea may lead to an arousal, which may prevent the patient from achieving sleep. Note the lack of deflections in the nasal pressure trace. The patient was short of breath, hyperventilating (the end-tidal Pco2 was low; oronasal CO2 was being monitored), and breathing through his mouth.

Atlas of Clinical Sleep Medicine   485 Cursor: 23:07:01, Epoch: 48 - AWAKE

30 sec/page

EMG1-EMG2 1.02 mV

C3-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

C3-A2 2.05 mV

1412

1415

1417

1420

1422

1425

1427

1430

1432

1435

1437 10 min/page

100

SaO2 %

90

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

100

Pulse bpm

ETCO2 mm Hg

60 30 0

POSITION CPAP PRES

NASAL PRES 100 mV

1460

1510

1560

1610

1660

1710

1760

1810

1860

1910

1960

Figure 48.45  ​Congestive heart failure with awake Cheyne-Stokes breathing. The top window is a 30-second epoch, and the bottom window is a 10-minute

epoch. Note the almost monotonous regularity of the periodic breathing pattern. Three or more cycles of periodic breathing are scored as Cheyne-Stokes breathing. Here, the patient was wide awake and had significant episodes of hypoxemia; hypocapnia was also present. Careful examination of the end-tidal Pco2 trace during apnea indicated that it was thicker than normal because of oscillations in the trace. The cause of such oscillations is shown in Figure 48.46.

Cursor: 00:36:57, Epoch: 303 - AWAKE

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2

1 min/page

ECG 2.5 mV

LEG(L) LEG(R)

1 min/page 100

SaO2 %

90

THOR RES x2

ABD RES x4

35

PCO2

mm Hg 0

AIRFLOW 41.7 V

Figure 48.46  ​Congestive heart failure with awake Cheyne-Stokes breathing with cardiogenic oscillations (the same patient shown in Fig. 48.45). The top and

bottom windows are 1-minute epochs. Examination of the Pco2 trace shows that when the patient is apneic, high-frequency oscillations in CO2 correspond to the heartbeat. These oscillations occur because the beating heart creates tiny puffs of airflow with CO2, which are detected by the CO2 analyzer. This proves that the upper airways are patent.

486  Gallery of Polysomnographic Recordings E2-M1

2

30s

E1-M2 C4-M1

Prone

C3-M2 CHIN1 ECG

04:36:57

831 832

04:38:57

2

2

2

Prone

Prone

Prone

Prone

THERM

2m

833 834

2

PTAF

THOR

832 833

ABD

SUM SaO2 (%)

100 87 75

86

91

98

99

99

98

96

93

92

91

91

90

98

99

99

98

89

95

91

87

86

88

95

99

99

99

98

96

93

Figure 48.47  ​Congestive heart failure (CHF) in a 9-year-old female patient. This patient had a history of rheumatic fever, Sydenham chorea, mitral regurgitation,

pulmonary hypertension, and CHF. The sleep study was done before mitral valve replacement. The patient is in stage N2 sleep. Cheyne-Stokes breathing is evident, with a large number of breaths per cycle, which is typical in CHF. A crescendo increase in depth of breathing, followed by a decrease, was evident. Note the significant oscillations in oxygen saturation. The patient’s apnea-hypopnea index was 66.

E2-M1

R

30s

E1-M2 C4-M1

Prone

C3-M2

CHIN1 ECG 05:32:57

943 944

PTAF

2m

THERM THOR

944 945

945 946

05:34:57

R

R

R

R

Prone

Prone

Prone

Prone

ABD

SUM SaO2 (%)

100 87 75

96

94

97

97

98

98

98

98

98

98

98

98

98

97

97

97

97

98

97

97

97

97

97

98

97

98

98

98

98

Figure 48.48  ​Congestive heart failure (CHF) in a 9-year-old female patient (the same patient shown in Fig. 48.47). Here, the patient is in rapid eye movement (REM) sleep, and the Cheyne-Stokes breathing pattern has normalized. This finding, in which breathing pattern improves in REM sleep, is common in patients with CHF and has also been described in the Cheyne-Stokes breathing of high altitude.

Atlas of Clinical Sleep Medicine   487 E2-M1

2

30s

E1-M2 C4-M1

Prone

C3-M2 CHIN1 ECG

04:35:27

828 829

829 830

830 831

831 832

832 833

833 834

834 835

835 836

836 837

04:40:27

PTAF

5m

THERM THOR

2 2 2 2 2 2 2 2 2 2

ABD

SUM SaO2 (%)

100 87 75

93

99

99

94

92

87

99

94

86

95

99

94

91

99 88

96 87

91

99

99

97 88

99

88

91

87

92

99

94

Figure 48.49  ​Congestive heart failure in a 9-year-old female patient (the same patient shown in Figs. 48.47 and 48.48). Although Cheyne-Stokes respiration is sometimes described as a breathing instability, in fact, the overall pattern can be extremely regular and repetitive for long periods. Note the almost monotonous regularity of the breathing pattern and oscillations in oxygen saturation over 5 minutes.

E2-M1

2

30s

E1-M2 C4-M1

Prone

C3-M2 CHIN1 ECG

04:32:57823 824

824 825

825 826

826 827

827 828

828 829

829 830

830 831

831 832

832 833

833 834

834 835

835 836

836 837

837 838

838 839

839 840

840 841

841 84204:42:57

PTAF

10m

THERM THOR

2 2 2 2 2 2 2 22 2 2 2 2 2 2 22 2 2 2

ABD

SaO2 (%)

100 87 75

95

98 87

91

Prone

Sum 96

95

98

93

99

99 87

99 86

91

99

99 87

99 88

91

92

94

97

94

100

96 87

97

85

Figure 48.50  ​Congestive heart failure in a 9-year-old female patient (the same patient shown in Figs. 48.47 to 48.49). The breathing pattern persists during this entire 10-minute epoch, with 13 central apnea episodes. The patient’s non–rapid eye movement sleep apnea index was about 100, and she was subsequently assessed on continuous positive airway pressure (CPAP) in preparation for her cardiac surgery. Her apnea-hypopnea index was 5 on a pressure of 6 cm H2O, and she used CPAP at home in preparation for surgery and perioperatively. After mitral valve replacement, the patient’s breathing pattern normalized, and she was asymptomatic with respect to sleep.

488  Gallery of Polysomnographic Recordings Cursor: 23:35:58, Epoch: 115 - STAGE 2

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mv 3422

3425

3427

3430

3432

3435

3437

3440

3442

3445

3447 5 min/page

mh L

LEG(L) LEG(R) SaO2

mh L

mh L

mh L

mh L

mh L

mh L

mh L

mh L

mh mh LI mh L

mh L

mh R

mh L

mh L

mh L

mh L

mh L

mh L

mh L

mh Lmh L

mh R

100

%

85 Period

Period

Period

Period

Period

Period

Period

Period

40 Period 30

Period

Period

Period

THOR RES x1

ABD RES x1 120

PULSE bpm

PCO2 mm Hg -4

AIRFLOW 62.5 V

3295

3320

3345

3370

3395

3420

3445

3470

3495

3520

3545

Figure 48.51  ​Congestive heart failure. This patient has well-developed Cheyne-Stokes breathing with periodic crescendo increases in efforts to breathe, followed

by decrescendo reductions in effort, resulting in the typical diamond-shaped pattern seen in the bottom 5-minute window. The nadir Sao2 occurs during the peak of hyperpnea (a rapidly responding ear oximeter is being used). This type of breathing pattern may resolve while the patient is in rapid eye movement (REM) sleep. The periodic breathing cycles may occur in the absence of arousals, suggesting that they are maintained by chemical control of breathing, which is blunted in REM sleep. This is one of the few conditions in which abnormal breathing patterns may improve in REM sleep. The electrocardiogram shows two types of beats: (1) narrow complex ventricular beats, which reflect the patient’s underlying atrial fibrillation, and (2) wide complex beats initiated by a cardiac pacemaker. Extremely short pacing pulses are missed entirely by the data acquisition system. The patient also had significant periodic limb movements, a common finding in heart failure.

Cursor: 22:34:19, Epoch: 144 - STAGE 4

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C3-A2 128 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

ABD RES x2

120

PULSE bpm

40 78

PCO2 mm Hg -4 30

CPAP cm H2O

2

AIRFLOW 15.6 V

Figure 48.52  ​Periodic breathing initiated by a big breath. Patients with congestive heart failure do not have periodic breathing the entire night. It was shown many years ago that breathing in such patients could be stable, and then an event such as a loud noise could result in temporary hyperventilation, in turn causing the instability leading to Cheyne-Stokes breathing shown here. At the orange vertical line, the patient takes a very big breath, which is soon followed by oscillations in Sao2.

Atlas of Clinical Sleep Medicine   489 Cursor: 23:12:02, Epoch: 15 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A2 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

625 muV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x1

ABD RES x1

70

PULSE bpm

30 40

PCO2

mm Hg -4

AIRFLOW 62.5 V

Figure 48.53  ​Congestive heart failure with multiple abnormalities. This 75-year-old patient had myocardial infarction and mitral valve replacement. The eye is

first drawn to the periodic limb movements. Other abnormalities include an underlying periodicity in the breathing pattern, a grossly irregular heart rate, and a ragged ear oximeter Sao2 trace; the latter is likely related to the poor perfusion through the ear caused by low cardiac output. Perhaps the last thing noted is the most important: the patient had about 3 seconds between R-R intervals between the second and third heartbeat of this epoch. The top window is a 30-second epoch, and the bottom window is a 5-minute epoch. Figure 48.54 shows the effect of treatment.

Cursor: 23:59:32, Epoch: 147 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

LEG(L)

5 min/page

125 V

LEG(R)

125 V 100

SaO2 %

85

THOR RES x1.5

ABD RES x1

120

PULSE bpm

40 50

PCO2 mmHg

-4

AIRFLOW 31.3 V

Figure 48.54  ​Congestive heart failure with multiple abnormalities (the same patient shown in Fig. 48.53). Thirteen days later, the heart rate is not as variable, the Cheyne-Stokes breathing pattern is more developed, and the Sao2 shows a clean oscillating signal with the nadir Sao2 occurring during the peak of hyperpnea. This is from a fast-responding ear oximeter. However, the electrocardiogram looks worse. The top window is a 30-second epoch, and the bottom window is a 5-minute epoch. Figure 48.55 drills down on the bottom window.

490  Gallery of Polysomnographic Recordings Cursor: 23:59:50, Epoch: 148 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

2 min/page

LEG(L) 125 V

LEG(R)

125 V 100

SaO2 %

85

THOR RES x1.5

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg -4

AIRFLOW 31.3 V

Figure 48.55  ​Congestive heart failure with multiple abnormalities (the same patient shown in Figs. 48.53 and 48.54). Another fragment from the same night.

The bottom window is a 2-minute epoch, and cardiogenic oscillations are clearly visible in the CO2 channel following the hyperpneic breaths in the middle of the epoch. The abnormal cardiac beats were initially scored as ventricular tachycardia. Indeed, the abnormal heartbeats are wide and complex and could be ventricular tachycardia or a low junctional rhythm (see Figs. 48.75 and 48.79). However, the pulse channel shows after the middle of the epoch an absolutely steady pulse rate. The abnormal beats, on careful inspection, occur initially after a slightly increased time between beats. In fact, a cardiac pacemaker had been placed in the patient, and the pacing pulses were missed entirely because of the sampling rate of the electrocardiogram. The abnormal beats are paced beats.

Cursor: 22:39:15, Epoch: 82 - AWAKE

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 uV

ECG 625 V

5 min/page

LEG(L) 125 V

100

SaO2 %

70

ABD RES x2

120

PULSE bpm

40 50

PCO2 mm Hg 0 20

CPAP cm H2O

2

Figure 48.56  ​Acute heart failure and obstructive sleep apnea (OSA). The top window is a 30-second epoch, and the bottom window is a 5-minute epoch. At

the time of this recording, the patient was awake, had severe oxygen desaturations, and was in florid pulmonary edema caused by acute left ventricular failure. The patient had a few unobstructed breaths, followed by shallow breaths, and then had evidence of OSA with large efforts but no airflow. Nadir Sao2 occurred long after breathing resumed (a fast-response ear oximeter was used). The heart-to-ear circulation time was long because of heart failure, and the patient was unable to achieve persistent sleep without ventilatory support (see Fig. 48.57).

Atlas of Clinical Sleep Medicine   491 Cursor: 02:25:33, Epoch: 535 - STAGE 4

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 625 V

5 min/page

LEG(L) 125 V

100

SaO2 %

70

ABD RES x8

120

PULSE bpm

40 50

PCO2 mm Hg 0 20

CPAP cm H2O

2

Figure 48.57  ​Acute heart failure and obstructive sleep apnea on ventilatory support (the same patient shown in Fig. 48.56). Note the regular deflections in the

bilevel pressure continuous positive airway pressure channel. Both a high inspiratory pressure and a high expiratory pressure were used. The pressure waves generated by the bilevel machine show clocklike regularity, which indicates that a timed backup rate was used. The apnea is completely resolved, hypoxemia is no longer present, and the patient is in slow-wave sleep.

Cursor: 23:47:08, Epoch: 113 - AWAKE

CHIN(1) 250 V C3-A2 125 V C4-A1 125 V O1-A2 125 V O2-A1 125 V ROC-A1 125 V LOC-A2

30 sec/page

125 V

ECG 625 V

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

75

THOR RES x1

ABD RES x1.5

120

PULSE bpm

40 50

PCO2 mm Hg

-4 20

CPAP cm H2O

0

AIRFLOW 62.5 V

Figure 48.58  ​Congestive heart failure (CHF) and apnea during wakefulness. This figure and Figures 48.59 to 48.61 are from a 61-year-old male patient with a 30-year history of snoring, 5 years of apnea observed by his wife, and, at the time of this recording, nightly paroxysmal nocturnal dyspnea, documented atrial fibrillation (AF), and mild CHF. The top window is a 30-second epoch showing that the patient was awake. The bottom window is a 5-minute epoch showing Cheyne-Stokes breathing. AF is noted by regularly irregular variation in the heart rate in the pulse channel and the lack of developed P waves in the electrocardiogram. Awake Cheyne-Stokes breathing is common in heart failure.

492  Gallery of Polysomnographic Recordings Cursor: 23:17:10, Epoch: 54 - STAGE 2

CHIN(1) 250 V C3-A2 125 V C4-A1

30 sec/page

125 V

O1-A2 125 V

O2-A1 125 V ROC-A1 125 V LOC-A2 125 V

ECG 625 V

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

75

THOR RES x2

ABD RES x4

120

PULSE bpm

40 50

PCO2 mm Hg -4 20

CPAP cm H2O

0

AIRFLOW 62.5 V

Figure 48.59  ​Heart failure and apnea during sleep (the same patient shown in Fig. 48.58). The patient now has features of both Cheyne-Stokes respiration and

obstructive apnea. Note that in the abdominal effort channel, at times efforts to breathe are not accompanied by airflow, as noted in the bottom channel. During these times, the CO2 channel shows some expiratory airflow and detects expiratory air that is rich in CO2.

Cursor: 05:08:21, Epoch: 756 - STAGE 1

CHIN(1) 250 V C3-A2 125 V C4-A1

30 sec/page

125 V

O1-A2 125 V

O2-A1 125 V ROC-A1 125 V LOC-A2 125 V

ECG 625 V

5 min/page

LEG(L) 125 V

LEG(R)

125 V 100

Sao2 %

75

THOR RES x1

ABD RES x4

120

PULSE bpm

40 50

PCO2

mm Hg -4 20

CPAP cm H2O

0

AIRFLOW 62.5 V

Figure 48.60  ​Heart failure and obstructive apnea on bilevel pressure (the same patient shown in Figs. 48.58 and 48.59). Note the deflections with flattened peaks in the continuous positive airway pressure (CPAP) channel. The patient is on a bilevel machine in spontaneous mode, which has no effect on his breathing pattern or oxyhemoglobin saturation. The patient is awake and was unable to achieve persistent sleep. Figure 48.61 shows the effect of raising pressures and changing the patient to fixed-pressure CPAP.

Atlas of Clinical Sleep Medicine   493 Cursor: 05:22:21, Epoch: 784 - STAGE 2

CHIN(1) 250 V C3-A2 125 V C4-A1

30 sec/page

125 V

O1-A2 125 V

O2-A1 125 V ROC-A1 125 V LOC-A2 125 V

ECG 625 V

20 min/page

LEG(L) 125 V

LEG(R) 125 V

100

Sao2 %

75

THOR RES x1

ABD RES x1.5

120

PULSE bpm

40 50

PCO2

mm Hg -4 20

CPAP cm H2O

0

AIRFLOW 62.5 V

Figure 48.61  ​Congestive heart failure (CHF) and obstructive sleep apnea (OSA) on continuous positive airway pressure (CPAP) therapy (the same patient shown in Figs 48.58 to 48.60). The bottom window now shows 20 minutes of data, during which time attempts were made to titrate the patient on bilevel pressure. Then, about one-third of the way into the 20-minute epoch, the patient was switched to fixed pressure (note the change in the channel labeled CPAP). Within about 10 minutes, the patient achieved sleep; shortly thereafter, his breathing pattern and oxygenation normalized. By the end of this epoch, he was in stage N2 sleep. Most of the time, titrations in patients with CHF and OSA are complicated and involve trial and error because it is difficult to predict how a patient will respond to a specific treatment. Because of this, it is inappropriate to attempt unattended home titration in a patient with heart failure.

Cursor: 01:22:30, Epoch: 344 - STAGE 2

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 625 V

20 min/page

LEG(L) 125 V

LEG(R) 125 V

100

Sao2 %

90

THOR RES x4

ABD RES x2

120

PULSE bpm

40 76

PCO2

mm Hg -4

AIRFLOW 62.5 V

Figure 48.62  ​Congestive heart failure, periodic breathing, and the effect of oxygen. The top window shows a 30-second epoch, and the bottom window shows

a 20-minute epoch. At the beginning of the 20-minute epoch, the patient has an apparent Cheyne-Stokes breathing pattern, a chaotic heart rate consistent with atrial fibrillation, and 2% to 4% oscillations in Sao2. The Sao2 does not go below 90%. The patient was started on oxygen, and airflow deflections in the bottom channel ceased. Within 4 to 5 minutes, the breathing pattern becomes regular, and the Sao2 is steady. For reasons not entirely clear, even though significant hypoxemia was not detected, the patient responded to oxygen administration.

494  Gallery of Polysomnographic Recordings CARDIAC RHYTHM ABNORMALITIES In sleep laboratories, cardiac arrhythmias are often observed related to blood gas and autonomic nervous system (ANS) changes seen in sleep pathology such as sleep apnea, arrhythmias related to primary heart disease, or a combination of both. Understanding the genesis of arrhythmias will facilitate interpretation of the abnormal rhythm. Because maintaining a heartbeat is so critical, if one pacemaker fails, others take over, but at a lower intrinsic rate. The main pacemaker is the sinoatrial (SA) node, which normally drives the heart at rates that vary between 60 and 100 beats/min. If the SA node fails, other atrial foci take over the pacemaker function and drive the heart at rates between 60 and 80 beats/ min. If atrial foci fail, tissues at the atrioventricular junction take over and drive the heart at rates that vary between 40 and

60 beats/min. If the junctional pacemakers fail, tissue in the ventricles with pacemaking properties will fire and drive the heart at a rate between 20 and 40 beats/min. The function and rate of these pacemakers can be affected by changes in the ANS, levels of catecholamines, blood gases, and myocardial pathology. Most arrhythmias seen in the sleep center fall into one of four general categories: (1) irregular rhythms, (2) escape rhythms, (3) premature beats, and (4) tachyarrhythmias. Most commonly seen are atrial fibrillation (AF) and premature ventricular contractions (PVCs). The optimal epoch length for evaluating cardiac rhythm abnormalities varies according to the type of abnormality and the abnormality’s relation to other sleep findings. Frequently the rhythm is best evaluated when different epoch lengths for the electrocardiogram (ECG) and the sleep breathing data are used.

Cursor: 01:23:32, Epoch: 340 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

625 V 5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

Sao2 %

75

THOR RES x1.5

ABD RES x1

120

PULSE bpm

40 76

PCO2 mm Hg -4

AIRFLOW 125 V

Figure 48.63  ​Sinus arrest and junctional escape rhythm in sleep apnea. A bradycardia/tachycardia pattern has long been recognized in patients with sleep

apnea. This pattern is easily appreciated when the heart rate is examined, as in the pulse channel shown. Such a pattern is usually present when the patient has an underlying sinus rhythm that responds to the autonomic nervous system changes associated with the apneic episodes. In this example, the patient developed sinus arrest toward the end of an apneic episode. The configuration of the P waves has changed in the preceding heartbeats. Note the electrocardiogram artifact in the electroencephalogram that accurately reflects QRS complexes. This is a junctional rhythm because the QRS complex is narrow and is similar to the QRS complexes before the sinus arrest. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

Atlas of Clinical Sleep Medicine   495 1 min/page

Cursor: 23:55:31, Epoch: 115 - STAGE 2

EMG1-EMG2 1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 128 V

3425

3430

3435

3440

3445

3450

3455

3460

3465

3470

3475 1 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

40 75

ETCO2 mm Hg

POSITION ETCO2

0

20 0

cm H2O

NASAL PRES 500 mV

3425

3430

3435

3440

3445

3450

3455

3460

3465

3470

3475

Figure 48.64  ​Atrial fibrillation (AF) in obstructive sleep apnea. AF is a common finding in sleep apnea patients. In some cases, in a sleep apnea patient who normally has a sinus rhythm, AF begins during sleep. The classic findings of absent P waves and disorganized electrical activity preceding the QRS waves are evident here. Extreme slowing of the cardiac rate occurs toward the end of an apneic episode, the result of increased parasympathetic activity. The top and bottom windows are 1-minute epochs.

Cursor: 00:58:42, Epoch: 242 - REM

EMG1

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 125 V

ECG1-ECG2 1.02 mV 100

5 min/page

SaO2 %

70

ABD EFFORT 4.1 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

0 20

CPAP Pres cm H2O

0

NASAL PRES 250 mV

Figure 48.65  ​Atrial fibrillation in obstructive sleep apnea (OSA). Here, atrial fibrillation and failure of the atrial foci to generate a heartbeat result in junctional

escape, as evidenced by a narrow QRS. The longest R-R interval here is more than 3 seconds, or a rate of 20 beats/min. This suggests either disease or suppression of the junction because the intrinsic rate is generally between 40 and 60 beats/min. Parasympathetic activity related to the effort to breathe has suppressed atrial and junctional pacemaking tissues. This patient had OSA and coronary artery disease. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

496  Gallery of Polysomnographic Recordings Cursor: 23:11:12, Epoch: 27 - STAGE 1

30 sec/page

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 1.02 mV

5 min/page 100

SaO2 %

80

ABD EFFORT 4.1 mV

120

Pulse bpm

40 40

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 250 mV

Figure 48.66  ​Atrial fibrillation in an awake patient with Cheyne-Stokes breathing with heart failure. No well-developed P waves are evident, and the ventricular

rate is irregular. Such patients may have severe sleep-onset insomnia. The top window shows a 1-minute epoch, and the bottom window shows a 5-minute epoch.

Cursor: 23:55:43, Epoch: 116 - AWAKE

1 min/page

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 1.02 mV

5 min/page 100

SaO2 %

80

ABD EFFORT 4.1 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

CPAP PRES

0 20

cm H2O

0

NASAL PRES 250 mV

Figure 48.67  ​Atrial fibrillation in an awake patient with Cheyne-Stokes breathing as a result of congestive heart failure. In the same patient shown in

Figure 48.66, but later during the night, no well-developed P waves are seen, and the ventricular rate is irregular. A sudden slowing of the heart rate to less than 40 beats/min (note the flat line at 40 beats on the pulse trace) occurs during a central apneic episode with significant hypoxemia. This is followed by tachycardia, during which the heart rate is about 100 beats/min but still irregular. The top window shows a 1-minute epoch, and the bottom window shows a 5-minute epoch.

Atlas of Clinical Sleep Medicine   497 Cursor: 01:22:30, Epoch: 344 - STAGE 2

30 sec/page

CHIN(1) 250 V

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 125 V

ECG

625 V 20 min/page

LEG (L) 125 V

LEG (R) 125 V

100

SaO2 %

90

THOR RES x4

ABD RES x2 120

PULSE bpm

40 76

PCO2 mm Hg -4

AIRFLOW 62.5 V

Figure 48.68  ​Irregular rhythm: atrial fibrillation (AF) in a patient with congestive heart failure and Cheyne-Stokes breathing. The pulse is the first clue that AF is present. The pulse rate is regularly irregular, it is actually random, and the patient appears to have a movement disorder. Most of the brisker movements occur during a peak of hyperpnea. At the vertical orange line, the patient is given oxygen. Within 1 minute, the breathing becomes more regular, a reduction in the leg movements is noted, and Sao2 normalizes. Cardiac rhythm is unaffected. The top window shows a 30-second epoch, and the bottom window shows a 20-minute epoch.

Cursor: 11:04:12, Epoch: 68 - STAGE 1

30 sec/page

ECG

2.5 mV

5 min/page 100

SaO2 %

70

THOR RES x1

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg 0

Figure 48.69  ​Irregular rhythm and escape beats with severe heart failure. The pulse channel indicates a chaotic rhythm, and atrial fibrillation is present. Occasion-

ally the patient has narrow-complex escape beats, most likely arising from the atrioventricular junction. Modern polysomnography systems have flexibility in which channels to examine, at different gains and differing epoch lengths. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

498  Gallery of Polysomnographic Recordings E2-M1

30s

E1-M2 C4-M1 C3-M2 CHIN1 ECG 04:41:44

760 761

762 763

761 762

R-R

60

34

35

38

38

38

39

38

38

38

42

38

37

38

0

40

RLeg

2m

Snore PTAF

THERM THOR ABD

95

SaO2 100 92 (%)

95

95

95

95

95

95

95

95

95

94

96

95

94

93

96

96

95

96

95

95

95

95

95

94

94

94

94

94

85

Figure 48.70  ​Heart blocks. Heart blocks interfere with the conduction of depolarization waves, resulting in missed beats. This can occur at the sinoatrial (SA)

node, at the atrioventricular (AV) node, or within the Purkinje fibers. SA and AV blocks are frequently seen in sleep studies. Bundle branch blocks and hemiblocks, which occur below the AV junction, are less frequently seen. With sinus block, the SA node fails to depolarize and results in an absent P wave, leading to missed beats. The three types of AV blocks are called first-, second-, and third-degree blocks. A first-degree block is simply a prolongation of the PR interval to more than 0.2 second. Here there are missed beats. To appreciate why the beats are missed, it is necessary to drill down. The top window shows a 30-second epoch.

E2-M1

10s

E1-M2 C4-M1 C3-M2 CHIN1 ECG 04:42:14

R-R

04:42:24 74

72

70

72

69

66

65

60

68

67

34

RLeg

10s

Snore PTAF

THERM THOR ABD SaO2 (%)

100 92 85

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

Figure 48.71  ​Wenckebach second-degree atrioventricular (AV) block. This is a 10-second epoch of the polysomnography fragment in Figure 48.70. This heart

block shows a gradual lengthening of the PR intervals. Compare the PR interval from the last conducted beat toward the middle of the epoch with the PR interval at the beginning of the epoch; it is much longer. It is believed that in this type of AV block, the nonconducted P wave is blocked entirely in the AV node, possibly as a result of increased parasympathetic activity. In this example, the patient is in rapid eye movement sleep, and possibly there has been a surge of parasympathetic tone.

Atlas of Clinical Sleep Medicine   499 E2-M1 E1-M2

30s

Microarousal [snr(l)]

C4-M1 C3-M2

CHIN1

RERA (3.0s)

ECG

02:24:14 ( 485 / 872 )

R-R

72

69

02:24:44

33

33

33

33

32

33

33

39

35

80

88

90

93

94

94

94

88

79

72

36

68

68

71

68

RLeg

30s

Snore PTAF

THERM THOR ABD Sum SaO2 (%)

100 92 85

94

94

94

94

94

94

95

94

95

94

94

94

94

94

93

93

93

93

93

93

93

94

94

95

95

96

96

97

97

Figure 48.72  ​In Mobitz second-degree atrioventricular (AV) block, one or more blocked P waves are followed by a conducted ventricular beat. In this example,

there are two P waves to each QRS in the beginning of the epoch. This is called a Mobitz 2 :1 AV block. In a 3:1 block, there are three P waves to each conducted QRS. This type of block occurs in the lower part of the AV node, or His bundle, or in the right or left bundle branches. If it occurs in the bundle branches, the QRS will be wider.

E2-M1 E1-M2 F4-M1 C4-M1 O2-M1 F3-M2

30s

C3-M2

O1-M2 CHIN1 CHIN2 ECG

68

68

68

68

68

68

63

63

60

53

54

49

54

52

49

50

C-FLOW THOR ABD SaO2 (%)

100 92 85

95

95

95

95

95

95

95

95

95

95

95

95

95

95

95

94

94

94

94

94

? ECG CHANGES

R-R

94

58

56

94

93

59

93

62

59

93

92

63

92

61

57

92

93

Figure 48.73  ​Third-degree heart block. Sinoatrial node–generated P waves are not followed by an escape rhythm. The three P waves that are not conducted are identical to the ones conducted before and after the cardiac pause. This patient had sleep apnea, but in this polysomnogram fragment, no apnea or hypoxemia is apparent. These episodes might be related to rapid eye movement sleep. Note the eye movements in the electrooculogram channels and the sawtooth waves on electroencephalogram; findings such as these should lead to a cardiology assessment because the patient may need a pacemaker.

500  Gallery of Polysomnographic Recordings E2-M1

30s

E1-M2 C4-M1 C3-M2

CHIN1 ECG

01:08:29

01:07:59 ( 335 / 887 )

R-R

66

64

64

91

92

92

66

65

61

64

65

67

62

66

33

65

66

94

94

69

65

68

65

65

64

61

65

61

65

68

67

68

94

94

70

67

64

66

RLeg

30s

LLeg

Snore

THERM THOR ABD Sum SaO2

100 92

(%)

92

92

93

93

93

94

94

94

94

94

94

94

94

94

94

94

94

94

94

94

93

93

85

Figure 48.74  ​Premature ventricular contraction (PVC). A PVC arises from an irritable focus in the ventricle that depolarizes. The depolarization wave travels to the remainder of that ventricle and then to the opposite ventricle, producing a large and wide ventricular complex, as seen in this example. It is likely that the SA node depolarizes, but the P wave is usually lost in the QRS and arrives at the ventricle when it is refractory. Thus a conducted beat is missed, but the following P wave is conducted, resulting in a compensatory pause.

EMG1-EMG2 1.02 mV

O3-A2 128 V

O2-A1 128 V

ROC-A1 128 V

2pvcs in a row

LOC-A2 128 V

ECG1-ECG2 2.05 mV

2:48:37

2:48:47

2:48:57

2:49:07

2:49:17

2:49:27

2:49

LAT+-LAT512 V

RAT+-RAT512 V

Sao2 %

85

6 sec/page

Cursor: 02:48:41, Epoch: 435 - AWAKE

100

99 99 99 9 99 99 9999 99 9 9 99 99 99999 9 55 55 55 5 55 55 5555 55 5 5 55 55 55555 5

9 9 9 9 9 9 99 9 9 5 5 5 5 5 5 55 5 5

THOR EFFORT 4.1 mV

ECG1ECG2 2.05 mV

ABD EFFORT 4.1 mV

120

Pulse bpm

2:48:41

2:48:43.5

2:48:45

40 75

ETCO2 mm Hg

0

POSITIONBA LE RI PR 20

cm H2O

2pvcs in a row

CPAP PRES

0

NASAL PRES 500 mV

2:48:37

2:48:47

2:48:57

2:49:07

2:49:17

2:49:27

2:49

Figure 48.75  ​Premature ventricular contraction (PVC). The underlying rhythm is sinus. The abnormal beats are early and wide complex and at times are fol-

lowed by a compensatory pause. Some data acquisition systems allow the clinician to drill down. The middle window shows a 6-second epoch that corresponds to the beats surrounded by the box on the electrocardiogram trace of the polysomnogram. This allows the clinician to better characterize the rhythm abnormality. More than six PVCs per minute should cause concern. Two PVCs in a row are called couplets; three are called triplets. When there are more than three, the event is called ventricular tachycardia.

Atlas of Clinical Sleep Medicine   501 5 min/page

Cursor: 03:20:52, Epoch: 462 - STAGE 1

CHIN(1) ARO Limb

C3-A2 C4-A1 O1-A2 O2-A1 LOC-A2 ECG

1.25 mV

13705

13730

LEG(L) LEG(R)

13805

13830

13855

13880

13905

13930

13955 5 min/page L mb L

mb L

mbR

125 V

%

13780

mb L

125 V

SaO2

13755

O2 up to 1.5L

ROC-A2

mbR

mbR

mbR

mbR

100 Period

90

THOR RES x2

Period

ABD RES x1

120

1 1

8

8

8 77 Period 526 55655 4 56657 5 5 4 4 435 537 18 7 333 4 15 22278 572 633 0 95 87 8 221 08 6

77 7 7 7 7 6 7 67 65 6 65 56 40 6 66 6556255 666 6 5 5 665 2 5565 5 565 2 5 4982 54 134434 44804 55564435456535 4466 54 543 76 944344 5 6 4454 4 545 8 42 5558 3 1 2 5 5544 0 8 9 438276

05

45 2 477 5 9421 9 4 3 8

9 918 0 53 4

676

3

2 180585 53

PCO2

mm Hg

-4

13705

13730

13755

13780

13805

13830

2

43

9 648566 587 49

13855

92

snun

bpm

O2 up to 1.5L

PULSE

13880

13905

13930

13955

Figure 48.76  ​Tachycardia in congestive heart failure and Cheyne-Stokes breathing. Although it is counterintuitive, examining a long epoch gives an impression

of the overall rhythm, and the eye is immediately drawn to differences from the underlying pattern. Here, the top and bottom windows are both 5-minute epochs. On examining the electrocardiogram (ECG), the overall impression is that the underlying rhythm is regularly irregular. A narrow, dense band on the ECG at the beginning of the epoch corresponds to an increased heart rate detected in the pulse channel. Once a suspected abnormality is detected, the epoch length can be changed to examine it in more detail. Figure 48.77 shows details of the beginning of the epoch.

30 sec/page

Cursor: 03:18:22, Epoch: 457 - AWAKE

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A2 LOC-A2 ECG

1.25 mV

13682

13685

13687

13690

13692

13695

13697

13700

13702

13705

LEG(L)

13707 30 sec/page

125 V

LEG(R) 125 V

SaO2

100

%

90

THOR RES x2

ABD RES x1

120

1111111111111111 0000111111111111

PULSE bpm

7777 6 6 555211111116 40 7766 5555555556 6 6666655555 5555556466659994 76 00995555555544 444444444444444444 43333444 44 44444445 55544444 555 3443333344444 355532220 999 99 1 98

3211111164 552 11266665444 11 111233343333111 0888822222222577601 75558 1

8777

209888815555

PCO2

mm Hg

-4

13682

13685

13687

13690

13692

13695

13697

13700

13702

13705

13707

Figure 48.77  ​Ventricular tachycardia. At this epoch length (both top and bottom windows are 30-second epochs), the configuration of the abnormal beats can be

more easily seen. This epoch length lets the clinician manually calculate the rate from the electrocardiogram (ECG). In fact, the rate is actually about 160 beats/min, not the 109 to 115 beats/min indicated on the pulse channel. In this example, the rate on the recording is obtained from the output of an oximeter, not from the R-R interval of the ECG; not all of the beats were detected.

502  Gallery of Polysomnographic Recordings Cursor: 03:51:07, Epoch: 635 - REM

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2

5 min/page

ECG

125 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x4

ABD RES x4

120

PULSE

40 40

bpm

Figure 48.78  ​Tachycardia. Through scanning by 5-minute epochs, an unusual pattern was detected that suggested a tachycardia on the electrocardiogram about 1 minute into the epoch. The pulse rate was 120 beats/min at this time, and rapid eye movement is apparent on the eye channels. At the same time, there is a reduction in the number of leg movements. This patient had severe sleep apnea and a movement disorder. Figure 48.79 examines a shorter epoch length in which the data are shown in greater resolution.

Cursor: 03:50:05, Epoch: 633 - REM

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2

1 min/page

ECG

2.5 mV

1 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x4

ABD RES x4

120

PULSE bpm

40 40

Figure 48.79  ​Ventricular tachycardia. The beginning of the epoch shows an irregular pattern without well-developed P waves, characteristic of atrial fibrillation.

This is followed by what appears to be a mirror image of bigeminy. Instead of a normal beat alternating with a wide-complex premature ventricular contraction, the narrow-complex beat follows the wide-complex beat. This suggests that the wide-complex beat is leading to retrograde conduction, which in turn leads to the narrow-complex beat. These wide-complex beats are likely junctional beats. A wide-complex beat falls on a T wave, leading to a run of sustained ventricular tachycardia. The rate is 90 beats and steady (see the pulse channel). A ventricular contraction on a T wave should alert to the possibility of impending ventricular fibrillation. It is likely that surges in sympathetic activity that occur during rapid eye movement sleep play a role in the genesis of the tachycardia.

Atlas of Clinical Sleep Medicine   503 NEUROLOGIC DISEASES Movement Disorders Digital Video

CHIN(1) 250 V

Cursor: 23:26:33, Epoch: 136 - STAGE 2

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV 5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

80

THOR RES x1

ABD RES x1

120

PULSE bpm

40 50

PCO2

mm Hg 0

AIRFLOW 62.5 V

Figure 48.80  ​Parkinson disease. This patient has sleep apnea, and his mouth is wide open. The nasal pressure channel overestimates the length of the apneas, which are more accurately detected by oronasal CO2. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

Cursor: 23:49:11, Epoch: 187 - AWAKE

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x1

ABD RES x1

120

PULSE bpm

40 40

PCO2 mm Hg 0

AIRFLOW 31.3 V

Figure 48.81  ​Restless legs syndrome. Sleep latency was prolonged. During the time the patient was trying to fall asleep, she was extremely fidgety, had difficulty

staying still, and demonstrated continuous movements in her legs. The movements caused artifacts in the abdominal and thoracic effort channels. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

504  Gallery of Polysomnographic Recordings Cursor: 22:54:04, Epoch: 50 - STAGE 2

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 uV

ECG 2.5 mV

2 min/page

LEG(L) 62.5 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x1

ABD RES x1

90

PULSE bpm

50 40

PCO2 mm Hg -4

AIRFLOW 62.5 V

Figure 48.82  ​Periodic limb movements during sleep. Note that the movements are followed by increases in heart rate (see the PULSE channel), presumably caused by increased sympathetic tone. This patient was a lifelong vegetarian who had reduced iron stores. The top window shows a 30-second epoch, and the bottom window shows a 2-minute epoch.

EMG1-EMG2 1.02 mV

Digital Video

Cursor: 22:47:50, Epoch: 93 - STAGE 3

30 sec/page

Close

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

85

THOR EFFORT 2.05 mV

ABD EFFORT 2.05 mV

80

Pulse bpm

40 40

ETCO2 mm Hg

0

NASAL PRES 500 mV

Figure 48.83  ​Periodic limb movements during sleep (PLMS). The patient, lying on his side, had typical findings of PLMS. There are small synchronous increases in heart rate. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

Atlas of Clinical Sleep Medicine   505 EMG1-EMG2 1.02 mV

Cursor: 23:53:33, Epoch: 224 - STAGE 2

Digital Video

30 sec/page

Close

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

5 min/page

LAT-LAT256 V

RAT-RAT512 V

100

SaO2 %

85

THOR EFFORT 4.1 mV

ABD EFFORT 2.05 mV

80

Pulse bpm

40 40

ETCO2 mm Hg

0

NASAL PRES 500 mV

Figure 48.84  ​Periodic limb movements during sleep. The patient, sleeping on his back, had a sleep breathing disorder. Limb movements are now synchronized with the peak of hyperpnea. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

30 sec/page

Cursor: 23:54:45, Epoch: 153 - STAGE 3

EMG1-EMG2 1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

4562

4565

4567

4570

4572

4575

4577

4580

4582

4585

4587 10 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

85

THOR EFFORT 4.1 mV

ABD EFFORT 2.05 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

0

NASAL PRES 500 mV

4340

4390

4440

4490

4540

4590

4640

4690

4740

4790

4840

Figure 48.85  ​Calf cramp. This patient had nightly leg cramps that awakened him. He had severe periodic limb movements during sleep (PLMS) with a PLMS index of about 150. The top window shows a 30-second epoch, and the bottom window shows a 10-minute epoch. Whether there is a relationship between his PLMS and cramps is not known.

506  Gallery of Polysomnographic Recordings Cursor: 03:31:39, Epoch: 587 - AWAKE

1 min/page

EMG1-EMG2 1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

17585

17590

17595

17600

17605

17610

17615

17620

17625

17630

17635 1 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 4.1 mV

ABD EFFORT 2.05 mV

120

Pulse bpm

30 50

ETCO2 mm Hg

0

NASAL PRES 500 mV

17585

17590

17595

17600

17605

17610

17615

17620

17625

17630

17635

Figure 48.86  ​The same patient shown in Figure 48.85, at the beginning of a 1-minute epoch, was in rapid eye movement sleep. Activity in the legs was noticeable beginning in the middle of the epoch. Within about 10 seconds of the first leg movement, the patient awakened abruptly with a painful cramp. The synchronized video shows a sudden, very high-speed movement, resembling a kick, just before awakening.

Genetic Disorders Cursor: 23:51:38, Epoch: 121 - STAGE 2

1 min/page

EMG1-EMG2 1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG3 2.05 mV

5 min/page

LAT-LAT256 V

RAT-RAT128 V

100

SaO2 %

90

THOR EFFORT 4.1 mV

ABD EFFORT 8.19 mV

120

Pulse bpm

40 75

PCO2

mm Hg 0

NASAL PRES 250 mV

Figure 48.87  ​Becker muscular dystrophy. This 35-year-old patient was diagnosed at 13 years of age. At 15 years of age, he started snoring and developed

daytime sleepiness; this polysomnogram fragment shows sleep apnea. A discrepancy between nasal pressure and oronasal CO2 is evident because the patient often breathed through his mouth. The top window shows a 1-minute epoch, and the bottom window shows a 5-minute epoch.

Atlas of Clinical Sleep Medicine   507 Cursor: 23:28:25, Epoch: 78 - STAGE 2

30 sec/page

CHIN(1) 250 V

C3-A1 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A1 125 V

ECG 2.5 mV

10 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x1

ABD RES x1

120

PULSE bpm

CPAP

40 20

cm H2O

2

AIRFLOW 31.3 V

Figure 48.88  ​Retinitis pigmentosa. These data are from a 75-year-old male patient with blindness as a result of retinitis pigmentosa. He had a 20-year history of

severe daytime sleepiness and a history of snoring, observed apnea, and restlessness in his legs. The patient also had white fingernails. The breathing abnormality shown, a variant of Cheyne-Stokes breathing, was also present during wakefulness. The patient responded well to active servoventilation with an end-expiratory pressure of 10 cm H2O. The top window shows a 30-second epoch, and the bottom window shows a 10-minute epoch.

Cursor: 02:12:20, Epoch: 407 - REM

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

12182

12185

12187

12190

12192

12195

12197

12200

12202

12205

12207 5 min/page

LEG(L) 125 V

LEG(R) 125 V

SaO2

100

%

70

THOR RES x1

ABD RES x1

120

bpm

40 76

PCO2 mm Hg -4

AIRFLOW 62.5 V

12205

12230

12255

12280

12305

12330

12355

12380

12405

12430

tech in to start CPAP

PULSE

12455

Figure 48.89  ​Huntington disease. This 60-year-old female patient had continuous choreoathetotic movements during wakefulness that decreased during sleep. She had no breathing abnormalities in non–rapid eye movement (REM) sleep, but during REM sleep (shown here), she had very long episodes of obstructive sleep apnea.

508  Gallery of Polysomnographic Recordings Stroke 30 sec/page

Cursor: 23:02:08, Epoch: 69 - STAGE 2

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A3 ECG

2042

2045

2047

2050

2052

2055

2057

2060

2062

2065

2067 5 min/page

LEG(L) 125 V

LEG(R)

125 V 100

SaO2 %

85

THOR RES x1

ABD RES x1

120

PULSE bpm 40 50

PCO2 mm Hg -4

POSITION AIRFLOW 62.5 V

1975

2000

2025

2050

2075

2100

2125

2150

2175

2200

2225

Figure 48.90  ​Stroke. This polysomnogram is of a 54-year-old male patient who developed excessive daytime sleepiness, snoring, and witnessed apnea during

sleep after a stroke at 51 years of age. There was also a history of excessive movements during sleep. The patient has central apnea with cardiogenic oscillations evident in the CO2 trace. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch. Note the electrocardiographic artifact in all channels in the top window.

Cursor: 10:34:46, Epoch: 2 - AWAKE

30 sec/page

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

20 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

85

THOR RES x1

ABD RES x2

90

PULSE bpm

40 76

PCO2

mm Hg -4 30

PCO2

cm H2O

2

AIRFLOW 62.5 V

Figure 48.91  ​Awake central apnea in stroke. These data are from an 81-year-old female patient with insomnia that began 3 years earlier, following a stroke that

resulted in right-sided weakness and some impairment of speech. The patient had central apnea the entire night and never achieved persistent sleep. The top window shows a 30-second epoch, and the bottom window shows a 20-minute epoch.

Atlas of Clinical Sleep Medicine   509 30 sec/page

Cursor: 23:10:16, Epoch: 101 - STAGE 2

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2 ECG

3002

3005

3007

3010

3012

3015

3017

3020

3022

3025

3027

5 min/page LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

80

THOR RES x1

ABD RES x1

120

PULSE bpm 40 76

PCO2 mm Hg -4

POSITION 30

CPAP cm H2O

2

AIRFLOW 62.5 V

3025

3050

3075

3100

3125

3150

3175

3200

3225

3250

3275

Figure 48.92  ​Central sleep apnea in stroke. These data are from a 72-year-old male patient who had daytime sleepiness that began after a stroke. His wife also

witnessed apnea during his sleep. The patient had a periodic breathing pattern, a variant of Cheyne-Stokes respiration, during both sleep (shown here) and wakefulness. The top window shows a 30-second epoch, and the bottom window shows a 20-minute epoch. Note the electrocardiographic artifact in the top window.

Cursor: 00:30:16, Epoch: 261 - STAGE 1

30 sec/page

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2 ECG

7802

7805

7807

7810

7812

7815

7817

7820

7822

7825

7827

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

80

THOR RES x1

ABD RES x1

120

PULSE bpm 40 76

PCO2

mm Hg -4

POSITION 30

CPAP cm H2O

2

AIRFLOW 62.5 V

7825

7850

7875

7900

7925

7950

7975

8000

8025

8050

8075

Figure 48.93  ​Central sleep apnea in stroke (the same patient shown in Figure 48.92). Here, later in the night, the patient was assessed on an active servoven-

tilation (ASV) system. The continuous positive airway pressure channel shows increases in pressure generated by the servoventilator when the patient became apneic. Figure 48.94 shows the 20 minutes of transition onto ASV. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

510  Gallery of Polysomnographic Recordings Cursor: 00:31:03, Epoch: 262 - STAGE 2

30 sec/page

CHIN(1) C3-A2 C4-A1 O1-A2 O2-A1 ROC-A1 LOC-A2 ECG

7832

7835

7837

7840

7842

7845

7847

7850

7852

7855

7857

20 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

80

THOR RES x1

ABD RES x1

120

PULSE bpm

40 76

PCO2 mm Hg -4

POSITION 30

CPAP cm H2O

2

AIRFLOW 62.5 V

7750

7850

7950

8050

8150

8250

8350

8450

8550

8650

8750

Figure 48.94  ​Central sleep apnea in stroke (the same patient shown in Figs. 48.92 and 48.93). The bottom window shows 20 minutes of data on active servoven-

tilation (ASV). There is a gradual normalization of Sao2 and a reduction of periodic breathing as ASV entrains and normalizes the breathing pattern. Symptoms improved dramatically with home use of ASV.

Narcolepsy

REMs

REM

N1

N2

N3 Hour

1

2

3

4

5

6

7

8

Figure 48.95  ​Narcolepsy. Sleep histogram from a 15-year-old female patient who complained of sleepiness (Epworth score of 19). The top part of the histogram

shows the presence of rapid eye movement (REM); the bottom part shows sleep stages. N3 is made up of stage 3 (shorter blue bands) and stage 4 (longer blue bands). The first episode of REM sleep occurred 6.5 minutes after lights out. The multiple sleep latency test done the next day was terminated after three naps, during which the patient was in REM sleep. The mean sleep latency was 6 minutes.

Atlas of Clinical Sleep Medicine   511 Cursor: 23:55:33, Epoch: 154 - REM

10 min/page

EMG1-EMG2 1.02 mV

C3-A2 128 V

C2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

10 min/page

LAT-LAT512 V

Moaning, trying to call for help

RAT-RAT512 V

100 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 9 9 9 9 9 99 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 9999 9 99 9 9 9 9 39 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 6 6 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 5 5 5 5 6 5 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 5 5 5 5 5 5 6 5 5 5 5 5 5 4 55 5 5 5 5 5 5 5 5 55 5 5 5 5 5 5 55 5 5 55 5 44 4 4 5 55 5 5 4 44 4 5 5 4 4 4 4 3 4 44 33 2 3 3 3 3 3 4 3 3 3 3 43 3 3 3 3 3 3 4 33 3 3 4 4 5 5 55 44 4 4 4 4 55 4 4 3 3 3 3 3 3 3 3 3 3 4 4 4 4 44 4 4 3 3 4 4 55 5 2 2 22 2 332 3 3 2

SaO2 %

80

THOR EFFORT 4.1 mV

ABD EFFORT 2.05 mV

120

Pulse bpm

40 40

ETCO2 mm Hg

0 20

CPAP PRES cm H2O

0

NASAL PRES 2.05 mV

Figure 48.96  ​Sleep paralysis. This 10-minute polysomnogram epoch is from a 49-year-old female patient with a 15-year history of sleep paralysis. Note the notation of moaning during the rapid eye movements. The patient stated that she was awake but paralyzed and was trying to call for help by making moaning noises. This patient did not have any other features of narcolepsy.

REM Sleep Behavior Disorder CHIN(+1/-1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

2.5 mV

LEG(L) LEG(R) SaO2

5:54:21

5:54:23.5

5:54:26

5:54:28.5

5:54:31

5:54:33.5

5:54:36

5:54:38.5

5:54:41

5:54:43.5

5:54:46

5:54:48.5

5:54

THOR RES ABD RES PULSE PCO2 POSITION CPAP SOUND Nasal pressure Flow 5:54:25

5:54:55

5:55:25

5:55:55

5:56:25

5:56:55

5:57:25

5:57:55

5:58:25

5:58:55

Figure 48.97  ​Rapid eye movement (REM) sleep behavior disorder. This female patient had a long history of reacting to dream content in which she was being attacked. The patient is in REM sleep and has movements noted in her legs. The blue vertical lines synchronize the top and bottom windows. The top window shows a 30-second epoch, and the bottom window shows a 5-minute epoch.

512  Gallery of Polysomnographic Recordings Cursor: 03:20:42, Epoch: 581 - REM

30 sec/page

EMG1-EMG2 1.02 mV

C3-A2 128 V

C2-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

ECG1-ECG2 2.05 mV

30 sec/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

0

THOR EFFORT 4.1 mV

ABD EFFORT 4.1 mV

Digital Video

120

Close

Pulse bpm

40 75

ETCO2 mm Hg

POSITION

0

BACK LEFT RIGHT PRONE 20

CPAP PRES cm H2O

0

NASAL PRES 500 mV

Figure 48.98  ​Rapid eye movement (REM) sleep behavior disorder. A 53-year-old female patient had a long history of reacting to dream content. Four to five

nights a week she would strike out during dreams about “a bad man who is deformed and ugly” who might be attacking her. On examination of synchronized digital video during this episode of REM sleep, the patient was seen moving her right hand.

Seizures 15 sec/page

Cursor: 23:02:41, Epoch: 15 - STAGE 2

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

422

425

427

430

432 30 sec/page

LEG(L) LEG(R) SaO2

100

%

0

THOR RES x1

ABD RES x1 120

PULSE bpm

40 76

PCO2

mm Hg -4

POSITION CPAP cm H2O

30 2

AIRFLOW 62.5 V

422

425

427

430

432

435

437

440

442

445

447

Figure 48.99  ​Seizure disorder. The spike-and-wave activity lasted about 5 seconds in this epoch and was not associated with any other recorded abnormality. The top window shows a 15-second epoch, and the bottom window shows a 30-second epoch.

Atlas of Clinical Sleep Medicine   513 1 min/page

Cursor: 01:08:45, Epoch: 277 - AWAKE

CHIN(1) 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV 1 min/page

LEG(L) 125 uV

LEG(R) 125 uV

100

SaO2 %

90

ABD RES x8

AIRFLOW 62.5 V

Figure 48.100  ​Seizure disorder. The first episode of central apnea is not associated with apparent seizure activity, but the second one is. The top and bottom windows are 1-minute epochs.

Cursor: 00:56:26, Epoch: 448 - STAGE 2

1 min/page

LOC-A1 ROC-A1 C3-A1 O2-A1 CHIN1-CHIN2 FP1-F7 F7-T3 T3-T5 T5-O1 FP2-F8 F8-T4 T4-T6 T6-O2 FP1-F3 F3-C3 C3-P3 P3-O1 FP2-F4 F4-C4 C4-P3 P3-O2 ECG1-ECG2 RIGHT IC 1-RIGHT IC 2

2

Airflow2

1

2

1 min/page

125 V

THOR 1.02 mV

ABD

1.37 mV 100.0

98

SaO2

99

98

99

98

99

98

99 94

%

80.0

2

1

2

Figure 48.101  ​Seizure disorder. A central apneic episode associated with significant oxygen desaturation is the sole manifestation of the seizure. The true

nature of the event, a right-sided seizure, would not be evident without a full seizure montage. EEG traces refer to the left side, and black lines to the right side. The top and bottom windows are 1-minute epochs. (Courtesy M. Mahowald, MD.)

514  Gallery of Polysomnographic Recordings Cursor: 04:55:41, Epoch: 703 - STAGE 3

LOC-A2 170.7 V

3

3

30 sec/page

ROC-A1 170.7 V

C3-A2

170.7 V

O2-A1

170.7 V

CHIN1-CHIN2 512 V

Fp1-F7 85.3 V

F7-T3 85.3 V

T3-T5 85.3 V

T5-O1 85.3 V

Fp2-F8 85.3 V

F8-T4 85.3 V

T4-T6 85.3 V

T6-O2 85.3 V

Fp1-F3 85.3 V

F3-C3 85.3 V

C3-P3 85.3 V

P3-O1 85.3 V

Fp2-F4 85.3 V

F4-C4 85.3 V

C4-P4 85.3 V

P4-O2 85.3 V

ECG1-ECG2 1.02 mV

Figure 48.102  ​Seizure disorder. Rare, localized spikes over the right anterior temporal region in a patient with nocturnal seizures. Only a few such spikes occurred

during the entire study, underscoring the necessity of personally reviewing each epoch when looking for evidence of spikes. This activity could not have been identified by using the conventional sleep-stage scoring montage. The window shows a 30-second epoch. (Courtesy M. Mahowald, MD.)

Cursor: 04:39:14, Epoch: 942 - NREM 3

E1-M2 125 V

3

3

3

1 min/page

E2-M2 125 V

C3-M2 125 V

O2-M1 125 V

CHIN1-CHIN2 125 V

Fp1-F7 125 V

F7-T3 125 V

T3-T5 125 V

T5-O1 125 V

Fp2-F8 125 V

F8-T4 125 V

T4-T6 125 V

T6-O2 125 V

Fp1-F3 125 V

F3-C3 125 V

C3-P3 125 V

P3-O1 125 V

Fp2-F4 125 V

F4-C4 125 V

C4-P4 125 V

P4-O2 125 V

ECG1-ECG2 2 mV

Figure 48.103  ​Seizure disorder. This is an example of an electrical seizure emanating from the right hemisphere followed by isolated spikes over the same

region. There are no clinical correlates of this electrical seizure, and it could not be identified on the sleep-scoring montage. The tendency is often for the technicians to mark only clinically obvious events, which are often nothing but movement artifact. The true nature of the events is identified only by finding subclinical electrical seizure activity, such as that shown on this epoch. (Courtesy M. Mahowald, MD.)

Atlas of Clinical Sleep Medicine   515 Cursor: 00:13:25, Epoch: 243 - STAGE 3

LOC-A2 128 V

3

3

30 sec/page

ROC-A1 128 V

C3-A2 128 V

O2-A1 128 V

CHIN1-CHIN2 125 V

Fp1-F7 128 V

F7-T3 128 V

T3-T5 128 V

T5-O1 128 V

Fp2-F8 128 V

F8-T4 128 V

T4-T6 128 V

T6-O2 128 V

Fp1-F3 128 V

F3-C3 128 V

C3-P3 128 V

P3-O1 128 V

Fp2-F4 128 V

F4-C4 128 V

C4-P4 128 V

P4-O2 128 V

ECG1-ECG2 2.05 mV

Figure 48.104  ​Seizure disorder. Infrequent periodic spikes emanate from the left midtemporal region (without clinical correlates). Localization would not be possible on the conventional sleep-scoring montage. The window shows a 30-second epoch. (Courtesy M. Mahowald, MD.)

2

Cursor: 04:29:39, Epoch: 945 - AWAKE

W

30 sec/page

E1

250 V

E2-M1 284.4 V

C3-M1 125 V

O2-M1 125 V

CHIN1-CHIN2 500 V

Fp1-F7 125 V

F7-T3 125 V

T3-T5 125 V

T5-O1 125 V

Fp2-F8 125 V

F8-T4 125 V

T4-T6 125 V

T6-O2 125 V

Fp1-F3 125 V

F3-C3 125 V

C3-P3 125 V

P3-O1 125 V

Fp2-F4 125 V

F4-C4 125 V

C4-P4 125 V

P4-O2 125 V

ECG1-ECG2 2 mV

Figure 48.105  ​Seizure disorder. On the conventional sleep-scoring montage, this would appear to be a simple, nonspecific arousal. The electroencephalogram

montage reveals periodic spikes from the right midtemporal region that culminate in an arousal, followed by residual postictal slowing over the same region. This “arousal” was actually the sole clinical manifestation of a focal temporal lobe epileptic discharge. (These may occur hundreds of times per night, resulting in frequent arousals [sleep fragmentation] presenting as excessive daytime sleepiness.) For this reason, it is prudent to use a full seizure montage in all patients with a history of seizures and complaints of excessive daytime sleepiness. If these arousals are associated with extremity movements, an erroneous diagnosis of periodic limb movements during sleep might be made. The window shows a 30-second epoch. (Courtesy M. Mahowald, MD.)

516  Gallery of Polysomnographic Recordings LOC-A2 85.3 V

Cursor: 00:21:57, Epoch: 323 - STAGE 3

3

30 sec/page

ROC-A1 170.7 V

C3-A2

170.7 V

O2-A1

170.7 V

CHIN1-CHIN2 128 V

Fp1-F7 85.3 V

F7-T3 85.3 V

T3-T5 85.3 V

T5-O1 85.3 V

Fp2-F8 85.3 V

F8-T4 85.3 V

T4-T6 85.3 V

T6-O2 85.3 V

Fp1-F3 85.3 V

F3-C3 85.3 V

C3-P3 85.3 V

P3-O1 85.3 V

Fp2-F4 85.3 V

F4-C4 85.3 V

C4-P4 85.3 V

P4-O2 85.3 V

ECG1-ECG2 1.02 mV

Figure 48.106  ​Seizure disorder. These spikes are characteristic of rolandic spikes seen in benign rolandic epilepsy. The spikes are most prominent over the

central and midtemporal regions. They are often only present during non–rapid eye movement sleep, when they may become very active. Clinically, there may be twitching of the mouth on the contralateral side with or without drooling. Occasionally, these usually trivial seizures will generalize. The prognosis is generally very good, with a natural history of spontaneous resolution over time, hence the name benign rolandic epilepsy. The window shows a 15-second epoch. ( Courtesy M. Mahowald, MD.)

Head Trauma Cursor: 00:35:07, Epoch: 302 - STAGE 3

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-2 128 V

ECG1-ECG2 2.05 V

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

90

THOR EFFORT 2.05 mV

ABD EFFORT 2.05 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

0

NASAL PRES 250 mV

Figure 48.107  ​Head trauma in non–rapid eye movement sleep. As a result of head trauma and fractures of his jaw and facial structures, this 57-year-old patient spent 3 years in the hospital for rehabilitation. He had a periodic breathing pattern but no history of snoring. During the sleep study, the patient’s breathing was inaudible.

Atlas of Clinical Sleep Medicine   517 Cursor: 01:15:41, Epoch: 383 - REM

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-2 128 V

ECG1-ECG2 2.05 V

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

90

THOR EFFORT 1.02 mV

ABD EFFORT 8.19 mV

120

Pulse bpm

40 50

ETCO2 mm Hg

0

NASAL PRESS 250 mV

Figure 48.108  ​Head trauma in rapid eye movement sleep (the same patient shown in Fig. 48.107). The breathing pattern now has the configuration of Cheyne-

Stokes breathing, with long central apneic episodes. The patient had an underlying breathing pattern that was slow. During the 5-minute epoch seen in the bottom window, he had fewer than 30 breaths. The top window shows a 15-second epoch, and the bottom window shows a 30-second epoch.

MULTIPLE SCLEROSIS

Cursor: 01:16:13, Epoch: 68 - STAGE 2

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

80

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg -4 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.109  ​Multiple sclerosis. This polysomnogram fragment is taken from a 56-year-old male patient with a 5-year history of multiple sclerosis. His main

symptom was severe daytime sleepiness, but he had gained between 50 and 60 pounds since the diagnosis of multiple sclerosis. During wakefulness, the patient had central apnea; during sleep, shown here, the patient demonstrated mixed apnea episodes. The top window shows a 15-second epoch, and the bottom window shows a 30-second epoch.

518  Gallery of Polysomnographic Recordings Cursor: 13:14:38, Epoch: 303 - REM

CHIN(1)

30 sec/page

250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V

LEG(R)

125 V 100

SaO2 %

80

ABDx4RES 120

PULSE bpm

40 50

PCO

2 mm Hg -4 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.110  ​Multiple sclerosis (the same patient shown in Fig. 48.109). The patient, now in rapid eye movement (REM) sleep, was treated with a bilevel

device, which led to resolution of his mixed apneas. He had a great deal of REM sleep upon starting bilevel treatment. The top window shows a 15-second epoch, and the bottom window shows a 30-second epoch.

ARTIFACTS IN SLEEP RECORDINGS

Cursor: 04:47:48, Epoch: 802 - REM

C3-A2

EMG1-EMG2 1.02 mV

04:47:30

30 sec/page

1 sec/page

C3-A2 128 V

C4-A1

C3-A2 128 V

128 V

Fr3-A2 128 V Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

EC1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 1.64 mV

120

PULSE bpm

40 75

ETCO2 mm Hg

0

POSITION BACK

LEFT RIGHT PRONE

ETCO2 cm H2O

20

0

NASAL PRES 500 mV

Figure 48.111  ​60-Hz interference. Note the obvious broad band of black that appears in four of the channels. Modern data acquisition systems allow the frequency analysis, either visual or numerical, of channels. The inset, which shows 1 second of one of the channels, clearly shows an underlying 60-Hz wave in the channel. This is 60-cycle electrical interference. Lead A2 is the cause because that artifact was found in all channels that include this lead. Figure 48.112 shows ways of dealing with such noise. The top window shows a 30-second epoch.

Atlas of Clinical Sleep Medicine   519 Cursor: 04:47:48, Epoch: 802 - REM

30 sec/page

EMG1-EMG2 1.02 mV

C3-A2 128 V

C4-A1 128 V

Fr3-A2 128 V

Fr4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

EC1-ECG2 2.05 mV

5 min/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

80

THOR EFFORT 1.64 mV

120

PULSE bpm

40 75

ETCO2 mm Hg

0

POSITION BACK LEFT RIGHT PRONE

ETCO2

20

cm H2O

0

NASAL PRES 500 mV

Figure 48.112  ​60-Hz interference corrected. This is the same epoch shown in Figure 48.111, except that the montage has been modified so the A1 lead is used instead of the A2 lead. Digital filters can also be used to remove 60-Hz noise.

Digital Video

CHIN(1) 250 V

Cursor: 22:37:42, Epoch: 31 - STAGE 1

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

100

LEG(L) 125 V LEG(R)

5 min/page

125 V

SaO2

80

%

THOR RES x1

ABD RES x1

120

PULSE bpm

40 40

PCO2

mm Hg

CPAP cm H2O

-4 20 2

AIRFLOW 62.5 V

Figure 48.113  ​Artifacts that affect electroencephalogram (EEG) and respiratory channels. What is the main finding in this epoch? Is it leg movements or sleep apnea? An electrocardiogram artifact appears in all the EEG channels, which sometimes makes scoring for sleep stage difficult. The bottom window shows an artifact that affects both the thoracic and abdominal respiration channels. The leg movements and breathing are very closely linked; leg movements occur precisely during the peak of respiratory effort. Many would interpret this as the apneas causing the movements, but in this situation, examining the synchronized video is helpful. The orange vertical lines synchronize the top window (30-second epoch) and the bottom window (5-minute epoch).

520  Gallery of Polysomnographic Recordings Digital Video

CHIN(1) 250 V

Cursor: 22:37:48, Epoch: 31 - STAGE 1

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

100

LEG(L) 125 V LEG(R) 125 V

SaO2

80

%

THOR RES x1

ABD RES x1

120

PULSE bpm

40 40

PCO2

mm Hg -4 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.114  ​Artifacts that affect electroencephalogram (EEG) and respiratory channels (the same patient shown in Fig. 48.113). The vertical orange lines have moved forward about 5.5 seconds. An arousal has occurred in the EEG channels, and a dramatic movement of the legs is evident in the synchronized digital video. The question remains whether the apneas are causing the movements. The answer comes in the fragment shown in Figure 48.115, after the patient has been placed on continuous positive airway pressure.

Digital Video

CHIN(1) 250 V

Cursor: 04:23:30, Epoch: 723 - STAGE 4

30 sec/page

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V LEG(R)

125 V 100

SaO2 %

80

THOR RES x2

ABD RES x2

120

PULSE bpm

40 40

PCO2

mm Hg -4 20

CPAP cm H2O

2

AIRFLOW 62.5 V

Figure 48.115  ​Artifacts that affect electroencephalogram and respiratory channels (the same patient shown in Figs. 48.113 and 48.114). With the patient

placed on continuous airway pressure (CPAP), the apneas have been abolished, but the movements remain. Note that they still cause an artifact in the thoracic and abdominal channels and that each twitch is associated with a reproducible increase in heart rate, suggesting that subcortical arousals are perhaps occurring. Their significance is unknown. The nasal pressure channel reflects the pressure being delivered by the CPAP machine. The patient is in stage N3 sleep.

Atlas of Clinical Sleep Medicine   521

250 V

30 sec/page

Cursor: 04:40:45, Epoch: 775 - REM

Digital Video

CHIN(1)

Close

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

5 min/page

LEG(L) 125 V LEG(R) 125 V

100

SaO2 %

80

THOR RES x2

ABD RES x4

120

PULSE bpm

40 40

PCO2 mm Hg

CPAP

-4 20

cm H2O

2

AIRFLOW 62.5 V

Figure 48.116  ​Artifacts that affect electroencephalogram (EEG) and respiratory channels (the same patient shown in Figs. 48.113 to 48.115). The patient is now in rapid eye movement sleep. There has been a dramatic decrease in both the leg movements and the artifacts in the thoracic and abdominal channels. The EEG still contains electrocardiogram artifact. Note the regular movements in the two eye channels. This patient has both obstructive sleep apnea and periodic limb movements during sleep.

CH1-CH2 250 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 mV

815

815

815

815

815

815

816

816

816

816

816

816

815

815

815

815

815

815

816

816

816

816

816

816

LEG(L) 125 V

LEG(R)

125 V 100

SaO2 %

85

THOR RES x5

ABD RES x5

120

PULSE bpm

40 76

P

CO2 mm Hg -4

FLOW 10 V

Figure 48.117  ​Cardiac artifact in an electroencephalogram (EEG). Two types of cardiac artifacts may be observed in the EEG; one is caused by the transmission

of electrical waves from the electrocardiogram to the EEG (see Fig. 48.116), whereas the other is related to, or caused by, a beating heart. Here, three of the EEG channels have a high-amplitude sinusoidal wave embedded in them. These waves are exactly synchronous with the heartbeat. In addition, examination reveals that the three channels have something in common: an A1 electrode as one of the pair. Figure 48.118 shows how this is remedied. The top and bottom windows are 30-second epochs.

522  Gallery of Polysomnographic Recordings CH1-CH2 250 V

C3-A2 125 V

C4-A2 125 V

O1-A2 125 V

O2-A2 125 V

ROC-A2 125 V

LOC-A2 125 V

ECG

1.25 mV 815

815

815

815

815

815

816

816

816

816

816

816

815

815

815

815

815

815

816

816

816

816

816

816

LEG(L) 125 V

LEG(R) 125 V

SaO2

100

%

85

THOR RES x5

ABD RES x5

120

PULSE bpm

40 76

PCO2

mm Hg -4

FLOW 10 V

Figure 48.118  ​Cardiac artifact in electroencephalogram rectified (the same epoch shown in Fig. 48.117). Modern computer systems allow the user to digitally

re-reference electrode pairs. By removing A1 from the montage and using A2 instead, the problem has been solved. Presumably the original artifact was caused by motion that affected the A1 electrode. The window shows a 30-second epoch.

4772

4775

4777

4780

4782

4785

4787

4790

4792

4795

4797

4772

4775

4777

4780

4782

4785

4787

4790

4792

4795

4797

Figure 48.119  ​When an artifact helps make a diagnosis. Here, a very high-amplitude, low-frequency wave is superimposed on all the electroencephalogram

channels. Clearly the high-amplitude deflections are synchronous with breathing. The technician might call this a sweat artifact, but it is really a breathing artifact in a sweaty patient. This patient did indeed have severe night sweats, and the electrocardiogram showed atrial fibrillation. Based on the clues presented in this polysomnogram fragment, the patient was evaluated for hyperthyroidism, and the diagnosis was confirmed. The window shows a 30-second epoch.

Atlas of Clinical Sleep Medicine   523 Cursor: 10:44:40, Epoch: 20 - STAGE 1

EMG1-EMG2

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

EC1-ECG2 1.02 mV

30 sec/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

70

THOR EFFORT 2.05 mV

ABD EFFORT 4.1 mV

120

PULSE bpm

40 75

ETCO2 mm Hg

0

CPAP PRES20 cm H2O

0

NASAL PRES 250 mV

Figure 48.120  ​Eye channel artifacts. Scoring technicians most often have no contact with the patient whose study they are scoring. Nighttime technicians are often too busy to evaluate findings that are abnormal and therefore may attribute them to artifact. Here, at the beginning of the night, a low-frequency oscillation in the left eye channel was dismissed, probably as a breathing artifact.

EMG1-EMG2

Cursor: 14:21:40, Epoch: 454 - REM

30 sec/page

1.02 mV

C3-A2 128 V

C4-A1 128 V

O1-A2 128 V

O2-A1 128 V

ROC-A1 128 V

LOC-A2 128 V

EC1-ECG2 1.02 mV

30 sec/page

LAT-LAT512 V

RAT-RAT512 V

100

SaO2 %

THOR EFFORT

70

1.02 mV

ABD EFFORT 2.05 mV

120

PULSE bpm

40 75

ETCO2 mm Hg

0

CPAP PRES 20 cm H2O

0

NASAL PRES 250 mV

Figure 48.121  ​Eye channel artifacts (the same patient shown in Fig. 48.120). The patient was originally scored as having no rapid eye movement sleep. The

eye movements in the left eye channel were interpreted as being artifacts. The clinician who evaluated the patient later that morning examined the patient’s extraocular movements, shown in Figure 48.122.

524  Gallery of Polysomnographic Recordings

A

B

Figure 48.122  ​Eye channel artifacts (the same patient shown in Figs. 48.120 and 48.121). A, When the patient looked straight ahead, everything seemed normal.

B, When he was asked to look to his right, only his right eye moved. What is going on, and how did this affect the eye channels the previous night? The patient had a glass eye in the left eye socket. The electrooculogram channel was detecting only the movements of the right eye. Figure 48.121 actually does show rapid eye movement sleep. The night technician had also mixed up the right and left eye channels and was actually recording movements of the right eye.

Cursor: 10:37:20, Epoch: 28 - STAGE 2

CHIN(1)

30 sec/page

250 uV

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG 2.5 mV

30 sec/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

90

THOR RES x16

ABD RES x10

120

PULSE bpm

40 50

PCO2 mm Hg 0

AIRFLOW 62.5 V

Figure 48.123  ​Recording artifact in both leg channels. An artifact-free leg movement recording could not be attained in this patient. She had massive periph-

eral edema related to right heart failure, with about 2 cm of edema fluid between the recording electrode and the anterior tibialis muscle. The electromyogram (EMG) channels were not recording EMG but rather electrical noise.

Atlas of Clinical Sleep Medicine   525 30 sec/page

Cursor: 23:18:21, Epoch: 106 - STAGE 4

CHIN(1) 125 V

C3-A2 125 V

C4-A1 125 V

O1-A2 125 V

O2-A1 125 V

ROC-A1 125 V

LOC-A2 125 V

ECG

1.25 mV 30 sec/page

LEG(L) 125 V

LEG(R) 125 V

100

SaO2 %

70

THOR RES x1

ABD RES x1

120

PULSE bpm

40 50

PCO2 mm Hg 0

AIRFLOW 62.5 V

Figure 48.124  ​Periodic artifact in the chin electromyogram (EMG) and in the electrocardiogram (ECG). High-frequency noise is present with regular periodicity

in both the chin EMG and the ECG. The noise is clearly linked to the patient’s breathing and is actually being caused by snoring. The top and bottom windows are 30-second epochs.

30s

Fp2-F8 F8-T4 T4-T6 T6-O2 F4-M1 C4-M1 O2-M1 Fp1-F7 F7-T3 T3-T5 T5-O1 F3-M2 C3-M2 O1-M2 E2-M1 E1-M1 CHIN1 CHIN2 ECG R-R RLeg LLeg SNORE THOR ABD SaO2 (%)

66

97

97

68

97

69

66

97

65

97

62

97

62

97

65

97

65

97

62

97

62

97

62

97

61

97

63

97

66

66

61

58

60

97

98

98

98

98

67

98

68

98

67

66

98

64

98

63

97

63

97

81

64

97

97

SEIZURE?

62

97

97

Figure 48.125  ​A seizure? On observing the high-amplitude activity and electrocardiogram (EEG) channels at the end of this epoch, the technician scored the

event as a seizure. Synchronized digital video showed that the patient was simply scratching himself at that time. The technician should always view the synchronized digital video when such a finding is made. Note also the electrocardiogram artifact in most of the EEG channels. The window shows a 30-second epoch.

Chapter

49

Gallery of Patient Interview Videos Meir H. Kryger

The video clips referred to in this chapter are interviews of patients with sleep disorders and are available at the Atlas of Clinical Sleep Medicine collection at eBooks.Health.Elsevier.com. SLEEP-RELATED BREATHING DISORDERS An 8-Year-Old Male Patient With Sleep Apnea (Video 49.1) This boy had a strong family history of sleep apnea and was treated with continuous positive airway pressure (CPAP). He had cardiovascular complications of obstructive sleep apnea.

A 43-Year-Old Female Patient With Down Syndrome (Video 49.3) This woman with Down syndrome had sleep apnea.

An 82-Year-Old Female Patient With Sleep Apnea (Video 49.2) This woman had been on CPAP for 13 years.

Apnea With Cardiovascular Comorbidities (Video 49.4) This patient had heart failure and hypertension resistant to drug therapy that resolved with treatment of his sleep breathing disorder.

526

Atlas of Clinical Sleep Medicine   527

Apnea Presenting as Restless Sleep (Video 49.5) This patient’s chief complaint was restless sleep and frequent awakenings. He also had difficulty walking because of osteoarthritis caused by his weight.

Explaining the Results (Video 49.7) The patient must understand the results of the sleep test. An effective way of accomplishing that is to show the patient the actual study and the synchronized digital video. This is often a “teachable moment” that can have a great effect on the patient but also is likely to improve CPAP compliance and motivate the patient to deal with comorbidities.

Apnea in a Truck Driver (Video 49.6) Sleepiness can be particularly dangerous in a truck driver. The patient recounts some near misses while driving.

Teaching and CPAP Mask Fitting (Video 49.8) Once a patient is diagnosed with sleep apnea, a critical aspect of management is to ensure proper teaching about and fitting of the CPAP mask. If unsuccessful, the patient may become noncompliant and will not benefit from treatment. This patient was apprehensive during the teaching about her mask.

528  Gallery of Patient Interview Videos NEUROLOGIC AND OTHER DISORDERS Undiagnosed Narcolepsy Patient With Cataplexy (Video 49.9) This young woman was evaluated for the first time for her sleep complaints and was found to have type 1 narcolepsy with prominent cataplexy symptoms.

Hallucinations in a Male Narcolepsy Patient (Video 49.11) Vivid hypnagogic hallucinations and dream imagery are common in narcolepsy. Some patients may have the perception that they are floating out of their bodies. This patient had almost all of the symptoms of narcolepsy.

Thirty-Five Years of Undiagnosed Narcolepsy (Video 49.10) Patients with classic narcolepsy frequently go undiagnosed for decades, as did this patient.

Narcolepsy Patient With Sleep Apnea (Video 49.12) This patient was referred for evaluation because of suspected obstructive sleep apnea. The history revealed some classic narcolepsy symptoms.

Atlas of Clinical Sleep Medicine   529 Restless Legs Syndrome in a Male Patient (Video 49.13) Restless legs syndrome is common and found in all age groups. This young adult male is French Canadian; the disorder is common in this population.

REM Sleep Behavior Disorder (Video 49.15) Rapid eye movement (REM) sleep behavior disorder can be terrifying. It is a sleep disorder in which the reaction to a dream can result in harm to the patient’s bed partner.

Middle-Aged Female Patient With Restless Legs Syndrome (Video 49.14) Different people use different terms to discuss the sensation of restless legs. This patient said it felt like insects were crawling under her skin.

Parkinson Disease With REM Sleep Behavior Disorder and Sleep Apnea (Video 49.16) This patient with Parkinson disease had several common sleep complications, including REM sleep behavior disorder and sleep apnea.

530  Gallery of Patient Interview Videos Multiple Sclerosis, Sleep Apnea, and Hypnagogic Hallucinations (Video 49.17) This patient had multiple sclerosis and developed central apnea that required treatment. He also had features of narcolepsy.

Syringomyelia (Video 49.19) In this patient, the syrinx affected the brainstem. Affected were the structures that control breathing and the centers involved in REM sleep as well as the motor pathways that control the legs.

Arnold-Chiari Malformation (Video 49.18) Patients with Arnold-Chiari malformation may have abnormal control of breathing and may develop sleep apnea.

Becker Muscular Dystrophy (Video 49.20) Muscular dystrophies may be associated with sleep apnea, as in this patient with Becker muscular dystrophy.

Psychiatric Disorders (Video 49.21) Psychiatric disorders and their treatment may result in sleep problems. Hypnagogic hallucinations—associated with sleep apnea in this patient—differ from psychotic delusions; both may be present in the same patient.

Chapter

Gallery of Sleep Laboratory Video Findings

50

Meir H. Kryger

This chapter contains examples of video findings obtained in a typical sleep medicine clinic polysomnography laboratory. They are grouped into categories. Most modern sleep laboratory acquisition systems allow the collection of synchronized digital videos. The videos can be played back in real time, or they can be sped up. Video clips referred to here were obtained during sleep studies of patients with sleep disorders and are available at the Atlas of Clinical Sleep Medicine collection at eBooks.Health.Elsevier.com. OBSTRUCTIVE SLEEP APNEA Apnea, Restlessness in a Child This 12-year-old male patient came to medical attention with restless sleep, a common presentation of sleep apnea in children of all ages. The restlessness is often present the entire night (Video 50.1).

Nasal Obstruction and Apnea This patient had been a boxer, had his nose fractured several times, and could not breathe through his nasal airway. During sleep, he demonstrated periods of silence, noisy breathing, and restlessness (Video 50.2).

531

532  Gallery of Sleep Laboratory Video Findings Arousal Threshold to Noise in Obstructive Sleep Apnea This patient with sleep apnea was snoring loudly and sleeping on his side when a fire alarm went off. The patient did not arouse or awaken in response to the noise (Video 50.3).

Obstructive Sleep Apnea, Violent Body Movements (310) In the same patient shown in Video 50.4, the video has been sped up by a factor of 10 to better show the frequency and vigor of the movements (Video 50.5).

10

Obstructive Sleep Apnea, Violent Body Movements Excessive body movements linked to episodes of apnea are evident in this patient with obstructive sleep apnea (OSA) (Video 50.4).

Atypical Snoring After Uvulopalatopharyngoplasty This patient had undergone a uvulopalatopharyngoplasty, which removed part of the soft palate. The patient continued to have sleep apnea, but the snoring noises were atypical and were quite different than those observed preoperatively (Video 50.6).

Atlas of Clinical Sleep Medicine   533 Vigorous Movements in Obstructive Sleep Apnea (310) In many patients with sleep apnea, vigorous movements are often associated with the apnea. These sometimes result in the patient being diagnosed as having periodic limb movement disorder (PLMD) or periodic limb movements during sleep (PLMS). These movements often resolve with treatment. This video has been sped up by a factor of 10 (Video 50.7).

10

OBSTRUCTIVE SLEEP APNEA IN SPECIAL POPULATIONS

Obesity Hypoventilation This patient had obesity hypoventilation syndrome and evidence of both OSA and hypoventilation (Video 50.8).

Obesity Hypoventilation, Heart Failure The same patient shown in Video 50.8 also had features of severe right-sided heart failure with massive peripheral edema. When he hypoventilated, he was relatively quiet. When obstructed, he demonstrated chest wall abdominal paradox and then loud snoring (Video 50.9).

534  Gallery of Sleep Laboratory Video Findings Obesity Hypoventilation, Treated The same patient shown in Videos 50.8 and 50.9 was treated with bilevel pressure and had an excellent response (Video 50.10).

Obesity Hypoventilation, Polysomnography with Synchronized Digital Video Annotated polysomnographic recording of a patient who had obesity hypoventilation with video showing key diagnostic features of an elevated transcutaneous Pco2 (see Video 50.10A).

Atlas of Clinical Sleep Medicine   535 Obstructive Sleep Apnea in Pregnancy This pregnant patient had severe OSA related to obesity. She had a very high breathing frequency that was especially noticeable during unobstructed breathing (Video 50.11).

Apnea in Acromegaly This 71-year-old female patient had acromegaly, with abnormalities in her jaw structure and an enlarged tongue. Stridor was noted (Video 50.14).

Postpartum Obstructive Sleep Apnea This patient was 4 months postpartum and had difficulty caring for her new baby. She had had undiagnosed sleep apnea for years. A previous pregnancy ended with a miscarriage (Video 50.12).

Apnea in Acromegaly (310) In the same patient shown in Video 50.14, the video has been sped up by a factor of 10 to show the marked movements of the jaw during sleep (Video 50.15).

10

Postpartum Obstructive Sleep Apnea, Treated The same patient shown in Video 50.12 is on continuous positive airway pressure (CPAP) and sleeps with her mouth closed. The CPAP is much quieter than her snoring (Video 50.13).

Apnea and Down Syndrome Sleep apnea is common in children and adults with Down syndrome (Video 50.16).

536  Gallery of Sleep Laboratory Video Findings UPPER AIRWAY RESISTANCE SYNDROME Upper Airway Resistance Syndrome, Quiet Snoring This female patient has upper airway resistance syndrome (UARS). Note the initially quiet and high-pitched snoring noises. At 1 minute, 10 seconds she closes her mouth and moves her head to reestablish breathing. When the patient breathes through her mouth, the nasal sensor does not detect the breaths (Video 50.17).

Upper Airway Resistance Syndrome, Variable Snoring This patient had UARS and snoring with different sounds. The sensor over the patient’s mouth is likely to miss when he breathes through his mouth. Note that he reestablishes unobstructed breathing at the end of the clip (Video 50.19).

Upper Airway Resistance Syndrome, Quiet Snoring (37) In the same patient shown in Video 50.17, the video has been sped up by a factor of 7. Note the jaw movements at the beginning and the end of the clip and that she closes her mouth to reestablish breathing (Video 50.18).

Upper Airway Resistance Syndrome, Variable Snoring (35) In the same patient shown in Video 50.19, the video has been sped up by a factor of 5. At such high speed, the movements of the mouth and jaw become apparent (Video 50.20).

7

35

Atlas of Clinical Sleep Medicine   537 CENTRAL SLEEP APNEA AND CHEYNE-STOKES RESPIRATION

Idiopathic Central Apnea This young male patient had idiopathic central apnea. During apnea, there is virtually no effort to breathe. At apnea termination, there is sometimes a snort (Video 50.21).

Obstructive Sleep Apnea and Cheyne-Stokes Breathing This patient with OSA developed heart failure, which led to Cheyne-Stokes breathing. Thus the patient had evidence of two types of abnormal breathing patterns and pathology (Video 50.24).

Retinitis Pigmentosa, Central Apnea An older male patient with retinitis pigmentosa had severe central apnea. There is little effort to breathe during the episodes (Video 50.22).

Pulmonary Edema This patient has OSA and pulmonary edema caused by left heart failure. He had Cheyne-Stokes breathing while awake and asleep. The loud gurgling noises are caused by the edema fluid (Video 50.25).

Central Apnea, Obesity An obese man with symptoms of obstructive apnea was found to have primarily central apnea. Note the deep, unobstructed breaths after apnea termination (Video 50.23).

538  Gallery of Sleep Laboratory Video Findings RESPIRATORY DISEASES Asthma Patients with asthma wheeze on expiration. This obese patient with asthma made loud inspiratory snoring noises and higher-pitched expiratory wheezing sounds (Video 50.26).

Chronic Obstructive Pulmonary Disease, Upper Airway Obstruction This is the same patient shown in Video 50.27. Here the sounds are inspiratory and result from the upper airway obstruction (Video 50.28).

Chronic Obstructive Pulmonary Disease This patient with chronic obstructive pulmonary disease (COPD) made loud sounds on expiration; these were attributable to his lung disease but could be confused with inspiratory snoring (Video 50.27).

Chronic Obstructive Pulmonary Disease, Airway Secretions, Periodic Limb Movement Disorder This patient with COPD had poor-quality sleep because of secretions in her airways that made her breathing noisy. She also has PLMD (Video 50.29).

Atlas of Clinical Sleep Medicine   539 Chronic Obstructive Pulmonary Disease, Airway Secretions, Periodic Limb Movements During Sleep (310) In the same patient shown in Video 50.29, the clip has been sped up by a factor of 10 to make the periodic limb movements more apparent. Note the patient’s feet beneath the cover (Video 50.30).

Overlap Syndrome, Treated This is the same patient shown in Video 50.31 treated with bilevel positive airway pressure (BiPAP) and oxygen. The machine generating the pressure changes is audible in the video (Video 50.32).

310

Overlap Syndrome This patient has overlap syndrome, a combination of COPD and OSA. This video shows the patient hypoventilating during rapid eye movement (REM) sleep. Toward the end of the clip, the upper airway obstruction becomes more apparent (Video 50.31).

Pulmonary Fibrosis This patient has severe interstitial pulmonary fibrosis caused by rheumatoid lung disease. This video shows severe dyspnea, and the patient had difficulty achieving persistent sleep (Video 50.33).

540  Gallery of Sleep Laboratory Video Findings NEUROLOGIC AND OTHER DISORDERS Restless Legs Syndrome, Insomnia This patient had sleepiness and obesity, which were believed to be caused by sleep apnea. Her main problem was severe restless legs syndrome (RLS), which led to her being awake for much of the night (Video 50.34).

Restless Legs Syndrome, Sleep Apnea The irresistible urge to move the legs and the onset of obstructed breathing caused sleep-onset insomnia in this patient (Video 50.36).

Restless Legs Syndrome and Periodic Limb Movements During Sleep (325) This patient with RLS was originally referred for sleep apnea. Her problem was a movement disorder caused by iron deficiency (her ferritin level was 12 ng/mL). Note that she keeps her feet exposed in this video, which is sped up by a factor of 25 to show the PLMS (Video 50.35).

Restless Legs Syndrome, Sleep Apnea (310) In the same patient shown in Video 50.36, the video has been sped up by a factor of 10 to emphasize the frequency and severity of the movements (Video 50.37).

325

310

Atlas of Clinical Sleep Medicine   541 Periodic Limb Movement Disorder, Apnea (310) This video shows PLMD masquerading as sleep apnea. The patient had frequent movements that resulted in overbreathing followed by apnea. This video has been sped up by a factor of 10 (Video 50.38).

310

Periodic Limb Movement Disorder, Subtle Movements (310) In the same patient shown in Video 50.38, the video has been sped up by a factor of 10 to show more subtle leg movements (Video 50.39).

310

Rapid Eye Movement Sleep Behavior Disorder This patient had REM sleep behavior disorder (RBD). At times, the movements during REM can be subtle, as in this study. This is REM sleep. Note the movement of the right hand toward the end of the clip (Video 50.40).

542  Gallery of Sleep Laboratory Video Findings Rapid Eye Movement Sleep Behavior Disorder, Loud Vocalization This patient had severe RBD. This video shows REM sleep. The patient had multiple episodes during the night. Facial features have been blurred (see Video 50.40A).

A

Non–Rapid Eye Movement Parasomnia, Confusional Arousal, Loud Vocalization This patient had episodes of confusion, yelling, and screaming coming abruptly out of N3 sleep. He also had episodes of sleep terrors. The patient had these episodes almost every night. Facial features have been blurred (see Video 50.40B).

B

Atlas of Clinical Sleep Medicine   543 Rapid Eye Movement Sleep Behavior Disorder, Obstructive Sleep Apnea This patient had OSA and was being treated with CPAP. This treatment, which restores more normal sleep and more of stages R and N3 sleep, may unmask parasomnia. This patient developed RBD on CPAP (Video 50.41).

Delayed Sleep Phase Syndrome This is a time-lapse video of the entire night of a patient referred for severe sleep-onset insomnia. Note the activities during the night, including watching a movie on a laptop. Once asleep, all findings were normal (Video 50.43).

Sleep Paralysis Sleep paralysis in a patient without narcolepsy. The patient recalled trying to call the technician, but only a moan was heard. REM was present throughout this segment (Video 50.42).

Epilepsy This patient had two seizures during the night. One occurred at approximately 12:29 am, and the other occurred at about 2:15 am (Video 50.44).

544  Gallery of Sleep Laboratory Video Findings Seizure Involving the Leg This patient had a history of seizures. During a multiple sleep latency test, she had a seizure that resulted in movement of only her right leg (Video 50.45).

Psychogenic “Seizures” (x5) This patient presented with “seizures” during sleep. This video is sped up to emphasize the movements. This patient had psychiatric problems, and it was concluded that she was simulating seizures. She was awake during this clip (Video 50.46).

Psychogenic “Seizures,” Edge Enhanced In the same patient shown in Video 50.46, the video is modified to show additional detail. Note that she straightens her hair at times during the seizure (Video 50.47).

Index

Page numbers followed by “f ” indicate figures, those followed by “t” indicate tables, and those followed by “b” indicate boxes.

A

AASM. See American Academy of Sleep Medicine Abdomen, in sleep apnea, 312, 312f, 313f Acromegaly, 374 clinical features of, 374b diagnosis of, 376 with obstructive sleep apnea, 468f sleep apnea in, sleep laboratory video on, 535, 535f treatment of, 376 Actigraphy, 409, 460, 461f Activation synthesis theory of dream generation, 131f Active sleep, 453 Acute inflammatory demyelinating polyneuropathy, sleep disturbances in, 273t Adams, Laurie Schneider, 3–4 Adaptation theory, in normal sleep in humans, 83 Adaptive servoventilation (ASV), for idiopathic central sleep apnea, 480f, 481f Adderall (dextroamphetamine/amphetamine), in wakefulness promotion, 143t Adenosine abnormalities in restless legs syndrome, 213 in sleep drive, 26f, 30f, 31f, 32f, 35f Adenotonsillectomy, 344 Adipokines, sleep and, 69–70 Adolescent(s) impact of sleep problems on, 148b sleep apnea in. See Sleep apnea sleep-disordered breathing in, 317 continuous positive airway pressure titration for, 322f, 331f, 332f craniofacial anomalies and, 328f Down syndrome and, 329f late-onset laryngomalacia and, 328f neuromuscular disease and, 329f obesity and, 329f prematurity and, 317, 330f sleep in, 113f Adrenocorticotropic hormone, hypersecretion of, 377–378 clinical findings of, 377, 378f diagnosis of, 377 pathophysiology of, 377, 377f treatment of, 377–378 Adults, sleep apnea in, 314–337. See also Sleep apnea Advanced liver disease, sleep disturbance in, 380–381, 380f, 381f, 382f, 383f Advanced sleep-wake phase disorder (ASWPD), 116f, 163, 163f, 167t Age human sleep and, 110f sleep changes related to, 109f histograms of, 107f neurophysiologic mechanisms of, 115 sleep stages changes with, 96–115, 110f, 453 variables that increase or decrease, 114t Aging growth hormone secretion and, 73, 74f immune, sleep and, 55f sleep and, 115f sleep changes with, 109f, 115 sleep efficiency with, 114f

Agrypnia excitata, 266–267, 267f AHI. See Apnea-hypopnea index Airway secretions, chronic obstructive pulmonary disease and, sleep laboratory video on, 538, 538f, 539f Alcohol dependence (AUD), sleep and, 402 Alpha 2 delta (a2d) ligands, for restless legs syndrome, 218t Alpha-delta sleep, in chronic fatigue syndrome, 434, 435f Alprazolam, for sleep promotion, 134t Alveolar plateau, 339 Alzheimer disease, 261–263 sleep and, 51–52, 55f sleep symptoms of, 263f treatment for, 262–263, 263b American Academy of Sleep Medicine (AASM) historical background on, 16 in polysomnography standardization, 438 American Psychiatric Association (APA), 175 American Sleep Disorders Association (ASDA), 16 Amphetamines, for central nervous system hypersomnias, 203–204t Amyotrophic lateral sclerosis (ALS), sleep disturbances in, 272, 273t Anacin PM (diphenhydramine in combination), for sleep promotion, 140t Angina, nocturnal, 64, 67t Animals sleep postures in, 101f sleep time in, 78–79, 78f, 79f Anterior horn cell diseases, 273t Anticonvulsants, effects on sleep, 250t Antidepressants sedating, for sleep promotion, 139–140, 140f Antipsychotics atypical, for sleep promotion, 140, 140t Anxiety, sleep disturbance and, 411 Apnea, 315–316. See also Sleep apnea Apnea-hypopnea index (AHI) after stroke, 255 menstrual cycle and, 422, 422f Appetite, sleep deprivation and, 75 APSS. See Association for the Psychophysiological Study of Sleep Arbilla, Sonia, 17 Aristotle, 10, 11f Arnold-Chiari malformation, patient interview video on, 530, 530f Arousal(s) cortical, 23, 26f EEG speeding and, in arousal scoring, 443 neurologic basis for, historical background on, 14 respiratory effort-related, 315–316, 317f during wakefulness, 22 Arousal disorder, 285–288 sleepwalking as, 285, 289f comorbid condition with, 286, 291b confusional arousal as, 285, 287f, 288f sleep terrors as, 285, 290f, 291f Arousal scoring, 443–444 cyclic alternating patterns in, 444, 444f, 445f EEG speeding and CNS arousals in, 443 Arousal systems, 22, 23f, 24f

Arousal threshold, 60f to noise, in obstructive sleep apnea, sleep laboratory video on, 532, 532f Arrhythmia. See Cardiac arrhythmia Art, sleep in, 1–9, 1f Arterial blood pressure, during sleep, 64, 65, 66f Ascending reticular activating system, 187–191 ASDA. See American Sleep Disorders Association Aserinsky, Eugene, 14 Association for the Psychophysiological Study of Sleep (APSS), 14 Asthma in overlap syndrome, 348 sleep laboratory video on, 538, 538f ASWPD. See Advanced sleep-wake phase disorder Asystole, in sleep apnea, 17f Athlete Sleep Behavior Questionnaire (ASBQ), 124, 125f Athlete Sleep Screening Questionnaire (ASSQ), 124, 125f Athletes disordered sleep in, 124, 124f, 129t screening, populations for sleep problems, 124 Athletic performance, sleep and, 124–130 addressing the needs, 130f, 129t, 127–129 disordered, 124, 124f, 129t educational materials provided to student, 130f insomnia and other sleep disorders, 126 obstructive sleep apnea, 126, 128f overscheduling and overtraining, 124–126, 126f Atomoxetine (Strattera) for central nervous system hypersomnias, 203–204t in wakefulness promotion, 143t Atonia, REM sleep, pathways of, REM sleep and, 100f Atrial fibrillation(s) with congestive heart failure, Cheyne-Stokes respirations and, 321f, 496f, 497f in obstructive sleep apnea, 495f stroke risk and, 254 Autoimmune conditions, sleep and, 51–52 Autosomal dominant nocturnal frontal lobe epilepsy, 235 Autosomal dominant sleep-related hypermotor epilepsy (ADSHE), 235 Awake state. See Wakefulness

B

Babiloni, Herrero, 410–411 Banging, in sleep-related rhythmic movement disorder, 225 Banking sleep, 117 Barbituric acid, discovery of, 11 Bass, Joe, 21 BAT. See Brown adipose tissue Becker muscular dystrophy, 506f patient interview video on, 530, 530f Behavioral interventions, for CNS hypersomnias, 202–205

545

546  Index Benzer, Seymour, 15 Benzodiazepine receptor agonists (BRAs), for insomnia, 183, 183t Benzodiazepines binding of, to GABA receptor, 136f historical background on, 14 Berger, Hans, 13 Berlin Apnea Questionnaire, 158, 159f Bilevel positive airway pressure (BiPAP) for central sleep apnea, 480f for heart failure with obstructive apnea while awake, 491f with obstructive sleep apnea, 491f Biobloc orthotropic therapy (BBO), 345–346 Biot's respirations, 316, 320f BiPAP. See Bilevel positive airway pressure Bipolar disorder, sleep and, 400 Blood flow coronary, in sleep, 64, 65f in REM sleep, 42f Blood pressure elevated, from obstructive sleep apnea, 362, 362f during sleep, 64, 65, 66f Body mass index (BMI), in clinical evaluation of sleep-disordered breathing, 156 Body rocking, in sleep-related rhythmic movement disorder, 225 Bonnard, Pierre, 3, 3f Botticelli, Sandro, 1–2, 2f Bradyarrhythmia, in REM sleep, 42f Brain activity of, in sleep staging, 438. See also Electroencephalography in control of sleep-wakefulness transition, 88 in dream experience, 131–132, 131f lesions of, causing loss of dreaming, 131, 131f regions of, of interest to neurobiology of sleep, 99f Brain-derived neurotrophic factor, sleep and, 54t Brain injury, traumatic, sleep disorder in, 268–269 Brainstem in arousal and sleep induction, 95f in interactive regulation of sleep and feeding, 68 BRAs. See Benzodiazepine receptor agonists Breath-by-breath response, during sleep, 41f Breathing central, 56f control of, 56–63 in normal sleep, 56, 56f, 57f, 58f, 59f patterns of, after stroke, 251, 251t in sleep apnea, 56, 60f, 61–62f, 61f, 63f modulators of, 57f overview, 56f periodic. See Cheyne-Stokes respirations during sleep, 40–42, 41f, 46f Breathing artifacts, on EEG, 519f, 520f, 521f Breathing disorders, sleep, in children, 338–347 Bremer, Frédéric, 24f Bright light exposure for delayed sleep-wake phase disorder, 162–163 for shift-work disorder, 165 Bromocriptine, for growth hormone hypersecretion, 376 Broughton, Roger, 15, 15f Brown adipose tissue (BAT), in interactive regulation of sleep and feeding, 70 Bruxism, 220–222 biology and pathophysiology of, 222 clinical significance of, 220–222, 222f evaluation of, 222, 223f, 224f treatment of, 222 BTBD9 polymorphism, historical background on, 20–21 Burwell, Sydney, 14, 14f

C

Caffeine, for wakefulness promotion, 145, 146f Cancer, circadian desynchrony and, 172–174, 174f CAP. See Cyclic alternating pattern Caravaggio, 4, 4f Cardiac arrhythmia(s) atrial fibrillation as. See Atrial fibrillation due to obstructive sleep apnea, 252f, 358, 360f, 361f from heart blocks, 498f Mobitz second degree, 476f, 499f third degree, 499f Wenckebach second-degree, 498f irregular rhythm and escape beats as, in heart failure, 497f in obstructive sleep apnea, 495f premature ventricular contractions as, 500f sinus arrest and junctional escape rhythm as, 494f upper airway resistance syndrome causing, 476f ventricular tachycardia as, 501f in heart failure, 502f Cardiac events, nocturnal, physiologic mechanisms underlying, 65, 67t Cardiac rhythm abnormalities, 494 Cardiopulmonary recorders, in home sleep testing, 450 Cardiorespiratory synchronization, 40–42, 46f, 47f, 48f Cardiovascular comorbidities, with sleep apnea, patient interview video on, 526, 526f Cardiovascular disease(s), 357–368 cardiac arrhythmia, 358, 360f, 361f circadian desynchrony and, 168–169, 169f coronary artery disease, 360, 361f heart failure as, 363. See also Heart failure impact of, 357, 357f systemic hypertension, 358f, 361–363, 362f, 363f Cardiovascular system COVID-19 and, 416 physiology of central and autonomic regulation in, 64–67, 64f, 65f effect of sleep disorders on, 357–358, 357f, 358f, 359f Carskadon, Mary, 16, 17f Cataplexy, 185–186, 187f, 188–189f, 190f, 191f narcolepsy with, 152, 152t, 153f patient interview video on, 528, 528f Caton, Richard, 12 Cauter, Eve Van, 19, 20f CBT. See Core body temperature Centers for Disease Control and Prevention, 21 Central nervous system hypersomnias, 185 Central pattern generators (CPGs), parasomnias and, 285 Central retinal artery, 405f Central retinal vein, 405f Central sleep apnea (CSA), 314 in adolescent, prematurity and, 317, 330f with Cheyne-Stokes respirations, 445 in chronic kidney disease, 391–393 diagnosis of, 393, 394f pathophysiology of, 391–393, 394f treatment for, 393 control of breathing in, 61–62f, 63f definitions of, 340, 445 polysomnography of, 477 scoring of respiratory events in, 320f scoring rules for, 445–447, 446f sleep laboratory video on, 537 idiopathic, 537, 537f obesity with, 537, 537f pulmonary edema and, 537, 537f retinitis pigmentosa with, 537, 537f

Cerebrospinal fluid hypocretin measurement, in narcolepsy diagnosis, 201 Cerebrovascular accidents. See Stroke Cerebrovascular disease sleep and, 251–257 stroke as. See Stroke Cesarean delivery, sleep and, 427, 428t Cetacean sleep, 80f Chest sweating, in sleep, 41f Chest wall disorders, sleep disturbances in, 277, 277f Cheyne, John, 11 Cheyne-Stokes respirations (CSRs), 251, 252f, 316, 321f in central sleep apnea, 445, 446f with congestive heart failure atrial fibrillation and, 496f, 497f cardiogenic oscillations, while awake and, 485f in child, 486f, 487f and multiple abnormalities, 489f, 490f and ventricular tachycardia, 501f while asleep, 488f while awake, 484f, 485f with heart failure historical background on, 13, 13f polysomnography of, 321f insomnia and, 180f sleep laboratory video on, 537 obstructive sleep apnea and, 537, 537f with systolic heart failure, 364 CHF. See Congestive heart failure Child(ren) congestive heart failure in, 486f, 487f obstructive sleep apnea in, 338, 339f, 464f, 465f common physical examination findings, 339 diagnostic considerations, 343, 344f, 345f historical symptoms of, 339 technical considerations, 339–340, 340f treatment options for, 343–346, 345f, 346f sleep breathing disorders in, 338–347 sleep changes in, 95–96, 111f Childhood epilepsy with centrotemporal spikes (CECTS), 235–238, 238f with occipital paroxysms, 238, 239f Chloroform, discovery of, 11 Cholecystokinin (CCK), sleep and, 69, 69t Choroid, 405f Chronic fatigue syndrome (CFS), 434–437 characteristics of, 433 clinical presentation and diagnosis of, 434, 436b diagnostic criteria for, 434b pathogenesis of, 434–436, 436f sleep, 436–437 treatment of, 437 Chronic kidney disease, sleep disorders in, 390–395 definitions and prevalence of, 390, 390f, 390t morbidity and mortality of, 390–391, 391f nonrespiratory sleep disorders and, 393–395 respiratory sleep disorders and, 391–393 treatment for, 391, 392f, 393f Chronic obstructive pulmonary disease (COPD) abnormal sleep physiology in, 348b all-night oximetry in, 349f with insomnia, 178–179, 178f, 179f in overlap syndrome, 348 severe, 348–351, 354f sleep disturbance in, 348, 348b sleep laboratory video on, 538, 538f, 539f Chronotherapy, for delayed sleep-wake phase disorder, 162–163

Index  547 Ciliary body, 405f Circadian clock core components of, 36, 36f melatonin and, 36, 38f misalignment of, in jet lag disorder, 166f timing of, 36, 37f, 38f timing of, changes in, in night worker, 165f Circadian clock gene, historical background on, 19, 20f Circadian function, normal, 94 Circadian misalignment, 150f Circadian regulation, of sleep and pain, 412–413 Circadian rhythm(s) age-related changes in, 115, 116f desynchrony of cancer, 172–174, 174f cardiovascular disease and, 168–169, 169f gastrointestinal disease, 171–172, 173f health and, 168–174 metabolism, 169–171, 170f, 171f microbiota, 171, 172f food intake timing and, 170 historical background on, 16 hormone plasma level variations and, 72, 73f of melatonin secretion, 105f physiology of, 29–30 regulation of, 36–38, 37f in regulation of sleep and wakefulness, 106f homeostatic drives opposing, 118f of sleep-wake cycles, 23, 28f Circadian rhythm disorders, 161–167 advanced sleep-wake phase disorder, 163, 163f, 167t clinical presentation, preferred sleep-wake times, and treatment options for, 167t delayed sleep-wake phase disorder as, 161–163, 161f, 162f, 167t irregular sleep-wake rhythm disorder, 164–165, 164f, 167t jet lag disorders as, 165, 166f, 167t non-24-hour sleep-wake disorder as, 164, 164f, 167t psychiatric disease and, 396, 434 shift-work disorder as, 165, 165f, 167t vision and, 406, 408f Circadian system, 168, 168f basic components of, 37f communication routes of, 37f disruption of, 168, 168f Circulatory homeostasis, during sleep, 64 Cirrhosis, sleep disturbance in, 380, 380f CKD. See Chronic kidney disease Cleopatra, 5, 5f Clomipramine, for central nervous system hypersomnias, 203–204t Clonazepam, for sleep promotion, 134t Clonidine, for nightmares, in PTSD, 401 CNS. See Central nervous system Cognitive behavioral therapy for insomnia (CBTI), 182, 183t, 184f in psychiatric illness, 434 Cognitive performance capability, subjective sleepiness and, 119f Colitis, circadian desynchrony and, 172 Complex sleep apnea, 483f mixed sleep apnea becoming, 482f Conditional reflexes, historical background on, 13, 13f Confusional arousal, 285, 287f, 288f sleep laboratory video on, 542, 542f Congenital central hypoventilation syndrome (CCHS), 338

Congestive heart failure (CHF) central sleep apnea and, Cheyne-Stokes respirations in, 321f Cheyne-Stokes respirations in. See CheyneStokes respirations drowsiness in, historical background on, 13, 13f with insomnia, 178–179, 178f, 180f mixed sleep apnea in, 322f Conjunctiva, 405f Continuity hypothesis, of dream content, 132 Continuous positive airway pressure (CPAP), 344–345 central sleep apnea on, 479f Cheyne-Stokes breathing, with systolic heart failure, 364 for chronic kidney disease, sleep disorder, 391, 393f for COPD, 351f flow generators for, 331f growth hormone secretion and, 73, 75f masks for, 331f, 332f, 335f for mixed sleep apnea, 322f with leg movement, 467f, 473f for obstructive sleep apnea, 406 with congestive heart failure, 492f, 493f in heart failure, 493f mortality rates and, 367 patient interview video on, 526, 526f for sleep apnea, from growth hormone hypersecretion, 376 for sleep-disordered breathing, COVID-19 and, 417–419 for sleep-related breathing disorders, 256–257, 256f, 257f teaching and mask fitting of, video on, 527, 527f titration of, 326, 332f, 333f, 334f Core body temperature (CBT), as circadian phase marker, 36 Core body temperature (CBT) rhythm, in delayed sleep-wake phase disorder, 161–162, 162f Cornea, 405f Coronary artery disease, from obstructive sleep apnea, 360, 361f Coronary blood flow, in sleep, 64, 65f Coronavirus disease 2019 (COVID-19), 414–419, 414f future of, 419, 419f long-haul cardiovascular outcomes of, 416, 418f long-haul neurologic and psychiatric outcomes of, 416 long-haul respiratory outcomes of, 414–415 neurologic effects of, 416, 417f phases of, 416f role of other preexisting sleep disorders in, 419 sleep disorder in, 269–270 symptoms and disorders of, 416–419 Cortical arousal, 23, 26f Cortisol, sleep and, 52 Cortisol awakening response, 52 Cortisol stress reactivity, sleep deprivation on, 122f COVID-19. See Coronavirus disease 2019 CPAP. See Continuous positive airway pressure Cradle, The, 5, 6f Craniofacial anomalies, sleep-disordered breathing in adolescents from, 328f C-reactive protein (CRP), sleep and, 51–52, 53t Creutzfeldt-Jakob disease (CJD), 267–268, 269f CRP. See C-reactive protein CSA. See Central sleep apnea CSRs. See Cheyne-Stokes respirations Cyclic alternating pattern (CAP) in arousal scoring, 444, 444f, 445f parasomnias associated with, 292f

Cystic fibrosis, in overlap syndrome, 348 Cytokines effects of, on brain, 54t sleep and, 51–55, 70 Czeisler, Charles, 16, 17f

D

da Caravaggio, Michelangelo Merisi, 4, 4f Danger, sleep and, 6–9 Daniels, Luman, 13 de Goya, Francisco José, 6, 7f De Mairan, Jean-Jacques d'Ortous, 10, 12f Death, sleep and, 6–9 Death of Bhishma, The, 8, 8f Delayed sleep-wake phase disorder (DSWPD), 161–163, 161f, 162f, 167t sleep laboratory video on, 543, 543f Delivery, sleep and, 427, 428f, 428t della Francesca, Piero, 3–4, 3f Delta waves, in stages 3 and 4 sleep, 105f Delvaux, Laurent, 5, 5f Dement, William, 14, 15, 15f, 16f, 18 Dementia Alzheimer. See Alzheimer disease sleep disorders and, 258 Dental bite abnormalities, 303t Deoxygenation, in obstructive sleep apnea, 357f Depression dreaming disruption in, 133 with insomnia, 179, 179f, 180f, 181f sleep disorder and, 397–400, 397f sleep architecture of, 398, 398f, 398t treatment of, 398–400, 399f, 399t, 400f sleep disturbance and, 411 Desynchronized circadian rhythms, 126 Dexmethylphenidate (Focalin), in wakefulness promotion, 143t Dextroamphetamine/amphetamine (Adderall), in wakefulness promotion, 143t Diabetes mellitus, 385–389 common types of, 385b risk of, sleep deprivation and, 73 sleep apnea and, 385–388 weight loss impact, 388 sleep deprivation and, 386t sleep quantity and quality in, 385 type 1, sleep apnea and, 388 Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V), 175 Diagnostic assessment methods arousal scoring, 443–444 cyclic alternating patterns in, 444, 444f, 445f EEG speeding and CNS arousals in, 443 electrocardiogram as, 448 home sleep testing as, 448–450, 449f, 450f, 451f, 452f maintenance of wakefulness test as, 460 for movements, 448, 448f of legs periodic, scoring rules for, 448, 448f recording technique for, 448 other, 448 multiple sleep latency test as, 459–460, 460f overall assessment in, 450–458 parameters, pathophysiology, and interpretation in, 453–458, 454t, 455f, 459f sleep center health and family questionnaire in, 457f sleep center screening questionnaire in, 455f sleep problems checklist in, 456f for sleep-related breathing disorders, 445–447 definitions and scoring rules for for hypopnea, 447, 447f for respiratory effort-related arousals, 447

548  Index Diagnostic assessment methods (Continued) for sleep apnea, 445, 446f recording technique for, 445 sleep stage changes across night, 453, 453f, 454t as function of age, 453 sleep staging as, 438–443. See also Sleep staging standardization of, 438 suggested immobilization test as, 460 Diazepam, for sleep promotion, 134t Dickens, Charles, 11, 12f Digit symbol substitution task (DSST), 119f Dim light melatonin onset (DLMO), 36, 38f Dionysius, 10, 11f Diphenhydramine (Nytol, Sleep-Eze, Sominex), for sleep promotion, 140t Diphenhydramine in combination (Anacin PM, Excedrin PM, Tylenol PM), for sleep promotion, 140t Disrupted nocturnal sleep, 186–187, 192f Dissolute Household, The, 4–5, 4f DLMO. See Dim light melatonin onset Dopamine abnormalities, in restless legs syndrome, 213, 215f Dopamine agonists, for restless legs syndrome, 218t Down syndrome obstructive sleep apnea in, polysomnography of, 472f sleep apnea in patient interview video on, 526, 526f sleep laboratory video on, 535, 535f Doxepin, for sleep promotion, 134t, 136, 138 Doxylamine (Unisom Nighttime), for sleep promotion, 140t Dream(s) content of factors influencing, 132 in REM sleep behavior disorder, 152–153, 154f in sleep, 6–9 Dream, The, 6–7, 7f Dream of Constantine, 3–4, 3f Dreaming, 131 brain in, 131, 131f definition of, 131–133 disruption of, 132–133, 133f in psychiatric disorders, 133 in sleep disorders, 132–133 learning task is associated with improved memory, 132f loss of, brain lesions causing, 131f Drowsiness. See Sleepiness DSST. See Digit symbol substitution task DSWPD. See Delayed sleep-wake phase disorder Duchenne muscular dystrophy, sleep disturbances in, 273t, 276, 276f Dysfunctional family, 4–5 Dystrophy, Becker muscular, patient interview video on, 530f

E

Ear oximeter, fiberoptic-based, historical background on, 16 Earthly Paradise, 3, 3f Eating disorder, sleep-related, 293b, 293f ECG. See Electrocardiography (ECG) Edgar, Rachel, 21 EDS. See Excessive daytime sleepiness EEG. See Electroencephalography Ekbom, Karl-Axel, 13 Elderly sleep in, 114f sleep timing and circadian changes in, 116f

Electrical status epilepticus, of sleep, 239 Electro-oculography (EOG) of stage N1 sleep, 106f of stage N2 sleep, 106f of stage N3 sleep, 106f in child, 108f of stage R sleep, 106f of stage W sleep, 101f Electrocardiography (ECG) artifact in, 525f in diagnostic assessment, 448 Electroencephalogram (EEG) speeding, CNS arousals and, in arousal scoring, 443, 444f Electroencephalography (EEG) artifacts in cardiac, 521f, 522f respiratory, 519f, 520f, 521f dream recall, 132f of mammals, 81 maturation of, in infant, 111f power spectral analysis, 411–412 in sleep and epilepsy, 227–231, 227f, 228f, 229f, 232–233f, 232f, 232t, 233f, 234f sleep stage rhythms and characteristics on, 105f in sleep staging, 438, 439f, 439t, 440f of stage N sleep, in child, 105f of stage N1 sleep, 106f of stage N2 sleep, 106f of stage N3 sleep, 106f in child, 108f of stage R sleep, 106f of stage W sleep, 101f waveform terminology, 228t Electrographic seizure, 229 Electromyography (EMG) chin, artifacts in, 525f of stage N sleep, in child, 108f of stage N1 sleep, 106f of stage N2 sleep, 106f of stage N3 sleep, 106f in child, 108f of stage R sleep, 106f of stage W sleep, 101f Encephalitis lethargica, 24f Endocrine physiology, 72–77 aging and, 73, 74f disease states reducing slow-wave sleep and, 73, 75f glucose regulation and hunger in, 73, 73f mechanism controlling pituitary hormone secretion in, 72, 72f, 72t overview of, 72–73 sleep deprivation and, 73–75, 76f temporal variations of plasma levels of hormones in, 72, 73f Energy conservation theory, in normal sleep in humans, 83 Environmental triggers, in narcolepsy, 192–198, 196f, 197–198f, 200f Epilepsy. See also Seizure(s) benign childhood, 235–238, 235t electroencephalography in, 227–231, 227f, 228f, 228t, 229f, 232–233f, 232f, 232t, 233f, 234f normal variants and non epileptic behaviors of, 243–247 interictal discharge, normal variants vs., 243, 244f, 245f, 246f, 247f, 248–249t, 248f parasomnia vs., 243–247, 249–250t seizures and, 227 sleep and, 227–250 sleep disorders in, 247–250 sleep laboratory video on, 543, 543f sleep-related hypermotor epilepsies, 235, 236f, 237f, 238b, 238f type of, 231–243, 235t

Epileptic encephalopathy with continuous spikes and waves during slow sleep, 239, 239f Epileptiform, term, 228 Epileptogenic, term, 228 Epworth Sleepiness Scale (ESS), 156, 158f, 201, 455–458, 455f Esmirtazapine, for sleep promotion, 141 ESS. See Epworth Sleepiness Scale Eszopiclone GABA-A receptor affinities of, 136t for insomnia, 183, 183f, 183t pharmacokinetics of, 138f for sleep promotion, 134t, 138 structure of, 138f Ethanol for sleep promotion, 140–141 structure of, 141f Etruscan Funerary Urns, 9f Excessive daytime sleepiness (EDS), 126, 185, 186 clinical evaluation, 150–152, 151b, 152f, 153f in delayed sleep-wake phase disorder, 161 in Parkinson disease, 258–259 sleep restriction and, 117 Experiential parasomnias, 294–298 Expiratory apnea/hypopnea, definitions of, 343, 343f Extrapulmonary lung restriction, in overlap syndromes, 353, 354f, 355f Extrathoracic upper airway obstruction, in overlap syndrome, 355, 355f, 356f Eye insomnia and, 406 sleep and, 405, 405f, 406f Eye movements, in sleep staging, 439, 439t. See also Electro-oculography Eyelid drooping, in sleep apnea, 301f Eyelid ptosis, upper, 407f

F

Face bony structures of, in examination for sleep apnea, 301–305, 302f inspection of, in examination for sleep apnea, 300–301, 301f Facioscapulohumeral muscular dystrophy, sleep disturbances in, 273t Family history, 156 Fatal familial insomnia, 267, 267f, 268f Fatigue, in Parkinson disease, 258 Fatigue Severity Scale, 201, 201b Feeding bidirectional relationship between sleep-wake activity and, 70–71 interactive regulation of, 68–71 brain circuits of, 68, 68f, 69f shared somatic signaling between sleep and, 68–70, 69t metabolic organs modulate, 70 Ferriman-Gallwey hirsutism scoring system, modified, 423f Fibromyalgia characteristics of, 433–434, 433f clinical presentation of, 433–434 commonly present in patients with, 433b diagnosis of, 433–434 diagnostic criteria for, 434b pathogenesis of, 434 sleep, 434, 434b, 435f tender point locations for, 433–434 treatment of, 434, 435b, 436f First night effects, 453 First trimester, of pregnancy, sleep during, 426, 426t Fischer, Emil, 13

Index  549 Floppy eyelid syndrome, obstructive sleep apnea and, 406, 407f Focal-onset seizures, 227, 235t Focalin (dexmethylphenidate), in wakefulness promotion, 143t Food intake, timing of, circadian rhythms and, 170 Forehead, hyperpigmentation of, in sleep apnea, 300–301, 301f Fovea, 405f Fracture, nasal, 306 Free-running sleep-wake disorder, 164f, 167t Friedman classification, in clinical evaluation of sleep-disordered breathing, 156, 157f Friedreich ataxia, 264 Frontal lobe epilepsy, seizure distribution in, 231–235 Fuseli, Henry, 6, 7f, 11f, 133f

G

GABA-A receptor complex, hypnotic agents acting on, 134, 134f, 136t GABAergic neurons, in wake to non-REM sleep transition, 29, 31f Gastaut, Henri, 14, 15f Gastroesophageal reflux disease (GERD), 379–384 Gastrointestinal disorders, 379–384 advanced liver disease as, 380–381, 380f, 381f, 382f, 383f circadian desynchrony and, 171–172, 173f gastroesophageal reflux disease as, 379 intestinal motility and lower bowel disorders as, 379–380, 379f mild liver disease as, 381–383, 384f nocturnal, 379 upper gastrointestinal tract, 379, 379f Gehrig, Lou, 271f Gélineau, Jean Baptiste Edouard, 13 Generalized idiopathic epilepsy, 227, 235t Generalized tonic-clonic seizures, on awakening, 235t Genetic factors, in narcolepsy, 198–200, 199f Gestational diabetes mellitus (GDM), 385 sleep apnea and, 388 GH. See Growth hormone Ghrelin levels of, sleep deprivation and, 75 sleep and, 68–69, 69f, 69t, 70f Gigantism, 374 Giorgione, 2, 3f Glaucoma, 406 Glucose impact of OSA treatment on, 386–388 metabolism of, effects of sleep deprivation on, 385–386, 388f regulation of, hunger and, 73, 73f Glutamate abnormalities, in restless legs syndrome, 213 Glymphatic theory, in normal sleep in humans, 83–85, 87f Goiter, toxic, hyperthyroidism from, 369t Goya, Francisco José, 6, 7f Gozal, David, 18 Graves disease “burned out,” hypothyroidism in, 371b, 371f hyperthyroidism from, 369t Graves ophthalmopathy, 370f Growth hormone (GH) hypersecretion of, 374–376. See also Acromegaly clinical features of, 376 diagnosis of, 376 pathophysiology of, 374, 374b, 374f, 375–376f, 375f treatment of, 376 secretion of aging and, 75f

Growth hormone (Continued) continuous positive airway pressure and, 73 Growth hormone-releasing hormone, sleep and, 54t Guilleminault, Christian, 16, 17–18, 17f Guthrie, Samuel, 11

H

Hall, Jeffrey, 17, 21 Hallucinations hypnagogic, patient interview video on, 530, 530f in narcolepsy, 132–133, 152, 186 patient interview video on, 528 Hamlet, 8 Hammond, William, 12 Harrison, W.R., 13, 13f He, Jiang, 17–18 Head banging, in sleep-related rhythmic movement disorder, 225 Head rolling, in sleep-related rhythmic movement disorder, 225 Head trauma, 516, 516f, 517f Headache, sleep disorder due to, 269 Heart blocks, 498f Mobitz second degree, 476f third degree, 499f Wenckebach second-degree, 498f Heart failure central sleep apnea and, Cheyne-Stokes respirations in, 321f Cheyne-Stokes respiration in, historical background on, 13, 13f congestive. See Congestive heart failure obstructive sleep apnea and, 363 abnormal breathing patterns in, 364–367, 365f, 366f treatment of, 366–367, 366f, 367f clinical features of, 363 epidemiology of, 363–364, 364f polysomnography of acute, and obstructive sleep apnea, 490f, 491f on ventilatory support, 491f Heart rate in sleep apnea, 43f surges in, in REM sleep, 64, 65f, 66f in wakeful and sleep states, 40, 42f, 43f, 44f, 45f, 48f Heart rhythm, pauses in, in REM sleep, 65, 66f Heartburn, 379. See also Gastroesophageal reflux disease Helicobacter pylori, 379–380 Hereditary ataxias, 264, 265f Hewlett-Packard, 16 Hippocrates, 10, 10f Hirsutism, 423f Histogram(s) actigraphy, 461f of age-related changes in sleep, 107f sleep, in narcolepsy, 510f sleep stage, from multiple sleep latency test, 460f HLA in narcolepsy susceptibility, 191, 196f, 197–198f typing of, in narcolepsy diagnosis, 201 Hobson, Allan, activation synthesis theory of dream generation of, 131, 131f Home sleep testing (HST), 448–450, 449f, 450f, 451f, 452f Homeostasis circulatory, during sleep, 64 during NREM sleep, 39 sleep, 29 Homeostat, sleep, 23, 26f

Homeostatic regulation, of sleep and wakefulness, 106f circadian drives opposing, 118f Hormone levels fluctuations in, during menopause, 430 plasma levels of, temporal variations of, 72, 73f Host defense, sleep and, 51–55 Hot flashes, during menopause, 430 HST. See Home sleep testing Hunger, glucose regulation and, 73, 73f Huntington disease, 264, 264b sleep disturbances in, 507f Hyperarousal, in insomnia, 176, 177f Hyperarousal state, historical background on, 15 Hypercapnia from obstructive sleep apnea, 357f obstructive sleep apnea and, 61f response to, during sleep, 57f, 58f Hypersomnia(s) after stroke, 255 central nervous system, 185 classification of, 185, 185b clinical features and epidemiology of, 185, 186f evaluation and diagnosis cerebrospinal fluid hypocretin measurement in, 201 Epworth Sleepiness Scale (ESS), 201 Fatigue Severity Scale in, 201, 201b HLA typing in, 201 overnight polysomnography in, 201, 202f, 203f evaluation and diagnosis of, 201 narcolepsy as. See Narcolepsy pathophysiology of, 187–200, 193f, 194–195f, 194f prevalence of, 185 treatment of, 202–205, 203–204t in chronic kidney disease, 395 COVID-19 and, 416 idiopathic, narcolepsy differentiated from, 152 menstrual-related, 422 Hypersomnolence central disorder of, 185–205 classification of, 185, 185b clinical features and epidemiology of, 185, 186f evaluation and diagnosis cerebrospinal fluid hypocretin measurement in, 201 Epworth Sleepiness Scale (ESS), 201 Fatigue Severity Scale in, 201, 201b HLA typing in, 201 overnight polysomnography in, 201, 202f, 203f evaluation and diagnosis of, 201 pathophysiology of, 187–200, 193f, 194–195f, 194f prevalence of, 185 treatment of, 202–205, 203–204t evaluation of, 151b Hypertension, systemic, from obstructive sleep apnea, 253, 358f, 361–363, 362f, 363f Hyperthyroidism, 369, 370f, 371f causes of, 369t Graves ophthalmopathy in, 370f sleep findings in, 369b symptoms of, 369b, 369f Hypnagogic hallucinations in narcolepsy, 152, 152t patient interview video on, 530, 530f Hypnic jerk, polysomnogram of, 207f Hypnogram of complex sleep apnea, 483f normal sleep, 107f

550  Index Hypnopompic hallucinations, in narcolepsy, 152, 152t Hypnotic agents, 134–141, 134t, 135f atypical antipsychotics as, 140, 141t in development, 141–142, 142f diphenhydramine as, 139, 140t doxepin as, 134, 134t eszopiclone as, 134t GABA-A receptor affinities of, 136t pharmacokinetics of, 138f structure of, 138f ethanol as, 140–141 ramelteon as, 136 latency to persistent sleep in insomniacs and, 138f structure of, 139f sedating antidepressants as, 139–140, 140f zaleplon as, 134t sleep latency in insomniacs and, 139f structure of, 138f zolpidem as, 136–137, 137f, 139f Hypocapnia, from obstructive sleep apnea, 357f Hypocretin in CSF low levels of, in Parkinson disease, 258, 259f measurement of, in narcolepsy diagnosis, 201, 202f deficiency of, in type 1 narcolepsy, 191, 194–195f Hypocretin receptor 2 (HcrtR2) gene, historical background on, 19–20, 20f Hypoglossal motor system, 59f Hypopnea(s), 315–316 definition of, 340, 342f, 447, 447f obstructive, upper airway resistance syndrome vs., 477f recurrent, cardiovascular consequences of, 358f scoring of, rules for, 445–447, 446f Hypothalamic temperature, during sleep, 40f, 41f, 42f Hypothalamus, in interactive regulation of sleep and feeding, 68, 68f, 69f Hypothyroidism, 369 causes of, 371b sleep findings in, 371b symptoms of, 371b, 373f facial, 372f hair, 372f Hypoventilation obesity, sleep laboratory video on, 533, 533f, 534f obstructive obstructive sleep apnea vs., 468f, 469f prolonged, respiratory effort-related arousal with, 476f Hypoxemia from obstructive sleep apnea, 358f obstructive sleep apnea and, 61f in overlap syndrome, 348, 349f, 350f, 352f Hypoxia, response to, during sleep, 57f, 58f

I

Ictal activity, during epilepsy, 228 Idiopathic central sleep apnea, sleep laboratory video on, 537, 537f Idiopathic generalized epilepsy, 227, 235t Immune aging, sleep and, 55f Immune system overview of, 51 sleep and, 53 Infant(s) maturation of EEG in, 111f rest/activity in, 111f sleep in, maturation and consolidation of, 112f

Infection narcolepsy secondary to, 201 in respiratory system, 414, 416f sleep and, 51, 52, 52f, 54f, 54t Infectious motor neuropathy, sleep disturbances in, 273–274 Inflammation, sleep and, 51–52, 54f, 55f Inflammatory bowel disease, circadian desynchrony and, 171–172 Influenza virus infection narcolepsy secondary to, 192 NREM sleep and, 54f Ingenious Hidalgo Don Quixote of La Mancha, The, 10 Innocence, sleep as, 5 Insomnia, 126, 175–184 after stroke, 255 in chronic kidney disease, 395 classification of, 175 clinical evaluation of, 148, 149b cognitive behavioral therapy for, 182, 183t, 184f common causes of, 151b comorbid, 177–179, 178f with congestive heart failure, 178–179, 178f, 180f with COPD, 178–179, 178f, 179f with depression, 179, 179f, 180f, 181f with medical condition, 178b with psychiatric conditions, 178b COVID-19 and, 415b, 416 epidemiology of, 175–176, 176f in epilepsy, 250 evolution of, 176, 177f eye and, 406 heart failure and, 363 historical background of, 16 hyperarousal in, 176, 177f isolated, 182 management of, 183–184, 183f, 183t, 184f menstrual cycle and, 422, 422f nonpharmacologic interventions for, 410 pathophysiology of, 176, 176f, 177f perpetuating factors in, 151b primary, definition of, 175 psychiatric disease and, 397, 397f, 400f restless legs syndrome with, sleep laboratory video on, 540, 540f secondary, definition of, 175 sleep disorders presenting with, 181, 181b, 182f types of, 176, 177b, 178f Insufficient sleep syndrome, excessive daytime sleepiness in, 150–152, 153f Insulin resistance, sleep deprivation and, 385 Interictal activity, during epilepsy, 228 Interictal epileptiform discharges (IEDs), 228 normal variants vs., 243, 244f, 245f, 246f, 247f, 248–249t, 248f Interleukin-1b (IL-1b), sleep and, 54t Interleukin-6 (IL6), sleep and, 51–52, 53t, 54t International Classification of Diseases (ICD), 175 International Classification of Sleep Disorders, 18 (ICSD-3), 175 III (ICSD-3), on parasomnias, 286b third edition (ICSD-3), 267 on CNS hypersomnias, 185 International Federation of Clinical Neurophysiology (IFCN), 228–229 Intestinal microbiota, brain and, 70, 71f Intestinal motility, sleep disturbance in, 379–380, 379f Iris, 405f Iron, for restless legs syndrome, 218t Iron deficiency, restless legs syndrome from, 211, 213f, 214f, 215f

Irregular sleep-wake rhythm disorder, 164–165, 164f, 167t Ischemic optic neuropathy, nonarteritic, 406 a-Isoforms, 136f

J

Jaw structures, in examination for sleep apnea, 302 Jet lag, conceptual model of, 126f Jet lag disorder, 165, 166f, 167t Jouvet, Michel, 14, 15f Junctional escape rhythm, in sleep apnea, 494f Jung, Carl, 14 Juvenile myoclonic epilepsy, 235t, 239–243, 243f, 244f

K

K complexes, on EEG, 103f Kales, Anthony, 15, 16f, 438 Keats, John, 4 Kelleher, John, 8 Kleine-Levin syndrome, 187, 192f, 422 Kleitman, Nathaniel, 13, 14, 14f, 18, 19f Klimt, Gustave, 5, 7f Klippel-Feil syndrome, neck abnormalities in, 311–312, 312f Konopka, Ron, 15 Kryger, Meir, 15, 17f, 18 Kyphoscoliosis in adolescent, sleep-disordered breathing in, 317, 326f in overlap syndrome, 353, 355f

L

Labor, sleep and, 427, 428f, 428t Lady Macbeth Sleepwalking, 10, 11f Lambert-Eaton myasthenic syndrome, sleep disturbances in, 273t Lancet, The, 16 Landau-Kleffner syndrome, 235t, 239, 240f Langer, Salomon, 17 Laryngomalacia, late-onset, sleep-disordered breathing in adolescents from, 328f Lazar, Mitchell, 21 Le Berceau (The Cradle), 5, 6f Leg cramps, sleep-related, 505f, 506f Leg movements monitoring of, in polysomnography of mixed sleep apnea, 467f of obstructive sleep apnea, 466f periodic. See Periodic limb movement recording of, 448 scoring rules for, 448, 449f L'Enfant du Regiment, 5, 6f Lens, 405f Leptin levels of, sleep deprivation and, 75 sleep and, 69–70, 69f, 69t, 73, 74f Life span parameters, in mammals, 82f Light, circadian rhythm and, 406, 408f Light exposure in circadian clock regulation, 36, 38f therapeutic. See Bright light exposure Lipopolysaccharide (LPS), sleep and, 52 Literature, sleep in, 1–9, 1f Long sleep, health risks associated with, 148t Loomis, Alfred, 13 Loprazolam, for sleep promotion, 134t Lorazepam, for sleep promotion, 134t Lotto, Lorenzo, 2, 2f Loud vocalization, sleep laboratory video on, 542, 542f Löwenfeld, Leopold, 13 Lower bowel disorders, sleep disturbance in, 379–380, 379f Lugaresi, Elio, 14

Index  551 M

Macbeth, 8 Machado-Joseph disease, 264, 265f Macroglossia, in hypothyroidism, 372f Macula, 405f Magoun, Horace, 14, 24f Mahowald, Mark, 17, 19f Maintenance of wakefulness test (MWT), 460 for excessive daytime sleepiness, 201, 202f, 203f sleep restriction and, 120f Mallampati classification, 306–308 in clinical evaluation of sleep-disordered breathing, 156, 157f Mammals, sleep in, 78–82, 78f, 79f, 80f, 81f, 82f Mandibular insufficiency, in examination for sleep apnea, 302, 303f, 303t Mars and Venus, 1–2, 2f Maxillary insufficiency, in examination for sleep apnea, 302, 303f, 303t McCarley, R.W., activation synthesis theory of dream generation of, 131f Median preoptic nuclei (MnPO), in sleep regulation, 22, 24f, 25f, 29, 30 Medical history, 155–156, 155t Meditation, sleep and, 8 Melatonin circadian clock and, 36, 37f, 38f for delayed sleep-wake phase disorder, 163 for non-24-hour sleep-wake disorder, 164 for sleep promotion, 140t Melatonin profile, for delayed sleep-wake phase disorder, 162f Memory consolidation theory, in normal sleep in humans, 83 Menaker, Michael, 16, 17f Menopause midlife transition and, 430–432 sleep disturbance during, 430, 430f, 431f symptoms, 430b Menstrual cycle, 420–425 function, impact of sleep on, 423, 425f impact of, on sleep disorders, 422, 422f insomnia symptoms and, 422 physiology of, 420–421, 420f sleep across, 421, 421f Mental health, postpartum sleep and, 427–429 Metabolic rate, during sleep, 40f Metabolism, circadian system and, 169–171, 170f, 171f Methylphenidate (Ritalin) for central nervous system hypersomnias, 203–204t in wakefulness promotion, 143t Microbiota, 171, 172f intestinal, brain and, 70 Midlife transition, menopause and, 430–432 vasomotor symptoms of, 430 Mignot, Emmanuel, 19–20 Mild liver disease, sleep disturbance as, 381–383, 384f Millais, John Everett, 5, 6f Millet, Jean-François, 5, 5f Minor, Vernon Hyde, 4–5 Mixed sleep apnea becoming complex, 482f in congestive heart failure, 322f definitions of, 340, 342f, 445 with idiopathic pulmonary fibrosis, 484f with leg movement, 467f polysomnography of, 467f, 471f response to CPAP, 322f scoring rules for, 445 treatment-emergent, 322f, 323f MnPO. See Median preoptic nuclei

Modafinil for central nervous system hypersomnias, 203–204t efficacy of, 145f historical background of, 18 mechanism of action of, 145f pharmacokinetics of, 144t as wakefulness-promoting agent, 142, 144f, 145f Monroe, Lawrence, 15 Moore, Robert, 15, 16f Morisot, Berthe, 5, 6f Moruzzi, Giuseppe, 14 Morvan syndrome, 266–267 Motor neuron disease, sleep disturbances in, 272, 274f Movement disorder, in sleep, 206–226, 206b, 206f, 207f after stroke, 254–255 bruxism as, 220–222 periodic limb movements as, 209, 217–220 restless legs syndrome as, 206–217. See also Restless legs syndrome sleep-related leg cramps as, 225–226 sleep-related rhythmic movement disorder as, 222–225, 225f MSLT. See Multiple sleep latency test Multiple sclerosis patient interview video on, 530, 530f polysomnography of, 517, 517f, 518f sleep disorder in, 264–266, 265f, 266f Multiple sleep latency test (MSLT), 338, 398, 460f for excessive daytime sleepiness, 201, 202f, 203f Multiple system atrophy (MSA), 263 Muscle disease, sleep disturbances in, 275–276 Muscle tone hypocretin system in promotion of, 188–189f skeletal, electromyogram for, 439–440 in sleep staging. See Electromyography Muscular dystrophy, Becker, patient interview video on, 530f MWT. See Maintenance of wakefulness test Myalgic encephalomyelitis, 434–437 clinical presentation and diagnosis of, 434, 436b pathogenesis of, 434–436, 436f sleep, 436–437 treatment of, 437 Myasthenia gravis, sleep disturbances in, 273t Myotonic dystrophy, sleep disturbances in, 273t, 276, 277f Mythology, sleep in, 1–2, 2f

N

NAION. See Nonarteritic ischemic optic neuropathy Narcolepsy autoimmune mechanism in, 192 dreaming disruption in, 132–133 environmental triggers in, 192–198, 196f, 197–198f, 200f evaluation and diagnosis of, 201 cerebrospinal fluid hypocretin measurement in, 201 Epworth Sleepiness Scale in, 201 Fatigue Severity Scale in, 201, 201b genetic risk factors for, 192–198, 199f HLA typing in, 201 overnight polysomnography in, 201, 202f, 203f with hallucinations, 132–133 historical background on, 13, 20f

Narcolepsy (Continued) idiopathic hypersomnia differentiated from, 152 in multiple sclerosis, 264–266 multiple sleep latency test in, 460f overnight polysomnography in, 185, 186f pathophysiology of, 187–200 patient interview videos on, 528, 528f cataplexy with, 528, 528f hallucinations in, 528 sleep apnea with, 528, 528f pregnancy and, 429 secondary, 198–200 brain lesion locations in, 200f neurologic diseases in, 200f sleep histogram of, 510f sleep paralysis in, 132–133 type 1, network responsible for, 32–33, 35f wakefulness-promoting agents for, 142, 142t. See also Stimulant(s) Nasal airway. See also Nose in examination for sleep apnea, 305–306 Nasal positive airway pressure, during pregnancy, 427 National Basketball Association (NBA), 126, 127f National College Health Assessment, 129t National Collegiate Athletic Association (NCAA), 129, 130f Nauta, Walle, 25f Neck abnormalities, 311–312, 312f Nerve growth factor, sleep and, 54t Nervous system, in sleep regulation, 22, 22f, 23f Neural regulation, physiologic systems under, 39 Neuralgic amyotrophy, sleep disturbances in, 274–275, 275f Neurodegenerative disorders, sleep in, 258–270, 258f Alzheimer disease, 261–263 COVID-19 as, 269–270 headache, 269 hereditary ataxias, 264, 265f Huntington disease, 264, 264b multiple sclerosis, 264–266, 265f, 266f paraneoplastic syndromes, 266–267, 266t Parkinson disease as, 258–261, 258f, 259f prion disease, 267–268 spinal cord injury, 268 traumatic brain injury, 268–269 Neurologic disorders patient interview videos on, 528–530 sleep laboratory video on, 540–544 delayed sleep phase syndrome, 543, 543f epilepsy, 543, 543f psychogenic “seizures,” 544, 544f seizure involving leg, 544, 544f Neuromuscular disease, 271–286 in adolescents, sleep-disordered breathing in, 329f chest wall disorders and scoliosis in, 277 common, 272–277, 274f compromised breathing mechanics, in sleep, 278, 278f Duchenne muscular dystrophy, 276, 276f impaired pulmonary physiology and symptoms of, 279–280, 279b, 280f impaired respiratory physiology in, 271–272, 272f motor neuron disease in, 272, 274f muscle disease in, 275–276 myotonic dystrophies in, 276 neuromuscular junction disease in, 275 noninvasive ventilation benefits in, 280–282, 281b, 281f, 282b, 282f peripheral nerve disease in, 273

552  Index Neuromuscular disease (Continued) phrenic nerve injury, neuralgic amyotrophy, parsonage Turner syndrome, 274–275, 275f polysomnography findings in, 278, 279f post-polio syndrome/infectious motor neuropathy, 273–274 spinal cord injury in, 272–273, 275f Neuromuscular junction disease, sleep disturbances in, 275 Neurons, in ventrolateral preoptic, 22 Neuropathy, nonarteritic ischemic optic, 406 Night sweats, during menopause, 430 Nightmare, The, 6, 7f, 133f Nightmares in posttraumatic stress disorder, 400–402, 401f sleep architecture of, 401 treatment of, 401–402 sleep terrors vs., 291t Nitrazepam, for sleep promotion, 134t Nocturnal angina, 64, 67t Nocturnal cardiac events, physiologic mechanisms underlying, 65, 67t Nocturnal frontal lobe epilepsy (NFLEs), 235 in parasomnias, 298, 298b, 299f, 299t Nocturnal hemodialysis, 391 Nocturnal leg cramps, 225–226 treatment for, 226b Non-rapid eye movement (NREM) parasomnias, 285 sleep laboratory video on, 542, 542f treatment for, 294t Non-rapid eye movement (NREM) sleep control of, 23, 27f dream recall during, 131–132 EEG in, historical background on, 13 EEG patterns in, 92f functions of, 83, 84f influenza virus infection and, 54f of mammals, 81 menstrual cycle and, 421, 421f network responsible for, 30–31, 31f physiologic regulation in, 39, 40f, 41f, 42f seizures facilitated by, 228–229, 230f, 231f sleep breathing disorders in children, 338 sleep-promoting neurotransmitters in, 29 sympathetic activity in, 64, 65f thermoregulatory responses in, 40t transition from wakefulness to, 91–94, 93f, 97f, 100f Non-24-hour sleep-wake disorder, 164, 164f, 167t Nonalcoholic fatty liver disease (NAFLD), 381–383 Nonapneic respiratory events, sleep-related, 317, 325f, 326f Nonarteritic ischemic optic neuropathy (NAION), 406 Noninvasive ventilation, in neuromuscular disease, 280–282, 281b, 281f, 282b, 282f longitudinal management of, 282, 283f, 283t Noon, 5, 5f Noon: Rest from Work, 5, 5f Noonday Rest, 5, 5f Noradrenaline reuptake inhibitors (NRIs), for central nervous system hypersomnias, 203–204t Nose diseases affecting, 306, 306f, 307f traumatic injury to, 306, 307f NREM. See Non-rapid eye movement NRIs. See Noradrenaline reuptake inhibitors NTS. See Nucleus tractus solitarii Nucleus accumbens activation, pain and, 410–411 Nucleus tractus solitarii (NTS), 68 Nytol (diphenhydramine), for sleep promotion, 140t

O

Obesity adolescent, obstructive sleep apnea in, 329f central sleep apnea with, sleep laboratory video on, 537, 537f as sleep-disordered breathing risk factor, 314 Obesity hypoventilation, sleep laboratory video on, 533, 533f, 534f Obstructive hypopneas, upper airway resistance syndrome vs., 477f Obstructive hypoventilation, definitions of, 343 Obstructive pulmonary diseases. See also Chronic obstructive pulmonary disease; Obstructive sleep apnea in overlap syndrome, 348–351, 348b, 350f, 351f Obstructive sleep apnea (OSA), 126, 128f, 314 in acromegaly, 374 in alcohol dependence, 402 in altered glucose metabolism, pathophysiology and mechanism of, 385–386 atrial fibrillation in, 495f cardiac arrhythmias caused by, 358, 360f, 361f in children, 338, 339f common physical examination findings, 339 historical symptoms of, 339 technical considerations, 339–340, 340f in children, polysomnography of, 464f, 465f in chronic kidney disease, 391, 391t, 392f control of breathing in, 56, 60f, 61f, 63f COVID-19 and, 417 definitions of, 340, 341f, 445 in diabetes, 385–388 development and progression mechanism of, 385–386, 388f prevalence and incidence of, 385, 387f, 387t weight loss impact, 388 effect on cardiovascular physiology, 357–358, 357f, 358f, 359f floppy eyelid syndrome and, 406 health care use prior to diagnosis of, 148, 149f in hypothyroidism, 371f menstrual cycle and, 422 ophthalmologic pathologies and, 405, 406, 406f parasomnias exacerbated by, 153 polysomnography of. See Polysomnography, of obstructive sleep apnea risk assessment of, 158 scoring rules, 445, 446f sleep laboratory video on, 531–533. See also Sleep laboratory video, on obstructive sleep apnea slow-wave sleep reduction in, 73 in stroke bidirectional relationship between, 255–256 diagnosis and treatment of, 256 impact of treatment for, 256–257, 256f impact on outcomes of, 256, 256f pathogenesis of, 252f, 253–254, 253f, 254f as risk factor for, 255, 255f systemic hypertension from, 253 treatment of, oral appliance in, 332–333 Occipital epilepsy, seizure distribution in, 238 Octreotide, for growth hormone hypersecretion, 376 Olanzapine, for insomnia, 141t Ophthalmologic disorders sleep and, 405–408 sleep-disordered breathing and, 406 Ophthalmopathy, Graves, 370f Opiates, central sleep apnea related to, 478f Opioids abnormalities in restless legs syndrome, 213 for restless legs syndrome, 218t

Optic disc, 405f Optic nerve, 405f Optic neuropathy, nonarteritic ischemic, 406 Oral appliance, for obstructive sleep apnea, 332–333 Orexin, 29 OSA. See Obstructive sleep apnea Osler, William, 13, 13f Overlap syndromes, 348–356 extrapulmonary lung restriction in, 353, 354f, 355f extrathoracic upper airway obstruction in, 355, 355f, 356f restrictive lung diseases in, 351–353, 352f, 353f sleep laboratory video on, 539, 539f Oximetry, all-night, in COPD, 350f Oxygen desaturation, from obstructive sleep apnea, 359f

P

Pain polysomnography and, 411–412 sleep and, 409–413 association between, 409 circadian regulation of, 412–413 clinical application of, 410 experimental studies of, 409 mechanisms of, 410 neurobiology of, 410–411, 410f, 411f, 412f psychosocial factors of, 411, 413f restorative, 409 Palate, in examination for sleep apnea, 306, 308f Panayiotopoulos syndrome, 238 Pandemic, sleep during, 414 Paralysis, sleep, 186 in narcolepsy, 132–133 Paraneoplastic syndromes, 266–267, 266t Parasomnia(s), 285–299 arousal disorder as, 285–288, 287f, 288f, 289f, 290f, 291f. See also Arousal disorder clinical features of, 285t epilepsy vs., 243–247, 249–250t experiential, 294–298 historical background on, 15 history of, 154b nocturnal frontal lobe epilepsy in, 298, 298b, 299f, 299t NREM, 285 overview of, 285 pathophysiology of, 285, 286f during pregnancy, 427 rapid eye movement, 288–294 REM sleep behavior disorder differentiated from, 152–155, 154t sleep enuresis in, 298 sleep paralysis of, 294, 297f, 298b treatments of, 293t Parasympathetic activation, during wake and sleep states, 42f Parkinson disease, 258–261 laboratory findings, 259 rapid eye movement in, 259, 260f, 261f REM sleep behavior disorder and sleep apnea, patient interview video on, 529, 529f sleep symptoms of, 258–259, 258f, 259f treatment of, 259–261 tremor in, polysomnography of, 261f, 262f Parsonage Turner syndrome, sleep disturbances in, 274–275, 275f Patient interview videos, 526–531 of Arnold-Chiari malformation, 530, 530f of Becker muscular dystrophy, 530, 530f of multiple sclerosis, 530, 530f of narcolepsy, 528, 528f

Index  553 Patient interview videos (Continued) cataplexy with, 528, 528f hallucinations in, 528 sleep apnea with, 528, 528f of REM sleep behavior disorder, 529, 529f Parkinson disease with, 529, 529f of restless legs syndrome, 529, 529f of sleep-related breathing disorders, 526–527 cardiovascular comorbidities with, 526, 526f with Down syndrome, 526, 526f explaining results of, 527, 527f restless sleep and, 527, 527f of syringomyelia, 530, 530f teaching and CPAP mask fitting for, 527, 527f in truck driver, 527, 527f Pavlov, Ivan, 13, 13f PCOS. See Polycystic ovarian syndrome Penitent Magdalene, 4, 4f Period gene, historical background on, 17, 21 Periodic breathing. See Cheyne-Stokes respirations Periodic limb movement disorder (PLMD), 217–220 Periodic limb movements (PLMs) in adolescent, polysomnography of, 330f in chronic kidney disease, 393–395 diagnosis of, 394 pathophysiology of, 393 treatment for, 394–395, 395t comorbid after CPAP, 473f with obstructive sleep apnea, 472f COPD and, sleep laboratory video on, 538, 538f, 539f historical background on, 20–21 polysomnography of, 504f, 505f restless legs syndrome with, sleep laboratory video on, 540, 540f scoring rules for, 448, 449f in sleep, 217–220 biology of, 220 definition of, 217–218, 219f evaluation and treatment of, 218–220, 221f, 222b genetic variants associated with, 220 history of, 217–218, 219f pathophysiology of, 220 prevalence and clinical significance of, 218, 220f, 221f sleep laboratory video on, 541, 541f Peripheral arterial tonometry, 317 Pharmacologic suppression, of periodic limb movements (PLMs), 220 Pharmacology, 134–146 for CNS hypersomnias, 203–204t with hypnotic properties, 134–141, 135f for insomnia, 182, 183t wakefulness-promoting agents for, 142, 142t Pharynx, abnormal findings in, 306–310, 308f, 309f Phase synchronization, 40–42, 46f, 47f, 48f Phasic REM sleep, 440–443, 443f Phrenic nerve injury, sleep disturbances in, 274–275, 275f Physiologic regulation, in sleep, 39–50, 39f Pickwick syndrome, 14 Pickwickian syndrome, historical background on, 11, 12f, 14 Pinto, Lawrence, 18, 19 Pitolisant, as wakefulness-promoting agent, 144–145 Pituitary gland diseases, 374–378 anatomy, 374 growth hormone hypersecretion in, 374–376 hypersecretion of adrenocorticotropic hormone, 377–378

PLM. See Periodic limb movements PLMD. See Periodic limb movement disorder PMDD. See Premenstrual dysphoric disorder PMS. See Premenstrual syndrome Polycystic ovarian syndrome (PCOS), 423, 423f, 424f Polysomnogram, 181f Polysomnography (PSG), 175, 462–525 of alpha-delta sleep, in chronic fatigue syndrome and fibromyalgia, 435f of apnea with possible hypopnea, 315f, 316f artifacts in in chin EMG, 525f in ECG, 525f EEG cardiac, 521f, 522f respiratory, 519f, 520f, 521f from electrical interference, 518f, 519f eye channel, 523f, 524f leg channel, 524f of cardiac arrhythmias atrial fibrillation as, in congestive heart failure, 488f, 496f from heart blocks, 498f Mobitz second degree, 476f, 499f third degree, 499f Wenckebach second-degree, 498f irregular rhythm and escape beats as, in heart failure, 497f in obstructive sleep apnea, 495f premature ventricular contractions as, 500f sinus arrest and junctional escape rhythm as, 494f of central sleep apnea, 477 with 5-minute epoch, 320f, 321f with 20-minute epoch, 332f with 60-second epoch, 319f on adaptive servoventilation, 480f, 481f on bilevel pressure, 480f with compressed 10-minute epochs, 320f on CPAP, 479f idiopathic, 477f, 479f opiate-related, 478f treatment-emergent, 322f, 323f of confusional arousals, 287f, 288f of congestive heart failure with Cheyne-Stokes breathing atrial fibrillation and, 321f, 496f, 497f cardiogenic oscillations, while awake and, 485f in child, 486f, 487f and multiple abnormalities, 489f, 490f on oxygen therapy, 493f and ventricular tachycardia, 501f while asleep, 488f while awake, 484f, 485f in child, 486f with obstructive apnea on bilevel pressure, 491f on CPAP, 492f, 493f while asleep, 492f while awake, 491f “first night,” normal value ranges for, 454t of heart failure acute, and obstructive sleep apnea, 490f, 491f on ventilatory support, 491f of mixed sleep apnea, 471f becoming complex, 482f with compressed 10-minute epochs, 322f with idiopathic pulmonary fibrosis, 484f with leg movement, 467f of multiple sclerosis, 517, 517f, 518f of narcolepsy, with cataplexy, 201, 202f of neurologic diseases

Polysomnography (Continued) genetic disorder, 506 Becker muscular dystrophy as, 506f Huntington disease as, 507f retinitis pigmentosa as, 507f head trauma as, 516, 516f, 517f movement disorder, 503 calf cramp as, 505f, 506f Parkinson disease as, 503f periodic limb movements as, 504f, 505f restless legs syndrome as, 503f REM sleep behavior disorder as, 511f, 512f seizure as, 512 in benign rolandic epilepsy, 516f with central apnea, 513f with no other abnormalities, 512f temporal lobe, 514f, 515f sleep paralysis as, 510, 511f stroke as awake central apnea, 508f central sleep apnea, 509f, 510f with excessive daytime sleepiness, 508f of neuromuscular disease, 278, 279f of obstructive sleep apnea, 462 with acromegaly, 468f with acute heart failure, 490f, 491f awake and asleep, 470f, 471f cardiorespiratory sensors in, 463f in child, 464f, 465f with congestive heart failure, 492f with Down syndrome, 472f end-tidal analyzer in, 463f hypoventilation vs., 468f, 469f nasal pressure monitors in, 462f, 463f with periodic limb movements, 472f, 473f sleep stage recording in, 469f thermal sensors in, 463f of overlap syndrome with COPD, 350f with kyphoscoliosis, 355f pain and, 411–412 parameters for, recommended, 454t of periodic limb movements, in adolescent, 330f of polycystic ovarian syndrome, 424f postcesarean, 428f of sleep-related breathing disorders, 255 of sleep-related rhythmic movement disorder, 225f in sleep staging, 438–443 classification in, 440 of stage N1, 442f of stage N2, 442f of stage N3, 442f of upper airway resistance syndrome, 476f with cardiac arrhythmia, 476f drilling down in, 474f obstructive hypopneas vs., 477f with respiratory effort-related arousal, 474f, 475f time compression in, 473f Positive airway pressure. See Bilevel positive airway pressure; Continuous positive airway pressure Post-polio syndrome, sleep disturbances in, 273–274, 273t Postcesarean polysomnography (PSG), 428f Posthumous Papers of the Pickwick Club, The, 11 Postpartum depression, 427–429 Postpartum sleep, 427–429 Posttraumatic stress disorder (PTSD) dreaming disruption in, 133 nightmares in, 400–402, 401f sleep architecture of, 401 treatment of, 401–402

554  Index Prazosin, for nightmares in PTSD, 401 Preeclampsia, sleep and, 426t, 427, 427t Pregnancy narcolepsy and, 429 restless legs syndrome in, 427 sleep and, 426–429, 426t first trimester, 426 second trimester, 426–427 summary, 429 third trimester, 427 sleep-disordered breathing and, 427, 427t Prematurity, sleep-disordered breathing in adolescent and, 317, 330f, 500f Premenstrual dysphoric disorder (PMDD), 422 Premenstrual syndrome (PMS), 422 Pressure support servoventilation, in CPAP for heart failure with central apnea, 366–367, 368f Principles and Practice of Medicine, 13 Principles and Practice of Sleep Medicine, 18, 19f Prion disease, sleep disorder in, 267–268 Progressive supranuclear palsy (PSP), 263–264 PSG. See Postcesarean polysomnography Psychiatric disorders, 396–404 alcohol dependence as, 402 depression as, 397–400, 397f. See also Depression dream disruptions in, 133 generalized anxiety disorder as, 402 mania as, 400 overview of, 396–397, 396f patient interview video on, 530, 530f posttraumatic stress disorder as, 400–402, 401f schizophrenia as, 402, 403f screening for sleep disorders in, 402–403, 403t Psychogenic “seizures,” sleep laboratory video on, 544, 544f Psychomotor vigilance test (PVT), 118, 119f total sleep deprivation effects on, 120f Ptosis, upper eyelid, 407f PTS. See Posttraumatic stress PTSD. See Posttraumatic stress disorder Pubertal maturation, 422, 422f Pulmonary disease(s) obstructive. See also Chronic obstructive pulmonary disease; Obstructive sleep apnea in overlap syndrome, 348–351, 348b, 350f, 351f restrictive, in overlap syndrome, 351–353, 352f, 353f Pulmonary edema, central sleep apnea and, sleep laboratory video on, 537, 537f Pulmonary fibrosis idiopathic, mixed sleep apnea with, 484f sleep laboratory video on, 539, 539f Pulse oximeters, for sleep-disordered breathing, COVID-19 and, 417–419 Pupil, 405f PVT. See Psychomotor vigilance test

Q

Quality of life, restless legs syndrome and, 206, 209f Quantitative sensory testing, for pain, 409 Quetiapine, for sleep promotion, 141t

R

Ramelteon latency to persistent sleep in insomniacs and, 138f for sleep promotion, 136 structure of, 139f

Rapid eye movement (REM) density, increased, in depression, 401 Rapid eye movement (REM) latency, decreased, in psychiatric diseases, 397, 397f Rapid eye movement (REM) sleep in animals, 78–79 changes in, in normal aging, 109f control of, 23, 27f dream recall during, 131–132 EEG patterns in, 92f EEG recordings of, 106f functions of, 83, 85f heart rate surges in, 64, 65f heart rhythm pauses in, 65, 66f network responsible for, 31–32, 32f physiologic regulation in, 39, 40f, 41f, 42f, 43f, 44f, 48f, 50f in recovering alcoholic, 141f REM sleep atonia pathways and, 100f seizures inhibited by, 231 sleep and pain after, 409 sleep-promoting neurotransmitters in, 29 sleep-wake neurophysiology of, 94f sympathetic activity in, 64, 64f thermoregulatory responses in, 40t tonic, 440–443, 443f tonic vs. phasic components of, 100f Rapid eye movement (REM) sleep behavior disorder (RBD), 288–294, 297b historical background of, 10, 17 network responsible for, 32, 34f in Parkinson disease, 259, 260f, 261f patient interview video on, 529, 529f Parkinson disease with, 529, 529f polysomnography of, 511f, 512f sleep laboratory video on, 541, 541f loud vocalization and, 542, 542f obstructive sleep apnea and, 543, 543f treatment for, 297t Rapid eye movement (REM) sleep parasomnias, 288–294, 294f, 295f, 296f Rapoport, David, 16, 18f RBD. See Rapid eye movement (REM) sleep behavior disorder Real-time quaking-induced conversion (RT-QuIC), 267–268 Rechtschaffen, Allan, 14, 15, 15f, 16f, 438 Religion, sleep in, 3–4 REM. See Rapid eye movement Renal disease chronic. See Chronic kidney disease circadian desynchrony and, 169 Reoxygenation, in obstructive sleep apnea, 358f Repose (Nonchaloire), 6f RERAs. See Respiratory effort-related arousals Respiratory artifacts, on EEG, 519f, 520f, 521f Respiratory diseases obstructive, 348–351, 348b, 350f, 351f. See also Chronic obstructive pulmonary disease; Obstructive sleep apnea restrictive, 351–353, 352f, 353f sleep laboratory video on, 538–539 Respiratory effort-related arousals (RERAs), 315–316, 317f definitions of, 340 prolonged obstructive hypoventilation with, 476f scoring rules for, 447 upper airway resistance syndrome with, 474f, 475f Respiratory events, in sleep breathing disorders, nonapneic, 317, 325f, 326f Respiratory muscle activity, during sleep, 41f Respiratory sinus arrhythmia (RSA), 40–42, 48f

Respiratory system, infection, SARS-CoV-2 and, 414, 416f Rest, sleep as, 4–5 Rest-activity cycle in advanced sleep-wake phase disorder, 163f in delayed sleep-wake phase disorder, 161f in irregular sleep-wake rhythm disorder, 164f in non-24-hour sleep-wake rhythm disorder, 164f Rest on the Flight into Egypt, 4, 4f Restless legs syndrome (RLS), 153–155, 155b, 206–217 adenosine and, 213 allelic variations increasing risk of, 216t antidepressants worsening, 206 biology of, 211–213, 214f in chronic kidney disease, 393–395 clinical features of, 211b dopamine and, 213, 215f evaluation and diagnosis of, 209–210, 210b, 211b, 211f, 212t genetic abnormalities in, 213, 216t glutamate and, 213 historical background on, 10, 13 in iron deficiency, 211, 214f, 215f medical evaluation of, 211, 213f opioids and, 213 in Parkinson disease, 260 pathophysiology of, 211–213, 214f patient interview video on, 529, 529f in pregnancy, 427 prevalence and clinical significance of, 206–209, 207f, 208f, 209f, 210f severity evaluation of, 210–211, 212b, 213f sleep laboratory video on, 540f treatment of, 213–217, 216b, 217f, 218f, 218t Restorative theory, in normal sleep in humans, 83 Restrictive lung diseases, in overlap syndromes, 351–353, 352f, 353f Retina, 405f Retinal arteriole, 405f Retinal venule, 405f Retinitis pigmentosa apnea with Cheyne-Stokes breathing in, 507f central sleep apnea with, sleep laboratory video on, 537, 537f Retrognathia, mandibular, sleep apnea and, 302–303, 304f Reversed Robin Hood syndrome, 256 Rhythmic movement disorder, sleep-related, 222–225, 225f diagnosis of, 224–225 Rimini Symposium on Hypersomnia and Periodic Breathing, 15, 16f Risperidone, for insomnia, 141t Ritalin (methylphenidate) for central nervous system hypersomnias, 203–204t in wakefulness promotion, 143t RLS. See Restless legs syndrome Robin Hood syndrome, reversed, 256 Rolandic epilepsy, 235–238 Rolandic spikes, in benign rolandic epilepsy, 516f Rosbash, Michael, 17, 21 Roth, Thomas, 16, 18, 18f Rousseau, Henri, 6–7, 7f RSA. See Respiratory sinus arrhythmia Rubens, Peter Paul, 10f Ruvoldt, Maria, 2 Rye, David, 20–21

S

Saavedra, Miguel de Cervantes, 10, 11f Sanders, Mark, 16, 18f

Index  555 Sargent, John Singer, 5, 5f, 6f SARS-CoV-2. See Severe acute respiratory syndrome coronavirus 2 SAST. See Serial addition/subtraction task Sawtooth waves, in REM sleep, 99f Scheemakers, Peter, 5, 5f Schenck, Carlos, 17, 18f Schizophrenia, sleep and, 402, 403f Sclera, 405f Sclerosis, multiple, patient interview video on, 530, 530f SCN. See Suprachiasmatic nuclei Scoliosis, sleep disturbances in, 277, 277f SDB. See Sleep-disordered breathing Second trimester, of pregnancy, sleep during, 426–427, 426t Secondary narcolepsy, 198–200 Seizure(s). See also Epilepsy central apnea and, 513f sleep laboratory video on, 544, 544f temporal, polysomnography of, 514f, 515f Seizure semiology, 229–231 Selective serotonin reuptake inhibitors (SSRI), for central nervous system hypersomnias, 203–204t Serial addition/subtraction task (SAST), 119f Serotonin and norepinephrine reuptake inhibitors (SNRIs), for central nervous system hypersomnias, 203–204t Servoventilation device adaptive, for idiopathic central sleep apnea, 480f, 481f in CPAP for heart failure with central apnea, 366–367, 368f Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), sleep in those infected with, 414–416 long-haul cardiovascular outcomes of, 416, 418f long-haul neurologic and psychiatric outcomes of, 416 long-haul respiratory outcomes of, 414–415 neurologic effects of, 416, 417f Shakespeare, William, 8, 10 Shift-work carcinogenicity of, 173 health risks associated with, 148t sleep disorder related to, 165, 165f, 167t Shivering, during sleep, 40f Short sleep, health risks associated with, 148t Sinus arrest, with obstructive sleep apnea, 360f, 494f Sleep abnormal behaviors and movements related to, 152–155, 154t across menstrual cycle, 421, 421f in adolescence, 113f age-related changes in, 109f histograms of, 107f neurophysiologic mechanisms of, 109f, 115 alcohol dependence and, 402 architecture of, 411 age-related changes in, 110f in depression, 398, 398f, 398t disturbances of, in psychiatric disease, 436 PCOS and, 423 in art and literature, 1–9, 1f athletic performance and, 124–130 addressing the needs, 130f, 129t, 127–129 disordered, 124, 124f, 129t educational materials provided to student, 130f insomnia and other sleep disorders, 126 obstructive sleep apnea, 126, 128f

Sleep (Continued) overscheduling and overtraining, 124–126, 126f changes in, in children, 95–96, 111f complex, mixed sleep apnea becoming, 482f coupling and network interactions among physiologic systems during, 40–44 COVID-19 and, 414–419, 414f current theories about, 83–85 cytokines and host defense in, 51–55 depression and, 397–400, 397f determinants of, 91f disrupted nocturnal, 186–187, 192f dreams, danger, and death in, 6–9 duration during the life cycle, 88b, 89f duration of, upper respiratory infection and, 52f dynamics of individual systems and functional changes in, 39–40 effect of stroke on, 254–255, 254b, 255f endocrine physiology, 72–77 epilepsy and, 227–250 evaluating duration and timing of, 156–158 extension, 126–127, 128f, 129t eye and, 405, 405f, 406f factors affecting, 95, 108t fibromyalgia and, 434, 434b, 435f function of, 83, 84f, 92f generalized anxiety disorder and, 402 as innocence, 5 interactive regulation of, 68–71 shared brain circuits in, 68, 68f, 69f shared somatic signaling between feeding and, 68–70, 69t in mammals, 78–82, 78f, 79f, 80f, 81f, 82f mania and, 400 maturation of, from infancy to adulthood, 113f mechanisms of, 22–28, 91 arousal systems as, 22, 23f, 24f in control of REM sleep, 23, 27f in control of timing of sleep, 23, 28f nervous system control of, 22, 22f, 23f sleep drive as, 23, 26f sleep-promoting systems as, 22–23, 24f, 25f, 26f on menstrual function, 423, 425f myalgic encephalomyelitis, 436–437 in mythology, 1–2, 2f neonatal, maturation and consolidation of, 112f neurobiology of, brain regions of interest to, 99f neurochemistry of, 96f in neurologic disorder, 258–270 neuromuscular disease and, 271–286 chest wall disorders and scoliosis in, 277 common, 272–277, 274f compromised breathing mechanics, in sleep, 278, 278f Duchenne muscular dystrophy, 276, 276f impaired pulmonary physiology and symptoms of, 279–280, 279b, 280f impaired respiratory physiology in, 271–272, 272f motor neuron disease in, 272, 274f muscle disease in, 275–276 myotonic dystrophies in, 276 neuromuscular junction disease in, 275 noninvasive ventilation benefits in, 280–282, 281b, 281f, 282b, 282f peripheral nerve disease in, 273 phrenic nerve injury, neuralgic amyotrophy, parsonage Turner syndrome, 274–275, 275f polysomnography findings in, 278, 279f

Sleep (Continued) post-polio syndrome/infectious motor neuropathy, 273–274 spinal cord injury in, 272–273, 275f neurotransmitters of, 92t normal, 94–95 control of breathing in, 56, 56f, 57f, 58f, 59f in humans, 83–116 hypnogram of, 107f ophthalmologic disorders and, 405–408 pain and, 409–413 association between, 409 circadian regulation of, 412–413 clinical application of, 410 experimental studies of, 409 mechanisms of, 410 neurobiology of, 410–411, 410f, 411f, 412f psychosocial factors of, 411, 413f restorative, 409 regulation of circadian and homeostatic regulation of, 106f physiologic, 39–50, 39f as rest, 4–5 schizophrenia and, 402, 403f sleep changes in, 95–96 stages of, 88t, 94, 101f, 102f, 103f, 104t synaptic plasticity and, 86f thermoregulatory responses in, 40t in those infected with SARS-CoV-2, 414–416 timing of, control of, 23, 28f total, in recovering alcoholic, 141f in uninfected individuals during pandemic, 414, 415b, 415f and wakefulness, transition between, 88, 98f, 99f Sleep and His Half-Brother Death, 8, 9f Sleep and Its Derangements, 12 Sleep and Poetry, 4 Sleep and Sleeplessness, 10 Sleep and Wakefulness, 13 Sleep apnea in adolescent and adult, 314–337 clinical assessment of, 315–317 examination in, 315 laboratory evaluation in, 315 scoring of respiratory events in, 315–316, 315f, 318f, 319f sleep study in, data obtained in, 315 symptoms in, 315, 315b definitions of, 314 home sleep apnea testing, 323f, 324f, 325f nonapneic respiratory events in, 317, 325f, 326f risk factors for, 314 sleep-disordered breathing in, 317, 327f, 328f, 329f, 330f treatment for, 317–333 continuous positive airway pressure, 322f, 331f, 332f oral appliance in, 332–333, 335f, 336f surgery in, 333, 336f, 337f central. See Central sleep apnea control of breathing in, 56, 60f, 61–62f, 61f, 63f central, 61–62f, 63f obstructive, 56, 60f, 61f, 63f definition of, 445 examination of, 300–313 of abdomen, 312, 312f, 313f of extremities, 312–313, 313f facial and jaw structures, 300–305, 300f bony structures in, 301–305, 302f

556  Index Sleep apnea (Continued) inspection in, 300–301, 301f for maxillary and mandibular insufficiency, 302, 303f for pervasive facial abnormalities, 301, 303f for small lower jaw, 302–305, 303f, 304f, 305f, 306f of nasal airway, 305–306, 306f, 307f of neck, 311–312, 312f overall inspection of patient, 300 of palate, 306, 308f of pharynx, 306–310, 308f, 309f of tonsils, 308–309, 309f, 310f historical background of, 15, 16, 17f obstructive. See Obstructive sleep apnea in Parkinson disease, 260 patient interview video on, 526, 526f, 530, 530f cardiovascular comorbidities with, 526, 526f Down syndrome with, 526, 526f narcolepsy with, 528, 528f Parkinson disease with, 529, 529f restless sleep and, 527, 527f in truck driver, 527, 527f during pregnancy, 427 recurrent, cardiovascular consequences of, 362f scoring rules for, 445 Sleep Apnea Syndromes, 16 Sleep apnea upper airway examination, 156b Sleep assessment instruments, 156–158 Sleep attacks, 186 Sleep breathing disorders, in children, 338–347 congenital central hypoventilation syndrome, 338 diagnostic considerations, 343, 344f, 345f history and physical examination, 339–343 treatment options for, 343–346, 345f, 346f Sleep bruxism, 220 biology and pathophysiology of, 222 clinical significance of, 220–222, 222f evaluation of, 222, 223f, 224f treatment of, 222 Sleep center health and family questionnaire, 457f Sleep center screening questionnaire, 455f Sleep debt, 117 Sleep deprivation on cortisol stress reactivity, 122f COVID-19 and, 419 in diabetes mellitus, 386t diabetes risk and, 76f effect of, 51, 52f ghrelin levels and, 77f leptin and, 69–70, 77f testosterone levels and, 76f total, psychomotor vigilance test after, 122f, 123f Sleep diaries, 156–158, 158f Sleep disorder(s) apnea as. See Sleep apnea associated with specific autoantibodies, 266t in chronic kidney disease, 390–395 circadian rhythm disorders, 161–167 classification schema of, 149b diagnosis of clinical evaluation in, 148–158 of excessive sleepiness, 150–152, 153f history of present illness in, 149–155 of insomnia, 150, 150b, 151f medical history in, 155–156, 155t physical examination in, 156, 156b on sleep-disordered breathing, 149, 150b self-administered instruments in Berlin Apnea Questionnaire as, 158, 159f

Sleep disorder(s) (Continued) Epworth Sleepiness Scale as, 156, 158f sleep diaries as, 156–158, 158f STOP-Bang questionnaire as, 158, 159f diagnostic testing of, 158 dreaming disruption in, 132–133 effect on cardiovascular physiology, 357–358, 357f, 358f, 359f future considerations: telemedicine, remote patient monitoring, and beyond, 160 impact of, 147–148, 147f on adolescents, 148b on patient, 152 on workplace productivity and daily activities, 148b insomnia as. See Insomnia menstrual cycle and, 422, 422f other, 126 in Parkinson disease, 258–261, 258f, 259f presentation of, 148–160 Sleep-disordered breathing (SDB), 185, 343–344. See also Sleep-related breathing disorders in chronic kidney disease, 390–395 clinical evaluation of, 148, 150b COVID-19 and, 417–419, 418f therapeutic considerations of, 417–419 definition of, 314 in neuromuscular disease, 279b ophthalmologic disorders and, 406 pregnancy and, 427, 427t Sleep disruption, 410–411 Sleep disturbances in depression, 397–400, 397f management options for, 430–432, 431f, 431t, 432f during menopause, 430, 430f, 431f psychiatric disorder and, 396–404 Sleep drive, 23, 26f Sleep drunkenness, in idiopathic hypersomnia, 186 Sleep enuresis, 298 Sleep-Eze (diphenhydramine), for sleep promotion, 140t Sleep homeostat, 23, 26f components of, pathogens amplifying production of, 52 Sleep hypnogram, 179, 180f Sleep inertia, in idiopathic hypersomnia, 186 Sleep journal, 16, 18f Sleep laboratory video, 531–544 on central sleep apnea and Cheyne-Stokes respiration, 537 idiopathic, 537, 537f obesity with, 537, 537f obstructive sleep apnea and, 537, 537f pulmonary edema and, 537, 537f retinitis pigmentosa with, 537, 537f on neurologic disorders, 540–544 delayed sleep phase syndrome, 543, 543f epilepsy, 543, 543f periodic limb movements, 541f psychogenic “seizures,”, 544, 544f rapid eye movement sleep behavior disorder, 541, 541f, 542f, 543f restless legs syndrome, 540f seizure involving leg, 544, 544f sleep paralysis, 543, 543f on obstructive sleep apnea, 531–533 in acromegaly, 535, 535f after uvulopalatopharyngoplasty, 532, 532f arousal threshold to noise in, 532, 532f in child, 531 Down syndrome and, 535, 535f nasal obstruction and, 531, 531f

Sleep laboratory video (Continued) obesity hypoventilation, 533, 533f, 534f postpartum, 535, 535f in pregnancy, 535, 535f vigorous movements in, 533, 533f violent body movements and, 532, 532f on respiratory diseases, 538–539 asthma, 538, 538f chronic obstructive pulmonary disease, 538, 538f overlap syndrome, 539, 539f pulmonary fibrosis, 539, 539f on upper airway resistance syndrome, 536 quiet snoring, 536, 536f variable snoring, 536, 536f Sleep medicine changes in practice of, 419 history of, 10–21 Sleep of Reason Produces Monsters, The, 6, 7f Sleep paralysis, 186, 294 in narcolepsy, 132–133 polysomnography of, 510, 510f sleep laboratory video on, 543, 543f Sleep problems checklist, 456f screening athlete populations for, 124 Sleep-promoting neurotransmitters, 29 Sleep-promoting systems, 22–23, 24f, 25f, 26f Sleep-related breathing disorders (SRBDs), 314t diagnostic assessment methods for, 445–447 patient interview videos on, 526–527 sleep apnea as, 314. See also Sleep apnea in stroke, 254b. See also Obstructive sleep apnea Sleep-related eating disorder, 293b, 293f Sleep-related epilepsy, 231–243, 235t Sleep-related hypermotor epilepsies, 235, 236f, 237f, 238b, 238f Sleep-related leg cramps, 225–226 treatment for, 226b Sleep-related rhythmic movement disorder, 222–225, 225f diagnosis of, 224–225 Sleep Research Society, historical background on, 14 Sleep restriction, 117, 117f, 118f, 119f, 120f, 121f, 122f historical background on, 19 recovery from, 117 vulnerability to, individual differences in, 118, 123f Sleep scoring manual, historical background on, 15, 16f Sleep spindles on EEG, 111f menstrual cycle and, 421 in stage N2 sleep, 99f Sleep stage(s) changes in, with age, 96–115, 110f EEG frequencies in, features of, 103f proportion of night spent in, 106f recording of, in obstructive sleep apnea, 469f stage N1 changes in, in normal aging, 110f electronic recordings of, 106f stage N2 changes in, in normal aging, 110f electronic recordings of, 106f in child, 108f stage N3, electronic recordings of, 106f stage R, electronic recordings of, 106f in child, 108f stage W. See Wakefulness Sleep-stage transitions, interactions between physiologic systems, 49f

Index  557 Sleep staging, 438–443 classification in, 440 of stage N1, 440, 442f, 443t of stage N2, 440, 442f, 443t of stage N3, 440, 443t of stage R, 440, 443f, 443t of stage W, 440, 441f, 443t of waves, 440, 443t recording in, 438–440 of electroencephalogram for brain activity, 438, 441t of electromyogram for skeletal muscle tone, 439–440 of eye movements, 439, 439t smoothing rules for, 440–443 Sleep terrors, 285, 290f, 291f nightmares vs., 291t Sleep testing, home, 448–450, 449f, 450f, 451f, 452f Sleep time from age 0 to 12 years, 112f developmental changes in, in children, 96, 109f total and nighttime, from 0 to 15 years, 112f Sleep-wake control, hypothalamic mechanisms in, 97f Sleep-wake cycle, 36, 38f activity of brain structures in, 68, 68f bidirectional relationship between feeding and, 70–71 disturbances of, in stroke, 254–255, 254b, 255f metabolic organs modulate, 70 physiology and pathophysiology of, 29–35 Sleep-wake dysregulation, in pathologic states, 32–33 Sleep-wake inversion, 380 Sleep-wake regulation external, 29–30 network responsible for, 32, 33f Sleepiness alpha waves in, 103f daytime, excessive. See Excessive daytime sleepiness disasters related to, 147, 147f fatigue/exhaustion differentiated from, 201 motor vehicle accidents and, 121f, 147f subjective, cognitive performance capability and, 119f Sleeping Apollo, 2, 2f Sleeping Boy, 8, 9f Sleeping Gypsy, 6–7, 7f Sleeping Venus, 1, 2, 3f Sleepwalking, 285, 289f comorbid condition with, 286, 291b confusional arousal as, 285, 287f, 288f sleep terrors as, 285, 290f, 291f Slow-wave sleep (SWS), 51 disease states reducing, 73 Slow waves, on EEG, 105f Social history, 155–156 Sodium oxybate for central nervous system hypersomnias, 203–204t for wakefulness promotion, 142–144 Solms, Mark, on brain lesions leading to loss of dreaming, 131, 131f Solriamfetol, as wakefulness-promoting agent, 144 Sominex (diphenhydramine), for sleep promotion, 140t Somnambulism. See Sleepwalking Spielman's 3-P model for insomnia, 176, 176f Spinal cord injury sleep disorder in, 268 sleep disturbances in, 272–273

Spinal muscle atrophy sleep-disordered breathing in adolescent and, 317, 329f sleep disturbances in, 272, 273t Spinocerebellar ataxias (SCAs), 264, 265f Spitz, Annie, 13, 14f SRBDs. See Sleep-related breathing disorders SRED. See Sleep-related eating disorder SRMD. See Sleep-related rhythmic movement disorder Stanford sleepiness score (SSS) self-ratings, 119f Steen, Jan, 4–5, 4f Stefansson, Hreinn, 20–21 Stephan, Frederick, 15 Sternbach, Leo, 14 Stimulant(s) amphetamines as, 142–145 caffeine as, 145, 146f for central nervous system hypersomnias, 203–204t clinical characteristics of, 143t mechanism of action of, 144f modafinil as, 142, 144f, 144t, 145f sodium oxybate as, 142–144 STOP-BANG questionnaire, 158, 159f, 449– 450 Strattera (atomoxetine) for central nervous system hypersomnias, 203–204t in wakefulness promotion, 143t Streptococcal infection, narcolepsy secondary to, 197–198f Stroke, 251 breathing patterns after, 251, 251t, 252f central apnea in, polysomnography of while asleep, 509f, 510f while awake, 508f effect of sleep, 254–255, 254b, 255f obstructive sleep apnea in bidirectional relationship between, 255–256 outcomes, impact of, 256, 256f pathogenesis of, 252f, 253–254, 253f, 254f risk factor for, 255, 255f treatment of, 256–257, 256f, 257f Study of Women's Health Across the Nations (SWAN), 421, 421f Subclinical seizure, 229 Substantia nigra abnormalities of, in Parkinson disease, 258 reduced iron levels in, in restless legs syndrome, 211–213, 214f, 215f Suggested immobilization test (SIT), in restless legs syndrome severity evaluation, 460 Sullivan, Colin, 16, 18f Sundowning, 261–262 Suprachiasmatic nuclei (SCN) in circadian system, 36, 37f, 38f, 168, 168f historical background on, 15 in sleep-wake cycles, 23, 28f Supraventricular tachycardia, with obstructive sleep apnea, 361f Suvorexant, for sleep promotion, 138 SWAN. See Study of Women's Health Across the Nations Sweating, chest, in sleep, 41f SWS. See Slow-wave sleep Sympathetic activation, during wake and sleep states, 42f Sympathovagal balance, with sleep-stage transitions, 39 Synaptic homeostasis theory, in normal sleep in humans, 83, 85f, 86f Synchronization cardiorespiratory, 40–42, 46f, 47f, 48f phase, 40–42, 46f, 47f, 48f

Syringomyelia, patient interview video on, 530, 530f Systemic hypertension, from obstructive sleep apnea, 358f, 361–363, 362f, 363f

T

Tachycardia supraventricular, with obstructive sleep apnea, 361f ventricular, 501f Tachypnea, thermal, in non-REM sleep, 40f, 41f Takahashi, Joseph, 18, 19 Teasing a Sleeping Girl, 5, 6f Teeth, crowded, in small mandible, 302, 303f Temporal lobe epilepsy, seizure distribution in, 235t Testosterone levels, sleep deprivation and, 76f Thalamocortical (TC) system, in sleep regulation, 26f Thermal tachypnea, in non-REM sleep, 40f Thermoregulatory function theory, in normal sleep in humans, 83 Thermoregulatory responses, in wakefulness and sleep, 40t Theta waves, in stage N1 sleep, 103f Third trimester, of pregnancy, sleep during, 426t, 427 Thorpy, Michael, 18, 19f Three Ages of Woman, The, 5, 7f Thyroid disease, 369–373 hyperthyroidism as, 369, 370f, 371f causes of, 369t Graves ophthalmopathy in, 370f sleep findings in, 369b symptoms of, 369b, 369f hypothyroidism as, 369 causes of, 371b sleep findings in, 371b symptoms of, 371b, 373f facial, 372f hair, 372f thyroid mass lesions as, 369 sleep findings with, 373b, 373f types of, 373b Thyroiditis, hyperthyroidism from, 369t TNF-a. See Tumor necrosis factor-a Tongue creased, in small mandible, 305, 306f enlarged, in hypothyroidism, 372f pharynx and, Mallampati classification of, 306–308, 308f scalloped, in small mandible, 305, 305f Tonic REM sleep, 440–443 Tonsil(s) examination of, 308–309, 309f, 310f variants in, 309–310, 310f, 311f hypertrophy of, obstructive sleep apnea in adolescent with, 317, 327f size of, grading of, in clinical evaluation of sleep-disordered breathing, 157f Torsades de pointes, in REM sleep, 65 Total sleep deprivation, psychomotor vigilance test after, 122f, 123f Toxic goiter, hyperthyroidism from, 369t Trauma, head, 516f Trauma-associated sleep disorder (TASD), 401 Travel fatigue, conceptual model of, 126f Traversi, Gaspare, 5, 6f Trazodone characteristics of, 141b sleep-onset time in insomniacs with, 140f for sleep promotion, 134t structure of, 140f Triazolam injection sites of, into medial preoptic area, 136 structure of, 136f

558  Index Tricyclic antidepressants, for central nervous system hypersomnias, 203–204t Trier Social Stress Test (TSST), 122f TSST. See Trier Social Stress Test Tumor necrosis factor-a (TNF-a), sleep and, 51–52, 53t, 54t Turek, Fred, 16, 17f, 18, 19, 20, 21f Tylenol PM (diphenhydramine in combination), for sleep promotion, 140t

U

UARS. See Upper airway resistance syndrome UCP-1. See Uncoupling protein 1 Uncoupling protein 1 (UCP-1), 70 Unisom Nighttime (doxylamine), for sleep promotion, 140t Upper airway collapse of, 58f muscles of, 60f obstruction chronic obstructive pulmonary disease with, sleep laboratory video on, 538, 538f extrathoracic, in overlap syndrome, 355, 355f, 356f Upper airway resistance syndrome (UARS), sleep laboratory video on, 536 quiet snoring, 536, 536f variable snoring, 536, 536f Urns, 8, 9f Uvulopalatopharyngoplasty, atypical snoring after, sleep laboratory video on, 532, 532f

V

Vagus nerve stimulation (VNS), for epilepsy, 247–250 Van Gogh, Vincent, 5, 5f van Rijn, Rembrant, 11f Vasomotor symptoms, of menopause, 430 Ventilatory instability, potential cycle of, 61f Ventricular tachycardia, 501f in heart failure, 502f Ventrolateral preoptic (VLPO) system GABAergic neurons of, in NREM sleep promotion, 29, 30, 31f in sleep regulation, 22

Videos patient interview, 526–531. See also Patient interview videos sleep laboratory, 531–544. See also Sleep laboratory video Vision, circadian rhythm disorders and, 406, 408f Vitaterna, Martha, 18 VLPO system. See Ventrolateral preoptic system Vogel, Gerry, 14 Voltage-gated potassium channel (VGKC) complex antibodies, 266–267 von Baeyer, Adolf, 11 von Economo, Baron Constantine, on brain in sleep-wake behavior, 24f von Liebig, Justus, 11 von Mering, Joseph, 13

W

Wadd, William, 10 Wake-promoting neurotransmitters, 29 Wake states coupling and network interactions among physiologic systems during, 40–44 dynamics of individual systems and functional changes in, 39–40 Wakefulness, 88 arousal during, 22 changes in, in normal aging, 96–115, 110f function of, 83, 85f network responsible for, 30, 30f neurochemistry of, 96f neurologic basis for, historical background on, 14 neurophysiology of, 88, 90f physiology and pathophysiology of, 29 regulation of, circadian and homeostatic regulation of, 106f and sleep, transition between, 88, 98f, 99f thermoregulatory responses in, 40t transition into NREM sleep from, 88, 97f Waking state, network responsible for, 30, 30f Waterhouse, John William, 8, 9f Waveforms, in sleep staging, 440, 441t, 443t Wells, William, 13

Wenckebach second-degree heart block, 498f Westphal, Karl, 13 White adipose tissue, in interactive regulation of sleep and feeding, 70 Willis, Thomas, 10, 12f Willis-Ekbom disease. See Restless legs syndrome Winkelmann, Juliane, 20–21 Women's health chronic fatigue syndrome and, 433b fibromyalgia. See Fibromyalgia menstrual cycle, 420–425 midlife transition/menopause and, 430–431 pregnancy. See Pregnancy Workplace productivity, impact of sleep problems on, 148b Wurtman, Richard, 14

Y

Yanagisawa, Masashi, 19–20 Young, Michael, 17, 21 Young, Terry, 18

Z

Zaleplon binding of, to GABA receptor, 136f GABA-A receptor affinities of, 136t sleep latency in insomniacs and, 139f for sleep promotion, 134t, 138 structure of, 138f Zee, Phyllis, 21, 21f Zolpidem binding of, to GABA receptor, 136f forms of, 136–137 GABA-A receptor affinities of, 136t historical background on, 17 for insomnia, 183, 183t plasma concentration of, 137f for sleep promotion, 134t, 136–137, 137f, 139f structure of, 136f Zopiclone GABA-A receptor affinities of, 136t for sleep promotion, 134t, 138 Zucker, Irving, 15

Conf idence is ClinicalKey Evidence-based answers, continually updated

The latest answers, always at your fingertips A subscription to ClinicalKey draws content from countless procedural videos, peer-reviewed journals, patient education materials, and books authored by the most respected names in medicine.

Your patients trust you. You can trust ClinicalKey. Equip yourself with trusted, current content that provides you with the clinical knowledge to improve patient outcomes.

Get to know ClinicalKey at store.clinicalkey.com. 2019v1.0