Essentials of Sleep Medicine: M. Safwan Badr Jennifer L. Martin Editors

Respiratory Medicine
Series Editors: Sharon I.S. Rounds · Anne Dixon · Lynn M. Schnapp
M. Safwan Badr
Jennifer L. Martin Editors
Essentials of
Sleep Medicine
A Practical Approach to Patients with
Sleep Complaints
Second Edition
Series Editors
Sharon I. S. Rounds, Brown University
Providence, RI, USA
Anne Dixon, University of Vermont, Larner College of Medicine
Burlington, VT, USA
Lynn M. Schnapp, University of Wisconsin - Madison
Madison, WI, USA
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M. Safwan Badr • Jennifer L. Martin
Editors
Essentials of Sleep Medicine

A Practical Approach to Patients with Sleep
Complaints
Second Edition
Editors
M. Safwan Badr Jennifer L. Martin
Department of Internal Medicine Geriatric Research Education and Clinical
Wayne State University School of Medicine Center, Veteran Affairs Greater Los Angeles
John D. Dingell VA Medical Center Healthcare System
Detroit, MI, USA Department of Medicine
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, CA, USA
ISSN 2197-7372 ISSN 2197-7380 (electronic)

ISBN 978-3-030-93738-6 ISBN 978-3-030-93739-3 (eBook)
https://doi.org/10.1007/978-3-030-93739-3
© Springer Nature Switzerland AG 2022

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Foreword
In the last few decades, we have learned more and more about how important sleep
is for our physical health, our mental health, and our general well-being. And yet,
sleep problems continue to become more prevalent. The was a time when patients
with problems sleeping would neglect to mention it to their health care professional.
But those times are changing. As more and more research is done, as more and more
articles are written about the importance of sleep, the general public has become
more and more aware and better educated. And now they are not hesitating to talk
about this major issue.
Which means that more general healthcare professionals and specialists, such as
physicians, psychologists, nurse practitioners, and nurses, will be faced with deal-
ing and treating these sleep problems. And that is where this book comes in.
But it is not just those first entering the field who will benefit from this book. As
someone with over 40 years’ experience in sleep medicine, I can attest to the fact
that even those of us with loads of experience have new things to learn, and this
book can help us all do just that.
The editors, Drs. Jennifer Martin and Safwan Badr, are internationally recog-
nized and highly respected sleep medicine specialists, each with a long list of cre-
dentials. In Introduction to Sleep Medicine, they have assembled other experts in the
field to cover everything from normal sleep, health disparity, and models of caring
to descriptions of and treatment of specific sleep disorders, such as obstructive sleep
apnea, insomnia, and circadian rhythm disorders, to name just a few. There are also
chapters on special populations such as hospitalized patients, pregnant women, and
older patients. And each chapter represents the very latest in research and clinical
findings. In other words, everything a professional dealing with sleep problems
needs to know.
No one book can be everything to everyone. But this book is an excellent addi-
tion to any private or public library collection, whether it be one filled with other
books on sleep or a new collection of sleep books that is just beginning. Having a
resource book such as this one can only help healthcare professionals better under-
stand their patients.
v
vi Foreword
Introduction to Sleep Medicine, in summary, is an extremely masterful and

scholarly book that can be used by all professionals wanting to help their patients
with sleep problems. I commend Drs. Martin and Badr on this comprehensive intro-
duction to sleep medicine.
November 8, 2021 Sonia Ancoli-Israel

University of California
San Diego, CA, USA
Preface
Sleep has fascinated poets, lovers, and philosophers since time immemorial. It was
a metaphor for rest, rejuvenation, and restoration. Physicians viewed sleep and
thought of sleep as a “safe harbor” keeping illness away, and as a cuddly “teddy
bear” giving warmth and serenity. Few physicians appreciated sleep complexity
beyond the elemental aspects: patients need rest and sleep. Disorders of sleep were
the subject of interesting discussions at teaching conferences, but the only condition
worthy of discussion was lack of sleep, and it was often due to tension, anxiety,
or stress.
The image of sleep as a quiescent period changed dramatically when scientists
began to uncover the mysteries of sleep: the good, the bad, and the ugly! The dis-
covery of REM sleep altered the popular image of sleep as a somewhat meaningless
state of rest and revealed a fascinating constellation of active processes throughout
the body and brain. However, it was the discovery of sleep apnea that propelled
sleep into mainstream medicine. This is a condition where sleep is anything but rest.
We learned that sleep can be seen as a “grizzly bear” as we discovered that sleep
apnea (broadly referred to as sleep disordered breathing) can have significant
adverse consequences and may contribute to mortality and to traffic fatalities.
The initial phase of sleep medicine was marked by different specialties providing
care for conditions deemed within their domain. Neurologists, psychiatrists, and
pulmonologists focused on different disorders and different approaches to diagnosis
and treatment. Fortunately, we soon discovered that sleep is an interdisciplinary
field, transcending traditional, system-based specialties, and that other health care
providers and public health experts are needed to address the modern epidemic of
sleep disorders.
Patients present with complaints and not diagnoses, and any one sleep disorder
accounts for only a small proportion of patients with sleep-related complaints. We
learned that snoring may represent a serious condition, that daytime sleepiness is
not always a sign of narcolepsy, and that insomnia is not typically accounted for by
co-occurring anxiety or depression. Therefore, healthcare providers who care for
any sleep disorder must learn about all sleep disorders.
vii
viii Preface
The focus of this book is practical; relevant facts help busy practicing clinicians
provide better care for sleep disorders as part of a comprehensive approach to
patient care. It is intended to equally address the needs of all clinicians who care for
patients with sleep disorders. Residents and fellows may find the focused descrip-
tion and practical approach beneficial. This revised edition includes new chapters to
address a broad range of considerations in delivering high quality care across the
spectrum of sleep disorders.
This book represents the collective effort of a team of professionals. Each chap-
ter was written by experts in the field, blending seasoned experts with emerging
leaders.
Editing a book is a challenging process as one tries to keep a group of busy aca-
demicians, many of whom crafted their chapter during the COVID-19 pandemic, on
schedule. We are grateful to Margaret Moore and Swathiga Karthikeyan of Springer
for their support, guidance, and superb organizational skills. We would like to thank
Springer Science and Business Media for supporting this project.
Detroit, MI, USA M. Safwan Badr

North Hills, CA, USA Jennifer L. Martin
Contents
Part I Introduction to Sleep Medicine

1 Normal Sleep�� 3
James A. Rowley and M. Safwan Badr
2 Pharmacology of Sleep�� 21
Janet H. Dailey and Susmita Chowdhuri
3 Sleep Health among Racial/Ethnic groups and Strategies
to achieve Sleep Health Equity �� 47
Azizi A. Seixas, Anthony Q. Briggs, Judite Blanc, Jesse Moore,
Alicia Chung, Ellita Williams, April Rogers, Arlener Turner,
and Girardin Jean-Louis
4 The Future of Sleep Medicine: A Patient-Centered
Model of Care �� 69
Barry G. Fields and Ilene M. Rosen
Part II Sleep Disordered Breathing

5 Obstructive Sleep Apnea: Clinical Epidemiology
and Presenting Manifestations�� 91
Eric Yeh, Nishant Chaudhary, and Kingman P. Strohl
6 Obstructive Sleep Apnea: Diagnosis with Polysomnography
and Portable Monitors�� 111
Janna Raphelson, Erica Feldman, and Atul Malhotra
7 A Brief Review of Treatment of Obstructive Sleep Apnea �� 129
Scott Hoff and Nancy Collop
8 Central Sleep Apnea: Pathophysiology and Clinical
Management �� 145
M. Safwan Badr and Geoffrey Ginter
ix
x Contents
9 Sleep and Hypoventilation�� 163

Amanda J. Piper
10 Perioperative Care of Patients with Obstructive Sleep Apnea
Syndrome�� 187
Kara L. Dupuy-McCauley, Haven R. Malish, and Peter C. Gay
11 Sleep-Disordered Breathing (SDB) in Pediatric Populations�� 215
Carol L. Rosen
Part III Non-respiratory Sleep Disorders

12 Diagnosis of Insomnia Disorder�� 253
Rachel Atkinson and Christopher Drake
13 Management of Insomnia Disorder�� 275
Gwendolyn C. Carlson, Michelle R. Zeidler,
and Jennifer L. Martin
14 Circadian Rhythm Sleep-Wake Disorders�� 297
Mia Y. Bothwell and Sabra M. Abbott
15 Narcolepsy and Idiopathic Hypersomnia�� 327
Imran Ahmed and Michael Thorpy
16 Non-REM Parasomnias�� 349
Nathan A. Walker and Bradley V. Vaughn
17 Rapid Eye Movement Parasomnias�� 381
Jordan Taylor Standlee and Margaret A. Kay-Stacey
18 Movement Disorders�� 399
Salam Zeineddine and Nidhi S. Undevia
Part IV Sleep in Special Conditions

19 Sleep in Critical Illness�� 431
Michael T. Y. Lam, Atul Malhotra, Jamie Nicole LaBuzetta,
and Biren B. Kamdar
20 Sleep in Hospitalized Patients �� 453
Nancy H. Stewart and Vineet M. Arora
21 Sleep in Pregnancy �� 471
Louise M. O’Brien
22 Sleep in Older Patients�� 495
Armand Michael Ryden and Cathy Alessi
Index�� 515
Contributors
Sabra M. Abbott Northwestern University Feinberg School of Medicine,

Department of Neurology, Chicago, IL, USA
Imran Ahmed Sleep-Wake Disorders Center, Montefiore Medical Center, and
Albert Einstein College of Medicine, Bronx, NY, USA
Cathy Alessi David Geffen School of Medicine at University of California, Los
Angeles, Los Angeles, CA, USA
Geriatric Research, Education and Clinical Center, Veterans Affairs Greater Los
Angeles Healthcare System, Los Angeles, CA, USA
Vineet M. Arora Department of Medicine, University of Chicago Medical Center,
Chicago, IL, USA
Rachel Atkinson University of Toledo College of Medicine and Life Sciences,
Toledo, OH, USA
M. Safwan Badr Division of Pulmonary, Critical Care and Sleep Medicine,
Department of Internal Medicine, Harper University Hospital, Wayne State
University School of Medicine, Detroit, MI, USA
Judite Blanc University of Miami, Miller School of Medicine, Miami, FL, USA
Mia Y. Bothwell University of Illinois at Urbana-Champaign Medical Scholars
Program, Champaign, IL, USA
Anthony Q. Briggs New York University Langone Health, Department of
Population Health, New York, NY, USA
New York University Langone Health, Department of Psychiatry, New York, NY, USA
Gwendolyn C. Carlson Department of Mental Health, VA Greater Los Angeles
Healthcare System, VA Health Services Research and Development Service
(HSR&D) Center for the Study of Healthcare Innovation, Implementation and
Policy, Los Angeles, CA, USA
xi
xii Contributors
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of

Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Nishant Chaudhary Division of Pulmonary, Critical Care, and Sleep Medicine,
Department of Medicine, University Hospitals of Cleveland, Case Western Reserve
University, Cleveland, OH, USA
Susmita Chowdhuri Sleep Medicine Section, Medical Service John D. Dingell
VA Medical Center, Detroit, MI, USA
Department of Medicine, Wayne State University, Detroit, MI, USA
Alicia Chung New York University Langone Health, Department of Population
Health, New York, NY, USA
Nancy Collop Emory Sleep Center, Emory University School of Medicine,
Atlanta, GA, USA
Janet H. Dailey Pharmacy Benefits Management Services, Veterans Health
Administration, Washington, DC, USA
Christopher Drake Henry Ford Sleep Disorders and Research Center,
Detroit, MI, USA
Kara L. Dupuy-McCauley Center for Sleep Medicine, Mayo Clinic,
Rochester, MN, USA
Erica Feldman University of California, San Diego, Department of Medicine,
Internal Medicine, La Jolla, CA, USA
Barry G. Fields Emory University, Division of Pulmonary, Allergy and Critical
Care Medicine, Atlanta, GA, USA
Peter C. Gay Department of Medicine, Mayo Clinic, Rochester, MN, USA
Geoffrey Ginter Department of Internal Medicine, Harper University Hospital,
Wayne State University School of Medicine, Detroit, MI, USA
Scott Hoff Emory Sleep Center, Emory University School of Medicine,
Atlanta, GA, USA
Girardin Jean-Louis University of Miami, Miller School of Medicine,
Miami, FL, USA
Biren B. Kamdar Department of Medicine, Division of Pulmonary, Critical Care
and Sleep Medicine, University of California San Diego Health, La Jolla, CA, USA
Margaret A. Kay-Stacey Northwestern University Feinberg School of Medicine,
Jamie Nicole LaBuzetta Department of Neurosciences, Division of Neurocritical
Care, University of California San Diego Health, La Jolla, CA, USA
Contributors xiii
Michael T. Y. Lam Department of Medicine, Division of Pulmonary, Critical

Care, Sleep Medicine and Physiology, University of California San Diego Health,
La Jolla, CA, USA
Atul Malhotra Department of Medicine, Division of Pulmonary, Critical Care,
Sleep Medicine and Physiology, University of California San Diego Health,
La Jolla, CA, USA
Haven R. Malish Sleep Medicine, Mayo Clinic, Rochester, MN, USA
Jennifer L. Martin Geriatric Research, Education and Clinical Center, Veteran
Affairs Greater Los Angeles Healthcare System, Department of Medicine, David
Geffen School of Medicine, University of California, Los Angeles, Los
Angeles, CA, USA
Jesse Moore New York University Langone Health, Department of Population
Louise M. O’Brien Division of Sleep Medicine, Department of Neurology,
Michigan Medicine, Ann Arbor, MI, USA
Department of Obstetrics & Gynecology, Michigan Medicine, Ann Arbor, MI, USA
Amanda J. Piper Department of Respiratory and Sleep Medicine, Royal Prince
Alfred Hospital, Camperdown, NSW, Australia
Faculty of Medicine and Health, University of Sydney, Camperdown, NSW,
Australia
Janna Raphelson University of California, San Diego, Department of Medicine,
Internal Medicine, La Jolla, CA, USA
April Rogers St. John’s University, New York, NY, USA
Carol L. Rosen Department of Pediatrics, Case Western Reserve University
School of Medicine, Cleveland, OH, USA
Ilene M. Rosen Division of Sleep Medicine, Perelman School of Medicine at the
University of Pennsylvania PCAM, Philadelphia, PA, USA
James A. Rowley Division of Pulmonary, Critical Care and Sleep Medicine,
Department of Internal Medicine, Harper University Hospital, Wayne State
University School of Medicine, Detroit, MI, USA
Armand Michael Ryden Pulmonary, Critical Care and Sleep Medicine Division,
Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
David Geffen School of Medicine at University of California, Los Angeles, Los
Angeles, CA, USA
Azizi A. Seixas University of Miami, Miller School of Medicine, Miami, FL, USA
Jordan Taylor Standlee Northwestern University Feinberg School of Medicine,
xiv Contributors
Nancy H. Stewart Department of Medicine, University of Kansas Medical Center,

Kansas City, KS, USA
Kingman P. Strohl Division of Pulmonary, Critical Care, and Sleep Medicine,
Department of Medicine, University Hospitals of Cleveland, Case Western Reserve
University, Cleveland, OH, USA
Michael Thorpy Sleep-Wake Disorders Center, Montefiore Medical Center, and
Albert Einstein College of Medicine, Bronx, NY, USA
Arlener Turner University of Miami, Miller School of Medicine, Miami, FL, USA
Nidhi S. Undevia Department of Medicine, Division of Pulmonary and Critical
Care Medicine, Loyola Center for Sleep Disorders, Loyola University Medical
Center, Maywood, IL, USA
Bradley V. Vaughn Department of Neurology, University of North Carolina,
Chapel Hill, NC, USA
Nathan A. Walker Department of Neurology, University of North Carolina,
Chapel Hill, NC, USA
Ellita Williams New York University Langone Health, Department of Population
Eric Yeh Division of Pulmonary, Critical Care, and Sleep Medicine, Department
of Medicine, University Hospitals of Cleveland, Case Western Reserve University,
Cleveland, OH, USA
Michelle R. Zeidler Sleep Disorders Center, VA Greater Los Angeles VA
Healthcare System, Department of Medicine, David Geffen School of Medicine,
University of California, Los Angeles, Los Angeles, CA, USA
Salam Zeineddine Department of Medicine, John D. Dingell VA Medical Center
and Wayne State University School of Medicine, Detroit, MI, USA
Part I
Introduction to Sleep Medicine
Chapter 1
Normal Sleep
James A. Rowley and M. Safwan Badr
Keywords NREM sleep · REM sleep · EEG · Upper airway resistance ·

Hypocapnic apneic threshold · Critical closing pressure (Pcrit) · Heart rate
variability · Esophageal sphincter
Normal Sleep Stages and Architecture
Normal human sleep is generally divided into four stages. Consensus definitions for
the visual scoring of sleep were published in 2007 and the reader is referred to the
American Academy of Sleep Medicine Scoring Manual for full definitions and cri-
teria for the scoring of sleep on polysomnograms as these are periodically updated
[1, 2]. The following will provide a brief overview of the electroencephalographic
(EEG) characteristics of the different sleep stages (see also Fig. 1.1).
Full wakefulness is characterized by mixed-frequency, low-amplitude EEG
activity, often in association with high chin muscle tone, eye blinks, and rapid eye
movements. As the patient transitions to sleep with eyes closed, wakefulness is
characterized by a 8–13 Hz sinusoidal activity called alpha sleep. Alpha sleep is best
recorded over the occipital region and is attenuated by eye opening.
Non-rapid eye movement (NREM) sleep composes the majority of the night
and is characterized by the predominance of homeostatic mechanisms for breath-
ing, cardiovascular and gastrointestinal function, and normal thermoregulation.
NREM sleep is divided into 3 stages. N1 sleep is a transitional period during
which the individual still usually has some awareness of his/her environment. N1
sleep is characterized by a slowing of the background wake EEG frequencies with
J. A. Rowley (*) · M. S. Badr

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine,
Harper University Hospital, Wayne State University School of Medicine, Detroit, MI, USA
e-mail: jrowley@med.wayne.edu; sbadr@med.wayne.edu
© Springer Nature Switzerland AG 2022 3

M. S. Badr, J. L. Martin (eds.), Essentials of Sleep Medicine,
Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3_1
4 J. A. Rowley and M. S. Badr
Fig. 1.1 Representative 30-second epochs of sleep stages. (a) Wakefulness with alpha rhythm; (b)
Stage N1; (c) Stage N2 with K-complex and spindle; (d) Stage N3 (slow-wave sleep); and (e)
Stage R. For all epochs: E1-M2: left electro-oculogram; E2-M2: right electro-oculogram; Chin 2:
chin EMG; F4-M1: right frontal EEG; C4-M1: right central EEG; O2-M1: right occipital EEG
1 Normal Sleep 5
a predominance of low amplitude activity in 4–7 Hz (often referred to as theta

activity). Slow eye movements are commonly observed during N1 sleep. N2
sleep, at which time the individual generally is no longer aware of his/her envi-
ronment, is characterized by the appearance of sleep spindles and K complexes
superimposed on a background of theta activity. Sleep spindles are rhythmic sinu-
soidal waves of 12–14 Hz, usually best recorded on central EEG leads. K com-
plexes are diphasic waves having a well-delineated sharp negative component
followed by a slow positive component. N3 sleep, commonly known as slow-
wave sleep, is scored when slow-wave activity is recorded on >20% of an epoch.
By definition, slow waves are of low frequency (generally 0.5–2 Hz) and have
large amplitude (>75 μV).
As opposed to NREM sleep, rapid eye movement (REM or Stage R) is character-
ized by variations and instability in cardiopulmonary function and instability of
body temperature control. In addition, Stage R is characterized by dreaming, rela-
tive atonia of all muscle groups except the diaphragm and in men, erections. On
EEG, Stage R is characterized by a low-amplitude, mixed-frequency EEG, similar
to that seen in Stage N1 sleep. In addition, Stage R is characterized by the presence
of rapid eye movements and decreased chin muscle tone. Stage R is a unique time
of the night in that dreaming occurs during Stage R sleep.
Sleep architecture describes the organization of the sleep stages over the course
of the night (Fig. 1.2). The normal sleep cycle in a young adult (generally consid-
ered the standard) begins with transitioning from wakefulness to N1 sleep and then
quickly transitioning to N2 and N3 sleep. The first occurrence of Stage R sleep is
generally at about 90 minutes and individuals then cycle between NREM and REM
sleep every 90–110 minutes throughout the night. In general, N3 sleep predomi-
nates in the first half of the night while Stage R predominates in the second half of
the night. For an average individual in their second decade, Stage N1 is 2–5% of the
total sleep time, Stage N2 is 45–55%, Stage N3 13–23%, and Stage R is 20–25% [3].
Stage R
Stage W
Stage N1
Stage N2
Stage N3
11 12 1 2 3 4 5 6 7
Clock Time
Fig. 1.2 Representative hypnogram showing normal sleep architecture

Overall sleep architecture is dependent upon stage of development and aging

(Fig. 1.3). For instance, infants generally spend up to 50% of the night in Stage R
sleep and often have a cycle of REM sleep prior to NREM sleep. In addition, the
duration of the NREM-REM cycle is 60 minutes through most of childhood. Over
the span of time between young adulthood to elderly, there are changes in most
sleep stages, including decreased total sleep time and sleep efficiency, increased
percentage of Stages N1 and N2, decreased percentage of Stage N3 and R. These
changes with aging have been shown to be more prominent in men than
women [3, 4].
Breathing During Sleep: Ventilation and the Upper Airway
Summary of Normal Breathing and Ventilation During Sleep
Ventilatory motor output during sleep decreases from its normal levels in wakeful-
ness, leading to decreased tidal volume and minute ventilation. The decreased ven-
tilation is accompanied by reduced upper-airway dilator muscle activity resulting in
decreased upper-airways caliber and increased airflow resistance. These biological
600
500
Sleep Latency
400 WASO
REM
300
SWS
200
Stage 2
100
Stage 1
0
5 10 15 25 35 45 55 65 75 85
Age
Fig. 1.3 Changes in sleep stages as a percentage of sleep time across the age span. WASO = wake
after sleep onset; REM = rapid eye movement sleep; SWS = slow-wave sleep. See text for details
1 Normal Sleep 7
changes may account for the observed increase in Paco2 and decrease in Pao2 during
sleep, despite the diminished overall metabolic rate. A decrease in chemorespon-
siveness during sleep may also explain the increased Paco2. Overall, breathing
becomes more dependent on chemical stimuli, especially PaCO2.
In contrast to NREM sleep, REM sleep is characterized by variability in ventila-
tion. This variability consists of sudden changes in respiratory amplitude and fre-
quency associated with the periods of phasic rapid eye movements. Because of this
variability, minute ventilation in REM sleep has been shown to be the same,
increased, or decreased compared with NREM sleep. Upper-airway resistance has
also been reported variably as either the same or increased compared to wakefulness
and NREM sleep. Finally, hypercapnic and hypoxic ventilatory chemoresponsive-
ness is decreased in REM sleep compared to wakefulness and possibly even
NREM sleep.
Effect of Sleep on Control of Breathing
Chemoresponsiveness refers to changing ventilation in response to changes in

chemical stimuli. Chemosensitivity is influenced by changes in neural activity
during sleep. Thus, hypoxic and hypercapnic chemoresponsiveness contribute to
maintaining ventilation during sleep. Conversely, hypocapnia is a potent inhibi-
tor of ventilation during NREM sleep and is a key mechanism of central
apnea [5].
The sleep state is characterized by decreased ventilatory response to hypercapnia
(HCVR) in human adults compared to wakefulness [6–12]. While the sensitivity to
Paco2 does not appear to differ within NREM sleep stages, the HCVR during REM
stage is depressed further compared with NREM sleep [6, 8]. Similarly, hypoxic
ventilatory responsiveness (HVR) is also diminished during NREM sleep compared
to wakefulness, with a further decrease in REM sleep [10, 13–15]. Nevertheless, the
effect of sleep on chemoresponsiveness is confounded by the sleep effect on upper
airway mechanics and associated decrease in ventilation.
The loss of wakefulness stimulus to breathe renders ventilation during NREM
sleep critically dependent on chemoreceptor stimuli (Pao2 and Paco2). Reduced
Paco2 is a powerful inhibitory factor of ventilation during sleep. Therefore, cen-
tral apnea develops when Paco2 is reduced below a highly reproducible hypo-
capnic apneic threshold, unmasked by NREM sleep (Fig. 1.4) [5]. Hypocapnia
is probably the most important inhibitory factor during NREM sleep. Hypocapnia,
secondary to hyperventilation, is key to the genesis of central sleep apnea in
congestive heart failure [16], and idiopathic central sleep apnea [17, 18], and
may be relevant to the pathogenesis of obstructive sleep apnea (OSA) as well
[19–21].
Before mechanical During mechanical After mechanical

ventilation ventilation ventilation
2
EEG –2
0
Flow (L/s) –0.2
300
VT (ml)
0
PSG (cmH2O) 10
6
44
PETCO2 (torr) 22
0
Pmask (cmH2O) 8
4
∆ PETCO2=3 torr 5 sec.
Fig. 1.4 Induced hypocapnic central apnea during NREM sleep. Nasal mechanical ventilation
was used to decrease end-tidal Pco2 (PETco2). Cessation of mechanical ventilation caused central
apnea. Psg, supraglottic pressure; Pmask, mask pressure
Effect of Sleep on Upper-Airway Structure and Function
The sleep state is a challenge, rather than a rest period, for the ventilatory system.
Consequences of loss of wakefulness include reduced activity of upper-airway dila-
tors, reduced upper-airway caliber, increased upper-airway resistance, loss of load
compensation, and increased pharyngeal compliance and collapsibility. Ultimately,
these changes lead to reduced tidal volume and hypoventilation.
The musculature of the upper airway consists of 24 pairs of striated muscles
extending from the nares to the larynx [22, 23]. There are at least 10 muscles that are
classified as pharyngeal dilators. There are two patterns of electrical discharge from
these muscles: tonic (constant) activity, independent of phase of respiration, and pha-
sic activity, occurring during one part of the respiratory cycle. It is widely accepted
that upper-airway narrowing during sleep is due to a sleep-related decrease in upper-
airway muscle activity. During NREM sleep, available evidence indicates a reduction
in either the tonic or phasic activity during NREM sleep for a variety of upper-airway
muscles [23], including the levator palatini [24], tensor palatini [25], palatoglossus
[24], and geniohyoid [26]. The effect of REM sleep on upper-airway muscle activity
is more compelling, with strong evidence that activity of phasic upper-airway dilating
muscles, such as the genioglossus, is greatly attenuated during REM sleep [27, 28],
particularly during periods of phasic rapid eye movements [29, 30].
The response of upper-airway muscle to chemical and mechanical perturbations
may be more relevant physiologically than reduced baseline activity. Pharyngeal
muscles display an attenuated response to negative pressure during NREM [31–33]
and REM sleep [34] compared to wakefulness. Similarly, responsiveness of the
genioglossus muscle to hypercapnia is also attenuated during sleep [35]. Decreased
responsiveness to challenges indicates that upper-airway muscles are less able to
maintain upper-airway patency in the face of chemical or mechanical
perturbations.
1 Normal Sleep 9
The evidence for increased upper-airway resistance during sleep is compelling,

even in normal subjects [36–39]. The preponderance of evidence is that there are no
further increases in upper-airway resistance as subjects transition from NREM to
REM sleep [38–40]. However, it is important to note that upper-airway resistance
provides only a partial picture of the dynamic behavior of the pharyngeal airway
during sleep. Specifically, upper-airway resistance is generally expressed as a single
number representing the slope of pressure-flow relationship during inspiration. This
computation is predicated on a constant relationship between driving pressure and
inspiratory flow, which is true during normal breathing in normal subjects. However,
many subjects exhibit inspiratory-flow limitation, in which the pressure-flow graph
demonstrates a changing relationship culminating in complete dissociation between
pressure and flow (pressure continues to decrease with no further increase in flow).
While many authors equate increased upper airway resistance to increased collaps-
ibility, it is in reality a rather limited surrogate for susceptibility to pharyngeal clo-
sure during sleep [41].
Using nasopharyngoscopy during naturally occurring sleep in normal subjects,
Rowley et al. have shown that pharyngeal cross-sectional area is decreased during
sleep at both the retropalatal and retroglossal levels [38, 39]. During NREM sleep,
both retropalatal cross-sectional area and retroglossal cross-sectional area decreased
to ~70% of the awake baseline cross-sectional area. The decreased cross-sectional
area is consistent with a decrease in upper-airway dilator activity with the onset of
NREM sleep. In REM sleep, retropalatal cross-sectional area did not decrease fur-
ther compared to NREM sleep [38]. In contrast, retroglossal cross-sectional area did
decrease further during REM compared to NREM sleep [39].
The ability of the ventilatory control system to compensate for changes in resis-
tance is essential for the preservation of alveolar ventilation. Increased resistance is
an example of resistive load, leading, during wakefulness, to increased effort to
maintain ventilation and Paco2. In contrast, hypoventilation occurs immediately
upon imposing a resistive load during NREM sleep, perhaps implying that loads are
not perceived during sleep [42]. Therefore, resistive loading results in decreased
tidal volume and minute ventilation and, hence, alveolar hypoventilation. The ensu-
ing elevation of arterial Paco2 restores ventilation toward normal levels.
Teleologically, failure to respond to loads preserves sleep continuity. The cost of
allowing sleep continuity is a mild elevation of Paco2. In fact, elevated Paco2 during
sleep is one of few physiologic situations where hypercapnia is tolerated.
The walls of the pharyngeal airway consist of compliant soft tissue structures,
amenable to changes in pressure during the respiratory cycle. During wakefulness,
upper-airway caliber is constant during inspiration, with a decreased caliber during
expiration, returning to inspiratory values at end-expiration. This finding has been
observed in both normal subjects [43, 44] and patients with sleep apnea [44] using
either computerized tomographic (CT) scanning or nasopharyngoscopy. Using
nasopharyngoscopy, NREM sleep was associated with significant dynamic within-
breath changes in cross-sectional area, reaching a nadir at midinspiration [44], with
a rapid increase in cross-sectional area during expiration [20].
The dynamic changes in upper-airway patency during sleep can be best investi-
gated using compliance as a measurement. Traditionally, compliance is the change
in volume for a given change in pressure. Compliance of the pharyngeal wall is an
important modulator of the effect of pressure changes on upper-airway patency.
Traditionally, upper-airway compliance has been measured in a static fashion by
measuring changes in cross-sectional area at different levels of pressure applied to
the upper airway [45–47]. Use of this technique has demonstrated that compliance
is increased as the pharyngeal caliber decreases [45, 46, 48]. In contrast, we have
combined measurement of cross-sectional area via fiberoptic nasopharyngoscopy
and measurement of intraluminal pressure at the same level during NREM and
REM sleep. These studies have confirmed that retropalatal compliance is increased
during NREM sleep compared to wakefulness; in contrast, retropalatal compliance
during REM sleep is similar to that in wakefulness [39]. At the retroglossal level,
however, compliance was not increased during either NREM or REM sleep com-
pared to wakefulness [38]. Thus, pharyngeal compliance was not increased, despite
the known absence of upper-airway muscle activity during REM sleep.
Collapsibility refers to the propensity of the upper airway to collapse or obstruct
under certain conditions. While often used interchangeably with compliance, it dif-
fers from compliance in that compliance measures the changes in upper-airway area
for given changes in pressure and not the propensity to collapse. Upper-airway col-
lapsibility has been primarily measured using the critical closing pressure or Pcrit.
Measurement of critical closing pressure or Pcrit is based upon the concept of the
Starling resistor (Fig. 1.5) [49]. In a Starling resistor, maximal flow through the
resistor is dependent upon the resistance of the segment upstream and the pressure
surrounding the collapsible segment. In normal subjects, the application of progres-
sively negative nasal pressure (upstream pressure) results in inspiratory-flow limita-
tion, followed by complete upper-airway obstruction [50]. Thus, this model of
upper-airway mechanics has several advantages as a method to study upper-airway
collapsibility. First, it most closely approximates the inspiratory-flow limitation that
characterizes the breathing of many subjects with snoring. Second, the model allows
a functional approach to the upper airway, which is key, given the complicated anat-
omy of the upper airway.
Applying this model to humans, it has been shown that across the spectrum of
sleep-disordered breathing, active Pcrit becomes progressively more positive, indica-
tive of increased propensity for airway collapse [50–52]. For instance, Pcrit in nor-
mal subjects is generally <10 cmH2O while in patients with predominant hypopneas
it is between 0 and −5 cmH2O and in patients with predominant apneas it is >0
cmH2O. Kirkness et al. found that in a group of 166 men and women with and with-
out sleep-disordered breathing, passive Pcrit is higher in men and increases with
increasing age and BMI [53]. In addition, in these studies sleep apnea was largely
absent in subjects with a passive or active Pcrit more negative than −5 cmH2O
[53, 54].
Since gender and aging are important influences on the prevalence of obstructive
sleep apnea, the influence of gender and aging on upper airway function has been
explored. With regard to upper airway reflexes, no gender differences in the upper
1 Normal Sleep 11
a Non Flow-Limited
b Occluded
Pcrit Pcrit
PUS PDS PUS PDS
PUS>PDS > Pcrit c Flow-Limited Pcrit > PUS,PDS
Pcrit
PUS PDS
PUS > Pcrit > PDS
Fig. 1.5 Starling resistor model of the upper airway. In a Starling resistor there is a collapsible
segment surrounded by an upstream and downstream non-collapsible segments. In this model, Pcrit
is assumed to be equal to the pressure surrounding airway. PUS, upstream (nasopharyngeal) pres-
sure; PDS: downstream (hypopharyngeal) pressure. In A, both the PUS and PDS are greater than Pcrit,
the airway is wide open and flow will be proportional to the difference between PUS and PDS. In B,
the Pcrit is greater than both PUS and PDS, the airway is closed, and there is no flow. In C, PUS is
greater than Pcrit but Pcrit is greater than PDS, creating a condition of flow limitation; flow is pro-
portional to the difference between PUS and Pcrit
airway negative pressure reflex were found during wakefulness [55]. However, the
influence of gender on this reflex during sleep has not been studied. With regard to
inspiratory loading, Pillar et al. performed a study comparing the inspiratory load-
ing response during sleep in 16 normal men and women that were matched for age
and body mass index [56]. They found that pharyngeal resistance increased more in
men than women, suggesting increased upper airway collapse. However, there was
no difference in the activity of the genioglossus or tensor palatini muscles to inspira-
tory loading. There was also no gender difference in central drive, suggesting that
gender differences in upper airway anatomy or tissue characteristics, rather than
upper airway reflexes, better explain changes in upper airway resistance during
sleep. Finally, gender differences in Pcrit have been studied by two groups. Rowley
et al. found no difference in Pcrit in a group of young, healthy men and women
without sleep-disordered breathing. In contrast, Kirkness et al. found, in a group
that included individuals with and without sleep-disordered breathing, that men had
a higher Pcrit than women, suggesting a higher propensity for upper airway collapse.
There are a limited number of studies on the influence of aging on upper airway
physiology. With regard to reflexes, the genioglossal reflex to negative pressure was
studied in a group of 38 men and women during wakefulness and found that the
reflex response decreased with age in the total group [57]. However, this effect of
aging was only significant in men, not in women. The influence of aging on this
reflex has not been studied during sleep. Another group compared the genioglossus
EMG response to hypoxia in a group of younger (20–40 years) compared to older
(41–60 years) subjects and found that the genioglossus response to hypoxia was
decreased in the older subjects [58]. These studies show that upper airway reflexes
are decreased in older subjects than younger subjects and could explain, in part,
age-related changes in upper airway collapsibility. With regard to collapsibility, the
aforementioned Kirkness study included an analysis of aging and found that Pcrit
increased with increasing age. However, this change in Pcrit with aging was seen
only in post-menopausal women, not men or pre-menopausal women.
Cardiovascular Function During Sleep
NREM sleep is characterized by autonomic stability, driven by increased vagal

nerve activity and parasympathetic tone when compared to wakefulness. The
increased vagal activity results in an overall decrease in heart rate during NREM
sleep and frequent sinus arrhythmia coupled to respiratory variation. In sinus
arrhythmia, there is an increase in heart rate during inspiration to accommodate
increased venous return with a decrease in heart rate during expiration. Because of
the increased vagal tone, NREM sleep is associated with an decrease in heart rate
variability compared to wakefulness [59, 60]. In addition, NREM sleep is associ-
ated with a decrease in cardiac output and an ~10% decrease in blood pressure [61,
62]. Loss of the usual nocturnal decrease in blood pressure is frequently seen in
patients with obstructive sleep apnea [62, 63]. Finally, NREM sleep is associated
with decrements in both global cerebral blood flow and metabolism, both of which
are particularly decreased during slow-wave sleep [64–66].
In contrast, during REM sleep, heart rate becomes increasingly variable with
transient increases in heart rate in association with the rapid eye movements. These
transient increases in heart rate are not observed following interruption of sympa-
thetic neural output to the heart in animals, suggesting that the surges in heart rate
are sympathetically driven [67]. In addition, heart rate variability is increased in
REM sleep compared to NREM sleep [60, 68]. In association with the transient
increases in heart rate, there are also transient increases in blood pressure. Both the
heart rate and blood pressure may approach those observed during wakefulness.
Finally, in contrast to NREM sleep, global cerebral blood flow and metabolism are
unchanged compared to wakefulness in REM sleep [66]. However, there is evidence
that there are significant regional differences in cerebral blood flow during REM
sleep, with increased blood flow to areas of the brain associated with the generation
of REM sleep such as the brainstem and thalamus with continued decreased blood
flow to other areas such as the pre-frontal and fronto-parietal cortices [64, 69].
1 Normal Sleep 13
Endocrine Function During Sleep
The levels of circulating endocrine hormones are generally influenced either by

circadian rhythms or the sleep-wake cycle [70, 71]. Growth hormone and prolactin
are examples of hormones whose circulating levels are related to the sleep-wake
cycle. Growth hormone secretion is tightly related to the sleep-wake cycle; when
the sleep period is shifted, the major growth hormone pulse is also shifted and the
growth hormone secretion is absent in sleep deprivation. Maximal growth hormone
secretion is during slow-wave sleep, though this pattern is more generally observed
in men than women. While prolactin levels generally increase in the afternoon after
the usual nadir at noon, there is a major elevation in prolactin levels shortly after
sleep onset. In addition, during naps, there is a generally a pulse of prolactin activity
irrespective of the time of day.
Adreno-corticotrophic hormone and cortisol follow a circadian pattern. Levels of
these hormones are generally increased in the later part of the night and are maximal
in the early morning; levels then decline through the day with minimal levels gener-
ally around midnight.
Circulating levels of thyroid-stimulating hormone (TSH) are influenced by both
circadian rhythms and the sleep-wake cycle. TSH levels are low during the day and
increase in the evening under circadian influences. With sleep onset, levels decrease
with the inhibitory influence primarily noted during slow-wave sleep. Consistent
with the sleep-wake cycle influence, TSH levels continue to increase during sleep
deprivation.
Gonadotrophic hormones, including both luteinizing hormone (LH) and follicu-
lar stimulating hormone (FHS), appear to be influenced by both circadian rhythm
and sleep-wake state. However, the secretion of these hormones also vary by gender
and stage of life. Both LH and FSH demonstrate pulsatile increases in children at
sleep onset. The amplitude of these pulses increases at puberty; however, the day-
time pulse amplitude also increases, and the diurnal rhythm is diminished during
puberty. In men, this leads to a diurnal rhythm in testosterone, with minimal levels
in late evening and maximal levels in early morning (with the increases possibly
linked to REM sleep as well). In older men, the LH pulses decrease further but the
circadian variation of testosterone remains, though dampened. In women, the
24-hour variation in plasma LH varies during the menstrual cycle. While levels are
elevated in post-menopausal women, there is no clear circadian rhythm.
Leptin and ghrelin are hormones important to energy balance with leptin promot-
ing satiety while ghrelin stimulates appetite. Ghrelin appears to be related to sleep-
wake state with levels typically increasing in the first half of the night while
decreasing in the second half. Leptin also peaks during the night with a nadir in
early afternoon. Increases in both hormones have been linked to increases in slow-
wave sleep.
Gastrointestinal Function During Sleep
The effects of sleep on the gastrointestinal system are driven by a variety of pro-
cesses, including increased parasympathetic activity and circadian rhythms [72].
An example of decreased parasympathetic activity is the observed decrease in sali-
vation during sleep. In contrast, basal gastric acid secretion follows a circadian
rhythm, with peak secretion between 10 pm and 2 am and relative absence of basal
secretion in the absence of meal simulation [73]. However, there is evidence that
the increased gastric acid secretion is not associated with nadirs in gastric pH,
which has been shown to be lower in awake patients than during NREM and REM
sleep [74].
Sleep also effects the mobility of the gastrointestinal tract. The frequency of
swallowing decreases significantly during sleep while there is also evidence of
decreased esophageal peristaltic waves during NREM sleep [72, 75]. Traditionally,
it has been believed that upper esophageal sphincter tone is unchanged during sleep
while lower esophageal sphincter tone is decreased. However, recent data indicate
that upper sphincter tone is more vulnerable to decreased tone during sleep with a
smaller change in the lower esophageal sphincter tone, which generally stays greater
than intragastric pressure [75–77]. Finally, there is evidence that the phasic myo-
electrical activity and motor function of the stomach and intestines is decreased
during sleep, with some evidence that the decrease could be in part circadian in
origin [72, 75, 78, 79].
One of the major effects of the changes in gastrointestinal function during sleep
is increased acid contact time [80]. Generally, during wakefulness, gastroesopha-
geal reflux is a post-prandial event and acid is rapidly cleared from the esophagus
because of increased salivary gland secretion, increased swallowing and primary
peristalsis. While GER events are less frequent during sleep, events are associated
with decreased acid clearance and increased acid contact time because of the sleep-
related decreases in salivation, swallowing, and peristalsis. In addition, heartburn is
a waking conscious phenomenon and this sensation is generally absent during sleep.
Increased acid contact time has been shown to be related to proximal migration of
refluxed gastric contents [81] and is a potential mechanism for the development of
esophagitis, chronic cough, and exacerbations of bronchial asthma [82].
Renal Function During Sleep
Urine formation decreases during sleep compared to wakefulness. Both glomerular

filtration rate and effective renal plasma flow [83, 84] and the urinary excretion of
sodium and potassium [84, 85] have been found to be maximal during wakefulness
with decreases during sleep; however, this is not a universal finding [86]. Water
reabsorption also increases during sleep, likely due to changes in the renin-
aldosterone levels. Studies have shown that both renin and aldosterone are increased
1 Normal Sleep 15
during sleep, with a shift in the peak increase with a shift in the sleep schedule [87,
88]. In addition, cortisol appears to exert a circadian rhythm effect on aldosterone,
as daytime oscillations in aldosterone are associated with daytime oscillations in
cortisol [88]. The importance of sleep to urinary function is becoming increasingly
evident as studies have shown that sleep deprivation is associated with larger
declines in renal function in both normal subjects [89] and patients with chronic
kidney disease [90].
References
1. Silber MH, Ancoli-Israel S, Bonnet MH, Chokroverty S, Grigg-Damberger MM, Hirshkowitz

M, Kapen S, Keenan SA, Kryger MH, Penzel T, Pressman MR, Iber C. The visual scoring of
sleep in adults. J Clin Sleep Med. 2007;3:121–31.
2. Berry RB, Quan SF, Abreu AR, Del Rosso L, Mao M, Plante D, Pressman MR, Troester D,
Vaughn BV. The AASM manual for the scoring of sleep and associated events: rules, terminol-
ogy and technical specifications. Darien: American Academy of Sleep Medicine; 2020.
3. 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;27:1255–73.
4. Redline S, Kirchner HL, Quan SF, Gottlieb DJ, Kapur V, Newman A. The effects of age,
sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med.
2004;164:406–18.
5. Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic
ventilation. J Appl Physiol. 1983;55:813–22.
6. Berthon-Jones M, Sullivan CE. Ventilation and arousal responses to hypercapnia in normal
sleeping humans. J Appl Physiol. 1984;57:59–67.
7. Davis JN, Loh L, Nodal J, Charnock M. Effects of sleep on the pattern of CO2 stimulated
breathing in males and females. Adv Exp Med Biol. 1978;99:79–83.
8. Douglas NJ, White DP, Weil JV, Pickett CK, Zwillich CW. Hypercapnic ventilatory response
in sleeping adults. Am Rev Respir Dis. 1982;126:758–62.
9. Gothe B, Altose MD, Goldman MD, Cherniack NS. Effect of quiet sleep on resting and CO2-
stimulated breathing in humans. J Appl Physiol. 1981;50:724–30.
10. Hedemark LL, Kronenberg RS. Ventilatory and heart rate responses to hypoxia and hypercap-
nia during sleep in adults. J Appl Physiol. 1982;53:307–12.
11. Browne HA, Adams L, Simonds AK, Morrell MJ. Ageing does not influence the sleep-related
decrease in the hypercapnic ventilatory response. Eur Respir J. 2003;21:523–9.
12. Morrell MJ, Harty HR, Adams L, Guz A. Changes in total pulmonary resistance and PCO2
between wakefulness and sleep in normal human subjects. J Appl Physiol. 1995;78:1339–49.
13. Berthon-Jones M, Sullivan CE. Ventilatory and arousal responses to hypoxia in sleeping
humans. Am Rev Respir Dis. 1982;125:632–9.
14. Douglas NJ, White DP, Weil JV, Pickett CK, Martin RJ, Hudgel DW, Zwillich CW. Hypoxic ven-
tilatory response decreases during sleep in normal men. Am Rev Respir Dis. 1982;125:286–9.
15. White DP, Douglas NJ, Pickett CK, Weil JV, Zwillich CW. Hypoxic ventilatory response dur-
ing sleep in normal premenopausal women. Am Rev Respir Dis. 1982;126:530–3.
16. Xie A, Skatrud JB, Puleo DS, Rahko PS, Dempsey JA. Apnea-hypopnea threshold for CO2 in
patients with congestive heart failure. Am J Respir Crit Care Med. 2002;165:1245–50.
17. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory
responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med.
1995;152:1950–5.
18. Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley TD. Interaction of hyperventilation and
arousal in the pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med.
1994;150:489–95.
19. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central
sleep apnea. J Appl Physiol. 1995;78:1806–15.
20. Sankri-Tarbichi AG, Rowley JA, Badr MS. Expiratory pharyngeal narrowing during central
hypocapnic hypopnea. Am J Respir Crit Care Med. 2009;179:313–9.
21. Salloum A, Rowley JA, Mateika JH, Chowdhuri S, Omran Q, Badr MS. Increased propensity
for central apnea in patients with obstructive sleep apnea: effect of nCPAP. Am J Respir Crit
Care Med. 2010;181(2):189–93.
22. van Lunteren E, Strohl KP. The muscles of the upper airways. Clin Chest Med. 1986;7:171–88.
23. Horner RL. Motor control of the pharyngeal musculature and implications for the pathogen-
esis of obstructive sleep apnea. Sleep. 1996;19:827–53.
24. Tangel DJ, Mezzanotte WS, White DP. Influences of NREM sleep on activity of palatoglossus
and levator palatini muscles in normal men. J Appl Physiol. 1995;78:689–95.
25. Tangel DJ, Mezzanotte WS, White DP. Influence of sleep on tensor palatini EMG and upper
airway resistance in normal men. J Appl Physiol. 1991;70:2574–81.
26. Wiegand DA, Latz B, Zwillich CW, Wiegand L. Geniohyoid muscle activity in normal men
during wakefulness and sleep. J Appl Physiol. 1990;69:1262–9.
27. Sauerland EK, Harper RM. The human tongue during sleep: electromyographic activity of the
genioglossus muscle. Exp Neurol. 1976;51:160–70.
28. Sauerland EK, Orr WC, Hairston LE. EMG patterns of oropharyngeal muscles during respira-
tion in wakefulness and sleep. Electromyogr Clin Neurophysiol. 1981;21:307–16.
29. Wiegand L, Zwillich CW, Wiegand D, White DP. Changes in upper airway muscle activation
and ventilation during phasic REM sleep in normal men. J Appl Physiol. 1991;71:488–97.
30. Eckert DJ, Malhotra A, Lo YL, White DP, Jordan AS. The influence of obstructive sleep apnea
and gender on genioglossus activity during rapid eye movement sleep. Chest. 2009;135:957–64.
31. Horner RL, Innes JA, Murphy K, Guz A. Evidence for reflex upper airway dilator muscle
activation by sudden negative airway pressure in man. J Physiol. 1991;436:15–29.
32. Wheatley JR, Mezzanotte WS, Tangel DJ, White DP. Influence of sleep on genioglossus mus-
cle activation by negative pressure in normal men. Am Rev Respir Dis. 1993;148:597–605.
33. Wheatley JR, Tangel DJ, Mezzanotte WS, White DP. Influence of sleep on response to
negative airway pressure of tensor palatini muscle and retropalatal airway. J Appl Physiol.
1993;75:2117–24.
34. Shea SA, Edwards JK, White DP. Effect of wake-sleep transitions and rapid eye movement
sleep on pharyngeal muscle response to negative pressure in humans. J Physiol. 1999;520(Pt
3):897–908.
35. Stanchina ML, Malhotra A, Fogel RB, Ayas N, Edwards JK, Schory K, White DP. Genioglossus
muscle responsiveness to chemical and mechanical stimuli during non-rapid eye movement
sleep. Am J Respir Crit Care Med. 2002;165:945–9.
36. Kay A, Trinder J, Bowes G, Kim Y. Changes in airway resistance during sleep onset. J Appl
Physiol. 1994;76:1600–7.
37. Kay A, Trinder J, Kim Y. Progressive changes in airway resistance during sleep. J Appl Physiol.
1996;81:282–92.
38. Rowley JA, Sanders CS, Zahn BR, Badr MS. Effect of REM sleep on retroglossal cross-
sectional area and compliance in normal subjects. J Appl Physiol. 2001;91:239–48.
39. Rowley JA, Zahn BR, Babcock MA, Badr MS. The effect of rapid eye movement (REM) sleep
on upper airway mechanics in normal human subjects. J Physiol. 1998;510(Pt 3):963–76.
40. Thurnheer R, Wraith PK, Douglas NJ. Influence of age and gender on upper airway resistance
in NREM and REM sleep. J Appl Physiol. 2001;90:981–8.
41. Rowley JA, Deebajah I, Parikh S, Najar A, Saha R, Badr MS. The influence of episodic
hypoxia on upper airway collapsibility in subjects with obstructive sleep apnea. J Appl Physiol.
2007;103:911–6.
1 Normal Sleep 17
42. Wiegand L, Zwillich CW, White DP. Sleep and the ventilatory response to resistive loading in
normal men. J Appl Physiol. 1988;64:1186–95.
43. Schwab RJ, Gefter WB, Hoffman EA, Gupta KB, Pack AI. Dynamic upper airway imaging
during awake respiration in normal subjects and patients with sleep disordered breathing. Am
Rev Respir Dis. 1993;148:1385–400.
44. Morrell MJ, Badr MS. Effects of NREM sleep on dynamic within-breath changes in upper
airway patency in humans. J Appl Physiol. 1998;84:190–9.
45. Isono S, Morrison DL, Launois SH, Feroah TR, Whitelaw WA, Remmers JE. Static mechanics
of the velopharynx of patients with obstructive sleep apnea. J Appl Physiol. 1993;75:148–54.
46. Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, Nishino T. Anatomy of pharynx in patients
with obstructive sleep apnea and in normal subjects. J Appl Physiol. 1997;82:1319–26.
47. Kuna ST, Bedi DG, Ryckman C. Effect of nasal airway positive pressure on upper airway size
and configuration. Am Rev Respir Dis. 1988;138:969–75.
48. Isono S, Feroah TR, Hajduk EA, Brant R, Whitelaw WA, Remmers JE. Interaction of
cross-sectional area, driving pressure, and airflow of passive velopharynx. J Appl Physiol.
1997;83:851–9.
49. Gold AR, Schwartz AR. The pharyngeal critical pressure. The whys and hows of using nasal
continuous positive airway pressure diagnostically. Chest. 1996;110:1077–88.
50. Schwartz AR, Smith PL, Wise RA, Gold AR, Permutt S. Induction of upper airway occlusion
in sleeping individuals with subatmospheric nasal pressure. J Appl Physiol. 1988;64:535–42.
51. Gold AR, Marcus CL, Dipalo F, Gold MS. Upper airway collapsibility during sleep in upper
airway resistance syndrome. Chest. 2002;121:1531–40.
52. Gleadhill IC, Schwartz AR, Schubert N, Wise RA, Permutt S, Smith PL. Upper airway col-
lapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis.
1991;143:1300–3.
53. Kirkness JP, Schwartz AR, Schneider H, Punjabi NM, Maly JJ, Laffan AM, McGinley BM,
Magnuson T, Schweitzer M, Smith PL, Patil SP. Contribution of male sex, age, and obesity to
mechanical instability of the upper airway during sleep. J Appl Physiol. 2008;104:1618–24.
54. Patil SP, Schneider H, Marx JJ, Gladmon E, Schwartz AR, Smith PL. Neuromechanical control
of upper airway patency during sleep. J Appl Physiol. 2007;102:547–56.
55. White DP, Edwards JK, Shea SA. Local reflex mechanisms: influence on basal genioglossal
muscle activation in normal subjects. Sleep. 1998;21:719–28.
56. Pillar G, Malhotra A, Fogel R, Beauregard J, Schnall R, White DP. Airway mechanics and
ventilation in response to resistive loading during sleep: influence of gender. Am J Respir Crit
Care Med. 2000;162:1627–32.
57. Malhotra A, Huang Y, Fogel R, Lazic S, Pillar G, Jakab M, Kikinis R, White DP. Aging influ-
ences on pharyngeal anatomy and physiology: the predisposition to pharyngeal collapse. Am
J Med. 2006;119:72–14.
58. Klawe JJ, Tafil-Klawe M. Age-related response of the genioglossus muscle EMG-activity to
hypoxia in humans. J Physiol Pharmacol. 2003;54(Suppl 1):14–9.
59. Penzel T, Kantelhardt JW, Grote L, Peter JH, Bunde A. Comparison of detrended fluctuation
analysis and spectral analysis for heart rate variability in sleep and sleep apnea. IEEE Trans
Biomed Eng. 2003;50:1143–51.
60. Vanoli E, Adamson PB, Ba L, Pinna GD, Lazzara R, Orr WC. Heart rate variability during
specific sleep stages. A comparison of healthy subjects with patients after myocardial infarc-
tion. Circulation. 1995;91:1918–22.
61. Veerman DP, Imholz BP, Wieling W, Wesseling KH, van Montfrans GA. Circadian profile of
systemic hemodynamics. Hypertension. 1995;26:55–9.
62. Suzuki M, Guilleminault C, Otsuka K, Shiomi T. Blood pressure "dipping" and "non-dipping"
in obstructive sleep apnea syndrome patients. Sleep. 1996;19:382–7.
63. Loredo JS, ncoli-Israel S, Dimsdale JE. Sleep quality and blood pressure dipping in obstructive
sleep apnea. Am J Hypertens. 2001;14:887–92.
64. Braun AR, Balkin TJ, Wesenten NJ, Carson RE, Varga M, Baldwin P, Selbie S, Belenky G,
Herscovitch P. Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O
PET study. Brain. 1997;120(Pt 7):1173–97.
65. Madsen PL, Schmidt JF, Holm S, Vorstrup S, Lassen NA, Wildschiodtz G. Cerebral oxy-
gen metabolism and cerebral blood flow in man during light sleep (stage 2). Brain Res.
1991;557:217–20.
66. Madsen PL, Schmidt JF, Wildschiodtz G, Friberg L, Holm S, Vorstrup S, Lassen NA. Cerebral
O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep.
J Appl Physiol. 1991;70:2597–601.
67. Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function.
Am J Physiol. 1989;256:H1378–83.
68. Cajochen C, Pischke J, Aeschbach D, Borbely AA. Heart rate dynamics during human sleep.
Physiol Behav. 1994;55:769–74.
69. Madsen PL, Holm S, Vorstrup S, Friberg L, Lassen NA, Wildschiodtz G. Human regional cere-
bral blood flow during rapid-eye-movement sleep. J Cereb Blood Flow Metab. 1991;11:502–7.
70. Collop NA, Salas RE, Delayo M, Gamaldo C. Normal sleep and circadian processes. Crit Care
Clin. 2008;24:449–60, v.
71. Leproult R, Spiegel K, van Cauter E. Sleep and endocrinology. In: Amlaner CJ, Fuller PM,
editors. Basics of sleep guide. 2nd ed. Westchester: Sleep Research Society; 2009. p. 157–63.
72. Orr WC, Fass R, Sundaram SS, Scheimann AO. The effect of sleep on gastrointestinal func-
tioning in common digestive diseases. Lancet Gastroenterol Hepatol. 2020;5:616–24.
73. Moore JG Jr, EE. Circadian rhythm of gastric acid secretion in man. Nature. 1970;226:1261–2.
74. Khanijow V, Prakash P, Emsellem HA, Borum ML, Doman DB. Sleep dysfunction and gastro-
intestinal diseases. Gastroenterol Hepatol (N Y). 2015;11:817–25.
75. Kanaly T, Shaheen NJ, Vaughn BV. Gastrointestinal physiology and digestive disorders in
sleep. Curr Opin Pulm Med. 2009;15:571–7.
76. Bajaj JS, Bajaj S, Dua KS, Jaradeh S, Rittmann T, Hofmann C, Shaker R. Influence of sleep
stages on esophago-upper esophageal sphincter contractile reflex and secondary esophageal
peristalsis. Gastroenterology. 2006;130:17–25.
77. Eastwood PR, Katagiri S, Shepherd KL, Hillman DR. Modulation of upper and lower esopha-
geal sphincter tone during sleep. Sleep Med. 2007;8:135–43.
78. Kumar D, Idzikowski C, Wingate DL, Soffer EE, Thompson P, Siderfin C. Relationship between
enteric migrating motor complex and the sleep cycle. Am J Physiol. 1990;259:G983–90.
79. Soffer EE, Adrian TE, Launspach J, Zimmerman B. Meal-induced secretion of gastrointestinal
regulatory peptides is not affected by sleep. Neurogastroenterol Motil. 1997;9:7–12.
80. Orr WC. Esophageal function during sleep: another danger in the night. Sleep Med.
2007;8:105–6.
81. Orr WC, Elsenbruch S, Harnish MJ, Johnson LF. Proximal migration of esophageal acid perfu-
sions during waking and sleep. Am J Gastroenterol. 2000;95:37–42.
82. Orr WC, Chen CL. Sleep and the gastrointestinal tract. Neurol Clin. 2005;23:1007–24.
83. Voogel AJ, Koopman MG, Hart AA, van Montfrans GA, Arisz L. Circadian rhythms in sys-
temic hemodynamics and renal function in healthy subjects and patients with nephrotic syn-
drome. Kidney Int. 2001;59:1873–80.
84. Koopman MG, Koomen GC, Krediet RT, de Moor EA, Hoek FJ, Arisz L. Circadian rhythm of
glomerular filtration rate in normal individuals. Clin Sci (Lond). 1989;77:105–11.
85. Staessen JA, Birkenhager W, Bulpitt CJ, Fagard R, Fletcher AE, Lijnen P, Thijs L, Amery
A. The relationship between blood pressure and sodium and potassium excretion during the
day and at night. J Hypertens. 1993;11:443–7.
86. Pechere-Bertschi A, Nussberger J, Biollaz J, Fahti M, Grouzmann E, Morgan T, Brunner HR,
Burnier M. Circadian variations of renal sodium handling in patients with orthostatic hypoten-
sion. Kidney Int. 1998;54:1276–82.
1 Normal Sleep 19
87. Brandenberger G, Charifi C, Muzet A, Saini J, Simon C, Follenius M. Renin as a biologi-

cal marker of the NREM-REM sleep cycle: effect of REM sleep suppression. J Sleep Res.
1994;3:30–5.
88. Charloux A, Gronfier C, Lonsdorfer-Wolf E, Piquard F, Brandenberger G. Aldosterone release
during the sleep-wake cycle in humans. Am J Physiol. 1999;276:E43–9.
89. McMullan CJ, Curhan GC, Forman JP. Association of short sleep duration and rapid decline in
renal function. Kidney Int. 2016;89:1324–30.
90. Ricardo AC, Knutson K, Chen J, Appel LJ, Bazzano L, Carmona-Powell E, Cohan J, Kurella
Tamura M, Steigerwalt S, Thornton JD, Weir M, Turek NF, Rahman M, Van Cauter E, Lash JP,
Chronic Renal Insufficiency Cohort Study Investigators. The association of sleep duration and
quality with CKD progression. J Am Soc Nephrol. 2017;28:3708–15.
Chapter 2
Pharmacology of Sleep
Janet H. Dailey and Susmita Chowdhuri
Keywords GABA γ(gamma)-aminobutyric acid · Histamine-3 inverse agonist ·

Benzodiazepines · Nonbenzodiazepine receptor agonists · Melatonin
and melatonin receptor agonist: ramelteon · Orexin antagonists: suvorexant
and lemborexant · Antidepressants, low-dose doxepin · Antipsychotics ·
Antihistamines · Amphetamines · Methylphenidate · Modafinil · Armodafinil ·
Sodium oxybate · Solriamfetol · Pitolisant
Introduction
Drugs that modulate sleep and wakefulness operate by modifying a complex net-
work of sleep–wake neurotransmitters and neuromodulators in multiple locations in
the brain. The pharmacologic agents used to treat two common sleep disorders,
chronic insomnia and disorders of central hypersomnia, i.e., narcolepsy and idio-
pathic hypersomnia, are reviewed with emphasis on current updates. Several drugs
target one or more of the sleep or wake–sleep-promoting neurotransmitters and neu-
romodulators [1], to treat insomnia and excessive daytime sleepiness, respectively.
J. H. Dailey
Pharmacy Benefits Management Services, Veterans Health Administration,
Washington, D.C, USA
e-mail: Janet.Dailey@va.gov
S. Chowdhuri (*)
Sleep Medicine Section, Medical Service John D. Dingell VA Medical Center,
Detroit, MI, USA
Department of Medicine, Wayne State University, Detroit, MI, USA
e-mail: schowdh@med.wayne.edu

22 J. H. Dailey and S. Chowdhuri
Nonpharmacologic therapies of these disorders and drugs indicated for other sleep
disorders and recreational drugs that affect sleep will not be reviewed.
Sleep-promoting Drugs
Overall, drugs that are agonistic to the sleep-promoting GABA (γ(gamma)-

aminobutyric acid) receptor or antagonistic to the wake-promoting neurotransmit-
ters, norepinephrine, serotonin, histamine, acetylcholine, dopamine, and orexin are
potentially sleep promoting. The major sleep-promoting region is located in the
GABAergic ventrolateral preoptic (VLPO) nucleus of the hypothalamus. Conversely,
inhibition of the wake-promoting regions of the brain, including the orexinergic
lateral hypothalamus, histaminergic tuberomammillary nucleus, cholinergic pedun-
culopontine, lateral dorsal tegmental nuclei, noradrenergic locus coeruleus, seroto-
nergic raphe nuclei, and the dopaminergic ventral tegmental area, could potentially
promote sleep onset and maintenance [1].
Most hypnotics potentiate sleep via GABA by binding to the GABAA receptor
[2] while others antagonize monoaminergic and/or orexin neurons or are agnostic to
melatonin receptors (Fig. 2.1). An ideal drug for insomnia aims to enhance sleep
onset and/or sleep maintenance without significant residual hangover, tolerance,
dependence, or rebound insomnia upon discontinuation.
Fig. 2.1 Demonstrates the potential sites of action of sleep-promoting drugs. *Off label use; flu-
razepam, quazepam, estazolam, temazepam and triazolam are FDA approved for insomnia
2 Pharmacology of Sleep 23
Benzodiazepines
Benzodiazepines (BDZs) had been the pharmacotherapy mainstay for insomnia for
decades, and despite current recommendations for short-term use, persistent inap-
propriately prolonged use of BDZs continues. Perhaps due to the established depen-
dence level of patients chronically taking BDZs and/or the lack of knowledge or
resources to implement non-pharmacological insomnia management, continuing
BDZs versus discontinuing them for treating insomnia is deemed the path of least
resistance. Benzodiazepines bind non-selectively to the GABAA receptor, and in
addition to sedation, also mediate antianxiety, anticonvulsant, anterograde amnesia,
and myorelaxant effects. They increase sleep duration and modify the sleep archi-
tecture by increasing slow-wave sleep (SWS) and decreasing rapid-eye movement
(REM) sleep [3–5]. Table 2.1 includes the FDA-approved hypnotic agents for the
treatment of insomnia; however, other BDZs are routinely used off-label despite
inadequate efficacy and safety data.
Efficacy A meta-analysis [6] of 52 randomized controlled trials (RCTs) in adults
treated with BDZs for chronic insomnia (4 weeks or more) decreased sleep onset
latency (SOL) and wake after sleep onset (WASO), with increased total sleep time
(TST) and sleep efficiency (SE) versus placebo. Compared with placebo,
BDZs (≤4 weeks of therapy in most studies) significantly decreased SOL by poly-
somnography (PSG) weighted mean difference (WMD): −10.0 minutes or by sleep
diary, WMD: −19.6 minutes, respectively. Additionally, objective WASO was
decreased −16.7 minutes, or subjectively using a sleep diary −39.9 minutes; SE was
Table 2.1 Pharmacokinetics and dosing of oral benzodiazepinesa in adults [71, 72]
Half-life Peak
Trade Daily dose range Longest active effect
Generic name name (mg) (h) metabolites half-life (h) (h)
Long acting (>24) h
Flurazepamb Dalmane 15-30 mg 2.3 47–100 1.5–4.5
Quazepamb Doral 7.5–15 39 73 2
Diazepam Valium 2–10 20–80 40–120 1–2
Intermediate acting (6–24 h)
Estazolamb ProSom 1–2 10–24 2 major metabolites; ~2
minimal hypnotic effect
Temazepamb Restoril 7.5–30 8-15 None 1–2
Lorazepam Ativan 0.5–2 10–20 None 1–6
Oxazepam Serax 10–15 5–15 None 1–4
Short acting (<6 h)
Triazolamb Halcion 0.125–0.5 2–6 None 1–5
h hours
a
Pregnancy: All BDZs cross the placenta. Symptoms of withdrawal occurring in newborns if
exposed in utero have been reported
b
FDA-approved agents for treatment of insomnia
Table 2.2 Effects on sleep parameters of FDA-approved sleep-promoting agents [2, 72–75]
Sleep continuity REM sleep
parameters NREM sleep parameters parameters
Stage Stage Stage N3 REM onset
Drugs SL SE TST N1 N2 (SWS) latency REM
BDZs ↓ ↑ ↑ ↓ ↑ ↓ ↑ ↓
Z-drugs ↓ ↑ ↑ ↔ ↑ ↔ ↔ ↔
Ramelteon ↓ ↑ ↑ ↔ ↑ ↔ ↔ ↔
Suvorexant ↓ ↑ ↑ ↓ ↓ ↔↓ ↓ ↑
Low-dose ↓ ↑ ↑ ↔ ↑ ↔ ↔ ↔
doxepin
BDZs benzodiazepines, Z-drugs zolpidem, zaleplon, eszopiclone; ↓ decreased, ↑ increased, ↔
minimal change, arrows do not represent the same degree of weight for each category. SL sleep
latency, SE sleep efficiency, TST total sleep time, SWS slow-wave sleep, NREM non-rapid eye
movement, REM rapid eye movement
increased 7.4% by PSG and 7.9% by sleep diary, and TST (by PSG) and sTST (by
sleep diary) increased 32.7 and 52.6 minutes, respectively. In a separate meta-
analysis [7] of 24 RTCs in the elderly with insomnia for at least 5 consecutive
nights, significant improvement in sleep quality (SQ) and TST along with decreased
nighttime awakening were experienced by those taking BDZs compared to placebo,
although the authors reported the benefits may not outweigh the increased risk of
adverse events (AEs). In one systematic review (SR) [8], BDZs were favored over
placebo in many outcomes including SE, SOL, SQ, TST, and WASO (Table 2.2).
Safety The pharmacokinetics and pharmacodynamics differences of BDZs can

often predict the potential incidence of AEs. Benzodiazepines are categorized
into short-, intermediate-, and long-acting agents based on the duration of
action (Table 2.1). Agents with longer duration of action are often associated
with more dose-dependent AEs, including daytime drowsiness due to hangover
effect, dizziness, anterograde amnesia, tolerance, drug dependence, withdrawal,
rebound insomnia, and REM rebound [3–5]. Gradual dose reduction of BDZs,
if taken chronically for the treatment of insomnia, is recommended versus
abrupt discontinuation to avoid physical and psychological withdrawal
effects [9].
Ingesting BDZs with opioid medicines, alcohol, or other CNS depressants can
cause severe drowsiness, breathing problems, coma, and death. Many BDZs are
identified as potentially inappropriate medications in patients 65 years and older
due to an increased risk of impaired cognition, delirium, falls, fractures, and motor
vehicle accidents.
Summary Treating insomnia with FDA-approved BDZs has demonstrated favor-
able short-term sleep outcomes. However, the increased risk of potential AEs pre-
cludes BDZs from being the ideal first-line therapy for treating insomnia especially
in the elderly and a limited role in treating individuals with chronic insomnia.
Nonbenzodiazepine Receptor Agonists (Non-BzRAs)
The non-BzRAs have no anxiolytic, myorelaxant, and anticonvulsant properties but

have strong hypnotic properties due to their selective binding to the GABAA recep-
tor [2]. The three non-BzRA agents available in the United States, zolpidem,
zaleplon, and eszopiclone are FDA-approved for treating insomnia. Zolpidem is
currently available as immediate-release (IR) tablets, oral spray, sublingual (SL)
tablets, and controlled/extended-release (ER) tablets. Zolpidem IR is indicated for
short-term treatment of insomnia characterized by difficulties with sleep onset. Two
zolpidem tartrate SL formulations are available. One SL product (Intermezzo IR®)
is used for middle-of-the-night awakening followed by difficulty returning to sleep
and only if >4 hours of bedtime remain. Edluar™ is a second sublingual zolpidem
product approved for sleep initiation and should only be taken if 7–8 hours remain
before arising. Agents with shorter-acting half-life such as zolpidem mist and
zaleplon should be administered immediately before bedtime.
The non-BzRAs used mostly for sleep maintenance insomnia, zolpidem ER, and
eszopiclone have been studied in clinical trials >6 months in duration. With many of
these agents, the recommended initial doses in women compared to men are differ-
ent because the non-BzRA clearance is lower in women. For faster sleep onset, all
zolpidem products including eszopiclone should not be administered with or imme-
diately after a meal.
Efficacy There are few head-to-head trials comparing the three U.S. available non-
BzRAs. A SR [8] reviewed 31 RCTs in adults with insomnia disorder. Because the
trials evaluated included various formulations, doses, and different frequency of
administration including short duration (i.e., <6 weeks), comparisons were difficult.
Four non-BzRAs (zolpidem, zaleplon, eszopiclone, and zopiclone) were objectively
evaluated to placebo and efficacy data were compiled. About one-half of studies
deemed of moderate quality, non-BzRAs were favored over placebo for objective
SE. In addition, SOL, SQ, TST, and WASO were improved with non-BzRAs com-
pared to placebo (Table 2.3).
Safety Despite non-BzRAs being effective in treating many sleep outcomes, all
these agents especially those with longer half-lives have the potential to cause next-
day impairment including residual sedation, somnolence, memory impairment,
confusion, lethargy, and dizziness. Several FDA warnings exist about rebound
insomnia, complex sleep behaviors including sleepwalking, and in some cases,
sleep-driving resulting in death. Falls and withdrawals have also been reported.
Adverse events (AEs) may occur even at the lowest dose and after one dose, and if
so, the drug should be discontinued immediately [10]. The risk of AEs can com-
pound when co-administered with other CNS depressants, alcohol, or with other
drugs that increase the blood levels. Eszopiclone can cause unpleasant taste and dry
mouth. Rare cases of anaphylactic and anaphylactoid reactions have been reported.
These agents should only be used during pregnancy if the potential benefit out-
weighs the risk to the fetus as no adequate and well-controlled studies in pregnant
26
Table 2.3 Characteristics of non-BzRAs [10, 76, 77]

Onset of Duration of Usual adult daily Dose in Controlled
Generic/trade name FDA indication(s) action (min) action dose (mg) elderlya Use in pregnancy substance
Zolpidem IR Sleep onset < 30 Short Men: 5–10 5 Zolpidem crosses the C-IV
Ambien® Women: 5 placenta; reports of
Zolpidem ER Sleep onset/ maintenance <30 Intermediate Men: 12.5 6.25 severe neonatal
Ambien CR® Women: 6.25 respiratory
Zolpidem sublingual depression and
sedation with other
Edular® Sleep initiation <30 Short Men: 5–10 5
CNS depressants
Women: 5
concurrently.
Intermezzo® MOTN 20 Ultra-short Men: 3.5 1.75
Women: 1.75
Zolpidem oral spray Sleep initiation 20 Short 10 (2 sprays) 5 No adequate and
Zolpimist™ well-controlled
Eszopiclone Sleep onset/ maintenance <30 Intermediate 2–3 1–2 studies in pregnant
Lunesta® women.
Zaleplon Sleep onset < 30 Ultra-short 10 5 Not recommended
Sonata®
IR intermediate release, ER extended release, CR controlled release, MOTN middle-of-the-night
a
Or in mild-moderate hepatic impairment
J. H. Dailey and S. Chowdhuri
women exists. Drugs that increase levels of all these non-BZRA agents include the
CYP3A4 inhibitors.
Summary Despite the strong evidence base that non-BzRAs have favorable sleep
outcomes, treating insomnia chronically with non-BZRAs may have a limited role
due to potential AEs. If prescribed, the lowest dose for the shortest period of time
possible should be exercised.
Melatonin
Melatonin is a neurohormone of the pineal gland that is modulated by the suprachi-

asmatic nucleus (SCN) of the hypothalamus. Regulation of melatonin synthesis by
the SCN determines the circadian rhythm of sleep and wakefulness.
Efficacy Clinical guidelines do not support the use of melatonin for insomnia [11].
In a meta-analysis [12] including 19 studies (n = 1683) in adults and children, the
study durations (average 50 days, range 7–182), dosing strategies (0.1 mg – 5 mg),
and formulations varied, making comparison of the results impossible. Although a
~7-minute SOL reduction, an 8-minute TST increase, and a very small improve-
ment in SQ favoring melatonin over placebo were seen, the clinical significance of
these findings was unclear. However, strategically timed melatonin is effective for
treating intrinsic circadian rhythm sleep-wake disorders such as delayed sleep phase
disorders, non-24-hour sleep-wake disorder, and also REM sleep behavior disor-
ders (RBD) [13]. In treating circadian rhythm sleep disorders with melatonin, opti-
mal administration at the proper circadian time, based on an individual’s circadian
timing, is essential. If not administered correctly, melatonin may fail to produce the
desired results or even produce opposite effects and perpetuate sleep disorders and
important to remember when treating elderly due to a decreased production of
endogenous melatonin during aging.
Melatonin is often used to treat insomnia because of its availability over-the-
counter (OTC). While marketed as a “nutritional supplement”, no proof of safety
and effectiveness is required for OTCs, thus composition of melatonin varies and
may have impurities [14]. To minimize potential differences in compositions, con-
sumers and healthcare systems should always purchase melatonin that bears a Good
Manufacturing Practices (GMP) seal as proof that the product is prepared, manufac-
tured, and properly stored to the highest standards.
Safety Overall, when reported, most studies report minimal side effects to melato-
nin. However, in a recent review, 50% of the melatonin trials reported AEs including
psychomotor and neurocognitive dysfunction, fatigue, or excessive sedation [15]. A
few AEs impacting the phase-shifting circadian rhythms of other physiological
functions besides sleep including endocrine/reproductive and cardiovascular param-
eters were reported. Other AEs attributed to dosage, dose timing, and drug-drug
interactions were seen.
Summary Providers and consumers often try melatonin first-line in treating insom-
nia due to its availability. However, melatonin is not recommended for treating
chronic insomnia due to inadequate supporting data with low quality of evidence
and potential for mild AEs.
Melatonin Receptor Agonist: Ramelteon
Ramelteon is a synthetic analog of melatonin. It is a melatonin receptor agonist and

acts by binding selectivity to the MT1 > MT2 receptors, two G-protein-coupled
receptors [16].
Efficacy A SR [17] determined the efficacy of short-term use of ramelteon
(n = 5812) for treating insomnia in mostly female individuals (62%) between 18 and
93 years old. The dose range of ramelteon was 4–32 mg/day (although the FDA-
approved dose is 8 mg/day) and mean duration of therapy was 38 days. Relative to
placebo, ramelteon significantly improved sSL and SQ, but not sTST. Ramelteon
improved secondary outcomes SE, SOL, and TST.
Safety The incidence of AEs with ramelteon was low. Somnolence was the only
significant AE. Angioedema and anaphylaxis, complex sleep-related behavior,
hyperprolactinemia, and lower testosterone levels have been reported in post-
marketing reports [16]. Ramelteon does not produce dependence and has no abuse
potential unlike the GABAergic drugs. There was no tolerance, rebound insomnia
on discontinuation, psychomotor, cognitive, or balance impairment [16].
Summary Ramelteon had a favorable safety profile and responses on many sleep
parameters. However, its clinical efficacy was small, therefore, is not an efficacious
agent for the treatment of chronic insomnia.
Orexin Antagonists: Suvorexant and Lemborexant
Orexin A and B (also called hypocretin-1 and 2) are neuropeptides located in the
perifornical regions of the lateral hypothalamus and project to the brain stem and
forebrain areas, innervating monoaminergic and cholinergic cells. While these neu-
ropeptides influence numerous functions such as food intake, appetite, autonomic
regulation, and endocrine function, they also serve to promote wakefulness and
inhibit REM sleep [18]. Suvorexant and lemborexant are dual orexin receptor antag-
onist agents (DORAs) and bind selectively to the G-protein-coupled receptors,
OX1R and OX2R thus, altering the action of orexin in the brain and suppressing the
sleep-wake drive. (See Table 2.4 for comparisons) [19, 20].
Efficacy Suvorexant was evaluated using dose ranges exceeding the current
approved doses; 5 mg – 20 mg daily. A two-period cross-over efficacy study [21]
examining suvorexant 10 and 20 mg versus placebo for 1 month included 254
patients with primary insomnia. The primary endpoint was SE. Secondary end-
points were WASO and latency to persistent sleep (LPS). After 4 weeks of therapy,
compared to placebo, the 10 and 20 mg doses improved SE (4.7% and 10.4%),
decreased WASO (−21.4 and −28.1 minutes) and LPS (−2.3 and −22.3 minutes),
and improved the exploratory endpoint TST (22.3 and 49.9 minutes), respectively
[21, 22]. To date, no head-to-head trials comparing suvorexant to other sedative
hypnotics exist.
One SR [23] reported patients responding to suvorexant 15 or 20 mg at 3 months,
a number to treat (NNT) of 13 and 16 would be required to achieve a ≥15% improve-
ment in mean sTST and mean sWASO versus placebo, respectively. Other authors
reported a NNT of eight to achieve a ≥6-point improvement in the patient-rated
insomnia severity index (ISI) at 3 months with suvorexant 15/20 mg doses versus
placebo [24].
The efficacy of lemborexant was shown in two Phase 3 RCTs [25, 26].
SUNRISE-1 trial [25] compared lemborexant 5 and 10 mg to placebo and active
comparator, zolpidem ER 6.25 mg for 1 month in adults (n = 1006) aged ≥55 years
with insomnia. Patients had a mean ISI score of 19 upon randomization and 86%
Table 2.4 Characteristics of orexin antagonists in adultsa [19, 20]

Generic name Suvorexant Lemborexant
Trade name Belsomra Dayvigo
Onset of action (min) 30 <30
Tmax, hrs (range) 2 (0.5–6) 1–3
Elimination half-life; hrs. 12 17–19
(range)
Duration Intermediate Intermediate
Metabolism CYP3A4 (major); CYP3A4
CYP2C19 (minor) (major);
CYP3A5
(minor)
Recommended daily dose, 10; 20 5; 10
adults; initial; maximum (mg)a
Exposure Higher in women versus men and in obesity N/A
(>30 kg/m2) vs. non-obesity
Use in pregnancy AEs observed in some animal reproduction studies. No
adequate studies in women during the use in pregnancy for
either agents.
Controlled substance IV
N/A not applicable; AE adverse events
a
Both agents are dosed ≥7 hours before planned time of awakening
were women. The primary endpoint was the mean change from baseline (CFB) in
LPS versus placebo on days 29/30. Pre-specified key secondary outcomes included
mean CFB in SE and WASO compared to placebo and WASO in the second half of
the night (WASO2H) compared to zolpidem ER 6.25 mg on days 29/30. Lemborexant
5 and 10 mg improved LPS 11.6 and 13.6 minutes versus placebo at 1 month,
respectively. The treatment effect of lemborexant 5 and 10 mg versus placebo at
6 months for SE was 3.9% and 4.9%; and for WASO was −7.7 and −9.1 minutes,
respectively.
SUNRISE-2 [26] trial compared lemborexant 5 and 10 mg versus placebo for
6 months (Period 1) (n = 959) followed by 6 months active-treatment only period
(Period 2-https://doi.org/10.1016/j.sleep.2021.01.048). The primary outcome of
Period 1 was a mean CFB in sSL and the pre-specified key secondary efficacy end-
points were CFB for sSE and sWASO using electronic sleep diaries. At 6 months,
both lemborexant doses demonstrated statistically significant superiority to placebo
for all primary and key secondary outcomes. Lemborexant 5 and 10 mg improved
LPS 11.2 and 14.1 minutes from placebo at 1 month, respectively. The treatment
effect of lemborexant 5 and 10 mg compared to placebo at 6 months for sSE was
4.6% and 4.7% and for sWASO, −17.5 and −12.7 minutes, respectively.
A SR and network meta-analysis [27] evaluated the efficacy and safety out-
comes between lemborexant and suvorexant. It included 4 double-blind, RCTs
(n = 3237, mean age 58 years). Treatment arms included lemborexant 10 mg/day
(n = 592); lemborexant 5 mg/day (n = 589); suvorexant 20/15 mg/day (n = 493);
zolpidem ER 6.25 mg/day (n = 263); and placebo (n = 1300). The quality of evi-
dence was rated low or very low. The analysis suggests that at 1 month, lembo-
rexant 10 mg performed better compared to other agents and doses including
placebo for subjective time to sleep onset (primary outcome), sTST and sWASO
(secondary outcomes from sleep diaries) but was associated with a higher discon-
tinuation rate due to AEs and a higher incidence of somnolence compared to
zolpidem ER 6.25 mg/day.
Safety Both DORAs are contraindicated in patients with narcolepsy. The most
common AEs with suvorexant during 1 year of treatment were somnolence, fatigue,
and dry mouth [28]. A dose-related increase of AEs is seen [24–26]. The incidence
of somnolence with suvorexant was 0.4%, 1.6%, and 4.9% for placebo, 10 and
20 mg/day, respectively [21]. The number needed to harm (NNH) using suvorexant
15 or 20 mg/day versus placebo was 28 [24]. Next-day somnolence, CNS depres-
sion, and sleep-related activities including sleepwalking, sleep-driving, and making
phone calls while asleep without patients remembering have been reported.
Suvorexant can impair next-day performance of activities that require mental alert-
ness and motor coordination as did some patients taking lemborexant 10 mg/day. Of
note, performance on some memory and attention tests was reduced with lemborex-
ant 10 mg dose compared to placebo; 5 mg dose did not differ significantly from
placebo in any of these measures.
No clinically significant respiratory depression in mild-to-moderate obstructive
sleep apnea (OSA) and mild-to-moderate chronic obstructive pulmonary disease
were noted with suvorexant. There were no cases of severe cataplexy, although
some reports of “weaknesses” were noted. In patients with mild OSA, lemborexant
did not increase the frequency of apneic events or cause oxygen desaturation.
Symptoms similar to mild cataplexy can occur with lemborexant. No evidence of
rebound insomnia, physical dependence, or withdrawal symptoms were seen with
either agents. The incidence of somnolence or fatigue in a combined analysis pool
(first 30 days) for SUNRISE-1 and SUNRISE-2 trials [22] for placebo, lemborexant
5 and 10 mg, was 1.3%, 6.9% (NNH = 18), 9.6% (NNH = 12), respectively. In
SUNRISE-2 trial [23], the incidence of somnolence was higher in patients ≥65 years
of age (19%) vs. subjects <65 years (10.9%) with lemborexant 10 mg (data on file,
Eisai Inc.).
Summary The DORAs are indicated for sleep onset and maintenance insomnia.
No comparative trials between these two agents exist. Long-term outcomes are not
known. Lemborexant 10 mg compared to zolpidem 6.25 ER had better outcomes in
many of the subjective sleep parameters, however with more somnolence. The inci-
dence of AEs is dose-dependent for both agents.
Antidepressants
Several antidepressants are used off-label to treat insomnia although few controlled,
short- or long-term studies to validate their efficacy and safety in patients with pri-
mary insomnia exists. The tolerability and safety of these agents used in high-
quality trials long term is lacking. Patients with depression or anxiety disorders
treated with SSRI (serotonin reuptake inhibitor) and SNRI (serotonin and norepi-
nephrine reuptake inhibitor) antidepressants often complain of insomnia or daytime
somnolence occurring with long-term treatment [29].
Low-dose doxepin Low-dose doxepin due to its antihistamine effects is FDA-
approved for the treatment of sleep maintenance insomnia. One SR [30] comprised
of 6 RCTs of low-quality evidence compared the efficacy of low-dose doxepin
versus placebo in individuals with insomnia disorder diagnosis with treatment
duration varying from 1 day to 12 weeks. The outcome, ISI, significantly improved
at week four in 2 RCTs in older adults, favoring doxepin 3 or 6 mg dose over
placebo.
None of the RCTs found significant differences in AE rates between low-dose
doxepin and placebo treatment, although the SR did not combine AEs from differ-
ent RCTs. Headache and somnolence were the most common AEs reported with
low-dose doxepin with no significant next-day residual effects or withdrawal effects.
Doxepin may potentially be an inappropriate medication in geriatric patients [31],
and should be avoided when used in doses >6 mg/day due to the possible orthostatic
hypotension, anticholinergic effects, or toxicity [32].
Antidepressants Used Off-Label
Trazodone Trazodone produces sedation by blocking the 5HT-2a/2c receptor.

Trazodone continues to be a highly prescribed drug for insomnia even though the
efficacy for treating insomnia has been studied in only small populations in
depressed individuals, usually with limited subjective sleep evaluations and without
objective PSG data.
In an SR, [33] three of 7 trazodone trials (n = 379) used doses between 25 and
150 mg. Moderate improvement in subjective sleep outcomes over placebo was
seen. Two PSG trazodone studies resulted in little or no difference in SE (low-
quality evidence). Two studies with low-quality evidence had more AEs with trazo-
done than placebo. Another SR [34] included seven trazadone trials of which only
one trial included patients with primary insomnia (n = 306). The trial of 2 weeks in
duration included three arms: trazodone 50 mg, zolpidem 10 mg, and placebo.
Patients self-reported that both trazodone and zolpidem had shorter sleep latency
than placebo, but similar in sleep duration.
Rates of AE were low in two of the trials; the other five studies did not present
this data [34]. Trazodone has an FDA blackbox warning for the possibility of
increasing suicidal thoughts and behaviors in pediatric and young adult patients
[35]. Due to numerous other AEs and drug-drug interactions, trazodone is not con-
sidered a treatment of choice for chronic insomnia.
Summary Only low-dose doxepin is FDA-approved for treatment of sleep mainte-
nance insomnia. There is limited clinical evidence for using other antidepressants
for managing insomnia.
Antipsychotic Agents
Traditional and atypical antipsychotics are sedating due to their antagonism of

dopaminergic, histaminergic, serotonergic, α(alpha)1-adrenergic systems.
Anticholinergic effects, including sedating and hypotensive effects, occur with all
antipsychotics in varying frequency and severity.
A SR [36] evaluated the benefits and AEs of atypical antipsychotics used to
treat insomnia. Only one low-quality study using quetiapine met the inclusion cri-
teria, and reported no statistically significant differences from baseline between
quetiapine and placebo for TST, SL reduction, or sleep satisfaction improvement.
No AEs were reported in the placebo group, but dry mouth and daytime drowsiness
were found in the quetiapine with undetermined frequency. Quetiapine has a
blackbox warning indicating a 1.6 to 1.7-fold increase in mortality in elderly popu-
lations with dementia-related psychosis and increased suicidal tendencies in chil-
dren, adolescents, and young adults [37]. In addition, all atypical antipsychotics
carry a strong recommendation to avoid their use in the elderly except in schizo-
phrenia or bipolar disorders due to an increased risk of cerebrovascular accident
and a greater rate of cognitive decline and mortality in persons with dementia [31].
Summary The atypical antipsychotic used off-label most commonly to treat insomnia
is quetiapine. There are limited number of studies with small sizes regarding efficacy
of antipsychotics for treating insomnia and the drugs have risk for AEs in the elderly.
OTC Drugs
Off-label use of antihistamines such as diphenhydramine and doxylamine produces

subjective drowsiness and reduced SL but tolerance develops within 2 weeks of use
[11]. The use of these agents and other antihistamines is not supported by rigorous
data for treating chronic insomnia [11]. Valerian available as OTC is a plant extract
with GABA activity and shortens SL and improves SE; however, evidence for its
efficacy for treatment of insomnia is limited [11].
Wake-promoting Drugs
Drugs that are agonistic to the wake-promoting nuclei can potentially increase alert-
ness. Thus, wake-promoting agents used to treat excessive daytime sleepiness
(EDS) act via the activation of the noradrenergic, dopaminergic, serotonergic sys-
tems, and/or histamine [1] (Fig. 2.2). Agents treat narcolepsy symptoms, primarily
EDS, but also REM sleep dysregulation symptoms (i.e., cataplexy, hypnagogic/
Mechanism of action Drugs/Drug categories
DA and NE transporter inhibition,

VMAT-2 inhibition, and Amphetamine
MOA activity inhibition
DA and NE transporter inhibition,

serotonin 1A receptor agonist
Methylphenidate
Probably DA reuptake inhibition Modafinil

Armodafinil
Wake-promoting drugs
Probably GABAo, NE, DA,

thalamocortical neurons Sodium oxybate
Probably DNRI Solriamafetol
Antagonist/inverse agonist
at H3 receptors; modulates Pitolisant
release of NE and DA
Fig. 2.2 Demonstrates the potential sites of action of wake-promoting drugs. DA dopamine, NE
norepinephrine, MAO monoamine oxidase, DNRI dopamine and norepinephrine reuptake inhibi-
tor, H3 histamine 3, VMAT-2 vesicular monoamine transporter, GABA gamma aminobutyric acid
Table 2.5 Pharmacology of wake-promoting agents [67, 78]

Usual daily
Generic/ dose range Controlled
(trade name) Half-life (h) (mg) Use in pregnancy substance
CNS stimulants Varies, 5–60 The safety of CNS II
(e.g., amphetamines; depending on (divided stimulants during human
detroamphetamine) the doses) pregnancy has not been
Desoxyn®; formulation established. There may be
Dexedrine®) risks to the fetus
Methylphenidates 1.5–3 20–30 associated with the use of
(Concerta®; Ritalin®) CNS stimulants.
Modafinil 15 200–400 Registry data suggest IV
(Provigil®) (narcolepsy; potentially a higher rate of
divided doses) major congenital
200 (OSA) malformations than in the
Armodafinil 15 150–250 general population
(Nuvigil®) exposed within 6 weeks
prior to conception or
pregnancy.
Sodium oxybate 0.5–1 4.5–9 g/night Insufficient data to III
(Xyrem®) divided into 2 determine developmental
doses risk.
Calcium, magnesium, 0.5–1 Same as Insufficient data to III
potassium, and Xyrem determine developmental
sodium oxybatesa risk.
(Xywav™)
Pitolisant ~20 8.9–35.6 Pre-clinical studies have N/A
(Wakix®) shown reproductive
toxicity. Insufficient
human data to establish
toxicity.
Solriamefetol 2–3 75–150 Insufficient data to IV
(Sunosi®) (narcolepsy) determine drug-associated
37.5–150 risk of major birth defects,
(OSA) miscarriage, or adverse
maternal or fetal
outcomes.
CNS central nervous system; N/A not applicable; OSA obstructive sleep apnea
a
Low-dose sodium oxybate
hypnopompic hallucinations, sleep paralysis) and disrupted nighttime sleep. The

pharmacology and dosing of the wake agents are described in Table 2.5.
Amphetamines and Methylphenidate
Amphetamines and methylphenidate are controlled substances that act by blocking

the reuptake and enhancing the release of norepinephrine, dopamine, and serotonin
[38]. Amphetamines reduce REM (rapid eye-movement) sleep, prolong REM
latency, increase SL, and reduce TST [39].
Efficacy Efficacy data for the wake-promoting drugs are limited. Methylphenidate,
methamphetamine, and dextroamphetamine are FDA-approved for EDS, but are not
considered first-line therapy due to lack of evidence on benefit-to-risk ratios [40].
Safety Adverse events include headaches, irritability, nervousness or tremors, psy-

chosis, anorexia, insomnia, gastrointestinal complaints, dyskinesias, and palpita-
tions. The drugs are contraindicated in patients with advanced arteriosclerosis,
symptomatic cardiovascular disease, moderate to severe hypertension, hyperthy-
roidism, history of drug abuse, or with administration of MAO inhibitors. Labeling
for amphetamines includes a “black box” warning due to the high potential for abuse.
Summary Amphetamines and related medications have been used to improve

alertness in patients with narcolepsy for decades but are not first-line therapy for
EDS. The drugs have significant AEs and potential for abuse in specific situations.
Modafinil and Armodafinil
Modafinil is a nonamphetamine indicated for treatment of EDS for patients with nar-
colepsy and shift-work disorder, and with obstructive sleep apnea (OSA) with resid-
ual daytime sleepiness on adequate positive airway pressure therapy (PAP).
Modafinil’s mechanism of action (MOA) is not well understood but may be dopa-
mine reuptake inhibition [41, 42].
Modafinil is comprised of two enantiomers, the S-isomer with a half-life of
3–4 hours and the R-isomer with a half-life of ~15 hours. Armodafinil is the
R-enantiomer of modafinil. Modafinil’s elimination half-life is almost 13 hours for
single dosing and up to 15 hours after multiple dosing; the maximum concentration
is achieved in 2–4 hours.
Modafinil Efficacy
Narcolepsy A meta-analysis pooled data from nine double-blind RCTs [43] in

patients with narcolepsy (n = 1054) with or without cataplexy and with 2–9 weeks
follow-up at daily doses of 200-, 300-, and 400 mg. Modafinil versus placebo sig-
nificantly decreased EDS assessed by Epworth Sleepiness Scale (ESS) with WMD
of −2.73 points, improved multiple sleep latency test (MSLT) and maintenance of
wakefulness test (MWT) results, WMD of 1.11 and 2.82 minutes, respectively.
Daytime sleepiness and the number of sleep attacks and naps per day decreased.
There were no changes in sleep architecture. Following 9 weeks of treatment with
200 or 400 mg/day, modafinil improved quality of life on the SF-36 questionnaire
and on a validated narcolepsy-specific questionnaire. Performance and clinical
global impression (CGI) scores also improved. The likelihood of falling asleep
increased after withdrawing modafinil [44]. Modafinil had a similar effect on EDS
as sodium oxybate [45] with no difference in the change in ESS scores and mean
sleep latency (MSL) on MWT. There are no RCTs comparing modafinil with
methylphenidate or other amphetamine-like stimulants. Withdrawal symptoms
such as those noted with amphetamines were absent, suggesting that modafinil is
not “addictive” and has a lower potential for abuse. Modafinil 400 mg once daily
or as a split dose in the morning and at midday improved wakefulness than
modafinil 200 mg taken once daily in the morning [46]. Modafinil had no effect on
cataplexy.
Obstructive Sleep Apnea

In one SR of 10 RCTs [47], modafinil/armodafinil used for the treatment of residual
daytime sleepiness in OSA after adequate PAP therapy improved ESS score by 2.2
points over placebo (effect size 0.55), MWT by 3 minutes (effect size 0·41), and
MSLT by 1.3 minutes (effect size 0.33).
Shift work disorder In shift work studies [48], the objective MSL increase was
small (approximately, 2 minutes at both 200- and 400 mg); however, patients’
subjective assessment of sleepiness was much improved, with an ESS score
reduction by approximately 4 points and 6 points at 200 and 400 mg dosage,
respectively.
Armodafinil Efficacy Armodafinil resulted in a small (2.3 minutes) but statisti-

cally significant increase from baseline MSL versus placebo on the first four
30 minutes MWT sessions in OSA patients with residual EDS [49, 50]. Armodafinil
significantly increased the MSL on MWT in narcoleptic patients [51]. In patients
with EDS associated with chronic shift-work disorder, armodafinil significantly
improved wakefulness during scheduled night work, raising mean nighttime SL
from 2.3 minutes at baseline, to 5.3 minutes over a period of 12 weeks [52]. The
effectiveness of armodafinil lasted after long-term use (≥12 month) and was well
tolerated in open-label trials in patients with EDS associated with treated OSA,
shift work disorder, or narcolepsy [52–54]. Armodafinil was also effective in reduc-
ing sleepiness due to jet lag following eastward travel through 6 time zones [55].
Safety Data compiled from six double-blind, RCTs demonstrated that modafinil
has a good safety profile with low potential for abuse [42, 56]. The most common
side effect is headache and anxiety. It does not affect the sleep architecture by PSG
or any cardiovascular parameters (blood pressure or heart rate). A serious but rare
side effect is drug rash. Psychiatric alterations have been noted in patients under
combined treatment with sodium oxybate and modafinil [57] and should be moni-
tored accordingly. These drugs induce cytochrome P450 enzyme, leading to reduced
levels of oral contraceptives. Hence, female patients should use another form of
contraception while on these medications. Neither modafinil nor armodafinil is
FDA-approved for use in pediatric patients for any indication.
Summary Modafinil and armodafinil are effective and safe agents in treating EDS
associated with narcolepsy, shift work disorder, and in OSA treated with PAP.
Sodium Oxybate
Sodium oxybate (Xyrem®) (SXB) and lower-sodium version (Xywav®) are oxy-
bate salts of the recreational drug, gamma-hydroxybutyric acid (GHB). Both agents
are FDA-approved for the treatment of cataplexy and EDS in patients with narco-
lepsy ≥7 years of age. While the MOA is unknown, both agents probably act by
binding to GABAB receptors. Given the abuse potential and CNS depressant effects,
the drugs are scheduled III controlled substances and available only through a
restricted distribution program. Both agents are rapidly absorbed with a high first-
pass metabolism; absorption is slowed by fatty meals, so should be taken a few hours
after a meal. The agents are metabolized to water and carbon dioxide and eliminated
rapidly from the circulation in 20–53 minutes, necessitating twice-nightly adminis-
tration, taken at bedtime while in bed and again 2.5–4 hours later [58]
Efficacy In one meta-analysis, 2 RCTs measured the improvement of EDS with
SXB using different MWT protocols (n = 192). At SXB doses, usually at 9 g/night
for 4–8 weeks, SXB was significantly superior to placebo for increasing MSL
(MD (mean difference): 5.18), and reducing mean sleep attacks (MD: −9.65) and
increased CGI scores. When compared with placebo, cataplexy attacks were statis-
tically significantly decreased with 4.5 g/night dose (pooled results: MD: −8.5,
https://doi.org/10.5664/jcsm.2048)
In another meta-analysis of 9 RCTs (n = 1154), SXB also significantly reduced
subjective daytime sleepiness (WMD −2.81) and sleep stage shifts (WMD −9.69,
[59]). In one of the RCTs, there was a significant reduction of 20% and 27% in the
ESS scores in the SXB monotherapy and SXB + modafinil combined therapy
groups, respectively [45]. After 8 weeks, significant changes in sleep architecture
among patients receiving SXB and SXB + modafinil included a median increase in
Stage 3 and 4 sleep (43.5 and 24.25 minutes, respectively) and delta power and a
median decrease in nocturnal awakenings (6.0 and 9.5, respectively) [60]. It did not
significantly increase REM sleep versus placebo.
The efficacy of lower-sodium oxybate was established in Phase 3 trial, 16 weeks
in duration with 2 weeks of data comparing it to placebo (n = 201, [61]). The sodium
content in a 6–9 g dose SXB and lower-sodium oxybate is 1100–1640 mg vs.
87–131 mg, respectively. The primary outcome was the change in weekly number
of cataplexy attacks from during the stable dose period (2 weeks) to withdrawal
period (2 weeks). The key secondary outcome was a change in EES score. Weekly
cataplexy scores and EES scores were significantly reduced compared to placebo.
Most patients randomized to lower-sodium oxybate reported better PGIc (Patient
Global Impression of Change) ratings, Short Form (SF)-36 physical component
summary scores, and SF-36 mental component summary scores than the pla-
cebo group.
Safety SXB was well tolerated but patients had statistically more AEs versus pla-
cebo, including nausea (relative risk [RR]: 7.74), vomiting (RR:11.8), and dizziness
(RR: 4.3). Enuresis was not significantly different from placebo [62]. Sleepwalking
was reported in 4% of 717 patients treated in clinical trials with SXB [63]. Post-
marketing data indicate a very low risk of abuse/misuse of SXB. Serious AEs,
reported in ~6% of patients, included depression, angina, and suicide attempt. No
acute withdrawal symptoms were observed after 2 weeks of discontinuation follow-
ing an average of 21 months of therapy. The abrupt cessation of SXB did not cause
acute rebound in cataplexy [64]. Caution is advised when treating narcoleptics with
concurrent SXB, and to ensure adherence to positive pressure therapy before start-
ing SXB. The overall safety profile including potential drug interactions of SXB is
expected to be similar to lower-sodium oxybate [61].
Synergistic interactions of SXB with alcohol or other CNS depressants may
increase the risk of intoxication or overdose. The agents should not be taken in
combination with sedative hypnotics or in patients with succinic semialdehyde
dehydrogenase deficiency. Patients with compromised liver function should have
their starting dose decreased by one-half and response to dose increments moni-
tored [58]. Most patients can be effectively transitioned from SXB to lower-sodium
oxybate without any difficulties.
Summary SXB is used in combination with other therapies to adequately control
all symptoms of narcolepsy. A lower-sodium oxybate offers another treatment option
for treating cataplexy in patients with narcolepsy and cardiovascular/renal disease
or other health condition/valid medical reason requiring a lower daily sodium
consumption.
Solriamfetol
Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) indicated

to improve wakefulness in adult patients with EDS. Solriamfetol was approved
based on two 12-week RCTs, in patients with narcolepsy [65] and OSA [66],
respectively. It is not approved for treating cataplexy.
Efficacy Narcolepsy: Treatment of Obstructive Sleep Apnea and Narcolepsy
Excessive Sleepiness (TONES 2 and 3) were double-blind randomized, placebo-
controlled parallel-group trials. In TONES 2 [65], patients with narcolepsy type 1 or
2 (n = 231) with baseline ESS of ≥10 (mean, 17.2) and a baseline mean SL of
<25 minutes based on 4-naps MWT were randomized to receive placebo, solriamfetol
75, 150, or 300 mg daily. The co-primary endpoints were change from baseline to
12 weeks in MWT and ESS. The PGI-C at 12 weeks was the key secondary end-
point. At week 12, solriamfetol 150 and 300 mg significantly increased the mean
change of SL versus placebo from baseline on MWT of 7.7 and 10.1 minutes,
respectively. Significant decreases of −2.2, −3.8, and −4.7 in ESS scores were
found with solriamfetol 75, 150, and 300 mg compared to placebo, respectively. The
NNT to achieve an ESS ≤ 10 using solriamfetol 150 and 75 mg versus placebo at
12 weeks was calculated to be 4 and 7 in a post-hoc analysis, respectively.
Improvements in MWT and EES scores were sustained throughout the trial’s dura-
tion. The improvement in PGI-C (Patient Global Impression scale) was dose-
dependent and significant at 150 and 300 mg doses versus placebo. However, the
recommended doses for patients with narcolepsy are 75 and 150 mg once daily.
Dosages above 150 mg increased dose-related AEs without additional benefit. No
trials comparing solriamfetol with other agents used for the treatment of EDS are
available.
OSA The TONES-3 trial randomized 476 adults with OSA and evaluated the effi-
cacy and safety of solriamfetol 37.5, 75, 150, and 300 mg, with placebo over
12 weeks [66]. The participants had a mean baseline ESS score of ~15 and a mean
MSL on MWT between 12 and 13 minutes. The participants had to either currently
use or had prior use of a primary OSA therapy including PAP, mandibular advance-
ment device, or surgical intervention. The severity of OSA was not specified. The
trial did not specify whether surgery was effective in treating OSA or the required
hours of PAP use. At baseline, primary OSA therapy was used by 69.7% of partici-
pants on placebo and 73.5% randomized to solriamfetol, of which ~90% were on
PAP. The primary OSA therapy nonadherence ranged from 27.1% - 31.6% in the
study. The inclusion criteria of baseline ESS score and endpoints were the same as
in TONES-2 trial, and the baseline SL for MWT was ≤30 minutes.
All solriamfetol doses increased wakefulness significantly relative to placebo in
patients with OSA. The SL mean change from baseline per MWT was 13.0, 11.0,
9.1, 4.7 minutes with 300, 150, 75, and 37.5 mg at 12 weeks, respectively. The dose-
dependent effects were sustained over the study duration. All solriamfetol doses
resulted in a decrease in sleepiness as indicated by the ESS score compared to pla-
cebo at 12 weeks. The ESS decrease was dose-dependent and ranged from −3.3 to
−7.9 with solriamfetol 37.5–300 mg daily. The key secondary endpoint of PGI-C
was met at all doses except for the 37.5 mg dose.
Safety In TONES 2, AEs incidence (≥5%) with all doses of solriamfetol included
headache (21.5%), nausea (10.7%), decreased appetite (10.7%), nasopharyngitis
(9%), dry mouth (7.3%), and anxiety (5.1%) [65]. Patients with previous history of
headache or migraines had a higher incidence of headache. Of note, blood pressure
(BP) taken 9 hours post dose showed an increase from baseline in systolic and dia-
stolic BP (1–2 mmHg) and heart rate (2–4 beats per minutes) for solriamfetol 150
and 300 mg doses compared to placebo. The discontinuation rate was higher in the
solriamfetol 300 mg group (27.1%), solriamfetol 75 mg (16.9%), placebo (10.3%),
and solriamfetol 150 mg (7.3%). The NNH in TONES 2 for any or all treatment-
emergent AEs was 8 and 3 for solriamfetol 75 mg and 150 mg, respectively, com-
pared to placebo at 12 weeks.
In TONES 3, AEs and discontinuations caused by AEs were dose-dependent

[66]. The most frequent AEs with solriamfetol occurring ≥5% were similar to
what was seen in TONES-2 trial. At week 12, BP was increased compared to
baseline with the highest increase noted when 300 mg dose was used; 2.5 and
1.5 mmHg systolic and diastolic, respectively. Small mean increase in heart rate
was also seen with solriamfetol 150 and 300 mg doses. Long-term cardiovascular
consequences are not available. The dose should be adjusted in patients with
renal disease. There is potential for abuse of this drug. It is unknown whether
solriamfetol in combination with other medications for the treatment of narco-
lepsy is safe and tolerated and whether this therapy can be extrapolated to those
that refuse primary OSA therapy.
Summary Solriamfetol is effective in reducing EDS in patients with narcolepsy
and OSA treated with PAP, but there is risk for dose-dependent AEs.
Pitolisant
Pitolisant is indicated for the treatment of EDS or cataplexy in adult patients with
narcolepsy. Pitolisant is a histamine-3 (H3) receptor antagonist/inverse agonist that
blocks the inhibitory effect of the H3 receptors and increases the synthesis and
release of histamine into the brain synapse, so the locus coeruleus NE neurons are
activated. The antagonism of the H3 receptors with pitolisant can increase the
release of other neurotransmitters such as acetylcholine, norepinephrine, and dopa-
mine levels in the prefrontal cortex [67].
Efficacy The efficacy of pitolisant in narcolepsy was established in two 8-week
Phase 3 RCT studies involving narcoleptic adults (n = 258) with EDS [68, 69].
Randomized patients received pitolisant, placebo, or the active comparator agent,
modafinil. In the first RCT (n = 95), 81% of narcoleptics had cataplexy upon
entry. Pitolisant 9–36 mg/day demonstrated a significant improvement in EDS
assessed by ESS compared to placebo at 8 weeks. The treatment effect changes
from baseline EES score between pitolisant and placebo was −3.1. The improve-
ment in objective test of wakefulness and attention tests with pitolisant versus
placebo was confirmed but were not significantly different with modafinil
100–400 mg daily. The SL increased 32% with pitolisant and decreased 10% with
placebo. Responder rates in the post-hoc analyses (defined as an EES score ≤10)
for pitolisant were significantly greater compared to placebo (45% vs. 13%,
respectively) but not compared with modafinil. Similarly, for the daily cataplexy
rates in the post-hoc analyses, in which 35% of the patients continued their usual
anticataleptic drugs (sodium oxybate, (n = 8); or antidepressants, (n = 25)),
pitolisant was superior to placebo in decreasing the number of daily cataplexy
attacks from baseline assessed by sleep diary entries but was not non-inferior to
modafinil [68].
The second RCT (n = 164) studied a lower daily dose range of pitolisant of
4.5–17.8 mg [69]. The maximum dose was reached by 76% of the patients and
~78% of the patients had cataplexy upon randomization. Pitolisant had a treat-
ment effect of −2.12 in the ESS score versus placebo after 8 weeks but there was
no significant improvement in EDS. Non-inferiority test between pitolisant and
modafinil 200 or 400 mg daily could not be concluded. On the objective tests
MWT and SART (sustained attention to response task), pitolisant was signifi-
cantly greater compared to placebo but not different from modafinil. In a post-
hoc analyses, responder rate (defined as an ESS score ≤10 or ESS score reduction
≥3), pitolisant was significantly greater (64%) compared to placebo (35%). No
significant difference between the responder rate for pitolisant and modafinil
groups was seen and there was no reduction in cataplexy rates compared to pla-
cebo at this lower dose [69].
Safety The AEs most frequently reported for pitolisant from pooled studies
(8 weeks) versus placebo were headache (18.7% vs. 14.9%), nausea (5.9 vs. 2.7%),
and insomnia (5.8% vs. 2.3%). The neuropsychiatric AEs seen were insomnia
(8.4%); dizziness (1.4%), depression (1.3%), tremor (1.2%), sleep disorders (1.1%),
and vertigo (1.0%) [69].
Pitolisant is contraindicated in patients with Child-Pugh C. Clinically rele-
vant interactions are expected with strong CYP2D6 inhibitors and CYP3A4
inducers. Concomitant administration of antihistamine-1 receptor antagonists
and sedating antihistamines may impair the efficacy of pitolisant [69] and lower
the efficacy of hormonal contraception. Supratherapeutic doses of pitolisant
have been associated with QTc interval prolongation and drug monitoring is
required in patients with cardiac disease. Pitolisant has no abuse, tolerance,
rebound or withdrawal potential and it is not a scheduled controlled substance
nor a stimulant.
Summary Pitolisant is an alternate agent that is not a scheduled controlled sub-
stance, effective in the treatment of EDS and cataplexy in narcolepsy, and to be used
with caution in patients with cardiac disease.
Novel Drugs in Pipeline
Several drugs for either insomnia or EDS are undergoing clinical trials or have
shown promise in animal studies and are awaiting clinical trials. These drugs and
their potential site(s) of action are presented in Table 2.6 [70].
Table 2.6 Novel drugs in development [79]

Compound/
NTC number Mechanism of action Target indication
Daridorexant Dual orexin receptor antagonist Insomnia
02839200
Seltorexant Selective orexin-2 receptor antagonist Insomnia and related mood
03682380 disorders (MDD)
SKP-1041 GABAA receptor enhancer- Insomnia with middle of the night
00878553 (experimental formulation of zaleplon) awakening
Lorediplon GABAA receptor enhancer: (longer Insomnia
(unknown) acting non-BDZ)
EVT-201 GABAA receptor enhancer Sleep initiation and maintenance
00380003
Esmirtazapine Antidepressant Sleep initiation and maintenance,
00631657 mental disorders
LY2624803 Histamine H1 receptor serotonin2A Insomnia
000784875 (5HT-2A) receptor modulator
Piromelatine NT1/2/3/5-HT1A/D receptor agonist Cognitive and sleep effects in
02615002 Alzheimer’s disease
Pentetrazol Non-competitive GABAA receptor Narcolepsy
BTD-001 antagonist
03542851
FT218 Sodium oxybate ER Long-acting sodium oxybate for
02720744 narcolepsy
THN102 Combination of modafinil and flecainide Parkinson’s disease and EDS
03624920
Reboxetine A selective norepinephrine reuptake Narcolepsy and cataplexy
(AXS-12) inhibitor
03881852
TAK-925 Hypocretin 2 receptor agonist Narcolepsy
03332784
Conclusion
In summary, the drugs promoting sleep and wakefulness have evolved over the
years to precisely target the sleep and wake-related neurons and neurotransmitters
in the brain. These agents are meant for use in conjunction with non-pharmacologic
therapies. Unlike the older pharmacologic agents, the newer medications for these
disorders have been studied in well-designed placebo-controlled RCTs, albeit
mostly industry-sponsored, with evaluation for efficacy and AEs. Many of the
agents reviewed are indicated in adults with limited or ongoing studies in pediatric
age groups. Personalized medicine has become increasingly important in effective
patient care, and the future of sleep pharmacology rests with developing agents that
target specific wake/sleep-promoting receptors, tailored for subpopulations of
patients suffering from these disorders.
Acknowledgments Merit Review Award, Department of Veterans Affairs, Grant

#1I01CX001938-01.
References
1. Eban-Rothschild A, Appelbaum L, de Lecea L. Neuronal mechanisms for sleep/wake regula-

tion and modulatory drive. Neuropsychopharmacology. 2018;43(5):937–52.
2. Atkin T, Comai S, Gobbi G. Drugs for insomnia beyond benzodiazepines: pharmacology,
clinical applications, and discovery. Pharmacol Rev. 2018;70(2):197–245.
3. Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: alternative pharmacologic
agents for the treatment of insomnia. Ann Pharmacother. 1998;32(6):680–91.
4. Roth T, Roehrs TA. A review of the safety profiles of benzodiazepine hypnotics. J Clin
Psychiatry. 1991;52(Suppl):38–41.
5. Mendelson WB. Clinical distinctions between long-acting and short-acting benzodiazepines. J
Clin Psychiatry. 1992;53(Suppl):4–7; discussion 8–9.
6. Buscemi N, Vandermeer B, Friesen C, et al. The efficacy and safety of drug treatments for
chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med. 2007;22(9):1335–50.
7. Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people
with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331(7526):1169.
8. Winkler A, Auer C, Doering BK, Rief W. Drug treatment of primary insomnia: a meta-analysis
of polysomnographic randomized controlled trials. CNS Drugs. 2014;28(9):799–816.
9. Baandrup L, Ebdrup BH, Rasmussen J, et al. Pharmacological interventions for benzodi-
azepine discontinuation in chronic benzodiazepine users. Cochrane Database Syst Rev.
2018;3:CD011481.
10. Prescribers’ digital reference [Internet]. Whippany: PDR, L.L.C; 2020. zolpidem tartrate-
Drug Summary; [cited 2020 July 31]; [about 1 page]. Available from: https://www.pdr.net/
drug-summary/Ambien-zolpidem-tartrate-2515.
11. VA/DoD Clinical Practice Guideline. The Management of Chronic Insomnia Disorder and
Obstructive Sleep Apnea. Washington, DC: U.S. Government Printing Office; 2019. https://
www.healthquality.va.gov/guidelines/CD/insomnia/index.asp.
12. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of pri-
mary sleep disorders. PLoS One. 2013;8(5):e63773.
13. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice
guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-
wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour
sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD).
An update for 2015: an American Academy of Sleep Medicine clinical practice guideline. J
Clin Sleep Med. 2015;11(10):1199–236.
14. Erland LA, Saxena PK. Melatonin natural health products and supplements: presence of sero-
tonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275–81.
15. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A criti-
cal systematic review of clinical evidence. Complement Ther Med. 2019;42:65–81.
16. Prescribers’ digital reference [Internet]. Whippany: PDR, L.L.C; 2020. ramelteon-Drug
Summary; [cited 2020 July 31]; [about 1 page]. Available from: https://www.pdr.net/
drug-summary/Rozerem-ramelteon-562.
17. Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of insomnia in adults: a
systematic review and meta-analysis. Sleep Med. 2014;15(4):385–92.
18. Liu L, Wang Q, Liu A, Lan X, Huang Y, Zhao Z, et al. Physiological implications of orex-
ins/Hypocretins on energy metabolism and adipose tissue development. ACS Omega.
2020;5(1):547–55.
19. Prescribers’ digital reference [Internet]. Whippany: PDR, L.L.C; 2020. suvorexant -Drug
Summary cited 2020 July 31]; Available from: https://www.pdr.net/drug-summary/
Belsomra-suvorexant-3605
20. Lemborexant. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf.
21. Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia: a
randomized clinical trial of suvorexant. Neurology. 2012;79(23):2265–74.
22. Patel KV, Aspesi AV, Evoy KE. Suvorexant: a dual orexin receptor antagonist for the treatment
of sleep onset and sleep maintenance insomnia. Ann Pharmacother. 2015;49(4):477–83.
23. Kuriyama A, Tabata H. Suvorexant for the treatment of primary insomnia: A systematic review
and meta-analysis. Sleep Med Rev. 2017;35:1–7.
24. Citrome L. Suvorexant for insomnia: a systematic review of the efficacy and safety profile for
this newly approved hypnotic - what is the number needed to treat, number needed to harm and
likelihood to be helped or harmed? Int J Clin Pract. 2014;68(12):1429–41.
25. Rosenberg R, Murphy P, Zammit G, et al. Comparison of lemborexant with placebo and zolpi-
dem tartrate extended release for the treatment of older adults with insomnia disorder: A phase
3 randomized clinical trial. JAMA Netw Open. 2019;2(12):e1918254.
26. Kärppä M, Yardley J, Pinner K, et al. Long-term efficacy and tolerability of lemborexant com-
pared with placebo in adults with insomnia disorder: results from the phase 3 randomized
clinical trial SUNRISE 2. Sleep. 2020;43(3)
27. Kishi T, Nomura I, Matsuda Y, et al. Lemborexant vs suvorexant for insomnia: A systematic
review and network meta-analysis. J Psychiatr Res. 2020;128:68–74.
28. Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant during 1-year treat-
ment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised,
double-blind, placebo-controlled trial. Lancet Neurol. 2014;13(5):461–71.
29. Thompson C. Onset of action of antidepressants: results of different analyses. Hum
Psychopharmacol. 2002;17(Suppl 1):S27–32.
30. Yeung WF, Chung KF, Yung KP, Ng TH. Doxepin for insomnia: a systematic review of ran-
domized placebo-controlled trials. Sleep Med Rev. 2015;19:75–83.
31. American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatric
Society 2019 Update AGS Beers Critieria® for potentially inappropriate medication use in
older adults. J Am Geriatr Soc. 2019;67(4):674–94.
32. Fung SJ, Yamuy J, Sampogna S, Morales FR, Chase MH. Hypocretin (orexin) input to trigemi-
nal and hypoglossal motoneurons in the cat: a double-labeling immunohistochemical study.
Brain Res. 2001;903(1):257–62.
33. Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, et al. Antidepressants for
insomnia in adults. Cochrane Database Syst Rev. 2018;5:CD010753.
34. Yi XY, Ni SF, Ghadami MR, Meng HQ, Chen MY, Kuang L, et al. Trazodone for the treat-
ment of insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Med.
2018;45:25–32.
35. Full prescribing information: Desyrel. U.S. Food and Drug Administration; 2017.
36. Thompson W, Quay TAW, Rojas-Fernandez C, Farrell B, Bjerre LM. Atypical antipsychotics
for insomnia: a systematic review. Sleep Med. 2016;22:13–7.
37. Prescribers’ digital reference [Internet]. Whippany: PDR, L.L.C; 2020. quetiapine -Drug
Seroquel-quetiapine-fumarate-2185.
38. Raiteri M, Bertollini A, Angelini F, Levi G. d-Amphetamine as a relaeser of reuptake inhibitor
of biogenic amines in SYnaptosomes. Eru J Pharmacol. 1975;34:189–95.
39. Nicholson A, Stone BM. Heterocyclic amphetamine derivatives and caffenine on sleep in man.
Br J Clin Pharmacol. 1980;9(2):195–203.
40. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narco-
lepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705–11.
41. Lammers GJ. Drugs used in narcolepsy and other hypersomnias. Sleep Med Clin.
2018;13(2):183–9.
42. Murillo-Rodríguez E, Barciela Veras A, Barbosa Rocha N, et al. An overview of the clinical
uses, pharmacology, and safety of modafinil. ACS Chem Neurosci. 2018;9(2):151–8.
43. Golicki D, Bala MM, Nieanda M, Wierzbika A. Modafinil for narcolepsy: systemic review and
meta-analysis. Med Sci Monit. 2010;16(8):177–86.
44. Moldofsky H, Broughton R, Hill J. A randomized trial of the ling-term, continued efficacy and
safety of modafinil in marcolepsy. Sleep Med. 2000;1:109–16.
45. Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy.
Sleep. 2006;29(7):939–46.
46. Schwartz J, Feldman N, Bogan R, Nelson M, Huges R. Dosing regimen effects of modafinil
for improving daytime wakefulness in patients with narcolepsy. Clin Neurpharmacol.
2003;164(9):252–7.
47. Chapman JL, Vakulin A, Hedner J, Yee BJ, Marshall NS. Modafinil/armodafinil in obstructive
sleep apnoea: a systematic review and meta-analysis. Eur Respir J. 2016;47(5):1420–8.
48. Czeisler CA, Walsh JK, Roth T, et al. Modafinil for excessive sleepiness associated with shift-
work sleep disorder. N Engl J Med. 2005;353(5):476–86.
49. Hirshkowitz M, Black J, Wesnes K, et al. Adjunct armodafinil improves wakefulness and
memory in obstructive sleep apnea/hypopnea syndrome. Respir Med. 2007;101(3):616–27.
50. Roth T, White D, Schmidt-Nowara W, et al. Effects of armodafinil in the treatment of residual
excessive sleepiness associated with obsturctive sleep apnea/hypopnea syndrome: A 12-week,
mulitcenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults.
Clin Ther. 2006;28(5):689–706.
51. Harsh J, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treat-
ment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin.
2006;22(4):761–74.
52. Czeisler C, Walsh J, Wesnes K, Arora S, Roth T. Armodafinil for treatment of excessive sleepi-
ness associated with shift-work disorder: a randomized controlled study. Mayo Clin Proc.
2009;84(11):958–72.
53. Black J, Hull S, Tiller J, Yng R, Harsh J. The long-term tolerability and efficacy of armodafinil
in patients with excessive sleepiness associated with treated obstructive sleep apnea, shift work
disorder, or narcolepsy: and open-label extension study. J Clin Sleep Med. 2010;6(5):458–66.
54. Schwartz J, Kahn A, McCall W, Weintraub J, Tiller J. Tolerability and efficacy of armodafinil
in naive patients with excessive sleepiness associated with obsturctive sleep apnea, shift work,
disorder, or narcolepsy: a 12-month, open-label, flexiable-does study with an extension period.
J Clin Sleep Med. 2010;6(5):450–7.
55. Rosenberg R, Bogan R, Tiller J, et al. A phase 3, double-blind, randomized, placebo-controlled
study of armodafinil for excessive sleepiness associated with jet lag disorder. Mayo Clin Proc.
2010;85(7):630–8.
56. Roth T, Schwartz J, Hirshkowitz M, et al. Evaluation of the safety of modafinil for treatment
of excessive sleepiness. J Clin Sleep Med. 2007;75(20):595–602.
57. Rossetti A, Heinzer R, Tafti M, Buclin T. Rapic occurance of depression following addition of
sodium oxybate. Sleep Med. 2010;11:500–1.
58. Xyrem (sodium oxybate) [prescribing information]. Palo Alto: Jazz Pharmaceuticals; September
2020. Xywav (calcium, magnesium, potassium, and sodium oxybates) October 2020.
59. Boscolo-Berto R, Viel G, Montagnese S, et al. Narcolepsy and effectiveness of gamma-
hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled tri-
als. Sleep Med Rev. 2012;16(5):431–43.
60. Black J, Pardi D, Hornfeldt C, Inhaber N. The nightly administration of sodium oxybate results
in significant reduction in the nocturnal sleep disruption of patients with narcolepsy. Sleep
Med. 2009;10(8):829–35.
61. Bogan RK, Thorpy MJ, Dauvilliers Y, et al. Efficacy and safety of calcium, magnesium, potas-
sium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled,
double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep.
2021;44(3)
62. Alshaikh MK, Tricco AC, Tashkandi M, et al. Sodium oxybate for narcolepsy with cataplexy:
systematic review and meta-analysis. J Clin Sleep Med. 2012;8(4):451–8.
63. Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates
sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J
Clin Sleep Med. 2005;1(4):391–7.
64. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause
withdrawl symptoms. J Toxicol Clin Toxicol 2003;41:131–5.
65. Thorpy MJ, Shapiro C, Mayer G, et al. A randomized study of solriamfetol for excessive
sleepiness in narcolepsy. Ann Neurol. 2019;85(3):359–70.
66. Schweitzer PK, Rosenberg R, Zammit GK, et al. Solriamfetol for excessive sleepiness in obstruc-
tive sleep apnea (TONES 3). A RCT. Am J Respir Crit Care Med. 2019;199(11):1421–31.
67. Thorpy MJ, Bogan RK. Update on the pharmacologic management of narcolepsy: mecha-
nisms of action and clinical implications. Sleep Med. 2020;68:97–109.
68. Dauviliers Y, Bassetti C, Lammers GJ, Amulf I, Mayer G, Rodenbeck A, Lehert P, Ding
CL, Lecomte JM, Schwartz JC, HARMONY I Study Group. Pitolisant versus placebo
or Modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol.
2013;12(11):1068–75.
69. Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. The European
medicines agency review of pitolisant for treatment of narcolepsy. Sleep Med. 2017;33:125–9.
70. Bouryi VA, Lewis DI. The modulation by 5-HT of glutamatergic inputs from the raphe pallidus
to rat hypoglossal motoneurones, in vitro. J Physiol. 2003;553(3):1019–31.
71. Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central
nervous system-mediated effects. Ochsner J. 2013;13(2):214–23.
72. Janto K, Prichard JR, Pusalavidyasagar S. An update on dual orexin receptor antagonists and
their potential role in insomnia therapeutics. J Clin Sleep Med. 2018;14(8):1399–408.
73. Reynolds AP, Adams R. Treatment of sleep disturbance in older adults. J Pharm Pract Res.
2019;49(3):296–304.
74. Wichniak A, Wierzbicka A, Walęcka M, et al. Effects of antidepressants on sleep. Curr
Psychiatry Rep. 2017;19:63.
75. Snyder E, Ma J, Svetnik V, Connor KM, et al. Effects of suvorexant on sleep architecture and
power spectral profile in patients with insomnia: analysis of pooled phase 3 data. Sleep Med.
2016;19:93–100.
76. Prescribers’ digital reference [Internet]. Whippany: PDR, L.L.C; 2020. zaleplon -Drug
Sonata-zaleplon-1491.
77. Prescribers’ digital reference [Internet]. Whippany: PDR, L.L.C; 2020. eszopiclone -Drug Summary
cited 2020 July 31]; Available from: https://www.pdr.net/drug-summary/Lunesta-eszopiclone-2082.
78. Ghaffari N, Robertson PA. Caution in prescribing modafinil and armodafinil to individuals
who could become pregnant. JAMA Intern Med. 2021;181(2):277–8.
79. U.S. National Library of Medicine. ClinicalTrials.gov [Internet]. Bethesda. MD. [cited 2020
July 30.] Available from: https://clinicaltrials.gov/.
Chapter 3
Sleep Health among Racial/Ethnic
groups and Strategies to achieve
Sleep Health Equity
Azizi A. Seixas, Anthony Q. Briggs, Judite Blanc, Jesse Moore,

Alicia Chung, Ellita Williams, April Rogers, Arlener Turner,
and Girardin Jean-Louis
Keywords Sleep quality · Rapid eye movement · Insomnia · Circadian rhythms ·

Social jetlag · Non-rapid eye movement (NREM) · Sleep architecture ·
Thyromental angle
Introduction
Relative to Whites, racial/ethnic minorities are more likely to experience a higher

burden of poor health, chronic disease, accelerated aging, and premature/excess
deaths [1–6]. These health burdens can be attributed to several biological, psycho-
social, and environmental factors and mechanisms. Notable biological explanations
include, but are not limited to, advanced cell aging, DNA methylation, telomeriza-
tion of cells, and multimorbidity [2, 7–14]. However, the pathogenesis of poor
health, accelerated aging, and disease burden among racial/ethnic minorities is not
solely a biological process; it also occurs epigenetically where chronic exposure to
Azizi A. Seixas (AS) and Anthony Q. Briggs (AB) are co-first authors.
A. A. Seixas (*) · J. Blanc · A. Turner · G. Jean-Louis

University of Miami, Miller School of Medicine, Miami, FL, USA
e-mail: azizi.seixas@nyulangone.org; azizi.seixas@nyumc.org
A. Q. Briggs
New York University Langone Health, Department of Population Health, New York, NY, USA
New York University Langone Health, Department of Psychiatry, New York, NY, USA
J. Moore · A. Chung · E. Williams
New York University Langone Health, Department of Population Health, New York, NY, USA
A. Rogers
St. John’s University, New York, NY, USA

48 A. A. Seixas et al.
noxious exogenous factors cause disease by introducing heritable changes in genetic

expression or chromosomal function into the biology of individuals to cause disease
[11, 12, 15–17]. Growing evidence highlights that the burden of poor health, chronic
disease, and accelerated cellular aging among racial/ ethnic minorities is observed
across the lifespan, suggesting that the roots of poor health begin as early as the in-
utero period and childhood [18]. However, extant etiological frameworks to explain
the burden of poor health, chronic disease, accelerated aging, and premature/excess
deaths heavily emphasize proximal and exogenous effects of life stressors and
exclude potential distal and upstream factors such as the cumulative effect of preju-
dice and discrimination, as well as environmental (noxious noise, light, and air qual-
ity), political (taxes, policies, governmental programs, and nativity/citizen status)
[19], and social determinants of health (poor access to health services, socioeco-
nomic status, neighborhoods, and education) [20].
Although it is difficult to identify a single cause for the burden of poor health
outcomes, chronic disease, accelerated aging, and premature/excess deaths, there
are some factors that may offer upstream (etiology) and downstream (consequences)
insights into the chronicity, pervasiveness, and ubiquity of poor health among racial/
ethnic minorities. Growing evidence points to sleep health (duration, sleep disor-
ders, efficiency, sleep quality, sleepiness (alertness), and timing/chronotype) as
being one such factor that might provide a unique upstream and downstream expla-
nation for the life-course burden of poor health, chronic disease, accelerated aging,
and premature/excess deaths among racial/ethnic minorities [21–25].
Sleep disruptions represent both a cause and consequence of poor health out-
comes in racial/ethnic minorities. Mounting evidence indicates that racial/ethnic
groups are unequally burdened by a wide range of sleep disruptions and poor sleep
health outcomes, which lead to further disparities in cardiovascular disease, cancer,
dementia, and mental health outcomes [21–28]. Although the burden of poor sleep
health outcomes affects most racial/ethnic groups, relative to Whites, their manifes-
tation and causes at the population level are specific to each group. For example,
Black and Latino children and adults alike have a predominantly higher risk for
poor sleep health (inconsistent sleep schedules, insufficient sleep duration, sleep-
disordered breathing problems, and daytime sleepiness) compared to their White
counterparts. It is likely that poor sleep health, experienced as a child, has residual
and insidious effects on later life, thus increasing likelihood of debilitating poor
sleep and adverse functional and health outcomes, such as poor cognitive perfor-
mance, car accidents and occupational accidents, cardiovascular disease, diabetes,
and mental health, all of which are higher among racial/ethnic minorities compared
to Whites [29, 30].
To better understanding sleep health burden among racial/ethnic groups, we will
describe the prevalence and burden of sleep health parameters: (1) sleep duration,
(2) sleep disorders, (3) sleep timing/chronotype, (4) sleep architecture, (5) sleep
quality, (6) sleepiness/alertness, and (7) sleep efficiency (See Fig. 3.1). Then, we
will describe upstream processes and causes of poor sleep health parameters among
racial/ethnic groups, which can be attributed to a variety of biological (circadian
rhythm), behavioral (diet and exercise mental health), psychosocial (stress, mental
3 Sleep Health among Racial/Ethnic groups and Strategies to achieve Sleep Health… 49
Fig. 3.1 Sleep health

components diagram
Duration
Architecture Sleepiness/
alertness
Sleep
health
Sleep Timing/
disorders chronotype
Satisfaction
+ Efficiency
quality
health, poverty, social demands), and environmental factors (noise and light), which
we describe in detail. Lastly, we will describe the downstream processes and conse-
quences of poor sleep health among racial/ethnic groups, which include but are not
limited to a variety of adverse health outcomes, chronic diseases (cardiovascular
disease, diabetes, and mental health), and poor functional and performance
outcomes.
Prevalence and Burden of Poor Sleep Health
Sleep health is characterized by seven sleep parameters: (1) sleep duration, (2) sleep
disorders, (3) sleep timing/chronotype, (4) sleep architecture (sleep stages divided
into rapid eye movement (REM) and non-REM sleep), (5) sleep quality, (6) sleepi-
ness, and (7) sleep efficiency [31]. Mounting evidence highlight an alarming trend
of sleep health disparities across certain demographic groups, most notably among
racial/ethnic minorities who compared to their White counterparts experience sig-
nificant burden in all seven sleep parameters which have been attributed to several
adverse health and functional outcomes and provide some explanation for elevated
and high burden of certain chronic diseases, such as cardiovascular disease, mental
health, and dementia. From this growing and heterogenous evidence, there is an
emerging coalescing definition of sleep health disparity, which the NIH describes as
any difference in one or more dimensions of sleep health (regularity, quality, alert-
ness, timing, efficiency, and duration)—on a consistent basis—that adversely affects
designated disadvantaged populations [29]. Although this definition of sleep health
disparity is not final or comprehensive, it represents an excellent start and working
definition that provides the critical lens through which one can identify, define, mea-
sure, and study the drivers and consequences of sleep health disparity. Therefore,
we use this definition of sleep health disparity as the lens to identify sleep health
disparities among racial/ethnic groups for the current book chapter. However, to
better understand sleep health disparity, it is important to go beyond identifying dif-
ferences (which is often restricted to numerical difference), and seek to understand
the fundamental causes and consequences of these differences.
Therefore, for the current chapter, we define sleep health disparity as differences
that are due to deeply entrenched cause[s] (biological, psychosocial, and environ-
mental) and downstream consequences that even the counterfactual cannot escape.
For example, sleep health disparity exists because both poor and wealthy racial/
ethnic minorities are more burdened by poor sleep health outcomes, compared to
their poor and wealthy White counterparts (even when comparing a wealthy minor-
ity with a poor White individual). This evidence should not be misunderstood as a
positing and privileging of ontogeny/biological causes over social causes but rather
an acknowledgment of the syndemic and epigenetic etiology of sleep health dispar-
ity. In fact, sleep health disparity may be due to omni-directional relationships
among latent hard-wired biological factors, noxious psychosocial and environmen-
tal terroir and contexts, and defunct system-level factors that would normally ame-
liorate health risk (such as the inability of our poor healthcare system to address
sleep health disparities and its consequences or poor labor policies that prevent
individuals from earning a living wage causing poorer populations to work multiple
jobs that induce stress and disrupt sleep health). For the sections below, we estab-
lish: (1) sleep health disparities by describing numerical differences across all sleep
health parameters (highlighting higher burden, prevalence rates, and likelihoods
among racial/ethnic minorities compared to their counterfactual counterparts), (2)
biological, psychosocial, and environmental antecedents and causes of sleep health
differences, and (3) functional and health consequences of sleep health differences
among racial/ethnic minorities (See Table 3.1).
Sleep Duration
There are significant differences in sleep duration and total sleep time among sev-
eral demographic groups (sex, geographic, and socioeconomic status). The most
compelling and robust evidence for group-based differences in sleep duration are
observed among racial/ethnic minorities and so for the current chapter we focus
only on racial/ethnic groups. Racial/ethnic differences in sleep duration have been
noticed as early as childhood and persist throughout the lifespan to adulthood.
Regardless of age group, racial/ethnic minorities do not receive adequate sleep
duration for their age sleep. Although the American Academy of Sleep Medicine
recommends that 3–5-year-old children receive on average 10–13 hours (including
naps) daily, 9–12 hours for 9–12-year-old children, and 7–9 hours for adults, racial/
ethnic minorities consistently experience insufficient sleep duration (See Table 3.1).
Table 3.1 Racial-ethnic disparities in health outcomes in selected sleep dimensions compared to
White adults
Chrono Social jet
type- lag-
Sleep Sleep circadian Sleep excessive Sleep
duration disorders rhythm architecture sleepiness quality
African-
American/ 64,21 23,43
Black 12–14,29,30– 6,19,31,32,44– 50,52,53 44,57,58,59
33 46
Hispanics-
Latinos 17,26,38 IES 64 43 57
20,31,35,47,49
Asian 31,20 IES IES IES IES
12
Native 44 IES 64 26 IES
Hawaiian 12
and Pacific
Islander
Note: The direction of the arrow refers to the direction of how these groups are more at risk to
experience sleep disparities in the selected categories (e.g., lower or higher)
Abbreviations: MR mixed results, IES insufficient evidence in sleep
Chronic insufficient sleep duration (such as short sleep duration <7 hours) has been
linked with increased risk for cognitive impairment, occupational hazards, mis-
takes, poor cardiovascular health and disease, mental illness, dementia, and cancer
[32–36].
Based on data from the National Health and Nutrition Examination Survey
(NHANES), short sleep duration is highly prevalent in the United States with a
conservative overall estimate of 37.1% across the lifespan. However, these same
data reveal that the greatest burden of short sleep duration is experienced among
middle age individuals: (1) 20–39 years of age (37.0%); (2) 40–59 years (40.3%);
and 60 years and older (32.0%), highlighting severe sleep deprivation across all age
groups [37]. Stratifying these results by race/ethnicity highlights the fact that among
children 6 months and 2 years old, only 6% of Black children slept the recom-
mended amount of 12 hours daily, while 83% of White children slept at least
12 hours daily. Similar trends have been observed among adolescents, where Asians
(76%) and Blacks (71%) had the highest rates of short sleep duration/insufficient
sleep relative to Whites (68%), except Latinx (67%). Similarly among adults, Native
Hawaiian-Pacific Islanders (46.3%); Blacks (45.8%); Other Multiracial (44.3%);
American Indian-Alaska Native (40.4%); Asian (37.5%); and Latins (34.5%) all
have higher prevalence of short/insufficient sleep relative to Whites (33.4%).
Sleep health disparities among minorities are not limited to adult populations
only. A review of 23 studies investigated racial/ethnic sleep health disparities among
American minority youth between the ages of 6–19 years and found that white
youth (adolescents) had more sufficient sleep compared to racial/ethnic minorities,
most notably Blacks and Hispanics/Latinos. Blacks had overall shorter sleep
duration and later bedtimes than Hispanics/Latinos [38]. Black and Hispanic youth
also spent more time traveling to school, had earlier start times, and spent more time
watching television, more likely to share a bedroom and partake in regular naps.
Evidently, napping decreased with age, and some studies have shown that Blacks
and Hispanics/Latino are more likely to nap on the weekday while other researchers
have suggested that naps are more likely to happen on the weekends [39]. In other
studies, Black and Hispanics slept an hour less than Whites [40–47].
Outside of epidemiological data, community-based findings with similar trends
further validate the notion that sleep health differences do exist across the lifespan.
In a cross-sectional community study of children, 39.1% of Black children reported
poorer sleep duration and more naps compared to 4.9% White children. To explain
this twin phenomenon of sleep deprivation and napping, it is likely that Black chil-
dren who are sleep deprived try to catch up on lost sleep, through napping, and
extended sleep duration over the weekend than weekday [44, 48, 49]. Further strati-
fication by sex also shows race-sex differences in sleep duration. In a community
study in Chicago, Illinois White men (6.7 hours) have the highest average sleep
(actigraphy), then White women (6.1 hours), then Black women (5.9 hours), and
then Black men (5.1 hours) [36], a trend observed across other studies [47, 50–53].
The burden of short sleep duration and sleep deprivation, among racial ethnic
minorities, is consequential as they are linked with several chronic health conditions
[46, 54–58].
Sleep Disorders
It is estimated that 50–70 million people have a sleep disorder, with obstructive
sleep apnea (OSA) and insomnia being the two most prevalent in the United States.
OSA is a sleep breathing disorder characterized by partial or complete blockage of
the upper airway, resulting in reflexive awakenings and transient cessation in breath-
ing patterns (apneas and hypopneas). Apnea and hypopnea events cause oxygen
desaturation and physiological stress, thus affecting key homeostatic physiological
processes. Key OSA symptoms include: sleep-related pauses in respiration, arous-
als, unrefreshing sleep, snoring, restlessness, poor concentration, fatigue, and exces-
sive daytime sleepiness [34]. OSA is considered one of the most common sleep
disorders, among middle and older aged adults, affecting around 24% and 49.7% of
the US population [52]. Obesity, large neck size, instability in respiratory control
system, and craniofacial structures are key OSA risk factors. OSA is associated with
cardiovascular disease, cardiometabolic conditions, cerebrovascular, low and
worsen cognitive performance, and dementia [34, 59, 60].
The burden of OSA risk and disease is high among racial-ethnic minorities
(among pediatric and adult populations), specifically Blacks (See Table 3.1). Blacks
children aged 2–18 were more likely to experience sleep-disordered breathing
(SDB), even after controlling for specific variables, obesity, respiratory problems,
smoking, and neighborhood of residence. Even racial and ethnic parents have
reported that their child snores more than non-ethnic parents. Other estimates indi-
cate that Black children are 4–6 times more likely to have OSA, Hispanic/Latinx
children have a greater severity, Native American children are 1.7 times more likely
to have moderate to severe OSA, and Asian Americans have similar or lower OSA
prevalence compared to White children [59]. In an adult population using data from
the Jackson Heart sleep study (n = 852), approximately 24% of the sample had
moderate to severe OSA based on apnea-hypopnea index (a measure of severity),
but only 5% had a diagnosis, indicating that the overwhelming majority of partici-
pants were undiagnosed (95%). Black men had a higher prevalence of OSA com-
pared with Black women [61]. The foregoing evidence suggests that even when
Blacks experience OSA symptoms, they were less likely to be diagnosed and
treated. Similar trends are observed among Latinx and Asian popualtions [34], with
49.4% of Latinos and 43.1% of Asians reporting significant snoring, a major OSA
symptom and risk factor. Although population estimates are high, community-level
estimates indicate even higher burden among racial/ethnic minorities. In a study
conducted in primary care community-based clinics in Brooklyn NY, almost half of
Black patients (45%) reported debilitating snoring and about one-third reported
excessive daytime sleepiness (33%) and difficulty maintaining sleep, a sign of
insomnia (34%) [6]. However, for Latinx population being overweight/obese was
the strongest marker and predictor of OSA risk, while for Asians craniofacial fea-
tures and not body adiposity was most predictive of OSA risk [62]. The heterogene-
ity in OSA risk across racial/ethnic groups has proved difficult for adequate
screening, assessment, and treatment, often leading to high rates of untreated indi-
viduals. The consequence of untreated OSA has proved consequential, especially
among Blacks, as it is linked to elevated, uncontrolled, and resistant blood pressure
and stroke [34, 59, 60].
OSA burden and disparity are not just observed and confined to differential esti-
mates of the disease but also rooted in the uneven distribution of upstream and
downstream consequences of OSA, as well as the lack of system level infrastruc-
tures to attenuate or buffer these burdens. Adherence to OSA treatments is a major
problem among racial and ethnic minority groups as Blacks have one of the poorest
OSA treatment (positive airway pressure [PAP]) adherence rates [63]. Poor treat-
ment adherence is credited more to system-level barriers in the healthcare system
such as poor insurance coverage, under-resourced sleep clinics in predominantly
low-income and minority neighborhoods, and the limited amount of board-certified
minority clinicians and providers.
Insomnia is another prevalent sleep disorder among racial/ethnic minorities.
Although the prevalence of an insomnia diagnosis is mixed among minority groups,
the prevalence of insomnia symptoms such as involuntary early morning awaken-
ings, difficulty falling asleep, and issues with staying asleep are high. For racial and
ethnic groups, insomnia is one of the most common sleep complaints and disorders,
with approximately 30% reporting at least one insomnia symptom, 5–10% meeting
threshold for an insomnia disorder, and approximately 6% with an actual diagnosis
[51, 64, 65]. Insomnia’s nocturnal symptoms and daytime consequences include
lack of energy, difficulty concentrating, fatigue, tiredness, irritability, and
moodiness. Insomnia disorder increases the risk of stress, anxiety, depression, and
decreased quality of life.
Several population studies show that Blacks are more likely to be affected by
insomnia symptoms compared to other racial/ethnic groups. In a US National
Institute of Health (NIH) study with 825 Black Americans (both men and women),
1 in 5 participants had insomnia and 6.7% an insomnia diagnosis. Another study
demonstrated that Blacks reported greater nighttime insomnia relative to their other
racial/ethnic counterparts.
Chronotype and Circadian Rhythms
Observed differences in circadian rhythms, chronotype, and sleep timing (irregular

sleep time between weekdays and weekends such as social jetlag) among racial/
ethnic minorities relative to Whites is well-documented (See Table 3.1). Circadian
rhythms is the 24-hour internal clock that regulates the scheduling of important bio-
behavioral activities such as eating, metabolizing food, sleep and rest, and when a
person is most active or stressed. The circadian master clock, the superchiasmatic
nucleus, coordinates, and synchronizes with peripheral clocks in the body (i.e.,
heart, cells) to ensure all biological and functional processes are aligned, synchro-
nized, and working optimally. Circadian rhythms are influenced by exogenous cues
and stimuli such as light, darkness, and sound that help punctuate the day and signal
shifts that help the body regulate itself. However, desynchronized and chronic expo-
sure to these cues and stimuli can result in circadian dysregulation and possible
misalignment. Circadian misalignment occurs when an individual’s central and
peripheral biological clocks become misaligned from their daily behavioral clock,
such as the time an individual the routine sleep, meal, and activity [45, 57, 66–69].
The desynchrony of exogenous, endogenous, and behavioral clocks can occur as
early as childhood and is linked to poor emotion regulation and obesity across the
lifespan [57, 70].
Chronotype among minorities Persons with evening chronotype are less likely to
have regular exercise and more likely to partake in unhealthy diets and lifestyle
choices that increase their cardiovascular risk. In a study made up of 61.5% of
racially and ethnically diverse women in the United States (N = 506) greater morn-
ingness was associated with a more favorable cardiovascular profile which included
BMI, blood pressure, cholesterol, and glucose levels compared to their white coun-
terparts. Conversely, compared to the morning chronotype, evening persons had a
greater than two-fold higher odds of having a poor cardiovascular profile and sleep
duration of less than 7 hours per night [71]. Among adults in the Southern region of
the United States, obesity was significantly associated with evening chronotype in
whites, but not blacks even after adjusting for important covariates like shift work,
physical activity, and sleep duration which could suggest the need for more pointed
research exploring the multidimensional nature of racial and ethnic chrono-

types [71].
Circadian rhythms among minorities Several studies show that Blacks have
shorter free-running circadian periods (tau) than Whites (24.07 hours vs 24.33 hours).
Shorter free-running circadian periods make it more difficult to adjust to night-shift
work and delayed (daytime) sleep schedule [67–69]. The health consequences of
shifts in circadian rhythms can be grave, as studies indicate that Black night shift
workers are more likely to have elevated blood pressure and hypertensive compared
to Black day workers. In a community sample of Blacks in New York City, Black
shift workers had 35% increased odds of having hypertension among Blacks
[OR = 1.35, CI: 1.06–1.72. P < 0.05], compared to their White counterparts.
Circadian rhythm disruption among Blacks who work non-traditional hours leads to
sleep deprivation and shorter sleep duration and 80% increased cardiovascular dis-
ease risk such as hypertension [OR = 1.81, CI: 1.29–2.54, P < 0.01] [67]. Blacks
who have shorter circadian periods and live closer to the equator with longer expo-
sure to sunlight were less likely to have disrupted circadian rhythms.
Social jetlag among minorities A prevalent phenomenon that may impact sleep
habits is the concept of “social jetlag”. Social jetlag occurs when an individual’s
weekday and weekend sleep time is significantly different from their body’s endog-
enous circadian clock. This results in poorer sleep quality, sleep time in deep sleep,
and may result in other adverse functional and health outcomes. Disruptions in
sleep timing can have ripple effects on the timing of other key social and biological
activities such as eating. It is highly likely that disruptions in sleep timing due to
social jetlag may also result in eating jet lag. Eating jetlag occurs when an individ-
ual’s meal timing is misaligned with their endogenous metabolic circadian clock.
Combined, irregular sleep, physical activity, and mealtimes are key contributors to
circadian misalignment and has been linked to adverse functional and health out-
comes. Social jetlag can have severe and adverse health consequences. For example,
the New Hoorn study cohort (n = 1585) investigated the association between social
jet lag, metabolic syndrome, cardiovascular health and found that individuals
younger than 61 years of age who reported social jetlag (1–2 hours) had approxi-
mately a two-fold greater risk of metabolic syndrome and prediabetes/diabetes
compared to their counterparts who reported less than 1 hour of social jetlag [72].
Sleep Architecture
Sleep architecture represents the cyclical pattern of sleep as it shifts between the
different sleep stages, non-rapid eye movement (NREM) and rapid eye movement
(REM) sleep. An individual’s sleep architecture is made up of sleep cycles and
stages marked by unique neurological, autonomic, and physiological signals that
correspond to the stage of sleep or wake an individual is experiencing [61, 73]. Each
full cycle of NREM and REM sleep lasts about 90 to 120 minutes. NREM sleep is
characterized by 3 stages of sleep (N1, N2, and N3). Stage 1 of NREM is the light-
est form of sleep marked by low amplitude alpha brain waves, Stage 2 is marked by
sleep spindles and K complexes, and Stage 3 is marked by higher amplitude delta
waves signifying deeper more restorative sleep. A normal pattern of sleep cycles (as
shown in the hypnogram) includes a greater portion of time spent in Stages 2 and 3
sleep at the beginning of the night and more REM sleep at the second half of the
night, with a few possible brief awakenings scattered throughout the sleep stages.
Racial/ethnic differences, in the quantity and quality of sleep architecture, are
well documented, where Blacks tend to get more light sleep and less deep sleep
compared to Whites (See Table 3.1) [48]. In the Outcomes of Sleep Disorders in
Older Men (Mr OS Sleep) Study with Black, Asian American, Hispanic and White
men (n = 2823), Black men relative to other races/ethnicities had the lowest percent-
age of Stage 1 non-REM sleep (6.59%) and slow-wave sleep Stage 3 sleep (7.99%).
However, Blacks had the highest percentage of Stage 2 non-REM sleep (64.79%)
and REM sleep (20.71%) [74]. Overall, Blacks spend less time in slow-wave sleep
and spend greater time in REM relative to Whites. Therefore, it is likely that sleep-
deprived Blacks are more likely to experience daytime sleepiness and physical
fatigue.
Sleep Efficiency
Sleep efficiency is another sleep health parameter that racial/ethnic differences can
be observed. Overall, sleep efficiency captures how much sleep an individual actu-
ally experiences and is predicated on several sleep characteristics, such as sleep
latency and wake after sleep onset. In a population-based study, Black men had
lower sleep efficiency (79.7%), due to longer sleep latency (29.4 minutes) and
greater WASO (90.4%) relative to Whites, Hispanic/Latinx, and Asian Americans
[74]. These results suggest that Blacks took a longer time to fall asleep, had less
efficient sleep (meaning that they spent less time sleeping while in bed), and had the
greatest levels of awakenings after sleep was initiated.
Sleep Quality and Sleepiness
Racial/ethnic minorities have a higher burden of daytime sleepiness and poor sleep
quality compared to Whites (See Table 3.1). In the Multi-Ethnic Study of
Atherosclerosis (MESA) study, Blacks had the highest rates of excessive daytime
sleepiness (using the Epworth Sleepiness Scale [ESS] score > 12) at 13.1%, com-
pared to Hispanic/Latinx at 9.2%, Whites at 8.0%, and Chinese at 7.5% [75].
However, Whites reported highest rate of being sleepy for more than 5 days of the
month (18.6%) compared to the other racial/ethnic groups (Black = 14.4%, H
ispanic/
Latinx = 16.9%, and Chinese = 12.3%). Compared to Whites, Blacks, Hispanic/

Latinx, and Chinese Americans had lower odds of excessive sleepiness ≤5 days/
month, after adjusting for demographic factors. However, after adjusting for physi-
cal health and psychosocial variables, differences in sleepiness between Whites and
Chinese Americans decreased suggesting that these factors play a crucial role in the
estimates on the amount of sleepy days among Chinese Americans. Relative to
Whites, Black Americans had the highest odds (and only, as Hispanic/Latinx and
Chinese were not significant) of excessive daytime sleepiness (ESS scale >12) (ORs
range across 4 adjusted models 1.43–1.74, adjusting for sociodemographic, psycho-
social, physical health, and sleep duration and disorders). The greatest attenuation
in the differential estimates of daytime sleepiness between Blacks and Whites was
observed when controlling for physical health and sleep variables, but not for psy-
chosocial factors.
Causes of Poor Sleep Health
The root cause of sleep health disparities among racial/ethnic minorities is multi-
farious and complex, as several biological, psychosocial, and environmental factors
may explain the burden of poor sleep health.
Biological Causes
Empirical studies highlight several biological causes of racial/ethnic differences on

sleep health parameters. Biological explanations for sleep health disparities include
genetic, circadian, and anthropometric. Although genetic causes of differential
sleep health estimates are intricate and inconclusive, initial evidence from large
genetic studies indicate a possible ancestry link. For example, in a study that inves-
tigated 1698 ancestry genetic markers, individuals with higher percentage of African
ancestry had lower percentage of slow-wave sleep SWS and explained 11% of the
variability in slow-wave sleep, a marker of sleep depth [76]. As indicated above,
Blacks or individual with African Ancestry have shortened free-running circadian
period (tau) compared with their White counterparts [68]. Anthropometric causes
may also explain differential estimates of sleep health outcomes. In a study compar-
ing the link between craniofacial features and risk for sleep apnea among Asian and
White Americans, neck circumference, body mass index, mallampati score (MS)
(measurement of tongue and mouth during a breath hold at end-tidal inspiration
with the mouth wide open and tongue fully protruded), thyromental distance
(TMD), and thyromental angle (TMA) (angle between the soft tissue of backside of
neck, the soft tissue mentum, and the thyroid) were the best predictors of OSA risk
and severity [77]. Asians had different MS, TMD and TMA compared to Whites
which was associated with greater sleep apnea severity and had higher MS, smaller
TMD, and larger TMA. In another study, obesity explained sleep apnea risk among
Whites, while skeletal restriction explained sleep apnea risk among Chinese.
Despite this difference, the ratio between obesity to craniofacial bone size, a deter-
minant of upper airway volume and OSA risk, was not statistically different between
Chinese and Whites [78].
Psychosocial Causes
There are several psychosocial factors that might explain sleep health disparities
among racial/ethnic minorities. These factors include but are not limited to social
stressors, beliefs, and attitudes and behaviors.
Social stressors Several researchers suggest that racial inequalities and social ineq-
uities developed through racial segregation, food desserts, lack of resources, educa-
tional attainment, employment status, and limited to no access to health care system
care can be linked to psychological distress, anxiety, depression and poor sleep and
unhealthy sleep behaviors [46, 79, 80].
In a sample of 4863 Black adults, psychosocial stressors such as perceived stress,
major life events stress, and weekly stress were associated with short sleep duration
and poorer sleep quality. The effects of weekly stress on sleep duration was most
pronounced among younger (<60 hears old) and college-educated Blacks [81].
Similar trends can be observed for the Latinx population, where depressive symp-
toms, employment status, and low education level were independently associated
with short sleep duration, while unemployment, low household income, and low
level of education were independently associated with long sleep [82]. In a study
that explored the influence of perceived racial discrimination and the risk of insom-
nia on middle-age elderly Black women (N = 26,139), participants with higher per-
ceived levels of discrimination had higher insomnia symptoms and shorter sleep
duration (<7 hours) [83]. While in another study, economic disadvantage and poor
physical and mental health were statistically were associated with insomnia among
older Blacks (N = 398) in Southern Los Angeles [35].
Beliefs and attitudes Racial ethnic minorities’ beliefs and attitudes about sleep and
sleep health play crucial roles in the amount of sleep an individual receives and the
quality of their sleep. The association beliefs and attitudes have on sleep outcomes
is likely to be indirect and reflects a mediated association between inadequate sleep
health literacy, unhealthy sleep behavior, and poor sleep health outcomes. Individuals
may not know or appreciate the importance of sleep and how it impacts their health
and functional outcomes. For example, some racial/ethnic minorities have consid-
ered deep habitual snoring or snoring as relatively good sleep and are unaware that
it may portend something more ominous such as a sleep breathing disorder like
sleep apnea. In a study of community-dwelling Black men, participants with ele-
vated and high risk for OSA were more likely to report false and maladaptive beliefs
about sleep [84]. In another study, Blacks reported using napping and consuming
caffeine to cope with sleep deprivation and sleepiness. In the same study, partici-
pants reported using electronic devices (such as TV and phone) to blunt racing and
ruminative thoughts that prevented them from falling asleep [85].
Behaviors There are a number of behaviors that can affect differential sleep esti-
mates across racial/ethnic groups. These include but are not limited to mental health,
diet, and physical activity. For example, studies have shown that Blacks with ele-
vated emotional distress are more likely to report short or long sleep durations [86].
In a nationally representative study, insufficient sleep (<7 hours) was associated
with unhealthy diets, suggesting a potential bi-directional relationship where poor
sleep leads to poor diet and food choices and poor food choices, such as night eating
and consumption of high-calorie foods close to bedtime may lead to later bedtime,
late sleep onset, and disrupted sleep [87]. Other studies have found that Blacks and
Whites respond differently to food stimulants like caffeine when they found that
Blacks who consume caffeinated drinks were more likely to have disrupted sleep
compared to Whites [50]. Physical activity/exercise is another behavior that might
cause differential sleep health estimates between racial/ethnic groups and Whites.
In a sample of 246 Black adolescents, physical activity protected against short sleep
duration [88]. Specifically, race and sleep duration appeared to be only significant at
lower levels of physical activity and Black adolescents who reported shorter sleep
durations had lower physical activity.
Physical and Built Environment Causes
There is growing evidence that environment, physical and built, can affect sleep
health outcomes. Patterns of Insufficient sleep is more prevalent in poor urban and
rural settings relative to their more affluent counterparts [89]. These findings high-
light that geographical effect on sleep health outcomes may traverse race/ethnicity,
as majority of the region is White, although the amount of Black (4%), Asian (26%),
and Hispanic (37%) residents have been increasing, according to a 2019 Pew Trust
research poll. Outside of geographic patterns of and effects on sleep health out-
comes, more granular evidence highlight the contribution of noxious noise, light
and temperature have on sleep health outcomes, as well as physical environment of
an individual’s community influences their sleep. For example, social cohesion,
safety, light, traffic, air quality and pollution, noise, greenspace, and neighborhood
cohesion/disorder and walkability may impact sleep health outcomes. Data shows
that racial/ethnic minorities might be particularly vulnerable to the effects of envi-
ronmental factors on sleep health outcomes.
Of the environmental factors listed above, the role of light on sleep has the most
robust evidence to date explaining racial/ethnic differences in sleep health out-
comes. The proliferation and exposure to artificial light presents the clearest and
most present danger to sleep health. Artificial light (ALAN) during the day and
mostly at night is harmful, and evidence points the unfortunate burden and vulner-
ability among racial/ethnic minorities [90]. Blacks and Hispanics when exposed to
ALAN 2 times greater than Whites [56]. Dominant artificial light exposure from
in-house sources such as laptops, individual’s computer, cellphones, televisions,
and outside sources including street lights are more likely to disrupt an individual’s
natural sleep-wake cycles causing circadian misalignment and sleep disruption.
Noise levels from several sources such as train, industrial activity, traffic, noctur-
nal noise can have deleterious effects on sleep health outcomes such as sleep distur-
bances, daytime sleepiness, irritated, frustrated, annoyance, inconsistent mood
changes, and adverse to long-term effects on cardiometabolic outcomes. Excessive
noise pollution may trigger stress hormones that can increase blood pressure, heart
rate during sleep times, and autonomic arousals thus leading to microarousal that
lead to shallow, fragmented, and unrestorative sleep. A study funded by Robert
Wood Johnson and National Cancer Institute found that neighborhoods with pre-
dominantly Asians, Blacks, and Hispanics residents had higher levels of noxious
noise levels during the day and at night (approximately 4 decibels higher on aver-
age) compared to neighborhoods without racial and ethnic groups [65].
Health Consequences of Poor Sleep Health
The third set of evidence to establish a health disparity is the higher burden of down-
stream consequences as a result of poor sleep health experienced by racial/ethnic
minorities. Racial/ethnic minorities as at significantly higher risk for a host of
adverse functional and health outcomes, such as cardiovascular disease, cardiomet-
abolic conditions, and poor brain health (mental health and dementia).
First, poor sleep health, which includes sleep deprivation, shorter sleep duration,
sleep disorders (sleep apnea and insomnia), and poor sleep quality, is directly linked
to increased cardiovascular risks such as heart disease, high blood pressure, stroke,
diabetes, and cardiovascular health and disease, among racial/ethnic minorities [36,
37, 86, 91–94]. For example, in the CARDIA study (n = 578; ages 33–45), shorter
sleep duration predicted hypertension (OR 1.37, 95% CI: 1.05, 1.78) [95]. The
direct association between poor sleep and adverse health outcomes among racial/
ethnic minorities is due to high prevalence of sleep deprivation, where they are
twice as likely to sleep less than their white counterparts.
Second, poor sleep health parameters are indirectly linked to adverse health out-
comes among racial/ethnic minorities. Evidence of these indirect associations
include the mediated role of shift work, where racial/ethnic minorities working
night shift are at increased risk for circadian misalignment and cardiometabolic
disease and poor mental health outcomes [25, 96–99]. The indirect association
between sleep and adverse health outcomes is significant and consequential because
Blacks and Latina/os are more likely to work non-traditional work shifts compared
to their White counterparts. Blacks who work night shifts are at greater risk and
burden for hypertension compared to Blacks that work day shifts, whereas, for
Whites no differences between day and night shift work were observed [50]. These
racial/ethnic differences in shift work may partly explain the burden of hypertension
in Blacks, as night shift workers have lower blood pressure dipping at night than day
shift workers at the same time causing a prolonged elevated blood pressure.
Prolonged elevated blood pressure can cause hypertension, resistant hypertension,
and elevated risk for stroke, all health conditions highly prevalent among Blacks
[53, 98, 100, 101].
The indirect and mediated relationships between sleep and adverse health out-
comes are not solely due to social determinants of health or psychosocial factors but
also may be engendered by biological, physiological, and anatomical factors [40].
Individuals who report insufficient sleep over a period of time have a higher caloric
intake (+30% of daily caloric requirement), compared to Whites. Insufficient sleep
and sleep deprivation may induce poor eating habits, thus increasing the higher
caloric intake of carbohydrates, snacks, unhealthy foods, age, gender, and BMI,
which can promote weight gain [102]. A meta-analysis of 72 studies found that in
restricted sleep short and long sleep durations were associated with cardiovascular
inflammatory markers such as: C-reactive protein and interleukin (IL)-6, factors
linked with cardio-metabolic conditions (obesity and type 2 diabetes), neurodegen-
erative and pulmonary disease [79].
Several studies note significant brain health consequences – cognitive decline,
cognition impairment, and neurodegenerative disease like dementia –as a result of
poor sleep health among racial/ethnic groups. For example, excessive daytime
sleepiness is associated with cognitive decline, impaired cognition, mood, execu-
tive decisions, minimal attention span, memory and emotionally memory, and
inflammation of the brain [9, 10, 56–62]. Race stratified analyses indicate that the
associations between sleep health parameters (notably daytime sleepiness, short
sleep duration, and long sleep duration) and cognitive impairment/decline are most
pronounced in Blacks and Hispanics compared to other racial/ethnic groups
[43, 47].
In one population-based study (n = 28,756), the majority of participants with
extreme sleep deprivation (less than 4 hours or more than 10 hours per night) expe-
rienced greater cognitive decline than individuals with at least 7 hours of sleep per
night, [62] with racial ethnic minorities appearing to be most affected. In another
study with middle-age adults, inconsistent sleep time had a negative impact on cog-
nitive functioning as individuals showed clinically significant signs of cognitive
decline after 3 weeks [103]. The adverse effects of poor sleep can have long-term
effects on cognition. In a sample of Japanese-Americans, individuals with high lev-
els of daytime sleepiness had a greater odds of dementia and cognitive decline in a
three-year follow-up [104]. Findings from these studies highlight that two possibili-
ties. First, poor sleep health may be a risk factor for acute and chronic cognitive
decline. Second, sleep may serve as an early sign of cognitive decline, which may
portend the onset of dementia.
Conclusion
The aim of this chapter was to describe extant estimates of poor sleep health
among racial/ethnic minorities, multilevel determinants of sleep health disparities
among racial/ethnic minorities, including biological, environmental, and psycho-
social factors, and associated downstream health outcomes among racial/ethnic
minorities. Over the past decades, important efforts have been made by health
disparities clinicians and researchers to raise awareness about new approaches to
tackle disparities in sleep health. However, data highlighted in this book chapter
indicates that there is still a long road to travel until we arrive at sleep health equity
in the United States [44, 49, 57, 59, 60, 63, 83, 105–108]. Building upon the sleep
health framework, we suggest that one of the first crucial steps in addressing racial/
ethnic disparities in sleep health is to define the concept of sleep health equity that
we conceptualized as the equal opportunity to experience and obtain healthy sleep
regardless of age, sex, race/ethnicity, geographical location, and socioeconomic
status to obtain satisfactory sleep that promotes physical and mental well-being
[28]. We also argue that achieving sleep health equity requires a multi-level and
multisystem approach that includes patients, providers, payers, and the entire
healthcare ecosystem. To achieve sleep health equity involves the following five
steps and initiatives [28]:
1. We encourage implementation of sleep health literacy programs for all ages –
from early screening and treatment for sleep disorders starting in preschool,
elementary schools, high schools, and university. This will provide sleep health
literacy modules, workshops, webinars, throughout websites, social media out-
lets, and mobile apps.
2. This awareness and sleep health access for ethnic and racial minorities could be
achieved through the creation and multilingual sleep centers in vulnerable com-
munities. Such multi-ethnic and multi-lingual initiatives could also be replicated
in additional health centers located in vulnerable communities.
3. Culturally tailored behavioral sleep health interventions may increase adher-
ence to physician’s recommendations among racial and ethnic minorities. For
instance, this could be achieved through required, culturally sensitive train-
ing in sleep medicine programs where physicians are better equipped in
administering sleep health medicine and interventions for vulnerable
populations.
4. We need training programs across all educational levels from high school to
university (Ex: the New York University’s PRIDE and COMRADE programs),
which aims to increase diversity in the sleep health medicine workforce.
5. Public health policies to address and reduce the burden of environmental (ex:
noise and light) exposures that are underpinning poor sleep health among racial/
ethnic minorities are strongly encouraged. This is very important because Blacks
and other minorities experience a higher rate of environmental risk living in
disfranchised neighborhoods and communities.
References
1. Geronimus AT, Hicken MT, Pearson JA, Seashols SJ, Brown KL, Cruz TD. Do US black
women experience stress-related accelerated biological aging? Hum Nat. 2010; https://doi.
org/10.1007/s12110-010-9078-0.
2. Geronimus AT, Hicken M, Keene D, Bound J. “Weathering” and age patterns of allostatic
load scores among blacks and whites in the United States. Am J Public Health. 2006; https://
doi.org/10.2105/AJPH.2004.060749.
3. Kaestner R, Pearson JA, Keene D, Geronimus AT. Stress, allostatic load, and health of
Mexican immigrants. Soc Sci Q. 2009; https://doi.org/10.1111/j.1540-6237.2009.00648.x.
4. Duru OK, Harawa NT, Kermah D, Norris KC. Allostatic load burden and racial disparities in
mortality. J Natl Med Assoc. 2012; https://doi.org/10.1016/S0027-9684(15)30120-6.
5. Levine ME, Crimmins EM. Evidence of accelerated aging among African Americans and its
implications for mortality. Soc Sci Med. 2014; https://doi.org/10.1016/j.socscimed.2014.07.022.
6. Wei MY, Levine DA, Zahodne LB, Kabeto MU, Langa KM. Multimorbidity and cognitive
decline over 14 years in older Americans. J Gerontol A Biol Sci Med Sci. 2020; https://doi.
org/10.1093/gerona/glz147.
7. Jung M, Pfeifer GP. Aging and DNA methylation. BMC Biol. 2015; https://doi.org/10.1186/
s12915-015-0118-4.
8. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and
healthspan. Aging (Albany NY). 2019; https://doi.org/10.18632/aging.101684.
9. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;
https://doi.org/10.1186/gb-2013-14-10-r115.
10. Richardson B. Impact of aging on DNA methylation. Ageing Res Rev. 2003; https://doi.
org/10.1016/S1568-1637(03)00010-2.
11. Unnikrishnan A, Freeman WM, Jackson J, Wren JD, Porter H, Richardson A. The role of
DNA methylation in epigenetics of aging. Pharmacol Ther. 2019; https://doi.org/10.1016/j.
pharmthera.2018.11.001.
12. Ciccarone F, Tagliatesta S, Caiafa P, Zampieri M. DNA methylation dynamics in aging:
how far are we from understanding the mechanisms? Mech Ageing Dev. 2018; https://doi.
org/10.1016/j.mad.2017.12.002.
13. Oeseburg H, De Boer RA, Van Gilst WH, Van Der Harst P. Telomere biology in healthy aging
and disease. Pflugers Arch Eur J Physiol. 2010; https://doi.org/10.1007/s00424-009-0728-1.
14. Marengoni A, Angleman S, Melis R, et al. Aging with multimorbidity: a systematic review of
the literature. Ageing Res Rev. 2011; https://doi.org/10.1016/j.arr.2011.03.003.
15. Horvath S, Gurven M, Levine ME, et al. An epigenetic clock analysis of race/ethnicity, sex,
and coronary heart disease. Genome Biol. 2016; https://doi.org/10.1186/s13059-016-1030-0.
16. Tajuddin SM, Hernandez DG, Chen BH, et al. Novel age-associated DNA methylation
changes and epigenetic age acceleration in middle-aged African Americans and whites. Clin
Epigenetics. 2019; https://doi.org/10.1186/s13148-019-0722-1.
17. Dhingra R, Nwanaji-Enwerem JC, Samet M, Ward-Caviness CK. DNA methylation age—
environmental influences, health impacts, and its role in environmental epidemiology. Curr
Environ Heal Rep. 2018; https://doi.org/10.1007/s40572-018-0203-2.
18. Javed R, Chen W, Lin F, Liang H. Infant’s DNA methylation age at birth and epigenetic aging
accelerators. Biomed Res Int. 2016; https://doi.org/10.1155/2016/4515928.
19. Mackenbach JP. Political determinants of health. Eur J Pub Health. 2013; https://doi.
org/10.1093/eurpub/ckt183.
20. Braveman P, Gottlieb L. The social determinants of health: it’s time to consider the causes of
the causes. Public Health Rep. 2014; https://doi.org/10.1177/00333549141291s206.
21. Grandner MA, Williams NJ, Knutson KL, Roberts D, Jean-Louis G. Sleep disparity, race/
ethnicity, and socioeconomic position. Sleep Med. 2016;18:7–18. https://doi.org/10.1016/j.
sleep.2015.01.020.
22. Dietch JR, Taylor DJ, Smyth JM, et al. Gender and racial/ethnic differences in sleep duration
in the North Texas heart study. Sleep Heal. 2017; https://doi.org/10.1016/j.sleh.2017.07.002.
23. Patel NP, Grandner MA, Xie D, Branas CC, Gooneratne N. “Sleep disparity” in the popula-
tion: poor sleep quality is strongly associated with poverty and ethnicity. BMC Public Health.
2010; https://doi.org/10.1186/1471-2458-10-475.
24. Grandner MA, Patel NP, Gehrman PR, et al. Who gets the best sleep? Ethnic and socio-
economic factors related to sleep complaints. Sleep Med. 2010; https://doi.org/10.1016/j.
sleep.2009.10.006.
25. Carnethon MR, De Chavez PJ, Zee PC, et al. Disparities in sleep characteristics by race/eth-
nicity in a population-based sample: Chicago Area Sleep Study. Sleep Med. 2016;18:50–5.
https://doi.org/10.1016/j.sleep.2015.07.005.
26. Redline S, Tishler PV, Hans MG, Tosteson TD, Strohl KP, Spry K. Racial differences in
sleep-disordered breathing in African-Americans and Caucasians. Am J Respir Crit Care
Med. 1997; https://doi.org/10.1164/ajrccm.155.1.9001310.
27. Loredo JS, Soler X, Bardwell W, Ancoli-Israel S, Dimsdale JE, Palinkas LA. Sleep health in
U.S. Hispanic population. Sleep. 2010; https://doi.org/10.1093/sleep/33.7.962.
28. Blanc J, Nunes J, Williams N, Robbins R, Seixas AA, Jean-Louis G. Sleep health equity.
Sleep Health. Elsevier. 2019:473–80. https://doi.org/10.1016/b978-0-12-815373-4.00035-6.
29. Jackson CL, Walker JR, Brown MK, Das R, Jones NL. A workshop report on the causes and
consequences of sleep health disparities. Sleep. 2020; https://doi.org/10.1093/sleep/zsaa037.
30. Reither EN, Krueger PM, Hale L, Reiter EM, Peppard PE. Ethnic variation in the asso-
ciation between sleep and body mass among US adolescents. Int J Obes. 2014; https://doi.
org/10.1038/ijo.2014.18.
31. Buysse DJ. Sleep health: can we define it? Does it matter? Sleep. 2014; https://doi.
org/10.5665/sleep.3298.
32. Anujuo K, Stronks K, Snijder MB, et al. Relationship between short sleep duration
and cardiovascular risk factors in a multi-ethnic cohort – the Helius study. Sleep Med.
2015;16(12):1482–8. https://doi.org/10.1016/j.sleep.2015.08.014.
33. Wang Y-H, Wang J, Chen S-H, et al. Association of longitudinal patterns of habitual sleep
duration with risk of cardiovascular events and all-cause mortality. JAMA Netw Open.
2020;3(5) https://doi.org/10.1001/jamanetworkopen.2020.5246.
34. He Z, Wallace DM, Barnes A, Tang X, Jean-Louis G, Williams NJ. Reporting results in
U.S. clinical trials for obstructive sleep apnea and insomnia: how transparent are they? Sleep
Heal. 2020; https://doi.org/10.1016/j.sleh.2019.11.009.
35. Bazargan M, Mian N, Cobb S, Vargas R, Assari S. Insomnia symptoms among African-
American older adults in economically disadvantaged areas of South Los Angeles. Brain Sci.
2019; https://doi.org/10.3390/brainsci9110306.
36. Seixas AA, Chung DP, Richards SL, et al. The impact of short and long sleep duration on
instrumental activities of daily living among stroke survivors. Neuropsychiatr Dis Treat.
2019;15 https://doi.org/10.2147/NDT.S177527.
37. Report MW. Effect of short sleep duration on daily activities--United States, 2005-2008.
MMWR Morb Mortal Wkly Rep. 2011;60(8):239–42. http://www.ncbi.nlm.nih.gov/
pubmed/21368739.
38. Knutson KL, Van Cauter E, Rathouz PJ, et al. Association between sleep and blood pressure
in midlife: the CARDIA sleep study. Arch Intern Med. 2009;169(11):1055–61. https://doi.
org/10.1001/archinternmed.2009.119.
39. Jackson CL, Patel SR, Jackson WB, et al. Agreement between self-reported and objec-
tively measured sleep duration among white, black, Hispanic, and Chinese adults in the
United States: Multi-Ethnic Study of Atherosclerosis. Sleep. 2018;41(6):1–12. https://doi.
org/10.1093/sleep/zsy057.
40. Sehgal A, Mignot E. Genetics of sleep and sleep disorders. Cell. 2011;146(2) https://doi.
org/10.1016/j.cell.2011.07.004.
41. Nevarez MD, Rifas-Shiman SL, Kleinman KP, Gillman MW, Taveras EM. Associations
of early life risk factors with infant sleep duration. Acad Pediatr. 2010;10(3) https://doi.
org/10.1016/j.acap.2010.01.007.
42. Williams NJ, Butler M, Roseus J, et al. 0373 blacks with obstructive sleep apnea Report
greater nighttime insomnia symptoms than whites, but don’t endorse daytime impairment.
Sleep. 2020;43(Supplement_1) https://doi.org/10.1093/sleep/zsaa056.370.
43. Nadybal SM, Collins TW, Grineski SE. Light pollution inequities in the continental United
States: a distributive environmental justice analysis. Environ Res. 2020;189:109959. https://
doi.org/10.1016/j.envres.2020.109959.
44. Guglielmo D, Gazmararian JA, Chung J, Rogers AE, Hale L. Racial/ethnic sleep disparities
in US school-aged children and adolescents: a review of the literature. Sleep Heal. 2018;4(1)
https://doi.org/10.1016/j.sleh.2017.09.005.
45. Kantermann T, Eastman CI. Circadian phase, circadian period and chronotype are repro-
ducible over months. Chronobiol Int. 2018;35(2) https://doi.org/10.1080/07420528.201
7.1400979.
46. Redline S, Sotres-Alvarez D, Loredo J, et al. Sleep-disordered breathing in Hispanic/
Latino individuals of diverse backgrounds. The Hispanic Community Health Study/Study
of Latinos. Am J Respir Crit Care Med. 2014;189(3):335–44. https://doi.org/10.1164/
rccm.201309-1735OC.
47. Rogers AJ, Kaplan I, Chung A, et al. Obstructive sleep apnea risk and stroke among blacks
with metabolic syndrome: results from Metabolic Syndrome Outcome (MetSO) Registry. Int
J Clin Res Trials. 2020;5(1):143. https://doi.org/10.15344/2456-8007/2020/143.
48. Crosby B, LeBourgeois MK, Harsh J. Racial differences in reported napping and nocturnal
sleep in 2- to 8-year-old children. Pediatrics. 2005;115(1):225–32. https://doi.org/10.1542/
peds.2004-0815D.
49. Smith JP, Hardy ST, Hale LE, Gazmararian JA. Racial disparities and sleep among pre-
school aged children: a systematic review. Sleep Heal. 2019;5(1) https://doi.org/10.1016/j.
sleh.2018.09.010.
50. Grandner MA, Knutson KL, Troxel W, Hale L, Jean-Louis G, Miller KE. Implications of
sleep and energy drink use for health disparities. Nutr Rev. 2014; https://doi.org/10.1111/
nure.12137.
51. Grandner MA, Patel NP, Jean-Louis G, et al. Sleep-related behaviors and beliefs associated
with race/ethnicity in women. J Natl Med Assoc. 2013;105(1):4–16. https://doi.org/10.1016/
s0027-9684(15)30080-8.
52. Zizi F, Jean-Louis G, Fernandez S, von Gizycki H, Lazar JM, Nunes JBC, Zizi F, Jean-
Louis G, et al. Symptoms of obstructive sleep apnea in a Caribbean sample. Sleep Breath.
2008;12(4):317–22. https://doi.org/10.1007/s11325-008-0190-x.
53. Ceïde ME, Pandey A, Ravenell J, Donat M, Ogedegbe G, Jean-Louis G. Associations of
short sleep and shift work status with hypertension among black and white Americans. Int J
Hypertens. 2015;2015 https://doi.org/10.1155/2015/697275.
54. 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(1):40–52. https://doi.org/10.1016/j.biopsych.2015.05.014.
55. Knutson KL, Van Cauter E, Rathouz PJ, et al. Association between sleep and blood pressure
in midlife. Arch Intern Med. 2009;169(11) https://doi.org/10.1001/archinternmed.2009.119.
56. Jackson CL, Agénor M, Johnson DA, Austin SB, Kawachi I. Sexual orientation identity
disparities in health behaviors, outcomes, and services use among men and women in the
United States: a cross-sectional study. BMC Public Health. 2016; https://doi.org/10.1186/
s12889-016-3467-1.
57. Moreno JP, Crowley SJ, Alfano CA, Hannay KM, Thompson D, Baranowski T. Potential
circadian and circannual rhythm contributions to the obesity epidemic in elementary school
age children. Int J Behav Nutr Phys Act. https://doi.org/10.1186/s12966-019-0784-7.
58. Malone SK, Patterson F, Lu Y, Lozano A, Hanlon A. Ethnic differences in sleep duration and
morning–evening type in a population sample. Chronobiol Int. 2016;33(1) https://doi.org/1
0.3109/07420528.2015.1107729.
59. Dudley KA, Patel SR. Disparities and genetic risk factors in obstructive sleep apnea. Sleep
Med. 2016;18 https://doi.org/10.1016/j.sleep.2015.01.015.
60. Wallace DM, Williams NJ, Sawyer AM, et al. Adherence to positive airway pressure treatment
among minority populations in the US: a scoping review. Sleep Med Rev. 2018;38:56–69.
https://doi.org/10.1016/j.smrv.2017.04.002.
61. Profant J, Ancoli-Israel S, Dimsdale JE. Are there ethnic differences in sleep architecture?
Am J Hum Biol. 2002; https://doi.org/10.1002/ajhb.10032.
62. Ma Y, Liang L, Zheng F, Shi L, Zhong B, Xie W. Association between sleep duration and
cognitive decline. JAMA Netw Open. 2020;3(9):–e2013573. https://doi.org/10.1001/
jamanetworkopen.2020.13573.
63. Zerón-Rugerio M, Hernáez Á, Porras-Loaiza A, et al. Eating jet lag: a marker of the variabil-
ity in meal timing and its association with body mass index. Nutrients. 2019;11(12) https://
doi.org/10.3390/nu11122980.
64. Petrov ME, Lichstein KL. Differences in sleep between black and white adults: an update and
future directions. Sleep Med. 2016;18 https://doi.org/10.1016/j.sleep.2015.01.011.
65. Shaw R, McKenzie S, Taylor T, et al. Beliefs and attitudes toward obstructive sleep apnea
evaluation and treatment among blacks. J Natl Med Assoc. 2012;104(11–12):510–9. https://
doi.org/10.1016/S0027-9684(15)30217-0.
66. Bauducco S, Richardson C, Gradisar M. Chronotype, circadian rhythms and mood. Curr
Opin Psychol. 2020;34 https://doi.org/10.1016/j.copsyc.2019.09.002.
67. Eastman CI, Suh C, Tomaka VA, Crowley SJ. Circadian rhythm phase shifts and endogenous
free-running circadian period differ between African-Americans and European-Americans.
Sci Rep. 2015;5(1) https://doi.org/10.1038/srep08381.
68. Eastman CI, Molina TA, Dziepak ME, Smith MR. Blacks (African Americans) have
shorter free-running circadian periods than whites (Caucasian Americans). Chronobiol Int.
2012;29(8) https://doi.org/10.3109/07420528.2012.700670.
69. Eastman CI, Tomaka VA, Crowley SJ. Circadian rhythms of European and African-
Americans after a large delay of sleep as in jet lag and night work. Sci Rep. 2016;6(1) https://
doi.org/10.1038/srep36716.
70. Reyes AN, Molina ML, Jansen K, et al. Biological rhythm and emotional and behavioral
problems among schoolchildren in Southern Brazil. Chronobiol Int. 2019;36(3) https://doi.
org/10.1080/07420528.2018.1545781.
71. Makarem N, Paul J, Giardina E-GV, Liao M, Aggarwal B. Evening chronotype is associ-
ated with poor cardiovascular health and adverse health behaviors in a diverse population of
women. Chronobiol Int. 2020; https://doi.org/10.1080/07420528.2020.1732403.
72. Wong PM, Hasler BP, Kamarck TW, Muldoon MF, Manuck SB. Social jetlag, chronotype,
and cardiometabolic risk. J Clin Endocrinol Metab. 2015;100(12) https://doi.org/10.1210/
jc.2015-2923.
73. Tomfohr L, Pung MA, Edwards KM, Dimsdale JE. Racial differences in sleep architecture:
the role of ethnic discrimination. Biol Psychol. 2012;89(1):34–8. https://doi.org/10.1016/j.
biopsycho.2011.09.002.
74. Song Y, Ancoli-Israel S, Lewis CE, Redline S, Harrison SLSK. The association of race/
ethnicity with objectively measured sleep characteristics in older men. Behav Sleep Med.
2011;10(1):54–69. https://doi.org/10.1080/15402002.2012.636276.
75. Baron KG, Liu K, Chan C, Shahar E, Hasnain-Wynia R, Zee P. Race and ethnic variation in
excessive daytime sleepiness: the multi-ethnic study of atherosclerosis. Behav Sleep Med.
2010; https://doi.org/10.1080/15402002.2010.509247.
76. Halder I, Matthews KA, Buysse DJ, et al. African genetic ancestry is associated with sleep
depth in older African Americans. Sleep. 2015; https://doi.org/10.5665/sleep.4888.
77. Lam B, Ip MSM, Tench E, Ryan CF. Craniofacial profile in Asian and white subjects with
obstructive sleep apnoea. Thorax. 2005; https://doi.org/10.1136/thx.2004.031591.
78. Sutherland K, Lee RWW, Cistulli PA. Obesity and craniofacial structure as risk fac-
tors for obstructive sleep apnoea: impact of ethnicity. Respirology. 2012; https://doi.
org/10.1111/j.1440-1843.2011.02082.x.
79. Li W, Youssef G, Procter-Gray E, et al. Racial differences in eating patterns and food pur-
chasing behaviors among urban older women. J Nutr Health Aging. 2017;21(10) https://doi.
org/10.1007/s12603-016-0834-7.
80. Jasani FS, Seixas AA, Madondo K, Li Y, Jean-Louis G, Pagán JA. Sleep
duration and health care expenditures in the United States. Med Care.
2020;58(9) https://journals.lww.com/lww-medicalcare/Fulltext/2020/09000/
Sleep_Duration_and_Health_Care_Expenditures_in_the.3.aspx.
81. Johnson DA, Lisabeth L, Lewis TT, et al. The contribution of psychosocial stressors to sleep
among African Americans in the Jackson heart study. Sleep. 2016; https://doi.org/10.5665/
sleep.5974.
82. Patel SR, Sotres-Alvarez D, Castañeda SF, et al. Social and health correlates of sleep duration
in a US Hispanic population: results from the Hispanic Community Health Study/Study of
Latinos. Sleep. 2015; https://doi.org/10.5665/sleep.5036.
83. Bethea TN, Zhou ES, Schernhammer ES, et al. Perceived racial discrimination and risk of
insomnia among middle-aged and elderly Black women. Sleep. 2020;43(1):1–10. https://doi.
org/10.1093/sleep/zsz208.
84. Williams NJ, Jean Louis G, Ceide ME, et al. Effect of maladaptive beliefs and attitudes about
sleep among community dwelling African American men at risk for obstructive sleep apnea.
J Sleep Disord Ther. 2017; https://doi.org/10.4172/2167-0277.1000269.
85. Baron KG, Gilyard SG, Williams JL, Lindich D, Koralnik L, Lynch EB. Sleep-related atti-
tudes, beliefs, and practices among an urban-dwelling African American community: a quali-
tative study. Sleep Heal. 2019; https://doi.org/10.1016/j.sleh.2019.06.004.
86. Seixas AA, Auguste E, Butler M, et al. Differences in short and long sleep durations between
blacks and whites attributed to emotional distress: analysis of the National Health Interview
Survey in the United States. Sleep Heal. 2017;3(1) https://doi.org/10.1016/j.sleh.2016.11.003.
87. Grandner MA, Jackson NJ, Izci-Balserak B, et al. Social and behavioral determinants of
perceived insufficient sleep. Front Neurol. 2015; https://doi.org/10.3389/fneur.2015.00112.
88. Gillis BT, Shimizu M, Philbrook LE, El-Sheikh M. Racial disparities in adolescent sleep
duration: physical activity as a protective factor. Cult Divers Ethn Minor Psychol. 2020;
https://doi.org/10.1037/cdp0000422.
89. Grandner MA, Smith TE, Jackson N, Jackson T, Burgard S, Branas C. Geographic distribu-
tion of insufficient sleep across the United States: a county-level hotspot analysis. Sleep Heal.
2015; https://doi.org/10.1016/j.sleh.2015.06.003.
90. Johnson DA, Billings ME, Hale L. Environmental determinants of insufficient sleep and
sleep disorders: implications for population health. Curr Epidemiol Rep. 2018; https://doi.
org/10.1007/s40471-018-0139-y.
91. Piccolo RS, Yang M, Bliwise DL, Yaggi HK, Araujo AB. Racial and socioeconomic dispari-
ties in sleep and chronic disease: results of a longitudinal investigation. Ethn Dis. 2013;
92. Sabanayagam C, Shankar A. Sleep duration and cardiovascular disease: results from the
National Health Interview Survey. Sleep. 2010; https://doi.org/10.1093/sleep/33.8.1037.
93. Ramos AR, Wallace DM, Pandi-Perumal SR, et al. Associations between sleep disturbances
and diabetes mellitus among blacks with metabolic syndrome: results from the Metabolic
Syndrome Outcome Study (MetSO). Ann Med. 2015; https://doi.org/10.3109/07853890.201
5.1015601.
94. Grandner MA, Buxton OM, Jackson N, Sands-Lincoln M, Pandey A, Jean-Louis G. Extreme
sleep durations and increased C-reactive protein: effects of sex and ethnoracial group. Sleep.
2013; https://doi.org/10.5665/sleep.2646.
95. Williams N, Jean-Louis G, Pandey A, Ravenell J, Boutin-Foster C, Ogedegbe G. Excessive

daytime sleepiness and adherence to antihypertensive medications among Blacks: analysis
of the counseling African Americans to control hypertension (CAATCH) trial. Patient Prefer
Adherence. 2014; https://doi.org/10.2147/PPA.S53617.
96. Ceïde ME, Williams NJ, Seixas A, Longman-Mills SK, Jean-Louis G. Obstructive sleep
apnea risk and psychological health among non-Hispanic blacks in the Metabolic Syndrome
Outcome (MetSO) cohort study. Ann Med. 2015; https://doi.org/10.3109/07853890.201
5.1107186.
97. Presser HB. Race-ethnic and gender differences in nonstandard work shifts. Work Occup.
2003; https://doi.org/10.1177/0730888403256055.
98. Yamasaki F, Schwartz JE, Gerber LM, Warren K, Pickering TG. Impact of shift work and
race/ethnicity on the diurnal rhythm of blood pressure and catecholamines. Hypertension.
1998; https://doi.org/10.1161/01.HYP.32.3.417.
99. Smith MR, Burgess HJ, Fogg LF, Eastman CI. Racial differences in the human endogenous
circadian period. PLoS One. 2009; https://doi.org/10.1371/journal.pone.0006014.
100. Suzuki M, Guilleminault C, Otsuka K, Shiomi T. Blood pressure “dipping” and “non-
dipping” in obstructive sleep apnea syndrome patients. Sleep. 1996; https://doi.org/10.1093/
sleep/19.5.382.
101. Esquirol Y, Perret B, Ruidavets JB, et al. Shift work and cardiovascular risk factors: new
knowledge from the past decade. Arch Cardiovasc Dis. 2011; https://doi.org/10.1016/j.
acvd.2011.09.004.
102. Thomas SAH, et al. Benefits of community-based approaches in assessing and address-
ing sleep health and sleep-related cardiovascular disease risk: a precision and personal-
ized population health approach. Curr Hypertens Rep. 1906; https://doi.org/10.1007/
s11906-020-01051-3.
103. Jean-Louis G, Kripke DF, Ancoli-Israel S, Klauber MR, Sepulveda RS. Sleep duration, illu-
mination, and activity patterns in a population sample: effects of gender and ethnicity. Biol
Psychiatry. 2000;47(10) https://doi.org/10.1016/S0006-3223(99)00169-9.
104. Foley D, Monjan A, Masaki K, et al. Daytime sleepiness is associated with 3-year incident
dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc. 2001;
https://doi.org/10.1046/j.1532-5415.2001.t01-1-49271.x.
105. Lucassen EA, Rother KICG. Interacting epidemics? Sleep curtailment, insulin resistance,
and obesity. Ann N Y Acad Sci. 2012;1264(1):110–34. https://doi.org/10.1111/j.1749-6632
.2012.06655.x.
106. Partonen T. Chronotype and health outcomes. Curr Sleep Med Rep. https://doi.org/10.1007/
s40675-015-0022-z.
107. Taveras EM, Gillman MW, Kleinman KP, Rich-Edwards JW, Rifas-Shiman SL. Reducing
racial/ethnic disparities in childhood obesity: the role of early life risk factors. JAMA Pediatr.
2013;167(8):731–8. https://doi.org/10.1001/jamapediatrics.2013.85.
108. Sun X, Gustat J, Bertisch SM, Redline S, Bazzano L. The association between sleep chrono-
type and obesity among black and white participants of the Bogalusa Heart Study. Chronobiol
Int. 2020;37(1) https://doi.org/10.1080/07420528.2019.1689398.
Chapter 4
The Future of Sleep Medicine:
A Patient-Centered Model of Care
Barry G. Fields and Ilene M. Rosen
Keywords Future of sleep medicine · Patient-centered care · Collaborative care ·

Sleep telemedicine · Artificial intelligence
Nearly 70 years ago, Nathaniel Kleitman, a professor of physiology at the University

of Chicago, and his graduate student, Eugene Aserinksy, studied eye movements
leading to a seminal paper in 1953 describing a new sleep state, rapid eye movement
(REM) sleep. In 1957, Kleitman and William Dement, another graduate student,
described the human sleep cycle of NREM sleep stages of increasing depth fol-
lowed by periods of REM sleep, with the cycles repeating through the night [1].
These discoveries established sleep as a scientific discipline. Over the next 30 years,
sleep medicine developed as its own clinical discipline with development of
American Academy Sleep Medicine (AASM)-accredited clinical training pathways
starting in 1988 and certification available through the American Board of Sleep
Medicine (ABSM) from 1991 to 2006. During this time, 3500 physicians were
ABSM certified in sleep medicine. In 2005, Sleep Medicine training was officially
recognized by the Accreditation Council of Graduate Medical Education (ACGME)
with approval by the American Board of Medical Specialties (ABMS) to offer a
certification examination.
Currently, there are approximately 200 positions available for one-year subspe-
cialty training in sleep medicine nationwide [2] and approximately 175–180 are
B. G. Fields
Emory University, Division of Pulmonary, Allergy and Critical Care Medicine,
Atlanta, GA, USA
I. M. Rosen (*)
Division of Sleep Medicine, Perelman School of Medicine at the University of Pennsylvania
PCAM, Philadelphia, PA, USA
e-mail: ilene.rosen@pennmedicine.upenn.edu; Ilene.Rosen@uphs.upenn.edu

70 B. G. Fields and I. M. Rosen
trained each year. In the last decade, there were 3500 first-time takers of the ABMS-
certification exam in sleep medicine; this number is down 1500 since 2018 [3]. In
the early years, many physicians practicing sleep medicine took the exam based on
a clinical-experience waiver; these physicians, along with those who were still only
certified by the ABSM, led to a peak number of nearly 6000 Board-Certified Sleep
Medicine Physicians (BCSMPs) in 2018. Since that time, those numbers have
waned. Starting in 2013, physicians needed to complete an ACGME-accredited
sleep fellowship in order to sit for the certification exam. Furthermore, the total
number of retired sleep physicians from 2013 to 2018 was 7 times the number of
new BCSMPs during the same time period (AASM, email communication,
October 2018).
As a result, the BCSMP workforce is insufficient to meet the demands of the
enormous population of patients who have a sleep disease, including an estimated
23.5 million U.S. adults with undiagnosed OSA and the 24.2 million individuals
with chronic insomnia [4]. This shortfall results from some unintended conse-
quences of recognition of sleep medicine as a specialty by the ACGME and
ABMS. First, there are now a limited number of ACGME-accredited training spots
that allow physicians to sit for the certification examination. Second, interest in
those slots has varied in recent years, perhaps because of the need for a full extra
year of training along with concerns regarding reduced reimbursements as home
sleep apnea testing becomes the norm [5].
These workforce pipeline issues interact with known factors at the individual (e.g.,
race), family (e.g., beliefs), and broader socio-cultural (e.g., insurance coverage) lev-
els to limit access to sleep medicine care [6]. Pre-existing geographic barriers and
accredited sleep centers’ clustering in more highly populated areas further exacerbate
these disparities. This situation highlights the need for shared responsibility among
BCSMPs and other providers for treating patients with sleep disorders. Given the
magnitude of individuals who suffer with a sleep disorder and the benefits associated
with treatment, patients deserve a collective response from our healthcare system.
There are six feeder specialties including Anesthesia, Family Medicine, Internal
Medicine, Neurology, Otorhinolaryngology (Ear, Nose &Throat/ENT), and Pediatrics.
Unfortunately, there has been a disconnect between the magnitude of the disease bur-
den, the broad relevance across many specialties, and the lack of success of the efforts
to infuse sleep education at all levels [7]. Not only is it difficult to gain traction for
sleep medicine curricula in medical schools, but also in the feeder specialties into
sleep medicine; only ENT has specific program requirements about education in sleep
beyond the general ACGME requirements of fatigue mitigation strategies.
Re-centering the spotlight on patient-centered care requires reconsideration of
the current model of care which presently involves nearly automatic referral of
patients with a sleep complaint to a sleep specialist or to a sleep center for testing.
Unfortunately, long waits and fragmented care have been the norm. Although the
spread of telemedicine during the COVID-19 pandemic has potentially improved
access to care by removing geographic barriers, the sleep field still suffers from a
conundrum: As the general public increasingly recognizes importance of sleep
health, there is a scarcity of providers to ensure it. Thus, we propose a patient-
centered point of care model that facilitates the patient receiving the best possible
4 The Future of Sleep Medicine: A Patient-Centered Model of Care 71
care for their sleep complaints to promote sleep health which utilizes patient, pro-
vider, educational, and technological resources.
A Patient-Centered Model of Sleep Care
Figures 4.1 and 4.2 outline our proposed integrated model for the future of sleep
care, and they will be referenced throughout the rest of this chapter. The emphasis
is on a patient-centered approach, so that a patient can get the sleep care they need
at a time and place that is convenient for them, regardless of the availability of a
one-on-one appointment with a sleep specialist. Figure 4.1 traces a patient’s evalu-
ation and diagnosis pathway from left to right, starting with their symptomatic con-
cerns and finishing with patient-centered education and treatment. This intervention
may occur through a referral to sleep specialist or non-sleep specialist workup.
Figure 4.2 follows a patient from treatment initiation through ongoing management.
Here, the stress is on ongoing collaboration between non-sleep medicine specialists
and sleep medicine specialists. Points A–F indicated throughout Figs. 4.1 and 4.2
refer to topics presented in each of the next five sections.
rimary Care and Broader Medical Community Collaboration

P
(Point A)
Existing Paradigms There is a growing body of evidence that espouses primary

care provider involvement in the care of patients with a sleep complaint.
Internationally, there have been randomized controlled trials that support primary
care physicians and nurses in the management of OSA [8–11]. Additionally, identi-
↑ prob OSA
↓ prob other non-
C insomnia sleep d/o D CBT-I Referral∗,
D
HSAT
A OR if appropriate
Primary care provider S ↑ prob OSA
Patient symptoms
c ↑ prob insomnia E E
↑ prob OSA
Specialty provider r ↑ prob other non- Patient-
- Pulmonology
- Cardiology e insomnia sleep d/o
Sleep D centered
Provider Medicine
- Neurology ↓ prob OSA
- Bariatric Medicine e ↑ prob other non-
comfortable w/ E Provider∗∗ treatment
dx & tx of sleep and
- Otolaryngology
n insomnia sleep d/o disorder
D
- Psychiatry education
↓ prob OSA E D
i ↑ prob insomnia
CBT-I
B Referral∗
n ↓ prob OSA F
Consider
g ↓ prob other non-
non-sleep
insomnia sleep d/o
related
work-up
Fig. 4.1 Patient-centered access to sleep care: entry, diagnosis, and initiation of treatment. A
Primary care and broader medical community collaboration, B Non-sleep specialty care collabora-
tion, C Development of sound screening protocols, D Leveraging telemedicine, E Provider-to-
provider interaction, F Ongoing sleep concerns requiring sleep medicine referral. *In person,
telemedicine, or online. **In person or telemedicine
A&B
NSS whom
Non-sleep specialist D&E patient sees
(NSS) +/-sleep
regularly with
medicine/team support
outreach to sleep
(embedded sleep
team (in person,
Patient- provider, e-consult)
e-consult,
centered Ongoing telehealth) for
treatment management concerning
and Lack of with provider of changes in status
education patient patient’s
Possible Sleep response preference and
Medicine referral inclusive of D&E Alternating visits
depending on primary collaboration with NSS and
care/non-sleep with Sleep sleep team (via
specialist knowledge medicine/Team telehealth or in
and workload Support∗ person)
D&E
Sleep Team
(in person or
via telehealth)
Collaborative guidelines
could be set for this
nationally with local
adjustments as needed
Fig. 4.2 Patient-centered access to sleep care: long-term care management, patient and provider
education and collaboration. A Primary care and broader medical community collaboration, B
Non-sleep specialty care collaboration, D Leveraging telemedicine, E Provider-to-provider inter-
action. *In person, telemedicine, or online
fication of OSA has been augmented by community pharmacist involvement in

screening and appropriate communication with primary care providers [12, 13]. In
the United States, similar models have been employed in family practice clinics, the
Wisconsin Department of Corrections [14], and the Veterans Health Administration,
as well as at Kaiser Permanente. However, the success of these programs has not
been systematically studied. Newer models involve healthcare businesses, such as
CVS Health, utilizing direct-to-consumer marketing and treatment [15].
Although the majority of these models have a primary focus on obstructive sleep
apnea, more recently there has been attention to models to treat insomnia outside of
sleep specialists and accredited-sleep centers [16–18]. A majority of patients with
insomnia present to their primary care provider with complaints of insomnia [19,
20], but primary care has a shortage of treatment options [21]. Many primary care
providers recognize the limitations of the use of prescription hypnotic medications;
they may or may not share sleep hygiene recommendations depending on their
knowledge of and comfort with such suggestions. Despite the recommendations for
non-pharmacologic treatments such as cognitive behavioral therapy for insomnia
(CBTi), [22–24] many non-sleep providers rarely provide such therapies likely due
to a lack of knowledge [25–27], training [25, 27, 28], and time [25, 29]. Despite
these barriers, improvement in important sleep variables has been noted when
nurses in primary care deliver strictly manual-based cognitive behavioral therapy
for insomnia (CBTi), [16, 17] mental health nurse practitioners provide brief behav-
ioral therapy for insomnia to elderly patients in a primary care practice [30], and
health district nurses offer cognitive-behavioral therapy for insomnia to patients in
primary health care center [21]. Additionally, it has been recognized that primary
care providers play an important role in the diagnosis and initial treatment of rest-
less leg syndrome [31].
We propose the integration of primary care into the paradigm of evaluation and
treatment of common sleep disorders including a combination of both stepped care
and hub and spoke models [32]. If the hub is the BSCMP, the Sleep Team and the
accredited sleep center, the spokes are primary care providers and non-sleep spe-
cialists. A stepped care model would outline patient populations and tasks that could
be shifted to these non-sleep medicine providers and appropriate team members in
the spokes that may not ever require interaction with the hub. Such models have
been proposed for obstructive sleep apnea [32] and chronic insomnia [33].
Accounting for the high prevalence of OSA and insomnia as well as the reality of
OSA with significant comorbid insomnia [34, 35], a truly patient-centered care
model would consider the management of both of these disorders. Given the known
barriers which typically limit access to the specialist in the stepped model, clear
delineations of hubs and the leveraging of telemedicine will need to be considered
[14, 18, 32, 36]. Additionally, identification of barriers and facilitators of care with
relevant stakeholders, inclusive of providers and patients, is required to ensure opti-
mal sleep care delivery [37].
Project ECHO To support the “proof of concept” programs described above, edu-
cational opportunities are needed for practicing primary care providers in sleep
medicine management (Fig. 4.1, Point A). One strategy utilized in the Veterans
Administration (VA) system has been Specialty Care Access Network-Extension
for Community Healthcare Outcomes (Scan-ECHO), subsequently re-labeled
Project ECHO. The program, developed at the University of New Mexico in 2003,
was implemented to better serve rural patients with limited access to specialty care.
Frequently, their challenge is not actually seeing a specialist; clinical video tele-
health is filling this role more and more. Rather, the challenge is the limited number
of specialists available. Project ECHO seeks to involve more primary care providers
in specialty care through education, thereby improving access to that care.
The VA-based program (VA-ECHO) leverages telehealth (described more below)
to drive educational outcomes. Specialists present short didactic sessions to primary
care clinicians through real-time video over the course of months. As the program
progresses, the generalists may engage in case discussions with the specialists.
Other professionals such as nurses, pharmacists, and technicians are often involved
on both sides of the camera to enhance a team-based approach to patient care [38].
VA-ECHO has been deployed in many specialties, with positive outcomes pub-
lished in hepatology, [39] geriatrics [40], and pain management [41]. Sleep
VA-ECHO has also emerged. A pilot program at the VA Puget Sound Health Care
System (VAPSHCS) found rural providers receptive to its curriculum over the
3-month course. Participants reported enhanced comfort managing common sleep
complaints (e.g., sleep-disordered breathing, insomnia, PTSD-related sleep prob-
lems) and providing appropriate patient education [42].
Programs like Project ECHO could enhance current sleep medicine care models
by expanding the number of providers from which that care can be delivered, even
if they are not BCSMPs. However, challenges remain. The authors at the VAPSHCS
surveyed rural providers who had not taken part in the training; lack of protected
time was the most common reason [42]. For already-overburdened providers, it can
be difficult to fit regular specialty training into their day. Another challenge is one
of generalizability. That is, how well does VA ECHO translate outside of a single-
payer health system? Significant investment is needed, in both time and money, for
any health system to implement the program. Strong business cases are required to
show that patient health and their healthcare expenditures could be optimized if
more non-subspecialist providers could integrate sleep medicine care into that
which they already provide. Data on the success of non-VA ECHO type programs is
lacking.
Non-Sleep Specialty Care Collaboration (Point B)
As noted above, a collaborative sleep care model involving non-BCSMPs hinges on

non-specialty trained providers’ sufficient education in the specialty. While board
certification in sleep medicine requires both completion of a 1-year Accreditation
Council for Graduate Medical Education (ACGME)-accredited fellowship and
passing a certification examination, many non-BCSMPs can participate substan-
tively in patients’ care. Opportunities for this education may come either during
professional training (i.e., medical school, residency, non-sleep medicine fellow-
ship) or after that training as part of continuing medical education (CME).
American medical schools allot just 2–4 hours to sleep education, 0.06% of their
preclinical curriculum [43]. There have been pilot projects aimed at increasing that
proportion. In one study, faculty presented 87 Johns Hopkins University medical
students with online learning modules. These students showed significant improve-
ment in sleep-related knowledge after viewing these 20- to 30-minute modules com-
pared to “sham” modules [44]. Nevertheless, similar efforts have not gained a
wide-scale footing. A frequently cited challenge is time; medical school faculty are
increasingly challenged to fit the breadth of human medicine into a limited schedule
while attending to other needs such as students’ wellness and early clinical exposure.
Neurology educators have suggested including sleep medicine content into medical
students’ neuroscience curriculum. They propose this content be presented for
2–4 hours per year as flipped-classroom sessions, didactics, and clinical opportuni-
ties depending on the year of training [45]. This dovetailing of sleep content with
existing curriculum blocks offers another strategy to expose medical students to
more substantive sleep education throughout their undergraduate medical training.
To augment these efforts, many non-BCSMPs would benefit from sleep medi-
cine exposure during their post-graduate training years (i.e., residency and fellow-
ship). While otolaryngology (ENT) residents are eligible for sleep medicine
fellowship training upon completion of their residency, they could also serve a
unique role in sleep disorders management without that subspecialty training. A
recent survey revealed that ENT attendings vary widely in their sleep surgical prac-
tice and, therefore, the amount of sleep training they provide to their residents. An
ENT surgeon having obtained sleep medicine board certification predicted the
extent of trainee exposure to the subspecialty [46]. Another survey used consensus
among academic otolaryngologists involved in sleep disorder treatment to create
sleep-related learning objectives for ENT residencies. These objectives form the
basis of online learning modules, enhancing the level of sleep education even among
non-sleep-focused otolaryngologists [47]. Such strategies may also help widen the
pipeline of ENT trainees entering sleep medicine fellowships. Neurologists found
that residency programs investing more heavily in sleep education report more pro-
gram graduates entering the subspecialty [48].
In addition to ENT and neurology trainees, pulmonary medicine fellows are
uniquely positioned to participate in collaborative sleep care whether or not they
subspecialize in sleep medicine. Indeed, sleep content accounts for about 10% of
the American Board of Internal Medicine’s pulmonary medicine examination [49].
A multi-society panel was convened to develop sleep-related curricular recommen-
dations for pulmonary medicine fellowships. After 5 rounds of voting, they created
52 elements, ranging from recognizing central apnea on sleep testing to insomnia
and narcolepsy evaluation. Therefore, they advocate pulmonologists not only be
well-versed in sleep-disordered breathing, but also in more psychologically and
neurologically based sleep disorders. Threshold for referral to a sleep medicine
specialist is left to the individual provider based on self-perception of knowledge
base and local availability of such subspecialization [50]. Of course, as in under-
graduate medical education, time in a pulmonary medicine fellowship is limited.
Program directors could integrate sleep content with training modules that already
exist to enhance efficiency of its delivery (e.g., nocturnal PAP therapy for severe
COPD) [51].
Development of Sound Screening Protocols (Point C)
Questionnaires Point of care interventions to further facilitate screening and man-

agement of sleep disorders have included clinician chart reminders [52] and efforts
to promote shared decision making [53] including patient decision aids [54–57] and
patient educational websites [58–60]. The promotion of screeners for sleepiness
[61] and questionnaires such as the STOP-BANG for OSA, [62–64] Insomnia
Severity Index for insomnia, [61, 65] and several for restless leg syndrome [66–69]
with appropriate clinical nudges [70] have been shown to facilitate appropriate
diagnosis and access to care for patients with these sleep disorders. Additionally,
there are several questionnaires that screen for multiple sleep disorders at one time
which may be suitable as a general sleep disorders screener [71].
Despite such available tools, a majority of the screening initiatives have focused
narrowly on OSA. While increased screening, evaluation, and treatment for OSA
alone will undoubtedly have a significant impact, broader consideration of sleep
disorders will better facilitate access to care in a patient-centered fashion. To our
knowledge, the only trans-sleep-disorders approach to be adopted exists in the
Veterans Health Administration (VHA) [72]. The VHA TeleSleep system utilizes
non-sleep specialists to increase patient screening with subsequent referral to a
Sleep Center “Hub” for diagnosis and treatment. However, this model of relying on
the provider to identify signs and symptoms of a sleep disorder has been noted to be
an inconsistent and unreliable paradigm [73]. Adding patient-administered screen-
ers, which then serves as a chart-based “nudge” to the busy primary care provider,
is an innovation that fundamentally changes sleep-care paradigms by leveraging
technology and patient empowerment [74].
Artificial Intelligence/Machine Learning Despite sleep disorders’ prevalence
and a myriad of available screening tools, sleep problems can be challenging to
screen for and identify in busy, non-sleep specialized clinical environments. Robust,
accessible tools are needed to guide the clinicians who work in them without disrup-
tion to their other duties. Artificial intelligence (AI) holds promise to fill this vital
role. AI refers to computers’ ability to perform tasks traditionally completed by
humans [75]. Machine learning (ML) is a term often used interchangeably with AI;
instead of relying on direct computer programming for each action, ML algorithms
“learn” from previous experience to enhance future performance on tasks such as
disease classification. A recent American Academy of Sleep Medicine (AASM)
Position Statement on AI suggests that multi-channel polysomnographic (PSG) data
lends itself particularly well to this type of ML analyses [75]. However, the oppor-
tunity for AI in sleep medicine care goes far beyond the sleep laboratory.
There are many opportunities for AI utilization throughout sleep medicine and
other specialties that interface with it. Patients possess a wealth of symptomatic,
demographic, and comorbidity-based data “channels” even at their initial presenta-
tion to primary care providers and non-sleep specialists (Fig. 4.1, Points A & B). It
is likely that AI will leverage ML using electronic medical record (EMR) data and
patients’ symptomatic reports to identify individuals at risk for a sleep disorder who
may benefit from a thorough sleep evaluation. For instance, there is growing evi-
dence that obstructive sleep apnea (OSA) symptom phenotypes can be clustered
into disturbed sleep, slightly sleepy, moderately sleepy, and excessively sleepy sub-
types [76, 77] Identifying patients with sleepier subtypes is important given these
subtypes’ association with worsened CVD, CHF, and CAD [78]. An ML system
integrated into the EMR could function in this manner, alerting providers that a
patient’s objective (e.g., age, gender, and BMI) and subjective (e.g., sleepiness) phe-
notype places that individual into a high-risk group if found to have OSA. More
detailed OSA screening could be prioritized for such a subset of patients.
The importance of AI-based phenotypic subtyping may also extend to OSA
treatment initiation. A more nuanced, personalized treatment plan could develop as
more is learned about etiologic OSA subtypes. Emerging data suggest that this
disorder is the final common endpoint of diverse, sleep-induced pathophysiological

processes such as impaired pharyngeal dilator muscle function, increased sensitiv-
ity to airway narrowing (low arousal threshold), and respiratory control instability
from the central nervous system. ML that incorporates these parameters could
reveal more targeted and personalized treatment options a given patient may tolerate
best [79]. If more conventional positive airway pressure (PAP) is the chosen inter-
vention, AI would once again have a role. Although some studies have cast doubt on
the cardiovascular disease benefits of PAP, many of the sleepiest patients were
excluded from these analyses [80, 81]. Given the increased CVD implications in
OSA patients with excessive sleepiness, AI may help identify those patients who
could benefit most from PAP use [82]. Providers would be better informed as to
whom to focus cloud-based PAP adherence monitoring, and patients could experi-
ence enhanced motivation to continue with that therapy.
AI’s involvement in sleep medicine may also extend to other disorders, such as
narcolepsy. Multiple sleep latency testing (MSLT) has limited specificity (73.3% at
the <8 minute mean sleep onset latency cutoff), due at least in part to suboptimal
interrater reliability among epochs scored [83]. Researchers have leveraged ML to
stage as little as 5 seconds of sleep, a level of precision much greater than the con-
ventional 30-second epoch scoring. They demonstrated 96% sensitivity and 91%
specificity for narcolepsy Type 1, a specificity that rises to 99% when adding HLA-
DQB1*06:02 typing to their model [84]. As the authors state, AI-guided diagnosis
should not supplant BCSMP review and judgment. On the contrary, AI can be uti-
lized as another type of twenty-first century “physician extender,” allowing them to
focus more efficiently on the most complex patient management issues while reach-
ing a larger population. Reviewing Fig. 4.1, one can foresee AI assisting both sleep
clinicians and non-clinicians at each step in the initial symptom presentation and
evaluation process. Indeed, even non-sleep clinicians could be guided to order home
sleep apnea testing (HSAT) in the higher risk patients for OSA (Fig. 4.1, Point D).
AI could then assist BCSMPs in interpreting the studies, prescribing the most effec-
tive therapies, and assisting clinicians with ongoing follow up (e.g., anticipate
needed changes in PAP settings or to other modes of treatment).
Patient and Provider Portals Whether it is a nudge from AI or from clinical judg-
ment that leads a provider to suspect a sleep disorder, further symptom-based
screening is typically indicated (Fig. 4.1). This screening is essential to gauge
potential sleep disorder severity, delineate among potential disorders, and create a
symptomatic baseline with which to compare symptoms after any treatment has
commenced. Screening tools can also help primary care physicians and non-sleep
providers triage this group of patients; as noted above, some clinicians may choose
to order HSAT for patients with a high probability of OSA but a low probability of
other sleep disorders (Fig. 4.1, Point D).
One strategy to expedite and streamline patients’ symptomatic information flow
to providers (both at initial presentation and during follow-up) has been through
dual-facing, internet-based patient and provider portals. Although there are no pub-
lished clinical trials utilizing such a portal, one is currently being conducted using
the Remote Veteran Apnea Management Platform (REVAMP). REVAMP has been
designed with input from veterans and clinicians throughout the VA system, under
the direction of the VA Office of Connected Care and the Office of Rural Health.
Now available at over 50 VA medical centers, REVAMP provides users with the 7
core elements of internet-based portals above. Veterans are offered REVAMP access
upon their initial referral to the sleep center. They complete several validated sleep
screening questionnaires, and sleep clinicians utilize those responses to help guide
patients to their next stage of testing. Patients started on PAP can view their night-
to-night PAP machine adherence and efficacy data through REVAMP, where they
can also complete follow-up questionnaires, access educational materials, and send
a message to their provider. Clinicians access REVAMP through a designated
provider-facing portal. There, they can view all pertinent data, offer the patient addi-
tional questionnaires to complete, and incorporate all patient- and PAP-machine
entered data into a comprehensive clinic note [85].
Leverage Telemedicine (Point D)
Of course, some patients cannot access such tools independently due to lack of
internet connectivity and physical challenges. Healthcare models should always
account for these situations, offering patients as diverse an array of modalities as
possible (e.g., telephone visits, clinical video telehealth, or in-person visits) [72]. As
noted above, potential strategies to improve patient access to sleep care include bet-
ter training for primary care providers and specialists, bringing more BCSMPs
through the training pipeline, and promoting the development of sleep teams.
Nevertheless, the AASM asserts “None of these solutions has more immediate
potential to overcome these challenges than telemedicine, which can dramatically
increase sleep medicine accessibility and clinical efficacy” [36].
Terminology Sharing a common language is important when considering telemed-
icine’s impact on future sleep medicine paradigms. According to the Health
Resources and Services Administration, “telehealth” is a broad term implying “the
use of electronic information and telecommunication technologies to support and
promote long-distance clinical health care [86], patient and professional health-
related education, public health and health administration.” In contrast, “telemedi-
cine” specifically refers to patient-provider interactions. The Federation of State
Medical Boards defines telemedicine as “the practice of medicine using electronic
communication, information technology, or other means between a physician in one
location, and a patient in another location, with or without an intervening health
care provider” [87]. Since the focus of this chapter is on patient care, we favor the
term “sleep telemedicine.” Sleep telemedicine can be categorized as either synchro-
nous or asynchronous, a key distinction with implications described below. (See
Feasibility section). Asynchronous telemedicine includes patient-provider messag-
ing through a secure email-style system and store-and-forward technologies such as
the patient- and provider-facing online platforms now available from most PAP
machine manufacturers. Figure 4.1 illustrates another use for asynchronous tele-
medicine: provider-to-provider interaction (Point E). As shown, there can be many
decision points for non-BCSMPs once screening and initial work-up are complete.
Collaboration with a BCSMP or team member through secure email systems,
portals, or a common electronic medical record (EMR) can be crucial to streamlined
patient management. For example, the VA health care system has employed
provider-to-provider asynchronous telemedicine through its use of “e-consults.”
Non-BCSMPs place relatively straightforward clinical questions directly into the
EMR; BCSMPs and their team members may answer those questions and guide
further work-up. Therefore, many veterans may begin their work-up and treatment
without waiting for, or traveling to, the sleep center [72].
As opposed to asynchronous telemedicine, synchronous telemedicine is real-
time communication between patients and providers. Telephone calls are one exam-
ple, as are the audio-visual interactions used for Clinical Video Telehealth (CVT).
CVT visits are currently accepted for initial visits, ongoing patient follow-up, and
encounter reimbursement, and they closely emulate a traditional in-person visit.
Long the CVT standard, Center-to-Center (C2C) telemedicine implies a provider (at
a distant site) and a patient (at an originating site) are both in clinical locations.
Emerging CVT modalities include Center-to-Home (C2H) telemedicine where the
patient is in a non-clinical location and Out-of-Center (OOC) telemedicine where
both patient and provider are at non-clinical locations. C2H and OOC telemedicine
provide progressive levels of patient-centered flexibility but also come with their
own complexities since distant-site providers are more reliant on originating site
patients’ technical savviness and troubleshooting.
Feasibility of Communication via Telemedicine Represented by Point D in
Figs. 4.1 and 4.2, telemedicine can be employed for many initial and follow-up
encounters. Sleep patients’ receptiveness to telemedicine has been demonstrated for
at least the past decade [88]. Nevertheless, questions persist as to how feasible it really
is to include telemedicine in future sleep care models. The COVID-19 pandemic
brought with it a rapid migration to telemedicine [89], forcing many sleep providers
to reckon with several aspects of its feasibility presently and moving forward: tech-
nology, privacy and security, reimbursement, licensing, and clinical outcomes.
Sleep telemedicine (specifically CVT) is technically feasible, and CVT visits
have been conducted for more than a decade. Various platforms allow real-time
audiovisual communication and several of them also offer tele-stethoscope and por-
table camera options; these physical exam tools are typically utilized only for C2C
telemedicine. The AASM recommends up-to-date software with a minimum con-
nection speed of 384 kbps and 640 × 480 video resolution transmitted at 30 frames
per second [90]. Sleep telemedicine is also feasible from a privacy and security
perspective, with the AASM making further recommendations that any CVT plat-
form be patched with the latest security updates, encrypted, and only accessible by
authorized users [90].
Financial feasibility has long been an impediment to sleep telemedicine’s prolif-

eration, though changes just before and during the Covid-19 pandemic have been
quite impactful. Most states now have “parity laws” that require private insurers to
reimburse providers the same for a telemedicine visit as for an in-person visit.
States’ Medicaid reimbursement has also become more favorable toward telemedi-
cine, but knowing terminology is key; “telemedicine” is typically limited to CVT-
style visits whether seeking private or Medicaid reimbursement. Researching
guidelines at both the distant and the originating site is key to understanding whether
reimbursement can occur [91]. Federal reimbursement from the Centers for
Medicare and Medicaid Services (CMS) has also been fraught with complexity.
Prior to the Covid-19 pandemic, C2C sleep telemedicine reimbursement was avail-
able only for the most rural originating sites, and it was not available at all for C2H
or OOC sleep telemedicine models. The Covid-19-associated public health emer-
gency loosened those restrictions at least temporarily. The CMS website should be
consulted for the latest guidance [92].
Sleep telemedicine’s feasibility from a licensing perspective has also been com-
plex. Providers must generally be licensed in the patient’s state (originating site) for
them to practice. The Federation of State Medical Boards has developed an Interstate
Medical Licensure Compact that now includes most states. The Compact allows a
physician in one state to have licensure facilitated in another state as long as both
states are part of the Compact. Additional strategies to facilitate interstate medical
licensing, and even to develop a unified national medical license, have been pro-
posed [93]. Further progress in this area will continue to lower the hurdles toward
telemedicine’s wider adoption.
The most important measure of sleep telemedicine’s feasibility may come
through the lens of clinical outcomes. That is, can we maintain the same level of
clinical care in the Fig. 4.1 model, or any model, using sleep telemedicine? Previous
work has suggested that OSA patients’ functional outcomes, PAP adherence, and
satisfaction do not differ when assessed and followed through telemedicine (CVT)
versus traditional in-person care [94, 95]. Those findings, especially in light of the
AASM’s OSA Quality Measures, [96] suggest that sleep telemedicine for OSA is
feasible from a clinical outcomes perspective assuming the other elements of feasi-
bility above are fulfilled (adequate technology, etc.). Similar results have emerged
recently from insomnia research. Cognitive behavioral therapy for insomnia (CBT-
I) provided through CVT produces similar improvements in Insomnia Severity
Index as CBT-I provided in-person [97]. CVT-based treatment outcome studies in
other sleep disorders remain lacking.
Special Considerations Sleep telemedicine is still a relatively nascent and devel-
oping field. Though its utilization appears more and more essential to the future of
sleep telemedicine paradigms (Figs. 4.1 and 4.2, Point D), its deployment remains
complex. Providers should consider carefully not only the feasibility issues above,
but also specific laws and regulations pertaining to their specific state(s) of practice.
As of the writing of this chapter, there has been no successful litigation of a sleep
provider simply due to the use of telemedicine. However, standards of care should
be upheld, and it is up to that provider to ensure that all applicable rules are followed
(e.g., interstate medication prescribing, licensing). The AASM provides a “check-
list” of regulatory issues to aid new and more experienced sleep telemedicine pro-
viders [98].
A discussion of sleep telemedicine must also address technology the patient
brings to the visit. Wearable consumer sleep technologies will undoubtedly play an
increasing role in sleep medicine as newer devices become more advanced and ful-
fill the broad definition of asynchronous, store-and-forward sleep telemedicine.
Though their accuracy and reliability in data reporting has long been suspect, cur-
rent device algorithms more closely mimic established tools such as home sleep
apnea testing (HSAT) and actigraphy [99]. Indeed, the evolution of sleep medicine
may rely increasingly upon the most patient-centered data of all: that which these
patients collect themselves in their natural environment. It will be up to the provider,
whether BCSMP or non-BCSMP, to integrate that information with evolving clini-
cal guidelines to devise collaborative sleep disorder management plans.
Putting It All Together
Ideally, given the importance of sleep health and how ubiquitous sleep complaints
are, a patient should be able to access sleep medical care in a way that is patient-
centered. Care should be convenient, timely, and evidenced based. We propose a
model of care that starts with the identification of a patient who has a sleep com-
plaint (Fig. 4.1, Point A–C). This identification could be based on provider inquiry
and/or patient self-screening. Artificial intelligence would also leverage information
in the electronic health record, and chart nudges would prompt formal screening
questionnaires and/or provider inquiry to the patient. If a patient is determined to
have a high pretest probability for obstructive sleep apnea with or without comorbid
insomnia, the involved provider would order a home sleep apnea test and place a
referral for CBT-I, if appropriate (Fig. 4.1, Point D). If the HSAT was positive for
OSA, the ordering provider would initiate treatment with CPAP and follow the
patient to ensure symptom improvement as well as ongoing adherence to CPAP as
part of routine care. If the patient is not responsive to usual therapy, a referral would
be made to a sleep medicine specialty team (Fig. 4.1, Point E). The guidelines for
and facilitation of such a referral should be predetermined, similar to how a provider
would refer a patient with difficulty to control diabetes or hypertension would be
referred to an endocrinologist or cardiologist, respectively. Importantly, patients
with concern or high risk for sleep-disordered breathing that is not straightforwad
OSA should be referred to a sleep medicine provider directly to expedite evaluation
and treatment.
Alternatively, if a patient is noted to have insomnia or another sleep disorder that
the engaged provider is comfortable diagnosing treating (e.g., restless leg syndrome),
a treatment plan can be initiated by the non-sleep specialist, as appropriate (Fig. 4.1,
Point E; Fig. 4.2, Point D). Again, if the patient is not responsive to usual therapy or
if the provider is not comfortable or feels uncertain with any aspect of diagnosis or
treatment, a referral would be made to a sleep medicine specialty team (Fig. 4.1,
Point E; Fig. 4.2, Point D). A patient who has a sleep complaint but who does not
screen positive for a sleep disorder should be evaluated for the appropriate non-sleep
disorders related to their complaint (e.g., mood disturbance, thyroid disease, asthma).
If no obvious cause is determined and ongoing concerns about sleep remain, a refer-
ral to a sleep medicine physician could be considered. (Fig. 4.1, Point F).
The model we propose identifies several areas for future development. These fall
under the categories of telemedicine, education, industry partners, and guidelines.
Leveraging telemedicine to facilitate patient identification, screening and provider
response is critical. Non-sleep provider education along with easy access to treat-
ment guidelines and pathways is vitally important as well. All primary care provid-
ers (e.g., internal medicine, family medicine, pediatrics, OB/GYN, and general
surgery) and relevant specialties (e.g., cardiology, pulmonary, and ENT) should
have ACGME and ABMS mandates to learn about basic sleep disorders as part of
their training. Similarly, advanced practice providers should be expected to learn
this as part of their specialty training. Providers who have already completed their
training could be encouraged to learn about important sleep disorders via state-
mandated licensure requirements, maintenance of certification, CME, and/or CNE
offerings. Additionally, we believe industry should be called upon to leverage artifi-
cial intelligence to facilitate initial patient identification (i.e., EHR vendors) as well
as those who would benefit from stepped up care. For example, PAP vendors could
create a dashboard that alerts a provider to all patients in their panel who are not
adherent to PAP or whose PAP is not effectively treating their sleep apnea, as
opposed to requiring a provider to log into a specific patient’s PAP data.
Last but not least, we enthusiastically support the development of national guide-
lines to further articulate the collaboration between sleep medicine specialists and
non-sleep trained providers. Such guidelines should have input from a diverse set of
applicable stakeholders, inclusive of patients, relevant industry and business part-
ners, leaders from appropriate professional organizations familiar with clinical
guideline development, and sleep and non-sleep providers. Insurers and self-insured
businesses should be called upon to work together as stakeholders to test these
guidelines and demonstrate value. Once such collaborative guidelines are outlined,
adjustments can be made locally between the spoke and hub providers, as needed,
to further facilitate access to patient-centered sleep care.
References
1. Shepard JW, Buysse DJ, Chesson AL, Dement WC, Goldberg R, Guilleminault C, et al. History
of the development of sleep medicine in the United States. J Clin Sleep Med. 2005;1(1):61–82.
2. FREIDA. AMA program results 2021. Available from: https://freida.ama-assn.org/search/
list?spec=43391%20Put%20out%20by%20the%20AMA.
3. American Board of Medical Specialties. ABMS board certification report 2021. Available
from: https://www.abms.org/board-certification/abms-board-certification-report/.
4. Frost & Sullivan; American Academy of Sleep Medicine. Medicine Hidden health crisis cost-
ing America billions: underdiagnosing and undertreating obstructive sleep apnea draining
health care system. 2016. Available from: http://aasm.org/wp-content/uploads/2017/10/sleep-
apnea-economic-crisis.pdf.
5. Quan SF. Graduate medical education in sleep medicine: did the canary just die? J Clin Sleep
Med. 2013;09(02):101–2.
6. Billings ME, Cohen RT, Baldwin CM, Johnson DA, Palen BN, Parthasarathy S, et al.
Disparities in sleep health and potential intervention models: a focused review. Chest.
2021;159(3):1232–40.
7. Owens J. Introduction to special section: NIH sleep academic award program. Sleep Med.
2005;6(1):45–6.
8. Chai-Coetzer CL, Antic NA, Rowland LS, Reed RL, Esterman A, Catcheside PG, et al.
Primary care vs specialist sleep center management of obstructive sleep apnea and daytime
sleepiness and quality of life: a randomized trial. JAMA. 2013;309(10):997–1004.
9. Sánchez-de-la-Torre M, Nadal N, Cortijo A, Masa JF, Duran-Cantolla J, Valls J, et al. Role
of primary care in the follow-up of patients with obstructive sleep apnoea undergoing CPAP
treatment: a randomised controlled trial. Thorax. 2015;70(4):346.
10. Sánchez-Quiroga MÁ, Corral J, Gómez-de-Terreros FJ, Carmona-Bernal C, Asensio-Cruz
MI, Cabello M, et al. Primary care physicians can comprehensively manage patients with
sleep apnea. A noninferiority randomized controlled trial. Am J Respir Crit Care Med.
2018;198(5):648–56.
11. Tarraubella N, Sánchez-de-la-Torre M, Nadal N, De Batlle J, Benítez I, Cortijo A, et al.
Management of obstructive sleep apnoea in a primary care vs sleep unit setting: a randomised
controlled trial. Thorax. 2018;73(12):1152.
12. Fuller JM, Wong KK, Grunstein R, Krass I, Patel J, Saini B. A comparison of screening meth-
ods for sleep disorders in Australian community pharmacies: a randomized controlled trial.
PLoS One. 2014;9(6):e101003.
13. Perraudin C, Fleury B, Pelletier-Fleury N. Effectiveness of intervention led by a community
pharmacist for improving recognition of sleep apnea in primary care – a cohort study. J Sleep
Res. 2015;24(2):167–73.
14. Rosen IM, Rowley JA, Malhotra RK, Kristo DA, Carden KA, Kirsch DB. Strategies to
improve patient care for obstructive sleep apnea: a report from the American Academy of
Sleep Medicine Sleep-Disordered Breathing Collaboration Summit. J Clin Sleep Med.
2020;16(11):1933–7.
15. Brennan T. A new approach to sleep apnea 2021. Available from: https://payorsolutions.
cvshealth.com/insights/new-approach-sleep-apnea.
16. Espie CA, MacMahon KMA, Kelly H-L, Broomfield NM, Douglas NJ, Engleman HM, et al.
Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior
therapy for persistent insomnia in general practice. Sleep. 2007;30(5):574–84.
17. Bothelius K, Kyhle K, Espie CA, Broman JE. Manual-guided cognitive-behavioural therapy
for insomnia delivered by ordinary primary care personnel in general medical practice: a ran-
domized controlled effectiveness trial. J Sleep Res. 2013;22(6):688–96.
18. Chai-Coetzer CL, Antic NA, McEvoy RD. Identifying and managing sleep disorders in pri-
mary care. Lancet Respir Med. 2015;3(5):337–9.
19. Morin CM, LeBlanc M, Daley M, Gregoire JP, Mérette C. Epidemiology of insomnia: preva-
lence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep
Med. 2006;7(2):123–30.
20. The Physicians Foundation. The Physicians Foundation 2016 Physician Survey 2016. Available
from: http://www.physiciansfoundation.org/healthcare-research/physiciansurvey.
21. Sandlund C, Hetta J, Nilsson GH, Ekstedt M, Westman J. Improving insomnia in primary
care patients: a randomized controlled trial of nurse-led group treatment. Int J Nurs Stud.
2017;72:30–41.
22. Morgenthaler TI, Owens J, Alessi C, Boehlecke B, Brown TM, Coleman J Jr, et al. Practice
parameters for behavioral treatment of bedtime problems and night wakings in infants and
young children. Sleep. 2006;29(10):1277–81.
23. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insom-
nia disorder in adults: a clinical practice guideline from the American College of Physicians.
Ann Intern Med. 2016;165(2):125–33.
24. Rios P, Cardoso R, Morra D, Nincic V, Goodarzi Z, Farah B, et al. Comparative effectiveness
and safety of pharmacological and non-pharmacological interventions for insomnia: an over-
view of reviews. Syst Rev. 2019;8(1):281.
25. Koffel E, Bramoweth AD, Ulmer CS. Increasing access to and utilization of cognitive behav-
ioral therapy for insomnia (CBT-I): a narrative review. J Gen Intern Med. 2018;33(6):955–62.
26. Maire M, Linder S, Dvořák C, Merlo C, Essig S, Tal K, et al. Prevalence and management of
chronic insomnia in Swiss primary care: cross-sectional data from the “Sentinella” practice-
based research network. J Sleep Res. 2020;29(5):e13121.
27. Ulmer CS, Bosworth HB, Beckham JC, Germain A, Jeffreys AS, Edelman D, et al.
Veterans affairs primary care provider perceptions of insomnia treatment. J Clin Sleep Med.
2017;13(8):991–9.
28. Davy Z, Middlemass J, Siriwardena AN. Patients’ and clinicians’ experiences and per-
ceptions of the primary care management of insomnia: qualitative study. Health Expect.
2015;18(5):1371–83.
29. Cheung JM, Atternäs K, Melchior M, Marshall NS, Fois RA, Saini B. Primary health care
practitioner perspectives on the management of insomnia: a pilot study. Aust J Prim Health.
2014;20(1):103–12.
30. Buysse DJ, Germain A, Moul DE, Franzen PL, Brar LK, Fletcher ME, et al. Efficacy
of brief behavioral treatment for chronic insomnia in older adults. Arch Intern Med.
2011;171(10):887–95.
31. Smallheer BA. Evaluation and treatment of restless legs syndrome in the primary care environ-
ment. Nurs Clin North Am. 2018;53(3):433–45.
32. Donovan LM, Yu L, Bertisch SM, Buysse DJ, Rueschman M, Patel SR. Responsiveness of
patient-reported outcomes to treatment among patients with type 2 diabetes mellitus and
OSA. Chest. 2020;157(3):665–72.
33. Espie CA. “Stepped care”: a health technology solution for delivering cognitive behavioral
therapy as a first line insomnia treatment. Sleep. 2009;32(12):1549–58.
34. Sweetman A, Lack L, Catcheside PG, Antic NA, Smith S, Chai-Coetzer CL, et al. Cognitive
and behavioral therapy for insomnia increases the use of continuous positive airway pressure
therapy in obstructive sleep apnea participants with comorbid insomnia: a randomized clinical
trial. Sleep. 2019;42(12):zsz178.
35. Sweetman AM, Lack LC, Catcheside PG, Antic NA, Chai-Coetzer CL, Smith SS, et al.
Developing a successful treatment for co-morbid insomnia and sleep apnoea. Sleep Med Rev.
2017;33:28–38.
36. Watson NF, Rosen IM, Chervin RD. The past is prologue: the future of sleep medicine. J Clin
Sleep Med. 2017;13(1):127–35.
37. Pendharkar S, Blades K, Kelly J, et al. Perspectives on primary care management of obstruc-
tive sleep apnea: a qualitative study of patients and health care providers. J Clin Sleep Med.
2021;17(1):89–98.
38. Stevenson L, Ball S, Haverhals LM, Aron DC, Lowery J. Evaluation of a national telemedicine
initiative in the Veterans Health Administration: factors associated with successful implemen-
tation. J Telemed Telecare. 2018;24(3):168–78.
39. Su GL, Glass L, Tapper EB, Van T, Waljee AK, Sales AE. Virtual consultations through the
veterans administration SCAN-ECHO project improves survival for veterans with liver dis-
ease. Hepatology. 2018;68(6):2317–24.
40. Guzman-Clark J, Harrell K, Leff A, Henriques D, Ines E, Rofail M, et al. Implementation of an
ECHO-based program to provide geriatric specialty care consultation and education to remote
primary care teams. Fed Pract. 2016;33(4):40–5.
41. Ball S, Wilson B, Ober S, McHaourab A. SCAN-ECHO for pain management: implementing
a regional telementoring training for primary care providers. Pain Med. 2018;19(2):262–8.
42. Parsons EC, Mattox EA, Beste LA, Au DH, Young BA, Chang MF, et al. Development of a
sleep telementorship program for rural Department of Veterans Affairs primary care providers:
sleep veterans affairs extension for community healthcare outcomes. Ann Am Thorac Soc.
2017;14(2):267–74.
43. Smith AG. A sleep medicine medical school curriculum: time for us to wake up. Neurology.
2018;91(13):587–8.
44. Salas RE, Gamaldo A, Collop NA, Gulyani S, Hsu M, David PM, et al. A step out of the dark:
improving the sleep medicine knowledge of trainees. Sleep Med. 2013;14(1):105–8.
45. Salas RME, Strowd RE, Ali I, Soni M, Schneider L, Safdieh J, et al. Incorporating sleep
medicine content into medical school through neuroscience core curricula. Neurology.
2018;91(13):597–610.
46. Lam AS, Wise SK, Dedhia RC. Practice patterns of sleep otolaryngologists at training institu-
tions in the United States. Otolaryngol Head Neck Surg. 2017;156(6):1025–31.
47. Cass N, Kominsky A, Cabrera-Muffly C. Otolaryngology sleep medicine curriculum objec-
tives as determined by sleep experts. Am J Otolaryngol. 2017;38(2):139–42.
48. Avidan AY, Vaughn BV, Silber MH. The current state of sleep medicine education in US
neurology residency training programs: where do we go from here? J Clin Sleep Med.
2013;9(3):281–6.
49. American Board of Internal Medicine. Pulmonary disease certification examination blue-
print 2021. Available from: https://www.abim.org/~/media/ABIM%20Public/Files/pdf/exam-
blueprints/certification/pulmonary-disease.pdf.
50. Schulman DA, Piquette CA, Alikhan MM, Freedman N, Kumar S, McCallister J, et al. A sleep
medicine curriculum for pulmonary and pulmonary/critical care fellowship programs: a multi-
society expert panel report. Chest. 2019;155(3):554–64.
51. Mehra R, Rosen IM. Clarifying requisite sleep medicine content for the pulmonary and
critical care medicine fellow: a key step forward, but where do we go from here? Chest.
2019;155(3):460–2.
52. Namen AM, Wymer A, Case D, Haponik EF. Performance of sleep histories in an ambulatory
medicine clinic: impact of simple chart reminders. Chest. 1999;116(6):1558–63.
53. Sepucha KR, Simmons LH, Barry MJ, Edgman-Levitan S, Licurse AM, Chaguturu
SK. Ten years, forty decision aids, and thousands of patient uses: shared decision making
at Massachusetts General Hospital 2016. Available from: https://www.healthaffairs.org/
doi/10.1377/hlthaff.2015.1376.
54. Maguire E, Hong P, Ritchie K, Meier J, Archibald K, Chorney J. Decision aid prototype devel-
opment for parents considering adenotonsillectomy for their children with sleep disordered
breathing. J Otolaryngol Head Neck Surg. 2016;45(1):57.
55. Fung CH, Martin JL, Liang LJ, Hays RD, Col N, Patterson ES, et al. Efficacy of a patient deci-
sion aid for improving person-centered decision-making by older adults with obstructive sleep
apnea. J Clin Sleep Med. 2021;17(2):121–8.
56. Chai-Coetzer CL, Antic NA, Rowland LS, Catcheside PG, Esterman A, Reed RL, et al. A sim-
plified model of screening questionnaire and home monitoring for obstructive sleep apnoea in
primary care. Thorax. 2011;66(3):213–9.
57. Epton MJ, Kelly PT, Shand BI, Powell SV, Jones JN, McGeoch GRB, et al. Development and
outcomes of a primary care-based sleep assessment service in Canterbury, New Zealand. NPJ
Prim Care Respir Med. 2017;27(1):26.
58. McPherson CJ, Higginson IJ, Hearn J. Effective methods of giving information in cancer: a sys-
tematic literature review of randomized controlled trials. J Public Health Med. 2001;23(3):227–34.
59. Mills ME, Sullivan K. The importance of information giving for patients newly diagnosed with
cancer: a review of the literature. J Clin Nurs. 1999;8(6):631–42.
60. Saunders CH, Petersen CL, Durand MA, Bagley PJ, Elwyn G. Bring on the machines: could
machine learning improve the quality of patient education materials? A systematic search and
rapid review. JCO Clin Cancer Inform. 2018;2:1–16.
61. Luyster FS, Choi J, Yeh CH, Imes CC, Johansson AE, Chasens ER. Screening and evaluation
tools for sleep disorders in older adults. Appl Nurs Res. 2015;28(4):334–40.
62. Chung F, Abdullah HR, Liao P. STOP-Bang questionnaire: a practical approach to screen for
obstructive sleep apnea. Chest. 2016;149(3):631–8.
63. Nagappa M, Liao P, Wong J, Auckley D, Ramachandran SK, Memtsoudis S, et al. Validation of
the STOP-Bang questionnaire as a screening tool for obstructive sleep apnea among different
populations: a systematic review and meta-analysis. PLoS One. 2015;10(12):e0143697.
64. Tan A, Yin JD, Tan LW, van Dam RM, Cheung YY, Lee CH. Predicting obstructive sleep apnea
using the STOP-Bang questionnaire in the general population. Sleep Med. 2016;27-28:66–71.
65. Martin JL, Song Y, Hughes J, Jouldjian S, Dzierzewski JM, Fung CH, et al. A four-session
sleep intervention program improves sleep for older adult day health care participants: results
of a randomized controlled trial. Sleep. 2017;40(8):zsx079.
66. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs
syndrome prevalence and impact: REST general population study. Arch Intern Med.
2005;165(11):1286–92.
67. Ferri R, Lanuzza B, Cosentino FI, Iero I, Tripodi M, Spada RS, et al. A single question for the
rapid screening of restless legs syndrome in the neurological clinical practice. Eur J Neurol.
2007;14(9):1016–21.
68. Nichols DA, Allen RP, Grauke JH, Brown JB, Rice ML, Hyde PR, et al. Restless legs syn-
drome symptoms in primary care: a prevalence study. Arch Intern Med. 2003;163(19):2323–9.
69. Walters AS, Frauscher B, Allen R, Benes H, Chaudhuri KR, Garcia-Borreguero D, et al.
Review of diagnostic instruments for the restless legs syndrome/Willis-Ekbom Disease (RLS/
WED): critique and recommendations. J Clin Sleep Med. 2014;10(12):1343–9.
70. Harrison JD, Patel MS. Designing nudges for success in health care. AMA J Ethics.
2020;22(9):E796–801.
71. Klingman KJ, Jungquist CR, Perlis ML. Questionnaires that screen for multiple sleep disor-
ders. Sleep Med Rev. 2017;32:37–44.
72. Sarmiento KF, Folmer RL, Stepnowsky CJ, Whooley MA, Boudreau EA, Kuna ST, et al.
National expansion of sleep telemedicine for veterans: the TeleSleep program. J Clin Sleep
Med. 2019;15(9):1355–64.
73. Senthilvel E, Auckley D, Dasarathy J. Evaluation of sleep disorders in the primary care setting:
history taking compared to questionnaires. J Clin Sleep Med. 2011;07(01):41–8.
74. Hwang D, Woodrum R. Inadequacy of current solutions to address provider shortage. Chest
J. 2020;157(5):1055–7.
75. Goldstein CA, Berry RB, Kent DT, Kristo DA, Seixas AA, Redline S, et al. Artificial intel-
ligence in sleep medicine: an American Academy of Sleep Medicine position statement. J Clin
Sleep Med. 2020;16(4):605–7.
76. Keenan BT, Kim J, Singh B, Bittencourt L, Chen NH, Cistulli PA, et al. Recognizable clinical
subtypes of obstructive sleep apnea across international sleep centers: a cluster analysis. Sleep.
2018;41(3):zsx214.
77. Kim J, Keenan BT, Lim DC, Lee SK, Pack AI, Shin C. Symptom-based subgroups of Koreans
with obstructive sleep apnea. J Clin Sleep Med. 2018;14(3):437–43.
78. Mazzotti DR, Keenan BT, Lim DC, Gottlieb DJ, Kim J, Pack AI. Symptom subtypes of
obstructive sleep apnea predict incidence of cardiovascular outcomes. Am J Respir Crit Care
Med. 2019;200(4):493–506.
79. Eckert DJ. Phenotypic approaches to obstructive sleep apnoea – new pathways for targeted
therapy. Sleep Med Rev. 2018;37:45–59.
80. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, et al. CPAP for prevention of car-
diovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10):919–31.
81. Peker Y, Glantz H, Eulenburg C, Wegscheider K, Herlitz J, Thunström E. Effect of positive
airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy
obstructive sleep apnea. The RICCADSA randomized controlled trial. Am J Respir Crit Care
Med. 2016;194(5):613–20.
82. Zinchuk A, Yaggi HK. Sleep apnea heterogeneity, phenotypes, and cardiovascular risk.
Implications for trial design and precision sleep medicine. Am J Respir Crit Care Med.
2019;200(4):412–3.
83. Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the main-
tenance of wakefulness test and the epworth sleepiness scale: failure of the MSLT as a gold
standard. J Sleep Res. 2000;9(1):5–11.
84. Stephansen JB, Olesen AN, Olsen M, Ambati A, Leary EB, Moore HE, et al. Neural net-
work analysis of sleep stages enables efficient diagnosis of narcolepsy. Nat Commun.
2018;9(1):5229.
85. Kuna ST. The MISSION act: challenges to sleep medicine and other specialties in the veterans
health administration. Am J Respir Crit Care Med. 2019;200(6):663–4.
86. Health Resources & Services Administration. Telehealth programs 2021. Available from:
https://www.hrsa.gov/rural-health/telehealth.
87. The Federation of State Medical Boards. House of delegates annual business meeting 2018.
Available from: https://www.fsmb.org/siteassets/annual-meeting/hod/april-28-2018-fsmb-
hod-book.pdf.
88. Kelly JM, Schwamm LH, Bianchi MT. Sleep telemedicine: a survey study of patient prefer-
ences. ISRN Neurol. 2012;2012:135329.
89. Johnson KG, Sullivan SS, Nti A, Rastegar V, Gurubhagavatula I. The impact of the COVID-19
pandemic on sleep medicine practices. J Clin Sleep Med. 2021;17(1):79–87.
90. Singh J, Badr MS, Diebert W, Epstein L, Hwang D, Karres V, et al. American Academy of
Sleep Medicine (AASM) position paper for the use of telemedicine for the diagnosis and treat-
ment of sleep disorders. J Clin Sleep Med. 2015;11(10):1187–98.
91. The Center for Connected Health Policy. Current state laws & reimburse-
ment policies 2021. Available from: https://www.cchpca.org/telehealth-policy/
current-state-laws-and-reimbursement-policies.
92. Centers for Medicare & Medicaid Services. Medicare telemedicine health care pro-
vider fact sheet 2020. Available from: https://www.cms.gov/newsroom/fact-sheets/
medicare-telemedicine-health-care-provider-fact-sheet.
93. Mehrotra A, Nimgaonkar A, Richman B. Telemedicine and medical licensure — potential
paths for reform. N Engl J Med. 2021;384(8):687–90.
94. Fields BG, Behari PP, McCloskey S, True G, Richardson D, Thomasson A, et al. Remote
ambulatory management of veterans with obstructive sleep apnea. Sleep. 2016;39(3):501–9.
95. Parikh R, Touvelle MN, Wang H, Zallek SN. Sleep telemedicine: patient satisfaction and treat-
ment adherence. Telemed J E Health. 2011;17(8):609–14.
96. Aurora RN, Collop NA, Jacobowitz O, Thomas SM, Quan SF, Aronsky AJ. Quality measures
for the care of adult patients with obstructive sleep apnea. J Clin Sleep Med. 2015;11(3):357–83.
97. Arnedt JT, Conroy DA, Mooney A, Furgal A, Sen A, Eisenberg D. Telemedicine versus face-
to-face delivery of cognitive behavioral therapy for insomnia: a randomized controlled nonin-
feriority trial. Sleep. 2021;44(1):zsaa136.
98. American Academy of Sleep Medicine. Download the sleep telemedicine implementation
guide – a FREE resource from AASM 2021 [February 28, 2021]. Available from: https://aasm.
org/download-the-sleep-telemedicine-implementation-guide-a-free-resource-from-aasm/.
99. Goldstein C. Current and future roles of consumer sleep technologies in sleep medicine. Sleep
Med Clin. 2020;15(3):391–408.
Part II
Sleep Disordered Breathing
Chapter 5
Obstructive Sleep Apnea: Clinical
Epidemiology and Presenting
Manifestations
Eric Yeh, Nishant Chaudhary, and Kingman P. Strohl
Keywords Epidemiology · Cardiovascular · OSA management · Pathogenesis

Obstructive sleep apnea · Renal disease · Psychiatric disease
Introduction
Obstructive sleep apnea (OSA) is a common chronic sleep condition. The clinical
diagnosis is called obstructive sleep apnea hypopnea syndrome (OSAHS), defined
by symptoms of unrefreshing and disturbed sleep, loud snorts and snoring, daytime
impairment from sleepiness or a fatigue-like state and a certain number (usually >5/
hour or an average of one every 12 minutes) of predominantly obstructive apneas
and hypopnea per hour (referred to as apnea-hypopnea index or AHI). If one remains
uncertain of the precise pathogenesis or risk, OSAHS is resolved of symptoms by
treatment of upper airway obstruction during sleep. In that regard, two treatments
are available where there is robust evidence for symptomatic and objective effec-
tiveness are tracheostomy [41], and excellent adherence to continuous positive air-
way pressure (CPAP) [36]. OSA is found at all stages of life, in all races, and with
all shapes and sizes of people, and can rise to the level of a disorder (OSAHS).
At this point in time, defining OSA and OSAHS are no longer the critical ques-
tions. Instead, the questions are how these conditions affect morbidity are chronic
medical conditions. The concepts for this chapter are those that consider the preva-
lence of the clinically recognized disorder, concepts summarized in Fig. 5.1. OSA
can be predicted on a sleep study to some degree by a constellation of risk factors
and presenting classical complaints, like sleepiness, disrupted sleep, snoring and
E. Yeh · N. Chaudhary · K. P. Strohl (*)

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine,
University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA
e-mail: kingman.strohl@uhhospitals.org

92 E. Yeh et al.
Risk factors Presenting symptom complexes
Causality
Sleep
Upper airway anatomy System control Muscle recruitment
AHI Hypoventilation Sleep disruption
Consequences
Tier 1: Sleepiness Unrefreshing sleep Sympathetic activation

Tier 2: Impact on cardiovascular and neurocognitive functions
Fig. 5.1 Shown are the pathway relationships from risk factors and presenting complaints to con-
sequences. The causal factors of sleep, upper airway anatomy, (ventilatory) system control, and
muscle recruitment lead to the apneas and hypopneas (AHI), hypoventilation, and sleep disrup-
tions leading to the Tier 1 (immediate) and Tier 2 (long term remodeling) of cardiovascular and
neural physiology
obesity [12], but those non-obese with non-traditional symptoms like insomnia or
parasomnia are also found to be enriched for OSA, compared to the general popula-
tion. There are no tests or biologic markers. It is that OSA is a complex disease in
which no one feature or genetic set point or biological marker alone sets it apart as
a diagnosis.
Risk factors and complaints are not causal factors. Sleep precipitates disordered
breathing in the otherwise healthy individual, and added to it are additional aspects –
the ventilatory control system which is a source of instability over time, the tendency
for the upper airway to close, and the degree of upper airway muscle activation in
sleep or in response to upper airway closure [40]. All conspire to increase or decrease
the measurable polysomnographic counts of sleep-disordered breathing [46].
The presence and severity of OSA is currently represented by the apnea-hypopnea
index (AHI), hypoventilation assessed by measures of hypoxic stress by oximetry
and of carbon dioxide excretion, and sleep disruption, often indicated by EEG
arousals. The consequences of these events can be considered as short-term and
chronic outcomes, and the associations with disease and treatment mitigation will
inform medical practitioner about the rationale for clinical recognition and treat-
ment. There is a feedback loop from consequences which over time can influence
risk factors and presenting complaints. For instance, the effects of AHI sympathetic
activation and hypoxia releases insulin which in turn promotes appetite and fat
5 Obstructive Sleep Apnea: Clinical Epidemiology and Presenting Manifestations 93
acquisition or heart failure which compromises upper airway patency or promotes

breathing instability, respectively [39].
Other chapters will go into detail on the relationships shown in Fig. 5.1. For our
purposes this schema sets the stage for our view of how the current body of knowl-
edge in OSA epidemiology has led to current management and identification strate-
gies. Thus, this chapter is designed less to provide facts and more to examine
presentations and recognition of pathways of clinical importance that present in
outpatient vs. inpatient care settings and consider potential policy changes or pre-
ventative medicine. The overall objectives are to introduce the scope of the epide-
miology in each setting rather than review all datasets, which are addressed in
several recent, more granular reviews. Finally, there is a goal for sleep medicine to
provide individual OSA management (personalized medicine). The rationale and
details of how disease evolves over time have now a body of literature that indicates
a heterogeneity in outcomes depending upon various domains of symptom presen-
tation, polysomnographic variables, and genetic predisposition to increase or
decrease risk of the consequences. These will be reviewed in more detail in other
chapters in this book. The epidemiology of OSA serves as an introduction to this
approach.
There are a variety of terms and abbreviations in the epidemiology literature with
the result that the one must notice definitions of OSA or OSAHS [47]. Conclusions,
while internally consistent with the definitions, might differ with another definition
making direct meta-comparisons among cohorts, even in the present time, problem-
atic. Table 5.1 lists some of the more common metrics and groupings of illness
severity that are generally used and inform many of the opinions in this review.
There are other measures coming on line in clinical medicine that begin to define
Table 5.1 Conservative odds ratio (OR) for finding sleep apnea in each of several individual
medical conditions and three reported behaviors, all other things being equal
Condition OR
Systemic hypertension 1.5–4
Stroke 1.2–3
Myocardial infarction 1.3–2.5
Nocturnal angina 8–15
Hyperlipidemia 2–3
Asthma 1.5–2.0
Diabetes 2
Menopause 1.27
Depression 1.92
Pulmonary hypertension 1.2
Activity
Regular physical exercise 0.5–0.9
Snoring 2–6
Obesity (BMI >30) 8–12
94 E. Yeh et al.
features of sleep hypoventilation (time > 55 mm Hg transcutaneous CO2), and of

features in sleep-disordered breathing (apnea time, cycle length, submental EMG
recruitment); however, reporting is just beginning to appear in retrospective studies
of cohorts.
Population Epidemiology
Figure 5.2 illustrates the OSA epidemiology regarding populations and prevalence,
in particular, the perspectives that might influence decision making. The large box
illustrates an unfiltered population, and the succession of boxes inside it represents
a range of sub-populations. Among population cohorts, prevalence rates for self-
proclaimed healthy individuals vary by gender and weight, and community as rep-
resented by race or ethnicity. The prevalence estimates in the community are lower
than in clinical settings, because the ascertainment attempts to be random or at least
a representative of the group living in any given region.
In the primary care population where the most common initial complaint for a
new appointment is fatigue, and obesity (~BMI >30), the result is a pre-test proba-
bility of ~37% [27]. In heart failure clinics estimates are the same or higher. In the
bariatric clinics, it does not make sense to even ask about sleep apnea, as the preva-
lence is generally greater than 60%; uncommon are the ~15% of patients who are
Fig. 5.2 This figure

represents the greater Prevalence estimates for
population at lare (whole sleep-disordered breathing
box) and the various
subsets in the general
population with estimates
of prevalence of sleep- General population: 8–12%
disordered breathing
Primary care: high risk 37%
Obese: 40–60%
Heart failure: 35–65%
Sleep clinic: 67%
Bariatric surgery
evaluation: 71–87%
OHS: 90%
morbidly obese who do not have symptoms of sleep apnea and low AHI values
(<10/h). A high prevalence of sleep apnea and obstructive apnea in particular is
present in the hospital setting enriched for chronic cardiopulmonary disorders
admitted for acute illness [34]. Obesity hypoventilation syndrome is more often
found during a hospitalization for acute medical illness or in the setting of a poor
recovery from a surgical procedure [24].
If a community prevalence is used as the standard, almost any adult clinical set-
ting will have a prevalence is higher than in the community. In specialty samples,
comparisons are made between clinical cohorts in which some have clinical symp-
toms of high risk, and those who do not, and this leads to interesting associations.
For instance, sleep apnea prevalence is higher than the general population in floppy
eyelid syndrome, nonarteritic anterior ischemic optic neuropathy, central serous
retinopathy, retinal vein occlusion, and glaucoma, and post-hoc ascribed to vascular
consequences of OSA [11, 35]. One is not really sure whether these reports repre-
sent a causal OSA factor, an epiphenomenon, or an ascertainment within an older
population. Whether ascertainment for OSA should lead to a routine referral of
floppy eyelid or other ophthalmologic condition should await data on whether iden-
tification and treatment of OSA makes sense. Likewise, a mandate to sleep special-
ists to assess ophthalmologic as well as cardiovascular conditions is not part of
routine practice. The burden of OSAHS estimated at any one time is also con-
founded by the uncertainty about the latency to clinical detection, a subtle effect of
co-morbidity, or susceptibility to other disorders.
The prevalence rate of OSA (AHI >5/h) in industrialized countries is 10–20% of
middle-aged adults with a syndromic group estimated at 4–8% of men and 2–4% of
women, and in the same cohort repeat testing some years later suggest prevalence
increasing from 1993 to 1998 [30]. Worldwide estimates have come up with a sleep
apnea prevalence of a little less than 1 billion individuals, with an AHI >5 cutoff,
and a half billion with an AHI >15. This estimate is seriously flawed by ascertain-
ment bias by study, selective reporting, differences in the methodology (testing,
questionnaire, AHI criteria, or derivation from estimates from BMI or other mea-
sures of body habitus) [4]. The data do not indicate who needs treatment or might
benefit from interventions. It does serve a purpose, however. While lower than
hypertension, the estimate puts OSA as potentially significant as a driver of chronic
illness; the estimate illustrates the population substrate out of which OSAHS is
derived; and the estimate serves to drive further the attention of international health
agencies to consider health policy initiatives and of industry to recognize market
opportunities, similar to what is seen worldwide in cardiovascular disease and dia-
betes. Treatment in non-Western-oriented medical systems which are resource-
limited may turn up inventive approaches that will in turn inform Western medicine.
In the US Wisconsin cohort, a group of employed state workers, the measure-
ment of sleep-disordered breathing was the primary outcome and a sense of the
impact of a report of snoring or the presence of obesity was demonstrated [50].
Shown in Fig. 5.3 is a graph of the cumulative percent of people with a given AHI
when parsed into those who do not snore, those who are habitual snorers (4–7 times
a week), and the obese (BMI >30). This graph does not indicate which patients
96 E. Yeh et al.
Fig. 5.3 This depicts the Prevalence of OSA events by thresholds

data from the 1993 and 0
2003 publications of the
Wisconsin cohort to
summarize the prevalence 20
of OSA in regard to AHI
categories and prevalence –
% of population
with AHI level
percent (%) of the 40
population – with a certain Non-snorer
AHI level of mild, Habitual snorer
moderate, and severe as Obese (BMI >30)
60
events/hour
80
5-15 15-30 >30
Mild Moderate Severe
100 0 10 20 30 40 50 60 70 80 90
Apnea/hypopnea index
would need or seek therapy given this information, but it does illustrate an instance
where differences exist in population estimates if there are differences in reportable
symptoms or BMI as a surrogate for weight.
High rates of community OSA have been recently published, albeit in the Western
literature. The first is the population-based Study of Health in Pomerania which
utilized objective measures to examine the prevalence and risk factors of obstructive
sleep apnea in a German cohort between 20 and 81 years old [15]. The OSA preva-
lence was 46% (59% men and 33% women) for an AHI ≥5%, and 21% (30% men,
13% women) for an AHI ≥15. However, adding symptoms, OSAHS prevalence
(apnea-hypopnea index ≥5; Epworth Sleepiness Scale >10) was 6%. Gender, age,
body mass index, waist-to-hip ratio, snoring, alcohol consumption (for women
only), and self-reported cardiovascular diseases were significantly positively associ-
ated with AHI >5. Diabetes, hypertension, and metabolic syndrome were positively
associated with AHI >30. A second report from Switzerland, a country that one
might think would have relatively low rates, included 3043 consecutive participants
who underwent polysomnography [16]. About 50% were men, median age of
57 years with a median BMI of ~25·6. Participants underwent complete polysomno-
graphic recordings at home. AHI >15 was ~23% in women and ~50% in men for
AHI >15. Association for trend indicated hypertension (OR 1.6), diabetes (OR 2.0),
metabolic syndrome (OR 1.8), and depression (OR 1.92). These two reports suggest
a cross-sectional community burden of sleep apnea in Western populations, associ-
ated with other common chronic diseases.
The reports from Asian countries take advantage of universal health coverage
and community-based health surveys. In the Taiwanese individuals, habitual snor-
ing overall was ~52%, a bit higher in males at 61% than females at 43%.
Corresponding rates for witnessed apnea during sleep was 2.6%, 3.4%, and 1.9%,
respectively. The prevalence of having both traits was also higher in males than in
females. Prevalence of hypertension, cardiovascular disease, diabetes mellitus,

arthritis, and backache was higher in those who snored or had witnessed apnea [9].
In South Korea, a similar pattern emerges with high risk for OSA at 16% and risk
for OSA being higher with age ≥70 years (OR 2.68) and body BMI ≥25 kg/m2 (OR
10.75), even though the BMI range is lower than in Caucasians [42]. As in other
samples, hypertension (OR 5.83), diabetes mellitus (OR 2.54), hyperlipidemia (OR
2.85), and anxiety (OR 1.63) were comorbid conditions. Interestingly, a report of
regular physical activity (OR 0.70) had a protective effect, giving a clue to direc-
tions for policy to mitigate OSA.
The literature is clear in greater susceptibility of men to snoring and sleep apnea
until the age where women experience menopause. The USA values generally cited
are on the order of 17% of women and 22% of men, if the threshold is an AHI of ≥5
[49]. Recognition strategies for sleep apnea built on such risk factors, with male sex
(1 point for male and 0 for female), reflect a greater positive predictive value,
although the relative proportion of risk in a multivariate tool like the STOP-BANG
is modest [10]. The obvious mechanism is a hormonal one and the potentially pro-
tective effects of progesterone and estrogen, opposed to testosterone in men.
In one large Chinese hypertensive population OSA prevalence is related to age in
women but only to BMI in men [6]. Reports appear which explain this by an impact
on hormonal milieu, for instance in the Nurses’ Health Study II during 1995–2013,
compared with natural menopause, surgical menopause by hysterectomy and/or
oophorectomy, the hazard ratio for OSA was 1.27 (95% confidence interval (CI):
1.17, 1.38), even after accounting for age, risk was higher among non-obese women.
Interestingly among women who never used hormone therapy AHI and hyperten-
sion risk was lower than those who had used some hormone therapy. Surgical as
compared with natural menopause was independently associated with higher OSA
risk in women in the postmenopausal phase of life [17]. These cohort studies start
to define risk factors.
The presence of OSA in otherwise healthy people has an impact on subsequent
health, as shown in the Wisconsin cohort where a dose-response association was
uncovered between AHI levels at baseline and the clinical presence of hypertension
4 years later, independent of many of the known risk factors confounding factors
including age, sex, and body weight [31]. Relative to a reference of 0/h, presence of
hypertension at follow-up for an AHI 1 to <5 was 1.42, for 5–14.9/h 2.03, and for
>15/h 2.89, significant at all levels [31]. These observations are consistent with
sleep apnea being a modifiable risk factor for cardiovascular disease, given that
hypertension is the greatest risk for heart failure, renal failure, and cardiac
arrhythmias.
Community studies also suggest a complex, and bidirectional interaction of OSA
with common respiratory disorders, one example of which is asthma. The Wisconsin
Sleep Cohort Study has longitudinal data on respiratory status and overnight poly-
somnography studies at 4-year intervals [43]. The associations of presence and
duration of asthma with OSA. Participants with incident asthma were found to
experience incident OSA more than those without asthma; the corresponding
adjusted relative risk was significant (RR 1.39), controlling for sex, age, baseline
98 E. Yeh et al.
and change in body mass index, and other factors. Asthma was also associated with
new-onset OSA with sleepiness, hallmarks of the development of OSAHS. Therefore,
one may look at the better-developed asthma surveillance systems for clues as to the
potential for new OSA cases.
Many suspect that the origins of disease start in childhood patterns of dietary
intake, exercise need and habit, and changes in head form, followed by habitual
alcohol and smoking, and in parallel risk of cardiovascular disease. There are few
long-term observational studies of individuals spanning the ages of 18 to about
55 years of age, about the sixth decade being the most common mean or median age
found in many cohorts including the initial reports from the Wisconsin Sleep Cohort
[50] and the Sleep Heart Health Study [29, 37]. It is difficult to “look back” at the
trajectory of disease, and consider which causal pathway drove the propagation of
sleep apnea, as captured by AHI, over time. One modest study showed that over a
five-year period the significant odds ratio for incident sleep-disordered breathing
started with being male (OR ~ 2.29), and then age and waist-hip ratio (both
OR ~ 1.5), and then BMI and cholesterol (at OR ~ 1.1) [44]. Over the past two
decades, with the increasing prevalence of adult obesity in the Western world, the
most important risk factor in sleep breathing disorders, the number of patient diag-
nosed as suffering from OSA has increased and it will increase over the coming
years unless this obesity trend is mitigated.
Office Epidemiology
The early reports of sleep apnea in primary care population surprised those who
believed that it would reflect community estimates. One such early study was a two-
step survey of primary care practices where a questionnaire was used to assess risk
and polygraphic study was used to measure suspected OSA [38]. Fifty percent of all
primary care patients reported to snore while 31% of snorers reported to snore every
night. Based on this first questionnaire algorithm 20% were at high risk for SDB,
compared to 18.5% for PLMD and 25% with insomnia. Daytime sleepiness and
fatigue were associated in patients with likelihood of any or all of these three sus-
pected conditions. SDB was twice as common in men than in women.
In 1997, a Berlin, Germany, conference of primary care practitioners and
sleep specialists resulted in a tool called the Berlin Questionnaire designed for
primary care office use. Its intent was to use a predictive approach that three
domains (snoring and disturbed sleep, sleepiness, and a combination of BMI >30
and/or hypertension) would constitute a high pre-test probability for OSA [28].
For the 100 patients who underwent sleep studies, risk grouping was generally
useful in the prediction of the number of events. While it could not tell one
whether high risk meant a need for therapy, it was useful for its negative predic-
tive value. The value of the tool was explored in relation to its domains and risk
in 8000 adults across primary care practices in the United States and Europe.
One-third (32%) had a high pretest probability for OSA, with a higher rate in the
United States (36%) than in Europe (26%). Sleepiness (32% vs 12%) followed
by obesity and/or hypertension (45% vs 37%, respectively; p < 0.01) contributed
to the OSA risk difference between participants in the United States and Europe,
as frequent snoring and breathing pauses were similarly reported (44%). A high
pretest probability for OSA was more often present in men than in women (38%
vs 28%) and in those that were obese, a condition more common in the United
States (28% vs 17%). The conclusions were that primary care physicians would
encounter a high demand for services to confirm or manage sleep apnea, sleepi-
ness, and obesity (Fig. 5.4).
A similar survey 15 years later expanded on this theme [2]. The target was five
different family medicine practice locations in North Carolina for assessment of the
burden of sleep complaints in the system. More than 50% of the respondents
reported excessive daytime sleepiness, one-third reported insomnia, 13–33% were
dealing with symptoms consistent with OSA and OSAHS; in addition, more than
one-quarter had clinical symptoms of restless legs syndrome. The correlation of
poor health and sleep disturbance was high, and comorbidities such as hyperten-
sion, pain syndromes, and depression were also shown to be associated with more
sleep complaints. Besides fatigue and excessive daytime sleepiness, complaints
such as headache, nocturia, undesired awakening with or without inability to fall
back to sleep, morning dry mouth, and nocturnal gastroesophageal reflux, and sub-
jective reduced concentration and memory, and “mood disorder”, were mapped to
sleep complaints. Sleep was noted to be important in the assessment of isolated
chief complaints like frequent nocturia particularly in older males that would before
lead to a only work up for benign prostate hypertrophy, or heartburn in obese
patients that lead to only GERD management, or dry mouth upon awakening being
Sleep symptoms city comparisons

45
40
35
30
25 Washington DC
20 Cleveland
%
15 Madrid
10 Ashland/OH
5
0
High risk Snore Sleepy Drowsy BMI>30
driving
Fig. 5.4 Shown are unpublished data from the study published as Netzer et al. (2003) is graphed
to compare among two large cities (Washington DC and Madrid Spain), a medium-sized city,
Cleveland Ohio, and a small town, Ashland Ohio, the computation of High Risk in the Berlin
Questionnaire and various factors including drowsy driving
100 E. Yeh et al.
attributed to medication side effects particularly if the sleep aid had anticholinergic
action. Though many of these previously routine referrals are still reasonable, one
should create a differential diagnosis that might include sleep apnea which has been
associated with all these complaints.
Management of OSA and OSAHS has become increasingly common. In a review
of annual stratified samples of patients identified as having sleep apnea in hospital-
based and non-hospital-based physician office visits in the U.S. National Ambulatory
Medical Care Survey database between 1993 and 2010, reports of a diagnosis of
sleep apnea increased 14.6-fold [26]. Thirty-three percent were reported by primary
care providers, 17% by pulmonologists, and 10% by otolaryngologists, with an
increasing number of “other practitioners” listing a diagnosis of sleep apnea as new.
Regions that reported a higher per capita rate of sleep apnea correlated with the rates
of obesity and health insurance status.
In 2013, the American College of Physicians reported on their consensus as
to the most effective therapy of obstructive sleep apnea and concluded that
weight loss was the most supported therapy [33]; the fact that obesity is present
in ~50% of patients did not deter the committee from their conclusions. Medicare
by that time had endorsed requirements for continuous positive pressure therapy
some time before [20]. It is time that practice pathways for the management of
OSAHS will be designed with primary care tools and decision trees to know
when and how to manage, engage sleep specialists and other providers, and pro-
vide value to patients. There is precedent for these to be developed and used in
diabetes, but in this instance, there is a relatively simple blood marker to begin
the process of prevention and treatment. Often primary care physicians are skep-
tical of patient-based sleep apnea risk assessments because of its subjective
nature. Yet, offices deploy the PHQ-2 to collect a depression risk in those with a
complaint of fatigue or low mood, and there are management guidelines. The
prevalence of sleep disorders is higher than depression. However, even tools like
the Berlin Questionnaire or the STOP-BANG require a decision about what to do
next. If a test is ordered, like home sleep testing, what to do with the data are not
embedded in practice guidelines. One can only compare the detailed directions
for what to do when diabetes is suspected by the primary care physician and
suspected by an elevated Hemoglobin A1c, to the lack of consensus we have as
to when and how to assess at a primary care level a report of AHI and severity
levels. Utilization of screening tools such as STOP-BANG and Berlin
Questionnaire is useful but not diagnostic and skewed toward elimination of
those without moderate or severe OSA, rather that suggest who should be treated
or who might accept treatment or the preventive approach to managing sleep-
disordered breathing. Reliance on testing and response to autotitration therapy
could be useful as a primary action, but not without a recognition and manage-
ment strategy for those who do not respond.
Sleep Medicine Practices
It is worthwhile to pause briefly to describe sleep medicine, as one other feature

of clinical care. The specialty started as a collection of sleep laboratories in the
United States and Europe when sleep disorders were considered rare and curious,
OSAHS being defined in 1964 when the first tracheostomy was performed, and
narcolepsy as a distinct syndrome described using symptoms and the combined
use of a polysomnogram and Multiple Sleep Latency Test. Organizing a profes-
sional society in the 1980s, the leaders of the field pushed for standards, training,
and medical codes for management of a host of sleep disorders. One measure of
progress was a survey in 2000 undertaken to determine the spectrum of sleep-
related disorders diagnosed in regional sleep centers and compare this informa-
tion to a previous survey published in 1982, at the origin of the sleep center. In a
two-month prospective point-prevalence survey, across 19 accredited regional
sleep centers in the United States.
The major referrals in 2000 are similar to today with snoring, sleepiness, and
other sleep-related reports as the presenting complaints (Fig. 5.5a). In 2000 most
patients underwent polysomnography as similar to that done in 1982. In 2000,
obstructive sleep apnea, narcolepsy, and restless legs syndrome were the top three
reported primary diagnoses with a prevalence of ~69%, ~5%, and ~3%, respec-
tively (Fig. 5.5b). The entire range of 93 sleep disorders, however, was represented
in the 2000 survey. In this sample, true even today, when a sleep specialist inter-
views a patient, nearly a third of patient had either a primary or secondary diagno-
sis of a non-respiratory sleep disorder, and many had more than one sleep
diagnosis. Compared to the previous survey from 1982, there has been an absolute
increase in patient referrals/center with a two- to four-fold increase in the number
of patients/center with a final diagnosis of a non-respiratory sleep-related prob-
lem. However, there had been a 20-fold increase in the diagnosis of obstructive
sleep apnea.
Since 2000 there has been a further increase in sleep centers and diagnostic facil-
ities, the creating of an American Board of Internal Medicine Sleep Medicine spe-
cialty examination, and a 1-year ACGME fellowship program. Sleep specialists are
encountering increasing referrals from family internal medicine, pulmonary medi-
cine, and otolaryngology, and a broad range of sleep-related disorders. Now, the
now mandatory for sleep medicine board certification eligibility has had the unin-
tended consequence of restricting the influx of young physicians to the field [45].
The number of sleep specialists who are retiring now exceeds the number that are
trained through ACGME-accredited programs leading to a specialty certificate in
Sleep Medicine. New training pathways are being developed to provide flexibility
in high-quality, comprehensive, and multidisciplinary sleep medicine training to
meet the sleep health needs of the present and future [32].
102 E. Yeh et al.
a
Frequency: sleep symptoms on referral for testing
n ~3000
Apnea
Sleepiness
Fatigue
Insomnia
Other
Snoring only
Leg kicks and sensations

Abnormal sleep behavior
Sleep walking
Nightmares
Seizures
Sexual dysfunction
0 10 20 30 40 50 60 70
Percent of encounters
b
Primary diagnosis from the history and/or polysomnogram (%)
Obstructive sleep apnea 67.8
Narcolepsy 4.9
Restless legs syndrome 3.2
Psychophsyiological insomnia 2.7
Periodic limb movements 2.6
Upper airway resistance syndrome 2.3
Idiopathic hypersomnia 2.2 Sample size = 3970
Primary snoring 2.1 with one primary diagnosis
Associated with mood disorders 1.7
Idiopathic insomnia 1.5
Central sleep apnea 1.2
Delayed sleep phase syndrome 1.0
Insufficient sleep syndrome 0.8
Other 6.1
0 10 20 30 40 50 60 70 80
Percent of encounters
Fig. 5.5 (a) This is a graphical representation of the data in Punjabi et al. (2003) on the percent of
encounters for referral for a polysomnography from 19 sleep centers in the United States over a
3-month period. (b) This is a graphical representation of the data in Punjabi et al. (2003) on the
percent of encounters with a given diagnostic outcome from 19 sleep centers in the United States
over a 3-month period
OSA in Medical, Neurologic, and Psychiatric Disorders
Diagnoses of sleep apnea during outpatient visits to hospital-based and non-

hospital-based practices in the United States were much more frequent in 2010 than
in 1993, as reported by outpatient practice clinicians participating in national sur-
veys [26]. Although 60% of diagnoses of sleep apnea were reported by a combina-
tion of pulmonary and ENT specialty and primary care offices, there was a
substantial increase in reports of sleep apnea by clinicians practicing other special-
ties during this period. This trend appears to continue. Discussed below are condi-
tions selected for data availability of prevalence rates influencing outcome.
Pulmonary Clinics In a cross-sectional study from the US National Health and
Nutrition Examination Survey (NHANES) data (year 2005–2008), subjects
≥20 years were identified who had no COPD or OSA, or only OSA, or had only
COPD, or had OSA/COPD overlap syndrome [13]. The COPD and OSA/COPD
overlap syndrome groups had significantly higher chance of all-cause mortality than
the group of subjects who did not have OSA or COPD (adjusted hazard ratio [HR]
=1.5 for the COPD group and 2.4 for the overlap syndrome group). OSA/COPD
overlap syndrome was associated with a modest likelihood of death than COPD
alone (HR =1.5; P = 0.160). Other factors associated with higher overall mortality
were aging, poorer family status, current smoker, serum vitamin D deficiency, car-
diovascular disease, history of cancer, diabetes, and impaired renal function. COPD
and the combination of OSA and COPD leading to symptoms and signs of hypoven-
tilation were markers of higher all-cause mortality compared to the control group.
Interestingly simple OSA did not significantly increase mortality in patients with
COPD. Hence the challenge in pulmonary clinics is to identify and manage OSA/
COPD patients with a complex co-morbidity.
Endocrine Clinics Given the community correlations of OSA to obesity, it should

come as no surprise that OSA and OSAHS are present in nearly all type 2 diabetes
mellitus patients. In patients with metabolic syndrome, OSAS is an independent
risk factor for the onset of type 2 diabetes and a worsening glycemic control [7]. In
diabetics, the well-known clinical appearance of accumulation of adipose tissue in
the neck and limited chest wall dynamics, hypoxia, and local micro-inflammation
link visceral obesity closely with OSAS, with bidirectional effects. Promoting exer-
cise, improving sleep habits, and diet weight loss can treat both metabolic syndrome
and OSAS, especially in obese patients. There is also a high incidence of OSAS in
acromegaly, although growth hormone treatments seem to be unrelated to the onset
of apnea in GH-deficient individuals.
Neurology Clinics In patients with spinal cord injury, approaching 60% in motor
complete persons with tetraplegia. Central apnea is more common in patients with
tetraplegia than in patients with paraplegia [8]. In this population there is a lack of
correlation between symptoms and SDB, and unfortunately there is insufficient
104 E. Yeh et al.
e vidence in the literature on the impact of treatment on morbidity, mortality, and

quality of life outcomes.
Neuromuscular specialists encounter a common and predictable development of
chronic sleep-disordered breathing in the neuromuscular syndromes which because
of the patterning of respiratory muscle output during sleep and smaller lung vol-
umes make patients particularly vulnerable to upper airway collapse, hypoventila-
tion, and disturbed sleep that reduce the quality of life [1, 3]. Obstructive and central
sleep apneas are common and noninvasive ventilation can improve survival and
quality of sleep. Early detection with monitoring at home and polysomnography
help guide therapy for sleep-disordered events, before and during non-invasive
ventilation.
There is likely a bidirectional relationship between sleep apnea and stroke,
resulting in close association between the two conditions. In addition, sleep apnea
is a potentially modifiable risk factor in stroke and stroke rehabilitation. For instance,
in a moderately sized group of stroke patients sleep apnea was determined by a vali-
date algorithm and functional outcome was measured using Barthel score on day 7
and at third month following the onset of stroke. A high pre-test probability of sleep
apnea was present in 31% patients, more in males (68%) and with advanced age
[25]. Hypertension was present in 66.6% of patients with sleep apnea. Recovery
scores at third month were somewhat better among patient with no apnea, but this
was not statistically significant. Gain in functional independence in no apnea group
was better than those in whom sleep apnea was strongly suspected. Sleep apnea is
amenable to treatment and should be considered in patients with acute ischemic
stroke to improve the chance of recovery, and to reduce the risk of recurrence.
Psychiatry Clinics Sleep disturbances have been associated with increased risk
for suicidal thought and behavior. The literature regarding sleep and suicide, how-
ever, has focused predominantly on generalized sleep disturbance or insomnia. A
secondary analysis of 2014 data from the National Survey on Drug Use and Health.
Respondents from a random sample of US households 18 years or older is informa-
tive [5]. The prevalence of a diagnosis of sleep apnea was 3%. Prevalence of suicid-
ality was ~10% for suicidal ideation, 3% for suicide planning, and 1% for suicide
attempt compared with 5%, 2%, and 1%, respectively, for those without sleep apnea.
Analyses revealed that sleep apnea was significantly but modestly associated with
both suicidal ideation (OR = 1.50) and suicide planning (OR = 1.56) after control-
ling for age, sex, ethnicity, past-year substance use disorder, self-rated overall
health, past-year sedative-hypnotic misuse, past-year depressive episode, heart dis-
ease, high blood pressure, stroke, diabetes, and body mass index. Sleep apnea was
not significantly associated with report of past-year suicide attempt. A consideration
of sleep apnea may represent an early opportunity for providers to discuss suicide
and mental health with their patients.
Obstetric Clinics Sleep-disordered breathing (SDB) is recognized in pregnancy

and may be a modifiable factor for adverse outcomes including pre-eclampsia and
premature birth. Nulliparous women (n = 3700) completed validated questionnaires
to assess for symptoms related to snoring, fatigue, excessive daytime sleepiness,

insomnia, and restless leg syndrome, along with an at-home portable monitor [21].
The prevalence of risk for sleep-disordered breathing was 3.6% and 8.3%, for early
and mid-pregnancy, respectively. At each time point in gestation, frequent snoring,
chronic hypertension, greater maternal age, body mass index, neck circumference,
and systolic blood pressure were associated most strongly with an increased risk of
sleep-disordered breathing. Current age, body mass index, and frequent snoring
predicted sleep-disordered breathing in early pregnancy, sleep-disordered breathing
in mid pregnancy, and new-onset sleep-disordered breathing in mid pregnancy. In
the follow-up analyses [14], the prevalence of preeclampsia was 6.0%, hypertensive
disorders of pregnancy 13.1%, and GDM 4.1%. In early and mid-pregnancy the
adjusted odds ratios for preeclampsia when sleep-disordered breathing was present
were 1.94 (95% CI 1.07–3.51) and 1.95 (95% CI 1.18–3.23), respectively; hyper-
tensive disorders of pregnancy 1.46 (95% CI 0.91–2.32) and 1.73 (95% CI
1.19–2.52); and GDM 3.47 (95% CI 1.95–6.19) and 2.79 (95% CI 1.63–4.77).
Increasing exposure-response relationships were observed between apnea-hypopnea
index and both hypertensive disorders and GDM. There appears a somewhat inde-
pendent association between sleep-disordered breathing and preeclampsia, hyper-
tensive disorders of pregnancy, and gestational diabetes mellitus. In a study from
another group of 1345 women, the overall prevalence of high risk for OSA was
10.1% (95% confidence intervals [CIs] 8.5–11.7), associated with pre-pregnancy
body mass index and stress [18]. An adjusted odds ratio (OR) for preeclampsia-
eclampsia in women with high risk for OSA was 2.72 (95% CI 1.33–5.57).
Disability Assessments There are reported associations between sleep apnea and
receipt of mortality or a disability pension [34]. In a prospective study of the
Swedish Patient Register from 2000 to 2009 (74,543 sleep apnea cases: 60,125
outpatient, 14,418 inpatient), cases were matched to 5:1 non-cases and tracked from
diagnosis/inclusion into the study. During ~5.1 years, 13% of men and 21% of
women with inpatient sleep apnea received a disability pension. Inpatient sleep
apnea was associated with higher total mortality (hazard ratio (HR) = for men 1.71,
and for women, 2.33) with associations to ischemic heart disease (for men,
HR = 2.27 and for women HR = 5.27), respiratory disorders (for men, HR = 3.29,
and for women, HR = 5.24), and suicide (for men, HR 2.60 and for women,
HR = 4.33). Notice that the HR was always higher in women. There were no asso-
ciations to ascertainment for inpatient sleep apnea with cancer mortality. Outpatient
sleep apnea was associated with a higher risk of receiving a disability pension but
not higher total mortality. In conclusion, inpatient sleep apnea was higher risk of
mortality and disability pension receipt, a decade after diagnosis.
Obesity Hypoventilation Syndrome (OHS) This condition is considered in more

detail in other chapters of this book. While it is a diagnosis often made while the
patient is awake, it is important in our Chapter as it is part of the spectrum of sleep-
disordered breathing. It is defined as a combination of obesity (body mass index
≥30 kg·m(−2)), daytime hypercapnia (arterial carbon dioxide tension ≥45 mmHg),
106 E. Yeh et al.
and sleep-disordered breathing, after ruling out other disorders that may cause alve-
olar hypoventilation. OHS prevalence has been estimated to be ∼0.4% of the adult
population [24], but becomes an important condition in acute hospitalizations. OHS
is typically diagnosed during an episode of acute-on-chronic hypercapnic respira-
tory failure or when symptoms of dyspnea lead to pulmonary or sleep consultation
in stable conditions. The most frequent comorbidities are heart failure, coronary
disease, uncontrolled diabetes, and pulmonary hypertension. A recognition strategy
and appropriate management with medications and rehabilitation programs are key
issues for improving prognosis.
Medical Training A prospective cross-sectional study was performed among

young doctors less than 40 years old, using questionnaires and home sleep apnea
testing [48]. Mean age and mean body mass index (BMI) were 31 years and 23,
respectively. The prevalence of OSA and OSAHS were 40.4 and 5.8%, respectively,
with one-third having at least moderate OSA. History of snoring, being male, and
perception of inadequate sleep were significant predictors for OSA with the odds
ratio of 34.5, 18.8, and 7.4, respectively. Only observed apnea was a significant
predictor for OSAS with odds ratio of 30.7 (p = 0.012, 95% CI = 2.12–442.6).
Number of naps per week was a significant predictor for excessive daytime sleepi-
ness. OSA and total number of call days per month were significant predictors for
tiredness with the odds ratio of 4.8 and 1.3, respectively. OSA was the only signifi-
cant predictor for perception of inadequate sleep. This is the only study that reports
prevalence of OSA and OSAS among young doctors and emphasizes the need for
detection at an earlier age. It is not that the subjects were doctors but the group in
early adulthood with demanding jobs and long hours of work, likely present in
many work settings.
Sleep Detection and Gaps in Knowledge
There are efforts to develop and validate a tool that does not rely on subjective
reports so that estimates of the burden of sleep apnea may be made using electronic
databases, relevant to both outpatient and inpatient settings. The symptomless
Multi-Variable Apnea Prediction index (sMVAP) has three variables (age, sex, and
weight) and was developed to identify OSA as a presumptive diagnosis and deployed
to assess the relationship between sMVAP and adverse outcomes in patients having
elective surgery for non-bariatric and bariatric procedures [22]. Using data from
40,432 elective inpatient surgeries, we used logistic regression to determine the
relationship between sMVAP and previous OSA, current hypertension, and postop-
erative complications: extended length of stay (ELOS), intensive-care-unit-stay
(ICU-stay), and respiratory complications (pulmonary embolism, acute respiratory
distress syndrome, and/or aspiration pneumonia). Higher sMVAP was associated
with increased likelihood of previous OSA, hypertension and all postoperative com-
plications, and the top quintile had increased odds of postoperative complications
compared to the bottom quintile. For ELOS, ICU-stay, and respiratory complica-
tions, respective significant odds ratios were 1.83, 1.44, and 1.85, respectively. With
propensity matching in patients having bariatric surgery, sMVAP was more strongly
associated with postoperative complications in non-Bariatric surgical groups. The
idea is that OSA risk measured by a symptomless calculation correlates with higher
risk for select postoperative complications. Interestingly, associations are stronger
for non-Bariatric surgeries. The implications are that preoperative screening with
variables collected from charted measures is sufficient to risk stratify for adverse
postoperative outcomes. The sMVAP as a risk stratifier in the assessment of com-
mercial motor vehicle operators was tested with and without the addition of symp-
toms and its accuracy was better with the additional information [23]. It should be
noted that the use of this tool does not preclude more precise individual assessments
[19] (Fig. 5.6).
The literature on the epidemiology has progressed from community surveys to
an understanding of OSA as a common condition. We are however still in lacking
information at early asymptomatic phases and from young adulthood, limiting the
ability to detect what human features alone or collectively can produce a propaga-
tion of events during sleep, prospectively. This gap occurs in those with clinical
collections, like obesity or neuromuscular disorders, where there is a high likeli-
hood of progression of objective markers and symptomatic outcomes. Established,
Systems integration
Self recognition
Testing
Risk grouping
Clinic recognition
Treatment
Profiling
Behavioral RX. Outcome
Fig. 5.6 Systems integration for the arc of recognition to outcome. Risk grouping along with
individualized (personal) medicine would determine the manner of testing and therapy, but ulti-
mately the outcome remains to be defined better
108 E. Yeh et al.
symptomatic patients must be present in many clinical systems, as OSA recognition

can be triggered by events like stroke, myocardial infarction, or detection of
hypoventilation. Some inroads are there in recognition profiling for perioperative
patients, and in the current literature on profiling using the EMR. The high preva-
lence of OSA and OSAHS, limited information on management outcomes, and
transparent costs of treating established disease justify research into more available
and less costly, but comparably reliable, alternative treatments. To this end, all lev-
els of medical care must be involved: (1) primary care or specialists not directly
involved with sleep, (2) second-level hospitals, which should have the ability to
perform simplified studies, and (3) tertiary hospitals with complex equipment and
multidisciplinary environment have to be prepared to receive patients with complex
sleep disorders of breathing as well as to solve the sleep-related diseases. Thus,
there appears value in recognition and management of OSAHS and a rationale for
prevention and early detection of OSA.
References
1. Aboussouan LS, Mireles-Cabodevila E. Sleep-disordered breathing in neuromuscular disease:

diagnostic and therapeutic challenges. Chest. 2017;152:880–92.
2. Alattar M, Harring JJ, Mitchell M, Sloane P. Sleep problems in primary care: a North Carolina
family practice research network (NC-FP-RN) study. J Am Board Fam Med. 2007;20:365–74.
3. Albdewi MA, Liistro G, El Tahry R. Sleep-disordered breathing in patients with neuromuscu-
lar disease. Sleep Breathing = Schlaf Atmung. 2018;22:277–86.
4. Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ, Nunez CM, Patel SR,
Penzel T, Pépin JL, Peppard PE, Sinha S, Tufik S, Valentine K, Malhotra A. Estimation of the
global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet
Respir Med. 2019;7:687–98.
5. Bishop TM, Ashrafioun L, Pigeon WR. The association between sleep apnea and sui-
cidal thought and behavior: an analysis of National Survey Data. J Clin Psychiatry.
2018;79:17m11480.
6. Cai A, Zhou Y, Zhang J, Zhong Q, Wang R, Wang L. Epidemiological characteristics and
gender-specific differences of obstructive sleep apnea in a Chinese hypertensive population: a
cross-sectional study. BMC Cardiovasc Disord. 2017;17:8.
7. Ceccato F, Bernkopf E, Scaroni C. Sleep apnea syndrome in endocrine clinics. J Endocrinol
Investig. 2015;38:827–34.
8. Chiodo AE, Sitrin RG, Bauman KA. Sleep disordered breathing in spinal cord injury: a sys-
tematic review. J Spinal Cord Med. 2016;39:374–82.
9. Chuang LP, Hsu SC, Lin SW, Ko WS, Chen NH, Tsai YH. Prevalence of snoring and witnessed
apnea in Taiwanese adults. Chang Gung Med J. 2008;31:175–81.
10. Chung F, Abdullah HR, Liao P. STOP-Bang questionnaire: a practical approach to screen for
obstructive sleep apnea. Chest. 2016;149:631–8.
11. Cristescu Teodor R, Mihaltan FD. Eyelid laxity and sleep apnea syndrome: a review. Romanian
J Ophthalmol. 2019;63:2–9.
12. Crummy F, Piper AJ, Naughton MT. Obesity and the lung: 2. Obesity and sleep-disordered
breathing. Thorax. 2008;63:738–46.
13. Du W, Liu J, Zhou J, Ye D, OuYang Y, Deng Q. Obstructive sleep apnea, COPD, the over-
lap syndrome, and mortality: results from the 2005-2008 National Health and Nutrition
Examination Survey. Int J Chron Obstruct Pulmon Dis. 2018;13:665–74.
14. Facco FL, Parker CB, Reddy UM, Silver RM, Koch MA, Louis JM, Basner RC, Chung JH,
Nhan-Chang CL, Pien GW, Redline S, Grobman WA, Wing DA, Simhan HN, Haas DM,
Mercer BM, Parry S, Mobley D, Hunter S, Saade GR, Schubert FP, Zee PC. Association
between sleep-disordered breathing and hypertensive disorders of pregnancy and gestational
diabetes mellitus. Obstet Gynecol. 2017;129:31–41.
15. Fietze I, Laharnar N, Obst A, Ewert R, Felix SB, Garcia C, Gläser S, Glos M, Schmidt
CO, Stubbe B, Völzke H, Zimmermann S, Penzel T. Prevalence and association analysis of
obstructive sleep apnea with gender and age differences – results of SHIP-trend. J Sleep Res.
2019;28:e12770.
16. Heinzer R, Vat S, Marques-Vidal P, Marti-Soler H, Andries D, Tobback N, Mooser V, Preisig
M, Malhotra A, Waeber G, Vollenweider P, Tafti M, Haba-Rubio J. Prevalence of sleep-
disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med.
2015;3:310–8.
17. Huang T, Lin BM, Redline S, Curhan GC, Hu FB, Tworoger SS. Type of menopause, age at
menopause, and risk of developing obstructive sleep apnea in postmenopausal women. Am J
Epidemiol. 2018;187:1370–9.
18. Jaimchariyatam N, Na-Rungsri K, Tungsanga S, Lertmaharit S, Lohsoonthorn V, Totienchai
S. Obstructive sleep apnea as a risk factor for preeclampsia-eclampsia. Sleep Breathing =
Schlaf Atmung. 2019;23:687–93.
19. Jonas DE, Amick HR, Feltner C, Weber RP, Arvanitis M, Stine A, Lux L, Middleton JC, Voisin
C, Harris RP. U.S. preventive services task force evidence syntheses, formerly systematic evi-
dence reviews. In: Screening for obstructive sleep apnea in adults: an evidence review for the
US preventive services task force. Rockville: Agency for Healthcare Research and Quality
(US); 2017.
20. Loube DI, Gay PC, Strohl KP, Pack AI, White DP, Collop NA. Indications for positive airway
pressure treatment of adult obstructive sleep apnea patients: a consensus statement. Chest.
1999;115:863–6.
21. Louis JM, Koch MA, Reddy UM, Silver RM, Parker CB, Facco FL, Redline S, Nhan-Chang
CL, Chung JH, Pien GW, Basner RC, Grobman WA, Wing DA, Simhan HN, Haas DM, Mercer
BM, Parry S, Mobley D, Carper B, Saade GR, Schubert FP, Zee PC. Predictors of sleep-
disordered breathing in pregnancy. Am J Obstet Gynecol. 2018;218:521.e521–12.
22. Lyons MM, Keenan BT, Li J, Khan T, Elkassabany N, Walsh CM, Williams NN, Pack AI,
Gurubhagavatula I. Symptomless multi-variable apnea prediction index assesses obstructive
sleep apnea risk and adverse outcomes in elective surgery. Sleep. 2017;40:zsw081.
23. Lyons MM, Kraemer JF, Dhingra R, Keenan BT, Wessel N, Glos M, Penzel T, Gurubhagavatula
I. Screening for obstructive sleep apnea in commercial drivers using EKG-derived respiratory
power index. J Clin Sleep Med. 2019;15:23–32.
24. Masa JF, Pépin JL, Borel JC, Mokhlesi B, Murphy PB, Sánchez-Quiroga M. Obesity hypoven-
tilation syndrome. Eur Respir Rev. 2019;28:180097.
25. Nair R, Radhakrishnan K, Chatterjee A, Gorthi SP, Prabhu VA. Sleep apnea-predictor of func-
tional outcome in acute ischemic stroke. J Stroke Cerebrovasc Dis. 2019;28:807–14.
26. Namen AM, Chatterjee A, Huang KE, Feldman SR, Haponik EF. Recognition of sleep apnea
is increasing. Analysis of trends in two large, representative databases of outpatient practice.
Ann Am Thorac Soc. 2016;13:2027–34.
27. Netzer NC, Hoegel JJ, Loube D, Netzer CM, Hay B, Alvarez-Sala R, Strohl KP. Prevalence of
symptoms and risk of sleep apnea in primary care. Chest. 2003;124:1406–14.
28. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin questionnaire to
identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999;131:485–91.
29. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman
AB, Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep
apnea, and hypertension in a large community-based study. Sleep Heart Health Study.
JAMA. 2000;283:1829–36.
110 E. Yeh et al.
30. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-
disordered breathing in adults. Am J Epidemiol. 2013;177:1006–14.
31. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-
disordered breathing and hypertension. N Engl J Med. 2000;342:1378–84.
32. Plante DT, Epstein LJ, Fields BG, Shelgikar AV, Rosen IM. Competency-based sleep medicine
fellowships: addressing workforce needs and enhancing educational quality. J Clin Sleep Med.
2020;16:137–41.
33. Qaseem A, Holty JE, Owens DK, Dallas P, Starkey M, Shekelle P. Management of obstructive
sleep apnea in adults: a clinical practice guideline from the American College of Physicians.
Ann Intern Med. 2013;159:471–83.
34. Rod NH, Kjeldgård L, Åkerstedt T, Ferrie JE, Salo P, Vahtera J, Alexanderson K. Sleep apnea,
disability pensions, and cause-specific mortality: a Swedish Nationwide Register Linkage
Study. Am J Epidemiol. 2017;186:709–18.
35. Santos M, Hofmann RJ. Ocular manifestations of obstructive sleep apnea. J Clin Sleep Med.
2017;13:1345–8.
36. Schwab RJ, Badr SM, Epstein LJ, Gay PC, Gozal D, Kohler M, Levy P, Malhotra A, Phillips
BA, Rosen IM, Strohl KP, Strollo PJ, Weaver EM, Weaver TE. An official American Thoracic
Society statement: continuous positive airway pressure adherence tracking systems. The
optimal monitoring strategies and outcome measures in adults. Am J Respir Crit Care Med.
2013;188:613–20.
37. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O'Connor GT, Boland LL,
Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional
results of the Sleep Heart Health Study. Am Rev Respir Crit Care Med. 2001;163:19–25.
38. Stoohs RA, Barger K, Dement WC. Sleep disordered breathing in primary care medicine.
Sleep Breathing = Schlaf Atmung. 1997;2:11–22.
39. Strohl KP. Diabetes and sleep apnea. Sleep. 1996;19(10 Suppl):S225–8.
40. Strohl KP, Butler JP, Malhotra A. Mechanical properties of the upper airway. Compr Physiol.
2012;2(3):1853–72.
41. Strohl KP, Cherniack NS, Gothe B. Physiologic basis of therapy for sleep apnea. Am Rev
Respir Dis. 1986;134:791–802.
42. Sunwoo JS, Hwangbo Y, Kim WJ, Chu MK, Yun CH, Yang KI. Prevalence, sleep characteris-
tics, and comorbidities in a population at high risk for obstructive sleep apnea: a nationwide
questionnaire study in South Korea. PLoS One. 2018;13:e0193549.
43. Teodorescu M, Barnet JH, Hagen EW, Palta M, Young TB, Peppard PE. Association between
asthma and risk of developing obstructive sleep apnea. JAMA. 2015;313:156–64.
44. Tishler PV, Larkin EK, Schluchter MD, Redline S. Incidence of sleep-disordered breathing in
an urban adult population: the relative importance of risk factors in the development of sleep
didordered breathing. JAMA. 2003;289:2230–7.
45. Watson NF, Rosen IM, Chervin RD. The past is prologue: the future of sleep medicine. J Clin
Sleep Med. 2017;13:127–35.
46. Wellman A, Edwards BA, Sands SA, Owens RL, Nemati S, Butler J, Passaglia CL, Jackson
AC, Malhotra A, White DP. A simplified method for determining phenotypic traits in patients
with obstructive sleep apnea. J Appl Physiol. 1985;114:911–22, 2013.
47. Whyte KF, Allen MB, Fitzpatrick MF, Douglas NJ. Accuracy and significance of scoring
hypopneas. Sleep. 1992;15:257–60.
48. Yasin R, Muntham D, Chirakalwasan N. Uncovering the sleep disorders among young doctors.
Sleep Breathing = Schlaf Atmung. 2016;20:1137–44.
49. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Bader S. The occurrence of sleep disor-
dered breathing in middle-aged adults. New Engl J Med. 1993;328:1230–5.
50. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered
breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.
Chapter 6
Obstructive Sleep Apnea: Diagnosis
with Polysomnography and Portable
Monitors
Janna Raphelson, Erica Feldman, and Atul Malhotra
Keywords Sleep · Apnea · Diagnosis · Lung · Monitoring · Breathing
Introduction
OSA is the leading cause of referral to sleep laboratories worldwide, accounting for
at least 75–80% of diagnoses [1]. In the last few decades, there have been consider-
able advances in knowledge regarding the underlying mechanisms, diagnostic
approaches, treatment options, and the impact of OSA on personal as well as public
health of OSA. The global prevalence of OSA was recently estimated at up to 1 bil-
lion people worldwide. Even using a stricter definition (based on Apnea–Hypopnea
Index AHI > 15/h) there are still up to 500 million estimated cases worldwide [2]. The
current definitions of sleep apnea are not uniform, but most of them attempt to char-
acterize the frequency of sleep-disordered breathing events (e.g., AHI “Apnea–
Hypopnea Index” or RDI “Respiratory Disturbance Index”) along with the severity
(e.g., oxygen desaturation) of each event (e.g., complete (apnea) and partial (hypop-
nea) cessation of breathing during sleep). By convention, an apnea is defined as
greater than 90% reduction of airflow for at least 10 s [3, 4]. A hypopnea is defined as
a reduction in airflow that is followed by an arousal from sleep or a decrease in oxy-
hemoglobin saturation. While AHI is the most commonly used parameter to assess
sleep apnea severity, several additional measures of sleep such as the degree of noc-
turnal oxyhemoglobin desaturation and the extent of carbon dioxide elevation have
been used to characterize disease severity in clinical and research settings (Table 6.1).
J. Raphelson · E. Feldman
University of California, San Diego, Department of Medicine, Internal Medicine, La Jolla,
CA, USA
e-mail: jraphelson@health.ucsd.edu
A. Malhotra (*)
Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine and
Physiology, University of California, San Diego Health, La Jolla, CA, USA
e-mail: amalhotra@ucsd.edu

112 J. Raphelson et al.
Table 6.1 Common OSA terminology

Apnea–- Hypopnea The number of apneas and hypopneas a patient has per hour of sleep
Index (AHI)
Respiratory A formula used in reporting polysomnography data: the number of
Disturbance Index apneas, hypopnea, and RERAs a patient has per hour of sleep
(RDI)
Apnea Complete cessation of breathing during sleep, defined by greater than
90% reduction in airflow for at least 10 s, has no requirement for a
desaturation or arousal
Hypopnea Reduction in airflow that is followed by an arousal from sleep or a
decrease in oxyhemoglobin saturation
Respiratory A series of respiratory cycles of increase/decreasing effort or flattening
effort-related arousal for at least 10 s, recorded by nasal manometry and leading to an arousal
(RERA) that cannot be defined as an apnea or hypogea
Sleep-disordered Umbrella term for a constellation of sleep-related breathing disorders
breathing and abnormalities of respiration during sleep that does not meet criteria
for a disorder
The mechanisms of sleep-disordered breathing are complex, but can involve

either obstruction of the upper airways (OSA) in the presence of intact respiratory
drive; the absence of ventilatory drive (CSA or central sleep apnea) in the presence
of a patent airway; or mixed apnea, which has features of both OSA and CSA [5–7].
Pure CSA is much less common than OSA in the general population; CSA occurs
most often in individuals with congestive heart failure (CHF) or occasionally with
neurological compromise or chronic narcotic intake [8–10].
Patients with OSA can frequently experience sleep fragmentation, daytime som-
nolence, or suboptimal psychomotor function. Untreated OSA can also lead to com-
mon comorbidities such as hypertension, diabetes, stroke, and depression.
Individuals with moderate and severe OSA have increased risks for hypertension,
cerebrovascular accident (CVA), cardiovascular diseases, diabetes mellitus, depres-
sion, road traffic crashes, poor performance in school and work, and decreased pro-
ductivity in the workplace [11–23].
Prevalence and Epidemiology
The estimated prevalence of symptomatic OSA in the United States in early 1990s
by Young et al. was 4% among adult men and 2% among adult women [24]. Since
then, prevalence data from other countries have emerged. The prevalence of OSA
associated with daytime sleepiness is conservatively 3–7% in adult men and 2–5%
in adult women. Subgroups of those populations have higher prevalence, including
persons with older age, male gender, and obesity [25]. Though diagnostic method-
ologies vary, most available epidemiological data on prevalence of OSA confirm
Young’s finding across the globe. Interestingly, the prevalence of OSA in
6 Obstructive Sleep Apnea: Diagnosis with Polysomnography and Portable Monitors 113
developing countries such as India and China is on the same order of magnitude as
that in the developed countries, despite less obesity [2]. Therefore, OSA is not only
a disease of more developed countries, but a common disease worldwide.
Additionally, there are huge and growing individual and public health costs associ-
ated with OSA, whether from lost productivity at workplaces, motor vehicle acci-
dents from drowsy driving, or the cardiovascular and metabolic comorbidities of
OSA [26]. Because the obesity epidemic is spreading worldwide, we can only imag-
ine an increasingly higher prevalence of OSA in the twenty-first century [27].
Risk Factors
Despite substantial research on OSA in the past several decades, OSA remains
underdiagnosed. This finding is due in part by the lack of awareness of the disease
by patients as well as the general public, and insufficient clinical suspicion on the
part of providers. Therefore, it is important for clinicians to gain proper knowledge
of OSA risk factors, so that timely diagnoses can be made and treatment can be
initiated as appropriate.
OSA risk factors include obesity, older age, male gender, postmenopausal status,
Asian/African American races, tobacco, and alcohol use [28]. Studies have shown
that up to 70% of men and 56% of women between age 65 and 99 years have some
form of OSA [29]. The mechanisms for age-related OSA include deposition of adi-
pose tissue in the parapharyngeal area and anatomical changes surrounding the
pharynx [30–32]. Disease prevalence for OSA is relatively low among premeno-
pausal women and increases postmenopausally [33]. Obesity is the single most
treatable factor predictive of OSA [34–36]. Data collected in Sleep Heart Health
Study (SHHS) have shown that moderate and severe OSA is independently associ-
ated with BMI, neck circumference, as well as waist circumference. Individuals
with OSA have significantly more visceral distribution of fat than central fat after
controlling for BMI. Visceral fat is significantly correlated with AHI. Waist–hip
ratio has also been shown in some studies to be more predictive of severe OSA than
obesity in general. Only 10–15% of the population with diagnosis of OSA have
body mass index (BMI) less than 25 kg/m2. Individuals with large neck circumfer-
ences (men >17 in., women >16 in.) should raise the clinician’s suspicion for OSA.
There are multiple theories as to why OSA prevalence in women is lower than
that in men. One of them is that male bed partners of women are less likely to report
bedtime symptoms of OSA than the female bed partners of men. Women with OSA
also tend to have less “classic” daytime symptoms of OSA; instead of reporting
daytime sleepiness they may report fatigue and lack of energy. Lastly, women have
different anatomical and functional properties of their upper airways and differ-
ences in control of breathing. Thus, both diagnostic biases and biological factors
contribute to the gender imbalance in sleep apnea prevalence [37–42].
Among different races, obesity plays a varying degree of importance. Middle-

aged (age 25–65 years) African Americans have similar disease prevalence than the
other racial groups, but adult African Americans younger than 25 years or older than
65 years have a higher prevalence than the others. Among the East Asian popula-
tion, though the prevalence of obesity is less than the whites, the prevalence of OSA
is not less than that in the West. Therefore, the relationship between obesity and
OSA is less clear-cut among Asians. However, differences in adipose tissue distri-
bution (i.e., peripheral vs. visceral) may play a more important role in Asians [43].
Table 6.2 risk factors for OSA.
Clinical History
A sleep history looking for OSA should be obtained either as a routine health main-
tenance evaluation, or as part of an assessment for potential OSA in symptomatic
people. In addition, a comprehensive evaluation should be considered in those at
high risk for OSA, and as a part of a screen for sleep disorders in commercial driv-
ers, other transportation operators and persons involved in safety-sensitive work. A
good sleep history should address both sleep and wakefulness. Because individuals
with OSA often disrupt their bed partners’ sleep, bed partners should be encouraged
to participate in this part of the evaluation process. Loud snoring, awakenings due
to choking and/or gasping, and witnessed apneic episodes during sleep are common
symptoms reported by OSA patients or their bed partners. OSA can make falling
asleep and maintaining sleep difficult. Excessive daytime sleepiness (EDS) is a
common complaint, although many patients do not report sleepiness per se [44]. For
an individual with OSA, EDS most likely will persist even after adequate amount of
total sleep time (TST) is achieved. The Epworth Sleepiness Scale (ESS), a self-
reported score, combines a series of answers for likelihood of dozing off in eight
different scenarios. An ESS of greater than 12 (out of 24) is usually considered
“sleepy.” Though subjective, ESS is frequently used to quantify EDS and is useful
as a reference scale for assessing future treatment effectiveness [27, 45, 46].
Questions on general sleep history such as TST, sleep fragmentation, sleep
Table 6.2 Common risk factors of obstructive sleep apnea (OSA)

Anthropometric BMI >28 kg/m2, neck circumference >17 in. (43 cm) for men, or
measures >16 in.(41 cm) for women
Physical exam Retrognathia, high modified Mallampati score (III/IV), large tonsils
(>2), macroglossia
Age Age 35 or greater
Ethnicity Asian, African American, Hispanic ethnicities
Gender Male gender
Hormone Postmenopausal status in women
Habits Alcohol, tobacco, physical inactivity
maintenance, as well as questions related to insomnia (difficulty falling asleep or

going back to sleep) should also be asked to generate a differential diagnosis. Lack
of concentration and/or cognitive abilities, decreased libido, risk of motor vehicle
accidents, mood disorders, morning headaches, and dry mouth are other common
complaints in OSA patients. History of common comorbidities such as hyperten-
sion, stroke, myocardial infarction, cor pulmonale, and arrhythmia should also be
obtained. In pediatric populations, the complaint of excessive sleepiness is often
replaced by hyperactivity, attention deficit, and mouth breathing. OSA is more fre-
quently present among children of OSA subjects, suggesting the role of genetic
factors in OSA [47, 48]. Table 6.3 lists questions that a healthcare provider should
ask of an individual suspected of having OSA. Other questionnaires have been
assessed in this context with variable predictive value, including the STOP-BANG
and NO-OSAS [27]. These questionnaires may be preferable to ESS in certain pop-
ulations, including bariatric surgery patients.
Taking a medical history from certain populations among whom symptoms and
signs of OSA may affect their employment status may be challenging. For example,
unlike the sleep clinic setting where patients are seeking diagnosis and treatment for
sleep difficulties, it is common for commercial vehicle drivers, pilots, and train
operators to avoid an OSA diagnosis because of its economic and occupational
implications. Thus, relying on self-reported symptoms by commercial drivers for
screening for OSA has a very low yield in these occupational settings. These groups
often do not report any symptoms. Furthermore, drivers with previously diagnosed
OSA initially have been reported to deny the presence of a sleep disorder until they
are told that based on screening criteria they are required to obtain a sleep study. A
2006 study in Israel showed 78% of its commercial drivers with BMI greater or
equal to 32 kg/m2 had polysomnography (PSG)-confirmed OSA and almost half had
objectively confirmed EDS as measured by a multiple sleep latency test (MSLT),
but 100% of the affected drivers denied symptoms of OSA or EDS [49]. Likewise,
most OSA-affected commercial motor vehicle (CMV) operators report very low
ESS score at driver certifications exams (range 3–4 or 2–5 out of 24), which are
markedly lower than average ESS scores among college and medical students
(range 7–8). Therefore, at the present time, examiners must rely primarily upon
anthropometric and other objective criteria when evaluating transportation operators.
A summary statement from the Joint Task Force (JTF) of American College of
Occupational and Environmental Medicine/American College of Chest Physicians/
National Sleep Foundation of screening criteria for OSA among CMV operators
Table 6.3 Five questions to screen patients for obstructive sleep apnea (OSA)
1. “Do you have trouble falling asleep or maintaining asleep at night?”
2. “Have you ever been told that you snore during sleep?”
3. “Have you ever woken up choking or gasping for air when you are asleep?”
4. “Has anyone ever witnessed you stop breathing during sleep?”
5. “Do you have trouble staying awake during the day?” (Epworth sleepiness scale
questionnaire)
was published in the journal Chest in 2006 [50]. The statement recommends a
3-month maximum certification, pending OSA evaluation, for the CMV operator if
the operator falls into any one of the five major categories. Of note, the only objec-
tively measurable major category in the JTF statement is the subject’s anthropomet-
ric characteristics and blood pressure measured during the office visit. Therefore, in
the setting of occupational certification, the suspicion for OSA should be elevated
with or without a clear subjective reporting of symptoms of OSA (i.e., EDS). Timely
referral for an OSA evaluation is warranted, if the examinee seeking certification
has two of the following three objectives measurements in clinic:
1. BMI >35 kg/m2

2. Neck circumference >17 in. in men or 16> in. in women
3. Hypertension
Patients with first-degree relatives with OSA are more likely to have OSA than
those without first-degree relatives with OSA. Additionally, multiple medical condi-
tions have been associated with OSA. In the field of endocrine disorders, type 2 dia-
betes, polycystic ovary syndrome (PCOS), and hypothyroidism are known to be
associated with OSA. Congenital diseases such as Down’s syndrome or microcephaly
are associated with OSA. Pregnant women can present with OSA as gestational
weight gain progresses. Occasionally, rare anatomical abnormalities of the airway
such as Eagle Syndrome can cause OSA. Table 6.4 illustrates complications from OSA.
Physical Exam
Vital signs can frequently reveal hypertension in people with OSA. Neck circumfer-
ence should be documented as it is an important anthropometric measurement.
Obesity (BMI of ≥30 kg/m2) is probably the most common finding among OSA
patients. The rest of the physical exam should include head and neck, airway or
respiratory, cardiac, neurologic exams. The head and neck exam of an OSA patient
can present with crowded posterior pharyngeal space (i.e., modified Mallampati III
or IV), large tongue with teeth mark (macroglossia), tonsillar hypertrophy, dental
Table 6.4 Complications of obstructive sleep apnea (OSA)

Cardiovascular Hypertension, coronary artery disease, atrial fibrillation, cardiac arrhythmia,
heart failure
Neurological Stroke, depression, psychosis, sexual dysfunction, inattention, cognitive
deficits
Pulmonary Group 3 pulmonary hypertension
Endocrine Metabolic syndrome, type 2 diabetes
Gastrointestinal Nonalcoholic fatty liver disease
Rheumatologic Gout
Trauma Motor vehicle accidents
malocclusion (class II), retracted mandible relative to the maxilla (retrognathism or

micrognathism), or deviated nasal septum. In children with OSA, hypertrophied
adenoids or tonsils are common, and children often compensate by becoming oblig-
atory mouth breathers. Nasopharyngeal fiberscope can be used in office to evaluate
for the shape and size of the retropalatal/retroglossal airway, though there is no cur-
rently available evidence-based guidelines using this as a diagnostic tool. Internal
jugular venous distension and peripheral edema should be assessed as part of the
heart exam. Cardiac auscultation and pulse palpation can be helpful, particularly
given the known association between atrial fibrillation and sleep apnea. Neurological
examination should focus on muscle strength and presence of any focal deficits,
since neuromuscular disease can present with sleep apnea and/or hypoventilation.
Diagnosis of OSA
There are currently two major methods to diagnose OSA: full in-lab PSG and por-
table monitoring (PM) or limited-channel testing (LCT) device. There is much
ongoing debate as to the utility of each diagnostic tool. In general, PSG offers more
thorough measurements of various aspects of sleep, but it is time-consuming,
expensive, and performed outside the home. PM offers convenience to patients, but
PM is limited by its reduced sensitivity, specificity, and measured information.
Patient history and physical exam are key determinants for diagnostic route. Due to
financial considerations, PM is becoming increasingly common in the USA and has
been used with reasonable success worldwide. There are four types of PMs Type
I–IV, in the order of decreasing measurements of sleep and respiratory variables
(see Table 6.5).
Table 6.5 Summary characteristics of polysomnogram (type I) and portable monitor (type
II–IV)
Type I Type II Type III Type IV
PSG PSG PSG PSG
Monitoring personnel Yes No No No
Oximetry Yes Yes Yes Yes
Respiratory effort Yes Yes Yes No
Airflow Yes Yes Yes No
Body positions Yes Yes/No Yes/No No
EMG-AT Yes Yes No No
EEG Yes Yes No No
ECG-heart rate Yes Yes Yes No
EOG Yes Yes No No
Surface EMG Yes Yes No No
Video recording Yes/No No No No
Sound recording Yes/No No No No
Minimum number of channels for CMS* 14–16 ≥7 ≥4 ≥3
reimbursement
Overnight Polysomnography (PSG)
The current gold standard test for assessing the severity of OSA is in-laboratory,
technician-monitored PSG. A full PSG (or type I monitor) has been performed since
the 1960s. The initial uses of PSG were to assess sleep physiology in normal indi-
viduals and those with various neurologic or sleep disorders such as seizures,
insomnia, narcolepsy, periodic limb movement, and the parasomnias, as well as to
examine the effect of hypnotics and other drugs on sleep. The pulmonary compo-
nents of the PSG were added later as OSA was becoming increasingly appreciated
in the 1970s.
PSG, which is usually performed as an overnight study, typically assesses physi-
ological parameters by recording sleep–wake stage, heart rhythm, skeletal muscle
activities, respiratory patterns, sound of snoring, and oxygen saturation. Each of the
above respective components is monitored by electroencephalogram (EEG), electro-
oculogram (EOG) or eye movement, heart rate and rhythm (ECG), electromyogram
(EMG) of skeletal muscle activity (usually at the chin and tibialis anterior), respira-
tory effort, snoring (microphone), respiratory airflow, thermistor, and pulse oxime-
try. Nasal pressure technology is also commonly used to detect subtle respiratory
events since it has been shown to be more sensitive than standard thermistor.
However, the specificity of nasal pressure has been less well studied, i.e., the conse-
quences of these subtle events (which are not observed in the thermistor) are unclear.
Occasionally, sleep studies are done at different times of the day, depending on the
suspected symptoms of the subjects (circadian rhythm disorder, etc.).
The definition of OSA currently involves the measured AHI, the average number
of apnea and hypopnea episodes over an hour. RDI has also been used as an alterna-
tive scale for those measures. We can think of AHI as a subset of RDI, as the defini-
tion of RDI is less strict than AHI. During a full overnight PSG, an apnea is defined
by AASM as cessation (more than 90% reduction) of air movement lasting 10 or
more seconds. As stated previously, the distinction between RDI and AHI is related
to “respiratory effort-related arousals” (RERA), which are subtle hypopneas. These
RERAs are included in RDI but not in AHI. Apnea can be distinguished from
hypopnea via a thermistor in PSGs, although the consequences of hypopneas vs.
apneas are generally felt to be similar. While the definition of apnea has been less
debated, the definition of hypopnea is far from settled. The ideal hypopnea defini-
tion is unknown. There are historically at least three different criteria to score
hypopneas: the AASM recommended criteria, and AASM alternative criteria and
the “Chicago Criteria” (see Table 6.6).
The “Chicago Criteria” was the 1999 version of the AASM recommended crite-
ria for hypopnea. These criteria were designed mainly for clinical research rather
than clinical practice. Nasal pressure was early in development at the time of
Chicago criteria and was suggested but not strongly recommended. The lack of
hypopnea criteria for clinical practice was further addressed by AASM in 2001. Via
the Clinical Practices Review Committee, AASM defined hypopnea as having at
least 30% reduction of airflow lasting at least 10 s, and with 4% reduction in
Table 6.6 Commonly used PSG criteria for scoring hypopnea

Criteria names Definitions of hypopnea (at least one of the followings)
“Chicago criteria” Reduction of airflow ≥50%
Discernable decrement in airflow with either EEG arousal of
oxyhemoglobin desaturation ≥3%.
AASM recommended or Reduction of nasal pressure ≥30%
“Medicare criteria” Oxyhemoglobin desaturation ≥4%
AASM alternative Reduction of nasal pressure ≥50% and oxyhemoglobin
desaturation ≥3%
Reduction of nasal pressure signal ≥50% and EEG evidence
of arousal
oxyhemoglobin saturation. Since then, the 2001 AASM definition has been adopted
by Center for Medicare and Medicaid Services (CMS) as its criteria for AHI scor-
ing. However, the 2007 Manual for Scoring of Sleep and Associated Events pub-
lished by AASM introduced only two definitions: “recommended” and “alternative”.
The AASM Recommended Criteria is the same as the desaturation-based Medicare
criteria, i.e., with no importance placed on arousal from sleep:
eduction of Nasal Pressure Signal ≥30% and Oxygen

R
Desaturation ≥4%
The alternative criteria by AASM defines hypopnea as one of the following two
features:
1. Reduction of nasal pressure signal ≥50% and oxygen desaturation ≥3%

2. Reduction of nasal pressure signal ≥50% and associated arousal
A common obstacle in communications between sleep specialists and primary

care physicians (PCPs) is that sleep reports often do not specify which criteria the
sleep lab has adopted as a standard for scoring OSA. The same obstacle is magnified
further in the case of diagnostic interpretation of OSA using PMs. Therefore, any
sleep report should include not only the calculated AHI or RDI, but also an explana-
tion of the criteria used for scoring.
The severity of sleep apnea is typically assessed by AHI, but AHI correlates only
loosely with EDS and other outcomes. Different parameters measured by a sleep
study are predictive of various outcomes of OSA. For example, the degree of oxy-
hemoglobin desaturation threshold may vary depending on the clinical or research
outcome of interests (i.e., hypertension vs. insulin resistance vs. memory consolida-
tion). Additional markers have been suggested as risk factors for disease severity;
for example, the degree of nocturnal hypoxemia and the frequency of arousal from
sleep. Therefore, when discussing sleep study findings, it is imperative for clini-
cians to integrate patient’s initial chief compliant, unique history, risk factor, and
lifestyle into the assessment. In addition, further data are required regarding which
disease indices have the best predictive value for various outcome measures.
The limitations of in-lab PSG include the “first-night” effect where sleep is less
than usual due to being in a foreign environment, night-to-night variability of the
findings, effects of sleep position (which may be different in home, with a bed part-
ner), and the effects of certain medications (i.e., selective serotonin receptor inhibi-
tors, benzodiazepines, hypnotics/alcohol, and stimulants). In-house PSG is quite
labor-intensive, requiring oversight by a skilled sleep technician. However, in-lab
PSG remains the gold standard for diagnosis of OSA given the reliability and quan-
tity of the data provided.
Split Night Study (Diagnosis Combined with Titration)
Frequently a “split-night” study can be done during a full in-laboratory PSG. In a

“split-night” study, an initial impression of the severity of OSA undergoes a “real-
time” assessment by a supervising technician. If the patient qualifies for moderate
or severe OSA during the first half of the overnight study, a titration study is initi-
ated in the second half of the night to determine an appropriate positive airway
pressure (PAP) for treatment. A split-night study is theoretically less sensitive than
a full nocturnal study because the AHI is assessed in half of the usual duration. A
recent study, however, showed that the AHI derived from the first 2 or 3 h of a split-
night study is of sufficient diagnostic accuracy to rule-in OSA at an AHI threshold
of five in patients suspected of having OSA [56]. However, medical history is
important in interpretation of the split-night study. For example, patient’s underly-
ing unusual circadian rhythm as well as sleep-onset/sleep-maintenance insomnia
can alter the diagnostic impression of the study. All things considered, the need to
extend the “split-night” study into a second nocturnal study is uncommon. Therefore,
a “split-night” study not only brings convenience to the patient by avoiding an extra
evening of titration study but also reduces the overall cost for the diagnosis and
treatment of OSA. A split-night study has become the “default” study type for indi-
viduals suspected of OSA.
Portable Monitoring (PM)
PM, or LCTs, is a simple methodology to diagnose OSA. PM testing gives limited

data (discussed in detail below) but perhaps is more comfortable for the subject and
thus offers a more natural perspective for the severity of OSA at home. However,
without a technician on site, the quality of PM studies is only as good as the tech-
nologies available.
Types of PMs (Type II–IV)
The American Academy of Sleep Medicine (AASM) has classified sleep studies
into four types, depending on the channels they record and evaluate [57]. Type I
PSG serves as a reference standard PSG, and it is usually a nocturnal, technician-
attended, full in-laboratory sleep study with 14–16 channel monitoring. Type II–IV
sleep studies are all simplified versions of Type I PSG. Type II records essentially
the same information as full in-lab PSG, except that technician attendance is not
present. SHHS, a large NIH-funded multiyear multicentered cohort study on the
cardiovascular and other consequences of sleep-disordered breathing, used Type II
portable monitors for diagnosis of OSA at home.
Type III PM has been the focus of an ongoing debate on the effectiveness and
utility of PMs in diagnosing OSA. Type III PM includes oximetry, at least two respi-
ratory channels (two airflow channels or one airflow plus one respiratory effort
channel) and ECG-monitored heart rate, but it does not include EEG, EMG, and
EOG. As a result, signals used to detect sleep stages and arousals from sleep (seen
in Type I and II sleep studies) are missing in Type III PM. Therefore, Type III PM
cannot calculate a true AHI, RDI, or sleep efficiency as it does not record the
denominator, sleep time. Instead, Type III PM can only report a value defined by
respiratory events divided by total recording time. However, the value reported by
Type III PMs does not necessarily imply sleep was recorded. Given that not all
study time is necessarily sleep time, reporting from Type III PM is a less sensitive
method than values from Type I or II PSG. Another major problem for Type III PM
is that without documenting sleep, an individual could wear the device (or give it to
someone else) and stay awake yielding an artifactually low AHI. It is worthwhile to
mention that “AHIs” or “RDIs” reported by different Type III PMs also vary with
different device manufacturers. Therefore, exact definitions of “AHI” or “RDI” vary
across different studies of Type III PMs.
The inability to detect respiratory event-related arousals (RERAs) may lead to
underestimation of the RDI and underrecognition of upper airway resistance syn-
drome (UARS). Positional OSA can also be underdiagnosed by those Type III PMs
that do not include body position. Naturally, a “split-night” study is not applicable
for individuals who undergo Type III PM. A separate overnight in lab titration study
will likely be necessary for CPAP set up should the individual be diagnosed of OSA
by a Type III PM device.
Pulse oximetry and airflow are the physiological variables that are most com-
monly measured in Type IV PM. As a result, the frequency of apneas or hypopneas
(AHI) as well as the baseline, mean, frequency, duration, and degree of oxyhemo-
globin desaturation can be estimated. Naturally, Type IV PMs share at least the
same shortcomings of Type III PM, and the current CMS requires a minimum of
three channels to meet the reimbursement criteria. However, we emphasize the sen-
sitivity and specificity of the various diagnostic techniques rather than the number
of channels per se.
When Should PM Be Considered for Diagnosis of OSA?
While PM has an obvious advantage over PSG in its ease of use, the safety, reliabil-
ity, and diagnostic accuracy of PMs have been controversial. Bodily injuries from
loose wires, faulty oximeter, and monitor disconnection by PMs have been reported.
Data loss in Type III and IV PMs has been estimated to be between 2 and 18%.
Additionally, interrater and intrarater reliability as well as night-to-night variability
of PM is greater than those of PSG. Currently, the scoring of apnea and hypopnea
events can be done either manually by a technologist or sleep physician, automati-
cally by the software of the PMs, or combined (manual correction on the automated
scoring is allowed). However, subtle points such as positional severity of OSA are
more difficult to characterize unattended PM than PSG. The lack of standardization
of testing and scoring protocols for PM is of greater concern as there are greater
differences in signals recorded by different PM devices. In a comprehensive litera-
ture review done by AASM, false-negative results in unattended PM studies could
be as high as 15–17%. Likewise, false-positive results in unattended home PM stud-
ies could be as high as 30%.
The American Academy of Sleep Medicine published its first guidelines for
usage of PM in the diagnosis and management of patients with OSA in 2007. The
guidelines stated the following principles for clinicians who consider PM as an
alternative to PSG. PM usage should only be considered as part of an integrative
patient evaluation for OSA, under the direction of a sleep specialist board certified
in sleep medicine.
The one-size-fits-all approach to screen for OSA in the general asymptomatic
population is not only medically and ethically unsound but also expensive and inac-
curate in terms of healthcare cost and clinical outcome. Whether an individual
should undergo PM vs. PSG depends on the individual’s OSA risk factors, physical
exam, medical comorbidities, suspicion of non-OSA sleep disorders, suspicion of
any secondary gain/loss from the test result, and an overall pretest probability for
OSA. PM should only be used for screening in subpopulations in which there is
substantial published knowledge on specificity and sensitivity of the test. PM can be
considered an alternative to PSG for patients with high pretest probability for mod-
erate to severe OSA. Furthermore, PM is not appropriate for diagnosis of OSA in
patients with major comorbid medical conditions that would lower the accuracy of
PM (i.e., severe pulmonary disease, neuromuscular disease, CHF, CSA). PM should
not be used for the diagnostic evaluation of OSA in patients suspected of having
other sleep disorders such as CSA, periodic limb movement disorder (PLMD),
insomnia, parasomnias, circadian rhythm disorders, or narcolepsy. The utility and
efficacy of Type III PM have not been adequately studied for use in the occupational
setting in diagnosing at risk operators of motor vehicle operators, who, unlikely the
general population, often avoid an OSA diagnosis. Figure 6.1 illustrates the
decision-making diagram clinicians can use to decide if PSG or PM should be used
to diagnose OSA in a patient.
Patient in clinic
Low risk factors for OSA?

High chance for unreliable
Portable No data? Known co-morbid Yes
PSG
monitor sleep condition?
Suspicion of co-morbid
sleep disorders?
Fig. 6.1 Portable monitor vs. in-lab PSG decision-making diagram
The United States CMS in 2008 approved reimbursement for the uses of PMs,
after Agency for Health Quality Research (AHQR) published a mostly positive
review of the PMs, particularly pertaining to its comparable clinical utility to predict
clinical outcomes (i.e., CPAP compliance rate) in a population with high pretest
probability.
Recent advances in wearable technologies may lead to a change in diagnostic
approach for sleep-disordered breathing. Although currently the data fall short of
recommending these devices as diagnostic tools, the data and technology are rap-
idly evolving. Currently, some devices can provide a reasonable estimate of sleep
architecture and sleep duration. However, estimation of the Apnea–Hypopnea Index
and other metrics of sleep-disordered breathing will require further study.
urrent Roles of Autotitrating Positive Airway

C
Pressure (APAP)
Autotitrating positive airway pressure (APAP) devices have been increasingly used
for titrating pressure and treating adult patients with OSA in the last decade. The
devices can be used in place of in-lab continuous positive airway pressure (CPAP)
titration study when attended CPAP titration is not possible or patient comfort is a
great concern. They work by changing the treatment pressure based on patients’
airflow, pressure fluctuations, or airway resistance.
As PMs are increasingly used as an initial diagnostic tool in populations with
high likelihood of moderate to severe OSA, APAP has been identified as a partner
strategy in the treatment phase to replace the more costly CPAP titration with in-lab
PSG. We note here that the 2008 AASM Guidelines for APAP stated that APAP
devices can only be used for unattended treatment of patients with moderate and
severe OSA without significant comorbidities such as CHF, COPD, and CSA. Since
then, a large VA study by Berry et al. demonstrated that diagnoses by PM followed
by APAP titration resulted in comparable CPAP adherence and clinical outcomes to
using traditional in-lab PSG. However, as APAP technology is fast evolving, differ-
ent APAP devices differ not only in their sensitivities to detect severity of disordered
breathing but also in their responses to disordered breathing. Therefore, overall
assessment of cost-effectiveness of APAP combining with PMs is complicated.
Cost-effectiveness of PSG vs. PM
Although the cost of PM devices has seen a substantial drop in recent years, the total
healthcare cost of evaluating and treating individuals with OSA using PM compared
to PSG has not been studied adequately and is largely controversial. Though gross
cost savings were frequently reported, the high false-negative rate of PMs along
with the current guideline that all negative tests of PMs should be referred to a full
in-lab PSG by a sleep specialist translates into high cost if the currently available
PMs were to become the mainstream of screening tools. Furthermore, few cost
analyses compared usage of PMs to increasingly popular use of split-night study
protocols, in which both diagnostic PSG and titration studies are done in a single
night. Further studies using a decision model are much needed to provide a theoreti-
cal framework as well as evidence to ascertain the pretest disease probability above
which portable studies would be economically attractive as an initial test in the
assessment of suspected OSA.
Utilities of Multiple Sleep Latency Test (MSLT) in OSA
MSLT is one of a few currently available de facto standard tests to measure physi-
ological sleep tendency in the absence of external alerting factors. The test is based
on the premise that the degree of sleepiness is correlated with and therefore reflected
by sleep latency (the amount of time it takes for the individual to fall asleep). MSLT
is usually ordered to diagnosis narcolepsy or other conditions of hypersomnia. The
individuals with these conditions typically have reduced sleep-onset latency and
early onset of REM sleep. However, MSLT is occasionally indicated to quantify
objectively sleepiness, e.g., residual daytime sleepiness despite presumed adequate
CPAP treatment of OSA. For example, professional drivers or pilots with OSA may
at times be subjected to medicolegal actions in order to objectify whether their
residual sleepiness is significant enough to keep them off the roads. The test is usu-
ally done immediately following an overnight in-lab PSG in order to control for the
patient’s sleep characteristics. The test asks the patient to have four or five naps (2 h
between each) in a naturally dim-light environment during the day. The sleep onset
latency is recorded for each nap. If the patient does not fall asleep within 20 min of
each nap, the sleep onset latency is assumed to be 20 min. The average of the sleep
onset latency is used as objective measure of sleepiness. With high test–retest reli-
ability and inter-rater/intra-rater reliabilities, MSLT has demonstrated its ability to
differentiate normal healthy subjects from those with pathologic sleepiness on both
driving simulators as well as long-term road accidents. However, MSLT is not a
reliable predictor of traffic accidents, emphasizing the need for more research in
this area.
Future Outlook
One of the ongoing research goals in OSA is to identify a relatively easily assayed
biomarker. For example, recent studies have shown that amylase in saliva (i.e., sali-
vary amylase activity as well as amylase mRNA levels) are elevated in individuals
with EDS and OSA. Among individuals with OSA, who are assumed to have higher
sleep drive, systemic inflammation may be involved in the pathogenesis of
OSA. Studies using microarrays looking at gene expression have shown that over-
night expression of oxidative stress response genes such as antioxidant enzyme
superoxidase dismutase 2 (SOD2) and catalase are up-regulated. Proteomic analy-
ses of serum and urine may yield future techniques for identifying individuals with
OSA. Even though there is a lack of data in the adult population, recent findings
suggest that proteins such as gamma-carboxyglutamic acid, perlecan, and gelsolin
are differentially expressed among children with OSA and the control. Specific sub-
populations of leukocytes such as TNF-alpha, IL-6, and some T lymphocytes have
been found to be elevated among patients with OSA. Brief paroxysmal bursts of
alpha activity have been identified before serious driving errors in simulation stud-
ies. Similarly, a significant increase of eye blinks, in both number and duration, have
been described before driving errors. Furthermore, an alteration of eyes blinking
duration has been observed with increased driving time. With identification of more
reliable biomarkers, the tasks of diagnosing OSA and sleepiness individuals will
become less challenging.
Given the recent appreciation that OSA is heterogeneous, there have been ongo-
ing efforts to define underlying mechanisms (endotypes) of disease as well as vari-
able clinical manifestations of disease (phenotypes). Recognition of the OSA
endotypes may be important since mechanisms can inform therapeutic interven-
tions or help predict response to various therapies. In addition, studies and clinical
experience have shown phenotypic variability with some patients have sleepiness
(with associated cardiovascular risk) whereas other OSA patients develop frag-
mented sleep (with insomnia) and other patients remain asymptomatic. Thus, future
efforts with diagnostic testing will likely focus on assessing disease severity, but
also prognosis and clinical guidance regarding response/need for various
interventions.
Summary Outline
• In clinic pretest screening questions (symptoms of snoring, daytime sleepiness,

and common comorbidities) for OSA are important to efficaciously diagnose
OSA. In some special clinical scenarios (i.e., occupational clinic), screening for
OSA should rely more on objective anthropometric measurements.
• OSA risk factors include obesity, older age, male gender, postmenopausal status,
Asian/African American races, tobacco, and alcohol use.
• The diagnostic criteria of sleep apnea are not uniform, but most of them try to
characterize the frequency of sleep-disordered breathing events along with the
degree of oxygen desaturation of each event.
• Three most commonly used diagnostic criteria for OSA are the AASM
“Recommended” Criteria (or the “Medicare” Criteria), AASM “Alternative”
Criteria, and “the Chicago” Criteria.
• There are four types of sleep studies available. Both in-lab PSG, or Type I, and
portable monitors (PM), or Type II–IV, are being used for diagnosis of OSA. PSG
is the gold standard test for diagnosis of OSA. PM offer a less-expensive and in-
home alternative, with limitations in both sensitivity and specificity.
• A “split-night” study not only brings convenience to the patient by avoiding an
extra evening of titration study but also reduces the overall cost for the diagnosis
and treatment of OSA. A split-night study has become the “default” study type
for individuals suspected of OSA.
• Whether an individual should undergo PM vs. PSG depends on the individual’s
OSA risk factors, physical exam, medical comorbidities, suspicion of non-OSA
sleep disorders, suspicion of any secondary gain/loss from the test result, and an
overall pretest probability for OSA.
References
1. Gottlieb DJ, Punjabi NM. Diagnosis and management of obstructive sleep apnea: a review.
JAMA. 2020;323(14):1389–400.
2. Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of
obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7(8):687–98.
3. AASM. Sleep-related breathing disorders in adults: recommendations for syndrome definition
and measurement techniques in adults. Sleep. 1999;22(5):667–89.
4. AASM. International classification of sleep disorders, Diagnostic and coding manual. 2nd ed.
Westchester: American Academy of Sleep Medicine; 2005.
5. Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: pathophysiology and treat-
ment. Chest. 2007;131(2):595–607.
6. Morrell M, Arabi Y, Zahn B, Badr M. Progressive retropalatal narrowing preceding obstructive
apnea. Am J Respir Crit Care Med. 1998;158:1974–81.
7. Badr MS, Dingell JD, Javaheri S. Central sleep apnea: a brief review. Curr Pulmonol Rep.
2019;8(1):14–21.
8. Javaheri S, Malik A, Smith J, Chung E. Adaptive pressure support servoventilation: a novel
treatment for sleep apnea associated with use of opioids. J Clin Sleep Med. 2008;4(4):305–10.
9. Javaheri S, McKane SW, Cameron N, Germany RE, Malhotra A. In patients with heart failure
the burden of central sleep apnea increases in the late sleep hours. Sleep. 2019;42(1):zsy195.
10. Javaheri S, Somers VK. Cardiovascular diseases and sleep apnea. Handb Clin Neurol.
2011;98:327–45.
11. Punjabi N, Sorkin J, Katzel L, Goldberg A, Schwartz A, Smith P. Sleep-disordered breathing
and insulin resistance in middle-aged and overweight men. Am J Respir and Crit Care Med.
2002;165:677–82.
12. Punjabi NM, Ahmed MM, Polotsky VY, Beamer BA, O'Donnell CP. Sleep-disordered breathing,
glucose intolerance, and insulin resistance. Respir Physiol Neurobiol. 2003;136(2–3):167–78.
13. Punjabi NM, Beamer BA. Alterations in glucose disposal in sleep-disordered breathing. Am J
Respir Crit Care Med. 2009;179(3):235–40.
14. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a pro-
spective cohort study. PLoS Med. 2009;6(8):e1000132.
15. Punjabi NM, Newman AB, Young TB, Resnick HE, Sanders MH. Sleep-disordered breathing
and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care
Med. 2008;177(10):1150–5.
16. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident
stroke: the sleep heart health study. Am J Respir Crit Care Med. 2010;182(2):269–77.
17. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea
and incident coronary heart disease and heart failure: the sleep heart health study. Circulation.
2010;122(4):352–60.
18. Gottlieb JD, Schwartz AR, Marshall J, et al. Hypoxia, not the frequency of sleep apnea,
induces acute hemodynamic stress in patients with chronic heart failure. J Am Coll Cardiol.
2009;54(18):1706–12.
19. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep
apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–41.
20. Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing
and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172(11):1447–51.
21. Arzt M, Young T, Peppard PE, et al. Dissociation of obstructive sleep apnea from hypersom-
nolence and obesity in patients with stroke. Stroke. 2010;41(3):e129–34.
22. Leung RS, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med.
2001;164(12):2147–65.
23. Raphelson JR, Kreitinger KY, Malhotra A. Positive airway pressure therapy in sleep-disordered
breathing. Neurotherapeutics. 2021;18(1):75–80.
breathing among middle-aged adults. New Engl J Med. 1993;32:1230–5.
25. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population
health perspective. Am J Respir Crit Care Med. 2002;165(9):1217–39.
26. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep
apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med.
1999;340(11):847–51.
27. Kreitinger KY, Lui MMS, Owens RL, et al. Screening for obstructive sleep apnea in a diverse
bariatric surgery population. Obesity (Silver Spring). 2020;28(11):2028–34.
28. Young T, Peppard P, Gottlieb D. The epidemiology of obstructive sleep apnea: a population
health perspective. Am J Respir Crit Care Med. 2002;165:1217–39.
29. Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the gen-
eral population: the HypnoLaus study. Lancet Respir Med. 2015;3(4):310–8.
30. Edwards BA, O’Driscoll DM, Ali A, Jordan AS, Trinder J, Malhotra A. Aging and sleep: phys-
iology and pathophysiology. Semin Respir Crit Care Med. 2010;31(5):618–33.
31. Edwards BA, Wellman A, Sands SA, et al. Obstructive sleep apnea in older adults is a dis-
tinctly different physiological phenotype. Sleep. 2014;37(7):1227–36.
32. Malhotra A, Huang Y, Fogel R, et al. Aging influences on pharyngeal anatomy and physiology:
the predisposition to pharyngeal collapse. Am J Med. 2006;119(1):72 e79–14.
33. Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in
the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med. 2003;167:1181–5.
34. Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight
change and sleep-disordered breathing. JAMA. 2000;284(23):3015–21.
35. Foster GD, Borradaile KE, Sanders MH, et al. A randomized study on the effect of weight loss
on obstructive sleep apnea among obese patients with type 2 diabetes: the sleep AHEAD study.
Arch Intern Med. 2009;169(17):1619–26.
36. Foster GD, Sanders MH, Millman R, et al. Obstructive sleep apnea among obese patients with
type 2 diabetes. Diabetes Care. 2009;32(6):1017–9.
37. Malhotra A, Huang Y, Fogel R, et al. The male predisposition to pharyngeal collapse: the
importance of airway length. Am J Resp Crit Care Med. 2002;166:1388–95.
38. Malhotra A, Mesarwi O, Pepin JL, Owens RL. Endotypes and phenotypes in obstructive sleep
apnea. Curr Opin Pulm Med. 2020;26(6):609–14.
39. Badr MS. Pathophysiology of upper airway obstruction during sleep. Clin Chest Med.
1998;19(1):21–32.
40. Badr MS. Pathogenesis of obstructive sleep apnea. Prog Cardiovasc Dis. 1999;41(5):323–30.
41. Rowley JA, Sanders CS, Zahn BR, Badr MS. Gender differences in upper airway compliance
during NREM sleep: role of neck circumference. J Appl Physiol. 2002;92(6):2535–41.
42. Rowley JA, Zhou X, Vergine I, Shkoukani MA, Badr MS. Influence of gender on upper airway
mechanics: upper airway resistance and Pcrit. J Appl Physiol. 2001;91(5):2248–54.
43. Lee YH, Johan A, Wong KK, Edwards N, Sullivan C. Prevalence and risk factors for obstruc-
tive sleep apnea in a multiethnic population of patients presenting for bariatric surgery in
Singapore. Sleep Med. 2009;10(2):226–32.
44. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
Sleep. 1991;14(6):540–5.
45. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continuous positive airway pressure
therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of
a meta-analysis. Arch Intern Med. 2003;163(5):565–71.
46. Jenkinson C, Davies RJ, Mullins R, Stradling JR. Comparison of therapeutic and subthera-
peutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised
prospective parallel trial. Lancet. 1999;353(9170):2100–5.
47. Pack AI. Obstructive sleep apnea. Adv Intern Med. 1994;39:517–67.
48. Pack AI. Further development of P4 approach to obstructive sleep apnea. Sleep Med Clin.
2019;14(3):379–89.
49. Dagan Y, Doljansky JT, Green A, Weiner A. Body Mass Index (BMI) as a first-line screening
criterion for detection of excessive daytime sleepiness among professional drivers. Traffic Inj
Prev. 2006;7(1):44–8.
50. Hartenbaum N, Collop N, Rosen IM, et al. Sleep apnea and commercial motor vehicle opera-
tors: statement from the joint task force of the American College of Chest Physicians, the
American College of Occupational and Environmental Medicine, and the National Sleep
Foundation. Chest. 2006;130(3):902–5.
Chapter 7
A Brief Review of Treatment
of Obstructive Sleep Apnea
Scott Hoff and Nancy Collop
Keywords Continuous positive airway pressure (CPAP) · Apnea hypopnea index

(AHI) · critical closing pressure (Pcrit)
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized

by repeated partial or complete collapse of segments of the upper airway compro-
mising airflow to varying degrees. These recurrent episodes can be associated with
transient activation of the sympathetic nervous system, intermittent hypoxemia, and
a higher risk for adverse cardiovascular outcomes. Of a limited number of treatment
options for OSA, continuous positive airway pressure (CPAP) remains the first
choice in most circumstances. Rationale for use of CPAP is strong, however adher-
ence to therapy remains suboptimal in many patients.
As with studies involving other biological conduits, pharyngeal collapsibility has
been studied using a model of flow through a collapsible tube. Differences in pha-
ryngeal collapsibility between normal subjects, snorers, and subjects with obstruc-
tive sleep apnea have been quantified using such a model [11]. The model depicts
the upper airway as a tube with rigid segments at either end and a collapsible seg-
ment housed within a fixed pressure box in between [11]. When the pressure within
the collapsible segment exceeds that surrounding it within the box, the collapsible
segment will remain open; however, if the pressure within the collapsible segment
falls below that surrounding it within the box, the segment will collapse. The criti-
cal closing pressure (Pcrit) is the pressure within the collapsible segment equaling
the pressure surrounding it within the box at which collapse of the segment occurs
halting the flow through it.
S. Hoff · N. Collop (*)

Emory Sleep Center, Emory University School of Medicine, Atlanta, GA, USA
e-mail: nancy.collop@emory.edu

130 S. Hoff and N. Collop
Flow through the collapsible segment is therefore dependent upon the differ-
ences between the pressure upstream (Pus) from the collapsible segment, Pcrit, and
that downstream from the collapsible segment. When the upstream pressure is less
than Pcrit, no flow occurs through the collapsible segment. If the upstream pressure
exceeds Pcrit and the pressure in the rigid segment downstream from the collapsible
segment does not, then there will be fluttering of the collapsible segment. When the
upstream pressure exceeds Pcrit, it will drive the collapsible segment open; how-
ever, if the downstream segment is at a pressure lower than Pcrit then it will cause
closure of the terminal point of the collapsible segment, which will be at Pcrit. The
cessation of flow would allow the intraluminal pressure throughout the collapsible
segment to equilibrate with that of the upstream segment again opening the col-
lapsed part of the tube and restoring flow. When both the upstream and the down-
stream segments have a pressure exceeding Pcrit, then flow will continue unimpeded
throughout the tube. Aspects of the upper airway behave in a manner described by
the model.
Aberrations of airflow that comprise OSA result from the pressure-flow relation-
ships described by the collapsible tube model. The upstream pressure in the human
airway is usually represented by nasal pressure (Pn), which is generally around
atmospheric pressure. Pcrit has been demonstrated to be based in the pharyngeal
airway as a result of nasopharyngeal intubation studies, not the laryngeal airway as
was originally speculated [30]. In the first instance described above, in which Pn is
less than Pcrit, an obstructive apnea results. In the second instance, when Pn > Pcrit,
but the downstream pressure is not, then hypopneas, flow limitation, and snoring
occur. In this situation, the maximum flow through the system will be limited by the
collapsible segment dynamics, and will be a function of the driving pressure (Pus –
Pcrit) relative to the resistance of the upstream segment. The resistance of the
upstream segment can be determined by measuring the flow through the system
while different pressures are applied, and then taking the reciprocal of the slope of
the plotted measures. The third instance reflects the normal functioning upper air-
way in which normal airflow is maintained throughout inspiration.
There are two main factors which contribute to collapsibility of the upper airway
transmural pressure and pharyngeal compliance. The transmural pressure is the dif-
ference in forces acting across the wall of the collapsible segment of the upper air-
way. Forces tending to promote airway collapse include the intraluminal negative
pressure generated by the respiratory apparatus during inspiration, and the pressure
exerted by tissues, such as fat, extrinsic to the airway. Those forces are opposed by
the pharyngeal dilator muscles, which act to expand the upper airway diameter.
Pharyngeal compliance has an important influence on transmural pressure.
Compliance is a function, in large part, of the intrinsic muscle activity of the upper
airway, but may also be contributed to by blood volume perfusing the upper airway
with greater perfusion associated with lower compliance.
Studies have demonstrated levels of Pcrit at which sleep-disordered breathing
events may be predicted. When the Pcrit exceeds atmospheric pressure, then the
patient will be prone to repeated obstructive apneas, and when the Pcrit remains
negative relative to atmospheric pressure, then the upper airway remains patent. A
7 A Brief Review of Treatment of Obstructive Sleep Apnea 131
Pcrit in the middle results in hypopneas, flow limitation, and snoring. Pcrit therefore
represents the susceptibility of the upper airway to collapse, and is different from
one person to another.
The effects of sleep stages on Pcrit remain uncertain. Some data demonstrate a
significant influence on upper airway closing pressure with a higher pressure,
implying a more collapsible airway, noted during stage N1, N2, and REM sleep than
during deep sleep [14]. Other data do not demonstrate a statistically significant
association between sleep stage and collapsibility [26]. Ultimately, the activity of
the genioglossus and other pharyngeal dilators must balance the negative intralumi-
nal pressure generated by the muscles of inspiration for airway patency to be pre-
served [4].
During the time studies were intensely investigating the upper airway dynamics
(the late 1970s and early 1980s), few options existed for the treatment of OSA aside
from weight loss and tracheostomy. Armed with new knowledge regarding pharyn-
geal airway collapsibility, Sullivan et al. sought to demonstrate that CPAP applied
through the nares would act as a “pneumatic splint” for the upper airway preventing
occlusion [36]. Subsequently, in order to evaluate whether CPAP activates upper
airway muscular reflexes, or acts passively via increasing intraluminal pressure,
EMG recordings were made during sleep while CPAP was applied in patients with
OSA. Use of 10–13 cm of water pressure resulted in elimination of apneas, improve-
ment in oxygen saturation, and reduction or elimination of EMG activity, and when
CPAP was abruptly lowered, EMG activity did not immediately return. The investi-
gators concluded that CPAP was indeed a pneumatic splint acting passively to open
the airway [34]. This was followed by another study in which application of positive
airway pressure between 10 and 12 cm of water resulted in a significant increase in
pharyngeal airway size demonstrated by computed tomography in awake, obese
patients with OSA, and in patients without OSA; however, the change in airway size
was smaller in patients with OSA. Concomitant EMG recordings of the genioglos-
sus and alae nasi muscles with and without positive airway pressure demonstrated a
decrease, or no change in activity associated with pressure [16].
It would appear that CPAP alleviates sleep-disordered breathing events through
its effects on transmural pressure. Application of positive airway pressure raises
intraluminal pressure counteracting the collapsing effects of external tissue pressure
thereby favorably affecting transmural pressure, overcoming Pcrit. Also, even small
enhancements of end-expiratory lung volume exert a caudal force on the trachea
likely stiffening the upper airway to some degree favorably affecting pharyngeal
compliance. In terms of the model of flow through a collapsible tube, as CPAP is
gradually increased, Pus increases until reaching a level that exceeds Pcrit at which
point apneas resolve. Further increases in pressure will gradually increase intralu-
minal pressure across the entire collapsible segment until the applied positive air-
way pressure is communicated to the downstream pressure at which point hypopneas,
flow limitation, and snoring should be abolished.
Positive airway pressure therapy can be delivered in two major modalities, con-
tinuous and bilevel. Continuous positive airway pressure, CPAP, is a continuous
stream of airflow unchanging throughout the respiratory cycle. Bilevel positive
airway pressure (BPAP), consists of two independent airflows: inspiratory positive

airway pressure (IPAP) and expiratory positive airway pressure (EPAP). Obviously,
these distinct flows are state-dependent on the respiratory cycle. The difference
between the IPAP and the EPAP describes the pressure support (PS), which can aug-
ment the inspired tidal volume improving ventilation.
Therapy with CPAP can be initiated by two methods, titration in the sleep lab, or
using autotitrating devices in an out-of-center setting. Manual titration of CPAP in
the sleep lab typically involves a night’s stay in the sleep lab during which CPAP is
initiated at a low level, typically 4 or 5 cm of water to overcome the resistance of the
tubing, while the patient is monitored using polysomnography. As airflow events
(apneas, hypopneas, respiratory effort-related arousals (RERAs), and snoring)
occur, the pressure is increased in 1–2 cm of water increments and the patient is
observed for recurrent airflow events for a minimum of 5 minutes of sleep time.
Apneas will resolve first as the pressure reaches the minimum level necessary to
stent the airway opened. Then, hypopneas, RERAs, and snoring will resolve as the
luminal pressure increases with increasing delivered CPAP level. Optimal pressure
will be recognized when snoring resolves and sleep remains continuous with mini-
mal fragmentation. It should be noted that REM sleep, which is a sleep stage com-
monly associated with worsened OSA, and sleep in the supine position, a sleep
position commonly associated with worsened OSA, ideally occur especially
together in order to truly determine an optimal pressure. At times, additional titra-
tion steps are made as exploratory measures after airflow events have apparently
resolved to determine whether sleep becomes better consolidated with fewer arous-
als and better architecture.
In instances in which manual titration of BPAP becomes necessary, the EPAP is
typically started at the CPAP level when obstructive apneas resolved and the IPAP
is initiated at 4 cm of water above the EPAP. Again, this EPAP will be the minimum
pressure required to maintain the patency of the upper airway. The EPAP is left at
this level as long as no obstructive apneas recur at which point both EPAP and IPAP
are raised equally. Other persistent obstructive events are managed by further
upward titration of the IPAP until hypopneas, RERAs, and snoring have resolved.
The act of increasing the IPAP relative to the EPAP will increase pressure support.
Titrations in which pressure support becomes necessary to manage hypercapnia can
be performed with transcutaneous carbon dioxide monitoring, which may provide
evidence of improvement in carbon dioxide levels with titration of PS.
Devices with autotitrating, or self-adjusting, algorithms are now the norm for
treating most uncomplicated cases of OSA. These devices employ mechanisms
through which airway patency assessments are made, and then adjustments to airflow
are enacted using programmed responses. There are both autotitrating CPAP and
BPAP devices on the market. The clinician programs a minimum pressure level and
a maximum pressure level (either CPAP, or EPAP and IPAP), and the machine oper-
ates between these boundaries making adjustments to airflow throughout the night
attempting to minimize generated upper airway pressure while maintaining airway
patency. This could prove useful when lab titration studies fail to provide optimal
pressure settings, or when specific situations occur that may lead to higher pressures
during the situation resulting in possible over titration of pressure for the remainder
of the sleep period. Examples of such situations may include a significant disparity in
severity of OSA during REM sleep, or in the supine position. A 90th or 95th percen-
tile pressure is reported by the device, depending on the manufacturer, which can then
be used to prescribe a fixed pressure for therapy. Alternatively, the patient can be
maintained on the autotitrating mode as a long-term therapy. Research has not dem-
onstrated improved adherence to therapy or greater therapeutic efficacy on fixed pres-
sure versus autotitrating modes. As there is a competitive marketplace for these
therapeutic devices, machines can have different sensing mechanisms and different
response characteristics both of which can result in different therapeutic efficacies for
individual patients. Although an AHI is reported by the devices, the patient’s reported
symptoms, if any, should be carefully monitored as a measure of efficacy.
There may be factors that steer therapy to one modality of PAP therapy versus
another. In most instances, CPAP suffices for treatment of OSA; however, some
patients intolerant of CPAP may find BPAP to be a more comfortable experience
and will acclimate better to BPAP. In cases involving hypoventilation, such as
hypercapnic COPD, use of BPAP with the ability to titrate PS by increasing IPAP
relative to EPAP can be highly advantageous. In patients with obesity hypoventila-
tion syndrome (OHS), use of BPAP results in improvements in PaCO2; however,
use of CPAP may also result in PaCO2 improvement, but only after adjustment for
adherence with therapy. Use of both CPAP and BPAP can improve nocturnal oxy-
genation and sleep quality in OHS patients [21]. A separate analysis of CPAP and
BPAP effects on PCO2 in patients with OHS without severe CPAP-resistant noctur-
nal hypoxemia demonstrated no significant treatment effect difference with both
positive airway pressure groups demonstrating significant improvements in PCO2.
The BPAP group experienced better improvements in sleep quality and psychomo-
tor vigilance test performance than the CPAP group [28]. In patients with OHS
followed up for a median of over 5 years, there was no difference in the change in
PCO2, or in cardiovascular outcomes or sleepiness between groups using CPAP or
BPAP [22]. A systematic review comparing CPAP and BPAP treatment effects in
patients with OSA found no differences in the improvement in either PCO2, PO2,
sleepiness, quality of life, or healthcare resource use with either PAP modality after
3 months of treatment. Because BPAP use generally has higher costs involved, the
authors recommended CPAP rather than BPAP for the initial treatment of patients
with OHS although acknowledged that the evidence was weak [33].
BPAP with a programmed backup respiratory rate can also be trialed in patients
who demonstrate emergence of central apneas while on CPAP, also known as com-
plex sleep apnea. Data in patients with complex sleep apnea randomized to either
non-invasive positive pressure ventilation (NPPV) or adaptive servoventilation, an
advanced form of bilevel positive airway pressure ventilation in which the device’s
algorithm seeks to learn and maintain an averaged, consistent minute ventilation
while eliminating apneas and hypopneas, demonstrated that NPPV with a backup
respiratory rate initially improved the AHI measured on CPAP to the same degree
as ASV did, after 6 weeks, the AHI in the NPPV group had crept up a little bit while
that in the ASV group had slightly decreased further [6].
Positive airway pressure therapy must be delivered into the upper airway through
the use of an interface applied to the nose, or nose and mouth. Nasal masks were the
original interface and continue to enjoy widespread use. This type of interface gen-
erally covers the nares and the bridge of the nose; however, alternatives include a
component under the nose bridging the nares with soft material that inflates to seal
along the sides of the nose when air circulates through the mask. Nasal pillows
consist of two soft prongs that sit on the perimeter of the nares to form a seal and
airflow is delivered directly into the nares. Full face masks generally cover the
external nose and mouth generating a pressure effect over both. As many people
tend to breathe through their mouths while they sleep, nasal-focused interfaces may
not maintain therapeutic efficacy as airflow intended to generate upper airway pres-
sure may instead leak out of the mouth. These patients may consider use of a full
face mask, or application of a chin strap, which runs from the top of the head to
under the jaw in order to resist mouth opening, in conjunction with a nasal interface.
There are small but significant data indicating some benefits of nasal masks over
full face, or oronasal masks. Oronasal masks have been demonstrated to have greater
time in large leak when compared to nasal masks, and the residual AHI using an
oronasal mask, while reduced when compared to baseline, was found to be higher
than that achieved with the use of nasal masks. In addition, patients reported more
restful sleep, overall higher satisfaction, and less mask noise with the use of a nasal
mask compared to an oronasal one. However, despite all of these positive findings
associated with nasal masks, there were no differences in adherence assessed after
4 weeks of use of each mask type [32]. Switching to an oronasal mask during the
course of outpatient CPAP therapy after optimal titration of pressure in the sleep lab
to an AHI less than 5 events/hour was associated with a higher residual AHI when
compared to that using a nasal mask. However, again, adherence to CPAP therapy
was no different between the groups [7]. Fewer patients may be successfully titrated
with CPAP using oronasal masks than with nasal masks, and the pressures needed
for a successful titration may be significantly higher with an oronasal mask. Titration
using an oronasal mask has been shown to be successful only in nasal breathers
[20]. Despite these findings, full face masks have remained in widespread use for
CPAP therapy.
There are numerous facets involved in assessing the efficacy of positive airway
pressure therapy. First, and foremost, improvement in the patient’s symptoms
should be considered. Snoring, awakenings associated with gasping, and other
sleep-related breathing issues should resolve with application of adequate positive
airway pressure. With improvement in arousals associated with respiratory events or
flow limitation, the resulting sleep fragmentation should improve resulting in
improvement in daytime fatigue, hypersomnolence, concentration lapses, and mem-
ory impairment that were attributable to the sleep-disordered breathing. Research
has demonstrated improvement in sleepiness associated with use of CPAP in
patients with OSA [10, 25]. Neurocognitive benefits have been demonstrated in
executive and frontal lobe function domains with the use of CPAP [17]. Driving
performance and reaction times have been demonstrated to improve after patients
are started on CPAP [23].
Another category of assessment of positive airway pressure efficacy consists of
PAP device-derived data. The data storage capabilities of current PAP machines
provide useful information regarding machine use, residual airflow events, and sys-
tem leak. Adherence to therapy can be measured as a percentage of time the device
is used over the course of a specified time interval, the average hours of use of PAP
therapy per night, or the percentage of nights with PAP use of at least 4 hours. The
Centers for Medicare and Medicaid Services (CMS) defines adherence as the use of
PAP therapy for at least 4 hours per night for an average of 70% of the audited time
frame, typically 30 days. Adherence to therapy is a critical metric in both clinical
practice and research studies; however, uncertainty exists regarding what represents
the most important benchmark for adherence. Data indicate that longer use of CPAP
on a nightly basis is generally associated with improved outcome measures; how-
ever, as CPAP use as a percentage of total sleep time increases, untreated sleep time
decreases, and this may also be an important factor influencing outcome measures.
Many factors can influence a patient’s adherence to PAP therapy. Mask-related
issues can have a significant effect on adherence. Leakage from a mask can cause
airflow into unintended places, such as the eyes, or can result in sleep-disrupting
noise or vibrations. Mask leak can also have a significant impact on the efficacy of
a level of pressure as well as on the ability of the PAP device to detect use and
residual AHI accurately. As the length of time a particular mask is used increases,
oils from the face can lead to a loss of integrity of the components contacting the
face resulting in an increased tendency for the mask to leak. Improperly sized
masks, or significant weight loss affecting the fit of a mask can be causes of mask
leak. Rotating the head when one changes sleeping positions, or use of a soft pillow
can result in dislodgment of the mask and significant mask leak. Intolerance of pres-
sure can have a significant negative impact on a patient’s adherence to therapy.
Overtitration of pressure can cause uncomfortable sensations associated with both
inhalation and exhalation, described as smothering, drowning, or increased work of
breathing, leading to discontinuation of therapy. Overtitration can also be associated
with the development of central apneas which can have a detrimental effect on sleep
continuity and sleep quality. Under titration of pressure can similarly cause uncom-
fortable sensations of breathing akin to air hunger or starvation.
There can be many different types of side effects associated with use of PAP
therapies. The most common complaint associated with PAP use is dry mouth. The
delivery of continuous airflow across surfaces will have a drying effect. Leak from
the system, be it from a poor sealing mask, or from an opened mouth, will result in
augmentation of airflow from the device to compensate for the pressure loss further
exacerbating the dryness. A poor sealing mask can also direct unintended airflow
toward the eyes resulting in dry and irritated eyes. Swallowing of excess air from the
upper airway, aerophagia, can cause abdominal cramps and excess eructation or
flatulence. Aerophagia may improve with a slight drop in CPAP level.
PAP Alternatives
Oral Appliances
Oral appliances are often considered as the first choice CPAP alternative for man-
agement of OSA for patients who are intolerant of CPAP, or for those who prefer an
alternative to CPAP, and are also effective as remedies for snoring in patients with-
out OSA. The most widely used type of oral appliance are the mandibular advance-
ment devices. The devices engage the maxillary and mandibular arches causing
protrusion of the mandible [29]. Doing so increases the lateral diameter of the phar-
ynx, provides stability to the hyoid bone and soft palate, stretches the tongue mus-
cles, and opposes the tendency for posterior rotation of the mandible [1]. Oral
appliances can consist of a single component that maintains the mandible in a fixed
position, or they can have two components which allow adjustments to the man-
dibular position in different spatial planes. The devices can be prefabricated or
custom-made. Prefabricated devices, or so-called “boil and bite plates,” are widely
available over-the-counter and are set up usually by immersing the device in hot
water to make it soft followed by gently biting into the material with the jaw in a
thrusted position to create an impression of the mandibular and maxillary arches.
Custom-made devices are fabricated off of impressions of the patient’s teeth made
in a qualified dentist’s office, and can then be progressively adjusted to maximize
efficacy while minimizing side effects.
Oral appliances can be highly efficacious for OSA management. OA reduce the
frequency and intensity of snoring, improve sleep quality for both patients who
snore and their bed partners, and improve QOL measures [29]. Research has dem-
onstrated no significant difference between the percentages of patients with mild
OSA achieving the target AHI using an OA versus using CPAP; however, there was
a statistically significantly greater odds for patients with moderate to severe OSA
achieving the target AHI using CPAP than those who used an OA [13]. Data evaluat-
ing a population with an average AHI of 13.1 events/hour randomized to use of
either a custom-made device, or a prefabricated device for a 3-month period. The
percentage of patients reaching an AHI less than 5 events/hour was 64% in the cus-
tom-made device group versus 24% in the prefabricated device group. The number
of patients failing to have at least a 50% drop in AHI also favored the custom device
with 4% of the patients in the custom device group having a treatment failure, and
36% in the prefabricated group having one [15]. An earlier trial using a different
prefabricated device demonstrated similar findings favoring the custom-made appli-
ance with 60% patients in the custom-made device group achieving an AHI less than
5 events per hour, or at least a 50% reduction in AHI, compared to 31% of patients
in the prefabricated device group. Treatment failure, again defined as a residual AHI
greater than 50% of the baseline AHI, was not statistically significantly different
between the groups (31% for the custom-made device group and 34% for the prefab-
ricated device group); however, 63% of the patients who had treatment failure with
the prefabricated device had treatment success with the custom-made device [37].
Positional Therapy
Positional therapy should be an option considered primarily for patients who dem-
onstrate a supine preponderance with respect to their OSA. Positional OSA is often
defined as an AHI of at least 5 events/hour with associated daytime sleepiness, or an
AHI of at least 15 events/hour, with a drop in the AHI of at least 50% and the AHI
falling to under 5 events/hour when the patient changes from the supine to a non-
supine position. Various methods for avoiding the supine position while sleeping
have been utilized, and studied. Most devices involve some sort of physical barrier
restricting the ability to lie supine, and there are many commercially available prod-
ucts some using foam wedges, while others use air-filled packages both of which are
held in place with a belt. Many have even used tennis balls attached to the back of a
night shirt to encourage avoidance of the supine position.
Data has demonstrated the efficacy of positional therapy devices. One study
recruited patients with mild to moderate OSA and used either CPAP or a commer-
cially available positional therapy device during a second night sleep study, switch-
ing to the other therapy for a third night sleep study. The authors found that the
positional therapy device reduced the AHI to under 5 events/hour in 92% of the
patients, and CPAP in 97% of the patients. The positional therapy device was not
associated with reductions of total sleep time or sleep efficiency [27]. Oksenberg
et al. identified patients with positional OSA and prescribed the tennis ball tech-
nique (TBT) for treatment. This involves use of a soft cloth belt wrapped around
the chest so that a pouch in the belt holding a tennis ball is positioned in the middle
of the back. After 6 months, a questionnaire was mailed to patients to assess their
use of the TBT. Of the 50 respondents, 38% indicated that they had continued to
use the belt; 24% reported initially using the belt, but stopping after learning to
maintain the lateral position; and 38% said they had stopped using the belt, but did
not maintain sleep in the lateral position. Patients continuing to use TBT reported
an improvement in sleep quality, a decrease in snoring loudness, and an improve-
ment in daytime alertness compared with the other groups. A PSG performed on 12
patients using the TBT demonstrated an improvement in AHI from 46.5 events/
hour at baseline to 17.5 events/hour with use of the TBT; 58% of these patients had
an AHI less than 10 events/hour and for 2 patients, the TBT did not work [24].
Another survey study with returned responses from 67 patients with positional
OSA who had been prescribed the tennis ball technique (TBT) found that after a
mean follow-up time of 2.5 yrs only 6% of respondents had continued using the
TBT. Of those who were no longer using the TBT, 13.4% had taught themselves to
avoid supine sleep. Of those who had discontinued TBT who had not taught them-
selves to avoid supine sleeping, 63% reported TBT was too uncomfortable, and
26% indicated it did not improve sleep quality or daytime alertness [3]. A more
recent study recruited patients with mild to severe positional OSA and embedded
an actigraph within a specialized positional device to assess hours of use of the
device. Efficacy of the device was assessed using the change in AHI from baseline
to 3 months, and demonstrated a drop in the AHI from 26.7 events/hour to 6.0
events/hour on the first night of use of the positional therapy device. The AHI
remained stable at the 3-month assessment, and statistically significantly improved
from baseline. The device was used about 73% of the nights for an average of
8 hours per night [12].
Newer devices which provide a vibrational stimulus to induce a positional change
have hit the medical market. The devices are usually applied to the center of the
chest, and held in place using soft straps that run around the patient’s back. Use of
a sleep position treatment (SPT) device has established efficacy. In a study of 101
patients with overall moderate positional OSA, use of a SPT device improved the
AHI from 18.1 events/hour to 10.4 events/hour after 2 months, and the AHI supine
from 35.3 events/hour to 17.5 events/hour. The changes in the AHIs were significant
when compared to the control group [18].
A sleep position treatment device (SPT) was compared with autotitrating CPAP
for the treatment of positional OSA. Patients used both a SPT device and the autoti-
trating CPAP device each for a 6-week period with the intent to demonstrate nonin-
feriority in both AHI and adherence time. The baseline AHI was 21.5 events/hour;
use of the SPT resulted in an AHI of 7.3 events/hour while use of CPAP led to an
AHI of 3.7 events/hour. The difference between the treatment’s AHIs was statisti-
cally significant, however was within the authors’ noninferiority difference range. A
greater number of patients in the autotitrating CPAP group compared to the SPT
group achieved an AHI less than 5 events/hour. The group overall was not sleepy as
reflected by an Epworth Sleepiness Scale less than 10, and although CPAP lowered
the ESS to a greater degree than the SPT, the difference is unlikely to be clinically
relevant. Average adherence to treatment, average nightly duration of use, and the
percentage of nights with use at least 4 hours was significantly greater on SPT than
on CPAP [2].
Surgery
Maxillomandibular Advancement (MMA)
A maxillomandibular advancement (MMA) is a multilevel skeletal procedure

involving a LeFort I combined with bilateral sagittal split rami osteotomies. The
procedures advance the soft palate, tongue base, and suprahyoid musculature lead-
ing to enlargement of the velo-orohypopharyngeal airway. In a meta-analysis of
patients with severe OSA with an average AHI of 54 events/hour, MMA reduced the
AHI by about 87% reaching values under 10 events/hour [5]. The analysis was
based solely on multiple case series. Other outcome measures, such as sleepiness
and cardiovascular metrics, were rarely reported. Although criteria for evaluating
patients for MMA are not standardized, hypopharyngeal with or without velo-oro-
pharyngeal narrowing are common, and usually associated clinically with retrogna-
thia. The procedure can be associated with dental malocclusion and facial
neurosensory deficits [5].
Uvulopalatopharyngoplasty (UPPP)
The uvulopalatopharyngoplasty is a soft palate procedure involving removal of tis-

sue from the soft palate, the uvula, and the tonsils with the goal of reducing or
restructuring the collapsible part of the soft palate. Meta-analysis of mostly male
patients with a baseline AHI of 40.3 events/hour who underwent UPPP ended up
with an AHI of 29.8 events/hour, an overall reduction of 33% [5]. Selection criteria
were variable. The analysis was based mostly on observational studies; however,
there were two small randomized controlled trials included. Reporting of side
effects was inconsistent in the included trials; however, previous reviews reported
difficulty swallowing, nasal regurgitation, taste disturbances, and voice changes [5, 8].
Laser-Assisted Uvuloplasty (LAUP)
This procedure uses laser to shorten the uvula and tighten the posterior soft palate.
When the 2 RCTs were combined with the 6 case series, the overall reduction in
AHI was 33%. Review of the RCTs however demonstrated minimal change in AHI,
or an increase in the AHI after LAUP. The case series suggested a larger range of
AHI improvement with 1 case series demonstrated a 73% reduction in AHI [5].
Radiofrequency Therapies
The use of thermal energy to different upper airway structures has been intended to
reduce the size of collapsible structures. Targeted structures include the soft palate,
the base of the tongue, and a multiple-level approach. The vast majority of the data
in meta-analysis is from observational reports. In the single RCT, the post-surgical
AHI was reduced by 21%. The observational reports demonstrated a combined AHI
reduction from 23.4 events/hour to 14.2 events/hour [5].
Multilevel Surgery
The upper airway demonstrates complex airflow physiology and may have multiple
levels of collapse. Many investigators have advocated a surgical approach to treat-
ment that addresses multiple levels of the upper airway either simultaneously, or in
a step-wise fashion. The vast majority of investigative reports regarding multilevel
surgery consists solely of case series, but generally demonstrate improvement in
AHI comparing the preoperative with postoperative measures. Simultaneous multi-
level surgeries usually combine a UPPP with a tongue-specific procedure, such as
radiofrequency treatment. A retrospective analysis was conducted [9] comparing a
series of patients who underwent UPPP combined with radiofrequency treatment to
the tongue base to a series of patients who underwent UPPP alone, and used the ESS
and polysomnographic measures as outcome assessments. The pre-operative AHI in
the UPPP-only group was 35.4 events/hour and in the UPPP + tongue base radiofre-
quency treatment was 43.9 events/hour (statistically significantly different). The
postoperative AHI was 26.5 event/hour and 28.1 events/hour in the UPPP and UPPP
+ tongue base radiofrequency treatment group, respectively, both measures repre-
senting statistically significant improvements compared to preoperative values, but
not when compared between groups. ESS was noted to improve from a preoperative
level of 15 to a postoperative level of 8 in the UPPP + tongue base radiofrequency
treatment group; similar data was not recorded in the UPPP-only group. A step-wise
multilevel surgical series of 306 patients [31] underwent phase 1 surgery consisting
of UPPP for palatal obstruction and genioglossus advancement with hyoid
myotomy-suspension for obstruction at the level of the base of the tongue. Phase 2
surgery, consisting of maxillomandibular advancement, was offered to patients who
failed phase 1 determined by a comparison between the residual RDI of patients
after surgery and patients using nasal CPAP, and with baseline measures. The pre-
operative RDI was 55.8 events/hour, the RDI on nasal CPAP was 7.2 events/hour,
and the post-operative RDI was 9.2 events/hour. A similar trend was found with
oxyhemoglobin saturation nadirs with the pre-operative value of 70.5%, nasal CPAP
minimum saturation 86.7%, and post-operative saturation nadir of 86.6%.
A randomized assessment of multilevel surgery, consisting of a modified UPPP
combined with radiofrequency tongue reduction, compared with ongoing medical
management in patients with moderate to severe OSA demonstrated a statistically
significantly greater improvement in AHI and sleepiness in patients who underwent
surgical treatment. The resulting mean AHI in the surgery group was 20.8 events/
hour (from a baseline of 47.9 events/hour), which is still in the moderate severity
OSA category; however, it should be emphasized that this was associated with
improvement in sleep-specific quality of life and general health status. The Epworth
Sleepiness Scale in the surgery group decreased from 12.4 at baseline to 5.3 after
surgery, where the ESS did not change medical management group (11.1 at baseline
vs 10.5) [19].
Hypoglossal Nerve Stimulation (HNS)
The relationship between activation of the genioglossus and upper airway patency
was the motivation for evaluating the use of stimulation of the hypoglossal nerve as
a therapy for OSA. An impulse generator is implanted in the subcutaneous tissues
of the upper chest, typically on the right side. The medial branch of the hypoglossal
nerve typically on the right is exposed, and a stimulation lead is wrapped around it.
A sensing lead is placed between the internal and external intercostal muscles at the
fourth intercostal level. When a respiratory effort ensues, the stimulator is activated
and provides an impulse to the hypoglossal nerve causing the tongue to move ante-
riorly. Patients with moderate-to-severe OSA who had either not tolerated PAP
therapy, or who declined to use it were recruited to undergo implantation of the

device. The patients had an AHI of 32 events/hour at baseline with a moderate
amount of fatigue, and daytime sleepiness with an Epworth sleepiness scale of 11.6.
Assessment after 12 months of treatment revealed a drop in the median AHI from
29.3 events/hour to 9.0 events/hour, and 66% of the participants had met the copri-
mary outcome of a drop in AHI by at least 50% and a reduction in AHI to 20 events/
hour or less. Adverse events included tongue weakness, tongue soreness, abrasion
on the underside of the tongue, and discomfort from the stimulation; however, none
of these caused permanent issues [35]. HNS have now been implanted in over
10,000 patients worldwide. Five-year data are available from the initial trial and
demonstrate persistent reductions in AHI, ESS, and QOL scores without the need
for increased stimulation voltage [38].
Conclusion
OSA is a highly prevalent disorder that can be associated with considerable daytime
impairment and significant cardiovascular consequences both of which provide a
compelling indication for treatment. The rationale for the use of CPAP and the body
of evidence that has accumulated provide a sound foundation supporting its use.
The variety of options for administering CPAP therapy should allow for tailoring of
treatment to an individual patient’s needs; however, a significant minority of patients
for whom CPAP is discussed and prescribed either do not tolerate the therapy, or
refuse to use it. Therefore, alternatives to CPAP exist and should be offered when
appropriate and in a judicious fashion.
References
1. Bartolucci ML, Bortolotti F, Corazza G, Incerti Parenti S, Paganelli C, Alessandri Bonetti

G. Effectiveness of different mandibular advancement device designs in obstructive sleep
apnoea therapy: a systematic review of randomised controlled trials with meta-analysis. J Oral
Rehabil. 2021;48:469–86.
2. Berry RB, Uhles ML, Abaluck BK, Winslow DH, Schweitzer PK, Gaskins RA Jr, Doekel
RC Jr, Emsellem HA. NightBalance sleep position treatment device versus auto-adjusting
positive airway pressure for treatment of positional obstructive sleep apnea. J Clin Sleep Med.
2019;15:947–56.
3. Bignold JJ, Deans-Costi G, Goldsworthy MR, Robertson CA, Mcevoy D, Catcheside PG,
Mercer JD. Poor long-term patient compliance with the tennis ball technique for treating posi-
tional obstructive sleep apnea. J Clin Sleep Med. 2009;5:428–30.
4. Block AJ, Faulkner JA, Hughes RL, Remmers JE, Thach B. Clinical conference in pulmonary
disease. Factors influencing upper airway closure. Chest. 1984;86:114–22.
5. Caples SM, Rowley JA, Prinsell JR, Pallanch JF, Elamin MB, Katz SG, Harwick JD. Surgical
modifications of the upper airway for obstructive sleep apnea in adults: a systematic review
and meta-analysis. Sleep. 2010;33:1396–407.
6. Dellweg D, Kerl J, Hoehn E, Wenzel M, Koehler D. Randomized controlled trial of nonin-

vasive positive pressure ventilation (NPPV) versus servoventilation in patients with CPAP-
induced central sleep apnea (complex sleep apnea). Sleep. 2013;36:1163–71.
7. Ebben MR, Narizhnaya M, Segal AZ, Barone D, Krieger AC. A randomised controlled trial on
the effect of mask choice on residual respiratory events with continuous positive airway pres-
sure treatment. Sleep Med. 2014;15:619–24.
8. Franklin KA, Anttila H, Axelsson S, Gislason T, Maasilta P, Myhre KI, Rehnqvist N. Effects
and side-effects of surgery for snoring and obstructive sleep apnea–a systematic review. Sleep.
2009;32:27–36.
9. Friedman M, Ibrahim H, Lee G, Joseph NJ. Combined uvulopalatopharyngoplasty and radio-
frequency tongue base reduction for treatment of obstructive sleep apnea/hypopnea syndrome.
Otolaryngol Head Neck Surg. 2003;129:611–21.
10. Gay P, Weaver T, Loube D, Iber C, Positive Airway Pressure Task, F., Standards of Practice,
C. & American Academy of Sleep, M. Evaluation of positive airway pressure treatment for
sleep related breathing disorders in adults. Sleep. 2006;29:381–401.
11. Gold AR, Schwartz AR. The pharyngeal critical pressure. The whys and hows of using nasal
continuous positive airway pressure diagnostically. Chest. 1996;110:1077–88.
12. Heinzer RC, Pellaton C, Rey V, Rossetti AO, Lecciso G, Haba-Rubio J, Tafti M, Lavigne
G. Positional therapy for obstructive sleep apnea: an objective measurement of patients' usage
and efficacy at home. Sleep Med. 2012;13:425–8.
13. Holley AB, Lettieri CJ, Shah AA. Efficacy of an adjustable oral appliance and comparison
with continuous positive airway pressure for the treatment of obstructive sleep apnea syn-
drome. Chest. 2011;140:1511–6.
14. Issa FG, Sullivan CE. Upper airway closing pressures in obstructive sleep apnea. J Appl
Physiol Respir Environ Exerc Physiol. 1984;57:520–7.
15. Johal A, Haria P, Manek S, Joury E, Riha R. Ready-made versus custom-made mandibu-
lar repositioning devices in sleep apnea: a randomized clinical trial. J Clin Sleep Med.
2017;13:175–82.
16. Kuna ST, Bedi DG, Ryckman C. Effect of nasal airway positive pressure on upper airway size
and configuration. Am Rev Respir Dis. 1988;138:969–75.
17. Kushida CA, Nichols DA, Holmes TH, Quan SF, Walsh JK, Gottlieb DJ, SIMON RD Jr,
Guilleminault C, White DP, Goodwin JL, Schweitzer PK, Leary EB, Hyde PR, Hirshkowitz
M, Green S, Mcevoy LK, Chan C, Gevins A, Kay GG, Bloch DA, Crabtree T, Dement
WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive
sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep.
2012;35:1593–602.
18. Laub RR, Tonnesen P, Jennum PJ. A sleep position trainer for positional sleep apnea: a ran-
domized, controlled trial. J Sleep Res. 2017;26:641–50.
19. Mackay S, Carney AS, Catcheside PG, Chai-Coetzer CL, Chia M, Cistulli PA, Hodge JC,
jones A, Kaambwa B, Lewis R, Ooi EH, Pinczel AJ, Mcardle N, Rees G, Singh B, Stow N,
Weaver EM, Woodman RJ, Woods CM, Yeo A, Mcevoy RD. Effect of multilevel upper airway
surgery vs medical management on the apnea-hypopnea index and patient-reported daytime
sleepiness among patients with moderate or severe obstructive sleep apnea: the SAMS ran-
domized clinical trial. JAMA. 2020;324:1168–79.
20. Madeiro F, Andrade RGS, Piccin VS, Pinheiro GDL, Moriya HT, Genta PR, Lorenzi-Filho
G. Transmission of oral pressure compromises oronasal CPAP efficacy in the treatment of
OSA. Chest. 2019;156:1187–94.
21. Masa JF, Corral J, Alonso ML, Ordax E, Troncoso MF, Gonzalez M, Lopez-Martinez S, Marin
JM, Marti S, Diaz-Cambriles T, chiner E, Aizpuru F, Egea C, Spanish Sleep, N. Efficacy of
different treatment alternatives for obesity hypoventilation syndrome. Pickwick study. Am J
Respir Crit Care Med. 2015;192:86–95.
22. Masa JF, Mokhlesi B, Benitez I, Gomez De Terreros FJ, Sanchez-Quiroga MA, Romero A,
Caballero-Eraso C, Teran-Santos J, Alonso-Alvarez ML, Troncoso MF, Gonzalez M, Lopez-
Martin S, Marin JM, Marti S, Diaz-Cambriles T, Chiner E, Egea C, Barca J, Vazquez-Polo FJ,
Negrin MA, Martel-Escobar M, Barbe F, Corral J, Spanish Sleep N. Long-term clinical effec-
tiveness of continuous positive airway pressure therapy versus non-invasive ventilation therapy
in patients with obesity hypoventilation syndrome: a multicentre, open-label, randomised con-
trolled trial. Lancet. 2019;393:1721–32.
23. Mazza S, Pepin JL, Naegele B, Rauch E, Deschaux C, Ficheux P, Levy P. Driving ability in
sleep apnoea patients before and after CPAP treatment: evaluation on a road safety platform.
Eur Respir J. 2006;28:1020–8.
24. Oksenberg A, Silverberg D, Offenbach D, Arons E. Positional therapy for obstructive sleep
apnea patients: a 6-month follow-up study. Laryngoscope. 2006;116:1995–2000.
25. Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of adult obstruc-
tive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine
Clinical Practice Guideline. J Clin Sleep Med. 2019;15:335–43.
26. Penzel T, Moller M, Becker HF, Knaack L, Peter JH. Effect of sleep position and sleep stage
on the collapsibility of the upper airways in patients with sleep apnea. Sleep. 2001;24:90–5.
27. Permut I, Diaz-Abad M, Chatila W, Crocetti J, Gaughan JP, D'alonzo GE, Krachman
SL. Comparison of positional therapy to CPAP in patients with positional obstructive sleep
apnea. J Clin Sleep Med. 2010;6:238–43.
28. Piper AJ, Wang D, Yee BJ, Barnes DJ, Grunstein RR. Randomised trial of CPAP vs bilevel
support in the treatment of obesity hypoventilation syndrome without severe nocturnal desatu-
ration. Thorax. 2008;63:395–401.
29. Ramar K, Dort LC, Katz SG, Lettieri CJ, Harrod CG, Thomas SM, Chervin RD. 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;11:773–827.
30. Remmers JE, Degroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion
during sleep. J Appl Physiol Respir Environ Exerc Physiol. 1978;44:931–8.
31. Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a review of 306
consecutively treated surgical patients. Otolaryngol Head Neck Surg. 1993;108:117–25.
32. Rowland S, Aiyappan V, Hennessy C, Catcheside P, Chai-Coezter CL, Mcevoy RD, Antic
NA. Comparing the efficacy, mask leak, patient adherence, and patient preference of three
different CPAP interfaces to treat moderate-severe obstructive sleep apnea. J Clin Sleep Med.
2018;14:101–8.
33. Soghier I, Brozek JL, Afshar M, Tamae Kakazu M, Wilson KC, Masa JF, Mokhlesi
B. Noninvasive ventilation versus CPAP as initial treatment of obesity hypoventilation syn-
drome. Ann Am Thorac Soc. 2019;16:1295–303.
34. Strohl KP, Redline S. Nasal CPAP therapy, upper airway muscle activation, and obstructive
sleep apnea. Am Rev Respir Dis. 1986;134:555–8.
35. Strollo PJ Jr, Soose RJ, Maurer JT, De Vries N, Cornelius J, Froymovich O, Hanson RD,
Padhya TA, Steward DL, Gillespie MB, Woodson BT, Van De Heyning PH, Goetting MG,
Vanderveken OM, Feldman N, Knaack I, Strohl KP, Group, S. T. Upper-airway stimulation for
obstructive sleep apnea. N Engl J Med. 2014;370:139–49.
36. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by con-
tinuous positive airway pressure applied through the nares. Lancet. 1981;1:862–5.
37. Vanderveken OM, Devolder A, Marklund M, Boudewyns AN, Braem MJ, Okkerse W,
Verbraecken JA, Franklin KA, DE Backer WA, Van De Heyning PH. Comparison of a custom-
made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir
Crit Care Med. 2008;178:197–202.
38. Woodson BT, Strohl KP, Soose RJ, Gillespie MB, Maurer JT, De Vries N, Padhya TA, Badr
MS, Lin HS, Vanderveken OM, Mickelson S, Strollo PJ Jr. Upper airway stimulation for
obstructive sleep apnea: 5-year outcomes. Otolaryngol Head Neck Surg. 2018;159:194–202.
Chapter 8
Central Sleep Apnea: Pathophysiology
and Clinical Management
M. Safwan Badr and Geoffrey Ginter
Keywords Central apnea · Hypoventilation · Hyperventilation · Hypocapnia ·

Cheyne–Stokes respiration · CPAP · Adaptive servo-ventilation
Central sleep apnea is a manifestation of breathing instability in a variety of clinical

conditions and is often bundled under the rubric of obstructive sleep apnea. Central
sleep apnea occurs because of a transient cessation of ventilatory motor output,
under several physiologic or pathologic conditions. This chapter will address the
pathogenesis, clinical features, and management of central sleep apnea.
Determinants of Central Apnea During NREM Sleep
Hypocapnia
The sleep state (specifically non-rapid eye movement or NREM sleep) removes the
wakefulness “drive to breathe” and renders respiration critically dependent on chem-
ical influences, especially partial pressure of carbon dioxide (PCO2). Central apnea
results if arterial PCO2 is lowered below a highly sensitive “apneic threshold.” [1, 2]
Hypocapnia is a potent but not an omnipotent mechanism of reduced ventilatory
motor output during NREM sleep. Several factors modulate and mitigate the effects
of hypocapnia on ventilatory motor output and promote stability of respiration.
M. S. Badr (*)
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine,
Harper University Hospital, Wayne State University School of Medicine, Detroit, MI, USA
e-mail: sbadr@med.wayne.edu
G. Ginter
Department of Internal Medicine, Harper University Hospital, Wayne State University School
of Medicine, Detroit, MI, USA

146 M. S. Badr and G. Ginter
Short-Term Potentiation
Actively induced hyperventilation (such as hypoxic hyperventilation) is associ-

ated with activation of an excitatory neural mechanism referred to as short-term
potentiation (STP) [3–5], which results in a gradual return of ventilation toward
the baseline upon cessation of the stimulus to breathe. STP has been demon-
strated in humans as well as in animals, and is unaffected by the state of con-
sciousness. STP may play a significant role in preserving rhythmic respiration by
preventing abrupt drop in ventilation during transient hypocapnia such as follow-
ing brief hypoxia or transient arousal. In fact, central apnea rarely occurs follow-
ing termination of brief hypoxia, despite hypocapnia at or below the apneic
threshold [3–5]. Similarly, although hypocapnia occurs during transient arousals
from sleep, the activation of STP may mitigate the occurrence of central apnea
under these conditions [6]. However, prolonged hypoxia may abolish STP, which
may explain the development of periodic breathing after 20–25 min of hypoxia
and the occurrence of central apnea upon termination of prolonged hypoxic expo-
sure [5, 7].
Duration of Hyperpnea
The duration of hyperpnea is another important determinant of reduced ventilatory

motor output following hyperventilation. Central apnea does not usually occur fol-
lowing brief arousal in sleeping humans [8] or dogs [9] possibly due to insufficient
reduction in PCO2 at the level of the central chemoreceptors.
In summary, the balance between hypocapnia and short-term potentiation deter-
mines the occurrence of post-hyperventilation apnea during stable sleep, while the
duration of hyperventilation may determine whether the reduction in medullary
PCO2 is enough for the development of central apnea.
Role of Upper Airway Reflexes
While hypocapnia is the most common influence leading to central apnea, other
mechanisms may also induce central apnea. For example, negative pressure–induced
deformation of the isolated upper airway causes central apnea in dogs during both
wakefulness and sleep [10]. Whether such reflexes contribute to the developments
of central apnea in sleeping humans remains speculative. Conversely, central apnea
occurs more frequently in the supine position [11–13] and may be reversed with
nasal continuous positive airway pressure (CPAP) [14]. Likewise, there is evidence
of supine dependency including that the lateral position amelioration of severity of
central apnea and Cheyne–Stokes respiration [11–13].
8 Central Sleep Apnea: Pathophysiology and Clinical Management 147
Mechanisms Perpetuating Breathing Instability
Central apnea does not occur as a single event, but as cycles of apnea/hypopnea
alternating with hyperpnea. Ventilatory control during sleep operates as a negative-
feedback closed-loop cycle to maintain homeostasis of blood gas tensions within a
physiologic range. Many authors have adopted the engineering concept of “loop
gain” as a measure of ventilatory stability or susceptibility to central apnea and
recurrent periodic breathing [15]. Loop gain represents the overall response of the
plant (representing the lung and respiratory muscles); the controller (representing
the ventilatory control centers and the chemoreceptors); and the delay, dilution, and
diffusion inherent in transferring the signal between the plant and the controller. The
formula for loop gain is as follows:
Loop gain Controller gain Plant gain

Ventilation PCO2

PCO2 Ventilation
The formula can be expanded to account for pulmonary blood flow (Q, equiva-
lent to cardiac output) and carbon dioxide–carrying capacity of the blood (β); the
derivation for this expanded equation can be found in the study by Ghazanshahi and
Khoo [16]. These two factors comprise the rate of carbon dioxide delivery to the
chemoreceptors and the lungs, which, when delayed, can increase loop gain by
producing lag between the disturbance (initial change in ventilation or carbon diox-
ide) and the response. A greater loop gain represents increased reactivity of the
ventilatory circuit to disturbances and, consequently, ventilatory instability [17].
Central sleep apnea is associated with increased loop gain, which can be observed
in conditions such as congestive heart failure (CHF – increased controller gain and
prolonged circulation time) or obesity and tetraplegia (increased plant gain resulting
from decreased lung volumes) [17–19]. Conversely, a lower loop gain corresponds
to greater ventilatory stability, as is observed during REM sleep [20]. A detailed
discussion of the dynamics of ventilatory control is beyond the scope of this chap-
ter; however, there are several excellent reviews that have discussed this aspect in
detail [21–23].
The occurrence of central apnea is associated with several consequences that
conspire to promote further breathing instability:
• Once ventilatory motor output ceases, rhythmic breathing does not resume at
eupneic arterial PCO2 (PaCO2) due to inertia of the ventilatory control system; an
increase in PaCO2 by 4–6 mmHg above eupnea is required for resumption of
respiratory effort [24].
• Central apnea is associated with narrowing or occlusion of the pharyngeal air-
way [25]. Thus, resumption of ventilation requires opening of a narrowed or
occluded airway and overcoming tissue adhesion forces [26] and craniofacial
gravitational forces.
Termination of central apnea is associated with variable changes in arterial blood

gases (hypoxia and hypercapnia) and transient EEG arousal, resulting in ventilatory
overshoot, subsequent hypocapnia, and a recurrence of apnea/hypopnea. This
sequence explains why apnea rarely occurs as a single event (i.e., “apnea begets
apnea”) and why there is an overlap between central and obstructive apnea (upper
airway obstruction often follows central apneas upon resumption of respiratory
effort, i.e., mixed apnea).
Pathophysiologic Classification of Central Sleep Apnea
Central apnea syndrome may be present in a diverse group of conditions including

heart failure and obstructive sleep apnea. The ICSD-3 lists several categories of
central apnea: (1) Primary Central Sleep Apnea, (2) Central Sleep Apnea Due to
Cheyne–Stokes Breathing Pattern, (3) Central Sleep Apnea Due to Medical
Condition Not Cheyne–Stokes, (4) Central Sleep Apnea due to High Altitude
Periodic Breathing, (5) Central Sleep Apnea Due to Drug or Substance Use, (6)
Central Sleep Apnea of Infancy, (7) Central Sleep Apnea of Prematurity, and (8)
Treatment-Emergent Central Sleep Apnea [27]. Central apneas are caused either by
hyperventilation or hypoventilation. Primary central sleep apnea (CSA), Cheyne–
Stokes respiration with central sleep apnea (CSA-CSR), and CSA at high altitude
are examples of CSA-related to hyperventilation. Central sleep apnea due to drug or
substance use is due to hypoventilation, whereas central apnea associated with other
medical conditions may be due to either hyperventilation or hypoventilation. The
underlying mechanisms influence the choice of therapy including optimization of
medical therapy in central apnea associated with other conditions such as heart fail-
ure, hypothyroidism, or acromegaly.
The level of arterial PCO2 during wakefulness is often used to classify central
apnea as hypercapnic or non-hypercapnic. However, such classification does not
capture the underlying pathogenesis as apnea represents hypoventilation or a conse-
quence of hyperventilation.
Central Sleep Apnea Secondary to Hypoventilation
The sleep state is associated with reduced ventilatory motor output, increased
upper airway resistance, and hypoventilation. This physiologic constellation
carries pathologic consequences in patients with an underlying abnormality in
ventilatory control or impaired pulmonary mechanics. Most afflicted patients
suffer from a central nervous system disease (e.g., encephalitis), neuromuscular
disease (e.g., post-polio syndrome), or severe abnormalities in pulmonary
mechanics (e.g., kyphoscoliosis [28]). Thus, the hallmark of this disease is alve-
olar hypoventilation representing nocturnal ventilatory failure or worsening of
the underlying chronic disease. Arousal from sleep restores alveolar ventilation
to a variable degree; resumption of sleep reduces ventilation in a cyclical
fashion.
Central apnea secondary to hypoventilation does not necessarily meet the strict
definition of “apnea,” since feeble ventilatory motor output may persist albeit below
the thresholds required to preserve alveolar ventilation. Likewise, it may not meet
the definition of “central” in patients with respiratory muscle disease or skeletal
deformities. Consequently, the presenting clinical picture includes both features of
the underlying ventilatory insufficiency (e.g., morning headache, cor pulmonale,
peripheral edema, polycythemia, and abnormal pulmonary function tests) and fea-
tures of the sleep apnea/hypopnea syndrome (e.g., poor nocturnal sleep, snoring,
and daytime sleepiness).
A rare but interesting group of patients present with primary alveolar hypoventi-
lation manifesting by daytime hypoventilation without an apparent identifiable
cause and blunted chemo responsiveness [29, 30]. Congenital central hypoventila-
tion syndrome (CCHS) results from a mutation in the gene that encodes the homeo-
box (PHOX) 2B gene.
The mechanism(s) responsible for hypercapnic central sleep apnea in a given
patient influence(s) the management strategy, which aims to restore effective alveo-
lar ventilation during sleep. Treatment of choice is assisted ventilation; nasal CPAP
and supplemental oxygen are unlikely to alleviate the condition.
Central Apnea Secondary to Hyperventilation
Hypocapnia secondary to hyperventilation is the most common underlying mecha-

nism of central apnea. A typical patient with non-hypercapnic central apnea has no
evidence of a neuromuscular disorder, abnormal lung mechanics, or impaired
responses to chemical stimuli. Accordingly, apnea is a result of a transient instabil-
ity rather than a ventilatory control defect.
How does the first apnea begin? Several transient perturbations may trigger the
initial event, including oscillation in sleep state [31], or transient hypoxia possibly
due to retention of secretions or reduced lung volumes at sleep onset. Thus, hypoxia
stimulates ventilation, subsequently leading to hypocapnia and apnea. The occur-
rence of apnea initiates the repetitive process of apnea–hyperpnea and leads to sus-
tained breathing instability, manifested as periodic breathing (see above). In
summary, non-hypercapnic central apnea is a heterogeneous entity that may be an
idiopathic or a secondary condition. The pathogenesis may vary depending upon the
clinical condition. However, hypocapnia secondary to hyperventilation is the com-
mon denominator in this group of disorders.
Central Apnea Risk Factors
Sleep State
Transient breathing instability and central apnea may occur during the transition
from wakefulness to NREM sleep. As sleep state oscillates between wakefulness
and light sleep [32–34], the level of PaCO2 is at or below the hypocapnic level
required to maintain rhythmic breathing during sleep (i.e., the “apneic threshold”),
resulting in central apnea. Recovery from apnea is associated with transient wake-
fulness and hyperventilation. The subsequent hypocapnia elicits apnea upon
resumption of sleep. Consolidation of sleep alleviates the oscillation in sleep and
respiration and stabilizes PaCO2 at a higher set point above the apneic threshold.
Sleep onset is also associated with another type of central apnea, not preceded by
hyperventilation. The transition from alpha to theta in normal subjects is associated
with prolongation of breath duration [35].
Central apnea at sleep onset if often considered “physiologic,” albeit not univer-
sal. Furthermore, events that occur during epochs scored as “wakefulness” are not
captured. Whether sleep-onset central apnea is truly physiologic, or a reflection of
increased loop gain is yet to be determined. The clinical implications and natural
history of this “phenomenon” is unknown.
Central sleep apnea is uncommon during REM sleep as many studies suggest
that breathing during REM sleep is impervious to chemical influences (REF), pos-
sibly due to increased ventilatory motor output during REM sleep [36, 37] relative
to NREM sleep. In addition, there is evidence in animal studies that hypocapnia, per
se, may decrease the amount of REM sleep [38]. The major barrier to answering this
question in humans is the difficulty in conducting such experiments without disrupt-
ing REM sleep.
The loss of intercostal and accessory muscle activity during REM sleep leads to
a reduction of alveolar ventilation. This may manifest as apparent central apnea or
hypopnea in patients with compromised lung mechanics or neuromuscular disease.
If severe diaphragm dysfunction is present, nadir tidal volume may be negligible
and the event may appear as central apnea. Thus, central apnea during REM sleep
represents transient hypoventilation rather than post-hyperventilation hypocapnia.
Age and Gender
Central sleep apnea is more prevalent in older adults relative to middle-aged indi-
viduals [39–41]. Physiologically, sleep state oscillations may precipitate central
apnea in older adults [42]. Increased prevalence of comorbid conditions such as
thyroid disease [43], congestive heart failure [44], atrial fibrillation [45], and cere-
brovascular disease [46] may also contribute to increased susceptibility to develop
central apnea in older adults.
Central sleep apnea is uncommon in premenopausal women [47]. There is evi-

dence that women are less susceptible to the development of hypocapnic central
apnea relative to men following mechanical ventilation. Physiologically, the hypo-
capnic apneic threshold is higher in men relative to women. Using nasal mechanical
ventilation during stable NREM sleep, Zhou et al. [2] have shown that the apneic
threshold was −3.5 versus −4.7 mmHg below room air level in men and women
respectively. This difference was not due to progesterone. In fact, administration of
testosterone to healthy premenopausal women for 12 days resulted in an elevation
of the apneic threshold and a diminution in the magnitude of hypocapnic required
for induction of central apnea during NREM sleep [48]. Conversely, suppression of
testosterone with leuprolide acetate in healthy males decreases the hypocapnic
apneic threshold and potentially stabilizing respiration [49]. Thus, male sex hor-
mones are the most likely factor elevating the apneic threshold in men.
Medical Conditions
Sleep apnea is highly prevalent in patients with CHF [44, 50–52]. Javaheri et al.
[51] demonstrated that 51% of male patients with CHF had sleep-disordered breath-
ing, 40% had central sleep apnea, and 11% obstructive apnea. Risk factors for CSA
in this group of patients include male gender, atrial fibrillation, age >60 years, and
daytime hypocapnia (PCO2 < 38 mmHg during wakefulness) [53]. Risk factors for
OSA differed by gender; the only independent determinant in men was body mass
index (BMI), whereas age over 60 was the only independent determinant in women.
Hyperventilation is a common breathing pattern in patients with CHF, who dem-
onstrate daytime hypocapnia and minimal or no rise in PET CO2 from wakefulness
to sleep [54]. Chronic hyperventilation results in decreased plant gain [55, 56],
which mitigates the magnitude of hypocapnia for a given increase in alveolar venti-
lation. In other words, steady-state hyperventilation and hypocapnia are potentially
stabilizing rather than destabilizing as is commonly thought. Increased propensity
to central apnea in patients with CHF is due to increased hypocapnic chemosensitiv-
ity (increased controller gain) and prolonged circulatory delay.
Sleep apnea is also common after a cerebrovascular accident (CVA) [46]; with
central apnea being the predominant type in 40% of patients with sleep apnea after
a CVA [57, 58]. Likewise, central apnea occurs in 30% of patients who are on stable
methadone maintenance treatment [59]. Finally, several medical conditions predis-
pose to the development of central apnea including hypothyroidism, acromegaly,
and renal failure have an unexpectedly high prevalence of sleep apnea [60–62].
Nocturnal hemodialysis is associated with improvement in sleep apnea indices in
patients with renal failure [62].
Cervical spinal cord injury (C-SCI) has also recently been identified as a risk
factor for the development of central sleep apnea [63]. The mechanism underlying
CSA in C-SCI is uncertain. Potential mechanisms include loss of intercostal muscle
activity or decreased lung volume [64]. A reduction in lung volume results in
increased plant gain, which causes an exaggerated change in PCO2 in response to

changes in ventilation [65]. SCI has also been shown to increase peripheral chemo-
sensitivity, possibly due to potentiation of the neurocircuitry regulating the produc-
tion of serotonin, which is implicated in plasticity of the respiratory circuit [66]. The
combination of increased plant gain and increased peripheral chemosensitivity may
promote instability via ventilatory overshoot in response to minor derangements in
ventilation or PCO2, leading to central apnea.
Some patients with central apnea have no apparent risk factor and are deemed to
have “idiopathic central apnea.” Typically, these patients demonstrate increased
chemo-responsiveness and sleep state instability [67]. It is plausible that these
patients will have occult cardiac or metabolic disease. For example, idiopathic cen-
tral sleep apnea is more prevalent in patients with atrial fibrillation [45].
Central sleep apnea can also develop during treatment of obstructive sleep apnea.
Treatment-emergent central sleep apnea (TECSA) is primarily associated with the
initiation of CPAP therapy, but has been observed in other OSA therapies, including
mandibular advancement devices and surgical intervention [68, 69]. TECSA may be
either transient or persistent, often resolving spontaneously with persistent positive
airway pressure (PAP) therapy [69]. Possible mechanisms underlying TECSA
include increased elimination of CO2 following relief of airway obstruction, hyper-
ventilation due to PAP-related arousals, and over-titration causing activation of lung
stretch receptors and subsequent inhibition of respiratory drive [68].
Clinical Features and Diagnosis
The clinical presentation includes features of the underlying disease and features of
sleep apnea syndrome. Patients with central apnea secondary to hyperventilation
may present with the usual symptoms of sleep apnea syndrome. Alternatively, they
may present with insomnia and poor nocturnal addition. Frequent oscillation
between wakefulness and stage 1 NREM sleep may promote sleep fragmentation
and poor nocturnal sleep as the presenting symptoms.
Central sleep apnea may also be a found as an incidental polysomnographic find-
ing in a patient with obstructive sleep apnea, either on the initial diagnostic study or
after restoring upper airway patency with nasal CPAP. The latter is referred to as
“complex sleep apnea,” implying a distinct clinical entity. However, it is likely that
this phenomenon represents unmasking of the underlying breathing instability in
patients with obstructive sleep apnea and may resolve spontaneously [70, 71].
Nocturnal polysomnography is the standard diagnostic method including mea-
surement of sleep and respiration, and also including detection of flow, measure-
ment of oxyhemoglobin saturation, and detection of respiratory effort. Detection of
respiratory effort is important to distinguish central from obstructive apnea. Most
clinical sleep laboratories utilize surface recording of effort to detect displacement
of the abdominal and thoracic compartments instead of esophageal pressure
recording.
The presence of cardiogenic oscillations (pulse artifacts) on the flow signal has
been used as an indirect index of central etiology. The underlying rationale is the
pulse artifacts represent transmission of a pulse waveform from the thorax, and
hence indicates a patent upper airway that allows the transmission of cardiogenic
oscillation. Morrell et al. [72] used fiber optic nasopharyngoscopy to evaluate upper
airway patency during central apnea; cardiogenic oscillations were present even
when the airway is completely occluded. Thus, the presence of cardiogenic oscilla-
tions does not prove upper airway patency or central etiology.
Management
Central sleep apnea is a disorder with protean manifestations and underlying condi-
tions. The presence of comorbid conditions and concomitant obstructive sleep
apnea influence therapeutic approach significantly. Specific therapeutic options
include positive pressure therapy, pharmacologic therapy, and supplemental oxygen.
Positive Pressure Therapy
CPAP therapy is the initial treatment of choice for central sleep apnea. Published
practice parameters by the American Academy of Sleep Medicine recommends
CPAP as a standard therapy, based on the preponderance of evidence supporting its
use [73]. Most of this evidence comes from investigations on central apnea related
to congestive heart failure (CHF), although other subtypes of central sleep apnea
appear to respond to CPAP as well, especially if it occurs in combination with epi-
sodes of obstructive or mixed apnea. In fact, “pure” central apnea with no concomi-
tant obstructive events is uncommon. If a comorbid clinical condition is present,
such as heart failure, hypothyroidism, or acromegaly, optimization of medical ther-
apy is also required and may ameliorate the severity of central apnea. Likewise,
central sleep apnea in patients with obstructive sleep apnea may resolve with alle-
viation of upper airway obstruction with positive pressure therapy. Many patients
with idiopathic central sleep apnea receive a trial of nasal CPAP, which has been
shown to reverse central sleep apnea, even in the absence of obstructive respiratory
events [14], especially supine-dependent central sleep apnea. The response may be
due to preventing upper airway occlusion during central apnea and subsequent ven-
tilatory overshoot [25]. Prevention of ventilatory overshoot may explain the reported
combination of reduced apnea frequency and increased PCO2 after CPAP [74].
Nasal CPAP is the initial option during a therapeutic titration study, despite the lack
of systematic studies on nasal CPAP therapy in patients with idiopathic cen-
tral apnea.
The exuberance regarding nasal CPAP therapy in patients with central apnea and
CHF did not withstand the rigors of controlled clinical trials. The Canadian
Continuous Positive Airway Pressure trial, or Can PAP [75] tested the hypothesis
that CPAP would improve the survival rate without heart transplantation in patients
with heart failure and central sleep apnea. This type of central apnea corresponds to
Central Sleep Apnea Due to Cheyne–Stokes Breathing Pattern, in the International
Classification of Sleep Disorders – Third Edition (ICSD-3). Participants were ran-
domly assigned to nasal CPAP or no CPAP. There was no difference in the overall
event rates (death and heart transplantation) between the two groups after a 2-year
follow-up, despite greater improvement in the CPAP group at 3 months in several
intermediate outcomes including apnea–hypopnea index, ejection fraction, mean
nocturnal oxyhemoglobin saturation, plasma norepinephrine levels, and the distance
walked in 6 min at 3 months. Thus, nasal CPAP had no measured effect on survival,
despite the effect on the “severity” of central apnea and several intermediate out-
come variables. Therefore, current evidence supports the use of CPAP to alleviate
the severity of central sleep apnea and improve daytime function and quality of life.
Noninvasive positive pressure ventilation (NIPPV) using pressure support mode
(bi-level nasal positive pressure) is effective in restoring alveolar ventilation during
sleep. Clinical indications include nocturnal ventilatory failure and central apnea
secondary to hypoventilation. There is evidence that NIPPV exerts a salutary effect
on survival in patients with ventilatory failure secondary to amyotrophic lateral
sclerosis [76]. It is unclear whether NIPPV exerts a similar effect in other neuro-
muscular conditions associated with nocturnal ventilatory failure. However, the
overall evidence supports the use of NIPPV in a pressure support mode to treat
central sleep apnea secondary to hypoventilation, such as neuromuscular or chest
wall–related nocturnal hypoventilation. If the ventilatory motor output is insuffi-
cient to “trigger” the mechanical inspiration, adding a backup rate ensure adequate
ventilation.
Treatment of central apnea secondary to hyperventilation using nasal pressure
support ventilation in the bi-level mode may result in worsening of central apnea
and breathing instability owing to augmented ventilatory overshoot and hypocapnia
[77]. The work of Meza et al. [78] provides empiric evidence that pressure-support
ventilation results in periodic breathing and recurrent central apnea when the pres-
sure gradient is above 7 cm H2O. The addition of a backup rate would be required
to maintain stable respiration, which would convert ventilatory support to controlled
mechanical ventilation. In general, bi-level positive pressure therapy is unlikely to
alleviate central apnea, without a backup rate. Nevertheless, bi-level PAP may ame-
liorate central apnea that accompanies severe obstructive apnea by preventing upper
airway obstruction and ventilatory overshoot.
Recent technological advances allowed for variations in the mode of delivering
positive pressure ventilation. One example is Adaptive Servo-Ventilation (ASV),
which provides a small but varying amount of ventilatory support and a back-up
rate, against a background of low level of CPAP. The device maintains ventilation
at 90% of a running 3-min reference period; thus, changes in respiratory effort
results in reciprocal changes in the magnitude of ventilatory support. There is
evidence that ASV is more effective than CPAP, bi-level pressure support ventila-
tion, or increased dead space in alleviating central sleep apnea [79, 80]. However,
the Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure
(SERVE-HF) trial demonstrated a significant increase in both all-cause and car-
diac mortality in individuals with CHF with a left ventricular ejection fraction
(LVEF) <45%, leading the American Academy of Sleep Medicine to recommend
against the use of ASV in this population [81, 82]. ASV is still permissible for
patients with CSA with CHF with LVEF >45% [82]. In patients for whom there
are no absolute contraindications to ASV, the decision to initiate ASV hinges on
the efficacy of the treatment in normalizing AHI, patient preference, payers’ pref-
erence, and the availability of the requisite support for adherence or
troubleshooting.
Pharmacological Therapy
Pharmacologic therapy for central apnea remains elusive, and there are no con-
trolled clinical trials demarcating the boundaries of effectiveness [83]. Several small
clinical trials indicate that acetazolamide, theophylline, or zolpidem may be benefi-
cial in the treatment of central apnea [84, 85]. Acetazolamide is a weak diuretic and
a carbonic anhydrase inhibitor that causes mild metabolic acidosis. Acetazolamide
ameliorates central sleep apnea when administered as a single dose of 250 mg
before bedtime [18, 84]. Likewise, theophylline ameliorates the severity of Cheyne–
Stokes respiration in patients with CHF [85], without adverse effect on sleep archi-
tecture. Zolpidem – a non-benzodiazepine sedative hypnotic – has been shown in
one study to reduce the severity of central sleep apnea and improve sleep continuity
[86]. However, there are no controlled studies demonstrating safety and efficacy;
therefore, zolpidem cannot be recommended for the treatment of central apnea.
Recently, serotonergic drugs have been investigated as possible therapies for central
sleep apnea due to the modulatory role serotonin plays in the respiratory circuit.
Buspirone, an anxiolytic and direct serotonin receptor agonist, has demonstrated
some efficacy in treating central sleep apnea [87, 88]. Nevertheless, safety and effi-
cacy of the pharmacologic agents await empiric proof. Pharmacologic therapy rep-
resents a major opportunity for future investigation.
Supplemental O2 and CO2
Several studies have demonstrated a salutary effect of supplemental O2 in patients

with idiopathic central sleep apnea and patients with Central Sleep Apnea Due to
Cheyne–Stokes Breathing Pattern [89]. Several potential mechanisms may explain
the stabilizing effect of supplemental oxygen on respiration. Oxygen dampens

peripheral chemoreceptor responsiveness and minimizes the subsequent ventilatory
overshoot. In addition, prolonged hyperoxia stimulates respiration, perhaps by ele-
vating cerebral PCO2 by the Haldane effect. Acute administration of oxygen is asso-
ciated with diminished propensity to develop central apnea in normal subjects
during sleep [90]. While long-term clinical trials are lacking, supplemental oxygen
therapy is a promising adjunct for central apnea, especially in patients with
CHF. Likewise, supplemental CO2 abolishes central apnea in patients with pure
central sleep apnea, by raising PCO2 above the apneic threshold [91, 92]. However,
this therapy is not practical given the need for a closed circuit to deliver supple-
mental CO2.
Transvenous Phrenic Nerve Stimulation
A recent development in the treatment of CSA is the use of implantable device-

based therapy to pace the diaphragm in response to cessation of respiratory drive.
Transvenous phrenic nerve stimulation (TPNS) involves an implantable 2-lead sys-
tem, including a sensory lead which detects pauses in respiration and a stimulatory
lead affixed to the phrenic nerve, which initiates contraction of the corresponding
hemidiaphragm via a pulse generator implanted in the pectoral region [93]. TPNS
significantly reduces the frequency of central apnea, nocturnal oxyhemoglobin
desaturations, and arousals while improving sleep architecture and subjective sleep
quality [94]. Benefits of TPNS include portability, effective control of central sleep
apnea symptoms, and avoidance of nonadherence. The most common adverse effect
of TPNS is discomfort, occurring in up to one-third of patients, but less than 5% of
patients receiving TPNS elect to discontinue therapy [95]. As a recent innovation,
there are no long-term clinical trials following the safety and efficacy of TPNS;
however, the implementation of implantable devices represents an area of signifi-
cant potential utility in the treatment of central sleep apnea.
A Suggested Approach
The heterogeneity of central sleep apnea dictates individualized treatment approach,

including optimal treatment of underlying medical conditions and attention to
potential medication effects. A trial of nasal CPAP in the sleep laboratory is war-
ranted to ascertain the magnitude of improvement with CPAP alone. The use of
BPAP in a pressure support mode is likely to aggravate the severity of central apnea,
unless accompanied by a backup rate. While contraindicated in patients with CHF
and LVEF <45%, ASV may be beneficial in patients with CSR secondary to CHF
with LVEF >45% who do not respond to nasal CPAP alone. Supplemental O2 may
be beneficial in patients with central apnea that persists on nasal CPAP, especially
in patients with CHF-CSR.
Summary of Key Points

• Sleep-related withdrawal of the ventilatory drive to breathe is the common
denominator among all cases of central apnea, whereas hypocapnia is the
final common pathway leading to apnea in non-hypercapnic central apnea.
• The pathophysiologic heterogeneity may explain the protean clinical man-
ifestations and the lack of a single effective therapy for all patients.
• Central sleep apnea is not a single clinical entity; instead, it is a manifesta-
tion of breathing instability in a variety of clinical conditions. Central
apnea syndrome may be present in a diverse group of conditions including
heart failure and obstructive sleep apnea.
• Central sleep apnea is caused either by hyperventilation or hypoventila-
tion. Hypocapnia is the most potent and ubiquitous trigger of central sleep
apnea. Central apnea rarely occurs as a single event; instead, it manifests
by cycles of apnea/hypopnea alternating with hyperpnea.
• Central sleep apnea is classified into the following specific categories
according to the ICSD-3: (1) Primary Central Sleep Apnea, (2) Central
Sleep Apnea Due to Cheyne–Stokes Breathing Pattern, (3) Central Sleep
Apnea Due to Medical Condition Not Cheyne–Stokes, (4) Central Sleep
Apnea due to High Altitude Periodic Breathing, (5) Central Sleep Apnea
Due to Drug or Substance Use, (6) Central Sleep Apnea of Infancy, (7)
Central Sleep Apnea of Prematurity, and (8) Treatment-Emergent Central
Sleep Apnea. The underlying mechanisms influence the choice of therapy
including optimization of medical therapy in central apnea associated
with other conditions such as heart failure, hypothyroidism, or acromegaly.
• Advanced age, male gender, and postmenopausal state in women are
known determinants of central apnea. In contrast, central apnea is less
common in REM sleep. Medical conditions which are associated with
higher risk of central sleep apnea include CHF, CVA, chronic narcotics
users, acromegaly, chronic renal failure, hypothyroidism, and spinal cord
injury. Treatment-emergent central sleep apnea may also arise during treat-
ment of obstructive sleep apnea.
• Clinical features are a combination of sleep apnea features and comorbid
conditions. The diagnosis requires nocturnal polysomnography. Specific
therapeutic options include positive pressure therapy, pharmacologic ther-
apy, supplemental oxygen, and transvenous phrenic nerve stimulation.
Nasal CPAP is the recommended initial treatment of choice.
References
1. Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic
ventilation. J Appl Physiol Respir Environ Exerc Physiol. 1983;55(3):813–22.
2. Zhou XS, Shahabuddin S, Zahn BR, Babcock MA, Badr MS. Effect of gender on the
development of hypocapnic apnea/hypopnea during NREM sleep. J Appl Physiol (1985).
2000;89(1):192–9.
3. Tawadrous FD, Eldridge FL. Posthyperventilation breathing patterns after active hyperventila-
tion in man. J Appl Physiol. 1974;37(3):353–6.
4. Eldridge FL, Gill-Kumar P. Central neural respiratory drive and after discharge. Respir
Physiol. 1980;40(1):49–63.
5. Badr MS, Skatrud JB, Dempsey JA. Determinants of poststimulus potentiation in humans dur-
ing NREM sleep. J Appl Physiol (1985). 1992;73(5):1958–71.
6. Badr MS, Morgan BJ, Finn L, et al. Ventilatory response to induced auditory arousals during
NREM sleep. Sleep. 1997;20(9):707–14.
7. Berssenbrugge A, Dempsey J, Iber C, Skatrud J, Wilson P. Mechanisms of hypoxia-induced
periodic breathing during sleep in humans. J Physiol. 1983;343:507–24.
8. Badr MS, Kawak A. Post-hyperventilation hypopnea in humans during NREM sleep. Respir
Physiol. 1996;103(2):137–45.
9. Chow CM, Xi L, Smith CA, Saupe KW, Dempsey JA. A volume-dependent apneic threshold
during NREM sleep in the dog. J Appl Physiol (1985). 1994;76(6):2315–25.
10. Harms CA, Zeng YJ, Smith CA, Vidruk EH, Dempsey JA. Negative pressure-induced defor-
mation of the upper airway causes central apnea in awake and sleeping dogs. J Appl Physiol
(1985). 1996;80(5):1528–39.
11. Sahlin C, Svanborg E, Stenlund H, Franklin KA. Cheyne-Stokes respiration and supine depen-
dency. Eur Respir J. 2005;25(5):829–33.
12. Oksenberg A, Arons E, Snir D, Radwan H, Soroker N. Cheyne-Stokes respiration during sleep:
a possible effect of body position. Med Sci Monit. 2002;8(7):Cs61–5.
13. Szollosi I, Roebuck T, Thompson B, Naughton MT. Lateral sleeping position reduces severity
of central sleep apnea / Cheyne-Stokes respiration. Sleep. 2006;29(8):1045–51.
14. Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest.
1986;90(2):165–71.
15. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing periodic breathing in
humans: a general model. J Appl Physiol Respir Environ Exerc Physiol. 1982;53(3):644–59.
16. Ghazanshahi SD, Khoo MC. Estimation of chemoreflex loop gain using pseudorandom binary
CO2 stimulation. IEEE Trans Biomed Eng. 1997;44(5):357–66.
17. Sands SA, Mebrate Y, Edwards BA, et al. Resonance as the mechanism of daytime periodic
breathing in patients with heart failure. Am J Respir Crit Care Med. 2017;195(2):237–46.
18. Ginter G, Sankari A, Eshraghi M, et al. Effect of acetazolamide on susceptibility to central
sleep apnea in chronic spinal cord injury. J Appl Physiol (1985). 2020;128(4):960–6.
19. Bokov P, Essalhi M, Delclaux C. Loop gain in severely obese women with obstructive sleep
apnoea. Respir Physiol Neurobiol. 2016;221:49–53.
20. Badr MS, Dingell JD, Javaheri S. Central sleep apnea: a brief review. Curr Pulmonol Rep.
2019;8(1):14–21.
21. Khoo MC. Determinants of ventilatory instability and variability. Respir Physiol.
2000;122(2–3):167–82.
22. Chapman KR, Bruce EN, Gothe B, Cherniack NS. Possible mechanisms of periodic breathing
during sleep. J Appl Physiol (1985). 1988;64(3):1000–8.
23. Cherniack NS, Longobardo GS. Mathematical models of periodic breathing and their usefulness
in understanding cardiovascular and respiratory disorders. Exp Physiol. 2006;91(2):295–305.
24. Leevers AM, Simon PM, Dempsey JA. Apnea after normocapnic mechanical ventilation dur-
ing NREM sleep. J Appl Physiol (1985). 1994;77(5):2079–85.
25. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central
sleep apnea. J Appl Physiol (1985). 1995;78(5):1806–15.
26. Olson LG, Strohl KP. Airway secretions influence upper airway patency in the rabbit. Am Rev
Respir Dis. 1988;137(6):1379–81.
27. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifica-
tions. Chest. 2014;146(5):1387–94.
28. Mezon BL, West P, Israels J, Kryger M. Sleep breathing abnormalities in kyphoscoliosis. Am
Rev Respir Dis. 1980;122(4):617–21.
29. Barlow PB, Bartlett D Jr, Hauri P, et al. Idiopathic hypoventilation syndrome: impor-
tance of preventing nocturnal hypoxemia and hypercapnia. Am Rev Respir Dis.
1980;121(1):141–5.
30. Weese-Mayer DE, Rand CM, Berry-Kravis EM, et al. Congenital central hypoventilation
syndrome from past to future: model for translational and transitional autonomic medicine.
Pediatr Pulmonol. 2009;44(6):521–35.
31. Pack AI, Cola MF, Goldszmidt A, Ogilvie MD, Gottschalk A. Correlation between oscilla-
tions in ventilation and frequency content of the electroencephalogram. J Appl Physiol (1985).
1992;72(3):985–92.
32. Trinder J, Whitworth F, Kay A, Wilkin P. Respiratory instability during sleep onset. J Appl
Physiol (1985). 1992;73(6):2462–9.
33. Dunai J, Wilkinson M, Trinder J. Interaction of chemical and state effects on ventilation during
sleep onset. J Appl Physiol (1985). 1996;81(5):2235–43.
34. Dunai J, Kleiman J, Trinder J. Ventilatory instability during sleep onset in individuals with
high peripheral chemosensitivity. J Appl Physiol (1985). 1999;87(2):661–72.
35. Thomson S, Morrell MJ, Cordingley JJ, Semple SJ. Ventilation is unstable during drowsiness
before sleep onset. J Appl Physiol (1985). 2005;99(5):2036–44.
36. Orem J. Neuronal mechanisms of respiration in REM sleep. Sleep. 1980;3(3–4):251–67.
37. Orem J, Lovering AT, Dunin-Barkowski W, Vidruk EH. Tonic activity in the respiratory system
in wakefulness, NREM and REM sleep. Sleep. 2002;25(5):488–96.
38. Lovering AT, Fraigne JJ, Dunin-Barkowski WL, Vidruk EH, Orem JM. Hypocapnia decreases
the amount of rapid eye movement sleep in cats. Sleep. 2003;26(8):961–7.
39. Phillips B, Cook Y, Schmitt F, Berry D. Sleep apnea: prevalence of risk factors in a general
population. South Med J. 1989;82(9):1090–2.
40. Phillips BA, Berry DT, Schmitt FA, Magan LK, Gerhardstein DC, Cook YR. Sleep-disordered
breathing in the healthy elderly. Clinically significant? Chest. 1992;101(2):345–9.
41. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Sleep-disordered
breathing in community-dwelling elderly. Sleep. 1991;14(6):486–95.
42. Pack AI, Silage DA, Millman RP, Knight H, Shore ET, Chung DC. Spectral analysis of ventila-
tion in elderly subjects awake and asleep. J Appl Physiol (1985). 1988;64(3):1257–67.
43. Kapur VK, Koepsell TD, deMaine J, Hert R, Sandblom RE, Psaty BM. Association of
hypothyroidism and obstructive sleep apnea. Am J Respir Crit Care Med. 1998;158(5 Pt
1):1379–83.
44. Bradley TD, Floras JS. Sleep apnea and heart failure: part II: central sleep apnea. Circulation.
2003;107(13):1822–6.
45. Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley TD. Association between atrial
fibrillation and central sleep apnea. Sleep. 2005;28(12):1543–6.
46. Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128
patients. Sleep. 1999;22(2):217–23.
47. Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women:
effects of gender. Am J Respir Crit Care Med. 2001;163(3 Pt 1):608–13.
48. Zhou XS, Rowley JA, Demirovic F, Diamond MP, Badr MS. Effect of testosterone on the
apneic threshold in women during NREM sleep. J Appl Physiol (1985). 2003;94(1):101–7.
49. Mateika JH, Omran Q, Rowley JA, Zhou XS, Diamond MP, Badr MS. Treatment with leup-
rolide acetate decreases the threshold of the ventilatory response to carbon dioxide in healthy
males. J Physiol. 2004;561(Pt 2):637–46.
50. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with
stable heart failure. Types and their prevalences, consequences, and presentations. Circulation.
1998;97(21):2154–9.
51. Javaheri S, Parker TJ, Wexler L, et al. Occult sleep-disordered breathing in stable congestive
heart failure. Ann Intern Med. 1995;122(7):487–92.
52. Javaheri S. Central sleep apnea-hypopnea syndrome in heart failure: prevalence, impact, and
treatment. Sleep. 1996;19(10 Suppl):S229–31.
53. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and
obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit
Care Med. 1999;160(4):1101–6.
54. Xie A, Skatrud JB, Puleo DS, Rahko PS, Dempsey JA. Apnea-hypopnea threshold for CO2 in
patients with congestive heart failure. Am J Respir Crit Care Med. 2002;165(9):1245–50.
55. Dempsey JA, Sheel AW, Haverkamp HC, Babcock MA, Harms CA. [The John Sutton Lecture:
CSEP, 2002]. Pulmonary system limitations to exercise in health. Can J Appl Physiol. 2003;28
Suppl:S2–24.
56. Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO(2) below
eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560(Pt 1):1–11.
57. Bassetti C, Aldrich MS, Chervin RD, Quint D. Sleep apnea in patients with transient ischemic
attack and stroke: a prospective study of 59 patients. Neurology. 1996;47(5):1167–73.
58. Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-
ever stroke or transient ischemic attack. Am J Respir Crit Care Med. 2000;161(2 Pt 1):375–80.
59. Grunstein RR, Ho KY, Berthon-Jones M, Stewart D, Sullivan CE. Central sleep apnea is asso-
ciated with increased ventilatory response to carbon dioxide and hypersecretion of growth
hormone in patients with acromegaly. Am J Respir Crit Care Med. 1994;150(2):496–502.
60. Grunstein RR, Ho KY, Sullivan CE. Sleep apnea in acromegaly. Ann Intern Med.
1991;115(7):527–32.
61. Grunstein RR, Sullivan CE. Sleep apnea and hypothyroidism: mechanisms and management.
Am J Med. 1988;85(6):775–9.
62. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who
undergo nocturnal hemodialysis. N Engl J Med. 2001;344(2):102–7.
63. Sankari A, Bascom AT, Chowdhuri S, Badr MS. Tetraplegia is a risk factor for central sleep
apnea. J Appl Physiol (1985). 2014;116(3):345–53.
64. Sankari A, Vaughan S, Bascom A, Martin JL, Badr MS. Sleep-disordered breathing and spinal
cord injury: a state-of-the-art review. Chest. 2019;155(2):438–45.
65. Naughton MT. Loop gain in apnea. Am J Respir Crit Care Med. 2010;181(2):103–5.
66. Sankari A, Bascom AT, Riehani A, Badr MS. Tetraplegia is associated with enhanced periph-
eral chemoreflex sensitivity and ventilatory long-term facilitation. J Appl Physiol (1985).
2015;119(10):1183–93.
67. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory
responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med.
1995;152(6 Pt 1):1950–5.
68. Zhang J, Wang L, Guo H-J, Wang Y, Cao J, Chen B-Y. Treatment-emergent central sleep
apnea: a unique sleep-disordered breathing. Chin Med J. 2020;133(22)
69. Zeineddine S, Badr MS. Treatment-emergent central apnea: physiologic mechanisms inform-
ing clinical practice. Chest. 2021;159(6):2449–57.
70. Dernaika T, Tawk M, Nazir S, Younis W, Kinasewitz GT. The significance and outcome of
continuous positive airway pressure-related central sleep apnea during split-night sleep stud-
ies. Chest. 2007;132(1):81–7.
71. Wang D, Teichtahl H, Drummer O, et al. Central sleep apnea in stable methadone maintenance
treatment patients. Chest. 2005;128(3):1348–56.
72. Morrell MJ, Badr MS, Harms CA, Dempsey JA. The assessment of upper airway patency dur-
ing apnea using cardiogenic oscillations in the airflow signal. Sleep. 1995;18(8):651–8.
73. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in
adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep.
2012;35(1):17–40.
74. Naughton MT, Benard DC, Rutherford R, Bradley TD. Effect of continuous positive airway
pressure on central sleep apnea and nocturnal PCO2 in heart failure. Am J Respir Crit Care
Med. 1994;150(6 Pt 1):1598–604.
75. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep
apnea and heart failure. N Engl J Med. 2005;353(19):2025–33.
76. Aboussouan LS, Khan SU, Banerjee M, Arroliga AC, Mitsumoto H. Objective measures of the
efficacy of noninvasive positive-pressure ventilation in amyotrophic lateral sclerosis. Muscle
Nerve. 2001;24(3):403–9.
77. Johnson KG, Johnson DC. Bilevel positive airway pressure worsens central apneas during
sleep. Chest. 2005;128(4):2141–50.
78. Meza S, Mendez M, Ostrowski M, Younes M. Susceptibility to periodic breathing with assisted
ventilation during sleep in normal subjects. J Appl Physiol (1985). 1998;85(5):1929–40.
79. Teschler H, Döhring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-
ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit
Care Med. 2001;164(4):614–9.
80. Morgenthaler TI, Gay PC, Gordon N, Brown LK. Adaptive servoventilation versus nonin-
vasive positive pressure ventilation for central, mixed, and complex sleep apnea syndromes.
Sleep. 2007;30(4):468–75.
81. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep
apnea in systolic heart failure. N Engl J Med. 2015;373(12):1095–105.
82. Aurora RN, Bista SR, Casey KR, et al. Updated adaptive servo-ventilation recommendations
for the 2012 AASM guideline: “The treatment of central sleep apnea syndromes in adults:
practice parameters with an evidence-based literature review and meta-analyses”. J Clin Sleep
Med. 2016;12(5):757–61.
83. Hudgel DW, Thanakitcharu S. Pharmacologic treatment of sleep-disordered breathing. Am J
84. DeBacker WA, Verbraecken J, Willemen M, Wittesaele W, DeCock W, Van deHeyning
P. Central apnea index decreases after prolonged treatment with acetazolamide. Am J Respir
Crit Care Med. 1995;151(1):87–91.
85. Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA. Effect of theophylline
on sleep-disordered breathing in heart failure. N Engl J Med. 1996;335(8):562–7.
86. Quadri S, Drake C, Hudgel DW. Improvement of idiopathic central sleep apnea with zolpidem.
J Clin Sleep Med. 2009;5(2):122–9.
87. Maresh S, Prowting J, Vaughan S, et al. Buspirone decreases susceptibility to hypocapnic
central sleep apnea in chronic SCI patients. J Appl Physiol (1985). 2020;129(4):675–82.
88. Giannoni A, Borrelli C, Mirizzi G, Richerson GB, Emdin M, Passino C. Benefit of buspirone
on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial.
Eur J Heart Fail. 2021;23(2):312–20.
89. Javaheri S, Ahmed M, Parker TJ, Brown CR. Effects of nasal O2 on sleep-related disordered
breathing in ambulatory patients with stable heart failure. Sleep. 1999;22(8):1101–6.
90. Chowdhuri S, Sinha P, Pranathiageswaran S, Badr MS. Sustained hyperoxia stabi-
lizes breathing in healthy individuals during NREM sleep. J Appl Physiol (1985).
2010;109(5):1378–83.
91. Xie A, Rankin F, Rutherford R, Bradley TD. Effects of inhaled CO2 and added dead space on
idiopathic central sleep apnea. J Appl Physiol (1985). 1997;82(3):918–26.
92. Badr MS, Grossman JE, Weber SA. Treatment of refractory sleep apnea with supplemental
carbon dioxide. Am J Respir Crit Care Med. 1994;150(2):561–4.
93. Ding N, Zhang X. Transvenous phrenic nerve stimulation, a novel therapeutic approach for
central sleep apnea. J Thorac Dis. 2018;10(3):2005–10.
94. Costanzo MR, Javaheri S, Ponikowski P, et al. Transvenous phrenic nerve stimulation for
treatment of central sleep apnea: five-year safety and efficacy outcomes. Nat Sci Sleep.
2021;13:515–26.
95. Schwartz AR, Goldberg LR, McKane S, Morgenthaler TI. Transvenous phrenic nerve stimula-
tion improves central sleep apnea, sleep quality, and quality of life regardless of prior positive
airway pressure treatment. Sleep Breath. 2021;25(4):2053–63.
Chapter 9
Sleep and Hypoventilation
Amanda J. Piper
Keywords Sleep hypoventilation · hypercapnia · respiratory failure · obesity

hypoventilation syndrome · neuromuscular disease · sleep disordered breathing
General Introduction
Sleep can present a significant challenge to respiration in people with respiratory or

ventilatory control disorders. The normal physiological changes in breathing asso-
ciated with sleep may be exaggerated in these populations, resulting in sleep disrup-
tion and hypoventilation. Sleep-related hypoventilation is most commonly seen in
patients with morbid obesity, neuromuscular disorders (NMD) or severe chronic
obstructive pulmonary disease (COPD). Failure to recognize and treat sleep
hypoventilation leads to eventual daytime hypercapnia and premature mortality.
However, signs and symptoms suggestive of sleep hypoventilation are often non-
specific and vague, and so the condition may be overlooked or misdiagnosed pre-
venting timely and appropriate intervention. In this chapter, the general mechanisms
relevant to the development of sleep hypoventilation will be reviewed as well as
issues specific to the major diagnostic groups likely to present with sleep
hypoventilation.
A. J. Piper (*)
Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital,
Camperdown, NSW, Australia
Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
e-mail: amanda.piper@sydney.edu.au

164 A. J. Piper
Normal Sleep Breathing
When an individual goes from awake to sleep, a number of physiological changes

occur within the respiratory system. These include a reduction in respiratory centre
output to the upper airway and respiratory muscles, along with reduced chemorecep-
tor responsiveness to oxygen (O2) and carbon dioxide (CO2). As a consequence,
upper airway resistance increases, lung volumes decrease and respiration can become
more variable and shallower, resulting in a small fall in minute ventilation of around
10–15% along with rises in CO2 of 2–7 mmHg [1, 2]. Oxygen saturation during sleep
is also lower by around 2%. During rapid eye movement (REM) sleep, inhibition of
postural muscles including the intercostal and accessory respiratory muscles leaves
the diaphragm to maintain ventilation [1, 3]. Chemosensitivity to both O2 and CO2 is
further reduced in this sleep stage [4]. These changes in ventilation and gas exchange
are relatively minor and of little clinical consequence. However, when overlaid on
pre-existing pulmonary or neuromuscular pathology, significant reductions in venti-
lation and abnormalities in gas exchange can occur [3]. These reductions are gener-
ally related to falls in tidal volume, and hence alveolar ventilation, and most marked
in REM sleep [3] (Fig. 9.1). However, over time with ongoing attenuation of ventila-
tory responsiveness to chemostimulation, extension of hypoventilation into non-
REM (NREM) and wakefulness eventually occurs. In addition, the reduction in lung
volumes [5] and reduced activation of the upper airway muscles with the onset of
sleep can produce flow limitation and upper airway collapse, resulting in an added
challenge to breathing during sleep in some at risk populations.
Compensatory Mechanisms in Hypoventilation Syndromes
A number of defensive or compensatory mechanisms can be brought into play to

minimize disturbance of gas exchange during sleep in those experiencing sleep
hypoventilation. The most obvious of these is arousal from sleep in the face of sig-
nificant changes in gas exchange. Through arousal, albeit brief, ventilation can be
restored at least to some extent, limiting the degree of oxygen saturation fall and
carbon dioxide accumulation. However, frequent arousal from sleep will impair
sleep quality, producing daytime symptoms, and if persistent will contribute to
attenuated chemosensitivity [6]. In addition, hypoxia impairs the arousal response
to compromised ventilation [7]. In an ongoing cycle, longer periods of abnormal gas
exchange occur before arousal produces some, although incomplete, restoration of
ventilation with consequent higher levels of CO2 and lower levels of oxygen. This
further impairs ventilatory responsiveness to changes in gas exchange, eventually
seeing the development of hypoventilation throughout the sleep period and eventu-
ally wakefulness [8].
In an attempt to improve sleep and breathing, patients may alter their sleeping
position. Vital capacity (VC) is reduced from the upright to supine position in those
9 Sleep and Hypoventilation 165
Fig. 9.1 In people with nocturnal hypoventilation, a significant fall in minute ventilation (Vi) dur-
ing sleep occurs, most marked during REM sleep. As shown in the top panel, this fall in ventilation
and oxygen saturation is primarily driven by a reduction in tidal volume (VT) (bottom panel).
(Reprinted with permission of the American Thoracic Society. Copyright © 2020 American
Thoracic Society. All rights reserved. Becker et al. [3]. The American Journal of Respiratory and
Critical Care Medicine is an official journal of the American Thoracic Society)
with diaphragmatic weakness or where diaphragmatic movement is restricted due to

abdominal obesity. In order to minimize orthopnoea, the supine position may be
avoided, or patients will use multiple pillows to assume a more upright position in
bed. Some morbidly obese individuals have spent months or years in a chair at night
in an attempt to both sleep and breathe.
166 A. J. Piper
Since the physiological changes occurring during sleep make breathing most
vulnerable during the REM period, a reduction or absence of this sleep stage mini-
mizes the likelihood of significant abnormalities in gas exchange occurring.
However, this also produces sleep disruption and has been shown to be associated
with poorer outcomes in some conditions [9].
Recruitment of accessory respiratory muscles such as the sternomastoid and sca-
lene during inspiration and the abdominal muscle during expiration occurs in some
patients with diaphragmatic dysfunction during wakefulness and NREM sleep.
This is thought to be an adaptive mechanism to maintain ventilation particularly in
NREM sleep in response to reduced neural drive [10]. With the normal loss of pos-
tural muscle tone during REM, accessory respiratory muscles are no longer able to
contribute to maintaining ventilation, resulting in deterioration in gas exchange [11,
12]. In some patients however, persistence of extradiaphragmatic muscle activity
during REM occurs [9, 13, 14]. In a group of patients with amyotrophic lateral
sclerosis (ALS) and diaphragmatic dysfunction, those in whom sternomastoid
activity continued in REM sleep not only maintained this sleep stage for longer but
survival was also better compared to those individuals not exhibiting this behaviour
[9]. More recently, persistence of neck muscle activity during sleep was evaluated
in a group of severe COPD patients recovering from an exacerbation [14]. While no
patient showed neck muscle activity while awake, 26 of the 29 studied demon-
strated inspiratory neck muscle activity during sleep. In 17 patients, this occurred
in Stage 3 sleep only while in 9, there was persistence of activity throughout sleep.
Compared to those showing no or intermittent sleep neck muscle activity, patients
where the neck muscles were activated throughout sleep experienced greater sleep
disruption, more exacerbations in the year prior to the study and were more likely
to be re-hospitalized over the next 6 months with an exacerbation. However, there
was no difference between groups in awake PaCO2 or nocturnal hypoventilation/
hypoxemia.
Irrespective of the primary underlying disorder, those with sleep hypoventila-
tion exhibit a reduced responsiveness to CO2. In response to abnormally low
breathing during sleep, CO2 rises transiently. If there is insufficient restorative
ventilation between these abnormal breathing periods, CO2 accumulates. In order
to maintain pH levels, renal compensation with retention of bicarbonate occurs.
However, these elevated blood bicarbonate levels blunt ventilatory responsive-
ness to CO2 [15], contributing to further progression of respiratory failure. In
obesity hypoventilation syndrome (OHS), patients with a lower ventilatory
response to CO2 spent a greater percentage of REM sleep in hypoventilation [16]
(Fig. 9.2). Studies investigating how nocturnal non-invasive ventilation (NIV)
achieves improved awake gas exchange in chronic hypoventilation found that an
increase in ventilatory responsiveness to CO2 was the main mechanism in patients
with restrictive thoracic disorders [17], and played a significant role along with
reduced gas trapping in those with chronic obstructive pulmonary disease
(COPD) [18].
Fig. 9.2 In obesity, 100

hypoventilation syndrome,
a significant relationship 80 y = –31.195*Ln(X) + 50.829
between baseline CO2 r = 0.54, p = 0.037
REM HypoVA, %
sensitivity and the amount
of hypoventilation during 60
REM sleep has been shown
such that patients with 40
lower CO2 ventilatory
responsiveness will spend
20
more of REM sleep in
hypoventilation. (From
Chouri-Pontarollo et al. 0
[16] with permission) 0 1 2 3 4 5 6
CO2 sensitivity 1/min/mmHg
Identifying and Defining Sleep Hypoventilation
Traditionally, arterial blood gas measurements have been performed to detect raised
CO2, which is the hallmark of hypoventilation. However, repeated arterial punctures
or the insertion of an arterial line to monitor CO2 during sleep is not practical or
appropriate to identify sleep hypoventilation. Furthermore, the development of
awake hypercapnic respiratory failure is considered to be a late manifestation of
sleep hypoventilation, particularly in those with neuromuscular or chest wall disor-
ders. Consequently, clinicians have sought simpler, less invasive methods of identi-
fying sleep hypoventilation before awake hypercapnia is present to prevent acute
respiratory decompensation.
Daytime Measures to Identify Sleep Hypoventilation
Patients with sleep hypoventilation may complain of an array of symptoms, related

to both sleep and daytime function (Table 9.1). However, symptoms alone are not a
good guide in identifying possible sleep hypoventilation due to their vague and non-
specific nature. Additionally, some individuals will not even be aware they are expe-
riencing symptoms until effective therapy has been established. In other cases,
reported symptoms may be erroneously attributed to the underlying disorder and
further investigation of potential sleep breathing problems overlooked.
In neuromuscular disorders (NMD), a number of simple clinic tests have been
used to identify those most at risk of sleep hypoventilation. The most widely used
measure is VC, with a previous study in a mixed group of muscular dystrophies and
myopathies finding a VC <40% of predicted identified those likely to have continuous
hypoventilation while daytime respiratory failure was likely to been seen with a VC
<25% of predicted [19]. Supine VC improves the predictive value of this measure
168 A. J. Piper
Table 9.1 Symptoms commonly associated with sleep hypoventilation

Daytime fatigue
Daytime sleepiness
Morning headaches
Sleep disruption
Orthopnoea
Dyspnoea
Confusion
Insomnia
Nightmares
[19], with a fall from the upright position >20% suggestive of diaphragm weakness
[20] and therefore a higher suspicion of sleep hypoventilation. In ALS, VC is widely
used as a predictor of survival and an indicator to commence nocturnal NIV [21], but
has limited predictive power in identifying sleep hypoventilation. For instance, in a
study of 250 patients with ALS, Boentert et al. [22] found that a third of those with an
upright VC >75% of predicted showed sleep hypoventilation while, in contrast,
almost half of those with a VC <in 50% predicted, no nocturnal hypoventilation was
seen. Other simple measures of inspiratory muscle strength used in conjunction with
VC measures are maximum inspiratory pressure (MIP) and sniff nasal inspiratory
pressure (SNIP). This latter measurement is particularly useful in patients with facial
muscle weakness who find it difficult to maintain a lip seal around a mouthpiece [23].
Nocturnal hypoventilation is unlikely to occur until MIP is <40 cmH2O [19], but this
test may give falsely low values in some patients due to leak around the mouthpiece
or from an inability to sustain a maximal inspiratory effort [24]. In ALS patients, a
SNIP <40 cmH2O correlates well with nocturnal hypoxia [23]. Although there is a
good correlation between MIP and SNIP in NMD, these tests are not interchangeable
and whenever possible should be performed concurrently [25].
Measures of daytime pulmonary function have not been shown to be sufficiently
sensitive to predict hypoventilation in OHS or COPD. In patients presenting with
obesity and potential sleep disordered breathing, the goal is to identify those in
whom an arterial blood gas should be taken in order to confirm a diagnosis of
OHS. In this population, oxygen saturation by pulse oximetry (SpO2) rather than
spirometric measures is generally used as a screening tool to identify those at risk
for awake hypercapnia. Chung et al. [26] showed an awake supine SpO2 <91% had
a 34.8% sensitivity and 96.6% specificity for detecting daytime hypercapnia in a
group of super-obese individuals (body mass index [BMI] >50 kg/m2) presenting to
a sleep laboratory. In another study, a combination of clinic SpO2 and FVC was
found to be highly sensitive in detecting awake hypercapnia in obese individuals
with an abnormal nocturnal oximetry, although specificity was low [27]. Only one
study has sought to identify obesity-related sleep hypoventilation, a potential early
stage of OHS [28, 29]. In a group of morbidly obese patients (BMI > 40 kg/m2), an
awake SpO2 measured in the supine position of ≤93% was found to predict sleep
hypoventilation with a sensitivity of 39% and specificity of 98% [30]. However,

recent guidelines on evaluating and managing OHS suggest that SpO2 during wake-
fulness should not be used to screen for OHS in obese patients with obstructive
sleep apnoea (OSA) due to insufficient data [31]. Although patients with low awake
PaO2 or SpO2 are more likely to desaturate at night [32], this is not necessarily
related to hypoventilation alone, and overall daytime awake pulmonary function
values do not correlate well with nocturnal desaturation [33].
Elevated levels of bicarbonate or base excess measured by venous or arterial
bloods can be useful to suggest or screen out sleep hypoventilation. Base excess
>3 mmol/L has been reported to be a significant predictor of sleep hypoventilation
in ALS [22] and Duchenne muscular dystrophy (DMD) [34], although with only
moderate sensitivity. In obese individuals with OSA, a serum bicarbonate
<27 mmol/L makes the diagnosis of OHS very unlikely [31]. However, caution
needs to be exercised when interpreting bicarbonate levels, as these can be influ-
enced by factors other than a raised CO2 [35].
Nocturnal Monitoring to Identify Sleep Hypoventilation
While awake testing in some populations can raise the suspicion of sleep hypoven-
tilation, as discussed previously these measures remain limited in their ability to
predict sleep hypoventilation and detect its severity. Consequently, more direct
monitoring of gas exchange during sleep is needed to identify sleep hypoventilation
at an earlier stage.
Nocturnal oximetry has been widely used as a potential surrogate for detecting
sleep disordered breathing and hypoxemia. Although cyclical episodes of desatu-
ration–resaturation may be suggestive of obstructive breathing, it does not reveal
anything about CO2 levels. Even if sustained hypoxemia is present, this cannot be
used as evidence for hypoventilation, as this pattern can also occur with ventila-
tion–perfusion mismatching. Furthermore, oximetry can miss sleep hypoventila-
tion in around a third of individuals with NMD [22], and is not informative in
those using supplemental oxygen. Adding a morning blood gas to nocturnal oxim-
etry may still miss the presence of nocturnal hypoventilation in 20–30% of patients
with neuromuscular disorders [22, 36]. Despite some technical limitations, trans-
cutaneous carbon dioxide (TcCO2) is now recommended to identify sleep hypoven-
tilation across a range of respiratory disorders [37], with monitoring able to be
performed both within sleep laboratories and in patient homes [38]. While
advances in technology have significantly improved the relationship between
PaCO2 and TcCO2 (Fig. 9.3), there may be an overestimation of CO2 over time due
to signal drift [40]. However, correction for this drift considerably improves the
reliability of the measurement [39]. The addition of polygraphy and polysomnog-
raphy to the assessment of patients with potential sleep hypoventilation provides
additional information about the nature of the respiratory events, or in the case of
polysomnography, sleep quality and duration. However, limited access, wait times,
170 A. J. Piper
Fig. 9.3 Significant fluctuations in nocturnal CO2 can occur which may be missed if a single blood
gas measure is made. In this illustration, continuous monitoring by two transcutaneous carbon
dioxide devices (the solid and broken lines) capture the variability in CO2 levels that are occurring
in this patient who is using nocturnal ventilatory support. Blood gases (represented by the grey
boxes) can only capture CO2 at a single point in time and can easily miss this variability.
Improvements in technology in recent years have significantly improved the accuracy and reliabil-
ity of transcutaneous CO2 monitoring. (From Storre et al. [39] with permission)
cost and a lack of facilities to properly care for individuals with significant physi-
cal impediments in sleep laboratories often mean that more limited nocturnal mon-
itoring is undertaken.
One of the difficulties in comparing studies of sleep hypoventilation has been the
various definitions that have been employed to describe this phenomenon. Ogna and
colleagues [41] compared the prevalence of hypoventilation in an unselected adult
NMD population according to eight different definitions commonly found in the
literature. Depending on the definition used, hypoventilation ranged from 10% to
61%, even when only definitions around TcCO2 were used (Fig. 9.4). The most
widely recognized definition at present is that proposed by the American Academy
of Sleep Medicine [37] which suggests “an increase in the arterial PaCO2 (or sur-
rogate) to a value > 55 mmHg for ≥ 10 minutes, or a ≥ 10 mmHg increase in PaCO2
(or surrogate) during sleep (in comparison to an awake supine value) to a value
exceeding 50 mmHg for ≥ 10 minutes.” However, these thresholds are based on
expert consensus and may be less sensitive than other definitions in identifying
patients with NMD and daytime normocapnia likely to require ventilatory support
70
61
60
PaCO2
50
43 BaseExc
Prevalence (%)
40
38 SpO2[1]
SpO2[2]
TcCO2[1]
30
TcCO2[2]
23
20 TcCO2[3]
20
13 TcCO2[4]
10 11
10
0
Hypoventilation definition
Fig. 9.4 Numerous definitions of sleep hypoventilation have appeared in the literature which will
significantly impact on the prevalence of the disorder. This is illustrated by a study of 232 patients
with neuromuscular disorders where the prevalence of sleep hypoventilation ranged from 10.3% to
61.2% depending on the definition used. Legend – PaCO2: awake PaCO2 >45 mmHg; BaseExc:
awake base excess ≥4 mmol/L; SpO2 [1]: nocturnal SpO2 ≤88% for 5 consecutive minutes; SpO2
[2]: mean nocturnal SpO2 <90% or SpO2 <90% during >10% of recording time; TcCO2 [1]:
TcCO2 >55 mmHg; TcCO2 [2]: increase in TcCO2 ≥10 mmHg (in comparison to an awake supine
value) to a value exceeding 50 mmHg for ≥10 min; TcCO2 [3]: peak TcCO2 >49 mmHg; TcCO2
[4]: mean TcCO2 >50 mmHg; TcCO2: transcutaneous carbon dioxide. (From Ogna et al. [41] with
permission)
within the next 24 months [42, 43]. There is also limited information around how
these definitions relate to other clinical and patient reported outcomes [44].
Disease-Specific Issues in Sleep Hypoventilation
Obesity Hypoventilation Syndrome
Obesity hypoventilation syndrome (OHS) is diagnosed in obese individuals

(BMI > 30 kg/m2) who present with awake hypercapnia (PaCO2 > 45 mmHg) when
other known causes of hypoventilation such as lung or neuromuscular disease can-
not be identified. Obstructive sleep apnoea is present in 90% of these individuals,
with 70% showing an apnoea hypopnea index ≥30/hour [45]. In the remaining 10%
hypoventilation alone is seen, particularly marked during REM sleep. The preva-
lence of OHS varies depending on the clinical setting these individuals are seen in
and the BMI of the population. Current estimates put the prevalence of OHS in the
general community at around 0.3%, [46] with the likelihood of OHS increasing with
BMI. In obese patients referred to sleep clinics, 10–20% will have OHS [47, 48].
172 A. J. Piper
This disorder represents one of the most common causes of sleep hypoventilation
seen in sleep laboratories and for some years has been a major indication for home
NIV [49, 50].
Although upper airway obstruction is common in this condition, OHS is more
than just severe OSA. This condition is associated with worse outcomes than eucap-
nic obesity with or without OSA, with patients presenting with more comorbidities
including chronic heart failure and pulmonary hypertension [51, 52], worse social
circumstances [53, 54], more healthcare resource use [54] and lower survival rates
even after therapy is commenced [55, 56]. Unfortunately, appropriate treatment is
often delayed with patients being misdiagnosed with obstructive pulmonary disease
or congestive cardiac failure [58], or the diagnosis overlooked completely [59]. In
some series, up to 70% of patients were diagnosed only after presenting with acute
on chronic respiratory failure [55].
The mechanisms around the development of hypoventilation in some obese
patients with or without OSA and not others are not fully understood, but involves
a complex interplay between abnormal lung mechanics, respiratory drive, neurohor-
monal factors and sleep disordered breathing. The degree to which each of these
factors contributes to hypoventilation in obesity likely varies between individuals
and may influence clinical presentation and outcomes. Two distinct phenotypes of
this disorder are currently recognized. Those with a high severity of OSA in
conjunction with OHS appear to be younger, generally male, more obese and hyper-
somnolent with worse nocturnal and daytime gas exchange but with a lower cardio-
vascular and metabolic risk compared to the OHS without OSA phenotype [60].
In morbid obesity, deposition of adipose tissue around the abdomen and chest
wall reduces lung volumes (particularly expiratory reserve volume) and thoracic
compliance [61]. Breathing at these lower volumes increases airway resistance and
promotes small airway closure, both of which place a further load on breathing [62].
This adds to an elevated work of breathing [63] and worsening ventilation perfusion
distribution. In response to these changes in respiratory loads and lung mechanics,
neural drive in morbid obesity is increased two to three times that seen in normal
weight controls [62]. However OHS patients lack this augmented drive [64], and as
a consequence minute ventilation is insufficient to maintain eucapnia, especially
given CO2 production is also increased due to obesity [65]. In addition, ventilatory
responses to O2 and CO2 are diminished compared to eucapnic OSA [16, 66], as is
the response to CO2 loading during sleep compared to those with eucapnic obesity
[67], further promoting CO2 retention. A more blunted ventilatory responsiveness to
CO2 is associated with more severe hypoventilation during rapid eye movement
(REM) sleep [16]. This reduced responsiveness appears to be secondary to sleep
disordered breathing as improvements are seen after PAP use in many individuals
even if BMI and lung function are unchanged [16, 66, 68].
The lower lung volumes associated with obesity increase the risk of upper airway
obstruction during sleep. The majority of patients with OHS have significant OSA
[45] which can be another contributor to CO2 retention during sleep. Indeed, even
awake upper airway resistance is significantly higher in OHS compared eucapnic
obesity [69]. Following obstructed nocturnal breathing differences in the pattern of
ventilation between eucapnic and hypercapnic patients with OSA have been
observed [70]. The length of the ventilation recovery period between events com-
pared to the event length is shortened [67, 71], while the magnitude by which ven-
tilation increases post event is diminished in those with hypercapnic compared to
their eucapnic counterparts [67]. This pattern permits an accumulation of CO2 dur-
ing the obstructed event with insufficient offloading of CO2 in the post-arousal
period. Over time, metabolic compensation by the kidneys to maintain pH produces
an increase in bicarbonate levels, thereby further blunting ventilatory drive [72].
A common thread between sleep disordered breathing, altered respiratory
mechanics and reduced respiratory drive in OHS may be some of the adipokines and
hormones associated with obesity. Leptin is a protein designed to regulate appetite
and energy expenditure which also acts as a powerful stimulant of ventilation. In
both obesity and OSA, serum leptin levels are elevated, suggesting a compensatory
response for the increased ventilatory load in order to maintain eucapnia [73].
Fasting serum leptin levels are higher again in OHS patients compared to eucapnic
obese individuals [73]. Hyperleptinemia has been shown to be associated with a
reduction in both respiratory drive and ventilatory responsiveness to CO2 [74], and
even when leptin levels are similar, the hypercapnic ventilatory response appears to
be significantly lower in hypercapnic patients compared with those who were
eucapnic [75]. It appears that the stimulatory effects of leptin are attenuated in OHS,
likely from reduced leptin permeability across the blood-brain barrier [76]. Leptin
also appears to be involved in maintaining neuromuscular drive to the upper airway
muscles during sleep [77] and could account for the high frequency of OSA in many
patients with OHS. In an interesting study in diet-induced obese mice, intra-nasal
leptin used to bypass the blood–brain barrier significantly reduced obstructed
breathing while also increasing minute ventilation during periods of non-flow lim-
ited breathing [78]. It remains unclear if similar benefits would be achieved in
humans [79], but it does provide interesting insights into the potential of improving
central concentrations of leptin in OHS.
Initial management of OHS involves commencing positive airway pressure
(PAP) to stabilize breathing and gas exchange during sleep. There has been some
debate around what form of PAP therapy is most appropriate both initially and as
long-term treatment. Since upper airway obstruction is seen in the majority of
patients, it is reasonable to start most OHS patients with concurrent OSA on con-
tinuous PAP (CPAP) therapy. This approach is supported by several RCTs [45,
80–82] and systematic reviews [83, 84] demonstrating that both medium (<3 months)
[45, 80, 82] and long-term (>3 years) [81, 83] outcomes including resolution of
awake PaCO2 and symptoms, changes in pulmonary artery pressure, healthcare use
and survival are similar whether CPAP or bilevel PAP therapy is used. Adherence to
therapy appears to be a more important factor in PAP choice than the type of PAP
[81, 85, 86]. Improvements with CPAP in terms of nocturnal gas exchange [82, 87],
awake CO2 [80, 81] and pulmonary hypertension [88] may be a little slower to
emerge over the first weeks or months of therapy, but so long as patients are adher-
ent to therapy, similar long-term outcomes including hospitalizations and survival
are achieved with CPAP and bilevel therapy [81]. However, close monitoring during
174 A. J. Piper
the early period of therapy is needed to identify non-responders. These include

patients with more restrictive pulmonary mechanics, higher initial awake CO2 levels
[80] and lower baseline AHI [89, 90]. Bilevel therapy is recommended in the OHS-
sleep hypoventilation only phenotype [91] and those presenting with acute on
chronic hypercapnic respiratory failure [92]. Despite control of sleep disordered
breathing and good adherence to PAP, at least 20% of patients with OHS will con-
tinue to experience some residual awake hypercapnia (generally 45–49 mmHg
range) [85, 86] but with minimal clinical symptoms.
As weight is a central issue involved in the development of OHS, steps to address
this should be undertaken. However, significant weight loss of around 25–35% is
probably needed to resolve OHS, while losses <10% are unlikely to achieve clini-
cally important outcomes [93]. Cardiovascular disease becomes the predominant
cause of death following the use of PAP therapy, so early identification and follow
up of cardiometabolic risk factors is needed [94].
A key aspect of defining OHS has been the presence of awake hypercapnia
(PaCO2 > 45 mmHg). Given the importance of identifying patients with OHS early,
it has been suggested that the presence of diurnal hypercapnia already represents an
advanced stage of OHS [28]. A recent European Respiratory Society task force
divided hypoventilation into five stages [28]. Stage 0 represented eucapnic
OSA. Stages I and II described obesity-related sleep hypoventilation (ORSH), with a
bicarbonate level <27 mmol/L or ≥27 mmol/L, respectively. The taskforce saw day-
time hypercapnia as being present only in the most advanced OHS stages of III and
IV, with Stage IV having concurrent comorbidities. Similar to patients with neuro-
muscular and chest wall restriction, eucapnic obese individuals with nocturnal-only
hypoventilation may eventually progress to these more advanced stages of
OHS. Although longitudinal studies have not been performed to confirm this pro-
gression, in a cross-sectional study of obese individuals, those with a raised serum
base excess (BE) ≥2 mmol/L were found to have ventilatory responses and sleep-
breathing measures lying between those with normal awake PaCO2 and BE and those
with awake hypercapnia [29]. Whether isolated sleep hypoventilation is part of the
OHS spectrum or whether it represents a distinct phenotype [30] has not been estab-
lished. It is also unknown if early identification and intervention can prevent the
development of full blown OHS with its attendant comorbidities and reduced survival.
Neuromuscular Disorders
Neuromuscular disorders (NMDs) cover a broad group of diseases where sleep

hypoventilation occurs as a consequence of involvement of the respiratory motor
neurons, peripheral nerves, the neuromuscular junction or the respiratory muscles
themselves. These disorders can be inherited or acquired, rapidly or slowly progres-
sive. Irrespective of the primary diagnosis, untreated many will develop respiratory
complications and awake hypercapnia, with death from respiratory infection and
respiratory failure common. Changes in respiratory muscle function and breathing
control during sleep interact to produce hypoventilation, earliest and most marked
in REM sleep, irrespective of the pathogenesis of the primary disorder.
The age of onset of sleep hypoventilation will vary considerably depending on
the primary diagnosis. Sleep hypoventilation can be expected during early child-
hood in spinal muscular atrophy (SMA) type I and in some with SMA type 2, while
in Duchenne muscular dystrophy (DMD) this usually occurs sometime during late
adolescence or early adulthood. People with ALS commonly present in the fifth and
sixth decades of life, with sleep hypoventilation generally occurring some 12 or so
months after diagnosis [95, 96]. The stage at which diaphragm involvement occurs
is central to the appearance of hypoventilation and this can vary considerably within
and between disorders. Obesity and chest wall deformity will also influence the
onset on sleep hypoventilation by further adding to respiratory muscle load/capacity
imbalance.
Upper airway obstruction during sleep in neuromuscular disorders is not uncom-
mon [22, 97]. These obstructive events may arise from the usual mechanical factors
associated with OSA such as obesity, the supine position, enlarged tonsils or retrog-
nathia. However, there are some aspects of NMD which may promote upper airway
instability such as low lung volumes from respiratory muscle weakness, pharyngeal
hypotonia and macroglossia [98]. A bimodal pattern of sleep disordered breathing
has been reported in some disorders including DMD, acid maltase deficiency and
ALS [22, 96, 99], with obstructive events more common initially, progressing to
more “pseudocentral” events and hypoventilation with disease progression. This
transition likely reflects increasing inspiratory muscle weakness, particularly that of
the diaphragm, whereby insufficient inspiratory pressure is generated to create com-
plete airway collapse [22, 98]. Obstructive events could also be related to obesity,
an enlarged tongue with posterior displacement or reduced pharyngeal tone. In
ALS, these obstructive events do not appear to be related to bulbar dysfunction [22],
but have been associated with shorter survival [100, 101].
In some neuromuscular diseases, a primary abnormality in ventilatory control
may be present in addition to peripheral muscle weakness. Myotonic dystrophy, the
most common type of muscular dystrophy, has a high prevalence of both excessive
daytime sleepiness and sleep disordered breathing [102]. However, there does not
appear to be a direct relationship between sleepiness and abnormal nocturnal breath-
ing, nor between pulmonary function and sleep disordered breathing [103, 104]. It
is thought that neuronal loss in CNS structures regulating central respiratory drive
might be an underlying contributor to sleep-breathing abnormalities in these patient
[104, 105]. In ALS, periodic clustering of desaturation during sleep has been found
in some patients despite normal respiratory function and neurophysiological phrenic
nerve and diaphragm tests [106, 107]. These episodes occur despite normal respira-
tory movements, suggesting instability in central respiratory control. During NIV,
upper airway obstruction with reduced respiratory drive has been shown to be a
common reason for inadequate ventilatory support during NIV, with shorter survival
even when these events are not associated with desaturation [100]. In investigating
mechanisms for this, Sancho and colleagues [108] found those exhibiting upper
airway obstruction with reduced respiratory drive during NIV had greater respira-
tory instability, with higher controller gain values and lower CO2 reserves compare
176 A. J. Piper
to ALS patients without these events. Moreover, these patients were more likely to
have upper motor neuron predominant dysfunction at the bulbar level. Increasing
EPAP or changing masks would have little effect on improving obstructive events if
they are caused by hyperreflexia and adduction of the vocal folds [108].
In NMD, poor cough with secretion accumulation can also contribute to hypoven-
tilation, with chest infection and pneumonia being major causes of respiratory mor-
bidity and mortality [109]. Reduced inspiratory muscle strength limits the inspired
volume able to be achieved pre-cough while impaired glottic control and weak expi-
ratory muscles adversely impact the effectiveness of expiratory flow rates needed to
expel secretions from the large airways. Cough augmentation and lung volume
recruitment techniques form an essential part of the holistic management of these
individuals, and may need to be introduced prior to the use of NIV.
COPD
Poor-quality sleep is common in COPD [110] and is predictive of exacerbations,

emergency healthcare utilization and mortality [111, 112]. Although the source of
this disruption may be caused by other factors such as medications, secretions, nico-
tine use and reflux, sleep disordered breathing is a common, frequently overlooked
contributor.
Worsening respiratory mechanics and reduced inspiratory neural drive [10, 113]
appear to underlie sleep hypoventilation in COPD. With the onset of sleep, neural
drive decreases in parallel with reductions in ventilation [10]. In addition, dia-
phragm inefficiency brought on by hyperinflation is offset to some extent by recruit-
ment of the accessory respiratory muscles in an attempt maintain ventilation.
However, when this activity is lost during REM sleep, tidal volume is reduced with
ensuing hypoventilation. Lung hyperinflation itself has been associated with
increased arousal from sleep [114]. In some patients with COPD, increased upper
airway resistance, even in the absence of frank obstruction may occur, contributing
further to sleep hypoventilation [115].
Once awake hypercapnia develops, prognosis is poorer than in patients with
hypoxemia alone [116]. However few studies have investigated isolated sleep-related
hypoventilation and its consequences in COPD. Prevalence rates of sleep hypoven-
tilation have varied considerably depending on how hypoventilation was defined and
measured [14, 33, 117]. In studies of hypercapnic COPD patients using long-term
oxygen therapy, prevalence rates of 21–43% have been reported [33, 117]. In a pro-
spective, observational study of 100 stable COPD patients attending an inpatient
rehabilitation program, Holmedahl et al. [118] identified sleep hypoventilation in 15
subjects, including 6 subjects with awake normocapnia. While BMI and AHI were
similar between awake hypercapnic and normocapnic groups with sleep hypoventi-
lation, FEV1 was significantly higher in the normocapnic group (1.45 vs 0.63L). In
a small study of 21 selected patients with stable severe COPD without significant
awake hypercapnia, Kitajima et al. [119] identified ten patients with episodic sleep
hypoventilation, defined as an increase of ≥5 mmHg in TcCO2 from baseline for
≥5 mins continuously accompanied by at least one episode of oxygen desaturation.

Those demonstrating episodic sleep hypoventilation had higher markers of pulmo-
nary hypertension and experienced more frequent admissions in the previous year
than the group without these episodic events. Although early identification of sleep
hypoventilation and intervention may reduce morbidity and mortality as seen in
other hypoventilating disorders, this premise has not been tested in COPD. Currently
non-invasive ventilatory support (NIV) is introduced in stable patients when awake
or persistent hypercapnia is detected, usually when awake PaCO2 values 50 mmHg
or greater [120–123]. Recently published evidence-based guidelines support the use
of NIV for COPD when the above conditions are present, with the suggestion that
NIV settings need to target a significant reduction in CO2 [124].
Generally, chronic hypoventilation is most likely seen in COPD with more severe
airflow limitation. However, if upper airway obstruction occurs in those with only
moderately altered respiratory mechanics, nocturnal and awake hypercapnia may be
present at levels of lung function not normally associated with hypoventilation
[125]. Obstructive sleep apnoea is not an uncommon finding in COPD, with preva-
lence rates ranging 3–65%, depending on the clinical population studied, severity of
the underlying lung disease, BMI and age [126–128]. The occurrence of both disor-
ders in the same patient is described as “overlap” and is of clinical relevance since
these individuals usually have more severe hypoxemia and hypercapnia, as well as
higher mortality rates compared to either disease alone [57, 126] (Fig. 9.5). Quality
Fig. 9.5 Unadjusted Kaplan–Meier event-free survival curves showing the impact of severe
obstructive sleep apnoea (OSA) (apnoea–hypopnea index >30) in people chronic obstructive pul-
monary disease (COPD) compared to either disease alone. Outcome was defined as a composite of
hospitalization due to myocardial infarction, stroke, congestive heart failure, cardiac revasculariza-
tion procedures or death from any cause. (Reprinted with permission of the American Thoracic
Society. Copyright © 2020 American Thoracic Society. All rights reserved. Kendzerska et al. [57].
Annals of the American Thoracic Society is an official journal of the American Thoracic Society)
178 A. J. Piper
of life among overlap patients is significantly worse than that of COPD-only

patients, in addition to more cardiovascular morbidity, more frequent exacerbations
and higher healthcare costs than either condition alone [127]. In contrast to COPD-
only patients where sleep hypoventilation appears to be mainly a consequence of
reduced neural respiratory drive [10], in overlap the fall in ventilation seen during
sleep is largely due to an increase in upper airway resistance [129]. A small pilot
study in overlap patients showed a high loop gain and low arousal threshold likely
contributes to the development of OSA and its severity in these individuals [130].
When applying PAP therapy in overlap, the mode of therapy needs to balance
reversal of abnormal respiratory mechanics against control of upper airway patency.
Where upper airway obstruction predominates, CPAP therapy with or without sup-
plemental oxygen can provide significant benefits including improved blood gases,
reduced excerbations [131] and a lower mortality risk [126]. The survival benefit
may be more marked in those with baseline hypercapnia [132] (Fig. 9.6). However,
higher awake CO2 levels and more time with SpO2 <90% during sleep are indepen-
dent factors predicting CPAP failure [133], when bilevel therapy would be the pre-
ferred management option. Close monitoring of hypercapnic overlap patients
commencing CPAP is needed to ensure persistent sleep hypoventilation is not
occurring.
Summary
Sleep hypoventilation is a frequent occurrence in patients with a wide range of

disorders where diaphragmatic weakness, abnormal chest wall mechanics or
altered respiratory drive are present. Hypoventilation during sleep can be present
a Hypercapnic b Normocapnic
100 100
95
Survival probability (%)
Survival probability (%)
90 90
85
80 80
75
70 70
65
60 60
55
50 50
0 20 40 60 80 100 0 20 40 60 80 100
Months Months
Fig. 9.6 Kaplan–Meier survival curves comparing continuous positive airway pressure (dotted
line) to non-treated patients (continuous line) for (a) those who were hypercapnic at baseline and
(b) normocapnic patients. In this study, CPAP treatment reduced the excess risk of death in the
hypercapnic group (log rank test 4.16; p = 0.04) but not the normocapnic group (Log rank test 0.63;
p = 0.42). (From Jaoude et al. [132] with permission)
months or years prior to the development of daytime hypercapnia. Recognition

and early treatment is considered important since sleep hypoventilation can have
a significant impact on quality of life, neurocognition function, health resource
use and mortality. Although daytime measures of respiratory function can be help-
ful in identifying some individuals at risk of sleep hypoventilation, these have a
limited ability to accurately detect nocturnal hypoventilation and its severity.
Consequently, some measure of CO2 during sleep is required to capture this disor-
der. Advancements in technology associated with transcutaneous carbon dioxide
monitoring have seen this technique become more widely used to identify the
presence and severity of sleep hypoventilation. However, more work is needed to
better understand thresholds of CO2 during sleep that are associated with poorer
clinical outcomes.
References
1. Douglas NJ, White DP, Pickett CK, Weil JV, Zwillich CW. Respiration during sleep in normal
man. Thorax. 1982;37:840–4.
2. Tabachnik E, Muller NL, Bryan AC, Levison H. Changes in ventilation and chest wall
mechanics during sleep in normal adolescents. J Appl Physiol. 1981;51(3):557–64.
3. Becker HF, Piper AJ, Flynn WE, et al. Breathing during sleep in patients with nocturnal
desaturation. Am J Respir Crit Care Med. 1999;159(1):112–8.
in sleeping adults. Am Rev Respir Dis. 1982;126(5):758–62.
5. Appelberg J, Nordahl G, Janson C. Lung volume and its correlation to nocturnal apnoea and
desaturation. Respir Med. 2000;94(3):233–9.
6. White DP, Douglas NJ, Pickett CK, Zwillich CW, Weil JV. Sleep deprivation and the control
of ventilation. Am Rev Respir Dis. 1983;128(6):984–6.
7. Hlavac MC, Catcheside PG, McDonald R, Eckert DJ, Windler S, McEvoy RD. Hypoxia
impairs the arousal response to external resistive loading and airway occlusion during sleep.
Sleep. 2006;29(5):624–31.
8. Piper A. Sleep abnormalities associated with neuromuscular disease: pathophysiology and
evaluation. Semin Respir Crit Care Med. 2002;23(3):211–9.
9. Arnulf I, Similowski T, Salachas F, et al. Sleep disorders and diaphragmatic function in
patients with amyotrophic lateral sclerosis. Am J Respir Crit Care Med. 2000;161(3):849–56.
10. Luo YM, He BT, Wu YX, et al. Neural respiratory drive and ventilation in patients
with chronic obstructive pulmonary disease during sleep. Am J Respir Crit Care Med.
2014;190(2):227–9.
11. Bye PT, Ellis ER, Issa FG, Donnelly PM, Sullivan CE. Respiratory failure and sleep in neu-
romuscular disease. Thorax. 1990;45(4):241–7.
12. White JE, Drinnan MJ, Smithson AJ, Griffiths CJ, Gibson GJ. Respiratory muscle activity
during rapid eye movement (REM) sleep in patients with chronic obstructive pulmonary
disease. Thorax. 1995;50(4):376–82.
13. Bennett JR, Dunroy HM, Corfield DR, et al. Respiratory muscle activity during REM sleep
in patients with diaphragm paralysis. Neurology. 2004;62(1):134–7.
14. Redolfi S, Grassion L, Rivals I, et al. Abnormal activity of neck inspiratory muscles during
sleep as a prognostic indicator in chronic obstructive pulmonary disease. Am J Respir Crit
Care Med. 2020;201(4):414–22.
15. Goldring RM, Turino GM, Heinemann HO. Respiratory-renal adjustments in chronic hyper-
capnia in man. Extracellular bicarbonate concentration and the regulation of ventilation. Am
J Med. 1971;51(6):772–84.
180 A. J. Piper
16. Chouri-Pontarollo N, Borel JC, Tamisier R, Wuyam B, Levy P, Pepin JL. Impaired objective
daytime vigilance in obesity-hypoventilation syndrome: impact of noninvasive ventilation.
Chest. 2007;131(1):148–55.
17. Nickol AH, Hart N, Hopkinson NS, Moxham J, Simonds A, Polkey MI. Mechanisms of
improvement of respiratory failure in patients with restrictive thoracic disease treated with
non-invasive ventilation. Thorax. 2005;60(9):754–60.
18. Nickol A, Hart N, Hopkinson N, et al. Mechanisms of improvement of respiratory failure in
patients with COPD treated with NIV. Int J Chron Obstruct Pulmon Dis. 2008;3(3):453–62.
19. Ragette R, Mellies U, Schwake C, Voit T, Teschler H. Patterns and predictors of sleep disor-
dered breathing in primary myopathies. Thorax. 2002;57(8):724–8.
20. Fromageot C, Lofaso F, Annane D, et al. Supine fall in lung volumes in the assessment of dia-
phragmatic weakness in neuromuscular disorders. Arch Phys Med Rehabil. 2001;82(1):123–8.
21. Baumann F, Henderson RD, Morrison SC, et al. Use of respiratory function tests to predict
survival in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11(1-2):194–202.
22. Boentert M, Glatz C, Helmle C, Okegwo A, Young P. Prevalence of sleep apnoea and cap-
nographic detection of nocturnal hypoventilation in amyotrophic lateral sclerosis. J Neurol
Neurosurg Psychiatry. 2018;89(4):418–24.
23. Morgan RK, McNally S, Alexander M, Conroy R, Hardiman O, Costello RW. Use of sniff
nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Am J Respir Crit
Care Med. 2005;171(3):269–74.
24. Fitting JW. Sniff nasal inspiratory pressure: simple or too simple? Eur Respir
J. 2006;27(5):881–3.
25. Oliveira MJP, Rodrigues F, Firmino-Machado J, et al. Assessment of respiratory muscle
weakness in subjects with neuromuscular disease. Respir Care. 2018;63(10):1223–30.
26. Chung Y, Garden FL, Jee AS, et al. Supine awake oximetry as a screening tool for daytime
hypercapnia in super-obese patients. Intern Med J. 2017;47(10):1136–41.
27. Mandal S, Suh ES, Boleat E, et al. A cohort study to identify simple clinical tests for chronic
respiratory failure in obese patients with sleep-disordered breathing. BMJ Open Respir Res.
2014;1(1):e000022.
28. Randerath W, Verbraecken J, Andreas S, et al. Definition, discrimination, diagnosis and treat-
ment of central breathing disturbances during sleep. Eur Respir J. 2017;49(1):1600959.
29. Manuel ARGM, Mbbs RG, Hart NP, Stradling JRMD. Is a raised bicarbonate, without
hypercapnia, part of the physiologic spectrum of obesity-related hypoventilation? Chest.
2015;147(2):362–8.
30. Sivam S, Yee B, Wong K, Wang D, Grunstein R, Piper A. Obesity hypoventilation syndrome:
early detection of nocturnal-only hypercapnia in an obese population. J Clin Sleep Med.
2018;14(9):1477–84.
31. Mokhlesi B, Masa JF, Brozek JL, et al. Evaluation and management of Obesity Hypoventilation
Syndrome. An official American Thoracic Society clinical practice guideline. Am J Respir
Crit Care Med. 2019;200(3):e6–e24.
32. Mulloy E, McNicholas WT. Ventilation and gas exchange during sleep and exercise in severe
COPD. Chest. 1996;109(2):387–94.
33. Tarrega J, Anton A, Guell R, et al. Predicting nocturnal hypoventilation in hypercapnic
chronic obstructive pulmonary disease patients undergoing long-term oxygen therapy.
Respiration. 2011;82(1):4–9.
34. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular
dystrophy. Am J Respir Crit Care Med. 2000;161(1):166–70.
35. Manthous CA, Mokhlesi B. Avoiding management errors in patients with obesity hypoventi-
lation syndrome. Ann Am Thorac Soc. 2016;13(1):109–14.
36. Georges M, Nguyen-Baranoff D, Griffon L, et al. Usefulness of transcutaneous PCO2 to assess
nocturnal hypoventilation in restrictive lung disorders. Respirology. 2016;21(7):1300–6.
37. 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.
38. Duiverman ML, Vonk JM, Bladder G, et al. Home initiation of chronic non-invasive ventila-
tion in COPD patients with chronic hypercapnic respiratory failure: a randomised controlled
trial. Thorax. 2020;75(3):244–52.
39. Storre JH, Magnet FS, Dreher M, Windisch W. Transcutaneous monitoring as a replace-
ment for arterial PCO(2) monitoring during nocturnal non-invasive ventilation. Respir Med.
2011;105(1):143–50.
40. Berlowitz DJ, Spong J, O’Donoghue FJ, et al. Transcutaneous measurement of carbon diox-
ide tension during extended monitoring: evaluation of accuracy and stability, and an algo-
rithm for correcting calibration drift. Respir Care. 2011;56(4):442–8.
41. Ogna A, Quera Salva MA, Prigent H, et al. Nocturnal hypoventilation in neuromuscular dis-
ease: prevalence according to different definitions issued from the literature. Sleep Breath.
2016;20(2):575–81.
42. Orlikowski D, Prigent H, Quera Salva MA, et al. Prognostic value of nocturnal hypoventila-
tion in neuromuscular patients. Neuromuscul Disord. 2017;27(4):326–30.
43. Ward S, Chatwin M, Heather S, Simonds AK. Randomised controlled trial of non-invasive
ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease
patients with daytime normocapnia. Thorax. 2005;60(12):1019–24.
44. Ogna A, Nardi J, Prigent H, et al. Prognostic value of initial assessment of residual hypoven-
tilation using nocturnal capnography in mechanically ventilated neuromuscular patients: a
5-year follow-up study. Front Med. 2016;3:40.
45. Masa JF, Corral J, Alonso ML, et al. Efficacy of different treatment alternatives for obesity
hypoventilation syndrome. Pickwick study. Am J Respir Crit Care Med. 2015;192(1):86–95.
46. Littleton SW, Mokhlesi B. The Pickwickian syndrome—obesity hypoventilation syndrome.
Clin Chest Med. 2009;30(3):467–78.
47. BaHammam AS. Prevalence, clinical characteristics, and predictors of obesity hypoventila-
tion syndrome in a large sample of Saudi patients with obstructive sleep apnea. Saudi Med
J. 2015;36(2):181–9.
48. Balachandran JS, Masa JF, Mokhlesi B. Obesity hypoventilation syndrome: epidemiology
and diagnosis. Sleep Med Clin. 2014;9(3):341–7.
49. Garner DJ, Berlowitz DJ, Douglas J, et al. Home mechanical ventilation in Australia and New
Zealand. Eur Respir J. 2013;41(1):39–45.
50. Melloni B, Mounier L, Laaban JP, Chambellan A, Foret D, Muir JF. Home-based care evolu-
tion in chronic respiratory failure between 2001 and 2015 (Antadir Federation Observatory).
Respiration. 2018:1–9.
51. Alawami M, Mustafa A, Whyte K, Alkhater M, Bhikoo Z, Pemberton J. Echocardiographic
and electrocardiographic findings in patients with obesity hypoventilation syndrome. Intern
Med J. 2015;45(1):68–73.
52. Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited:
a prospective study of 34 consecutive cases. Chest. 2001;120(2):369–76.
53. Jennum P, Ibsen R, Kjellberg J. Social consequences of sleep disordered breathing on patients
and their partners. A controlled national study. Eur Respir J. 2014;43(1):134–44.
54. Jennum P, Kjellberg J. Health, social and economical consequences of sleep-disordered
breathing: a controlled national study. Thorax. 2011;66(7):560–6.
55. Castro-Añón O, Pérez de Llano LA, De la Fuente SS, et al. Obesity-hypoventilation syn-
drome: increased risk of death over sleep apnea syndrome. PLoS One. 2015;10(2):e0117808.
56. Kreivi HR, Italuoma T, Bachour A. Effect of ventilation therapy on mortality rate among
obesity hypoventilation syndrome and obstructive sleep apnoea patients. ERJ Open Res.
2020;6(2)
57. Kendzerska T, Leung RS, Aaron SD, Ayas N, Sandoz JS, Gershon AS. Cardiovascular out-
comes and all-cause mortality in patients with obstructive sleep apnea and chronic obstruc-
tive pulmonary disease (overlap syndrome). Ann Am Thorac Soc. 2019;16(1):71–81.
182 A. J. Piper
58. Marik PE, Desai H. Characteristics of patients with the “malignant obesity hypoventilation
syndrome” admitted to an ICU. J Intensive Care Med. 2013;28(2):124–30.
59. Quint JK, Ward L, Davison AG. Previously undiagnosed obesity hypoventilation syndrome.
Thorax. 2007;62(5):462–3.
60. Masa JF, Corral J, Romero A, et al. Protective cardiovascular effect of sleep apnea severity in
obesity hypoventilation syndrome. Chest. 2016;150(1):68–79.
61. Pelosi P, Croci M, Ravagnan I, Vicardi P, Gattinoni L. Total respiratory system, lung, and
chest wall mechanics in sedated-paralyzed postoperative morbidly obese patients. Chest.
1996;109(1):144–51.
62. Steier J, Jolley CJ, Seymour J, Roughton M, Polkey MI, Moxham J. Neural respiratory drive
in obesity. Thorax. 2009;64(8):719–25.
63. Lee MY, Lin CC, Shen SY, Chiu CH, Liaw SF. Work of breathing in eucapnic and hypercap-
nic sleep apnea syndrome. Respiration. 2009;77(2):146–53.
64. Lopata M, Onal E. Mass loading, sleep apnea, and the pathogenesis of obesity hypoventila-
tion. Am Rev Respir Dis. 1982;126(4):640–5.
65. Javaheri S, Simbartl LA. Respiratory determinants of diurnal hypercapnia in obesity
hypoventilation syndrome. What does weight have to do with it? Ann Am Thorac Soc.
2014;11(6):945–50.
66. Fernandez Alvarez R, Rubinos Cuadrado G, Ruiz Alvarez I, et al. Hypercapnia response
in patients with obesity-hypoventilation syndrome treated with non-invasive ventilation at
home. Arch Bronconeumol (Engl Ed). 2018;54(9):455–9.
67. Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. Postevent venti-
lation as a function of CO2 load during respiratory events in obstructive sleep apnea. J Appl
Physiol. 2002;93(3):917–24.
68. Redolfi S, Corda L, La Piana G, Spandrio S, Prometti P, Tantucci C. Long-term non-invasive
ventilation increases chemosensitivity and leptin in obesity-hypoventilation syndrome.
Respir Med. 2007;101(6):1191–5.
69. Lin CC, Wu KM, Chou CS, Liaw SF. Oral airway resistance during wakefulness in eucapnic
and hypercapnic sleep apnea syndrome. Respir Physiol Neurobiol. 2004;139(2):215–24.
70. Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. CO(2) homeosta-
sis during periodic breathing in obstructive sleep apnea. J Appl Physiol. 2000;88(1):257–64.
71. Ayappa I, Berger KI, Norman RG, Oppenheimer BW, Rapoport DM, Goldring
RM. Hypercapnia and ventilatory periodicity in obstructive sleep apnea syndrome. Am J
72. Berger KI, Goldring RM, Rapoport DM. Obesity hypoventilation syndrome. Semin Respir
Crit Care Med. 2009;30:253–61.
73. Phipps PR, Starritt E, Caterson I, Grunstein RR. Association of serum leptin with hypoventi-
lation in human obesity. Thorax. 2002;57(1):75–6.
74. Campo A, Fruhbeck G, Zulueta JJ, et al. Hyperleptinemia, respiratory drive and hypercapnic
response in obese patients. Eur Respir J. 2007;30:223–31.
75. Makinodan K, Yoshikawa M, Fukuoka A, et al. Effect of serum leptin levels on hypercapnic
ventilatory response in obstructive sleep apnea. Respiration. 2008;75(3):257–64.
76. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr. Cerebrospinal fluid leptin levels:
relationship to plasma levels and to adiposity in humans. Nat Med. 1996;2(5):589–93.
77. Polotsky M, Elsayed-Ahmed AS, Pichard L, et al. Effects of leptin and obesity on the upper
airway function. J Appl Physiol. 2012;112(10):1637–43.
78. Berger S, Pho H, Fleury-Curado T, et al. Intranasal leptin relieves sleep disordered breathing
in mice with diet induced obesity. Am J Respir Crit Care Med. 2019;199(6):773–83.
79. Ip MSM, Mokhlesi B. Activating leptin receptors in the central nervous system using intra-
nasal leptin. A novel therapeutic target for sleep-disordered breathing. Am J Respir Crit Care
Med. 2019;199(6):689–91.
80. Howard ME, Piper AJ, Stevens B, et al. A randomised controlled trial of CPAP versus
non-invasive ventilation for initial treatment of obesity hypoventilation syndrome. Thorax.
2017;72(5):437–44.
81. Masa JF, Mokhlesi B, Benitez I, et al. Long-term clinical effectiveness of continuous posi-
tive airway pressure therapy versus non-invasive ventilation therapy in patients with obesity
hypoventilation syndrome: a multicentre, open-label, randomised controlled trial. Lancet.
2019;393(10182):1721–32.
82. Piper AJ, Wang D, Yee BJ, Barnes DJ, Grunstein RR. Randomised trial of CPAP vs bilevel
support in the treatment of obesity hypoventilation syndrome without severe nocturnal desat-
uration. Thorax. 2008;63(5):395–401.
83. Royer CP, Schweiger C, Manica D, Rabaioli L, Guerra V, Sbruzzi G. Efficacy of bilevel
ventilatory support in the treatment of stable patients with obesity hypoventilation syndrome:
systematic review and meta-analysis. Sleep Med. 2018;53:153–64.
84. Soghier I, Brozek JL, Afshar M, et al. Noninvasive ventilation versus CPAP as initial treat-
ment of obesity hypoventilation syndrome. Ann Am Thorac Soc. 2019;16(10):1295–303.
85. Bouloukaki I, Mermigkis C, Michelakis S, et al. The association between adherence to posi-
tive airway pressure therapy and long-term outcomes in patients with obesity hypoventilation
syndrome: a prospective observational study. J Clin Sleep Med. 2018;14(9):1539–50.
86. Mokhlesi B, Tulaimat A, Evans AT, et al. Impact of adherence with positive airway pressure
therapy on hypercapnia in obstructive sleep apnea. J Clin Sleep Med. 2006;2(1):57–62.
87. Salord N, Mayos M, Miralda RM, et al. Continuous positive airway pressure in clinically sta-
ble patients with mild-to-moderate obesity hypoventilation syndrome and obstructive sleep
apnoea. Respirology. 2013;18(7):1135–42.
88. Masa JF, Mokhlesi B, Benítez I, et al. Echocardiographic changes with positive airway pres-
sure therapy in obesity hypoventilation syndrome. Long-term Pickwick randomized con-
trolled clinical trial. Am J Respir Crit Care Med. 2020;201(5):586–97.
89. Banerjee D, Yee BJ, Piper AJ, Zwillich CW, Grunstein RR. Obesity hypoventila-
tion syndrome: hypoxemia during continuous positive airway pressure. Chest.
2007;131(6):1678–84.
90. Perez de Llano LA, Golpe R, Ortiz Piquer M, et al. Clinical heterogeneity among
patients with obesity hypoventilation syndrome: therapeutic implications. Respiration.
2008;75(1):34–9.
91. Masa JF, Benítez I, Sánchez-Quiroga M, et al. Long-term noninvasive ventilation in obesity
hypoventilation syndrome without severe OSA: the Pickwick randomized controlled trial.
Chest. 2020:S0012-3692(20)30711-X.; https://doi.org/10.1016/j.chest.2020.03.068.
92. Carrillo A, Ferrer M, Gonzalez-Diaz G, et al. Noninvasive ventilation in acute hypercapnic
respiratory failure caused by obesity hypoventilation syndrome and chronic obstructive pul-
monary disease. Am J Respir Crit Care Med. 2012;186(12):1279–85.
93. Kakazu MT, Soghier I, Afshar M, et al. Weight loss interventions as treatment of obesity
hypoventilation syndrome. A systematic review. Ann Am Thorac Soc. 2020;17(4):492–502.
94. Borel J-C, Burel B, Tamisier R, et al. Comorbidities and mortality in hypercapnic obese
under domiciliary noninvasive ventilation. PLoS One. 2013;8(1):e52006.
95. Lo Coco D, Marchese S, Corrao S, et al. Development of chronic hypoventilation in amyo-
trophic lateral sclerosis patients. Respir Med. 2006;100(6):1028–36.
96. Prell T, Ringer TM, Wullenkord K, et al. Assessment of pulmonary function in amyotrophic
lateral sclerosis: when can polygraphy help evaluate the need for non-invasive ventilation? J
Neurol Neurosurg Psychiatry. 2016;87(9):1022–6.
97. Reyhani A, Benbir Senel G, Karadeniz D. Effects of sleep-related disorders on the prognosis
of amyotrophic lateral sclerosis. Neurodegener Dis. 2019;19(3-4):148–54.
98. Aboussouan LS. Sleep-disordered breathing in neuromuscular disease. Am J Respir Crit Care
Med. 2015;191(9):979–89.
99. Suresh S, Wales P, Dakin C, Harris MA, Cooper DG. Sleep-related breathing disorder in
Duchenne muscular dystrophy: disease spectrum in the paediatric population. J Paediatr
Child Health. 2005;41(9-10):500–3.
100. Georges M, Attali V, Golmard JL, et al. Reduced survival in patients with ALS with upper
airway obstructive events on non-invasive ventilation. J Neurol Neurosurg Psychiatry.
2016;87(10):1045–50.
184 A. J. Piper
101. Quaranta VN, Carratù P, Damiani MF, et al. The prognostic role of obstructive sleep apnea at
the onset of amyotrophic lateral sclerosis. Neurodegener Dis. 2017;17(1):14–21.
102. Bianchi ML, Losurdo A, Di Blasi C, et al. Prevalence and clinical correlates of sleep disor-
dered breathing in myotonic dystrophy types 1 and 2. Sleep Breath. 2014;18(3):579–89.
103. Laberge L, Dauvilliers Y, Bégin P, Richer L, Jean S, Mathieu J. Fatigue and daytime sleepi-
ness in patients with myotonic dystrophy type 1: to lump or split? Neuromuscul Disord.
2009;19(6):397–402.
104. van der Meche FG, Bogaard JM, van der Sluys JC, Schimsheimer RJ, Ververs CC, Busch
HF. Daytime sleep in myotonic dystrophy is not caused by sleep apnoea. J Neurol Neurosurg
Psychiatry. 1994;57(5):626–8.
105. Ono S, Takahashi K, Jinnai K, et al. Loss of catecholaminergic neurons in the medullary
reticular formation in myotonic dystrophy. Neurology. 1998;51(4):1121–4.
106. Atalaia A, De Carvalho M, Evangelista T, Pinto A. Sleep characteristics of amyotrophic lat-
eral sclerosis in patients with preserved diaphragmatic function. Amyotroph Lateral Scler.
2007;8(2):101–5.
107. de Carvalho M, Costa J, Pinto S, Pinto A. Percutaneous nocturnal oximetry in amyotrophic
lateral sclerosis: periodic desaturation. Amyotroph Lateral Scler. 2009;10(3):154–61.
108. Sancho J, Burés E, Ferrer S, Ferrando A, Bañuls P, Servera E. Unstable control of breathing
can lead to ineffective noninvasive ventilation in amyotrophic lateral sclerosis. ERJ Open
Res. 2019;5(3):00099-2019.
109. Benditt JO. Respiratory care of patients with neuromuscular disease. Respir Care.
2019;64(6):679–88.
110. McSharry DG, Ryan S, Calverley P, Edwards JC, McNicholas WT. Sleep quality in chronic
obstructive pulmonary disease. Respirology. 2012;17(7):1119–24.
111. Omachi TA, Blanc PD, Claman DM, et al. Disturbed sleep among COPD patients is longitudi-
nally associated with mortality and adverse COPD outcomes. Sleep Med. 2012;13(5):476–83.
112. Shorofsky M, Bourbeau J, Kimoff J, et al. Impaired sleep quality in COPD is associated with
exacerbations: the CanCOLD cohort study. Chest. 2019;156(5):852–63.
113. Jolley CJ, Luo YM, Steier J, et al. Neural respiratory drive in healthy subjects and in
COPD. Eur Respir J. 2009;33(2):289–97.
114. Kwon JS, Wolfe LF, Lu BS, Kalhan R. Hyperinflation is associated with lower sleep effi-
ciency in COPD with co-existent obstructive sleep apnea. COPD. 2009;6(6):441–5.
115. O’Donoghue FJ, Catcheside PG, Eckert DJ, McEvoy RD. Changes in respiration in NREM
sleep in hypercapnic chronic obstructive pulmonary disease. J Physiol. 2004;559(2):663–73.
116. Costello R, Deegan P, Fitzpatrick M, McNicholas WT. Reversible hypercapnia in chronic
obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prog-
nosis. Am J Med. 1997;102(3):239–44.
117. O'Donoghue FJ, Catcheside PG, Ellis EE, et al. Sleep hypoventilation in hypercap-
nic chronic obstructive pulmonary disease: prevalence and associated factors. Eur Respir
J. 2003;21(6):977–84.
118. Holmedahl NH, Overland B, Fondenes O, Ellingsen I, Hardie JA. Sleep hypoventilation and
daytime hypercapnia in stable chronic obstructive pulmonary disease. Int J Chron Obstruct
Pulmon Dis. 2014;9:265–75.
119. Kitajima T, Marumo S, Shima H, et al. Clinical impact of episodic nocturnal hypercapnia and
its treatment with noninvasive positive pressure ventilation in patients with stable advanced
COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:843–53.
120. Kohnlein T, Windisch W, Kohler D, et al. Non-invasive positive pressure ventilation for the
treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre,
randomised, controlled clinical trial. Lancet Respir Med. 2014;2(9):698–705.
121. Murphy PB, Rehal S, Arbane G, et al. Effect of home noninvasive ventilation with oxygen
therapy vs oxygen therapy alone on hospital readmission or death after an acute COPD exac-
erbation: a randomized clinical trial. JAMA. 2017;317(21):2177–86.
122. Struik FM, Lacasse Y, Goldstein RS, Kerstjens HAM, Wijkstra PJ. Nocturnal noninvasive
positive pressure ventilation in stable COPD: a systematic review and individual patient data
meta-analysis. Respir Med. 2014;108(2):329–37.
123. Windisch W, Geiseler J, Simon K, Walterspacher S, Dreher M. German national guideline
for treating chronic respiratory failure with invasive and non-invasive ventilation - revised
edition 2017: part 2. Respiration. 2018;96(2):171–203.
124. Ergan B, Oczkowski S, Rochwerg B, et al. European Respiratory Society guidelines
on long-term home non-invasive ventilation for management of COPD. Eur Respir
J. 2019;54(3):1901003.
125. Crummy F, Piper AJ, Naughton MT. Obesity and the lung: 2. Obesity and sleep-disordered
breathing. Thorax. 2008;63(8):738–46.
126. Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic
obstructive pulmonary disease and obstructive sleep apnea. The overlap syndrome. Am J
127. Shawon MS, Perret JL, Senaratna CV, Lodge C, Hamilton GS, Dharmage SC. Current evi-
dence on prevalence and clinical outcomes of co-morbid obstructive sleep apnea and chronic
obstructive pulmonary disease: a systematic review. Sleep Med Rev. 2017;32:58–68.
128. Soler X, Gaio E. High prevalence of obstructive sleep apnea in patients with moderate to
severe chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2015;12(8):1219–25.
129. He BT, Lu G, Xiao SC, et al. Coexistence of OSA may compensate for sleep related reduction
in neural respiratory drive in patients with COPD. Thorax. 2017;72(3):256–62.
130. Messineo L, Lonni S, Magri R, et al. Lung air trapping lowers respiratory arousal threshold
and contributes to sleep apnea pathogenesis in COPD patients with overlap syndrome. Respir
Physiol Neurobiol. 2020;271:103315.
131. Konikkara J, Tavella R, Willes L, Kavuru M, Sharma S. Early recognition of obstructive sleep
apnea in patients hospitalized with COPD exacerbation is associated with reduced readmis-
sion. Hosp Pract (1995). 2016;44(1):41–7.
132. Jaoude P, Kufel T, El-Solh A. Survival benefit of CPAP favors hypercapnic patients with the
overlap syndrome. Lung. 2014;192(2):251–8.
133. Kuklisova Z, Tkacova R, Joppa P, Wouters E, Sastry M. Severity of nocturnal hypoxia and
daytime hypercapnia predicts CPAP failure in patients with COPD and obstructive sleep
apnea overlap syndrome. Sleep Med. 2017;30:139–45.
Chapter 10
Perioperative Care of Patients
with Obstructive Sleep Apnea Syndrome
Kara L. Dupuy-McCauley, Haven R. Malish, and Peter C. Gay
Keywords Perioperative complications · Postoperative monitoring · Obstructive

sleep apnea · Questionnaires · Perioperative guidelines · Sleep apnea guidelines ·
Postoperative CPAP · Hospital sleep apnea
Introduction
Obstructive sleep apnea (OSA) is a prevalent chronic condition, which is character-

ized by repeated episodes of collapse of the upper airway during sleep, leading to
episodic hypoxemia, sympathetic nervous system activation, and arousal from sleep
[1, 2]. Patients with obstructive sleep apnea have anatomical narrowing of the upper
airway (UA) leading to increased resistance, such that the force of the UA dilator
muscles is insufficient to prevent collapse [1]. As anesthesia, sedation, and analge-
sia can approximate certain aspects of the sleep state, patients with OSA are at risk
for worsening of disordered breathing events in the postoperative period and
increased postoperative cardiopulmonary complications.
Several anesthesia and sleep societies have proposed guidelines for the postop-
erative management of this patient population, aimed at reducing the risk of postop-
erative cardiopulmonary complications [3–8], although there are limited data
regarding the impact of implantation of these guidelines. This chapter will review
the most recent evidence regarding postoperative risks to the patient with OSA and
K. L. Dupuy-McCauley
Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA
H. R. Malish
Sleep Medicine, Mayo Clinic, Rochester, MN, USA
P. C. Gay (*)
Department of Medicine, Mayo Clinic, Rochester, MN, USA
e-mail: gay.peter@mayo.edu

188 K. L. Dupuy-McCauley et al.
the current recommendations regarding the care of patients with OSA during the
perioperative period.
Epidemiology and Risk Factors for OSA
The prevalence of OSA is thought to be 15–30% in males and 10–15% in females in

the general population of North America, but prevalence is increasing [9, 10] and
may vary based on population characteristics. For instance, OSA is more common in
older age, increased body mass index (BMI), and male gender [11]. Craniofacial
structure may also influence the presence of OSA [12], as well as ethnicity with OSA
being more common in those of East Asian and African American descent [13, 14].
The association between obesity and OSA warrants special consideration owing
to the alarming increase in the prevalence of obesity in the United States. Obesity is
associated with increased risk of OSA [10, 15], and may account for 58% of cases
of OSA with an AHI ≥ 15 [16]. In 2015–2016, the prevalence of obesity was 37.9%
in men and 41.1% in women [17]. The prevalence of severe obesity (BMI ≥ 40 kg/
m2) has increased from 5.7% to 7.7% from 2007 to 2016. Projections from this data
suggest that by 2030, almost half of United States adults will be obese and almost
one-fourth will be severely obese [17], and with this increase in weight, we will
certainly see an increase in prevalence of OSA.
In a population of patients presenting for bariatric surgery, prevalence of OSA
was very high and increased as BMI increased: For BMI 35–39.9 kg/m2 – 71%,
BMI 40–49.9 kg/m2 – 74%, and BMI > 60 kg/m2 – 95% [18].
Postoperative Risks Associated with OSA
OSA is a well-established risk factor for increased complications after surgery [19–
35]. The most common of these would be respiratory-related adverse outcomes
including worsening of OSA, acute respiratory failure requiring non-invasive venti-
lation or tracheal intubation with mechanical ventilation, pulmonary edema, acute
respiratory distress syndrome (ARDS), and oxyhemoglobin desaturation [20, 24–26,
36–39]. Patients also may be at risk for cardiovascular complications including atrial
fibrillation, myocardial infarction, cardiac arrest, congestive heart failure (CHF),
cerebrovascular accident (CVA), venous thromboembolism (VTE), and shock [19,
20, 22, 24, 26, 39–41]. Several studies have shown increased risk of mortality, and
other miscellaneous complications such as acute renal failure, wound hematomas or
seromas, ICU transfer, and prolonged length of stay in hospital [24, 31].
Patients who have OSA overlapping with either obesity hypoventilation syn-
drome (OHS) or chronic obstructive pulmonary disease (COPD) have higher risk of
pulmonary and cardiac complications, ICU transfer, and increased length of stay
compared with OSA alone [23, 29].
10 Perioperative Care of Patients with Obstructive Sleep Apnea Syndrome 189
It is important to note that these studies are heterogeneous as far as surgical pro-
cedures performed, methods and statistical analysis, and the evidence is of varying
quality. In a more recent meta-analysis of the existing literature, OSA remained
associated with myocardial infarction, atrial fibrillation, pneumonia, respiratory
failure, oxygen desaturation, postoperative delirium, acute kidney injury, venous
thromboembolism, length of hospital stay, 30-day mortality, unplanned ICU admis-
sion, and increased hospital admission costs, but was not found to be associated
with CHF, CVA, risk of reintubation, in-hospital mortality, surgical site infection, or
postoperative bleeding [42]. As an example of variance between postoperative risk
and procedure performed, a meta-analysis examining outcomes after cardiac sur-
gery specifically determined OSA was associated with increased risk of pooled
major adverse cardiovascular and cerebrovascular events up to 30 days after surgery
(all-cause mortality, myocardial infarction, myocardial injury, nonfatal cardiac
arrest, revascularization process, pulmonary embolism, deep venous thrombosis,
newly documented atrial fibrillation, CVA, and CHF), new-onset atrial fibrillation,
postoperative tracheal intubation and mechanical ventilation, but not with ICU or
hospital length-of-stay, infection, sepsis, or ICU readmission [43].
It is also important to acknowledge that some of these studies separate out mild,
moderate, and severe OSA, whereas others do not. This is an important consider-
ation because mild OSA may not portend the same postoperative consequences as
moderate or severe disease. For instance, Chan and colleagues found in a post hoc
analysis of their study on OSA and postoperative cardiovascular complications that
severe OSA was associated with a higher risk of postoperative cardiac death, myo-
cardial injury, CHF, new-onset atrial fibrillation, unplanned admission or readmis-
sion to the ICU, and unplanned tracheal intubation or lung ventilation, while
moderate OSA was associated with postoperative cardiac death, unplanned ICU
readmission, unplanned tracheal intubation, and infections, and mild OSA was only
associated with unplanned ICU admission or readmission to the ICU, unplanned
tracheal intubation or lung ventilation, and pneumonia [22].
Despite limitations in ability to determine precisely how severity of OSA, and
type of surgery being performed might influence the risk of specific postoperative
outcomes, it is clear that OSA does lead to a general increased postoperative risk
and therefore it would follow that there may be a benefit to identifying people with
OSA prior to surgery.
Preoperative Evaluation
Preoperative Risk Assessment and OSA Screening Protocols
Despite the increasing prevalence of OSA, many patients presenting for outpatient sur-
gery (67%) remain undiagnosed [22]. In the case of elective, outpatient surgery, it may
be possible to capture this population of patients through routine screening during pre-
operative evaluation and refer for evaluation of sleep-disordered breathing in advance
of a planned surgical procedure if screening is positive. The American Society of

Anesthesiologists (ASA) recommends that screening for OSA, which is now encour-
aged in most US hospitals, should begin with a thorough history and physical exam [3].
The history should focus on eliciting any risk factors for OSA that the patient may have
including age, gender, ethnicity, presence of obesity, and common comorbid associated
conditions including hypertension, history of stroke, history of myocardial infarction,
diabetes mellitus, or abnormal cephalometric measurements. This would also include
assessment of any congenital conditions and disease states that may be associated with
OSA including Down’s syndrome, acromegaly, neuromuscular disease, and cerebral
palsy. Questions regarding the symptoms of OSA may include considering the pres-
ence of snoring, witnessed apneic episodes, frequent arousals during sleep, morning
headaches, and daytime somnolence. Other important aspects of the history may
include difficulty with previous anesthetic administration or history of difficult intuba-
tion. The physical exam should include assessment of the craniofacial structure, nasal
passages, features of the posterior oropharynx (including tonsils and tongue size), and
neck circumference. A neck circumference of >17 inches (43 cm) in men, and > 16
inches (40 cm) in women is a positive predictor for the presence of OSA [3, 7].
After preoperative evaluation, the decision may be made to manage the patient
expectantly despite suspected OSA, or to delay surgery and have the patient pursue
a more urgent evaluation and treatment for sleep disordered breathing.
Preoperative Screening for Suspected OSA
Several questionnaires have been developed for the purpose of screening for OSA
and most have been assessed for use in the preoperative population and compared
via meta-analysis [44, 45]. The ASA, Society of Anesthesia and Sleep Medicine
(SASM), and the American Academy of Sleep Medicine (AASM) recommend rou-
tine preoperative screening for OSA to identify patients at increased risk of periop-
erative complications [46–48]. While there is consensus that risk of OSA should be
evaluated and documented, this does not necessarily mean that the plan for surgery
must be altered. The SASM guidelines state that there is insufficient evidence to
advocate cancelling or delaying surgery with the intent of pursuing a sleep evalua-
tion in patients with suspected OSA unless there is significant evidence of serious
uncontrolled comorbid disease or gas exchange abnormality [5].
The Berlin Questionnaire
The Berlin Questionnaire was designed for use in an outpatient primary care setting
and assesses five questions on snoring, three on excessive daytime sleepiness, one
on sleepiness while driving, and one on history of hypertension [49]. Age, gender,
weight, height, and neck circumference are also recorded. The Berlin Questionnaire’s
predictive performance is population dependent: In a primary care setting of 744
patients, it carried a sensitivity of 0.89, and specificity of 0.71. Half of high-risk
patients it identifies are subsequently found to have at least moderate OSA (at
AHI > 15) by polysomnography. In the preoperative setting, one study found the
Berlin Questionnaire classified 24% of patients presenting for elective surgery as
high risk [50]. Another study of preoperative use of the Berlin Questionnaire deter-
mined it had a sensitivity and specificity of 69% and 56% respectively in detecting
OSA with AHI > 5, 79% and 51% respectively in detecting OSA with AHI > 15, and
87% and 46% respectively in detecting OSA with AHI > 30 [51]. Despite its varied
performance in different patient populations, this data regarding use in the pre-
surgical population suggests a moderately high sensitivity especially in moderate-
to-severe OSA, and therefore supports the Berlin Questionnaire as a reasonable tool
to rule out OSA in the preoperative setting [51].
The American Society of Anesthesiologists’ Checklist
In the 2006 edition of the guidelines for the perioperative management of patients
with OSA, the ASA taskforce on OSA developed a 14-item, provider-administered
checklist to assist anesthesiologists in identifying OSA [52]. Patients endorsing
symptoms or signs in two or more of the three categories (physical characteristics,
history of airway obstruction during sleep, and complaints of somnolence) are con-
sidered high risk of having OSA. Like the Berlin Questionnaire and the STOP-Bang
Questionnaire, the ASA checklist exhibits a relatively good sensitivity in detective
OSA with an AHI of >5, >15, and > 30; 72%, 79%, and 87%, respectively. The
specificity remains rather low at 38%, 37%, and 36%, respectively, making is
another reasonable screening tool to rule out OSA [51].
The STOP Questionnaire
A condensed modification of the questions in the Berlin Questionnaire, the STOP

Questionnaire was developed and validated to facilitate widespread OSA screening
in surgical patients (S: Snore loudly, T: daytime Tiredness, O: Observed to stop
breathing during sleep, P: high blood Pressure). In the presurgical population, the
sensitivity of the STOP questionnaire at an AHI of >5, >15, and > 30 events/h cutoff
levels was found to be 66%, 74%, and 80%, respectively, with a specificity of 60%,
53% and 49%, respectively [46].
The STOP-Bang Model
The STOP-Bang Questionnaire adds demographic and physical features (B: BMI
>35 kg/m2, A: Age > 50 years, N: Neck circumference > 40 cm, G: male Gender) to
the STOP Questionnaire, and has the highest sensitivity in ruling OSA, especially in
moderate-to-severe disease.
A meta-analysis of the use of the STOP-Bang Questionnaire in the presurgical

population found a pooled prevalence of 68.4%, 39.2%, and 18.7% for any OSA,
moderate-to-severe OSA, and severe OSA respectively, with corresponding sen-
sitivities of 84%, 91%, and 96% respectively and specificity of 43%, 32%, and
29%, respectively [53]. A recent prospective cohort study of preoperative patients
found that a STOP-Bang score of 5–8 may be significantly more suggestive of
moderate-to-severe OSA than scores of 3–4: 78% prevalence versus 53% respec-
tive prevalence of moderate-to-severe OSA [54]. A study of an ethnically diverse
population of bariatric patients found that the STOP-Bang previously validated
cutoff of ≥4 achieved a sensitivity of >80% and specificity of 50–60%, which is
similar to other populations [55]. The STOP-Bang has also been assessed in a
variety of ethnic groups (Chinese, Indian, Malay, Caucasian) and there are recom-
mendations in those groups for alternative BMI thresholds and STOP-Bang score
cutoffs for optimal sensitivity and specificity in these patient populations [56].
Taken together, these data suggest that the STOP-Bang may be an appropriate
assessment tool for a wide variety of patient populations but with alternative cut-
offs for certain groups.
Sleep Apnea Clinical Score
The Sleep Apnea Clinical Score (SACS) was validated in the outpatient sleep labo-
ratory environment and shown to have a high positive predictive value for OSA
[57]. The SACS score was initially validated in postsurgical patients to identify
patients who desaturated in the postoperative hospital ward area [58]. A large pro-
spective study enrolled nearly 700 patients using the SACS and showed a higher
risk of OSA (32% of all patients) was associated with a much higher likelihood of a
postoperative 4% oxygen desaturation index (ODI) >10 events/h and recurrent post
anesthesia care unit (PACU) respiratory events [59]. Subsequent postoperative hos-
pital ward episodes of respiratory complications were also associated with a high
SACS (odds ratio 3.5, P < 0.001), especially if they also had recurrent respiratory
events in the PACU during 90 min of observation, whereby the likelihood of a post-
operative respiratory event was profoundly increased (odds ratio 21.0, P < 0.001).
There was no significant benefit with the SACS questionnaire in predicting cardiac
complications or prolonged hospital stay.
Preoperative Screening in Suspected OSA
The use of one screening tool over another is not mandatory, and most guidelines
leave this decision of which tool to use up to the provider who is performing the
preoperative assessment. Optimal preoperative evaluation must also include consid-
eration of the risk inherent to the particular type of surgery being performed, risk of
other patient comorbidities, and past difficulties with anesthesia or intubation in

addition to screening for OSA [60].
The left side of Fig. 10.1 summarizes one possible preoperative approach in the
suspected OSA patient. Those with ≥2 on the STOP, or ≥ 3 on the STOP-Bang
Questionnaire are considered high risk of having undiagnosed OSA.
In certain situations, preoperative assessment by a sleep physician may be war-
ranted for consideration of polysomnography or home sleep testing if time and
resources permit. An early consult would typically allow the sleep physician ade-
quate time to prepare a perioperative management plan, which may include a
period of at-home positive airway pressure (PAP) treatment prior to surgery for the
Suspected OSA patient Known OSA patient
Screening using STOP or Severity Assessment from History

STOP-Bang questionnaire or Polysomnography
High risk of OSA Low risk of OSA Moderate or

≥ 2 on STOP ≤ 2 on STOP Mild OSA
Servere OSA
≥ 3 on STOP-Bang ≥ 3 on STOP-Bang AHI 5 1 15
AHI > 15
Oximetry ≥ 94 %
Oximetry < 94%
on room air
on room air
Major Elective Surgery &
Significant Comorbidities Changes is OSA Status
• Heart failure • Recent exacerbation
• Arrhythmias of OSA symptoms
• Uncontrolled hypertension Rountine mangement. • Non-compliant to
• Cerebrovascular disease No peroperative PAP PAP therapy‡
• Metabolic syndrome therapy required. • Recently undergone
• Obesity with BMI > kg/m2 OSA-related surgery
• Lost to sloop
medicine follow-up
No Yes
Yes No
Possibility of Consider
moderate preoperative referral
OSA: to sleep medicine
Preoperative PAP
Perioperative physician,
therapy‡,
OSA polysomnography,
Perioperative OSA
precautions and PAP therapy‡.
precautions
Fig. 10.1 An approach to those with suspected or known obstructive sleep apnea (OSA) prior to
surgery in the ambulatory setting. ‡ Positive airway pressure (PAP) therapy may include continu-
ous, bi-level, or auto-titrating PAP. (Adapted with kind permission from Springer Science + Business
Media [60])
purpose of acclimatization. Ultimately, the decision for further preoperative sleep

study testing would depend on the clinical judgment and expertise of the team of
physicians providing perioperative care after careful screening and assessment.
Patients determined to be at low risk for presence of OSA may be managed expec-
tantly with no further diagnostic testing prior to surgery. For those deemed at high
risk for OSA, there are a variety of possible courses of action. In some cases,
major elective surgery may be deferred in patients with a high clinical suspicion
of complicated, severe OSA. In other cases, there may be patients who are deemed
high risk according to an OSA screening questionnaire, but who otherwise are
without significant comorbidities or are scheduled to undergo a low risk proce-
dure, and in that case, the physician team may elect to proceed to surgery without
delay [61]. And there may be other situations where the risk of delaying the sur-
gery outweighs the benefits of identifying and treating OSA preoperatively and so
the patient is taken to surgery even in the setting of clinical suspicion of severe or
complicated OSA. The literature is vague and lacking in the scientific evidence to
support definitive guidelines regarding risks and benefits of cancelling most types
of procedures.
Preoperative Screening in Known OSA
A potential preoperative evaluation approach for patients with known OSA is illus-
trated on the right side of Fig. 10.1. Although the original severity of the sleep-
disordered breathing must be known or estimated in this case, the treatment status
would be an important factor in preoperative risk assessment. The use of PAP
devices (CPAP, bi-level PAP [BPAP], auto-titrating CPAP [APAP]), and the compli-
ance should be assessed for those who have been prescribed PAP therapy. Patients
who have been lost to sleep medicine follow-up and/or those who are noncompliant
with therapy, those who have had recent exacerbation of OSA symptoms, and those
who have undergone OSA-related airway surgery may benefit from preoperative
referral for additional evaluation with a sleep medicine physician. Long-standing
OSA, especially in the case of suboptimal treatment or lack of treatment, may have
systemic complications, including hypoxemia, hypercarbia, polycythemia, and cor
pulmonale. Pulse oximetry may be a simple screening tool in the preoperative
clinic. Some advocate that an oxygen saturation value of <94% on room air in the
absence of other causes should be a red flag for possible severe long-standing OSA
[60], which may be another reason to refer to sleep preoperatively.
Preoperative OSA Treatment
The ASA, SASM, and AASM agree that patients with OSA who have been on PAP
therapy should continue PAP therapy in the preoperative period [3, 5, 7]. The ASA
recommends that initiation of PAP should be considered, particularly in patients
with severe OSA, but that the preoperative use of an oral appliance, or weight loss,
may also be acceptable considerations [3]. Initiation of PAP therapy for those with
untreated OSA or re-initiation of preoperative PAP in the non-PAP-adherent OSA
patient should be considered, although the benefit of using PAP in the time period
leading up to surgery as a means to reduce postoperative cardiopulmonary risk in
patients with OSA is uncertain [62].
Intraoperative OSA Management
Tracheal Intubation
The surgical and anesthesia team should be aware of a patient’s previous diagnosis
of OSA, or that the patient is “high risk” for OSA but has not undergone a formal
sleep evaluation. The ASA guidelines state that patients with OSA should be pre-
sumed to have a “difficult airway,” meaning there would potentially be difficulty
with tracheal intubation, facemask ventilation, or both [3], and the patient should be
managed in accordance with the ASA practice guidelines for management of the
difficult airway [63]. The SASM advocates that patients at high risk for OSA should
proceed to surgery in the same manner as those who have confirmed OSA, but that
known or suspected OSA should be considered an independent risk factor for dif-
ficult intubation, difficult mask ventilation, or a combination of both [5, 6]. The
AASM recommends that the patient be considered a “high-risk intubation,” and
advocates against the use of unsupervised preoperative sedation [7].
These recommendations are based upon literature suggesting OSA is associated
with difficult intubation [36, 37, 64–68]. The reverse association is true as well,
patients with a history of difficult intubation have a high prevalence of OSA. This
was discovered retrospectively by Hiremath and colleagues [36], and subsequently
confirmed with a prospective study done by Chung and colleagues [69]. A variety
of other studies examining this association exist as well. A retrospective case-
controlled study of 253 patients was conducted to determine the occurrence of dif-
ficult intubation in OSA patients. The OSA patients were matched with controls of
the same age, gender, and type of surgery. Difficult intubation was assessed by
laryngoscopy using the Cormack and Lehane classification [70], and was found to
occur eight times as often in OSA patients versus controls (22% vs. 3%, P < 0.05)
[37]. In OSA patients undergoing ear, nose, and throat surgery, a 44% prevalence of
difficult intubation has similarly been reported [71]. Furthermore, patients with
severe OSA (AHI >40) were found to have a much higher prevalence of difficult
intubation [72]. Increased prevalence of obesity in the OSA population is not the
only factor that explains this association. A study of more than 1500 nonobese and
obese patients concluded that increased age, male gender, pharyngo-oral pathology,
and the presence of OSA are all associated with a more frequent occurrence of dif-
ficult intubation [73]. This suggests that patients who are found to have a difficult
airway in the absence of any documented OSA should be referred for evaluation by
a sleep medicine provider.
Choice of Anesthetics/Anesthetic Technique
One aspect of planning and preparation for surgical procedures in patients with
OSA is the choice of anesthesia strategy, which may present an opportunity to
reduce risk in patients with OSA. Sedative, anesthetic, and analgesic medications
mimic the sleep state by increasing collapsibility of the upper airway, reducing
hypoxic and hypercapnic respiratory drives, decreasing activity of the respiratory
muscles, increasing dependence upon the diaphragm, decreasing respiratory stimu-
lation, and decreasing lung volumes, which may be especially detrimental to patients
with OSA [74–81]. The ASA recommends general anesthesia with tracheal intuba-
tion as opposed to deep sedation without a secure airway [3]. The ASA also recom-
mends that CPAP or a mandibular advancement device may be used during sedation
to facilitate the airway remaining open.
Patients with OSA are felt to be at higher risk for adverse respiratory events from
the use of propofol and neuromuscular blockade, but there is insufficient data to
assess the risk associated with inhalational anesthetic agents, alpha-2-agonists (such
as dexmedetomidine and clonidine), and ketamine [6]. However, data from studies
of obese patients suggest that desflurane and sevoflurane may facilitate or more
rapid and consistent postoperative recovery, which may be relevant to many patients
with OSA, given the high association between OSA and obesity [82]. A strategy of
regional anesthesia is preferred over general anesthesia in patients with OSA due to
findings from several population-based studies showing decreased odds for mechan-
ical ventilation, critical care admission, and prolonged hospital length of stay [3, 6,
52, 83–86].
Use of intravenous benzodiazepines may put patients with OSA at increased
risk for upper airway collapse and subsequent respiratory complications. Much of
this literature comes from the use of intravenous benzodiazepines during drug-
induced sleep endoscopy (DISE), where IV benzodiazepines are used to induce
collapse of the upper airway [87]. There are additional retrospective studies to
suggest that patients with OSA are more prone to hypoxia and airway collapse
when subjected to IV midazolam than those with primary snoring and no OSA
diagnosis [88].
There are no prospective, randomized, controlled trials comparing the safety,
efficacy, and impact on respiratory status of different anesthetic, analgesic, and sed-
ative strategies in patients with OSA. However, a promising technique of opioid-
free analgesia is emerging and may be a safer approach to anesthesia in the OSA
population. This opioid-free strategy is based in the principle of multimodal anes-
thesia and would typically consist of using multiple anesthetic and analgesic agents
in subtherapeutic doses simultaneous. For example, a continuous infusion of lido-
caine and dexmedetomidine might be supplemented with a low dose of a volatile
anesthetic agent and intermittent dosing of acetaminophen, ketamine, ibuprofen,
and ketorolac. This innovative technique may provide adequate anesthesia and anal-
gesia without exposing patients to the unwanted respiratory side-effects and possi-
ble addictive properties of opioids [89].
Extubation
The ASA and AASM recommend that patients with OSA be extubated awake and
in the non-supine position unless contraindicated [3, 7], and the ASA adds that neu-
romuscular blockade should be fully reversed prior to extubation [3].
Postoperative OSA Management
Postoperative Pain Control
Postoperative analgesia can adversely influence respiration in surgical patients with

OSA. In the acute setting, analgesia is commonly achieved with opioids, which may
affect the central nervous system and whose effects may be potentiated by other
sedative and anesthetic agents. Opioids depress the central respiratory drive,
decrease consciousness, and decrease supraglottic muscle tone, leading to increased
risk of upper airway obstruction [90]. In a retrospective study of 1600 patients who
had received postoperative patient-controlled analgesia with IV opioids, eight cases
of serious respiratory depression were reported [91]. Contributing factors were the
concurrent use of a background infusion of opioids, advanced age, concomitant
administration of sedative or hypnotic medications, and a preexisting history of
sleep apnea. A review conducted to identify the risk factors for respiratory depres-
sion subsequent to patient-controlled analgesia concluded that there is no single
indicator for respiratory depression but that OSA, whether suspected or verified by
patient history, is a risk factor [92].
A recent review of critical perioperative complications (including death) in
patients with OSA identified morbid obesity, male sex, undiagnosed/untreated
OSA, suboptimal use of postoperative CPAP, need for opioid analgesia, and lack of
appropriate postoperative monitoring as risk factors [28]. The majority of patients
who had adverse outcomes in this study had consumed a typical, or even a less-than-
typical amount of opioids, which may suggest increased sensitivity to opioids in this
population as an explanation [93].
Because of the myriad effects of opioids on the CNS and respiratory systems,
and the complex interaction between sleep disordered breathing, obesity, and sleep
architecture, it is difficult to predict the respiratory consequences of opioid admin-
istration in the OSA population. Opioids can cause increased severity of obstructive
events, elicitation of centrally mediated apneic events (central sleep apnea [CSA] or
ataxic breathing), and hypoventilation. For instance, a randomized study of remi-
fentanil use in patients with moderate OSA actually showed a decrease in the num-
ber of obstructive events with an increase in central apneas [94]. This decrease in
obstructive events may be attributed to the decrease in REM sleep that typically
occurs on the first night after surgery, but this report highlights the complex interac-
tion between multiple factors postoperatively. And the literature on this subject
must be interpreted with caution as there may be varying measures of respiratory

changes.
The ASA guidelines recommend avoidance of opioids when possible in patients
with OSA, especially in the form of continuous infusion, and they recommend cau-
tion with other known respiratory depressants such as benzodiazepines and barbitu-
rates [3]. The AASM and SASM recommend caution with the use of sedatives,
hypnotics, and anxiolytics in the postoperative period [6, 7]. Bearing in mind these
guidelines, one might consider strategies to minimize opioid exposure in this popu-
lation. One such strategy might involve careful titration of opioids so as to provide
the minimum amount required to achieve adequate pain control [7]. Another poten-
tial strategy would be a multimodal approach using combinations of analgesics
from different classes and different sites of analgesic administration for periopera-
tive pain management [95–97]. Such an approach may include peripheral nerve
block catheters or neuro-axial catheters dispensing local anesthetic agents (without
opioids) and opioid-sparing analgesic agents, such as nonsteroidal anti-inflammatory
drugs, COX-2 inhibitors, acetaminophen, pregabalin, tramadol, and dexamethasone
[98]. But caution should still be exercised even despite opioid-sparing techniques. A
large retrospective study of patients who had undergone laparoscopic surgery found
an association between use of gabapentin and respiratory depression. This associa-
tion tended to be present in patients who were older, had received midazolam, and
had a slightly higher intraoperative dose of opioids [99]. This might suggest that
even in the absence of postoperative opioid use, there may still be consequences to
polypharmacy, and an effective postoperative monitoring strategy to identify those
at risk for respiratory complications is important.
Postoperative Monitoring
The preservation of arousal mechanisms is vital when it comes to self-protection

from airway obstruction and hypoventilation. When arousal responses are sup-
pressed by sedative, anesthetic, and analgesic medications, the patient can have
increased risk of asphyxia, cardiopulmonary arrest, and death [100]. Proper moni-
toring for return of these arousal mechanisms is key in ensuring patient safety in the
postoperative setting. In patients with OSA, most respiratory complications occur
on the general hospital ward in the first 24 hours post-surgery [28, 35, 101]. A
closed claims analysis of postoperative opioid-induced respiratory depression
revealed that 25% of claims were related to OSA [101], highlighting the importance
of proper postoperative monitoring, especially for those patients who are within the
24-hour postoperative window, who have a diagnosis or are at high risk for OSA,
and who are receiving opioid analgesia. A recent review of postoperative critical
events associated with OSA by Bolden and colleagues found events were most
likely to occur in the first 24 hours after surgery and that death or brain damage was
less common in patients receiving supplemental oxygen and in patients with respi-
ratory monitoring in place at the time of the event. Death or brain damage was more
common in patients receiving sedatives in addition to opioids, and in patients who
were not being closely observed [102]. This would seem to advise use of supple-
mental oxygen when appropriate, close observation, and avoidance of polyphar-
macy with multiple CNS depressants if feasible.
Oximetry
While there is no general consensus on an appropriate postoperative monitoring

strategy for patients with OSA, the ASA and AASM both recommend continuous
pulse oximetry postoperatively for this patient population [3, 7], although no men-
tion is made of the setting in which this monitoring should occur (e.g., PACU vs.
general medical ward), and the ASA acknowledges that the optimal duration for
postoperative monitoring has not been established [3].
Gali and colleagues found that patients at risk for OSA who had recurrent respi-
ratory events (bradypnea, apnea, oxygen desaturation, and pain–sedation mismatch)
in the immediate postoperative period had the highest oxygen desaturation index on
continuous pulse oximetry and were at the highest risk of postoperative respiratory
complications. In this study, patients were assessed at 30, 60, and 90 minutes post-
operatively, which may be an acceptable strategy to identify patients who may ben-
efit from a higher level of care or more intensive monitoring [58].
Chan and colleagues also looked at postoperative patients at high risk for OSA
and found that prolonged oxygen desaturations <80% during the first three postop-
erative nights portended a higher risk of postoperative cardiovascular events [103],
again suggesting that oximetry may provide a clue as to which patients may benefit
from closer monitoring.
These two studies would suggest that continuous pulse oximetry might be an
important tool for risk stratification; however, other studies have failed to show a
significant impact on clinical outcomes as a results of continuous pulse oximetry in
the postoperative setting. A systematic review and meta-analysis of continuous
pulse oximetry and capnography monitoring found that continuous remote pulse
oximetry improved detection of oxygen desaturation and was associated with a
trend toward decreased ICU transfer when compared to intermittent oxygen assess-
ment, but did not significantly reduce mortality [104]. In the previously mentioned
closed claims analysis by Lee and colleagues, it should be noted that one-third of
the patients who experienced complications from postoperative opioid-induced
respiratory depression were being monitored with oximetry [101], which reinforces
concerns that while continuous pulse oximetry may bring attention to oxygen desat-
uration, we are not currently able to translate that into definitively improved patient
outcomes.
Capnography
One conjecture as to why continuous oximetry does not necessarily translate into
improved postoperative outcomes is that oxygen desaturation is a late sign of
hypoventilation particularly for patients receiving supplemental oxygen, and per-
haps continuous capnography monitoring might more effectively predict respiratory
failure. In the assessment of capnography, a systematic review found that capnogra-
phy derangements preceded changes in oxygen saturation in the setting of supple-
mental oxygen administration [104].
But capnography may not be accurate in the setting of PAP use. End-tidal carbon
dioxide tension (ET-CO2) and transcutaneous carbon dioxide monitoring (tc-CO2)
accuracy have been compared in a sleep laboratory with PaCO2 levels in patients
wearing a nasal cannula or using nocturnal positive-pressure ventilatory assistance
[105]. ET-CO2 tension and tc-CO2 during diagnostic and therapeutic sleep studies
did not accurately reflect the simultaneous PaCO2 levels when PAP therapy was
applied. It may be that ET-CO2 and tc-CO2 could be used to identify trends in CO2
levels in patients on PAP rather than serving as a surrogate for arterial PaCO2 levels,
but more research is needed to define the clinical utility of such a strategy.
Capnography is not used on a routine basis in a clinical setting and there is no
prospective data on whether capnography may improve outcomes or reduce postop-
erative complications. But although there are no current guideline recommenda-
tions advocating its use in postoperative patients, emerging research suggests that
capnography may soon become more widely adopted as a tool for early detection of
respiratory failure. A prospective, blinded, multicenter, observational trial found
that adding capnography and the Integrated Pulmonary Index algorithm, an
algorithm-derived value based on SpO2, EtCO2, pulse, and respiratory rate, to tradi-
tional pulse oximetry afforded an average additional 8–11 minutes lead time prior
to an adverse respiratory event when compared to standard postoperative monitor-
ing with pulse oximetry alone [106]. This suggests that capnography may soon
become an important tool to facilitate early detection of postoperative respiratory
compromise, hopefully leading to early intervention and decreased respiratory risk.
Management Algorithms
PACU
While the literature is insufficient to provide evidence-based guidance regarding

specific postoperative monitoring strategies, one might consider the surgery type
and risk, patient characteristics, as well as anesthesia and analgesia-specific factors
when planning for the postoperative period. The 2006 ASA guidelines, directed by
expert consensus in the absence of good clinical evidence at the time, urged guid-
ance of OSA patient disposition by a weighted scoring system and patient risk fac-
tors [52]. Perioperative risk was broadly divided into severity and treatment of OSA,
invasiveness of the surgery, anesthesia used, and postoperative opioid requirements.

The scoring system was somewhat involved and did not recognize the importance
of recurrent PACU events in predicting more episodes of oxygen desaturation and
increased postoperative respiratory complications [59].
Taking into account 2006 ASA guidelines and recent evidence for identifying
patients most at risk for postoperative respiratory complications, Seet and Chung
[60] proposed an algorithm using recurrent PACU events as a predictive indicator to
guide postoperative disposition of the known or suspected OSA patient (Fig. 10.2).
A PACU event occurs if in one 30-min time block, the patient has any of the follow-
ing: (1) apnea for ≥10 s (only one episode needed for yes), (2) bradypnea of ≤8 bpm
(three episodes needed for yes), (3) desaturations to <90% (three episodes needed
for yes), or (4) pain-sedation mismatch, as characterized by high pain scores and
high sedation levels observed simultaneously.
A recurrent PACU event occurs when any one of the PACU respiratory events
occur in two separate 30-min time blocks (not necessarily the same event or con-
secutive blocks). Patients who are at high risk of OSA on the screening question-
naires and have recurrent PACU respiratory events are more likely to have
postoperative respiratory complications. It may be prudent to monitor these patients
postoperatively with continuous oximetry in an area where early medical interven-
tion can occur. The monitoring can occur in the step-down unit, on the surgical ward
near the nursing station, or with remote pulse oximetry with telemetry (Fig. 10.2).
Close postoperative monitoring would certainly be called for in patients with
known OSA with recurrent PACU events, but also in the absence of recurrent events
if the patient’s OSA is severe or if they are not using PAP (left side of Fig. 10.2). In
the absence of severe OSA, nonadherence, and recurrent PACU events, patients
with at least moderate OSA, or parenteral/higher dose oral opioids (codeine 60 mg
every 4 h or equivalent) may be managed postoperatively on the surgical ward with
periodic oximetry monitoring. The ASA also recommends that all patients be pro-
vided supplemental oxygen on a continuous basis until they are able to maintain
their baseline oxygen saturation while on room air [3].
For those with previously undiagnosed but suspected OSA in the postoperative
or medical inpatient setting, our institution has developed an obstructive apnea sys-
tematic intervention strategy (OASIS) protocol, as outlined in the top half of
Fig. 10.3. PACU utilization, overnight oximetry, ABG, inpatient events, and discus-
sion with the primary team are often enough to guide initial decision-making.
Appropriate setting (outpatient vs. inpatient) and timing (before or after discharge)
of a comprehensive sleep medicine assessment may be determined based on local
resources and testing availability.
Postoperative Use of Positive Airway Pressure
When possible, patients with known OSA who are already on PAP therapy should
bring their own equipment to the hospital and PAP should be used liberally periop-
eratively unless a contraindication exists [3]. Contraindications to PAP therapy
Prolonged stay in PACU

(> 30-60 min after modified Aldrete criteria met)
Known OSA Suspected OSA

(≥2 on STOP, 3 STOP-Bang)12
Non-compliant with PAP therapy‡, Recurrent PACU Respiratory Event (30-

Severe OSA (AHI > 30), or min block)’
Recurrent PACU Respiratory Event (30-min • Oxygen saturation <90% (3 episodes)
block)’ • Bradypnea < 8 breaths/min (3 episodes)
• Oxygen saturation <90% (3 episodes) • Apnea ≥ 10 s (1 episodes)
• Bradypnea < 8 breaths/min (3 episodes) • Pain sedation mismatch
• Apnea ≥ 10 s (1 episodes)
• Pain sedation mismatch
No Yes Yes No
Moderate OSA (AHI > 16-30),

Postoperative parenteral or
oral opioids required
(> codeine 60 mg q4h, or
equivalent)
No Yes
Discharger to Postoperative Postoperative PAP Discharger to home if

home if care on the therapy‡ and care in the minor surgery or
minor surgical ward. monitored bed‡ with postoperative care on
surgery. continuous oximetry. the surgical ward.
Fig. 10.2 Postoperative management of the known or suspected OSA patient after general anes-
thesia Number of occurrences of more than one set of events in each 30-min evaluation period
while in the post-anesthesia care unit (PACU), including repeat occurrence of the same event set.
‡PAP therapy may include continuous, bi-level or auto-titrating PAP. †Monitored bed – inpatient
area that would lend itself to early nursing intervention and includes continuous oximetry monitor-
ing (e.g., intensive care unit, step-down unit, or remote pulse oximetry with telemetry in surgical
ward). (Adapted with kind permission from Springer Science + Business Media [60])
include cardiac or respiratory arrest, severe encephalopathy, severe upper gastroin-

testinal bleeding, hemodynamic instability, cardiac arrhythmia, upper airway
obstruction, high risk for aspiration, copious secretions, recent facial trauma, inabil-
ity to clear secretions, and lack of cooperation from the patient [108]. Patients with-
out a formal diagnosis of OSA, or who have OSA but are not on PAP therapy in the
outpatient setting may warrant consideration of initiation of PAP postoperatively
while hospitalized. CPAP and APAP are equally effective in the perioperative man-
agement of OSA as demonstrated by decrease in AHI, improvement in oxygenation,
and shortened length of stay [109]. If the patient has a home machine, it is reason-
able to start at the home pressure setting, but with the acknowledgement that the
Sleep consult submitted

Oximetry/ABG obtained
Call requesting service

What’s the issue?
Previous evaluation?
Discharge pending?
Patient refusing CPAP?
Follow-up as outpatient: Perform consultation: based

Sleep lab or home study on oximetry, comorbidities,
converience (eg, paraplegic)
Sleep lan follow-up: Begin empirical CPAP/BPAP*: Polysomnogram now: either

Outpatient return visit Unit: start BPAP portable in-hospital (because
scheduled Ward: CPAP, continue BPAP of medical issues) or in sleep
lab (bed availability)
*Criteria Contact respiratory therapy
1. Bad overnight oxygenation
• 4% desaturation index > 20
• Saturation ≤ 75% or New CPAP introduction?
• Mean saturation ≤ 88% or Auto-adjusting PAP
• Saturation ≤ 90% ≥ 15% of study • Introduction: before 4 pm
2. Or coronary artery disease+ • Fit with mask and pillows
3. Or congestive heart failure+ • Assess patient’s willingness
4. Or arrhythmia
5. Or reason to delay PSG Respiratory therapy
contacts sleep service
Patient agrees Patient intolerent
APAP (min/max 4/20 cm H2O) RT records why?

• Heated humidification • Mask discomfort
• Repeat oximetry on APAP • Pressure
• If initial oximetry on O2 then APAP on O2 • Claustrophobia
• If initial oximetry on room ari, then APAP alone • Refusal
BPAP for Paco2> 50 mm Hg or pH < 7.35
Heated humidification (1 or 2 setting)
Oxygen decided as above
Setting per ICU or previous use
Dowload
APAP and
oximetry
Continue CPAP/BPAP Patient non-adherent Sleep Service contacts
• Order standard fixed or refuses to continus: primary service:
CPAP, set at > 95% • Why? • Recommend bed elevation
time pressure off and avoid back position
• Download data • Minimize narcotics,
sedatives
• Follow-up scheduled in
sleep lab
Discharge from hospital
Supplemental oxygen
Follow-up PSG scheduled Continue CPAP (prescription given)

(No home CPAP) with follow-up PSG scheduled in sleep lab
Fig. 10.3 Obstructive apnea systematic intervention strategy (OASIS) for assessing postoperative
or medical patients for sleep-disordered breathing, with follow-through management algorithm
based on patients’ PAP willingness. ABG Arterial blood gas, CPAP continuous PAP, BPAP bi-level
PAP, PSG polysomnography, APAP auto-adjusting PAP, PSG polysomnography, RT respiratory
therapy. (Adapted from [107])
pressure need may need to be titrated to meet the fluctuating needs of the postopera-
tive patient and to accommodate for increased time in the supine position, thoracic
pain, postoperative distortions in sleep architecture, and CNS depressant medica-
tions. Sleep-related breathing disturbances are typically the highest on the third
night postoperatively, likely due to “REM rebound,” or increased proportion of
REM sleep after the distortion in sleep architecture, (with decreased sleep effi-
ciency, slow wave sleep and REM sleep) which typically accompanies postopera-
tive night one [110]. This fluctuating severity of sleep disordered breathing in the
postoperative period reinforces the concept that PAP needs may also vary and
patients should be continuously monitored, and PAP adjusted appropriately. For
patients who do not have a prior pressure setting, use of APAP or manual bedside
titration may be more appropriate [111].
In those for which inpatient PAP initiation is desired, early assessment (prior to
4 p.m.) by the respiratory therapist mask fit and patient willingness is recom-
mended. Once PAP is initiated, close follow-up is needed to assess patient toler-
ance. In the case of intolerance, troubleshooting may be attempted, including mask
fit, pressure setting, addressing claustrophobia, and assessing if the treatment aligns
with the patient’s wishes and values. Upon discharge, the patient may need a formal
sleep evaluation in the outpatient setting if continuation of PAP therapy is desired.
In certain institutions, the patient may be qualified for PAP therapy in the inpatient
setting and discharged with a prescription and routine sleep medicine follow up.
The recommended follow through of inpatient PAP initiation is outlined in the bot-
tom half of Fig. 10.3.
As there are no universal guidelines for discharge into an unmonitored setting,
patients with known or suspected OSA should be discharged at the discretion of the
inpatient care team when they are able to maintain oxygen saturation on room air
[3], taking into account severity of OSA, type of surgery performed, and postopera-
tive course (Fig. 10.2). Ambulatory surgical centers managing OSA patients should
have transfer agreements to inpatient facilities and should be equipped to manage
contingencies associated with OSA.
Positive Airway Pressure and Postoperative Risk Reduction
No consensus has emerged regarding the ability of PAP to reduce cardiopulmonary

complications in patients with OSA. It is difficult to assess this body of literature as
a whole due to its heterogeneous characteristics when it comes to the timing of PAP
initiation (i.e., was PAP used in the preoperative period leading up to surgery vs.
implementation during hospital admission), and low PAP compliance. Low PAP
compliance has been a consistent hinderance to assessing OSA outcomes associated
with PAP use in general, and PAP use tends to be even lower in the perioperative
period [112]. Nagappa and colleagues performed a systematic review and meta-
analysis of the existing studies on outcomes in OSA patients undergoing surgery.
They examined six studies of 904 patients and found that use of perioperative CPAP
did not decrease postoperative complications but it did lower the AHI and provided
a trend toward decrease length of hospital stay [62]. A large cohort study by Mutter
et al. deduced that CPAP decreased cardiovascular complications by demonstrating
increased risk in patients who had undiagnosed OSA (versus diagnosed OSA), and
patients who had a preoperative diagnosis of OSA and a CPAP prescription [40]. A
smaller retrospective case–control study suggested that despite CPAP use being low
in general, those who had been using CPAP prior to admission were at less risk of
serious postoperative complications, total ICU length-of-stay, unplanned ICU
admission, and length of hospital stay [35].
More recently, a large retrospective database study of over 28,000 patients was
performed to assess differences in postoperative outcomes between those with pre-
viously diagnosed OSA and preoperatively suspected OSA. The rate of adverse
perioperative outcomes (reintubation, mechanical ventilation, direct ICU admission
after surgery, prolonged hospital length-of-stay, and all-cause 30-day mortality) was
higher in those with suspected OSA after adjusting for potential confounders. But a
subgroup analysis did not find any link between those who were diagnosed with
OSA and compliant with CPAP versus those who were diagnosed and who were not
compliant with CPAP, suggesting that PAP may not influence postoperative out-
comes. However, this was based on self-reported PAP compliance, which can be
inaccurate [113].
A review of perioperative CPAP use by Chung and colleagues highlighted sev-
eral studies examining the perioperative benefits of CPAP and while some of the
case series and cohort studies showed benefits from CPAP including decreased
postoperative complications, and decreased length of hospital admission and ICU
stay, the two RCTs did not show the same benefit [114].
The bariatric population offers an exceptional opportunity to study CPAP-related
postoperative outcomes due to the high prevalence of OSA. A retrospective study of
53 patients undergoing bariatric surgery found no differences in postoperative com-
plications, or hospital length of stay; however, similar to other literature on the
subject, there were significant limitations including retrospective nature of the
study, small sample size, use of oxygen desaturation index from pulse oximetry to
define OSA presence and severity, and lack of CPAP adherence data [115].
Additionally, all patients with moderate-to-severe OSA were treated with CPAP,
which may be a major confounder, being that other studies have shown varying
postoperative risk based upon severity of OSA [22].
Although many of the studies suggesting benefit from perioperative CPAP use
have significant limitations, they appear to be building the foundation of a body of
evidence that may eventually show definitive reduction in postoperative complica-
tions as a result of PAP use.
And looking beyond the OSA population, there are compelling RCTs in patients
without OSA that show a more conclusive postoperative PAP benefit. A meta-
analysis of 9 RCTs of abdominal surgery patients without OSA found that CPAP
reduced postoperative pulmonary complications when used perioperatively [116].
Similar benefits have been shown when prophylactic CPAP is used after cardiotho-
racic surgery [117, 118].
Although the data surrounding risk reduction afforded by CPAP in OSA patients
is inconclusive, it’s important to acknowledge the lack of large, prospective data,
and also to consider some of the roadblocks such as poor adherence that have lim-
ited this type of investigation. Therefore, it’s reasonable to consider the possibility
that we simply do not have all the information at this point in time to make a fair
assessment and it therefore may be reasonable to advocate for perioperative PAP
use in patients with OSA when possible.
Conclusion
While it is clear that patients with OSA are at increased risk of postoperative cardio-
pulmonary complications, there is less certainty when it comes to what periopera-
tive interventions might mitigate these risks. Emphasis has been placed on
preoperative screening for suspect OSA and minimizing risk for known and sus-
pected OSA patients by optimizing management of comorbidities and initiating
OSA treatment preoperatively. The better question to ask is not who has OSA but
who has an OSA phenotype that will result in postoperative complications. Our
institution his implemented in-hospital sleep consultative services in combination
with OASIS with a close follow-through protocol to aid workup and initial manage-
ment of perioperative inpatients with suspected OSA. Many hospitals throughout
the country have adopted their own approaches in screening and monitoring sus-
pected and known OSA patients perioperatively, and have developed in-hospital
sleep consultative services. But more evidence-based guidelines will need to be
established before there can be a single algorithm to manage patients within the
OSA population presenting for surgery.
OSA is a common entity and will likely continue to increase in prevalence in the
coming years. We must strive to develop best practices to manage and monitor
patients with OSA from the preoperative period to their discharge home from the
hospital with the aim of reducing unnecessary postoperative risk. By combining
preoperative screening, perioperative optimization of comorbidities, and identifica-
tion of recurrent postoperative and PACU events, optimal risk identification,
prevention, and intervention strategies will hopefully be achieved as we pursue
more robust prospective outcomes data.

• OSA is a common, chronic health condition associated with increased risk
of cardiopulmonary complications in the post-surgical period.
• Several organizations have developed recommendations for management
of patients with OSA presenting for surgery.
• Questionnaires have been validated for use in the preoperative setting to
assess for risk of OSA and provide an opportunity for sleep medicine refer-
ral if deemed necessary.
• When additional factors were included, the STOP-Bang Questionnaire had

the highest sensitivity in detecting those at risk for OSA, especially
moderate-to-severe disease.
• Algorithms developed to minimize perioperative risk in those with known
or suspected OSA consider the patients’ risk of suspected OSA, severity of
known OSA, type of surgery, comorbidities, and changes in OSA status.
• Early identification of patients with OSA may forewarn the clinician of
potential difficulty with airway maintenance intra- and postoperatively,
perhaps influencing choice of anesthetic/sedation/analgesia technique and
postoperative monitoring environment.
• We advocate an algorithm using recurrent PACU events as a predictive
indicator to guide postoperative disposition of the known or suspected
OSA patient.
• For those with previously undiagnosed but suspected OSA in the postop-
erative or medical inpatients setting, our institution has developed an
OASIS protocol.
• More prospective data is needed to guide recommendations for periopera-
tive strategies to reduce postoperative risk in this patient population
References
1. Patil SP, Schneider H, Schwartz AR, Smith PL. Adult obstructive sleep apnea: pathophysiol-
ogy and diagnosis. Chest. 2007;132:325–37.
2. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstruc-
tive sleep apnea. J Clin Invest. 1995;96:1897–904.
3. American Society of Anesthesiologists Task Force on Perioperative Management of patients
with obstructive sleep a. Practice guidelines for the perioperative management of patients with
obstructive sleep apnea: an updated report by the American Society of Anesthesiologists Task
Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology.
2014;120:268–86.
4. Ayas NT, Laratta CR, Coleman JM, Doufas AG, Eikermann M, Gay PC, Gottlieb DJ,
Gurubhagavatula I, Hillman DR, Kaw R, Malhotra A, Mokhlesi B, Morgenthaler TI,
Parthasarathy S, Ramachandran SK, Strohl KP, Strollo PJ, Twery MJ, Zee PC, Chung FF,
Sleep ATSAo, Respiratory N. Knowledge gaps in the perioperative management of adults
with obstructive sleep apnea and obesity hypoventilation syndrome. An official American
Thoracic Society workshop report. Ann Am Thorac Soc. 2018;15:117–26.
5. Chung F, Memtsoudis SG, Ramachandran SK, Nagappa M, Opperer M, Cozowicz C,
Patrawala S, Lam D, Kumar A, Joshi GP, Fleetham J, Ayas N, Collop N, Doufas AG,
Eikermann M, Englesakis M, Gali B, Gay P, Hernandez AV, Kaw R, Kezirian EJ, Malhotra
A, Mokhlesi B, Parthasarathy S, Stierer T, Wappler F, Hillman DR, Auckley D. Society of
Anesthesia and Sleep Medicine Guidelines on preoperative screening and assessment of adult
patients with obstructive sleep apnea. Anesth Analg. 2016;123:452–73.
6. Memtsoudis SG, Cozowicz C, Nagappa M, Wong J, Joshi GP, Wong DT, Doufas AG, Yilmaz
M, Stein MH, Krajewski ML, Singh M, Pichler L, Ramachandran SK, Chung F. Society of
Anesthesia and Sleep Medicine Guideline on intraoperative management of adult patients
with obstructive sleep apnea. Anesth Analg. 2018;127:967–87.
7. Meoli AL, Rosen CL, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, Troell
R, Kramer R, Casey KR, Coleman J Jr, Clinical Practice Review C, American Academy of
Sleep M. Upper airway management of the adult patient with obstructive sleep apnea in the
perioperative period–avoiding complications. Sleep. 2003;26:1060–5.
8. Adesanya AO, Lee W, Greilich NB, Joshi GP. Perioperative management of obstructive sleep
apnea. Chest. 2010;138:1489–98.
9. Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: ratio-
nale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ. 2009;108:246–9.
10. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of
sleep-disordered breathing in adults. Am J Epidemiol. 2013;177:1006–14.
breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.
12. Dempsey JA, Skatrud JB, Jacques AJ, Ewanowski SJ, Woodson BT, Hanson PR, Goodman
B. Anatomic determinants of sleep-disordered breathing across the spectrum of clinical and
nonclinical male subjects. Chest. 2002;122:840–51.
13. Li KK, Kushida C, Powell NB, Riley RW, Guilleminault C. Obstructive sleep apnea syndrome:
a comparison between Far-East Asian and white men. Laryngoscope. 2000;110:1689–93.
14. Pranathiageswaran S, Badr MS, Severson R, Rowley JA. The influence of race on the severity
of sleep disordered breathing. J Clin Sleep Med. 2013;9:303–9.
15. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults.
JAMA. 2004;291:2013–6.
16. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol
(1985). 2005;99:1592–9.
17. Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe
obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016.
JAMA. 2018;319:1723–5.
18. Lopez PP, Stefan B, Schulman CI, Byers PM. Prevalence of sleep apnea in morbidly obese
patients who presented for weight loss surgery evaluation: more evidence for routine screen-
ing for obstructive sleep apnea before weight loss surgery. Am Surg. 2008;74:834–8.
19. Abdelsattar ZM, Hendren S, Wong SL, Campbell DA Jr, Ramachandran SK. The impact of
untreated obstructive sleep apnea on cardiopulmonary complications in general and vascular
surgery: a cohort study. Sleep. 2015;38:1205–10.
20. Mokhlesi B, Hovda MD, Vekhter B, Arora VM, Chung F, Meltzer DO. Sleep-disordered
breathing and postoperative outcomes after bariatric surgery: analysis of the nationwide inpa-
tient sample. Obes Surg. 2013;23:1842–51.
21. Memtsoudis SG, Stundner O, Rasul R, Chiu YL, Sun X, Ramachandran SK, Kaw R, Fleischut
P, Mazumdar M. The impact of sleep apnea on postoperative utilization of resources and
adverse outcomes. Anesth Analg. 2014;118:407–18.
22. Chan MTV, Wang CY, Seet E, Tam S, Lai HY, Chew EFF, Wu WKK, Cheng BCP, Lam
CKM, Short TG, Hui DSC, Chung F. Postoperative vascular complications in u nrecognized
obstructive sleep apnea study I. Association of unrecognized obstructive sleep apnea with
postoperative cardiovascular events in patients undergoing major noncardiac surgery.
JAMA. 2019;321:1788–98.
23. Raveendran R, Wong J, Singh M, Wong DT, Chung F. Obesity hypoventilation syndrome,
sleep apnea, overlap syndrome: perioperative management to prevent complications. Curr
Opin Anaesthesiol. 2017;30:146–55.
24. Kaw R, Chung F, Pasupuleti V, Mehta J, Gay PC, Hernandez AV. Meta-analysis of the
association between obstructive sleep apnoea and postoperative outcome. Br J Anaesth.
2012;109:897–906.
25. Memtsoudis S, Liu SS, Ma Y, Chiu YL, Walz JM, Gaber-Baylis LK, Mazumdar
M. Perioperative pulmonary outcomes in patients with sleep apnea after noncardiac surgery.
Anesth Analg. 2011;112:113–21.
26. Opperer M, Cozowicz C, Bugada D, Mokhlesi B, Kaw R, Auckley D, Chung F, Memtsoudis

SG. Does obstructive sleep apnea influence perioperative outcome? A qualitative systematic
review for the Society of Anesthesia and Sleep Medicine Task Force on preoperative prepara-
tion of patients with sleep-disordered breathing. Anesth Analg. 2016;122:1321–34.
27. Lindenauer PK, Stefan MS, Johnson KG, Priya A, Pekow PS, Rothberg MB. Prevalence,
treatment, and outcomes associated with OSA among patients hospitalized with pneumonia.
Chest. 2014;145:1032–8.
28. Subramani Y, Nagappa M, Wong J, Patra J, Chung F. Death or near-death in patients with
obstructive sleep apnoea: a compendium of case reports of critical complications. Br J
Anaesth. 2017;119:885–99.
29. Kaw R, Bhateja P, Paz YMH, Hernandez AV, Ramaswamy A, Deshpande A, Aboussouan
LS. Postoperative complications in patients with unrecognized obesity hypoventilation syn-
drome undergoing elective noncardiac surgery. Chest. 2016;149:84–91.
30. Hai F, Porhomayon J, Vermont L, Frydrych L, Jaoude P, El-Solh AA. Postoperative
complications in patients with obstructive sleep apnea: a meta-analysis. J Clin Anesth.
2014;26:591–600.
31. D'Apuzzo MR, Browne JA. Obstructive sleep apnea as a risk factor for postoperative compli-
cations after revision joint arthroplasty. J Arthroplast. 2012;27:95–8.
32. Masaracchia MM, Sites BD, Herrick MD, Liu H, Davis M. Association between sleep apnea
and perioperative outcomes among patients undergoing shoulder arthroscopy. Can J Anaesth.
2018;65:1314–23.
33. Fiorentino M, Hwang F, Pentakota SR, Livingston DH, Mosenthal AC. Pulmonary complica-
tions in trauma patients with obstructive sleep apnea undergoing pelvic or lower limb opera-
tion. Trauma Surg Acute Care Open. 2020;5:e000529.
34. Golaz R, Tangel VE, Lui B, Albrecht E, Pryor KO, White RS. Post-operative outcomes and
anesthesia type in total hip arthroplasty in patients with obstructive sleep apnea: a retrospec-
tive analysis of the State Inpatient Databases. J Clin Anesth. 2021;69:110159.
35. Gupta RM, Parvizi J, Hanssen AD, Gay PC. Postoperative complications in patients with
obstructive sleep apnea syndrome undergoing hip or knee replacement: a case-control study.
Mayo Clin Proc. 2001;76:897–905.
36. Hiremath AS, Hillman DR, James AL, Noffsinger WJ, Platt PR, Singer SL. Relationship
between difficult tracheal intubation and obstructive sleep apnoea. Br J Anaesth.
1998;80:606–11.
37. Siyam MA, Benhamou D. Difficult endotracheal intubation in patients with sleep apnea syn-
drome. Anesth Analg. 2002;95:1098–102, table of contents.
38. Rennotte MT, Baele P, Aubert G, Rodenstein DO. Nasal continuous positive airway pressure
in the perioperative management of patients with obstructive sleep apnea submitted to sur-
gery. Chest. 1995;107:367–74.
39. Mokhlesi B, Hovda MD, Vekhter B, Arora VM, Chung F, Meltzer DO. Sleep-disordered
breathing and postoperative outcomes after elective surgery: analysis of the nationwide inpa-
tient sample. Chest. 2013;144:903–14.
40. Mutter TC, Chateau D, Moffatt M, Ramsey C, Roos LL, Kryger M. A matched cohort study
of postoperative outcomes in obstructive sleep apnea: could preoperative diagnosis and treat-
ment prevent complications? Anesthesiology. 2014;121:707–18.
41. Karimi N, Kelava M, Kothari P, Zimmerman NM, Gillinov AM, Duncan AE. Patients at high
risk for obstructive sleep apnea are at increased risk for atrial fibrillation after cardiac surgery:
a cohort analysis. Anesth Analg. 2018;126:2025–31.
42. Ng KT, Lee ZX, Ang E, Teoh WY, Wang CY. Association of obstructive sleep apnea and post-
operative cardiac complications: a systematic review and meta-analysis with trial sequential
analysis. J Clin Anesth. 2020;62:109731.
43. Nagappa M, Ho G, Patra J, Wong J, Singh M, Kaw R, Cheng D, Chung F. Postoperative
outcomes in obstructive sleep apnea patients undergoing cardiac surgery: a systematic review
and meta-analysis of comparative studies. Anesth Analg. 2017;125:2030–7.
44. Abrishami A, Khajehdehi A, Chung F. A systematic review of screening questionnaires for

obstructive sleep apnea. Can J Anaesth. 2010;57:423–38.
45. Ramachandran SK, Josephs LA. A meta-analysis of clinical screening tests for obstructive
sleep apnea. Anesthesiology. 2009;110:928–39.
46. Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, Khajehdehi A,
Shapiro CM. STOP questionnaire: a tool to screen patients for obstructive sleep apnea.
Anesthesiology. 2008;108:812–21.
47. Seet E, Chua M, Liaw CM. High STOP-BANG questionnaire scores predict intraoperative
and early postoperative adverse events. Singap Med J. 2015;56:212–6.
48. Proczko MA, Stepaniak PS, de Quelerij M, van der Lely FH, Smulders JF, Kaska L,
Soliman Hamad MA. STOP-Bang and the effect on patient outcome and length of hos-
pital stay when patients are not using continuous positive airway pressure. J Anesth.
2014;28:891–7.
49. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin questionnaire to
identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999;131:485–91.
50. Chung F, Ward B, Ho J, Yuan H, Kayumov L, Shapiro C. Preoperative identification of
sleep apnea risk in elective surgical patients, using the Berlin questionnaire. J Clin Anesth.
2007;19:130–4.
51. Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, Khajehdehi A, Shapiro
CM. Validation of the Berlin questionnaire and American Society of Anesthesiologists
checklist as screening tools for obstructive sleep apnea in surgical patients. Anesthesiology.
2008;108:822–30.
52. Gross JB, Bachenberg KL, Benumof JL, Caplan RA, Connis RT, Cote CJ, Nickinovich DG,
Prachand V, Ward DS, Weaver EM, Ydens L, Yu S, American Society of Anesthesiologists
Task Force on Perioperative M. Practice guidelines for the perioperative management of
patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists
Task Force on Perioperative Management of patients with obstructive sleep apnea.
Anesthesiology. 2006;104:1081–93; quiz 1117-1088
53. Nagappa M, Liao P, Wong J, Auckley D, Ramachandran SK, Memtsoudis S, Mokhlesi B,
Chung F. Validation of the STOP-Bang questionnaire as a screening tool for obstructive
sleep apnea among different populations: a systematic review and meta-analysis. PLoS One.
2015;10:e0143697.
54. Seguin L, Tamisier R, Deletombe B, Lopez M, Pepin JL, Payen JF. Preoperative screening
for obstructive sleep apnea using alternative scoring models of the sleep tiredness observed
pressure-body mass index age neck circumference gender questionnaire: an external valida-
tion. Anesth Analg. 2020;131:1025–31.
55. Kreitinger KY, Lui MMS, Owens RL, Schmickl CN, Grunvald E, Horgan S, Raphelson JR,
Malhotra A. Screening for obstructive sleep apnea in a diverse bariatric surgery population.
Obesity (Silver Spring). 2020;28:2028–34.
56. Waseem R, Chan MTV, Wang CY, Seet E, Tam S, Loo SY, CKM L, Hui DS, Chung
F. Diagnostic performance of the STOP-Bang questionnaire as a screening tool for obstruc-
tive sleep apnea in different ethnic groups. J Clin Sleep Med. 2020;17:521.
57. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clini-
cal prediction rule. Am J Respir Crit Care Med. 1994;150:1279–85.
58. Gali B, Whalen FX Jr, Gay PC, Olson EJ, Schroeder DR, Plevak DJ, Morgenthaler
TI. Management plan to reduce risks in perioperative care of patients with presumed obstruc-
tive sleep apnea syndrome. J Clin Sleep Med. 2007;3:582–8.
59. Gali B, Whalen FX, Schroeder DR, Gay PC, Plevak DJ. Identification of patients at risk for
postoperative respiratory complications using a preoperative obstructive sleep apnea screen-
ing tool and postanesthesia care assessment. Anesthesiology. 2009;110:869–77.
60. Seet E, Chung F. Management of sleep apnea in adults – functional algorithms for the peri-
operative period: continuing professional development. Can J Anaesth. 2010;57:849–64.
61. Stierer TL, Wright C, George A, Thompson RE, Wu CL, Collop N. Risk assessment of
obstructive sleep apnea in a population of patients undergoing ambulatory surgery. J Clin
Sleep Med. 2010;6:467–72.
62. Nagappa M, Mokhlesi B, Wong J, Wong DT, Kaw R, Chung F. The effects of continuous
positive airway pressure on postoperative outcomes in obstructive sleep apnea patients under-
going surgery: a systematic review and meta-analysis. Anesth Analg. 2015;120:1013–23.
63. Apfelbaum JL, Hagberg CA, Caplan RA, Blitt CD, Connis RT, Nickinovich DG, Hagberg
CA, Caplan RA, Benumof JL, Berry FA, Blitt CD, Bode RH, Cheney FW, Connis RT, Guidry
OF, Nickinovich DG, Ovassapian A, American Society of Anesthesiologists Task Force on
Management of the Difficult A. Practice guidelines for management of the difficult airway:
an updated report by the American Society of Anesthesiologists Task Force on Management
of the Difficult Airway. Anesthesiology. 2013;118:251–70.
64. Acar HV, Yarkan Uysal H, Kaya A, Ceyhan A, Dikmen B. Does the STOP-Bang, an obstruc-
tive sleep apnea screening tool, predict difficult intubation? Eur Rev Med Pharmacol Sci.
2014;18:1869–74.
65. Corso RM, Petrini F, Buccioli M, Nanni O, Carretta E, Trolio A, De Nuzzo D, Pigna A, Di
Giacinto I, Agnoletti V, Gambale G. Clinical utility of preoperative screening with STOP-
Bang questionnaire in elective surgery. Minerva Anestesiol. 2014;80:877–84.
66. Gokay P, Tastan S, Orhan ME. Is there a difference between the STOP-BANG and the Berlin
Obstructive Sleep Apnoea Syndrome questionnaires for determining respiratory complica-
tions during the perioperative period? J Clin Nurs. 2016;25:1238–52.
67. Kheterpal S, Han R, Tremper KK, Shanks A, Tait AR, O'Reilly M, Ludwig TA. Incidence and
predictors of difficult and impossible mask ventilation. Anesthesiology. 2006;105:885–91.
68. Nagappa M, Wong DT, Cozowicz C, Ramachandran SK, Memtsoudis SG, Chung F. Is obstruc-
tive sleep apnea associated with difficult airway? Evidence from a systematic review and
meta-analysis of prospective and retrospective cohort studies. PLoS One. 2018;13:e0204904.
69. Chung F, Yegneswaran B, Herrera F, Shenderey A, Shapiro CM. Patients with difficult intu-
bation may need referral to sleep clinics. Anesth Analg. 2008;107:915–20.
70. Cormack RS, Lehane J. Difficult tracheal intubation in obstetrics. Anaesthesia.
1984;39:1105–11.
71. Gentil B, de Larminat JM, Boucherez C, Lienhart A. Difficult intubation and obstructive
sleep apnoea syndrome. Br J Anaesth. 1994;72:368.
72. Kim JA, Lee JJ. Preoperative predictors of difficult intubation in patients with obstructive
sleep apnea syndrome. Can J Anaesth. 2006;53:393–7.
73. Ezri T, Medalion B, Weisenberg M, Szmuk P, Warters RD, Charuzi I. Increased body mass
index per se is not a predictor of difficult laryngoscopy. Can J Anaesth. 2003;50:179–83.
74. Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in sleep apnea
patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest.
1992;89:1571–9.
75. Eastwood PR, Platt PR, Shepherd K, Maddison K, Hillman DR. Collapsibility of the upper
airway at different concentrations of propofol anesthesia. Anesthesiology. 2005;103:470–7.
76. Eastwood PR, Szollosi I, Platt PR, Hillman DR. Comparison of upper airway collapse during
general anaesthesia and sleep. Lancet. 2002;359:1207–9.
77. Hillman DR, Chung F. Anaesthetic management of sleep-disordered breathing in adults.
Respirology. 2017;22:230–9.
78. Dahan A, Teppema LJ. Influence of anaesthesia and analgesia on the control of breathing. Br
J Anaesth. 2003;91:40–9.
in sleeping adults. Am Rev Respir Dis. 1982;126:758–62.
80. Horner RL, Hughes SW, Malhotra A. State-dependent and reflex drives to the upper airway:
basic physiology with clinical implications. J Appl Physiol (1985). 2014;116:325–36.
81. Rehder K, Sessler AD, Marsh HM. General anesthesia and the lung. Am Rev Respir Dis.
1975;112:541–63.
82. Ogunnaike BO, Jones SB, Jones DB, Provost D, Whitten CW. Anesthetic considerations for
bariatric surgery. Anesth Analg. 2002;95:1793–805.
83. Memtsoudis SG, Stundner O, Rasul R, Sun X, Chiu YL, Fleischut P, Danninger T, Mazumdar
M. Sleep apnea and total joint arthroplasty under various types of anesthesia: a population-
based study of perioperative outcomes. Reg Anesth Pain Med. 2013;38:274–81.
84. Ambrosii T, Sandru S, Belii A. The prevalence of perioperative complications in patients with
and without obstructive sleep apnoea: a prospective cohort study. Rom J Anaesth Intens Care.
2016;23:103–10.
85. Liu SS, Chisholm MF, Ngeow J, John RS, Shaw P, Ma Y, Memtsoudis SG. Postoperative
hypoxemia in orthopedic patients with obstructive sleep apnea. HSS J. 2011;7:2–8.
86. Naqvi SY, Rabiei AH, Maltenfort MG, Restrepo C, Viscusi ER, Parvizi J, Rasouli
MR. Perioperative complications in patients with sleep apnea undergoing total joint arthro-
plasty. J Arthroplast. 2017;32:2680–3.
87. Vroegop AV, Vanderveken OM, Boudewyns AN, Scholman J, Saldien V, Wouters K, Braem
MJ, Van de Heyning PH, Hamans E. Drug-induced sleep endoscopy in sleep-disordered
breathing: report on 1,249 cases. Laryngoscope. 2014;124:797–802.
88. Lee CH, Mo JH, Kim BJ, Kong IG, Yoon IY, Chung S, Kim JH, Kim JW. Evaluation of soft
palate changes using sleep videofluoroscopy in patients with obstructive sleep apnea. Arch
Otolaryngol Head Neck Surg. 2009;135:168–72.
89. Boysen PG 2nd, Pappas MM, Evans B. An evidence-based opioid-free anesthetic technique
to manage perioperative and periprocedural pain. Ochsner J. 2018;18:121–5.
90. Macintyre PE, Loadsman JA, Scott DA. Opioids, ventilation and acute pain management.
Anaesth Intensive Care. 2011;39:545–58.
91. Etches RC. Respiratory depression associated with patient-controlled analgesia: a review of
eight cases. Can J Anaesth. 1994;41:125–32.
92. Hagle ME, Lehr VT, Brubakken K, Shippee A. Respiratory depression in adult patients with
intravenous patient-controlled analgesia. Orthop Nurs. 2004;23:18–27; quiz 28-19
93. Lam KK, Kunder S, Wong J, Doufas AG, Chung F. Obstructive sleep apnea, pain, and opi-
oids: is the riddle solved? Curr Opin Anaesthesiol. 2016;29:134–40.
94. Bernards CM, Knowlton SL, Schmidt DF, DePaso WJ, Lee MK, McDonald SB, Bains
OS. Respiratory and sleep effects of remifentanil in volunteers with moderate obstructive
sleep apnea. Anesthesiology. 2009;110:41–9.
95. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21:185–211.
96. White PF. The changing role of non-opioid analgesic techniques in the management of post-
operative pain. Anesth Analg. 2005;101:S5–22.
97. Joshi GP. Multimodal analgesia techniques for ambulatory surgery. Int Anesthesiol Clin.
2005;43:197–204.
98. Raghavendran S, Bagry H, Detheux G, Zhang X, Brouillette RT, Brown KA. An anesthetic
management protocol to decrease respiratory complications after adenotonsillectomy in chil-
dren with severe sleep apnea. Anesth Analg. 2010;110:1093–101.
99. Cavalcante AN, Sprung J, Schroeder DR, Weingarten TN. Multimodal analgesic therapy
with gabapentin and its association with postoperative respiratory depression. Anesth Analg.
2017;125:141–6.
100. Lynn LA, Curry JP. Patterns of unexpected in-hospital deaths: a root cause analysis. Patient
Saf Surg. 2011;5:3.
101. Lee LA, Caplan RA, Stephens LS, Posner KL, Terman GW, Voepel-Lewis T, Domino
KB. Postoperative opioid-induced respiratory depression: a closed claims analysis.
102. Bolden N, Posner KL, Domino KB, Auckley D, Benumof JL, Herway ST, Hillman D, Mincer
SL, Overdyk F, Samuels DJ, Warner LL, Weingarten TN, Chung F. Postoperative critical
events associated with obstructive sleep apnea: results from the Society of Anesthesia and
Sleep Medicine Obstructive Sleep Apnea Registry. Anesth Analg. 2020;131:1032–41.
103. Chan MT, Wang CY, Seet E, Tam S, Lai HY, Walker S, Short TG, Halliwell R, Chung F,
Investigators P. Postoperative vascular complications in unrecognised Obstructive Sleep
apnoea (POSA) study protocol: an observational cohort study in moderate-to-high risk
patients undergoing non-cardiac surgery. BMJ Open. 2014;4:e004097.
104. Lam T, Nagappa M, Wong J, Singh M, Wong D, Chung F. Continuous pulse oximetry and
capnography monitoring for postoperative respiratory depression and adverse events: a sys-
tematic review and meta-analysis. Anesth Analg. 2017;125:2019–29.
105. Sanders MH, Kern NB, Costantino JP, Stiller RA, Strollo PJ Jr, Studnicki KA, Coates JA,
Richards TJ. Accuracy of end-tidal and transcutaneous PCO2 monitoring during sleep. Chest.
1994;106:472–83.
106. Chung F, Wong J, Mestek ML, Niebel KH, Lichtenthal P. Characterization of respiratory
compromise and the potential clinical utility of capnography in the post-anesthesia care unit:
a blinded observational trial. J Clin Monit Comput. 2020;34:541–51.
107. Gay PC. Sleep and sleep-disordered breathing in the hospitalized patient. Respir Care.
2010;55:1240–54.
108. Organized jointly by the American Thoracic Society tERStESoICM, the Societe de
Reanimation de Langue F, approved by Ats Board of Directors D. International Consensus
Conferences in Intensive Care Medicine: noninvasive positive pressure ventilation in acute
respiratory failure. Am J Respir Crit Care Med. 2001;163:283–91.
109. Liao P, Luo Q, Elsaid H, Kang W, Shapiro CM, Chung F. Perioperative auto-titrated continu-
ous positive airway pressure treatment in surgical patients with obstructive sleep apnea: a
randomized controlled trial. Anesthesiology. 2013;119:837–47.
110. Chung F, Liao P, Yegneswaran B, Shapiro CM, Kang W. Postoperative changes in sleep-
disordered breathing and sleep architecture in patients with obstructive sleep apnea.
111. Hillman DR, Jungquist CR, Auckley D. Perioperative implementation of noninvasive positive
airway pressure therapies. Respir Care. 2018;63:479–87.
112. Guralnick AS, Pant M, Minhaj M, Sweitzer BJ, Mokhlesi B. CPAP adherence in patients
with newly diagnosed obstructive sleep apnea prior to elective surgery. J Clin Sleep Med.
2012;8:501–6.
113. Fernandez-Bustamante A, Bartels K, Clavijo C, Scott BK, Kacmar R, Bullard K, Moss AFD,
Henderson W, Juarez-Colunga E, Jameson L. Preoperatively screened obstructive sleep apnea
is associated with worse postoperative outcomes than previously diagnosed obstructive sleep
apnea. Anesth Analg. 2017;125:593–602.
114. Chung F, Nagappa M, Singh M, Mokhlesi B. CPAP in the perioperative setting: evidence of
support. Chest. 2016;149:586–97.
115. Meurgey JH, Brown R, Woroszyl-Chrusciel A, Steier J. Peri-operative treatment of sleep-
disordered breathing and outcomes in bariatric patients. J Thorac Dis. 2018;10:S144–52.
116. Ferreyra GP, Baussano I, Squadrone V, Richiardi L, Marchiaro G, Del Sorbo L, Mascia L,
Merletti F, Ranieri VM. Continuous positive airway pressure for treatment of respiratory
complications after abdominal surgery: a systematic review and meta-analysis. Ann Surg.
2008;247:617–26.
117. Zarbock A, Mueller E, Netzer S, Gabriel A, Feindt P, Kindgen-Milles D. Prophylactic nasal
continuous positive airway pressure following cardiac surgery protects from postoperative
pulmonary complications: a prospective, randomized, controlled trial in 500 patients. Chest.
2009;135:1252–9.
118. Squadrone V, Coha M, Cerutti E, Schellino MM, Biolino P, Occella P, Belloni G, Vilianis
G, Fiore G, Cavallo F, Ranieri VM, Piedmont Intensive Care Units N. Continuous positive
airway pressure for treatment of postoperative hypoxemia: a randomized controlled trial.
JAMA. 2005;293:589–95.
Chapter 11
Sleep-Disordered Breathing (SDB)
in Pediatric Populations
Carol L. Rosen
Keywords Pediatrics · Infant · Child · Adolescent · Polysomnography · Sleep

apnea syndromes · Sleep-disordered breathing · Obstructive sleep apnea · Central
sleep apnea · Central hypoventilation · Control of breathing · Hypoventilation ·
Apnea of prematurity · Airway obstruction · Achondroplasia · Cleft lip and palate ·
Chiari malformation · Congenital central hypoventilation syndrome · Craniofacial
abnormalities · Craniosynostosis · Down’s syndrome · Joubert syndrome ·
Muscular dystrophy · Neuromuscular weakness · PHOX2B · Pierre Robin
syndrome · Prader · Willi syndrome · Rett syndrome · ROHHAD · Sickle cell
disease · Spina bifida · Spinal muscular atrophy
Introduction
When evaluating sleep-disordered breathing (SDB) in children, the sleep medicine

specialist will see a broad range of respiratory problems beyond collapse of the
upper airway. In addition to obstructive sleep apnea (OSA), the specialist should be
prepared to evaluate control of breathing disorders, hypoventilation due to neuro-
muscular or thoracic cage disorders, and worsening sleep-related gas-exchange
associated with chronic pulmonary conditions. The age spectrum will include
infants to young adults with intellectual and other disabilities. Many referred chil-
dren will have other comorbidities associated with increased risk of SDB such as
obesity, genetic or craniofacial disorders, central nervous system (CNS) disorders,
C. L. Rosen (*)
Department of Pediatrics, Case Western Reserve University School of Medicine,
Cleveland, OH, USA
e-mail: carol.rosen@case.edu

216 C. L. Rosen
Pediatric sleep disordered breathing
Upper airway Control of breathing Neuromuscular

obstruction abnormalities weakness Chronic airway, lung,
(OSA and Obstructive (Central Apnea and (Motoneurons and or chest wall disease
SDB) Hypoventilation) Muscles)
Upper airway Brain → Periphery Lower respiratory tract
Fig. 11.1 Overview of pediatric sleep-disordered breathing
or neuromuscular disorders. Figure 11.1 presents a useful framework for thinking

about the SDB in children in terms of understanding symptoms, signs, comorbidi-
ties, Polysomnography (PSG) findings, and planning a diagnosis and/or manage-
ment approach.
This chapter provides summaries of the differences between pediatric and adult
presentation of OSA, obstructive SDB in children, distinctive patient groups who
are at high risk for SDB and respiratory-related hypoventilation and commonly
referred for SDB evaluation, unique features of SDB in the first year of life, control
of breathing disorders (central hypoventilation and central sleep apnea), and the
basics of accommodating and evaluating children in sleep laboratory. More compre-
hensive references are listed for many topics.
bstructive Sleep Apnea and Obstructive SDB in Children

O
and Teens [1–4]
OSA is characterized by repeated episodes of partial upper airway obstruction and/

or intermittent complete obstruction associated with disruption of gas exchange and
sleep patterns. Anatomic and neuromotor problems contribute to its pathophysiol-
ogy. The prevalence of OSA in healthy children is 1–5% but can exceed 50% in
children with certain medical conditions (e.g., Down’s syndrome, neuromuscular
diseases, and craniofacial disorders). OSA has two age peaks in childhood. The first
peak is in early childhood from ages 2–6 years, coinciding with normal lymphoid
hyperplasia of tonsils and adenoids that surround the upper airway. The second peak
appears after puberty, coinciding with weight gain and/or obesity. Table 11.1 sum-
marizes risk factors for OSA in children.
Habitual snoring, prevalence 10%, is often the key presenting symptom, but not
all snoring children have OSA. Table 11.2 lists symptoms and signs typically seen
in children with OSA [1].
Clinical assessment does not reliably predict the presence or severity of OSA in
children, but history and physical examination aids in risk assessment for OSA. In
a large randomized controlled study of adenotonsillectomy in school-aged children
11 Sleep-Disordered Breathing (SDB) in Pediatric Populations 217
Table 11.1 Risk factors for obstructive OSA

Adenotonsillar hypertrophy
Comorbid conditions (obesity, craniofacial, neuromuscular, genetic)
Airway inflammation (nasal allergies, asthma)
Positive family history (two- to four-fold ↑ risk)
African American heritage (two- to four-fold ↑ risk)
Perinatal influences (prematurity, three-fold ↑ risk)
Prior adenotonsillectomy (unmasks anatomic and functional influences)
Socio-demographic (environmental tobacco smoke, neighborhood disadvantage, sleep
deprivation)
Table 11.2 Symptoms and signs of OSA in children

History Physical exam
Frequent snoring (≥3 nights/week) Underweight or overweight
Labored breathing during sleep Tonsillar hypertrophy
Gasping or snorting Adenoidal facies or open mouth posture
Sleep enuresis (especially secondary) Micro- or retrognathia
Sleeps sitting up or with neck hyperextended High-arched palate
Cyanosis during sleep Pectus deformity
Morning headaches Hypertension
Daytime sleepiness
Attention, behavior, or learning problems
in which all participants had snoring, adenotonsillar hypertrophy, a standardized

clinical history, and physical examination by pediatric ENT specialists, clinical
parameters explained only 3% of the variance in the AHI [5, 6].
Laboratory-based PSG plays an important role in the diagnosis of OSA in chil-
dren [1, 2, 7–12]. Although home-based sleep apnea testing (HSAT) is widely used
in adults to diagnosis OSA in adult patients with high pretest probability of OSA, its
use in children has been much more limited, reflecting concerns about safety feasi-
bility, and reliability of collecting multiple respiratory signals in this population.
Home sleep apnea testing (HSAT) devices are currently not recommended for use
in children, but further research is needed to validate these approaches in children.
More references on this topic are supplied later in the chapter.
Untreated OSA is associated with adverse consequences (attentional, behavioral,
or learning problems; reduced quality of life, impaired growth, hypertension/cardio-
vascular stress, metabolic alterations and systemic inflammation, increased health-
care costs). In healthy children, adenotonsillar hypertrophy is the commonest cause
of OSA and adenotonsillectomy is the first line of treatment, but success rates
decrease significantly in children with underlying comorbidities. In a large random-
ized controlled trial of adenotonsillectomy in school-aged children with adenoton-
sillar hypertrophy and mild to moderate OSA, surgical treatment improved OSA
symptoms, quality of life, PSG findings, behavior, and sleepiness [5, 13–15].
218 C. L. Rosen
Patients should be reevaluated postoperatively for residual signs and symptoms

to determine whether further treatment is required [9]. In otherwise healthy chil-
dren, risk factors for persistence of OSA post-surgery includes obesity, African-
American race/ethnicity, and higher obstructive apnea hypopnea indices [5]. In
children with complex chronic conditions, residual SDB is common (30–60%) and
anatomic and neuromotor problems are major contributors, so other surgical proce-
dures and nonsurgical management may be needed [16].
Most children who do not respond to adenotonsillectomy or who are not candi-
dates for adenotonsillectomy can be managed with PAP therapy [17, 18], but like
adults, adherence is a challenge. Intranasal corticosteroids are an option for children
with mild postoperative OSA or those who have not undergone adenotonsillectomy.
Watchful waiting with supportive care may be appropriate for mild-moderate OSA
[5]. Weight management and other lifestyle changes (exercise, sufficient and regular
sleep) are recommended for patients who are overweight or obese. Novel dental or
orthodontic treatments (e.g., rapid maxillary expansion, oral appliance to advance
the mandible) may have a role in selected patients but more studies are needed to
develop guidelines for this treatment of pediatric OSA. Positioning therapy may
have a role in some selected patients.
ifferences Between OSA Presentation Between Children

D
and Adults
The clinical presentation and management of OSA differs between children and
adults, but preteens and teens often present with a more adult-like picture
(Table 11.3).
In children, adenotonsillar hypertrophy is the biggest risk factor for OSA, while
obesity begins to play a stronger role in adolescence. There is no gender
Table 11.3 Comparison of OSA presentation in a child, adult, or obese child/teen

Child Adult Obese child/teen
Gender M=F M>> > F M> > F
Peak age 2–8 years Mid-life Preteen/Teen
Obesity + ++++ ++++
Craniofacial, genetic, or +++ + ++
neuromuscular disorders
Chief complaint for seeking Snore Sleepiness Snore, sleepiness
medical attention Behavior/learning Behavior/learning
Arousal ± ++++ + to ++++
Respiratory pattern Obstructive hypopneas OSA Obstructive
± hypoventilation hypoventilation to frank
OSA
Treatment role for Common Rare Yes, but ↑ likelihood of
adenotonsillectomy residual OSA after surgery
Table 11.4 Comparison of OSA severity by obstructive AHI in pediatric and adult patients
Pediatric Adult
Mild 1–4.99 5–14.99
Moderate 5–9.99 15–29.99
Severe ≥10 ≥30
predisposition in prepubertal children, but a male predominance appears in puberty.

Overall children are much better defenders against upper airway collapse than
adults, so their obstructive apnea hypopnea indices (AHI) are lower and OSA sever-
ity is scaled differently (Table 11.4) [19].
Association with Obesity
The prevalence of obesity across all age groups has more than doubled in school-
aged children and tripled in teens, up to 18% in both age group. Obesity and OSA
are independently associated with longer-term adverse cardiovascular, metabolic,
and neuropsychological consequences. OSA occurs more often and may be more
severe in children and adolescents who are overweight or obese compared with lean
children. In a large randomized controlled trial of adenotonsillectomy in school-
aged children with adenotonsillar hypertrophy and mild-to-moderate OSA, surgery
normalized weight in children who had failure to thrive, but increased in risk for
obesity in overweight children [20]. While treatment options for obesity-related
OSA includes adenotonsillectomy, “cure” is less likely [5, 21]. Obese teens with
OSA have enlarged tonsils and smaller airways compared to lean controls or obese
controls without OSA [22]. PAP therapy is generally successful in relieving OSA
but limited by generally poor compliance. There is increasing experience with bar-
iatric surgery in youth with extreme obesity which may be a future OSA treatment
option to this special population.
pecial Populations at Higher Risk for OSA and Obstructive

S
SDB [23–30]
Table 11.5 lists patient groups with genetic, craniofacial, CNS, or neuromuscular
disorders who have higher risk of OSA/obstructive SDB due to a combination of
factors (craniofacial anatomy, muscular weakness, hypotonia, control of breathing
abnormalities, association with obesity).
In some patient groups, PSG is needed to evaluate SDB status before and after
prescribing advanced ventilatory support or applying newer medical, surgical, or
gene therapies, so key features of these unique patient groups are reviewed.
220 C. L. Rosen
Table 11.5 Conditions associated with obstructive SDB

Down’s syndrome (trisomy 21)
Prader–Willi syndrome
Craniofacial (Pierre Robin sequence, craniosynostoses, Treacher Collins syndrome, cleft lip/
palate)
Skeletal dysplasias or connective tissue disorders (achondroplasia, Marfan syndrome)
Sickle cell disease
Neuromuscular disorders (spinal muscular atrophy, Duchenne muscular dystrophy, myotonic
muscular dystrophy)
Storage diseases (mucopolysaccharidoses, glycogen storage diseases)
Epilepsy and vagal nerve stimulator
Down’s Syndrome [31–34]
Down’s Syndrome (also known as trisomy 21) is a common (prevalence 1/800 live
births) genetic disorder and the most frequent genetic form of intellectual disability.
Hallmarks of the syndrome include intellectual disability, hypotonia, craniofacial
abnormalities, short stature, increased incidence of hypothyroidism, and congenital
cardiac defects (50% of individuals). Life expectancy is now 60 years. OSA is
highly prevalent in children with Down’s syndrome (estimates are 30–60% depend-
ing on selection criteria) and 90% in adults (almost 70% in the severe range).
Worsening of OSA over time is related to increasing age, obesity, and associated
hypothyroidism. Predisposing factors for OSA include midfacial hypoplasia, man-
dibular hypoplasia, small crowded airways, hypotonia, and development of obesity.
Symptoms and signs of OSA are underreported by caregivers and managing clini-
cians. Because sleep disturbances are either unrecognized or thought to be normal
in children with Down’s syndrome, the American Academy of Pediatrics guidelines
for health care supervision in this group recommends referral to a sleep laboratory
for polysomnography before 4 years of age [35]. Adenotonsillectomy is the first line
of treatment in many cases, but often does not “cure” OSA. PAP therapy is highly
effective, can be challenging to implement in this patient group, but often successful
with behavioral support. Recognition and treatment of other comorbidities, such as
gastroesophageal reflux (GER) in infants, weight management, rhinitis, asthma, or
hypothyroidism (seen in up to one-third of children) is essential. Hypoglossal nerve
stimulation in another therapy currently under investigation for this patient group.
Some specialists have suggested that the increased prevalence of Alzheimer’s dis-
ease in adults with Down’s syndrome may be related in part to hypoxemia and sleep
fragmentation from untreated OSA.
Prader–Willi Syndrome [36–42]
Prader–Willi syndrome is a rare (1 in 10,000–25,000 live births) autosomal domi-

nant disorder resulting from the partial deletion or lack of expression of a region of
genes on the paternal chromosome 15 or maternal uniparental disomy 15. Clinical
features in infancy include diminished fetal activity, infantile hypotonia, and failure
to thrive. In early childhood, progressive significant weight gain due to ravenous
appetite appears to result in risk for morbid obesity. Other features include short
stature, small hands and feet, hypogonadotropic hypogonadism, and intellectual
disability. Several features predispose these patients to ventilatory problems: gener-
alized hypotonia, abnormal arousal and ventilatory responses to hypoxia and hyper-
capnia, scoliosis, and developing obesity. Elevated central apnea indices can be seen
in infancy, sometimes with sleep-related desaturation. In childhood and adulthood,
obstructive SDB is common. A combination of factors (hypotonia, craniofacial dys-
morphism, and viscous secretions) lead to OSA along with adenotonsillar hypertro-
phy and obesity. Finally, excessive daytime sleepiness (out of proportion to SDB
and related to hypothalamic dysfunction) can appear in childhood and affects up to
50% of adults with a narcolepsy-like phenotype. Sleep architecture is also unusual
with shorter REM latencies and increased REM cycles. Sleep apnea or sleep distur-
bance is a minor diagnostic criterion. GH is now routinely prescribed to improve
development, growth, and body composition (increased muscle mass and decreased
fat mass). Some studies report improvement in resting ventilation and inspiratory
drive with this therapy. PSG is often performed prior to GH therapy. Untreated
respiratory disorders can contribute to morbidity and premature death in PWS.
Craniofacial Abnormalities [24, 26]
Children with craniofacial syndromes are at high risk for obstructive SDB and
OSA. OSA can develop because of both anatomic features that reduce the size of
the airway and neuromotor deficits that impair the airway patency during sleep.
Midface hypoplasia in children with craniosynostosis and glossoptosis and/or
micrognathia in children with Pierre Robin sequence are well-recognized OSA risk
factors but the etiology is multifactorial with multilevel airway obstruction.
Screening questionnaires for OSA are not validated in this patient population and
should not be a surrogate for objective diagnostic testing, so the threshold PSG is
low. Some treatments are like those used in healthy children such as adenotonsil-
lectomy, positive airway pressure, positive pressure ventilation, and in refractory
cases, tracheostomy. However, distinct treatments include positioning, nasopharyn-
geal airways, tongue lip adhesion, and mandibular distraction osteogenesis in chil-
dren with Pierre Robin sequence and midface advancement in children with
craniosynostoses.
Pierre Robin Sequence
Pierre Robin sequence (prevalence 1 in 8500–14,000 individuals) is a triad of

micrognathia, glossoptosis, and airway obstruction. Infants with this condition are
at increased risk of oropharyngeal obstruction and feeding difficulties. About
20–40% of cases of Pierre Robin sequence occur in isolation (by itself) but the rest
222 C. L. Rosen
of cases occur as part of a syndrome that affects other organs and tissues in the body
(e.g., Stickler syndrome, Treacher Collins syndrome). Pierre Robin sequence is the
most common cause of syndromic micrognathia. Hypoplasia of the mandible leads
to OSA due to obstruction at the base of the tongue from glossoptosis and reduced
oropharyngeal size.
Cleft Lip/Palate [43]
Cleft lip/palate (1 per 1600 births) is an isolated condition in 70% of cases and part
of a syndrome with other anomalies in the rest. Upper airway obstruction is more
common in infants who have a cleft palate as part of the Pierre Robin sequence but
breathing abnormalities during sleep are seen across the cleft lip/palate spectrum.
Most children with cleft palate undergo primary palatoplasty between 9 and
12 months of age, but some children are left with velopharyngeal insufficiency
needing further corrective surgery. OSA occurring after surgical correction of velo-
pharyngeal insufficiency is well documented in children with cleft palate.
Craniosynostosis
Craniosynostosis, affecting 1 in 2500 births, occurs as part of a syndrome in 40% of

cases. Apert, Crouzon, and Pfeiffer are well-known syndromes with craniosynosto-
sis and are associated with mutations in the fibroblast growth receptor gene. Between
40% and 70% of children with syndromic craniosynostosis will have OSA. Although
midface hypoplasia is the predominant causal factor for OSA in these children,
multiple other factors such as adenotonsillar hypertrophy and choanal atresia con-
tribute. Central apneas are also reported in some children with craniosynostosis and
may be explained by pressure on the respiratory centers due to an underlying Chiari
malformation or narrowing of the craniocervical junction.
Treacher Collins Syndrome
Treacher Collins syndrome is a rare (1 in 50,000 live births) autosomal dominant

disorder associated with severe OSA. Family history is negative in about 50% of
patients. Patients with this syndrome carry mutations in the TCOF1 gene that encodes
instructions for a protein involved in forming bones and other tissues of the face.
Classic features include micrognathia, zygomatico-temporo-maxillary dysostosis,
mandibular hypoplasia, choanal atresia, underdevelopment of the auricles, down
slant of the eyelids, coloboma of the eyelids, and hypoplasia of the zygomatic bone
and lateral orbital wall. Abnormalities in these structures explain the high frequency
of OSA, 54% in children to 41% in adults. Surgical relief of upper airway obstruc-
tion is complicated due to multiple sites of obstruction. Skillful determination of the
most useful site(s) for reconstructive surgery is key to a successful outcome.
Skeletal Dysplasias [44–46]
Skeletal dysplasias are rare genetic disorders that affect bones and joints leading to
impaired growth and development, leaving affected children with short and/or
deformed limbs. Achondroplasia is the most common (incidence 1 in 15–40,000
live births) form of disproportionate short stature. Over 80% of individuals with
achondroplasia have parents with normal stature and are born with a de novo gene
mutation. Two specific gain of function mutations in the fibroblast growth receptor
3 gene cause more than 95% of cases. Clinical features include short stature, short-
ened limbs, macrocephaly, frontal bossing, and midface hypoplasia. Although life
expectancy is near normal, mortality rates are increased at all ages. One-third or
more patients may have significant obstructive SDB. Patients with achondroplasia
are at higher risk for OSA because of craniofacial dysmorphism, but also at greater
risk for central sleep apnea because of cervicomedullary compression. They are
also at higher risk for nocturnal sleep–related hypoxemia with or without hypoven-
tilation because of thoracolumbar kyphosis, a small thorax, hypotonia, and ten-
dency for obesity. PSG results are often abnormal and include a range of findings:
central apnea, obstructive apneas, hypopneas, gas exchange abnormalities. The
American Academy of Pediatrics recommends increased monitoring and evalua-
tion for neurologic signs, especially in the first years of life [47]. Medical and surgi-
cal therapies that can improve OSA include adenotonsillectomy, targeted
craniofacial surgeries, PAP therapy, and weight management. Other neurosurgeries
may be needed for signs of brainstem compression. Evidence-based best practices
are not established.
Sickle Cell Disease [48, 49]
Sickle cell disease (SCD), the most common inherited blood disorder in the US,
affects 1 in 500 African Americans. It is characterized by chronic hemolytic ane-
mia and complications related to recurrent vaso-occlusion. One of the strongest
triggers for vaso-occlusion is oxyhemoglobin desaturation which has been linked
to several complications of SCD, such as increased pain, greater risk of CNS
events, cognitive dysfunction, history of acute chest syndrome. The prevalence of
OSA in children with SCD is higher than in the general pediatric population.
Habitual snoring and lower waking SpO2 values were the strongest OSA risk fac-
tors in a cohort study of children with sickle cell anemia, unselected for OSA
symptoms or asthma [50]. Because OSA is a treatable condition with adverse
health outcomes, greater efforts are needed to screen, diagnose, and treat OSA in
the high-risk vulnerable population. Of note, in patient with sickle cell disease,
lower than normal SpO2 values during sleep may not always be true hypoxemia
because the oxyhemoglobin dissociation curve for Hb S is shifted to the right,
compared to Hb A.
224 C. L. Rosen
Neuromuscular Diseases
The term neuromuscular disease (NMD) encompasses a large variety of disorders

that result in abnormal muscle function. Advances in understanding these diseases,
their natural history, and increasing availability of mechanical ventilation for these
patients have improved survival. [51, 52] Both spinal muscular atrophy (SMA) and
Duchenne muscular dystrophy (DMD) are fatal monogenic neuromuscular disor-
ders caused by loss-of-function mutations. The availability of advanced home-based
options for ventilatory support and development of novel genetic and molecular
therapies [53–56] provides an opportunity to use SDB as an outcome measure while
also allowing the use of polysomnography as a validation tool in the assessments of
effectiveness of therapies.
Spinal Muscular Atrophy [55, 57–59]
Spinal muscular atrophy (SMA), prevalence 1 in 7000–10,000 live births, is a

diverse group of hereditary motor neuron disorders. Most cases are caused by a
progressive loss of motor neurons due to the absence of the survival motor neuron
(SMN1) protein. Historically five types have been described. Type 1 patients have a
fatal course before age 2 years. Type 2 patients live into adulthood, and types 3 and
4 have a normal life span. Especially in type 1 patients, clinical features include
progressive proximal weakness with intercostal muscles affected more than the dia-
phragm resulting in thoracoabdominal asynchrony (paradox) and a bell-shaped
chest. Cardiac muscle is not affected. SDB is characterized by hypoventilation
related to neuromuscular weakness. However, bulbar dysfunction and acquired
maxillary hypoplasia can lead to upper airway obstruction while aspiration, impaired
cough, and scoliosis lead to hypoxemia from to lower airway, parenchymal, and
chest wall problems. Two novel genetic therapies, an RNA transcript modifier and a
gene replacement are changing the natural history of this disease. Infants who his-
torically would have succumbed by age 2 years are now sitting and standing, and
some are walking. Children with more advanced disease are either experiencing
disease stabilization or a return of recently lost abilities.
Duchenne Muscular Dystrophy [55, 58, 60–63]
Duchenne muscular dystrophy (DMD), affecting 20 per 100,000 live male births, is
an X-linked, recessive disorder of the dystrophin gene which supplies structure and
function to skeletal and cardiac muscle. Progressive weakness appears around 3 to
6 years of age, wheelchair is needed for mobility by 12 years of age, and scoliosis
appears when the patient becomes nonambulatory. Chronic respiratory insufficiency
and cardiomyopathy leading to premature death appears in the second decade of
life. OSA is the predominant phenotypic of SDB at younger ages, sleep-related
hypoventilation at older ages, with significant overlap given the propensity for
obesity and variable progression of muscle weakness. Twenty-five percent of unex-

pected deaths occur at night. There is poor correlation between patient-reported
symptoms and the presence of SDB, so the threshold for PSG should be low. PSG
is the gold standard evaluation for SDB in children with DMD. Overnight oximetry
can show sleep-related hypoxemia, but hypoventilation will be missed by oximetry
alone, so PSG must include CO2 monitoring. Central sleep apnea has been descripted
in this patient groups, but it is unclear whether these “central” events are truly cen-
tral or are classified as central on PSG due to poor signaling in the setting of
decreased muscle strength. Noninvasive ventilatory support has changed the natural
history, but novel gene therapies are in clinical trials may further improve outcomes.
Myotonic Muscular Dystrophy
Myotonic muscular dystrophy (prevalence 1 in 8000) is an autosomal dominant

neuromuscular disease linked to cardiotocography (CTG) repeat expansions of two
different genes with variable severity affecting all ages. Features of the adult-onset
form of this multisystem disorder include progressive muscle weakness, excessive
daytime sleepiness, fatigue, cataracts, endocrine dysfunction, and cardiac arrhyth-
mias [64, 65]. Sleep apnea is highly prevalent. In the rare congenital form, inherited
maternally in 90% of cases, infants present with severe skeletal, neuromuscular, and
cognitive abnormalities [66]. The mortality rate is high related to need for ventila-
tory support. The childhood form is later onset and less severe.
Storage Diseases
Mucopolysaccharidosis refers to a heterogeneous group of rare (0.6–5:100,000 live

births) genetic lysosomal storage diseases inherited disorders in which the body is
unable to properly breakdown mucopolysaccharides with life expectancies of
20 years. Hunter and Hurler syndromes are examples of older names for these con-
ditions. The cardinal abnormalities are musculoskeletal and cardiovascular. Upper
airway obstruction is common in all forms of these disorders due to adenotonsillar
enlargement, large and protruded tongue, reduced retropalatal and retroglossal
space, narrow trachea, narrow airway, short neck, and small thoracic cage. Early
recognition of OSA and proper treatment may reduce the high cardiovascular mor-
tality and improve quality of life. There is no cure, but treatments such as bone
marrow transplantation and enzyme replacement therapy may help with manage-
ment of one subtype.
Glycogen storage diseases are caused by defective enzymes involved in the
breakdown or synthesis of glycogen. The build-up of glycogen causes progressive
muscle weakness and affects the function of the heart, skeletal muscles, liver, and
nervous system. Of those, type 2, also known as Pompe disease (1: 40,000 live
births) significantly affects respiratory muscles and is associated with SDB. There
are three phenotypes based on the amount of residual enzyme activity that present
226 C. L. Rosen
in infancy, childhood, or adulthood. Skeletal muscle weakness and respiratory dys-

function are the hallmarks of the phenotype in adults, and respiratory failure is
progressive in all forms. In the infantile form, clinical features of hypotonia, cardio-
myopathy, and weakness are present within the first days to months of life.
Enzyme replacement therapy become the standard of care for the treatment of
Pompe disease and has been available for more than a decade. The majority of
patients with adult onset phenotype show improved ambulatory function and mus-
cle strength, stabilization of pulmonary function, and increased survival that seems
to peak at 3–5 years of treatment and is followed by a plateau or secondary decline
with considerable individual variation after 10 years [67]. In infants and children
with infantile or late onset forms, OSA and hypoventilation are common PSG find-
ings, even in the absence of symptoms, with stabilization and improvements in PSG
findings after 3 years of enzyme replacement therapy [68, 69]. They also have
improved outcomes in terms of survival, remaining ventilator-free, and cardiac,
skeletal muscle, and pulmonary function [70–74].
Epilepsy and Vagal Nerve Stimulators
All types of seizures can occur during sleep and some seizures occur only in sleep.
Seizures during sleep can be associated with cardiopulmonary events: ictal and
post-ictal apnea, tachypnea, tachycardia, bradycardia, and hypoxemia. Central or
obstructive apneas may precede the seizure, occur during the seizure, or be the only
clinical manifestation of the seizures. Ictal apnea can potentially contribute to sud-
den unexpected death in epilepsy which occurs more often during sleep.
Patients with vagal nerve stimulators (VNS) for intractable epilepsy should be
screened for SDB. [75] About one-third will develop mild OSA and a small number
will develop severe OSA. Apneas, hypopneas, desaturations, and tachypnea have
been reported to occur exclusively during VNS activation, but not when the VNS is
inactive. VNS may affect breathing either by its effect on the upper airway muscu-
lature or by its effect on central control of breathing. Vagal efferent nerves alter
neuromuscular signal to the upper airway musculature of the pharynx and larynx,
resulting in airway narrowing and obstruction. Vagal projection to the brainstem can
also affect the rate and depth of respiration. Severity of the airway obstruction is
related to the frequency of the VNS. Treatment needs to be individualized, but
options include PAP therapy, changing the VNS settings, or stopping therapy.
isorders Associated with Central Control of Breathing

D
Abnormalities [76–78]
Central control of breathing abnormalities are a unique part of SDB in childhood.

Table 11.6 list conditions associated with central apnea respiratory patterns with or
without hypoventilation.
Table 11.6 Conditions associated with central apnea respiratory patterns with or without
hypoventilation
Immature control of breathing
High altitude–induced periodic breathing
State-related changes in control of breathing
Transition to sleep
Low apnea hypocapnia threshold
High loop gain
High ventilatory response to arousal
Treatment emergent central apnea
Obesity hypoventilation syndrome (usually with another syndrome, e.g., Prader–Willi)
Cardiomyopathy and Cheyne–stokes respiration with congestive heart failure
Medication effect (e.g., narcotic-induced, baclofen, valproic acid)
Impaired central control of breathing/autonomic dysfunction
CCHS
ROHHAD
Familial dysautonomia
Rett syndrome
Genetic syndromes (e.g., Prader–Willi syndrome, Joubert syndrome)
CNS malformations or CNS tumors
Hindbrain malformations (Chiari I, Chiari II with myelomeningocele)
Foramen magnum stenosis or cervical medullary compression
Mitochondrial disorders
Central Sleep Apnea
Central sleep apnea in early infancy is usually part of immaturity of respiratory

control. Although the mean central sleep apnea index during sleep is usually under
1/h, some normal children have values up to 4–5 events/h.
Elevated central apnea indices in children are reported in the setting of high alti-
tude [79–82], state-related changes in control of breathing [83], certain genetic or
metabolic disorders [84–88], CNS malformation or tumors [89–92], cardiac dys-
function [93], and as a medication effect [94–96]. One group has reported on “idio-
pathic” central apnea in pediatric patients, but potentially explanatory medical
conditions were present [97]. Frequent prolonged (>20–25 s) central apneas, brad-
ypnea with slow respiratory rates for age (rates less than 12/h), extreme elevation of
periodic breathing indices or Biot’s breathing suggest a problem requiring CNS
imaging.
Central Hypoventilation Syndromes [98]
Hypoventilation refers to an increased arterial concentration of carbon dioxide due

to inadequate gas exchange. Central hypoventilation means a deficiency in the cen-
tral nervous system, rather than the respiratory system, is the root of the problem.
Central hypoventilation is uncommon and may be due to a variety of conditions
228 C. L. Rosen
which are either congenital or acquired (Table 11.6). Current therapy for central
hypoventilation focuses on achieving normal gas exchange, primarily through
mechanical ventilatory support. Early identification of central hypoventilation and
initiation of ventilatory support can improve adverse outcomes associated with
chronic hypoxemia.
CCHS [99–101]
Congenital central hypoventilation syndrome (CCHS) is a rare, lifelong genetic dis-

order that causes central alveolar hypoventilation. Paired-like homeobox 2B
(PHOX2B) mutations are found in almost all patients with CCHS. This gene encodes
a key transcription factor that regulates neural crest cell migration and development
of the autonomic nervous system. Deficiencies in central integration of chemore-
ceptor inputs cause autonomic dysfunction and loss of respiratory drive in CCHS. In
addition, many patients have other symptoms of autonomic dysfunction (e.g.,
Hirschsprung disease and neural crest tumors) in addition to hypoventilation. Most
patients present during the neonatal period, but late onset CCHS may present in
later infancy, childhood, or even adulthood under various circumstances (e.g., respi-
ratory infection, anesthesia). Since its original description in 1970 [102], this condi-
tion has evolved from a life-threatening neonatal onset disorder to include broader
and milder clinical presentations, affecting children, adults, and families. Genes
other than PHOX2B have been found to cause CCHS in rare cases.
In CCHS, the hypoventilation is worse in sleep compared to wakefulness. CCHS
is unique in that it is the only respiratory disorder in which SDB is worse in NREM
compared to REM sleep. Hypercapnia is greatest in NREM sleep because intact
central chemoreception is essential to support normal ventilation in that state.
Hypercapnia is milder in REM sleep and minimal to absent in wakefulness because
central chemoreception is less important to ventilatory control in those states. The
hypoventilation is caused by a shallow, low tidal volume (2 cc/kg) pattern of breath-
ing rather than recurrent prolonged central apneas or slow respiratory rate. Patients
with CCHS have absent or negligible ventilatory and reduced arousal sensitivity to
hypercapnia and hypoxemia, so they do not show signs of respiratory distress when
challenged with hypercarbia or hypoxia. Residual peripheral chemoreceptor func-
tion may allow for adequate ventilation during wakefulness.
Most PHOX2B mutations occur de novo, but 5–10% of cases are inherited in an
autosomal dominant pattern with variable penetrance depending on the genotype.
Most patients (90%) with CCHS will be heterozygous for extra polyalanine repeats
in a specific region of the PHOX2B gene. The normal genotype is referred to as
20/20, while the mutated proteins produce extra repeats described as 20/24 to 20/33.
The length of the polyalanine repeat expansion correlates with disease severity. A
larger repeat region is associated with a more severe clinical phenotype more likely
to present in the newborn period. In contrast, late-onset CCHS is more likely to be
associated with a smaller repeat region and a milder clinical phenotype. The remain-
ing 10% of patients, typically those with the most severe CCHS phenotypes, will be
heterozygous for a non-polyalanine repeat-type mutations causing missense, non-

sense, or frameshifts in the PHOX2B gene. Testing for a PHOX2B gene mutation is
needed to confirm the diagnosis. Between 5% and 10% of cases are inherited in an
autosomal dominant pattern from an affected and/or asymptomatic parent with
somatic mosaicism for the expansion mutation. Parents and siblings should also be
screened the mutation since there will be a 50% chance of recurrence with each
future pregnancy. Genotype–phenotype associations allow for anticipatory guid-
ance and improved clinical care. At present, management relies on lifelong ventila-
tory support (invasive and noninvasive ventilation and diaphragmatic pacing) and
close follow up of dysautonomic progression. Infants with CCHS often require
mechanical ventilation 24 h per day until wake–sleep periods are more stable and
predictable, so they undergo tracheostomy.
ROHHAD [103–106]
ROHHAD (rapid onset obesity with hypothalamic dysfunction, hypoventilation,

and autonomic dysregulation) is a rare disorder that presents between 3 and 10 years
of age. Rapid onset weight gain usually occurs first; but hypoventilation, hypotha-
lamic dysfunction, or tumors may bring the patient to medical attention. The hypo-
thalamic dysfunction either precedes or follows weight gain and includes central
hypothyroidism, growth hormone deficiency, diabetes insipidus, hyperprolac-
tinemia, precocious/delayed puberty, thermal dysregulation, or corticotrophin defi-
ciency. Once severe hypoventilation develops, ventilatory support is needed.
Children are at high risk for respiratory arrest and mortality is high. Children with
ROHHAD are also at risk for developing neural crest tumors. Developmental delay,
regression, and behavioral problems are common. PHOX2B mutations are not seen
and no candidate genes have been found. The cause is unknown but may be related
to autoimmune inflammation of the CNS. ROHHAD can be diagnosed in children
older than 18 months based on the development of rapid weight gain, endocrine
defects, and central hypoventilation with other features of hypothalamic dysfunc-
tion. Repeated evaluations are needed in children as the syndrome evolves.
Treatment is supportive and includes ventilatory support at night, as needed.
Unrecognized or inadequately treated hypoventilation may have devastating conse-
quences including death.
Familial Dysautonomia [107–109]
Familial dysautonomia is a rare autosomal recessive disorder affecting infants and

children of Jewish Ashkenazi population which has a high carrier rate (1:30). It is
caused by a mutation in the ELP1 gene that encodes scaffold proteins and regulators
of different kinases. The discovery of this mutation made prenatal diagnosis possible
and resulted in a dramatic reduction in new patients. The pathophysiology is due to
230 C. L. Rosen
progressive autonomic neuropathy (blood pressure and heart rate instability, impaired
sensation, swallowing dysfunction, ataxia) associated with progressive loss of small
myelinated and unmyelinated fibers. The clinical manifestations may be present at
birth. Over time, affected children and adults suffer from cardiovascular, respiratory,
gastrointestinal, musculoskeletal, renal dysfunction, and developmental abnormali-
ties. Patients have abnormal ventilatory responses to hypoxia and hypercapnia.
Breath-holding spells appear during infancy and persist throughout life. Overall, 91%
of pediatric patients and 85% of adults have some degree of SDB (obstructive apnea,
central apnea, desaturation, hypoventilation). SDB is a consequence of chemoreflex
failure causing impaired ventilatory drive, neuromuscular dysfunction causing or
aggravating upper airway obstruction, scoliosis, and chronic lung disease. Untreated
sleep apnea is a risk factor for sudden unexpected death during sleep in these patients.
Rett Syndrome [110–114]
Rett syndrome is a rare X-linked genetic disorder (1:10,000 female infants) that typi-
cally appears after 6–18 months of age. Symptoms and signs include loss of acquired
speech; stereotypic hand movements; deceleration of head and brain growth; autistic
behaviors; seizures; scoliosis; dysautonomia in the form of respiratory, cardiac, and
gastrointestinal dysfunction; and sleeping problems. More than 95% of girls show a
de novo loss of function mutation in the gene for the MECP2 protein involved in
transcriptional silencing and epigenetic regulation of methylated DNA.
Breathing abnormalities are a prominent clinical feature and included in the diag-
nostic criteria. The classic breathing abnormality in girls with Rett syndrome occurs
during wakefulness. It is characterized by rapid shallow breathing (causing hyper-
ventilation), followed by central apnea with breath holding, often followed by pro-
found desaturation and cyanosis. Rett girls can have daily severe breathing
abnormalities while awake but breathe more normally when asleep. This unexpected
finding suggests an imbalance between the behavioral and metabolic control of respi-
ratory. Rett girls also have markedly impaired sleep–wake patterns (delayed sleep
onset, more night waking, and excessive daytime sleep) which may worsen over time
but may be amenable to behavioral modification and melatonin. Other night behav-
iors include nighttime laughter, night screaming, nighttime seizures, and severe brux-
ism. Approximately 25% of patients die prematurely of cardiorespiratory failure.
Hindbrain Malformations (Chiari I and Spina Bifida) [29, 115]
Chiari I [86, 116–121]
Chiari I malformation, occurring in 1 per 1000–5000 births, includes malformations

of the cerebellum and brainstem in which the cerebellar tonsils are displaced below
the foramen magnum. Patients with Chiari I malformation may present with
headaches, snoring, apnea, and dysphagia. SDB, including obstructive sleep apnea,
central sleep apnea, and central alveolar hypoventilation, is estimated to occur in
one-quarter of non-syndromic patients. SDB prevalence increases when Chiari I is
part of a syndrome with other malformations. SDB is more severe when cervicome-
dullary compression and/or syringomyelia is present. Compression of the brainstem
and respiratory centers is thought to be the mechanism involved in producing cen-
tral apneas while compression of cranial nerves IX and X leads to decreased upper
airway patency and OSA.
Chiari II [92, 122–124]
Spina bifida includes a Chiari II malformation with herniation of the cerebellum and
medulla into the spinal canal in association with a myelomeningocele. Over one-
half of the children have SDB which is associated with sudden death in young
adults. SDB includes central respiratory control abnormalities [apnea (central and/
or obstructive), bradypnea, hypoventilation, impaired ventilatory and arousal
responses to CO2 and O2, breathing holding spells] and restrictive lung disease due
to neuromuscular weakness and scoliosis.
CNS Tumors [89]
Medulloblastoma and brainstem gliomas are tumors that can cause both central and
obstructive apnea by compression of the respiratory nuclei or cranial nerves that
innervate the tongue and pharynx. Tumors that affect the hypothalamus can affect
sleep–wake patterns and produce fragmented sleep, increased daytime sleepiness,
obesity, and secondary narcolepsy. Medullary nuclei involved in breathing include
the dorsal respiratory nucleus (inspiration), the ventral respiratory nucleus (inspira-
tion and expiation), the pre-Bötzinger complex and retrotrapezoid nucleus (respira-
tory pacemaker), and the nucleus of the tractus solitarius (vagal afferents). Cranial
nerves that innervate the tongue and pharyngeal muscles emerge from nuclei in the
medulla (hypoglossal nucleus and nucleus ambiguous). Damage to these nuclei by
tumor compression or as a complication of surgical resection can affect breathing,
producing central or obstructive apnea. Patients treated for CNS tumors may also
present with more daytime sleepiness compared to patient treated for other
malignancies.
Sleep-Disordered Breathing in Infants [125]
Infants can show a wide range of SDB patterns including: [1] apnea of prematurity,
[2] apnea of infancy with central apnea, [3] periodic breathing, and [4] obstructive
sleep apnea. Apnea is extremely common in infants decreasing in frequency as
232 C. L. Rosen
central control of breathing matures during the first year of life [126]. Immaturity of
the central respiratory control system is a major factor underlying apnea in infants.
Fig. 11.2 shows multiple factors that can trigger apnea in infants.
Infants and young children have more variable breathing during REM, including
normal central apneas and central events that even occasionally last longer than 20 s
[127]. Among healthy full-term infants recorded at home, 43% had central apneas
longer than 20 s and 2% had apnea longer than 30 s. Regular breathing is seen in
NREM sleep while irregular breathing is typical of REM sleep. Thoracoabdominal
asynchrony in REM sleep is normal up to age 2–3 years [128]. Desaturations fol-
lowing these central apneas are typically brief, but can be associated with SpO2
nadirs below 90%, even in healthy infants [129, 130]. Other factors that predispose
infants to respiratory instability include low functional residual capacity, neuronal
instability, increase time in REM sleep stage, and lower apneic threshold.
Apnea of Prematurity [131–134]
Immaturity of central control of breathing is major factor in apnea of prematurity.

Almost 100% of infants born less than 28-week gestational age will have apnea of
prematurity, 25–30% of infants born at 34 weeks, but it is rare in infants born after
38-week gestational age. The earlier the gestational age, the longer apnea of prema-
turity persists [135]. In former preterm infants, it disappears by the time the infant
reaches 44-week postmenstrual age. Especially in former preterm or low-birth-
weight infants, external events can trigger apnea spells in infants who were previ-
ously stable. For example, there is an increased risk of apnea events within 2–3 days
of routine 2-month immunizations, post anesthesia, and in association with RSV
infection.
Premature infants have impaired ventilatory and arousal responses to hypercap-
nia and hypoxia as well as more compliant chest walls, lower end-expiratory vol-
umes, greater distal airway closure, and greater bradycardia in response to
stimulation of the carotid bodies by hypoxia. Although apnea of prematurity is often
considered a centrally mediated problem with cessation of respiratory effort, pha-
ryngeal upper airway obstruction can precipitate up to 50% of the central apneas.
Upper airway collapse can appear at the end of a prolonged central apnea. The
infant’s highly compliant airway and relative ventilatory instability contribute to the
propensity for upper airway obstruction during sleep. Of note, infants have a robust
laryngeal chemoreceptor reflex in response to upper airway collapse which is char-
acterized by repeated swallows, central apnea, and bradycardia.
For diagnostic purposes, the American Academy of Sleep Medicine’s latest
International Classification of Sleep Disorders (ICSD-3) defines “apnea of prema-
turity” as observed apnea or cyanosis or a detected central apnea, bradycardia, or
desaturation on a hospital’s cardiorespiratory monitoring, when the infant is <37-
week postmenstrual age at the time of presentation [136]. The term “apnea of
infancy” uses the same cardiorespiratory signs, but applied to an infant who is now
Fig. 11.2 Factors that

precipitate apnea in infants
Prematurity
Thermal
Infection
instability
Impaired Secretions
oxygenation or GER
Apnea
Metabolic CNS
disturbance disturbance
Autonomic
Drugs
reflex
≥37-week gestational or postmenstrual age. Caffeine is effective in the treatment of

apnea of prematurity with evidence of long-term safety [137]. Home cardiorespira-
tory monitoring may be useful as part of an individualized plan for some infants
with persistent apnea of prematurity [138].
Periodic Breathing [139]
Periodic breathing, repetitive short cycles of respiratory pauses and breathing, is a

normal pattern of breathing that occurs during sleep in most newborns. It is distinct
from apnea of prematurity in that it occurs in term as well as preterm infants, peaks
later, and lasts longer. Periodic breathing is absent in the first days of life, becomes
more frequent at 2–4 weeks postnatal age, then decreases, but may continue for up
to 6 months or longer. A major contributing factor to this immature breathing pat-
tern is altered sensitivity to changes in blood oxygen and carbon dioxide content
with increased gain in the receptors. In newborns, the PCO2 apneic threshold is only
slightly below the eupneic PCO2 making these infants more prone to respiratory
oscillations and favoring the appearance of periodic breathing [140]. Supplemental
oxygen reduces percent time spent in periodic breathing and respiratory instability
even in preterm infants with normal baseline SpO2 values [141]. Of note, oxygen
desaturations frequently occur during sleep, and the majority of desaturations are
associated with periodic breathing [129, 130, 142]. Periodic breathing is also asso-
ciated with low lung volumes which predispose toward decreased oxygen reserves
and increased intrapulmonary shunting.
234 C. L. Rosen
Periodic breathing persists longer in infants born at lower gestational age and
lower birth weight, but rarely occupies more than 10% of recording time once term
postmenstrual age is reached [125, 126, 142]. While periodic breathing is a normal
immature breathing pattern in neonates, excessive periodic breathing or an abrupt
increase over prior baseline warrants consideration for potential pathology. In older
infants and children, elevated periodic breathing outside of wake–sleep transitions
can also be a marker for a CNS pathology, hindbrain malformation, or metabolic
disorder. Finally, periodic breathing is elevated in any age group at high altitude.
For PSG scoring purposes, periodic breathing is defined as clusters of three or
more episodes of central apneas lasting for at least 3 seconds each and separated by
≤20 seconds of normal breathing [143]. Periodic breathing occurs in both REM and
NREM sleep. In NREM, periodic breathing is characterized by a regular pattern of
pauses separated by consistent intervals of respiratory efforts, while in REM, both
irregular and regular patterns are seen. In infants, periodic breathing is more com-
mon in REM sleep. In adults (and some children), periodic breathing is most often
seen during NREM sleep at sleep onset or sleep-wake transitions.
Apnea of Infancy with Central Apnea [125]
Breathing is irregular in newborns whose respiratory rates are faster and more vari-
able than in older children. Distinguishing between normal and abnormal breathing
during sleep can be challenging, especially in infants born prematurely or with con-
genital abnormalities. For PSG scoring purposes in infants, a central apnea is
defined as a prolonged pause in breathing (≥ 20 s) or a shorter pause with physio-
logical corroboration (≥ 3% desaturation, arousal, or bradycardia with heart
rate < 60 bpm for at least 15 s). Hypopneas have similar duration and physiological
corroboration and require a 30% reduction in airflow or its estimate. Obstructive
apneas in infants and children are defined by >90% reduction in airflow lasting at
least a two missed breaths in duration (compared with the baseline respiratory rate),
but no physiological corroboration is required [143]. Central apneas are common in
newborns and infants and central apnea indices are higher, so age appropriate nor-
mative data are required to interpret PSG data [144–147].
Terminology: Apnea of Infancy, ALTE, and BRUE
The terminology and the approach to evaluation and management of apnea of

infancy has evolved over the last decade. In 1986, NIH Consensus Conference on
Infantile Apnea coined the term “apparent life-threatening event (ALTE)” to
replace the term “near miss sudden infant death syndrome (SIDS).” [148] An
ALTE was defined as an episode that is frightening to the observer and that is char-
acterized by some combination of apnea (central or occasionally obstructive),
color change (usually cyanotic or pallid, but occasionally erythematous or pletho-

ric), marked change in muscle tone (usually marked limpness), choking, or gag-
ging. In some cases, the observer fears that the infant has died. A broad range of
disorders can present as an ALTE including arrhythmias, child abuse, congenital
abnormalities, epilepsy, inborn errors of metabolism, and infections. This term was
problematic for several reasons. First, for most well-appearing infants with ALTE-
like symptoms, the risk of recurrent events or a serious underlying disorder was
extremely low. It created a feeling of uncertainty for both the caregiver and clini-
cian. Clinicians felt compelled to perform costly, sometimes risky, often unneces-
sary tests (including PSG) and to hospitalize the patient even though this
management plan often was unlikely to lead to a treatable diagnosis or prevent
future events.
In 2016, the American Academy of Pediatrics (AAP) published a clinical prac-
tice guideline that recommended replacement of the term ALTE with a new term,
“brief resolved unexplained event” (BRUE) [149]. This term describes an event in
an infant less than 1 year when the observer reports a sudden, brief, and now
resolved episode of at least one of the following: (1) cyanosis or pallor; (2) absent,
decreased, or irregular breathing; (3) marked change in tone (hyper- or hypotonia);
and (4) altered level of responsiveness. Clinicians should diagnosis a BRUE only
when there is no explanation for a qualifying event after conducting a history and
physical examination. This newer guideline shows an approach to evaluation and
management that is based on the risk that the infant will have a repeat event or has
a serious underlying disorder. It identifies (1) lower-risk patients based on history
and physical examination, for whom evidence-based guidelines for evaluation and
management are offered and (2) higher-risk patient, whose history and physical
examination suggest the need for further investigation, monitoring, and/or treat-
ment. Overnight PSG was not recommended for the management for infants who
met criteria for having experienced a low-risk BRUE. The criteria for a higher-risk
BRUE are listed in Table 11.7.
In an updated clinical practice guideline to provide a framework for evaluation of
in the higher-risk group, PSG may be considered to characterize and quantify apnea
type and is indicated in select patients with prematurity, noisy respirations, or recur-
rent and/or severe BRUE in whom SDB is suspected [150].
Table 11.7 Higher-risk BRUE criteria [150]
Age < 60 days

Prematurity: Gestational <32 weeks and postmenstrual age < 45 weeks
Recurrent event or occurring in clusters
Duration of event ≥1 min
CPR required by trained medical professional
Concerning historical features
Concerning physical examination findings
236 C. L. Rosen
SUID, SIDS and Other Sleep-Related Infant Deaths [151, 152]
Each year, 3500 infants die in the US from sleep-related infant deaths, including the
following ICD-10 diagnosis categories: sudden infant death syndrome (SIDS), ill-
defined deaths, and accidental suffocation and strangulation in bed. SIDS is a sub-
category of sudden unexpected infant death (SUID) and a cause assigned to infant
deaths that cannot be explained after a through case investigations including autopsy,
a scene investigation, and review of clinical history. In 2018, the SUID rate was 90.9
per 100,000 live births with about 1300 deaths due to SIDS, about 1300 deaths due
to unknown causes, and about 800 deaths due to accidental suffocation and strangu-
lation in bed. SIDS rates declined significantly from 130.3 deaths per 100,000 live
births in 1990 to 35.2 deaths per 100,000 live births in 2018 [153]. After this first
decrease in SIDS deaths by more than 50% through several public health initiatives,
the overall death rate attributable to sleep-related infant deaths has not declined
further. SIDS is still the leading cause of post-neonatal (28 days to 1 year of age)
death. These SIDS and SUID mortality rates, like other causes of infant mortality,
have notable and persistent racial and ethnic disparities. The rates in non-Hispanic
black and American Indian/Alaska Native infant were more than double the rate in
non-Hispanic white infants.
The American Academy of Pediatrics updated recommendations for a safe sleep
environment (Fig. 11.3) that can reduce the risk of all sleep-related infant deaths
includes supine position, the use of a firm sleep surface, room-sharing without bed-
sharing, and the avoidance of soft bedding and overheating. Other recommenda-
tions for SIDS risk reduction include the avoidance of exposure to environmental
tobacco smoke, alcohol, or illicit drugs; breastfeeding; routine immunizations; and
use of a pacifier.
No tobacco
No smoke,
Overheating alcohol, or
Share room, drug exposure
not bed
Pacifer
Firm surface
Breast feeding
Safe
infant Routine
Back
sleep immunizations
Fig. 11.3 Safe infant sleep

OSA and oSDB Presenting in Infants [3, 19, 154, 155]
Obstructive sleep apnea in infants has a distinctive pathophysiology, natural history,

and treatment that is different from older children and adults. Infants are particularly
vulnerable to obstructive SDB related to their upper airway structure, adverse pul-
monary mechanics, ventilatory control, arousal threshold, laryngeal chemoreflex,
and a REM-predominant sleep state distribution. OSA in infants can arise from
diverse airway abnormalities extending from the nose to the larynx. Especially in
infants, the highly compliant airway and the relative ventilatory instability further
contribute to a propensity for upper airway obstruction during sleep. In addition to
history of prematurity, other abnormalities that predispose to OSA and obstructive
SDB in infants are summarized in Table 11.8.
Table 11.8 Predisposing factors and medical conditions associated with OSA in infants [125, 155]
Craniofacial Neurological
Maxillary hypoplasia Cerebral palsy
Down syndrome Chiari malformations
Achondroplasia Spinal muscular atrophy
Craniosynostosis Nemaline rod myopathy
Treacher Collins Mitochondrial disorders
Micrognathia and/or retrognathia Respiratory mechanics/ventilatory
control
Non-syndromic Pierre Robin sequence (cleft High chest wall compliance
palate)
Syndromic Pierre Robin sequence (Stickler, Rib configuration round/horizontal
Treacher Collins)
Hemifacial microsomia Small diaphragmatic zone of apposition
Nager syndrome (acrofacial dysostosis) High metabolic rate
Macroglossia NREM apneic threshold close to eupneic
CO2 level
Down syndrome Ventilation-perfusion mismatch
Achondroplasia Miscellaneous
Beckwith-Wiedemann Prader-Willi syndrome
Hemangioma, lymphangioma Mucopolysaccharidoses
Laryngeal Gastroesophageal reflux
Laryngomalacia Chronic lung disease of infancy
Vocal cord paralysis Obesity
Laryngeal webs/cysts; edema Adenotonsillar hypertrophy
Congenital or acquired subglottic stenosis Increased REM sleep
Hemangiomas Neck flexion
Nasal obstruction Respiratory infection
Choanal atresia or stenosis Sleep deprivation
Nasogastric tube Sedating medications
Allergic rhinitis Maternal smoking during gestation
Upper respiratory tract infection
Septal deviation
Nasolacrimal duct cysts
238 C. L. Rosen
OSA in infants has been associated with failure to thrive, behavioral deficits, and
sudden unexpected death. Especially in infants, the clinical history and physical
examination alone are poor predictors of objectively measured upper airway
obstruction. Many otherwise healthy infants without obstructive sleep apnea will
snore [156]. Snoring has not been found to be predictive of OSA presence or sever-
ity in infants with cleft palate and micrognathia [157, 158]. The presence and sever-
ity of the OSA can be confirmed by PSG. Infants with severe OSA can have marked
hypoxemia, hypoventilation, and/or sleep fragmentation. PSG can be challenging in
infants and interpretation requires comparison with normative infant data and con-
sideration of the infant’s gestational and postmenstrual ages [159]. Direct endo-
scopic visualization is essential to show the specific cause of airway collapsibility
and critical to selecting the optimal therapy. The management plan should be
patient-centered and consider the natural history of the disorder, severity of the
OSA, and other co-occurring medical problems and family preferences. A high per-
centage of infants diagnosed with OSA have a history of prematurity or underlying
congenital conditions and require coordination of care by multiple subspecialties
[160]. Nonsurgical treatment options can include nasopharyngeal stents, PAP ther-
apy, supplemental oxygen, positional therapy, and treatment of reflux. Surgical
options should target the underlying anatomic etiology. Examples include supra-
glottoplasty for severe laryngomalacia, mandibular distraction for micrognathia,
tonsillectomy and/or adenoidectomy for lymphoid hyperplasia, choanal atresia
repair, laryngeal reconstruction, and/or tracheostomy. A recent review provides
diagnostic and management guidance for obstructive SDB in infants and toddlers
less than 2 years of age, including those with complex conditions like Down’s and
Prader–Willi syndromes [3].
olysomnography and Diagnostic Testing: Special

P
Considerations in Children [161]
The American Academy of Sleep Medicine (AASM) endorses the usefulness of

PSG in the evaluation of SDB in children of all ages. [7, 8] The AASM Scoring
Manual supplies guidance for technical PSG performance standards and respiratory
and non-respiratory signal scoring rules for infants and children [143]. Table 11.9
takes an updated look at the respiratory indications for PSG in children.
In laboratory, attended PSG has been the “gold standard” for the diagnosis of
OSA in children. The American Academy of Pediatrics also recommends that PSG
be performed in children with snoring and symptoms or signs of OSA [1] and for
high-risk BRUE infants in whom there are clinical concerns for SDB [150]. PSG is
also the “gold standard” for diagnosis of pediatric SDB including nocturnal
hypoventilation in need of ventilatory support with the goal of identification of SDB
before patients become symptomatic [162]. PSG is also helpful in assessing for
residual SDB prior to removing a tracheostomy [163].
Table 11.10 summarizes the differences for acquisition, scoring, and reporting
of respiratory parameters in children versus adults [143]. In brief, carbon dioxide
is measured, respiratory events shorter than 10 s are scored, and periodic breath-
ing and hypoventilation are reported in children. In children, central apneas are
scored if they are at least 2 breaths in duration (compared to the child’s baseline
respiratory rate) and are associated with a ≥ 3% desaturation, an arousal or bra-
dycardia, or are ≥20 second in duration. This differs from adult criteria for scor-
ing central apneas where the duration of the pause must be ≥10 seconds, and
Table 11.9 Updated view of respiratory indications for PSG assessment in children
Diagnosis Management
OSA Reevaluate residual OSA, s/p adenotonsillectomy
or craniofacial surgery
Central sleep apnea ± hypoventilationa Initiate PAP titration or PAP respiratory supporta
CCHS or other control of breathing Evaluate oral appliance
disorders
Sleep-related hypoxemia/hypoventilation Prior to tracheostomy decannulationa
due to other disordersa
Apnea of infancy Reassess adequacy of ventilatory support therapies,
Higher risk BRUE with concerns for SDB noninvasive or via tracha
aWith these diagnostic concerns, the sleep laboratory will need CO2 monitoring equipment (both
end-tidal CO2 and transcutaneous CO2) and must be prepared to accommodate ventilatory support
either noninvasively or via tracheostomy in medically stable patients
Table 11.10 Differences for acquisition, scoring, and reporting respiratory parameters in children
versus adults [143]
Child Adult
Obstructive 2 missed breaths duration ≥10 s duration
No corroboration required No corroboration required
Central 2 missed breaths duration associated ≥10 s duration
with Score/report Cheyne–stokes
≥3% desaturation, arousal, or HR respiratory pattern if criteria met
<50 for 5 s*
If ≥20 s duration, no corroboration
needed
Score/report periodic breathing
* If age < 1 yr., use <60 bpm for 15 s
Hypopnea 2 missed breaths duration ≥10 sec duration
≥30% ↓nasal pressure or back-up ≥30% ↓nasal pressure + ≥3%
associated with ≥3% desaturation or desaturation or arousal or
arousal ≥30% ↓nasal pressure + ≥4%
desaturation
Hypoventilation >25% total sleep time with ↑ CO2 > 55 mmHg for ≥10 min
CO2 > 50 mmHg ↑ CO2 ≥ 10 mmHg from wake supine
EtCO2 or tcCO2 or arterial to sleep with values >50 mmHg for
Measure/report hypoventilation ≥10 min
recommended Report hypoventilation: optional
240 C. L. Rosen
there is no requirement for associated desaturation, arousal, or bradycardia.

Desaturation with central apneas usually shows a decreased pulmonary reserve,
while prolonged central apneas are more likely to indicate a CNS abnormality or
immature control of breathing. Central apneas are also more common in infants
and children because of a vigorous Hering–Breuer reflex characterized by com-
pensatory central respiratory pauses after stimulation of pulmonary stretch recep-
tors following a large breath, such as with a sigh or body movement. Normative
respiratory and sleep PSG data are available for infants and children [145–147,
164–170].
When assessing the severity of OSA in children, it is useful to consider the
obstructive apnea and hypopneas indices together and separate from the central
apnea index. Since central events can be frequent and normal in children (especially
post movement, post sigh, in REM sleep, and in transition from waking), they
should not contribute to measuring the severity of the obstruction, unless they are
clearly related to unmasking of the apnea–hypocapnia phenomenon sometimes seen
post arousal or waking after an obstructive event. It is also important to capture
baseline cardiorespiratory data in quiet wakefulness prior to the sleep recording to
confirm that any abnormal cardiorespiratory findings are truly sleep related, and not
just related to the patient’s chronic health problems.
PSG, long considered to be the “gold standard” for diagnosis of OSA in children,
allows for simultaneous, continuous comprehensive monitoring of sleep, breathing,
and other signals and can detect the presence and severity of physiological distur-
bances. Comprehensive assessment and attended studies may be more important
when testing children with complex medication conditions. On the downside, it is
expensive, burdensome for families, may not be tolerated by all children, and access
is limited to facilities with pediatric expertise.
In the COVID era, pediatric sleep medicine was thrust into telemedicine and
HSAT quickly became a safer “option” for selected patients with other options were
simply not available. The future role for HSAT in the diagnosis of OSA in children
is a topic of active investigation and keen interest to improve disparities in diagno-
sis, access to care, and treatment outcomes [171–175].
PSG Interpretation in Pediatrics
Compared to adults, healthy children are much better defenders of upper airway
patency and have many more normal central pauses. They have healthier lungs with
higher baseline oxyhemoglobin saturation values, more robust chemo- and
mechano-reflexes, and are less arousable during sleep [19]. These protective factors
result in lower obstructive apnea hypopnea indices, higher central apnea indices
(especially in infants), less sleep-related hypoxemia, and less sleep fragmentation.
In terms of OSA thresholds in children, many pediatric sleep specialists consider an
oAHI <1 as “normal,” 1–1.99 as “very mild,” 2–4.99 as “mild,” 5–9.99 as “moder-
ate,” and ≥ 10 as “severe.”
The obstructive AHI derived from the PSG has been the primary disease defining
metric to decide the presence and severity of OSA. However, in the presence of
medical comorbidities (e.g., chronic pulmonary conditions, neuromuscular weak-
ness, thoracic cage deformities) some of the respiratory events that meet scoring
criteria for hypopneas may not be true signs of upper airway obstruction. Failure to
recognize the contribution that lower respiratory tract problems make to scoreable
hypopneas in the AHI can lead to overestimation of upper airway obstruction, mis-
diagnosis of OSA, and inappropriate therapies.
In children, when reviewing all the comprehensive physiologic data contained
in a PSG, it is important to “read beyond the AHI.” The reader should not only
confirm obstructive AHI, but look for other markers of respiratory dysfunction:
oximetry metrics (lower baseline SpO2 values, frequency of desaturation events,
time spent with low saturation values); the presence of paradoxical respiratory
efforts, tachypnea, or loss of nasal airflow/mouth breathing; determine whether
REM supine time was captured, track hypoventilation, unexpected central apneas,
respiratory-related arousals or movements; sleep disruption or abnormal sleep
architecture; and sinus tachycardia for age or other cardiac arrhythmias. When
reviewing PSG studies in children, focusing on the AHI alone as the primary dis-
ease-defining metric can lead to an underestimation of sleep disordered breathing
especially in the presence of comorbid medical condition. SDB can also be overes-
timated if normal central pauses that meet AHI scoring criteria are counted as
evidence of disease.
Finally, in terms of clinical utility, the read should understand that the oAHI
metric has not been the best predictor of OSA-related impairments or their response
to treatments like adenotonsillectomy. In fact, OSA symptom scores were better
than the oAHI at reflecting OSA-related impairments of behavior, quality of life,
and sleepiness and better at predicting improvements after adenotonsillec-
tomy [176].
Accommodating Children in the Sleep Laboratory
Most sleep laboratories are adult-oriented with more than half of AASM accredited
sleep center only performing studies in children aged 13 years and above and very
few dedicated solely to pediatrics [177]. Specifically for young children or older
children and adults with intellectual or developmental disabilities, initiation of PAP
therapy will likely require mask desensitization techniques prior to scheduling a
titration study [178]. Several references describe best practices for accommodating
children and families in the sleep lab [179–181]. Table 11.11 summarizes some of
those basics.
242 C. L. Rosen
Table 11.11 Basics of accommodating children in the sleep laboratory

Know all about the patient who is coming for testing
Comorbidities, medications, wake–sleep schedule, mobility concerns, special needs
Create protocols to offer child-friendly and family-centered services
For example, allow earlier arrival and later sleep times; lower staff-to-patient ratios,
accommodate caregiver
Prepare the child and family for the PSG procedure prior to their arrival
Train staff to work with children and families
Offer comfortable, in-room sleeping arrangements for the parent
Assure availability of pediatric-sized sensors, CO2 monitoring, PAP masks
Engage the children and caregiver with the PSG procedure
Interpret studies using pediatric normative data
Improve quality by following up with families about their experience

• Sleep-disordered breathing (SDB) in children includes not only obstruc-
tive sleep apnea (OSA) related to adenotonsillar hypertrophy in otherwise
healthy children, but also OSA in children with complex medical condi-
tions, control of breathing problems (central sleep apnea, hypoventilation),
and worsening breathing in sleep in children with genetic, craniofacial,
central nervous system, neuromuscular, chest wall, or other chronic pul-
monary disorders.
• There are important differences in the clinical presentation, evaluation,
PSG approach, and management of OSA between children and adults.
–– The nature of SDB changes in preterm neonates, term neonates, and
infants depending on gestational age, chronological age, and postmen-
strual age as control of breathing matures and stabilizes over the first
year of life.
• The sleep medicine specialist and sleep center should be prepared to com-
prehensively assess and manage a broad range of sleep-related breathing
problems across the age spectrum, from infants to young adults.
• A child-focused and family-centered approach to PSG evaluation of SDB
in children is part of best practices for diagnosis and treatment.
References
1. Marcus CL, Brooks LJ, Draper KA, et al. Diagnosis and management of childhood obstruc-
tive sleep apnea syndrome. Pediatrics. 2012;130(3):576–84.
2. Marcus CL, Brooks LJ, Draper KA, et al. Diagnosis and management of childhood obstruc-
tive sleep apnea syndrome. Pediatrics. 2012;130(3):e714–55.
3. Kaditis AG, Alonso Alvarez ML, Boudewyns A, et al. ERS statement on obstructive sleep
disordered breathing in 1- to 23-month-old children. Eur Respir J. 2017;50(6):1700985.
4. Kaditis AG, Alonso Alvarez ML, Boudewyns A, et al. Obstructive sleep disordered breathing
in 2- to 18-year-old children: diagnosis and management. Eur Respir J. 2016;47(1):69–94.
5. Marcus CL, Moore RH, Rosen CL, et al. A randomized trial of adenotonsillectomy for child-
hood sleep apnea. N Engl J Med. 2013;368(25):2366–76.
6. Mitchell RB, Garetz S, Moore RH, et al. The use of clinical parameters to predict obstructive
sleep apnea syndrome severity in children: the childhood Adenotonsillectomy (CHAT) study
randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2015;141(2):130–6.
7. Aurora RN, Zak RS, Karippot A, et al. Practice parameters for the respiratory indications for
polysomnography in children. Sleep. 2011;34(3):379–88.
8. Wise MS, Nichols CD, Grigg-Damberger MM, et al. Executive summary of respira-
tory indications for polysomnography in children: an evidence-based review. Sleep.
2011;34(3):389–398aw.
9. Kothare SV, Rosen CL, Lloyd RM, et al. Quality measures for the care of pediatric patients
with obstructive sleep apnea. J Clin Sleep Med. 2015;11(3):385–404.
10. Mitchell RB, Archer SM, Ishman SL, et al. Clinical practice guideline: tonsillectomy in
children (update)—executive summary. Otolaryngology Head Neck Surg (United States).
2019;160(2):187–205.
11. Mitchell RB, Archer SM, Ishman SL, et al. Clinical practice guideline: tonsillectomy in chil-
dren (update). Otolaryngol Head Neck Surg. 2019;160(1_suppl):S1–S42.
12. Lloyd R, Kirsch DB, Carden KA, Malhotra RK, Rosen IM, Ramar K. Letter to the edi-
tor regarding the updated American Academy of Otolaryngology-Head and Neck Surgery
Foundation clinical practice guideline on tonsillectomy in children. J Clin Sleep Med.
2019;15(2):363–5.
13. Garetz SL, Mitchell RB, Parker PD, et al. Quality of life and obstructive sleep apnea symp-
toms after pediatric adenotonsillectomy. Pediatrics. 2015;135(2):e477–86.
14. Paruthi S, Buchanan P, Weng J, et al. Effect of adenotonsillectomy on parent-reported sleepi-
ness in children with obstructive sleep apnea. Sleep. 2016;39(11):2005–12.
15. Thomas NH, Xanthopoulos MS, Kim JY, et al. Effects of adenotonsillectomy on parent-
reported behavior in children with obstructive sleep apnea. Sleep. 2017;40(4):zsx018.
16. Amin R, Holler T, Narang I, Cushing SL, Propst EJ, Al-Saleh S. Adenotonsillectomy for
obstructive sleep apnea in children with complex chronic conditions. Otolaryngol Head Neck
Surg. 2018;158(4):760–6.
17. Parmar A, Baker A, Narang I. Positive airway pressure in pediatric obstructive sleep apnea.
Paediatr Respir Rev. 2019;31:43–51.
18. Khaytin I, Tapia IE, Xanthopoulos MS, et al. Auto-titrating CPAP for the treatment of
obstructive sleep apnea in children. J Clin Sleep Med. 2020;16(6):871–8.
19. Arens R, Marcus CL. Pathophysiology of upper airway obstruction: a developmental per-
spective. Sleep. 2004;27(5):997–1019.
20. Katz ES, Moore RH, Rosen CL, et al. Growth after adenotonsillectomy for obstructive sleep
apnea: an RCT. Pediatrics. 2014;134(2):282–9.
21. Mitchell RB, Kelly J. Outcome of adenotonsillectomy for obstructive sleep apnea in obese
and normal-weight children. Otolaryngol Head Neck Surg. 2007;137(1):43–8.
22. Schwab RJ, Kim C, Bagchi S, et al. Understanding the anatomic basis for obstructive sleep
apnea syndrome in adolescents. Am J Respir Crit Care Med. 2015;191(11):1295–309.
23. Gadoth N, Oksenberg A. Sleep and sleep disorders in rare hereditary diseases: a reminder
for the pediatrician, pediatric and adult neurologist, general practitioner, and sleep specialist.
Front Neurol. 2014;5:133.
24. Cielo CM, Marcus CL. Obstructive sleep apnoea in children with craniofacial syndromes.
Paediatr Respir Rev. 2015;16(3):189–96.
25. Cielo CM, Konstantinopoulou S, Hoque R. OSAS in specific pediatric populations. Curr
Probl Pediatr Adolesc Health Care. 2016;46(1):11–8.
26. Tan HL, Kheirandish-Gozal L, Abel F, Gozal D. Craniofacial syndromes and sleep-related
breathing disorders. Sleep Med Rev. 2016;27:74–88.
244 C. L. Rosen
27. Dosier LBM, Vaughn BV, Fan Z. Sleep disorders in childhood neurogenetic disorders.
Children (Basel). 2017;4(9):children4090082.
28. ElMallah M, Bailey E, Trivedi M, Kremer T, Rhein LM. Pediatric obstructive sleep apnea in
high-risk populations: clinical implications. Pediatr Ann. 2017;46(9):e336–9.
29. Yates JF, Troester MM, Ingram DG. Sleep in children with congenital malformations of the
central nervous system. Curr Neurol Neurosci Rep. 2018;18(7):38.
30. Zaffanello M, Antoniazzi F, Tenero L, Nosetti L, Piazza M, Piacentini G. Sleep-disordered
breathing in paediatric setting: existing and upcoming of the genetic disorders. Ann Transl
Med. 2018;6(17):343.
31. Lal C, White DR, Joseph JE, van Bakergem K, LaRosa A. Sleep-disordered breathing in
down syndrome. Chest. 2015;147(2):570–9.
32. Nation J, Brigger M. The efficacy of adenotonsillectomy for obstructive sleep apnea
in children with down syndrome: a systematic review. Otolaryngol Head Neck Surg.
2017;157(3):401–8.
33. Horne RS, Wijayaratne P, Nixon GM, Walter LM. Sleep and sleep disordered breathing in
children with down syndrome: effects on behaviour, neurocognition and the cardiovascular
system. Sleep Med Rev. 2019;44:1–11.
34. Waters KA, Castro C, Chawla J. The spectrum of obstructive sleep apnea in infants and chil-
dren with Down Syndrome. Int J Pediatr Otorhinolaryngol. 2020;129:109763.
35. Bull MJ, Committee on G. Health supervision for children with Down syndrome. Pediatrics.
2011;128(2):393–406.
36. Nixon GM, Brouillette RT. Sleep and breathing in Prader-Willi syndrome. Pediatr Pulmonol.
2002;34(3):209–17.
37. McCandless SE, Committee on G. Clinical report-health supervision for children with
Prader-Willi syndrome. Pediatrics. 2011;127(1):195–204.
38. Sedky K, Bennett DS, Pumariega A. Prader Willi syndrome and obstructive sleep apnea: co-
occurrence in the pediatric population. J Clin Sleep Med. 2014;10(4):403–9.
39. Pavone M, Caldarelli V, Khirani S, et al. Sleep disordered breathing in patients with Prader-
Willi syndrome: a multicenter study. Pediatr Pulmonol. 2015;50(12):1354–9.
40. Gillett ES, Perez IA. Disorders of sleep and ventilatory control in Prader-Willi syndrome.
Diseases. 2016;4(3):diseases4030023.
41. Tan HL, Urquhart DS. Respiratory complications in children with Prader Willi syndrome.
Paediatr Respir Rev. 2017;22:52–9.
42. Zimmermann M, Laemmer C, Woelfle J, Fimmers R, Gohlke B. Sleep-disordered breathing
in children with Prader-Willi syndrome in relation to growth hormone therapy onset. Horm
Res Paediatr. 2020;93(2):85–93.
43. MacLean JE. Sleep frequently asked questions: question 1: what abnormalities do babies
with cleft lip and/or palate have on polysomnography? Paediatr Respir Rev. 2018;27:44–7.
44. Afsharpaiman S, Saburi A, Waters KA. Respiratory difficulties and breathing disorders in
achondroplasia. Paediatr Respir Rev. 2013;14(4):250–5.
45. Tenconi R, Khirani S, Amaddeo A, et al. Sleep-disordered breathing and its management in
children with achondroplasia. Am J Med Genet A. 2017;173(4):868–78.
46. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis.
2019;14(1):1.
47. Trotter TL, Hall JG, American Academy of Pediatrics Committee on G. Health supervision
for children with achondroplasia. Pediatrics. 2005;116(3):771–83.
48. Raghunathan VM, Whitesell PL, Lim SH. Sleep-disordered breathing in patients with sickle
cell disease. Ann Hematol. 2018;97(5):755–62.
49. Katz T, Schatz J, Roberts CW. Comorbid obstructive sleep apnea and increased risk for sickle
cell disease morbidity. Sleep Breath. 2018;22(3):797–804.
50. Rosen CL, Debaun MR, Strunk RC, et al. Obstructive sleep apnea and sickle cell anemia.
Pediatrics. 2014;134(2):273–81.
51. Shi J, Al-Shamli N, Chiang J, Amin R. Management of rare causes of pediatric chronic respi-
ratory failure. Sleep Med Clin. 2020;15(4):511–26.
52. Bach JR, Turcios NL, Wang L. Respiratory complications of pediatric neuromuscular dis-
eases. Pediatr Clin N Am. 2021;68(1):177–91.
53. Iftikhar M, Frey J, Shohan MJ, Malek S, Mousa SA. Current and emerging thera-
pies for Duchenne muscular dystrophy and spinal muscular atrophy. Pharmacol Ther.
2020;220:107719.
54. Abreu NJ, Waledrop MA. Overview of gene therapy in spinal muscular atrophy and Duchenne
muscular dystrophy. Pediatr Pulmonol. 2020;56:710.
55. Fay AJ, Knox R, Neil EE, Strober J. Targeted treatments for inherited neuromuscular diseases
of childhood. Semin Neurol. 2020;40(3):335–41.
56. Roy B, Griggs R. Advances in treatments in muscular dystrophies and motor neuron disor-
ders. Neurol Clin. 2021;39(1):87–112.
57. Fauroux B, Griffon L, Amaddeo A, et al. Respiratory management of children with spinal
muscular atrophy (SMA). Arch Pediatr. 2020;27(7s):7s29–27s34.
58. Gurbani N, Pascoe JE, Katz S, Sawnani H. Sleep disordered breathing: assessment and ther-
apy in the age of emerging neuromuscular therapies. Pediatr Pulmonol. 2020;56:700.
59. Waldrop MA, Elsheikh BH. Spinal muscular atrophy in the treatment era. Neurol Clin.
2020;38(3):505–18.
60. Hoque R. Sleep-disordered breathing in Duchenne muscular dystrophy: an assessment of the
literature. J Clin Sleep Med. 2016;12(6):905–11.
61. LoMauro A, D'Angelo MG, Aliverti A. Sleep disordered breathing in Duchenne muscular
dystrophy. Curr Neurol Neurosci Rep. 2017;17(5):44.
62. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular
dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet
Neurol. 2018;17(4):347–61.
63. Sawnani H. Sleep disordered breathing in Duchenne muscular dystrophy. Paediatr Respir
Rev. 2019;30:2–8.
64. Bianchi ML, Losurdo A, Di Blasi C, et al. Prevalence and clinical correlates of sleep disor-
dered breathing in myotonic dystrophy types 1 and 2. Sleep Breath. 2014;18(3):579–89.
65. West SD, Lochmuller H, Hughes J, et al. Sleepiness and sleep-related breathing disorders in
myotonic dystrophy and responses to treatment: a prospective cohort study. J Neuromuscul
Dis. 2016;3(4):529–37.
66. Ho G, Carey KA, Cardamone M, Farrar MA. Myotonic dystrophy type 1: clinical manifesta-
tions in children and adolescents. Arch Dis Child. 2019;104(1):48–52.
67. Harlaar L, Hogrel JY, Perniconi B, et al. Large variation in effects during 10 years of enzyme
therapy in adults with Pompe disease. Neurology. 2019;93(19):e1756–67.
68. Kansagra S, Austin S, DeArmey S, Kishnani PS, Kravitz RM. Polysomnographic findings in
infantile Pompe disease. Am J Med Genet Part A. 2013;161a(12):3196–3200.
69. Kansagra S, Austin S, DeArmey S, Kazi Z, Kravitz RM, Kishnani PS. Longitudinal polysom-
nographic findings in infantile Pompe disease. Am J Med Genet Part A. 2015;167a(4):858–61.
70. Amdani SM, Sanil Y. Infantile Pompe disease and enzyme replacement therapy. J Paediatr
Child Health. 2017;53(12):1242–3.
71. van der Meijden JC, Kruijshaar ME, Harlaar L, Rizopoulos D, van der Beek N, van der Ploeg
AT. Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme
replacement therapy. J Inherit Metab Dis. 2018;41(6):1205–14.
72. van Capelle CI, Poelman E, Frohn-Mulder IM, et al. Cardiac outcome in classic infantile
Pompe disease after 13 years of treatment with recombinant human acid alpha-glucosidase.
Int J Cardiol. 2018;269:104–10.
73. Baba S, Yoshinaga D, Akagi K, et al. Enzyme replacement therapy provides effective, long-
term treatment of cardiomyopathy in Pompe disease. Circ J. 2018;82(12):3100–1.
74. ElMallah MK, Desai AK, Nading EB, DeArmey S, Kravitz RM, Kishnani PS. Pulmonary
outcome measures in long-term survivors of infantile Pompe disease on enzyme replacement
therapy: a case series. Pediatr Pulmonol. 2020;55(3):674–81.
75. Hsieh T, Chen M, McAfee A, Kifle Y. Sleep-related breathing disorder in children with vagal
nerve stimulators. Pediatr Neurol. 2008;38(2):99–103.
246 C. L. Rosen
76. Kritzinger FE, Al-Saleh S, Narang I. Descriptive analysis of central sleep apnea in childhood
at a single center. Pediatr Pulmonol. 2011;46(10):1023–30.
77. Felix O, Amaddeo A, Olmo Arroyo J, et al. Central sleep apnea in children: experience at a
single center. Sleep Med. 2016;25:24–8.
78. McLaren AT, Bin-Hasan S, Narang I. Diagnosis, management and pathophysiology of central
sleep apnea in children. Paediatr Respir Rev. 2019;30:49–57.
79. Burg CJ, Montgomery-Downs HE, Mettler P, Gozal D, Halbower AC. Respiratory and
polysomnographic values in 3- to 5-year-old normal children at higher altitude. Sleep.
2013;36(11):1707–14.
80. Duenas-Meza E, Bazurto-Zapata MA, Gozal D, González-García M, Durán-Cantolla J,
Torres-Duque CA. Overnight polysomnographic characteristics and oxygen saturation of
healthy infants, 1 to 18 months of age, born and residing at high altitude (2,640 meters).
Chest. 2015;148(1):120–7.
81. Hill CM, Carroll A, Dimitriou D, et al. Polysomnography in Bolivian children native to high
altitude compared to children native to low altitude. Sleep. 2016;39(12):2149–55.
82. Hughes BH, Brinton JT, Ingram DG, Halbower AC. The impact of altitude on sleep-disordered
breathing in children dwelling at high altitude: a crossover study. Sleep. 2017;40(9):zsx120.
83. DelRosso LM, Martin K, Marcos M, Ferri R. Transient central sleep apnea runs triggered by
disorder of arousal in a child. J Clin Sleep Med. 2018;14(6):1075–8.
84. d'Orsi G, Demaio V, Scarpelli F, Calvario T, Minervini MG. Central sleep apnoea in Rett
syndrome. Neurol Sci. 2009;30(5):389–91.
85. Wolfe L, Lakadamyali H, Mutlu GM. Joubert syndrome associated with severe central sleep
apnea. J Clin Sleep Med. 2010;6(4):384–8.
86. Losurdo A, Dittoni S, Testani E, et al. Sleep disordered breathing in children and adolescents
with Chiari malformation type I. J Clin Sleep Med. 2013;9(4):371–7.
87. Ramezani RJ, Stacpoole PW. Sleep disorders associated with primary mitochondrial dis-
eases. J Clin Sleep Med. 2014;10(11):1233–9.
88. Khayat A, Narang I, Bin-Hasan S, Amin R, Al-Saleh S. Longitudinal evaluation of sleep dis-
ordered breathing in infants with Prader-Willi syndrome. Arch Dis Child. 2017;102(7):634–8.
89. Rosen G, Brand SR. Sleep in children with cancer: case review of 70 children evaluated in a
comprehensive pediatric sleep center. Support Care Cancer. 2011;19(7):985–94.
90. White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlation between
sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?
Am J Med Genet Part A. 2016;170a(1):32–41.
91. Zaffanello M, Sala F, Sacchetto L, Gasperi E, Piacentini G. Evaluation of the central sleep
apnea in asymptomatic children with Chiari 1 malformation: an open question. Childs Nerv
Syst. 2017;33(5):829–32.
92. Shellhaas RA, Kenia PV, Hassan F, Barks JDE, Kaciroti N, Chervin RD. Sleep-disordered
breathing among newborns with myelomeningocele. J Pediatr. 2018;194:244–247.e241.
93. Al-Saleh S, Kantor PF, Chadha NK, Tirado Y, James AL, Narang I. Sleep-disordered breath-
ing in children with cardiomyopathy. Ann Am Thorac Soc. 2014;11(5):770–6.
94. Amos LB, D'Andrea LA. Severe central sleep apnea in a child with leukemia on chronic
methadone therapy. Pediatr Pulmonol. 2013;48(1):85–7.
95. Guichard K, Micoulaud-Franchi JA, McGonigal A, et al. Association of valproic acid with
central sleep apnea syndrome: two case reports. J Clin Psychopharmacol. 2019;39(6):681–4.
96. Locatelli F, Formica F, Galbiati S, et al. Polysomnographic analysis of a pediatric case of
baclofen-induced central sleep apnea. J Clin Sleep Med. 2019;15(2):351–4.
97. Gurbani N, Verhulst SL, Tan C, Simakajornboon N. Sleep complaints and sleep architecture
in children with idiopathic central sleep apnea. J Clin Sleep Med. 2017;13(6):777–83.
98. Cielo C, Marcus CL. Central hypoventilation syndromes. Sleep Med Clin. 2014;9(1):105–18.
99. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An official ATS clinical policy state-
ment: congenital central hypoventilation syndrome: genetic basis, diagnosis, and manage-
ment. Am J Respir Crit Care Med. 2010;181(6):626–44.
100. Weese-Mayer DE, Rand CM, Zhou A, Carroll MS, Hunt CE. Congenital central hypoventila-
tion syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment
and improved survival and quality of life. Pediatr Res. 2017;81(1–2):192–201.
101. Trang H, Samuels M, Ceccherini I, et al. Guidelines for diagnosis and management of con-
genital central hypoventilation syndrome. Orphanet J Rare Dis. 2020;15(1):252.
102. Mellins RB, Balfour HH Jr, Turino GM, Winters RW. Failure of automatic control of ventila-
tion (Ondine's curse). Report of an infant born with this syndrome and review of the litera-
ture. Medicine (Baltimore). 1970;49(6):487–504.
103. Ize-Ludlow D, Gray JA, Sperling MA, et al. Rapid-onset obesity with hypothalamic dys-
function, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics.
2007;120(1):e179–88.
104. Carroll MS, Patwari PP, Kenny AS, Brogadir CD, Stewart TM, Weese-Mayer DE. Rapid-
onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation
(ROHHAD): response to ventilatory challenges. Pediatr Pulmonol. 2015;50(12):1336–45.
105. Reppucci D, Hamilton J, Yeh EA, Katz S, Al-Saleh S, Narang I. ROHHAD syndrome and
evolution of sleep disordered breathing. Orphanet J Rare Dis. 2016;11(1):106.
106. Harvengt J, Gernay C, Mastouri M, et al. ROHHAD(NET) syndrome: systematic review of
the clinical timeline and recommendations for diagnosis and prognosis. J Clin Endocrinol
Metab. 2020;105(7):2119–31.
107. Palma JA, Norcliffe-Kaufmann L, Perez MA, Spalink CL, Kaufmann H. Sudden unexpected
death during sleep in familial dysautonomia: a case-control study. Sleep. 2017;40(8):zsx083.
108. Singh K, Palma JA, Kaufmann H, et al. Prevalence and characteristics of sleep-disordered
breathing in familial dysautonomia. Sleep Med. 2018;45:33–8.
109. Kazachkov M, Palma JA, Norcliffe-Kaufmann L, et al. Respiratory care in familial dys-
autonomia: systematic review and expert consensus recommendations. Respir Med.
2018;141:37–46.
110. Marcus CL, Carroll JL, McColley SA, et al. Polysomnographic characteristics of patients
with Rett syndrome. J Pediatr. 1994;125(2):218–24.
111. Weese-Mayer DE, Lieske SP, Boothby CM, Kenny AS, Bennett HL, Ramirez JM. Autonomic
dysregulation in young girls with Rett syndrome during nighttime in-home recordings.
Pediatr Pulmonol. 2008;43(11):1045–60.
112. Katz DM, Dutschmann M, Ramirez JM, Hilaire G. Breathing disorders in Rett syndrome:
progressive neurochemical dysfunction in the respiratory network after birth. Respir Physiol
Neurobiol. 2009;168(1–2):101–8.
113. Amaddeo A, De Sanctis L, Arroyo JO, Khirani S, Bahi-Buisson N, Fauroux
B. Polysomnographic findings in Rett syndrome. Eur J Paediatr Neurol. 2019;23(1):214–21.
114. Sarber KM, Howard JJM, Dye TJ, Pascoe JE, Simakajornboon N. Sleep-disordered breathing
in pediatric patients with Rett syndrome. J Clin Sleep Med. 2019;15(10):1451–7.
115. Dauvilliers Y, Stal V, Abril B, et al. Chiari malformation and sleep related breathing disor-
ders. J Neurol Neurosurg Psychiatry. 2007;78(12):1344–8.
116. Gosalakkal JA. Sleep-disordered breathing in Chiari malformation type 1. Pediatr Neurol.
2008;39(3):207–8.
117. Dhamija R, Wetjen NM, Slocumb NL, Mandrekar J, Kotagal S. The role of nocturnal poly-
somnography in assessing children with Chiari type I malformation. Clin Neurol Neurosurg.
2013;115(9):1837–41.
118. Losurdo A, Testani E, Scarano E, Massimi L, Della MG. What causes sleep-disordered
breathing in Chiari I malformation? Comment on: "MRI findings and sleep apnea in children
with Chiari I malformation". Pediatr Neurol. 2013;49(5):e11–3.
119. Khatwa U, Ramgopal S, Mylavarapu A, et al. MRI findings and sleep apnea in children with
Chiari I malformation. Pediatr Neurol. 2013;48(4):299–307.
120. Pomeraniec IJ, Ksendzovsky A, Awad AJ, Fezeu F, Jane JA Jr. Natural and surgical his-
tory of Chiari malformation type I in the pediatric population. J Neurosurg Pediatr.
2016;17(3):343–52.
248 C. L. Rosen
121. Ferre A, Poca MA, de la Calzada MD, et al. Sleep-related breathing disorders in chiari mal-
formation type 1: a Prospective Study of 90 patients. Sleep. 2017;40(6).
122. Waters KA, Forbes P, Morielli A, et al. Sleep-disordered breathing in children with myelome-
ningocele. J Pediatr. 1998;132(4):672–81.
123. Kirk VG, Morielli A, Gozal D, et al. Treatment of sleep-disordered breathing in children with
myelomeningocele. Pediatr Pulmonol. 2000;30(6):445–52.
124. Patel DM, Rocque BG, Hopson B, et al. Sleep-disordered breathing in patients with myelo-
meningocele. J Neurosurg Pediatr. 2015;16(1):30–5.
125. Katz ES. Chapter 34 – Disorders of central respiratory control during sleep in children. In:
Barkoukis TJ, Matheson JK, Ferber R, Doghramji K, editors. Therapy in sleep medicine.
Philadelphia: W.B. Saunders; 2012. p. 434–47.
126. MacLean JE, Fitzgerald DA, Waters KA. Developmental changes in sleep and breathing
across infancy and childhood. Paediatr Respir Rev. 2015;16(4):276–84.
127. Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded
on home monitors: comparison of healthy infants with those at increased risk for
SIDS. JAMA. 2001;285(17):2199–207.
128. Gaultier C, Praud JP, Canet E, Delaperche MF, D'Allest AM. Paradoxical inward rib cage
motion during rapid eye movement sleep in infants and young children. J Dev Physiol.
1987;9(5):391–7.
129. Hunt CE, Corwin MJ, Lister G, et al. Longitudinal assessment of hemoglobin oxygen satura-
tion in healthy infants during the first 6 months of age. Collaborative Home Infant Monitoring
Evaluation (CHIME) Study Group. J Pediatr. 1999;135(5):580–6.
130. Hunt CE, Corwin MJ, Weese-Mayer DE, et al. Longitudinal assessment of hemoglo-
bin oxygen saturation in preterm and term infants in the first six months of life. J Pediatr.
2011;159(3):377–383 e371.
131. Martin RJ, Abu-Shaweesh JM. Control of breathing and neonatal apnea. Biol Neonate.
2005;87(4):288–95.
132. Edwards BA, Sands SA, Berger PJ. Postnatal maturation of breathing stability and
loop gain: the role of carotid chemoreceptor development. Respir Physiol Neurobiol.
2013;185(1):144–55.
133. Di Fiore JM, Martin RJ, Gauda EB. Apnea of prematurity–perfect storm. Respir Physiol
Neurobiol. 2013;189(2):213–22.
134. Eichenwald EC, Committee on F, Newborn AAoP. Apnea of prematurity. Pediatrics.
2016;137(1):e20153757.
135. Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in
infants delivered at 24 to 28 weeks. Pediatrics. 1997;100(3 Pt 1):354–9.
136. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed.
Darien: American Academy of Sleep Medicine; 2014.
137. Marcus CL, Meltzer LJ, Roberts RS, et al. Long-term effects of caffeine therapy for apnea of
prematurity on sleep at school age. Am J Respir Crit Care Med. 2014;190(7):791–9.
138. Committee on Fetus and Newborn. American Academy of Pediatrics. Apnea, sudden infant
death syndrome, and home monitoring. Pediatrics. 2003;111(4 Pt 1):914–7.
139. Patel M, Mohr M, Lake D, et al. Clinical associations with immature breathing in preterm
infants: part 2-periodic breathing. Pediatr Res. 2016;80(1):28–34.
140. Khan A, Qurashi M, Kwiatkowski K, Cates D, Rigatto H. Measurement of the CO2 apneic
threshold in newborn infants: possible relevance for periodic breathing and apnea. J Appl
Physiol (1985). 2005;98(4):1171–6.
141. Simakajornboon N, Beckerman RC, Mack C, Sharon D, Gozal D. Effect of supplemental
oxygen on sleep architecture and cardiorespiratory events in preterm infants. Pediatrics.
2002;110(5):884–8.
142. Hunt CE, Corwin MJ, Lister G, et al. Precursors of cardiorespiratory events in infants detected
by home memory monitor. Pediatr Pulmonol. 2008;43(1):87–98.
143. Berry RB, Quan SF, Abreu AR, et al. for the American Academy of Sleep Medicine. The
AASM manual for the scoring of sleep and associated events: rules, terminology, and techni-
cal specifications, version 2.6. American Academy of Sleep Medicine: Darien; 2020.
144. Brockmann PE, Poets A, Urschitz MS, Sokollik C, Poets CF. Reference values for pulse
oximetry recordings in healthy term neonates during their first 5 days of life. Arch Dis Child
Fetal Neonatal Ed. 2011;96(5):F335–8.
145. Brockmann PE, Poets A, Poets CF. Reference values for respiratory events in overnight
polygraphy from infants aged 1 and 3months. Sleep Med. 2013;14(12):1323–7.
146. Daftary AS, Jalou HE, Shively L, Slaven JE, Davis SD. Polysomnography reference values
in healthy newborns. J Clin Sleep Med. 2019;15(3):437–43.
147. Ng DK, Chan CH. A review of normal values of infant sleep polysomnography. Pediatr
Neonatol. 2013;54(2):82–7.
148. National Institutes of Health Consensus Development Conference on Infantile Apnea and
Home Monitoring, Sept 29 to Oct 1, 1986. Pediatrics. 1987;79(2):292–9.
149. Tieder JS, Bonkowsky JL, Etzel RA, et al. Brief resolved unexplained events (Formerly
Apparent Life-Threatening Events) and evaluation of lower-risk infants: executive summary.
Pediatrics. 2016;137(5):e20160591.
150. Merritt JL, 2nd, Quinonez RA, Bonkowsky JL, et al. A framework for evaluation of the higher-
risk infant after a brief resolved unexplained event. Pediatrics. 2019;144(2):e20184101.
151. Moon RY, Task Force On Sudden Infant Death S. SIDS and other sleep-related infant deaths:
evidence base for 2016 updated recommendations for a safe Infant sleeping environment.
Pediatrics. 2016, 138(5):e20162940.
152. Task Force On Sudden Infant Death S. SIDS and other sleep-related infant deaths: updated
2016 recommendations for a safe Infant sleeping environment. Pediatrics. 2016:138(5).
153. CDC Centers for Disease Control and Prevention. Sudden Unexpected Infant Death and
Sudden Infant Death Syndrome 2014–2018. https://www.cdc.gov/sids/data.htm.
154. Katz ES, Mitchell RB, D'Ambrosio CM. Obstructive sleep apnea in infants. Am J Respir Crit
Care Med. 2012;185(8):805–16.
155. Mehta B, Waters K, Fitzgerald D, Badawi N. Sleep disordered breathing (SDB) in neonates
and implications for its long-term impact. Paediatr Respir Rev. 2020;34:3–8.
156. Kahn A, Groswasser J, Sottiaux M, et al. Clinical symptoms associated with brief obstructive
sleep apnea in normal infants. Sleep. 1993;16(5):409–13.
157. MacLean JE, Fitzsimons D, Fitzgerald DA, Waters KA. The spectrum of sleep-disordered
breathing symptoms and respiratory events in infants with cleft lip and/or palate. Arch Dis
Child. 2012;97(12):1058–63.
158. Anderson IC, Sedaghat AR, McGinley BM, Redett RJ, Boss EF, Ishman SL. Prevalence and
severity of obstructive sleep apnea and snoring in infants with Pierre Robin sequence. Cleft
Palate-Craniofac J. 2011;48(5):614–8.
159. Cielo CM. Question 3: what are the indications for and challenges in performing polysom-
nography in infants? Paediatr Respir Rev. 2019;30:27–9.
160. Qubty WF, Mrelashvili A, Kotagal S, Lloyd RM. Comorbidities in infants with obstructive
sleep apnea. J Clin Sleep Med. 2014;10(11):1213–6.
161. Stowe RC, Afolabi-Brown O. Pediatric polysomnography—a review of indications, technical
aspects, and interpretation. Paediatr Respir Rev. 2019;34:9.
162. 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.
163. Lee J, Soma MA, Teng AY, Thambipillay G, Waters KA, Cheng AT. The role of polysomnog-
raphy in tracheostomy decannulation of the paediatric patient. Int J Pediatr Otorhinolaryngol.
2016;83:132–6.
164. Montgomery-Downs HE, O'Brien LM, Gulliver TE, Gozal D. Polysomnographic
characteristics in normal preschool and early school-aged children. Pediatrics.
2006;117(3):741–53.
165. Tapia IE, Karamessinis L, Bandla P, et al. Polysomnographic values in children undergoing
puberty: pediatric vs. adult respiratory rules in adolescents. Sleep. 2008;31(12):1737–44.
166. Beck SE, Marcus CL. Pediatric polysomnography. Sleep Med Clin. 2009;4(3):393–406.
250 C. L. Rosen
167. Accardo JA, Shults J, Leonard MB, Traylor J, Marcus CL. Differences in overnight polysom-
nography scores using the adult and pediatric criteria for respiratory events in adolescents.
Sleep. 2010;33(10):1333–9.
168. Scholle S, Beyer U, Bernhard M, et al. Normative values of polysomnographic parameters in
childhood and adolescence: quantitative sleep parameters. Sleep Med. 2011;12(6):542–9.
169. Scholle S, Wiater A, Scholle HC. Normative values of polysomnographic parameters in
childhood and adolescence: cardiorespiratory parameters. Sleep Med. 2011;12(10):988–96.
170. Scholle S, Wiater A, Scholle HC. Normative values of polysomnographic parameters in
childhood and adolescence: arousal events. Sleep Med. 2012;13(3):243–51.
171. Certal V, Camacho M, Winck JC, Capasso R, Azevedo I, Costa-Pereira A. Unattended
sleep studies in pediatric OSA: a systematic review and meta-analysis. Laryngoscope.
2015;125(1):255–62.
172. Kirk V, Baughn J, D'Andrea L, et al. American Academy of sleep medicine position paper for
the use of a home sleep apnea test for the diagnosis of OSA in children. J Clin Sleep Med.
2017;13(10):1199–203.
173. Brockmann PE, Alonso-Alvarez ML, Gozal D. Diagnosing sleep apnea-hypopnea syndrome
in children: past, present, and future. Arch Bronconeumol. 2018;54(6):303–5.
174. Hassan F, D'Andrea LA. Best and safest care versus care closer to home. J Clin Sleep Med.
2018;14(12):1973–4.
175. Ross KR, Redline S. Is it time to head home for the night? Home sleep testing in young chil-
dren. Ann Am Thorac Soc. 2020;17(10):1207–9.
176. Rosen CL, Wang R, Taylor HG, et al. Utility of symptoms to predict treatment outcomes in
obstructive sleep apnea syndrome. Pediatrics. 2015;135(3):e662–71.
177. Gregus M. Written communication, AASM unpublished data. In:Feb 2020.
178. 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 hypoventila-
tion syndromes. J Clin Sleep Med. 2010;6(5):491–509.
179. Das S, Mindell J, Millet GC, et al. Pediatric polysomnography: the patient and family per-
spective. J Clin Sleep Med. 2011;7(1):81–7.
180. Zaremba EK, Barkey ME, Mesa C, Sanniti K, Rosen CL. Making polysomnography more
"child friendly:" a family-centered care approach. J Clin Sleep Med. 2005;1(2):189–98.
181. Ibrahim S, Stone J, Rosen CL. Best practices for accommodating children in the polysom-
nography lab: enhancing quality and patient experience (in press). In: Gozal D, Kheirandish-
Gozal L, editors. Pediatric sleep medicine. SpringerNature; 2021.
Part III
Non-respiratory Sleep Disorders
Chapter 12
Diagnosis of Insomnia Disorder
Rachel Atkinson and Christopher Drake
Keywords Insomnia · Hyperarousal · Depression · Sleep reactivity ·

Circadian rhythm · CBT-I
Introduction
Insomnia disorder is one of the most prevalent sleep disorders and is characterized
by trouble falling asleep, staying asleep, or awakening earlier than desired, and
experiencing related daytime dysfunction [1, 2]. It is estimated that approximately
one-third of adults experience insomnia symptoms, and 10% or more of the general
population have insomnia disorder [3–5]. In addition to the high prevalence of
insomnia disorder, this condition is characterized by its chronicity, with approxi-
mately three-quarters of individuals experiencing symptoms for at least 1 year, and
almost half of individuals experiencing symptoms for over 3 years [5]. Although
there are effective treatments for insomnia, almost a quarter of individuals who
enter remission will go on to experience a relapse of symptoms [5]. Insomnia is also
a risk factor for a variety of chronic illnesses if left untreated, particularly cardiovas-
cular disease, hypertension, type 2 diabetes, and neurodegenerative diseases such as
dementia and cortical atrophy [6–13]. Moreover, the strong bidirectional relation-
ship between insomnia and depression is now well established [14–17]. The odds of
an individual with insomnia developing depression are 2.6 times higher than those
of an individual with good sleep [14]. Regardless of the presence of depression,
R. Atkinson
University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
C. Drake (*)
Henry Ford Sleep Disorders and Research Center, Detroit, MI, USA
e-mail: CDRAKE1@hfhs.org

254 R. Atkinson and C. Drake
insomnia symptoms are associated with suicidal ideation, particularly in younger

individuals [17]. Compounding the physical and mental effects of insomnia disor-
der on the patient are the consequences of untreated insomnia on the public, particu-
larly in terms of healthcare costs, reduced productivity, and risk of accidents.
Chronic untreated insomnia can lead to decreased productivity at work and increased
use of sick leave, as well as increased physician visits and an increased risk of motor
vehicle accidents [18, 19]. Furthermore, the economic burden of insomnia is
immense, with the annual direct cost of healthcare for patients with insomnia aver-
aging $851 more than those without insomnia and the nationwide cost due to
decreased work performance is estimated at $63.2 billion [20, 21].
For these reasons, it is essential for healthcare providers to be able to recognize
the symptoms of insomnia disorder across both specialty and primary care settings
in order to properly diagnose insomnia disorder and recommend appropriate treat-
ments to prevent the downstream deleterious effects of insomnia on both the patient
and society. This chapter will focus on the current diagnostic criteria for insomnia
disorder, various biopsychosocial contributors to insomnia, challenges in insomnia
assessment, appropriate evaluation tools, and briefly discuss goals for treatment.
The purpose of this chapter is to prepare health care providers with the tools and
guidance necessary to efficiently and successfully evaluate and consider treatments
for insomnia disorder.
Pathophysiology and Neuropsychology of Insomnia
A characteristic feature of insomnia disorder is hyperarousal, which involves a path-

ological increase in the physiologic, affective, or cognitive activities of the body and
mind, subsequently leading to difficulty disengaging from one’s surroundings and
significantly disrupting sleep [22]. At the cognitive level, hyperarousal can present
in the form of racing thoughts, rumination, and perseverative thinking. Hyperarousal
can also manifest at other levels, including increased high-frequency electroenceph-
alogram (EEG) activation (e.g., elevated beta frequency activity during sleep), dys-
regulation of hormone secretion (e.g., cortisol), increased metabolic rate, and
elevated sympathetic nervous system activity, including increased heart rate and
blood pressure [23]. On a molecular basis, insomnia is reflected in a dysregulation
of the molecules involved in regulating the sleep–wake cycle, such as gamma-
amino-butyric acid (GABA), as evidenced by widespread depletion of GABA in the
brains of people with insomnia [22, 24]. From an integrative lens of sleep psycho-
physiology, hyperarousal can stimulate emotional and cognitive systems, which
results in activation of wake-promoting brain regions but also suppression of sleep-
promoting regions of the brain [22, 25]. As sleep-promoting regions are suppressed,
wake-promoting regions may become disinhibited leading to increased wakefulness
[22, 25, 26]. Thus, the balance between wake-promoting and sleep-promoting brain
regions is disturbed. However, the exact nature of this dysregulation remains poorly
understood, in terms of which specific brain system(s) and neuropeptides represent
12 Diagnosis of Insomnia Disorder 255
differences underlying the pathophysiology of insomnia in contrast to those differ-

ences which are a consequence of the chronic sleep disruption and comorbid disor-
ders associated with insomnia.
In addition to the role of hyperarousal in insomnia disorder, changes in the nor-
mal two-process model of sleep regulation involving processes S (wake-dependent
process, or homeostatic “sleep drive”) and C (wake-independent process, or circa-
dian rhythm) plays a similarly important role in sleep–wake cycle regulation [27,
28]. Normally, processes S and C are synchronized with each other leading to a
regular sleep–wake rhythm. However, in individuals with insomnia, it is suggested
that dysfunction in process C, which controls an individual’s circadian rhythm, may
lead to desynchronization between process S and C, resulting in the symptoms
observed in insomnia disorder [22]. However, direct evidence supporting this role
for circadian dysregulation as a pathophysiological process involved in insomnia
remains scant.
Several studies provide evidence for a moderate genetic component of insomnia
disorder. However, current evidence points to the potential role of multiple genes
involved with a variety of physiological processes such as brain function and regula-
tion of arousal and sleep–wake cycle pathways in insomnia emphasizing the com-
plexity and heterogeneity of the molecular aspects of insomnia disorder [22, 29].
At the psychological level, one of the most prominent models of insomnia is the
3-P model which emphasizes predisposing, precipitating, and perpetuating factors
that play a role in the progression and prolongation of insomnia [30, 31]. Of rele-
vance to hyperarousal, specifically, are predisposing and perpetuating factors.
Predisposing factors include individual traits or attributes such as female gender or
a family history of insomnia that increase the likelihood of developing insomnia
disorder, while perpetuating factors are those that further the development and
maintenance of insomnia once it occurs [30]. For example, with regard to perpetuat-
ing factors, remaining in bed awake when unable to fall asleep may lead to increased
anxiety about insomnia and unfavorable associations with the bedroom, leading to
maintenance and exacerbation of insomnia symptoms. Precipitating factors can be
severely stressful or anxiety-provoking events such as divorce or the death of a
loved one that serve as the “tipping point” for the onset of insomnia and lead to
overactivation of the stress response, leading to hyperarousal [30]. It is also impor-
tant to understand that predisposing factors can interact with stressful precipitating
events, which can significantly elevate the risk of developing insomnia for certain
individuals [32].
One predisposing factor, sleep reactivity, plays a crucial role in understanding
the onset and course of insomnia disorder. Sleep reactivity is defined as the degree
to which an individual’s sleep is disrupted during exposure to an external stressor
[33]. Sleep reactivity has recently been shown to be a major predictive factor for the
development of insomnia disorder, and its interaction with cognitive and emotional
factors such as rumination and worry has been increasingly explored [33].
Specifically, there appears to be a synergistic relationship between sleep reactivity
and cognitive-emotional arousal such that as stress progressively disrupts sleep pat-
terns in vulnerable individuals, the cognitive-emotional response is further
exacerbated due to additional time awake that permits continued rumination in bed
[33, 34]. Thus, as stress heightens the cognitive-emotional response, the sleep sys-
tem responds with increased wakefulness and a vicious cycle ensues [33].
While our knowledge of the neurobiology and psychology of insomnia is still
evolving, the advances in the field that have been made over the last several decades
have led us to a point where we are able to use this knowledge to better evaluate
patients in the clinic and point them toward appropriate treatment options.
Understanding the biopsychosocial aspects that contribute to the development and
maintenance of insomnia disorder is fundamental to understanding how to assess
and treat patients with this chronic and challenging condition. The remainder of this
chapter will outline how to appropriately use diagnostic criteria to evaluate insom-
nia patients in the clinical setting.
Diagnostic Criteria
The diagnosis of insomnia disorder is symptom based, with objective sleep mea-
surements recommended only in cases of suspected comorbid sleep conditions
(e.g., obstructive sleep apnea). There are myriad reasons for the reliance on
patient-reported symptoms rather than objective polysomnographic (PSG)
electroencephalogram-based laboratory measures of sleep for insomnia diagnostic
criteria. One critical element is that cortical EEG assessment of sleep (usually
based on limited cortical brain sites) does not necessarily reflect the subcortical-
limbic hyperarousal that is observed in insomnia using more sophisticated imag-
ing approaches, nor is PSG assessment always reflective of insomnia symptoms at
home [35]. The purely clinical aspect of the diagnosis stresses the significance of
being familiar with the appropriate clinical assessments and information to gather
from the patient, as more often than not, there will be a lack of objective PSG sleep
data to support a diagnosis.
Patients with insomnia disorder will typically present with a straightforward list
of chief nocturnal complaints. These include trouble falling asleep or staying asleep,
increased early morning awakenings, and impaired daytime function [1, 2].
Importantly, diagnostic criteria from the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) and the International Classification of
Sleep Disorders, Third Edition (ICSD-3) emphasize the daytime dysfunction and
distress to the patient caused by their sleeping difficulties, as well as the duration
and frequency of their insomnia symptoms [1, 2]. Both the DSM-5 and ICSD-3
require an insomnia diagnosis to be made on the basis that symptoms cause distress
to the patient and interfere with their daily functioning, in addition to nocturnal
symptoms having occurred at least 3 days per week for at least 3 months [1, 2]. In
addition to the distress experienced by the patient, the sleeping difficulties must
occur despite adequate opportunity for sleep; individuals who have decreased
opportunities for sleep exclusively due to scheduling constraints, for example, do
not meet criteria for insomnia disorder [1, 2]. Similar to other disorders listed in the
DSM-5 and ICSD-3, the sleeping difficulties must not be explained more com-
pletely by another sleep disorder (e.g., obstructive sleep apnea, restless legs syn-
drome), although the presence of another sleep disorder does not preclude diagnosis
of insomnia disorder [1, 2]. Table 12.1 provides a complete review of all diagnostic
criteria for insomnia disorder from the DSM-5 and ICSD-3.
A point of confusion for many healthcare providers may be the outdated catego-
rization of primary versus secondary insomnia disorder. Prior to 2005, the DSM-5
separated secondary insomnia, or insomnia due to other physical/mental disorders,
from primary insomnia [36]. The DSM-5 now emphasizes that diagnostic criteria
for insomnia disorder may only be met if coexisting physical and mental conditions
do not sufficiently explain the patient’s insomnia symptoms [1]. This union of pri-
mary and secondary insomnia diagnoses takes into account the comorbid nature of
the disorder and encourages treatment of insomnia symptoms even in the context of
a comorbid condition [37]. In terms of comorbidities, obstructive sleep apnea treat-
ment with continuous positive airway pressure (CPAP) may precipitate significant
sleep disturbance that may require separate treatment for sleep and may be a pre-
cipitating factor for more chronic sleep disturbance leading to insomnia disorder.
Although the role of objective PSG sleep assessment in evaluating insomnia has
been debated, recent research points to its utility in differentiating a particular phe-
notype of insomnia disorder termed insomnia with objective short sleep duration (<
6 hours of sleep per night), which is the most severe phenotype of insomnia disorder
in terms of morbidity [10]. It is associated with increased cognitive-emotional and
cortical arousal, as well as activation of both the hypothalamic–pituitary–adrenal
(HPA) and sympatho-adrenal-medullary (SAM) axes of the stress response system
as compared to insomnia with objectively normal sleep duration [10, 38]. The
objective short sleep phenotype of insomnia may respond better to medications,
while insomnia with objective normal sleep duration may be successfully treated
with cognitive behavioral therapy for insomnia (CBT-I) [10], which is the first-line
recommended treatment for insomnia disorder. While the use of PSG assessment
may be valuable in detecting objective short sleep in an insomnia patient and there-
fore selecting the most beneficial treatment, there is no current consensus for this
approach and it remains an active area of study [39]. Even if PSG is able to provide
specific and sensitive objective data, there remains a lack of consensus regarding
quantitative cutoffs for sleep parameters that should be used for making an insomnia
diagnosis [40]. Nevertheless, for accurate objective assessment PSG would need to
be combined with longer-term objective monitoring as insomnia disorder has a
characteristic longstanding pattern of sleep disruption that cannot be accurately
determined from one or even two nights in the sleep laboratory.
For the reasons outlined above, it is not advantageous to either the patient or the
provider to employ the use of PSG data in the insomnia disorder diagnosis. The
expenses to both the patient and the healthcare system are too great, and there is not
satisfactory evidence to support the finding that the objective data offered by PSG
studies is necessary in making an insomnia disorder diagnosis. The subjective com-
plaints proffered by the patient are sufficient for the proper diagnosis of insomnia,
given that the provider is able to accurately elicit the appropriate information and
Table 12.1 Comparison of diagnostic criteria for insomnia disorder based on the Diagnostic and
Statistical Manual, 5th edition (DSM-5), the International Classification of Sleep Disorders, 3rd
edition (ICSD-3), and the International Classification of Diseases, 10th edition (ICD-10)
DSM-5 [1] ICSD-3 [2] ICD-10 [76]
A. A predominant complaint of A. The patient reports, or the Disturbance of sleep
dissatisfaction with sleep patient’s parent or caregiver onset or sleep
quantity or quality, associated observes, one or more of the maintenance, or poor
with one (or more) of the following: sleep quality
following symptoms: 1. Difficulty initiating sleep
1. Difficulty initiating sleep. 2. Difficulty maintaining sleep
(In children, this may manifest 3. Waking up earlier than
as difficulty initiating sleep desired
without caregiver intervention) 4. Resistance to going to bed
2. Difficulty maintaining sleep, on appropriate schedule
characterized by frequent Difficulty sleeping without
awakenings or problems parent or caregiver intervention
returning to sleep after
awakenings. (In children, this
may manifest as difficulty
returning to sleep without
caregiver intervention)
3. Early-morning awakening
with inability to return to
sleep.
B. The sleep disturbance causes B. The patient reports, or the The afflicted individuals
clinically significant distress or patient’s parent or caregiver focus extremely on their
impairment in social, observes, one or more of the sleep disorder (especially
occupational, educational, following related to the nighttime during the night) and
academic, behavioral, or other sleep difficulty: worry about the negative
important areas of functioning 1. Fatigue/malaise consequences of
2. Attention, concentration or insomnia.
memory impairment The insufficient sleep
3. Impaired social, family, duration and quality is
occupational or academic coupled with a high
performance degree of suffering or
4. Mood disturbance/ impairs daily activities.
irritability
5. Daytime sleepiness
6. Behavioral problems (e.g.,
hyperactivity, impulsivity,
aggression)
7. Reduced motivation/energy/
initiative
8. Proneness for errors/
accidents
9. Concerns about or
dissatisfaction with sleep
Table 12.1 (continued)

DSM-5 [1] ICSD-3 [2] ICD-10 [76]
E. The sleep difficulty occurs C. The reported sleep–wake
despite adequate opportunity for complaints cannot be explained
sleep purely by inadequate opportunity
(i.e., enough time is allotted for
sleep) or inadequate
circumstances (i.e., the
environment is safe, dark, quiet,
and comfortable) for sleep
C. The sleep difficulty occurs at D. The sleep disturbance and Sleep disturbances occur
least 3 nights per week associated daytime symptoms at least three times a
occur at least three times per week over a period of
week 1 month
D. The sleep difficulty is present E. The sleep disturbance and
for at least 3 months associated daytime symptoms
have been present for at least
3 months
F. The insomnia is not better F. The sleep/wake difficulty is
explained by and does not occur not explained more clearly by
exclusively during the course of another sleep disorder
another sleep–wake disorder
(e.g., narcolepsy, a breathing-
related sleep disorder, a circadian
rhythm sleep–wake disorder, a
parasomnia)
G. The insomnia is not
attributable to the physiological
effects of a substance (e.g., a drug
of abuse, a medication)
H. Coexisting mental disorders
and medical conditions do not
adequately explain the
predominant complaint of
insomnia
rule out other causes. The following section will detail the information that must be
gathered from the patient and will outline an appropriate patient encounter when
insomnia disorder is suspected.
Clinical Evaluation of Insomnia Disorder
Challenges in Insomnia Assessment
When evaluating patients for insomnia disorder, it is important for practitioners to

be aware of common challenges they may experience during the office visit. The
primary issue that practitioners may face will be the time it takes to properly assess
a patient with insomnia symptoms, as practitioners are frequently pressed on time

and have a myriad of other important factors to address during the visit. Therefore,
it is imperative for practitioners to have a solid roadmap in place when evaluating
insomnia symptoms in order to conduct the interview in the most efficient manner
possible. The Structured Clinical Interview for Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) Sleep Disorders (SCISD) has been shown
to have excellent interrater reliability and is a reasonable tool for clinicians to utilize
as it takes approximately 10–20 minutes to administer [41].
An additional challenge that practitioners may face is lacking assurance of the
most appropriate treatment option for their patients, as these guidelines have
recently changed. Cognitive behavioral therapy for insomnia (CBT-I) has recently
been recommended as the first-line treatment for insomnia disorder, and it is no
longer recommended that medications be used as an initial treatment approach for
most patients [42]. However, approved hypnotics may be acceptable in combination
with CBT-I, as a second-line therapy, or in circumstances where CBT-I may not be
feasible (e.g., cognitively impaired patients) or desirable for a given patient. As
discussed above, insomnia disorder typically has both psychological and physiolog-
ical elements, and CBT-I has been shown to be highly effective in providing long-
term benefits for insomnia disorder in comparison to pharmacotherapy with fewer
potential risks [43].
Most importantly, the rapport that a practitioner has with their patient is para-
mount in uncovering insomnia symptoms as well as encouraging the patient to
adhere to appropriate insomnia treatment. Practitioners may struggle to form a gen-
uine connection with their patients during short office visits, especially with new
patients. Compounding this issue, many patients are unsure of how to discuss insom-
nia symptoms with their practitioner; therefore, practitioners should actively create
a welcoming space to discuss their patients’ sleep habits. As many physicians’
offices are now administering the Patient Health Questionnaire-9 (PHQ-9) to detect
symptoms of depression in patients, a logical opening to the conversation of sleep
difficulties may be the patient’s answer to item three on the PHQ-9 (“Trouble falling
or staying asleep, or sleeping too much”) [44]. If the patient has endorsed this item
(“Several days,” “More than half the days,” “Nearly every day”), the practitioner has
a natural opportunity to address this sleep concern with the patient even if the patient
does not have depression. If the office does not offer the PHQ-9 or the patient has
not endorsed item three, the practitioner still ought to inquire about the patient’s
sleep [44]. While the use of an open-ended question such as “How is your sleep?” is
a sufficient opening into a conversation about sleep, it must be followed with more
definitive, closed-ended questions that address more specific aspects of the patient’s
sleep. Examples of apt follow-up questions include “How many hours of sleep did
you get on average over the past 2 weeks?”, “When you get into bed, how long does
it take you to fall asleep?”, “On a typical night, how many times do you wake up?
And how long does it take to fall back asleep?” These closed-ended questions that
address explicit characteristics of the patient’s sleep allow ample opportunity for the
patient to discuss any sleep difficulties they may be suffering from as well as help
the patient to feel that the practitioner genuinely cares about their health and
well-being, thereby building rapport. Finally, this type of quantitative assessment of

insomnia (i.e., minutes to fall asleep, sleep duration, etc.) will allow the health pro-
vider to [1] assess the patients sleep relative to others with insomnia in terms of
severity and [2] provide a good basis for assessing response to treatment.
Identifying Patients to Evaluate for Insomnia Disorder
Sleep is a vital aspect of a patient’s physical and emotional well-being and ought to
be, at a minimum, briefly discussed with the practitioner at every visit. However,
there are particular social, psychological, and biological conditions that practitio-
ners ought to pay special attention to, as these may be predisposing factors for
patients to develop insomnia disorder. In particular, older adults and women are at
heightened risk for developing insomnia disorder, as well as patients with signifi-
cant life stressors or comorbid disorders such as chronic pain, psychiatric illnesses,
and substance abuse problems [45]. The latter is particularly important as alcohol is
frequently used by patients to address sleep problems and this pattern can lead to
increased risk for exacerbation of substance use problems. The practitioner should
take extra care to assess pregnant and peri-menopausal women for insomnia disor-
der, as these are transient periods where women are vulnerable to developing insom-
nia symptoms that can develop into insomnia disorder as well as an increased risk
of depression and suicidal ideation [46, 47]. Recent data suggest CBT-I is highly
efficacious in these populations of pregnant and peri-menopausal women [48, 49].
Additionally, it is of principal importance that the practitioner gathers a full social
history for each patient, as patients who work the night shift are unemployed, have
lower socioeconomic status, reside in dangerous neighborhoods, or experience dis-
crimination are also at risk of developing insomnia disorder [50, 51]. While there is
no known gene directly responsible for insomnia disorder, individuals with past or
current diagnosis of insomnia disorder are more likely to report having a family his-
tory of insomnia than individuals without a past or current insomnia diagnosis, and
these individuals rate their insomnia as more severe than those without a family
history [52]. This points to the significance of gathering a family insomnia history
from patients, as it may lead to increased support for an insomnia disorder diagno-
sis. Taken together, these “red flags” for insomnia disorder susceptibility can help
guide the practitioner toward an insomnia disorder diagnosis and will aid in preven-
tion efforts and early intervention.
Approach to Assessment of Insomnia Disorder
When weighing an insomnia disorder diagnosis, having a standardized format for

the patient interview will allow for consistency across patients, as well as efficiency
during the office visit. The assessment of insomnia disorder can be viewed similarly
to the evaluation of any routine complaint, as the practitioner should conduct a his-
tory of present illness for the chief complaint followed by sleep-specific follow-up
questions. The characterization of each type of complaint – difficulty falling asleep,
nighttime awakenings, time to fall back asleep, early morning awakenings, and day-
time functioning – should be addressed in full, followed by the onset, duration,
frequency, severity, course (progressive, intermittent, chronic), and remitting or
exacerbating factors related to the specific symptoms.
Patients often pursue insomnia treatments on their own before talking with a
healthcare provider, and inquiring about these attempts can inform the clinical pic-
ture. When evaluating self-treatments, it is critical to inquire about the use of alco-
hol or other substances of abuse, over-the-counter sleep medications, and off-label
medications. These substances are common methods of self-medication for insom-
nia symptoms that are often maladaptive and may be harmful to the patient. As one
becomes tolerant to many medications or substances over time, dose escalation can
occur leading to additional risks such as substance abuse. Additionally, withdrawal
symptoms from these substances, particularly alcohol, may contribute to the
patient’s insomnia symptoms and continued use of alcohol for sleep [53]. Of note,
the impact of the insomnia symptoms on the patient’s daytime function should be
evaluated, as the patient may instead simply be a short sleeper if they do not experi-
ence any dissatisfaction or daytime dysfunction as a result of their sleep problems.
Information regarding the patient’s past or current treatment attempts for insomnia
disorder should also be gathered, as this may affect the future course of treatment
and it is not always clear if a patient’s previous treatment(s) were appropriately
selected and implemented [50, 54].
Following the history of present illness portion of the interview, practitioners
should gauge the pre-sleep conditions of their patients, including their sleeping
environments, bedtime routines, and states of mind prior to sleep. If a practitioner
uncovers that their patient is sleeping in a noisy, light-filled environment and eats a
large meal or exercises directly before bedtime, this is an appropriate time to edu-
cate the patient on proper sleep hygiene. However, it should be recognized that sleep
hygiene is not a suitable standalone treatment for patients with insomnia disorder
and should only be used as a primary treatment for insomnia symptoms if the prac-
titioner determines that the patient’s poor sleep habits are the major factor in the
patients presenting complaint [50]. The practitioner should also assess the patient’s
perspective of why they may be experiencing insomnia symptoms, as this may
uncover any potential stressors in the patient’s life or maladaptive beliefs that could
be countered through cognitively focused treatment [55, 56]. Additionally, inquir-
ing about the patient’s coping responses when they are unable to sleep (e.g., watch-
ing television, remaining in bed, moving to a different room) can be useful in
informing the treatment approach.
Uncovering the sleep–wake schedule of the patient is valuable in narrowing the
differential diagnosis and distinguishing insomnia disorder from circadian rhythm
disorders (advanced/delayed sleep phase type) and behaviorally induced insuffi-
cient sleep due to restricted time in bed. If a patient works several jobs and does not
have a sufficient amount of opportunity to sleep, they will not meet criteria for an
insomnia diagnosis. Similarly, if a patient’s natural sleep–wake schedule is signifi-

cantly advanced or delayed, leaving them with a constrained amount of time for
sleep due to social responsibilities such as work or school, a diagnosis of a circadian
rhythm disorder may be more appropriate along with a referral to a sleep specialist
for the application of circadian interventions. When assessing the sleep–wake
schedule, the practitioner should determine the patient’s time to bed, estimated time
to fall asleep, number and length of awakenings, wake time, time out of bed during
the night, and any naps during the daytime. Use of a sleep diary or sleep log can be
an effective approach to gathering reliable information on these and other sleep
habits. Patients who take frequent daytime naps will have a decreased sleep drive in
the evening which can manifest as an increased sleep onset latency or a later time to
bed. Counseling the patient against frequent daytime napping can be a beneficial
recommendation in the outpatient setting before referring the patient for more inten-
sive treatment such as CBT-I. Additionally, the practitioner should ask the patient to
differentiate between their sleep–wake schedules on work and school days versus
weekend and vacation days. This may allow the practitioner to clue in on maladap-
tive behaviors such as “catching up on sleep” or may point to a circadian rhythm
disorder if the patient’s sleep–wake schedule varies drastically between weekdays
and weekends or vacation days [50, 54, 57].
Inquiring about the nocturnal behaviors that the patient engages in when they are
unable to sleep can point to comorbid conditions that the patient may have. For
example, if a patient reports that they lie awake in bed allowing their thoughts to race
or engages in rumination, there is cause for suspicion that they may respond well to
a course of CBT-I. Similarly, if a patient endorses severe snoring, gasping or chok-
ing, or frequent leg movements or discomfort, comorbid diagnoses of OSA or rest-
less legs syndrome (RLS), respectively, is appropriate to consider. Bed partner
reports, if possible, are also critical to include in the evaluation of nocturnal behav-
iors, as a bed partner may report snoring that the patient themselves is unaware of,
leading to consideration of OSA, or may counter the patient’s reports that they do not
sleep at night, pointing toward a potential paradoxical insomnia diagnosis [50, 54].
To thoroughly assess the patient’s daytime functioning, there are an assortment
of aspects that must be considered. In addition to feeling a lack of energy during the
day or the presenting complaint of “fatigue,” patients may endorse problems with
their work or school, difficulties with concentration and memory, and cognitive-
emotional problems such as irritability or mental health conditions [58, 59]. Notably,
most patients with insomnia disorder will present with feelings of fatigue rather
than sleepiness, so it is essential to consider these two facets of insomnia separately.
The eight-item Epworth Sleepiness Scale (ESS) should be used to assess daytime
sleepiness, as this questionnaire can also be used to support an OSA diagnosis when
scores are elevated [60]. If a patient scores 10 or greater on the ESS, the patient
should be educated about the risks of excessive sleepiness while driving or operat-
ing heavy machinery, as the patient is exhibiting excessive sleepiness [60]. The
number, length, and timing (morning, afternoon, evening) of naps is also a useful
indicator of a patient’s daytime sleepiness and provides an additional opportunity
for sleep hygiene education. On the contrary, the nine-item Fatigue Severity Scale
(FSS) is useful in evaluating fatigue as opposed to sleepiness [61]. Assessing the

patient’s mood disturbances and cognitive difficulties as well as the effect of their
insomnia symptoms on their overall quality of life is also critical when evaluating
the patient’s daytime function. The fatigue, irritability, and cognitive challenges
associated with insomnia disorder may result in an inability to engage in one’s nor-
mal daytime activities, leading to decreased quality of life. Finally, the bidirectional
relationship between comorbid conditions and insomnia disorder (e.g., depression,
pain disorders) may result in the exacerbation of comorbid conditions such as
depression, anxiety, or joint pain. Therefore, if applicable, the practitioner ought to
ask the patient how their insomnia symptoms have impacted their comorbid condi-
tions. As the symptom-based nature of insomnia disorder requires evidence for day-
time impairment, appropriate evaluation of the effect of the patient’s insomnia
symptoms on their daily activities is a critical element of the assessment [50, 54].
To conclude the patient interview, obtaining a detailed medical history, social
and psychiatric history, and medication list can provide important supplemental
information to support or detract from a potential insomnia disorder diagnosis.
Information attained from a detailed medical history, particularly for new patients,
may inform the practitioner of comorbid conditions that may impact the patient’s
insomnia symptoms. Understanding these comorbid conditions can ensure that the
chosen treatment method will optimize the reduction of both the symptoms of
insomnia and those of the patient’s comorbid conditions. Inquiring about the
patient’s social and psychiatric history will allow the practitioner to learn that the
patient may be a shift worker or have a concomitant anxiety or depression diagno-
sis, which may alter the diagnosis and treatment approach. Similarly, discussing the
patient’s work or school hours as well as any current stressors in their life will pro-
vide the practitioner with useful information for formulating a differential diagno-
sis. Examining the patient’s current medications (including route of administration,
dosage, frequency, timing, and side effects) and inquiring specifically about caf-
feine and alcohol use may also point to a contributor of the patient’s insomnia
symptoms and may provide an initial option for symptom relief from reduction of
these substances [62, 63]. Beyond caffeine and alcohol use, the use of antidepres-
sants ought to be considered, as medications such as imipramine, desipramine,
fluoxetine, paroxetine, venlafaxine, reboxetine, and bupropion can have either
sedating or activating effects on the patient that must be addressed by moving the
medication dose from evening to morning or transitioning to a more appropriate
antidepressant that has fewer sleep disrupting side effects [64]. Over-the-counter
allergy medications such as pseudoephedrine or phenylephrine as well as asthma
medications such as albuterol have stimulatory properties that may also contribute
to insomnia symptoms, and patients need to be advised not to take these medica-
tions within at least several hours of bedtime. Finally, the use of beta-blockers
should be assessed and moved to morning administration as these medications can
suppress melatonin and disrupt sleep [65].
Due to the symptom-based nature of the insomnia disorder diagnosis, it is vital
that the patient interview be conducted in a manner that emphasizes the concerns of
the patient in a trusted environment, while also maintaining logical order and
efficiency for the practicality of an outpatient office visit. The following section on
useful tools for insomnia disorder diagnosis will provide strategies for both building
rapport with the patient without compromising efficiency.
Tools for Assessment of Insomnia Disorder
Utilizing a variety of tools and questionnaires may drastically expedite obtaining

information necessary to make an insomnia disorder diagnosis. The Insomnia
Severity Index (ISI) is useful in questioning the patient about their insomnia-specific
symptoms such as their sleep onset latency and nighttime awakenings [66]. It is
common for patients to have a sleep onset latency of ≤35 minutes; however, sleep
onset latencies of >30–35 minutes should be broached by the clinician [57].
Similarly, several brief nighttime awakenings are benign, but the clinician should
address nighttime awakenings that lead to prolonged wakefulness during the night
known as wake after sleep onset (WASO). A duration of wakefulness >40 minutes
is outside the normal range and indicates potential insomnia if occurring on a fre-
quent basis [67]. In addition to measures such as sleep onset latency and WASO, the
Pittsburgh Sleep Quality Index (PSQI) asks questions such as “During the past
month, how often have you taken medicine (prescribed or ‘over the counter’) to help
you sleep?” in order to ascertain aspects of the patient’s sleep problem that may
otherwise not be addressed by the patient interview [68]. Both of these instruments
allow for the evaluation of the patient’s insomnia complaints in the context of nor-
mative data so that a clear picture of the severity of the sleep disturbance can be
obtained. Normative cutoffs for the ISI vary, but a frequently used cutoff in the com-
munity setting is ≥ 10 while the cutoff for the PSQI is >5 [68, 69].
Sleep Diary
A valuable tool for the practitioner is a 2-week “sleep diary” that the patient com-
pletes each morning immediately after awakening. The sleep diary includes the
patient’s self-reported bedtime, “lights out time,” sleep onset latency, number and
duration of nighttime awakenings, amount of wake after sleep onset, time in bed,
total sleep time, sleep efficiency (total sleep time divided by time in bed), self-
reported sleep quality, number and duration of naps, and any caffeine, alcohol, or
sleep aid use (prescription or over the counter). The sleep diary allows the practitio-
ner to gain an accurate picture of the patient’s sleep habits and sense any trends in the
patient’s sleep schedule, such as a phase advance/delay or excessive use of caffeine
or alcohol. The advantage to using the sleep diary as opposed to asking the patient to
recall this information during the office visit is that the patient may struggle to recol-
lect information about their sleep or may misperceive their long-term sleep habits.
Having a patient fill out a sleep diary each morning for 2 weeks provides the most
accurate picture of their sleep and should be utilized prior to full clinical evaluation
whenever possible. If the practitioner is aware in advance that a patient is scheduling
a visit for insomnia symptoms, they may request office staff to send a sleep diary
worksheet or recommend app-based sleep diaries to the patient to fill out for 2 weeks
prior to the visit. Alternatively, it may be beneficial to schedule a 2-week follow-up
visit with the patient and request that they fill out the sleep diary during this 2-week
interval to better ascertain their sleep habits and develop a successful treatment plan.
When used properly, sleep diaries are a valuable part of the treatment process as they
allow both the patient and the practitioner to track the progress of the treatment and
adjust the treatment as needed. The National Sleep Foundation is an excellent source
for obtaining a free to use standardized sleep diary [70].
Despite the rise in popularity of “wearable” devices such as Fitbits, Apple
watches, etc., their questionable validity makes them less than ideal methods for
tracking the sleep of insomnia patients. When compared to PSG sleep measures,
wearable technology demonstrated a high sensitivity of over 90% for detecting
sleep; however, its specificity for detecting wake was substantially diminished,
leading to an artificially inflated total sleep time and diminished WASO [71]. Sleep
onset also tended to be delayed when measured with wearable technology, with a
typical delay of about 20 minutes when compared to PSG [71]. While results
remained consistent across various categories of body mass indices and sexes,
results tended to vary across age groups [71]. Additionally, wearable technology is
generally programmed to detect a certain amount of sleep, typically at least an hour,
leading to extreme inaccuracies in detecting napping [71]. Therefore, it is important
for practitioners evaluating patients for insomnia disorder to not rely only on data
from wearable devices but rather on information presented from sleep diaries filled
out by patients themselves. In most cases, patient reports of symptoms should be
taken at face value given the frequent discrepancy between subjective and objective
sleep assessments (including actigraphy) in insomnia disorder. However, wearable
devices are particularly useful for tracking sleep in patients who may be unable to
provide accurate self-assessments (e.g., young children, cognitively impaired) or
for those with widely varying sleep schedules such as night shift workers.
Taken together, the information provided through validated questionnaires such
as the ESS, ISI, and PSQI in combination with sleep diary worksheets that track the
patient’s sleep habits will provide the practitioner with the most accurate depiction
of the patient’s insomnia symptoms.
Differential Diagnosis
In the differential diagnosis for insomnia disorder, a variety of other sleep and non-
sleep-related disorders should be considered. Primarily, depression often presents
with symptoms of insomnia, so it is imperative that the practitioner utilizes
screening questionnaires such as the PHQ-9 and ISI to establish whether the patient
is experiencing symptoms of depression, insomnia, or both. In many cases, due to
the high comorbidity between insomnia and mental illness, the patient may be expe-
riencing both depression and insomnia, and the patient ought to have both condi-
tions treated at the time of the office visit. Although certain atypical antidepressants
such as trazodone and mirtazapine have been used to treat insomnia, they are off-
label and guidance on efficacy and appropriate doses for treatment of insomnia
disorder are limited [72].
The symptoms of OSA may also present similarly to insomnia disorder, with
patients reporting fatigue during the daytime and frequent awakenings at night. To
differentiate between insomnia disorder and OSA, the practitioner should use tools
that assess risks and symptoms of sleep-disordered breathing and OSA, such as the
ESS and the four-item STOP/STOP-BANG [73, 74]. If a patient screens positive on
either or both of these questionnaires, the practitioner should schedule a diagnostic
study (home sleep apnea test or PSG) or make an appropriate referral to further
investigate a potential diagnosis of OSA.
Movement disorders such as RLS may also present similarly to insomnia disor-
der, as the unpleasant sensations and urge to move at nighttime may prevent the
patient from falling asleep. Questioning the patient about the symptoms of RLS and
following up with a PSG study if positive symptoms are endorsed will help the
practitioner to differentiate RLS from insomnia disorder. There are several unique
characteristics of RLS that facilitate this process including a circadian rhythm of
symptoms, unpleasant sensations in the legs, and the patient reports some relief with
movement.
As previously mentioned, circadian rhythm disorders may also present as
insomnia disorder, as a patient with phase delay may be unable to fall asleep
until far past the patient’s usual bedtime. Patients with a circadian rhythm disor-
der can show either a phase delay (i.e., delayed sleep onset and waketime) or a
phase advance (i.e., earlier sleep onset than desired and early morning awaken-
ings). Therefore, closely examining a patient’s sleep diary and paying particular
attention to weekday and weekend, holiday, or vacation data will inform the
practitioner of a possible circadian rhythm disorder. When a patient presents
with a consistently extreme early or consistently extreme late bedtime additional
assessment is warranted by a sleep specialist to rule out a circadian rhythm dis-
order. If there is substantive discord between the objective and subjective data
and all other disorders have been ruled out, paradoxical insomnia could be con-
sidered [75].
In summary, insomnia disorder has a host of comorbid conditions that can con-
tribute to insomnia symptoms or that may present similarly to insomnia disorder. If
the practitioner is uncertain that an insomnia disorder diagnosis is the most appro-
priate for a given patient, a variety of screening questionnaires and the use of a PSG
study in conjunction to sleep specialist referral are important aspects for obtaining
an accurate diagnosis.
Treatment Options and Goals
Evaluation of insomnia should conclude with a discussion of treatment options and

the patient’s treatment goals. The primary goals in treating patients with insomnia
disorder are typically to improve their sleep quality, thereby improving the patient’s
subjective experience of their sleep [50] and improving their daytime functioning.
For patients wishing to discontinue the use of sleep medications, tapering and even-
tual discontinuation of pharmacological treatment may occur in concert with CBT-I
once the patient’s insomnia symptoms are below the threshold for severe insomnia
for several weeks (ISI < 22) [50, 66]. Secondary goals of insomnia disorder treat-
ment should be to reduce any psychological distress or correct any maladaptive
belief systems that the patient has regarding sleep by referring the patient to a CBT-I
provider [42, 50]. Importantly, when discussing treatment goals with the patient, the
practitioner ought to ask the patient for their desired outcome and any treatment
preferences they may have. Engaging in shared decision-making and goal formula-
tion in this way will not only help to guide treatment options but also help the
patient to be actively engaged in their treatment and build rapport [42].
Assessment of insomnia remission after initiation of treatment should include
the same measures and questionnaires used for the initial evaluation of the diagnosis
rather than exclusively asking the patient if their symptoms have improved. Of note,
many patients will learn to tolerate their symptoms or believe that poor sleep is
acceptable yet will still be displaying insomnia symptoms and experiencing day-
time impairment [40]. Repeating the initial measures and questionnaires will pro-
vide a more accurate picture of the progression of the patient’s sleep pattern before
and after treatment. Importantly, emphasis should be placed on if the patient’s day-
time functioning has improved, as this is one foundation of the insomnia disorder
diagnosis. If the patient is still exhibiting impaired daytime functioning or display-
ing other symptoms of insomnia, the practitioner should question the patient about
treatment adherence (both behavioral and pharmacological), or consider if a differ-
ent diagnosis is more appropriate. In some cases where remission does not occur, it
can be effective to have the patient to use an alternative or additional treatment
approach. Furthermore, as over a quarter of individuals in remission will relapse
within 3 years, it is essential that the practitioner follow-up with the patient at all
future appointments [5]. Thorough documentation in the medical record of the
insomnia disorder diagnosis and treatment efforts will help in future visits with the
patient and will aid other providers if insomnia recurrence occurs.
Summary
Insomnia disorder is a highly pervasive and persistent sleep disorder that negatively
impacts both the patient and society as a whole. The clinical management of insom-
nia disorder in a primary care setting can be challenging, but given the proper tools,
any practitioner can be prepared to efficiently and effectively treat insomnia disor-
der. Keeping in mind the potential etiology of the disorder, the practitioner will be
able to understand the myriad underlying reasons for the patient’s symptom presen-
tation and use this knowledge to inform the patient of their appropriate treatment
options. Being familiar with the signs, symptoms, and treatments of insomnia dis-
order will allow general practitioners including those in primary care to be optimal
first-line interventionists for these patients and deliver high-quality, compassionate
care to those suffering from this debilitating disorder.
Key Summary Points

1. Insomnia disorder is a common clinical condition impacting at least 10%
of adults.
2. Insomnia disorder is diagnosed based on a thorough clinical history; diag-
nosis does not require the patient to undergo polysomnography.
3. First-line treatment for insomnia disorder is cognitive behavioral therapy
for insomnia (CBT-I).
4. If left untreated, insomnia disorder can contribute to the development of
depression and increase a patient’s risk of suicidality.
5. Insomnia disorder can often present similarly to other sleep disorders such
as obstructive sleep apnea (OSA), restless legs syndrome (RLS), and cir-
cadian rhythm disorders; therefore, the practitioner must consider these
alternate diagnoses in patients presenting with sleep difficulties.
References
1. DSMTF, editor. Diagnostic and statistical manual of mental disorders: DSM-5. American
Psychiatric A, American Psychiatric Association. Arlington: American Psychiatric
Association; 2013.
2. Medicine AAoS. International classification of sleep disorders—third edition (ICSD-3) online
version. Westchester: American Academy of Sleep Medicine; 2014.
3. Roth T, Coulouvrat C, Hajak G, Lakoma MD, Sampson NA, Shahly V, et al. Prevalence and
perceived health associated with insomnia based on DSM-IV-TR; international statistical clas-
sification of diseases and related health problems, tenth revision; and research diagnostic cri-
teria/international classification of sleep disorders, second edition criteria: results from the
America insomnia survey. Biol Psychiatry. 2011;69(6):592–600.
4. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep
Med Rev. 2002;6(2):97–111.
5. Morin CM, Belanger L, LeBlanc M, Ivers H, Savard J, Espie CA, et al. The natural history of
insomnia: a population-based 3-year longitudinal study. Arch Intern Med. 2009;169(5):447–53.
6. Sofi F, Cesari F, Casini A, Macchi C, Abbate R, Gensini GF. Insomnia and risk of cardiovascu-
lar disease: a meta-analysis. Eur J Prev Cardiol. 2014;21(1):57–64.
7. Fernandez-Mendoza J, He F, Vgontzas AN, Liao D, Bixler EO. Interplay of objective sleep
duration and cardiovascular and cerebrovascular diseases on cause-specific mortality. J Am
Heart Assoc. 2019;8(20):e013043.
8. Cheng P, Pillai V, Mengel H, Roth T, Drake CL. Sleep maintenance difficulties in insomnia are
associated with increased incidence of hypertension. Sleep Health. 2015;1(1):50–4.
9. Jarrin DC, Alvaro PK, Bouchard MA, Jarrin SD, Drake CL, Morin CM. Insomnia and hyper-
tension: a systematic review. Sleep Med Rev. 2018;41:3–38.
10. Vgontzas AN, Fernandez-Mendoza J, Liao D, Bixler EO. Insomnia with objective short
sleep duration: the most biologically severe phenotype of the disorder. Sleep Med Rev.
2013;17(4):241–54.
11. Lin CL, Chien WC, Chung CH, Wu FL. Risk of type 2 diabetes in patients with insomnia: a
population-based historical cohort study. Diabetes Metab Res Rev. 2018;34(1)
12. Sexton CE, Storsve AB, Walhovd KB, Johansen-Berg H, Fjell AM. Poor sleep quality
is associated with increased cortical atrophy in community-dwelling adults. Neurology.
2014;83(11):967–73.
13. Hung CM, Li YC, Chen HJ, Lu K, Liang CL, Liliang PC, et al. Risk of dementia in patients
with primary insomnia: a nationwide population-based case-control study. BMC Psychiatry.
2018;18(1):38.
14. Baglioni C, Battagliese G, Feige B, Spiegelhalder K, Nissen C, Voderholzer U, et al. Insomnia
as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological stud-
ies. J Affect Disord. 2011;135(1–3):10–9.
15. Cheng P, Kalmbach DA, Tallent G, Joseph CL, Espie CA, Drake CL. Depression prevention
via digital cognitive behavioral therapy for insomnia: a randomized controlled trial. Sleep.
2019;42(10)
16. Bishop TM, Crean HF, Hoff RA, Pigeon WR. Suicidal ideation among recently returned vet-
erans and its relationship to insomnia and depression. Psychiatry Res. 2019;276:250–61.
17. Russell K, Rasmussen S, Hunter SC. Insomnia and nightmares as markers of risk for suicidal
ideation in young people: investigating the role of defeat and entrapment. J Clin Sleep Med.
2018;14(5):775–84.
18. Kucharczyk ER, Morgan K, Hall AP. The occupational impact of sleep quality and insomnia
symptoms. Sleep Med Rev. 2012;16(6):547–59.
19. Brossoit RM, Crain TL, Leslie JJ, Hammer LB, Truxillo DM, Bodner TE. The effects of sleep
on workplace cognitive failure and safety. J Occup Health Psychol. 2019;24(4):411–22.
20. Asche CV, Joish VN, Camacho F, Drake CL. The direct costs of untreated comorbid insom-
nia in a managed care population with major depressive disorder. Curr Med Res Opin.
2010;26(8):1843–53.
21. Klemas N. Clinical Economics. Insomnia Med Econ. 2015;92(6):24–5, 30
22. Levenson JC, Kay DB, Buysse DJ. The pathophysiology of insomnia. Chest.
2015;147(4):1179–92.
23. Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science. Sleep Med Rev.
2010;14(1):9–15.
24. Winkelman JW, Buxton OM, Jensen JE, Benson KL, O'Connor SP, Wang W, et al. Reduced
brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spec-
troscopy (1H-MRS). Sleep. 2008;31(11):1499–506.
25. Saito YC, Maejima T, Nishitani M, Hasegawa E, Yanagawa Y, Mieda M, et al. Monoamines
inhibit GABAergic neurons in ventrolateral preoptic area that make direct synaptic connec-
tions to hypothalamic arousal neurons. J Neurosci. 2018;38(28):6366–78.
26. Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG. Orexin a stimulates
cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-
dependent signaling cascade. J Clin Endocrinol Metabol. 2001;86(2):778–82.
27. Borbely AA, Daan S, Wirz-Justice A, Deboer T. The two-process model of sleep regulation: a
reappraisal. J Sleep Res. 2016;25(2):131–43.
28. Achermann P, Borbély AA. Chapter 37 - Sleep homeostasis and models of sleep regulation. In:
Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 5th ed.
Philadelphia: W.B. Saunders; 2011. p. 431–44.
29. Drake CL, Friedman NP, Wright KP Jr, Roth T. Sleep reactivity and insomnia: genetic and
environmental influences. Sleep. 2011;34(9):1179–88.
30. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment.
Psychiatr Clin North Am. 1987;10(4):541–53.
31. Perlis M, Shaw PJ, Cano G, Espie CA. Chapter 78 – Models of insomnia. In: Kryger MH,
Roth T, Dement WC, editors. Principles and practice of sleep medicine. 5th ed. Philadelphia:
W.B. Saunders; 2011. p. 850–65.
32. Drake CL, Pillai V, Roth T. Stress and sleep reactivity: a prospective investigation of the stress-
diathesis model of insomnia. Sleep. 2014;37(8):1295–304.
33. Kalmbach DA, Anderson JR, Drake CL. The impact of stress on sleep: pathogenic sleep reac-
tivity as a vulnerability to insomnia and circadian disorders. J Sleep Res. 2018;27(6):e12710-e.
34. Kalmbach DA, Buysse DJ, Cheng P, Roth T, Yang A, Drake CL. Nocturnal cognitive arousal is
associated with objective sleep disturbance and indicators of physiologic hyperarousal in good
sleepers and individuals with insomnia disorder. Sleep Med. 2020;71:151–60.
35. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuro-
imaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126–8.
36. Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG, et al. European
guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26(6):675–700.
37. Seow LSE, Verma SK, Mok YM, Kumar S, Chang S, Satghare P, et al. Evaluating DSM-5
insomnia disorder and the treatment of sleep problems in a psychiatric population. J Clin Sleep
Med JCSM. 2018;14(2):237–44.
38. Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, et al. Chronic
insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal
axis: clinical implications. J Clin Endocrinol Metab. 2001;86(8):3787–94.
39. Edinger JD, Ulmer CS, Means MK. Sensitivity and specificity of polysomnographic criteria
for defining insomnia. J Clin Sleep Med. 2013;9(5):481–91.
40. Pillai V, Roth T, Drake CL. Towards quantitative cutoffs for insomnia: how current diagnostic
criteria mischaracterize remission. Sleep Med. 2016;26:62–8.
41. Taylor DJ, Wilkerson AK, Pruiksma KE, Williams JM, Ruggero CJ, Hale W, et al. Reliability
of the structured clinical interview for DSM-5 sleep disorders module. J Clin Sleep Med.
2018;14(3):459–64.
42. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insom-
nia disorder in adults: a clinical practice guideline from the American College of Physicians.
Ann Intern Med. 2016;165(2):125–33.
43. Mitchell MD, Gehrman P, Perlis M, Umscheid CA. Comparative effectiveness of cognitive
behavioral therapy for insomnia: a systematic review. BMC Fam Pract. 2012;13:40.
44. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity mea-
sure. J Gen Intern Med. 2001;16(9):606–13.
45. Klink ME, Quan SF, Kaltenborn WT, Lebowitz MD. Risk factors associated with complaints
of insomnia in a general adult population. Influence of previous complaints of insomnia. Arch
Intern Med. 1992;152(8):1634–7.
46. Kalmbach DA, Cheng P, Ong JC, Ciesla JA, Kingsberg SA, Sangha R, et al. Depression and
suicidal ideation in pregnancy: exploring relationships with insomnia, short sleep, and noctur-
nal rumination. Sleep Med. 2020;65:62–73.
47. Kalmbach DA, Cheng P, Arnedt JT, Cuamatzi-Castelan A, Atkinson RL, Fellman-Couture C,
et al. Improving daytime functioning, work performance, and quality of life in postmenopausal
women with insomnia: comparing cognitive behavioral therapy for insomnia, sleep restriction
therapy, and sleep hygiene education. J Clin Sleep Med. 2019;15(7):999–1010.
48. Drake CL, Kalmbach DA, Arnedt JT, Cheng P, Tonnu CV, Cuamatzi-Castelan A, et al. Treating
chronic insomnia in postmenopausal women: a randomized clinical trial comparing cognitive-
behavioral therapy for insomnia, sleep restriction therapy, and sleep hygiene education. Sleep.
2019;42(2)
49. Kalmbach DA, Cheng P, O'Brien LM, Swanson LM, Sangha R, Sen S, et al. A randomized
controlled trial of digital cognitive behavioral therapy for insomnia in pregnant women. Sleep
Med. 2020;72:82–92.
50. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation
and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504.
51. Grandner MA, Williams NJ, Knutson KL, Roberts D, Jean-Louis G. Sleep disparity, race/
ethnicity, and socioeconomic position. Sleep Med. 2016;18:7–18.
52. Beaulieu-Bonneau S, LeBlanc M, Merette C, Dauvilliers Y, Morin CM. Family history of
insomnia in a population-based sample. Sleep. 2007;30(12):1739–45.
53. Hodges CJ, Ogeil RP, Lubman DI. The effects of acute alcohol withdrawal on sleep. Hum
Psychopharmacol. 2018;33(3):e2657.
54. Krystal AD, Prather AA, Ashbrook LH. The assessment and management of insomnia: an
update. World Psychiatry. 2019;18(3):337–52.
55. Harvey AG. A cognitive model of insomnia. Behav Res Ther. 2002;40(8):869–93.
56. Harvey AG, Tang NK, Browning L. Cognitive approaches to insomnia. Clin Psychol Rev.
2005;25(5):593–611.
57. Drake CL, Vargas I, Roth T, Friedman NP. Quantitative measures of nocturnal insomnia symp-
toms predict greater deficits across multiple daytime impairment domains. Behav Sleep Med.
2015;13(1):73–87.
58. Zammit GK. Subjective ratings of the characteristics and sequelae of good and poor sleep in
normals. J Clin Psychol. 1988;44(2):123–30.
59. Carey TJ, Moul DE, Pilkonis P, Germain A, Buysse DJ. Focusing on the experience of insom-
nia. Behav Sleep Med. 2005;3(2):73–86.
60. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
Sleep. 1991;14(6):540–5.
61. Lerdal A. Fatigue severity scale. In: Michalos AC, editor. Encyclopedia of quality of life and
well-being research. Dordrecht: Springer Netherlands; 2014. p. 2218–21.
62. Treur JL, Gibson M, Taylor AE, Rogers PJ, Munafo MR. Investigating genetic correla-
tions and causal effects between caffeine consumption and sleep behaviours. J Sleep Res.
2018;27(5):e12695.
63. Thakkar MM, Sharma R, Sahota P. Alcohol disrupts sleep homeostasis. Alcohol.
2015;49(4):299–310.
64. Wichniak A, Wierzbicka A, Jernajczyk W. Sleep and antidepressant treatment. Curr Pharm
Des. 2012;18(36):5802–17.
65. Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, et al. Influence of
beta-blockers on melatonin release. Eur J Clin Pharmacol. 1999;55(2):111–5.
66. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome
measure for insomnia research. Sleep Med. 2001;2(4):297–307.
67. Lineberger MD, Carney CE, Edinger JD, Means MK. Defining insomnia: quantitative criteria
for insomnia severity and frequency. Sleep. 2006;29(4):479–85.
68. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep
Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res.
1989;28(2):193–213.
69. Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psychometric
indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011;34(5):601–8.
70. National Sleep Foundation. Sleep Diary 2020 [Available from: https://www.sleepfoundation.
org/sites/default/files/inline-files/SleepDiaryv6.pdf.
71. de Zambotti M, Cellini N, Goldstone A, Colrain IM, Baker FC. Wearable sleep technology in
clinical and research settings. Med Sci Sports Exerc. 2019;51(7):1538–57.
72. Atkin T, Comai S, Gobbi G. Drugs for insomnia beyond benzodiazepines: pharmacology,
clinical applications, and discovery. Pharmacol Rev. 2018;70(2):197–245.
73. Silva GE, Vana KD, Goodwin JL, Sherrill DL, Quan SF. Identification of patients with sleep
disordered breathing: comparing the four-variable screening tool, STOP, STOP-Bang, and
Epworth sleepiness scales. J Clin Sleep Med. 2011;7(5):467–72.
74. Vana KD, Silva GE, Goldberg R. Predictive abilities of the STOP-Bang and Epworth sleepi-
ness Scale in identifying sleep clinic patients at high risk for obstructive sleep apnea. Res Nurs
Health. 2013;36(1):84–94.
75. Castelnovo A, Ferri R, Punjabi NM, Castronovo V, Garbazza C, Zucconi M, et al. The paradox
of paradoxical insomnia: a theoretical review towards a unifying evidence-based definition.
Sleep Med Rev. 2019;44:70–82.
76. World Health O. ICD-10 : international statistical classification of diseases and related health
problems: tenth revision. 2nd ed. Geneva: World Health Organization; 2004.
Chapter 13
Management of Insomnia Disorder
Gwendolyn C. Carlson, Michelle R. Zeidler, and Jennifer L. Martin
Keywords Insomnia · Sleep medicine · Clinical practice guidelines · CBT-I
Management of Insomnia Disorder
Insomnia disorder is characterized by difficulty initiating and maintaining sleep. It

is estimated that 10–30% of the population experiences insomnia [1–3]. There are
two primary diagnostic systems for the identification of clinically significant insom-
nia symptoms: (1) the American Psychiatric Association’s (APA) Diagnostic and
Statistical Manual of Mental Disorder-fifth Edition (DSM-5) [4] and (2) the
International Classification of Sleep Disorders-Third Edition (ICSD-3) of the
American Academy of Sleep Medicine (AASM) [5]. A diagnosis of insomnia
G. C. Carlson
Department of Mental Health, VA Greater Los Angeles Healthcare System, VA Health
Services Research and Development Service (HSR&D) Center for the Study of Healthcare
Innovation, Implementation and Policy, Los Angeles, CA, USA
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine,
University of California, Los Angeles, Los Angeles, CA, USA
M. R. Zeidler
Sleep Disorders Center, VA Greater Los Angeles VA Healthcare System, Department of
Medicine, David Geffen School of Medicine, University of California, Los Angeles,
J. L. Martin (*)
Geriatric Research, Education and Clinical Center, Veteran Affairs Greater Los Angeles
Healthcare System, Department of Medicine, David Geffen School of Medicine, University
of California, Los Angeles, Los Angeles, CA, USA
e-mail: Jennifer.martin@va.gov

276 G. C. Carlson et al.
disorder is characterized by poor sleep, with daytime consequences, that persists for
3 months and occurs at least three times per week. Per the ICSD-3, a diagnosis of
chronic insomnia requires that a patient report sleep disturbance for at least
3 months, with short-term insomnia characterized by sleep disturbance that is less
than 3 months in duration [5]. Consequences associated with sleep disturbance
include increased risk for other medical and mental health comorbidities, lost pro-
ductivity and increased absenteeism, and increase risk for accident, injury, and
death [6].
Given the prevalence of and impairment associated with poor sleep, interven-
tions have been developed to treat the symptoms of insomnia disorder [2, 7, 8].
Interventions include both behavioral (i.e., non-medication) treatments and medica-
tion treatments. This chapter describes the best practices for the treatment of insom-
nia disorder. Based on the AASM Clinical Practice Guidelines [8], Fig. 13.1
describes a decision-making framework for the treatment of insomnia disorder.
Evidence-based treatments, patients’ preferences, sleep disorder comorbidities, and
treatment responses will inform decision-making. The following sections describe
the treatments included in this framework and factors that may influence treatment
delivery and referral.
Does the patient meet

diagnostic criteria for
insomnia disorder?
Yes No
Evaluate for other sleep

Are there comorbid
Are they interested in disorders and refer for
conditions that can be
behavioral treatment? sleep study if not
treated simultaneously?
previously conducted
Yes No Yes No
Provide medication with Were there previous

Practice or Pratice or refer to
lowest risk or refer to attempts to treat this
refer to CBT-I CBT-I
prescriber condition(s)?
Treatment Treatment Yes No Treatment Treatment

Response Non-Response Response Non-Response
Evaluate for other sleep Pratice or refer to CBT- Evaluate for other sleep
disorders and refer for Was there a treatment I and implement disorders and refer for
sleep study if not response? treatment for comorbid sleep study if not
previously conducted conditions previously conducted
Consdier implementation Consider

of other behavioral Yes No Implementation of
treatments for insomnia other behavioral
treatments for insomnia
Evaluate for other sleep
Continue treatment for
disorders and refer for
comorbid condition and
sleep studt if not
refer to CBT-I
previously conducted
Supplement
with medication
as needed
Fig. 13.1 Treatment decision-making framework for the treatment of insomnia disorder
13 Management of Insomnia Disorder 277
Behavioral Interventions
Cognitive behavioral therapy for insomnia The first line treatment for insomnia
is cognitive behavioral therapy for insomnia (CBT-I) [7]. The AASM Clinical
Practice Guidelines strongly recommend clinicians use multicomponent CBT-I for
the treatment of chronic insomnia disorder in adults [9]. A “strong recommenda-
tion” indicates that clinicians should implement or refer to this treatment under
most circumstances. A “conditional” recommendation indicates that clinicians
should consider knowledge of the patient (i.e., patient values and preferences) and
clinical knowledge and experience to determine the best intervention. While multi-
component CBT-I is strongly recommended, individual components of CBT-I are
also conditionally recommended for the treatment of chronic insomnia disorder in
adults. The following sections will describe the components of CBT-I.
The “3-Ps” model underlies the rationale for CBT-I. This model proposes that
insomnia develops from and is maintained by predisposing factors, precipitating
factors, and perpetuating factors [10]. Predisposing factors increase an individual’s
risk of developing insomnia (e.g., family history of sleep disorders). Precipitating
factors include circumstances or events that lead patients to experience clinically
significant sleep difficulties (e.g., injuries/medical conditions, interpersonal events)
[11]. Attempts to cope with precipitating factors can lead to perpetuating factors
(e.g., compensatory daytime napping, prolonged time awake in bed at night, caf-
feine use during that day). According to the 3-Ps model, perpetuating factors lead to
chronic insomnia [10]. Insomnia is maintained by the interrelations among prob-
lematic emotions, thoughts, and behaviors. Patients can develop anxiety or other
emotions regarding their sleep difficulties, experience inaccurate and unhelpful
thoughts about their sleep difficulties, and engage in maladaptive behaviors to cope
with difficulties initiating and maintaining sleep [12, 13]. CBT-I intervenes on this
problematic cycle by changing problematic behaviors and thoughts [8]. CBT-I ses-
sions typically incorporate the following intervention components: (1) stimulus
control, (2) sleep restriction, (3) sleep hygiene recommendations, (4) relaxation
strategies, and (5) cognitive therapy exercises. Of these components, the strongest
evidence supports stimulus control and sleep restriction as stand-alone treatments,
while evidence for the other components remains more modest [14, 15].
Stimulus control Stimulus control is a behavioral phenomenon that underlies mul-
tiple behaviors, including sleep [16]. In basic terms, sleep is considered an instru-
mental behavior, and cues (or stimuli) in a patient’s environment provide information
about whether sleep will be reinforced or not [17, 18]. Example of discriminative
stimuli for sleep include darkness/nighttime or being in bed. However, if these stim-
uli are inconsistently paired with sleep, difficulty sleeping may be the result of inad-
equate discriminative stimulus control. Patients who undergo CBT-I are provided
with education about classical and operant conditioning to ensure they understand
the rationale for stimulus control therapy [19]. The provider and patient discuss the
associations that can develop between the bed (i.e., place of sleep) and anxiety and/
or other non-sleep behaviors/activities and how these associations lead to condi-

tioned insomnia [14]. The intervention of stimulus control involves using the sleep
area only for sleeping, refraining from doing other activities in the sleep area, and
avoiding sleeping in areas other than the designated sleep area. Per the AASM
Clinical Practice Guidelines, it conditionally recommended that clinicians imple-
ment stimulus control as a single-component therapy for the treatment of insomnia
disorder.
Sleep restriction In addition to stimulus control, patients are oriented to the ratio-
nale for tracking sleep. Behavior monitoring is a common component of many
behavioral therapies [20]. Patients are oriented to the sleep diary and are asked to
complete a weekly sleep diary, which includes daily bedtimes, sleep onset latencies,
wake times after sleep onset, number of nighttime awakenings, rise times, and day-
time awakenings (see Fig. 13.2 for an example of sleep diary information). Based
on data on the sleep diary, patients are oriented to the concept of sleep efficiency.
Sleep efficiency is calculated by dividing total sleep time by total time in bed (min-
utes from bedtime to rise time) and converting the quotient to a percentage. Patients
and providers discuss how low sleep efficiency can exacerbate problematic associa-
tions between bed and wakefulness, maintaining insomnia symptoms [15]. Patients
may develop inaccurate beliefs that more time in bed provides a greater opportunity
for sleep. In fact, excessive time in bed not sleeping can further contribute to inad-
equate stimulus control. Sleep restriction involves reducing the amount of time a
patient spends in bed in an effort to improve sleep efficiency [18, 21]. This involves
setting a sleep window based on a patient’s sleep diary total time in bed. Patients are
Complete on: Sun Mon Tues Wed Thurs Fri Sat [date] ______________
Day 1
Morning questions Bedtime questions

1. What time did you got to bod last night? ___:___ am/pm 7. Did you take any naps or doze off at any time today
before getting into bed for the night? No Yes
2. How long did it take you to fall asleep last night? a. If yes, How many times did you spend napping or
minutes dozing? minutes
3. Did you wake up during the night last night? No Yes 8. Did you drink any beverages containing caffeine
No Yes
today?
a. If yes, How many times did you wake up? a. If yes, About how many cups or glasses? ___ cups/glasses
times
b. If yes, What was the total amount of time that b. If yes, What time did you have your last one? ___:___ am/pm
you wereawake? minutes 9. Did you drink any beverages containing alcohol
No Yes
today?
4. Last night, did you take any medication to help
you sleep? No Yes a. If yes, About how many drinks did you have?
(Please refer to the “Drink Conversion Table” on the inside back
cover) _________ drinks
a. If yes, What did you take? (write down any sleep aid below)
b. What time did you have your last drink? ___:___ am/pm
b. What time did you take this? ___:___ am/pm

10. Did you remove the sleep watch for any reason
No Yes
5. What time did you wake up for the last time this today?
___:___ am/pm
morning? a. If yes, what time?
6. This morning, what time did you get up for the
___:___ am/pm Time off ____:____ am/pm Time on: ____:____ am/pm
day?
b. Reason removed ______________________________________
Fig. 13.2 Example of information collected in sleep diary

instructed to only sleep within this window of time (i.e., between prescribed bed-
time and rise time). Patients should not go to bed earlier than their prescribed bed-
time or wake up later than their prescribed rise time, and should avoid napping
outside of their sleep window [15, 22]. It is conditionally recommended that provid-
ers implement sleep restriction as a single-component treatment for insomnia dis-
order [9].
Sleep hygiene recommendations CBT-I providers present information about day-

time and nighttime activities that can help or hinder good sleep. Patients receive
information about how factors (e.g., light exposure, alcohol/substances, medica-
tions, caffeine, food intake, and exercise) can impact wakefulness and sleepiness
[23]. The patient and provider also discuss the sleep environment and what environ-
mental factors can help or hinder sleep (e.g., temperature, noise, light, bodily dis-
comfort, bed partner, etc.). The patient and provider discuss changes the patient can
implement to improve their sleep [23]. Sleep hygiene education, as a standalone
intervention, has been shown to be less effective than multicomponent CBT-I [24];
however, sleep hygiene is conditionally recommended as a single-component treat-
ment for insomnia disorder [8].
Relaxation strategies Anxiety and hyperarousal at bedtime serve as barriers to

sleep initiation. CBT-I providers educate patients about the problematic relation-
ships among thoughts, emotions, and sleep behaviors that occur in the context of
insomnia. The goal of relaxation strategies in the context of insomnia is to reduce
hyperarousal at bedtime. Consistent with the principle of counter-conditioning, an
undesired response (i.e., arousal) is reduced as the stimulus (i.e., place of sleep) is
consistently paired with a more desired response (i.e., relaxation) [25]. Relaxation
strategies, including breathing exercises [26] and progressive muscle relaxation
[27], are often presented as part of CBT-I protocols [28]. Additionally, patients are
encouraged to implement a relaxing bedtime routine (i.e., buffer zone) each night in
an effort to (1) reduce anxious thoughts at bedtime [22] and (2) weaken the associa-
tion between hyperarousal and bedtime that may have developed due to poor sleep
habits. Relaxation therapy is conditionally recommended as a single-component
treatment for insomnia disorder [8].
Cognitive therapy techniques As a form of cognitive behavioral therapy, CBT-I

incorporates cognitive techniques to challenge unhelpful and inaccurate thoughts
that lead to problematic sleep behavior (i.e., “I have to go to bed early, and then I
will sleep more tonight”) [29]. To identify and adapt problematic thoughts related to
sleep, providers will utilize Socratic questioning [30]. Additionally, providers may
ask patients to examine their thoughts by looking at their sleep diary data (i.e., “Do
you actually sleep more if you spend more time in your bed?”) or encourage patients
to test these thoughts by engaging in a behavioral experiment. Sleep diary informa-
tion can also help to challenge inaccurate or problematic thoughts about daytime
functioning (e.g., “If I don’t get eight hours of sleep, I will not be able to function
the next day”). By providing evidence to the contrary regarding the relationship
between total sleep time and daytime functioning, data gathered during CBT-I ses-
sions can lessen anxiety about sleep difficulties and the perceived consequences of
insomnia. Additionally, cognitive techniques can be used if patients express reluc-
tance to engage in other components of CBT-I (e.g., sleep restriction). Other cogni-
tive techniques include but are not limited to (1) evaluating the evidence for or
against a thought, (2) exploring alternative explanations or interpretation, (3) and/or
presenting new information to patients [31].
Multiple meta-analyses have demonstrated the effectiveness of CBT-I at improv-
ing wake/sleep patterns among patients with insomnia, including patients with
comorbid medical and psychiatric conditions [28, 32, 33]. The intervention compo-
nents of CBT-I and their implementation are described in Table 13.1. It should be
noted that the delivery of CBT-I is individualized for each patient, with the empha-
sis and timing of each intervention component depending on the clinical presenta-
tion of each individual patient.
Individual format CBT-I interventions have been most commonly studied using a
one-on-one, in person therapy format [28, 32]. Most protocols consist of four to six,
60-minute sessions with a trained CBT-I provider. However, CBT-I has also been
delivered using telemedicine platforms, with high feasibility and acceptability
reported by patients and providers [34]. Meta-analyses have consistently found
individual-based CBT-I to be an effective treatment for insomnia symptoms [32,
33]. As previously stated, the multicomponent, individual-based form of CBT-I is
strongly recommended by the AASM Clinical Practice Guidelines for the Treatment
of Insomnia [8]. This means that under most circumstances (or when possible),
providers should refer patients to or implement individual-based CBT-I [8].
Group format Despite the efficacy of this intervention, we recognize that there
are circumstances when one-on-one CBT-I may not be readily available or acces-
sible to patients [35]. Fortunately, there is also research demonstrating the efficacy
for group-based CBT-I, though there is less evidence for group-based CBT-I com-
pared to one-on-one CBT-I [36]. This form of CBT-I involves providing psycho-
education about sleep, including the rationales for stimulus control, sleep
restriction, and the other intervention components of CBT-I to a group of patients
[37]. Each patient tracks their sleep using a sleep diary, and sleep windows are
prescribed to each patient based on individual data from patients’ respective sleep
diaries.
Telehealth Telehealth modalities have been used to deliver CBT-I in several stud-
ies and can increase access to treatment for patients with insomnia disorder who
many find it difficult to travel to in-person sessions or to navigate a self-guided
treatment without provider support. There is evidence that CBT-I can be delivered
via telehealth in both individual and group format, and it is non-inferior to in-person
delivery [38, 39]; however, there are challenges to group delivery including privacy
consideration and technological challenges.
Table 13.1 Typical intervention components of cognitive behavioral therapy for insomnia (CBT-I)
Topics covered Session activities Homework
Getting started with CBT-I (sleep education, sleep hygiene, and stimulus control)
Sleep education: sleep regulation, Discuss classical Implement action plan
insomnia (3P model), sleep stages conditioning and insomnia (sleep hygiene practices,
and macrostructure Action plan: sleep hygiene stimulus control)
Introduce stimulus control concepts changes, stimulus control Daily sleep diary
Lifestyle habits that enhance or
hinder sleep
Introduce and explain daily sleep
diary
Scheduling sleep (sleep restriction therapy)
Learn about the homeostatic and Review/discuss sleep diary Implement action plan
circadian sleep processes Action plan: daily sleep (sleep schedule)
Introduce sleep restriction schedule Daily sleep diary
Thoughts about sleep (cognitive therapy)
Adjust time in bed Review/discuss sleep diary Implement action plan
Discuss validity and utility of Action plan: revise sleep (sleep schedule, coping
unhelpful sleep-related thoughts schedule, develop coping cards)
cards Daily sleep diary
CBT-I: progress and obstacles (cognitive therapy)
Adjust time in bed Review/discuss sleep diary Implement action plan
Review progress and obstacles Addressing barriers and (sleep schedule, strategies
Use cognitive strategies to address obstacles using cognitive- to address obstacles)
barriers to adherence therapy methods Daily sleep diary
Action plan: identify
obstacles and strategies to
address them
CBT-I: sleeping well over the long-term (relapse prevention)
Adjust time in bed Review/discuss sleep diary Use tools/skills for future
Discuss relapse prevention and Action plan for relapse sleepless nights
coping prevention
Self-guided formats To increase access to CBT-I, online, self-guided protocols and

CBT-I informed apps have been developed. Evidence-based examples include the
Veteran Health Administration’s (VHA) “Path to Better Sleep” [40] and “CBT-I
Coach.” [41] Online behavioral interventions for insomnia have been shown to
improve sleep outcomes [42–44]. There is also evidence that face-to-face CBT-I is
more effective than guided online interventions [45]. That being said, CBT-I provid-
ers report using CBT-I Coach when delivering one-on-one CBT-I, and research
demonstrates that the app is viewed favorably by patients [46, 47]. It should be
noted that use of CBT-I Coach or other apps alone is not comparable to the delivery
of CBT-I by a trained provider.
Brief behavioral treatment for insomnia Given that stimulus control and sleep
restriction are the intervention components of CBT-I with the strongest evidence,
brief behavioral treatment for insomnia (BBT-I) was derived from CBT-I. BBT-I is
shorter than CBT-I [48, 49], typically involving four sessions, and focuses on help-
ing patients to make behavioral changes to improve their sleep. BBT-I provides
education about homeostatic (i.e., sleep drive) and circadian drives (i.e., biological
clock) and how waking behaviors associated with insomnia disorder can interfere
with these processes [50]. Similar education is provided in CBT-I protocols as well
[22]. Intervention components of BBT-I include (1) sleep restriction to increase
sleepiness at the prescribed bedtime, (2) stimulus control to reduce time spent
awake in bed, (3) adherence to prescribed bedtimes and rise times, (4) and elimina-
tion/reduction of bad sleep hygiene behaviors and promotion of good sleep hygiene
behaviors. BBT-I encourages patients to modify waking behaviors to normalize
homeostatic and circadian drives. BBT-I does not target sleep-related thoughts and
does not incorporate cognitive strategies [50]. While CBT-I remains the first line
treatment for insomnia disorder, a recent noninferiority clinical trial found no sig-
nificant differences between BBT-I and CBT-I on sleep-related outcomes [51]. The
AASM Clinical Practice Guidelines recommend that providers may use multicom-
ponent brief therapies for insomnia [9].
Consistent with CBT-I, patients who undergo BBT-I complete a sleep diary each
week, which guides treatment recommendations. If a patient’s sleep onset latency is
>20 minutes, it is recommended they leave their sleeping area and engage in a low-
stimulating activity until they are sleepy, at which point they are instructed to return
to bed. Generally, if a patient is taking >30 minutes to fall asleep or they are awake
>30 minutes after sleep onset, it is recommended that the patient reduce their time
in bed by 15 minutes. Alternatively, if the patient is taking <30 minutes to fall asleep
or they are awake <30 minutes after sleep onset, it is recommended that the patient
increase their time in bed by 15 minutes [22, 50]. This is known as the 30/30 rule in
BBT-I [50, 52].
Due to the high incidence and persistence of untreated insomnia [53], an impor-
tant part of both CBT-I and BBT-I is relapse prevention. Patients are encouraged to
consider the strategies they have learned in insomnia treatment and to identify a
plan for how they will intervene on their own behavior in the future should they
have trouble initiating or maintaining sleep again. A recent meta-analysis showed
the effects of CBT-I remain significant a year after therapy [54]. The focus on
relapse prevention in the termination session highlights the importance of patient
education in both CBT-I and BBT-I, ensuring that patients understand the treatment
rationales and develop a sense of agency regarding their sleep.
Novel behavioral approaches Despite the body of research demonstrating the
efficacy and effectiveness of CBT-I, challenges with treatment completion remain.
Estimates of treatment dropout in clinical settings range from 13.7% to 34.0% [55,
56]. Shorter total sleep time and greater depression symptoms at baseline predict
treatment attrition in clinical trials of CBT-I. Adherence challenges have also led
practitioners and researchers to explore adaptations of CBT-I [57]. Mindfulness and
acceptance-based approaches (so-called third-wave cognitive behavioral therapies)
are receiving growing attention. Kabat-Zinn (1994) defined mindfulness as “paying

attention in a particular way: on purpose, in the present moment, and nonjudgmentally”
(p. 4) [58]. Components of mindfulness (e.g., present moment awareness, observa-
tion, description) have been incorporated into cognitive behavioral therapies, with
the goal of noticing thoughts, rather than challenging or changing said thoughts [59].
Mindfulness-based Ong et al. (2012) proposed a model of insomnia consist with

third-wave approaches. The model suggests that sleep-related arousal is caused first
by sleep difficulties and their consequences, and then the arousal is exacerbated by
“meta-cognitive” factors, such as distress about concerns regarding the insomnia
[60]. Addressing meta-cognitive factors may improve the general effectiveness of
treatment and reduce non-adherence through increased tolerance of discomfort
[60]. Mindfulness-based therapy for insomnia (MBTI) incorporates (1) experiential
mindfulness practices (e.g., body scan, sitting meditation), (2) education about
mindfulness, and (3) behavioral strategies to improve insomnia (i.e., stimulus con-
trol, sleep restriction, and targeted sleep hygiene recommendations). Similar to
CBT-I and BBT-I, patients undergoing MBTI are asked to keep a sleep diary, but
they are also asked to keep a meditation diary [61]. MBTI has been found to be
effective at improving insomnia symptoms [62].
Acceptance-based A third-wave cognitive behavioral therapy that incorporates

mindfulness is Acceptance and Commitment Therapy (ACT) [63, 64]. CBT and
ACT have similarities and distinct differences. Both emphasize the role of cognition
in psychopathology, but each model proposes different mechanisms of change [65].
In CBT, adaptive changes in thoughts and behaviors contribute to therapeutic
change [66]. The ACT model suggests that thoughts do not directly cause problem-
atic behaviors and a decrease in dysfunctional thoughts is not a prerequisite for
therapeutic change [67]. Therapeutic change occurs by changing the relationship
one has with “dysfunctional thoughts” through contacting the present moment, and,
based on what that situation affords, acting in accordance with one’s chosen values.
This process is referred to as psychological flexibility [64].
Within the ACT framework, there are six interrelated processes which promote
psychological flexibility including (1) present moment awareness, (2) acceptance of
current experience, (3) self as context (i.e., non-identification with thoughts), (4)
cognitive defusion (i.e., creating “space” between self and thoughts), (5) values
(i.e., activities that give lives meaning), and (6) committed actions (i.e., behaviors in
service of these values) [63, 64]. While ACT has been used to treat multiple psychi-
atric conditions and improve distress among individual with multiple comorbid
medical conditions, few studies have examined insomnia as a primary outcome
variable [68]. However, there was a recent meta-analysis that examined the impact
of ACT on insomnia and sleep quality, and findings indicated that engagement in
ACT was associated with improved sleep outcomes [69]. While case studies and
developmental study findings for ACT-based insomnia treatment are promising [70,
71], additional clinical trials are needed.
Behavioral Treatment for Insomnia: Safety Considerations
The risks associated with participation in CBT-I or other behavioral treatments for
insomnia are minimal [8]. However, there are times when sleep restriction is contra-
indicated. For instance, if a patient has a history of bipolar disorder, disruptions to
the sleep schedule can trigger hypomanic/manic symptoms [72, 73]. Generally, it is
not recommended that providers prescribe a sleep window less than 5 hours [22],
even when patients are reporting total sleep time of less than 5 hours. BBT-I guide-
lines recommend a sleep window of no less than 6 hours [50]. CBT-I providers and
patients should also discuss the utility of sleep outside of the prescribed sleep win-
dow when patients are sleepy and they must engage in activities where sleep depri-
vation is dangerous (e.g., driving).
Additionally, while CBT-I has been shown to be effective at treating insomnia in
patients with comorbid sleep conditions, assessment of sleep disorders (e.g.,
obstructive sleep apnea [OSA], restless leg syndrome) [8, 74, 75] is recommended
prior to initiation of behavioral insomnia treatment. This ensures that patients
receive treatments for their other sleep disorders (e.g., continues positive airway
pressure [CPAP], medications/supplements) and optimizes the effectiveness of
behavior treatments for insomnia. Research has also shown that participation in
CBT-I increases CPAP use in patients with comorbid insomnia and OSA [76].
Finally, research has demonstrated that insomnia is a risk factor for suicidal ideation
[77, 78]. While research has shown CBT-I and attendance of sleep medicine appoint-
ments reduces depression symptoms and lowers risk of suicide [79, 80], risk assess-
ment and safety planning should be conducted prior to initiating CBT-I with patients
to ensure that patients are not a harm to themselves or others.
ehavioral Treatments for Insomnia: Considerations

B
for Special Populations
Since insomnia disorder is highly comorbid with a variety of medical and mental
health disorders [3, 81], special considerations should be made with some patients.
Providers should involve caregivers when patients with insomnia present with cog-
nitive impairment or are dependent on caregivers to complete activities of daily
living. Caregivers may also benefit from components of CBT-I to both optimize
their sleep and caregiving abilities [82]. Additionally, patients with limited mobil-
ity or pain may require modification to traditional stimulus control recommenda-
tions. Understanding the unique factors that contribute to nighttime awakenings
(e.g., pain, need to urinate, hot flashes) is critical in developing effective behavioral
treatment plans [3, 83, 84]. Patients with psychiatric comorbidities may require
greater emphasis on interventions for problematic thoughts related to sleep and
avoidance of sleep (e.g., patients with posttraumatic stress disorder [PTSD] may
avoid sleep due to fear of nightmares) [85]. Finally, for a patient to be diagnosed
with insomnia, the patient must report sleep problems, despite having the opportu-
nity to sleep [4]. This differentiation is important when assessing patients who may
not have a consistent opportunity to sleep (e.g., parents of infants) and/or patients
who do not have a consistent/safe place to sleep (i.e., individual with unstable
housing). In these circumstances, it may be best to delay initiation of behavioral
treatments for insomnia and first address barriers to consistent and safe opportuni-
ties for sleep.
Medication Treatments for Insomnia
While CBT-I is the gold standard first line treatment for insomnia disorder, pharma-
cotherapy plays a role in several clinical situations. Medications are often used for
short-term insomnia, for individuals who cannot or choose not to undergo CBT-I,
for individuals who did not respond fully to CBT-I treatment, and for individuals
who require intermittent medication in addition to CBT-I. A limited number of
medications are FDA approved for treatment of insomnia (Table 13.2), although
many other prescription medications, dietary supplements, and over-the-counter
medications with sedating properties are used off-label in clinical practice.
Importantly, off-label use of medications to treat insomnia but that are not FDA
approved is also not recommended for use in clinical practice guidelines, generally
due to the fact that the potential side effects from these medications outweigh the
potential benefits for treating insomnia disorder [86, 87].
Table 13.2 FDA medications approved for treatment of insomnia disorder in adults
Prescription medications Over-the-counter agents
Ambien (zolpidem) Benadryl (diphenhydramine)a
Belsomra (suvorexant) Unisom (doxylamine)a
Butisol (butabarbital)
Doral (quazepam)
Edluar (zolpidem)
Estazolam
Flurazepam
Halcion (triazolam)
Hetlioz (tasimelteon)
Intermezzo (zolpidem)
Lunesta (eszopiclone)
Restoril (temazepam)
Rozerem (ramelteon)
Seconal (secobarbital)
Silenor (doxepin)
Sonata (zaleplon)
Zolpimist (zolpidem)
Source: US Food and Drug Administration [104]
a
Note: agents also in many cold and headache combination products
The choice of pharmacotherapy agent should be made using a shared decision-

making approach. Factors to consider include type of insomnia (sleep onset, main-
tenance, or early awakening), consideration of the patients’ age, comorbidities
inclusive of renal and hepatic dysfunction, additional medications including poly-
pharmacy, response to prior therapy, cost and availability of medications, prior his-
tory of dependence on controlled substances, and patient and clinician preferences.
Medication alone rarely results in a full remission of insomnia disorder, and over
time increased dosage is needed to obtain the same efficacy. In addition, unlike
CBT-I, where the effects of treatment are long lasting, discontinuation of pharmaco-
therapy for insomnia results in return of the insomnia symptoms.
Several randomized controlled studies comparing pharmacotherapy vs. CBT-I
have been performed with consistent findings that behavioral therapies are superior
in treating insomnia when compared to medication and that the effects achieved
with behavioral therapy are long lasting. Morin et al. compared CBT-I with temaze-
pam for an 8-week treatment period and then a 2-year follow-up [88]. In this study,
CBT-I was superior to temazepam in improving sleep time after sleep onset imme-
diately post-treatment, and at 24 months follow-up, CBT-I gains in sleep time were
sustained while the temazepam group was similar to the placebo group. Similar
results were noted by Jacobs et al. using CBT-I compared to zolpidem when using
sleep latency as a primary outcome [89]. CBT-I resulted in more sustained benefits
than medications in both studies.
Non-Benzodiazepine receptor agonists (non-BZRAs) Non-BZRAs are com-
monly used to treat insomnia and include eszopiclone, zaleplon, and zolpidem.
Middle of the night formulations (dissolving tablets or spray) of zolpidem are avail-
able. The mechanism of action is enhancement of the neurotransmitter gamma-
aminobutyric acid (GABA) function at the GABA-A receptor within the central
nervous system (CNS). These medications are FDA approved for sleep onset and
sleep maintenance insomnia and, due to their shorter half-life (1–6 hours), are con-
sidered to have a better safety profile and less daytime impairment when compared
with benzodiazepines. They are all Schedule IV controlled substances although
appear to have less potential for abuse when compared with traditional benzodiaz-
epines. All the non-BZRAs are metabolized by CYP enzymes resulting in potential
drug interactions and in reduced recommended dosages in older patients. For mid-
dle of the night awakenings, zolpidem spray and sublingual dissolving tablets offer
a faster onset of action. Zaleplon can also be considered due to its very short half-
life (1 hour). For middle of night awakening, these medications can be used if there
is remaining 4 hours of sleep after the awakening. Zolpidem extended release has
the longest half-life and can be considered in patients where the other non-BZRAs
wane in efficacy over the course of the night. In addition to the usual central nervous
system impairment noted with all insomnia medication, the non-BZRAs carry an
FDA box warning for sleep behaviors such as sleepwalking, sleep driving, sexsom-
nia, and sleep eating among others. They should not be prescribed in patient with
preexisting parasomnias. According to a meta-analytic review, these medications
decrease sleep latency by 10–20 minutes and increase sleep time by 10–30 min-
utes [90].
Benzodiazepine receptor agonists (BZRAs) BZRAs with FDA approval for

insomnia include estazolam, flurazepam, quazepam, temazepam, and triazolam. All
are Schedule IV controlled substances and tend to be avoided for treatment of
insomnia due to their longer half-life when compared with non-BZRAs, increased
potential for dependence, and increased risk for side effects with abrupt discontinu-
ation. Benzodiazepines also function by enhancing GABA at the GABA receptor
within the CNS but have less affinity for the GABA-A receptor, and thus tend to
cause more sedation than their non-BZRA counterparts. They are metabolized by
CYP-34A, and like the non-BZRA medications, adjustments must be made for age
and polypharmacy. Due to the long half-life of these sedatives, the FDA has placed
a box warning to avoid with use of narcotics due to the concern for respiratory sup-
pression. Studies on the efficacy of BZRAs use both self-reported and polysomnog-
raphy data, and the results vary. On average this class of medication reduces sleep
latency by 10–20 minutes and increases nighttime sleep by 30–60 minutes [90].
Melatonin receptor agonists Ramelteon is a MT1 and MT2 melatonin receptor

agonist which is FDA approved for the treatment of sleep onset insomnia. Ramelteon
is cleared by CYP1A2 and CYP2C9 and should be avoided in individuals with
severe liver disease and those on medications inhibiting these enzymes (i.e., fluvox-
amine). Effect size of ramelteon is small, but a meta-analysis showed a reduction in
sleep latency of approximately 5 minutes and increase in overall sleep time of
7 minutes [91].
Orexin receptor antagonists Lemborexant and suvorexant are dual orexin recep-
tor antagonists (DORAs) which function at the OX1R and OX2R receptors. Both
are FDA approved for sleep onset and sleep maintenance insomnia. The orexin/
hypocretin system initiates at the hypothalamus and communicates with multiple
wake-promoting regions of the brain responsible for secreting acetylcholine, dopa-
mine, histamine, norepinephrine, and serotonin. As with other insomnia medica-
tions, DORAs cause somnolence. This class should specifically be avoided in
individuals with narcolepsy and individuals on medications which inhibit CYP3A
and those with hepatic impairment. Both medications improve sleep onset latency
and increase sleep time [92].
Antidepressants Trazadone is one of the most commonly prescribed antidepres-

sants for insomnia, and it improves some sleep parameters over the short-term [93].
Its mechanism of action is via antagonism of 5-HT2A, 5-HT2B, alpha-1A, and 2C
receptors, agonism of 5-HT1, and inhibition of serotonin reuptake. The AASM
clinical practice guidelines recommend against use of trazadone for insomnia as
there is minimal data regarding its efficacy and a very small size effect which was
not sustained over time noted in the one randomized trial available for inclusion in
the guidelines [87]. There are many potential side effects of trazadone including QT
prolongation, orthostatic hypotension, priapism, increased suicidal ideation, mania
and hypomania, closed-angle glaucoma, and serotonin syndrome, among others.
Due to the potential side effects at higher doses, it is not recommended to increase
doses over 150 mg nightly for the treatment of insomnia. Trazadone also has a long
half-life (10–12 hours) leading to the risk of increased daytime sleepiness in
patients [94].
Low-dose doxepin (3 or 6 mg tablets) is FDA approved for the treatment of sleep
maintenance insomnia. Doxepin is a tricyclic antidepressant with primarily antihis-
tamine antagonist (H1 receptor) features at a low dose. As with all other tricyclic
antidepressants, MAOI inhibitors need to be avoided, and it should not be used in
patients with urinary retention or those with untreated closed-angle glaucoma. Due
to the cost of the low-dose tablets, providers may sometimes prescribe the liquid
formulation or the 10 mg tablets, which are significantly lower priced in the
USA. On average doxepin increases sleep time by 25–40 minutes.
Antipsychotics Quetiapine is a commonly prescribed anti-psychotic medication
for insomnia although there is minimal data on its effect on sleep in patients without
psychiatric disease, and it poses significant side effect risks [87]. Its mechanism of
action is not wholly understood but is known to be a D2 and 5-HT2 antagonist, and
it is metabolized by CYP3A4. It has a high side effect profile including orthostatic
hypotension, dizziness, suicidality in younger patients, and extrapyramidal symp-
toms, among others. Due to its high side effect profile and the paucity of data on
sleep, it is not recommended for the treatment of insomnia, especially in individuals
without mood disorders or schizophrenia [95].
Nutritional Supplements
Several dietary supplements are marketed for insomnia. Dietary supplements are
not FDA regulated, resulting in variability of concentration and purity of active
ingredients [96]. Although there is scant evidence for the efficacy of supplements
for the treatment of insomnia, overall, the risk for adverse effects is low. Hepatic
failure, however, has been reported with valerian root and kava root.
Melatonin Melatonin is a commonly used dietary supplement for the treatment of
insomnia. It is a melatonin receptor agonist acting at the suprachiasmatic nucleus,
among other areas. As with endogenous melatonin, exogenous melatonin assists
with sleep onset by reducing arousal caused by the suprachiasmatic nucleus. It is
typically dosed between 1 and 5 mg for insomnia. Studies of efficacy of melatonin
for the treatment of insomnia show a minimal effect on sleep onset and total sleep
time, which may not be clinically meaningful [97]. Potential side effects include
headache, nightmares, dizziness, and daytime sleepiness. Exogenous melatonin is

not recommended for use by AASM clinical practice guidelines due to the lack of
efficacy data [87].
Medication Treatments for Insomnia: Safety Considerations
All medications for treatment of insomnia can result in depression of the central
nervous system and motor impairment leading to increased risk of falls, motor vehi-
cle accidents, and occupational accidents. This is confounded in individuals with
polypharmacy inclusive of other sedating medications, individuals with cognitive
impairment, individuals with obstructive sleep apnea, and in those who drink alco-
hol. The benzodiazepines can also suppress respiratory drive. This is enhanced by
addition of opiates and other sedating medications leading to a potential deadly
combination.
Special consideration in the pharmacologic treatment of insomnia needs to occur
in individuals where side effects are particularly problematic or may increase risk
for adverse outcomes. This includes:
• Advanced age
• Cognitive impairment
• Fall risk
• Obstructive sleep apnea or hypoventilation
• Hepatic and renal impairment
• Concomitant medications which induce or inhibit CYP P450 3
• Polypharmacy inclusive of opiates or other sedating medications
• History of dependence on controlled or illicit substances
• History of significant depression, especially in those with active or historical
suicidal ideation or attempts
• Abnormal sleep behaviors
There is also extensive epidemiological data indicating increased mortality with
hypnotic use. Kripke et al. [98] reviewed 10,529 patients who received hypnotic
prescriptions in the USA (mean age 54) and 23,676 matched controls between 2002
and 2007. After controlling for other co-factors associated with increased mortality
the group prescribed hypnotics had a mortality hazard ratio (HR) from 3.6 to 5.32
compared to controls, with increasing HR in individuals with higher number of
prescriptions for hypnotics. Similar findings were reported in a later study by Linnet
et al. in multi-morbid and non-multi-morbid patients with increasing mortality
noted in individuals with high numbers of hypnotic prescriptions [99]. Although the
specific cause of death is not delineated in these cohort studies, there is ample evi-
dence to suggest increased mortality with increasing number of prescriptions for
hypnotics.

Insomnia is highly prevalent with the population [100]. CBT-I is the first line
treatment for insomnia disorder, and a large body of research shows that
CBT-I is highly effective for the treatment of insomnia in patients with mul-
tiple medical and psychiatric comorbidities [8, 32]. The strongest research is
for the delivery of CBT-I in an individual treatment format, but there is also
research demonstrating the helpfulness of group-based CBT-I, self-guided
CBT-I, and apps as a supplement to traditional CBT-I treatment [45, 47].
There is also research support for BBT-I and mindfulness-based intervention
for insomnia [51, 62]. The risks associated with behavioral treatments for
insomnia are minimal, though there are circumstances in which some inter-
vention components (e.g., sleep restriction) may be contraindicated [72, 73].
It is important to thoroughly assess daytime activities, comorbid sleep disor-
ders, medical conditions, and mental health conditions, as well as potential
safety concerns prior to initiating behavioral treatments with patients endors-
ing insomnia symptoms. CBT-I has been shown to be superior for the treat-
ment of insomnia when compared with pharmacologic treatment in terms of
immediate effect on sleep and longevity of treatment. Ideally, pharmacother-
apy should not be used without a behavioral component to address factors that
contribute to insomnia maintenance over time; however, pharmacotherapy
can be used in specific situations with emphasis on a time-limited treatment
plan and monitoring of side effects.
Patient preferences are important considerations when providers collabo-
rate with patients to develop a treatment plan. The shared decision-making
model of clinical practice involves presenting evidence-based treatment
options to the patient [101]. In the case of insomnia, this would involve edu-
cating patient about the strong recommendation for the use of CBT-I to treat
insomnia disorder and conditional recommendations for behavioral compo-
nents of CBT-I to treat insomnia disorder. Providers should also describe the
risks associated with CBT-I relative to medication treatments for insomnia
and the impact of CBT-I and/or medications on any comorbid conditions (e.g.,
sleep apnea) and their corresponding treatments (e.g., CPAP). This informa-
tion will allow patients to make informed choices about their treatment. While
each patient is unique, research suggests that patients prefer non-medication
treatment for insomnia over medication treatment [102]. Additionally, when
patients with comorbid insomnia, depression, and PTSD are presented with
evidence-based treatments for each condition, a study found that patients
report preference for CBT-I [103]. Figure 13.1 includes a decision-making
framework for providers to follow after they have educated patients about
evidence-based treatments for insomnia. Through a collaborative and trans-
parent process, providers can connect patients with insomnia symptoms to the
most effective interventions available.
References
1. Buysse DJ, Angst J, Gamma A, Ajdacic V, Eich D, Rössler W. Prevalence, course, and comor-
bidity of insomnia and depression in young adults. Sleep. 2008;31(4):473–80.
2. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evalua-
tion and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504.
3. Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of
chronic insomnia with medical problems. Sleep. 2007;30(2):213–8.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders
(DSM-5®). Arlington: American Psychiatric Pub; 2013.
5. American Academy of Sleep Medicine. International classification of sleep disorders,
Diagnostic and coding manual. Darien: American Academy of Sleep Medicine; 2005.
p. 51–5.
6. Medic G, Wille M, Hemels ME. Short-and long-term health consequences of sleep disrup-
tion. Nat Sci Sleep. 2017;9:151.
7. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic
insomnia disorder in adults: a clinical practice guideline from the American College of
Physicians. Ann Intern Med. 2016;165(2):125–33.
8. Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for
chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical prac-
tice guideline. J Clin Sleep Med. 2021;17(2):255–62.
9. Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for
chronic insomnia disorder in adults: an American Academy of Sleep Medicine systematic
review, meta-analysis and GRADE assessment. J Clin Sleep Med. 2020;0(0):jcsm.8988.
Psychiatr Clin. 1987;10(4):541–53.
11. Carlson GC, Kelly MR, Grinberg AM, Mitchell MN, McGowan S, Culver NC, Kay M, Alessi
CA, Washington DL, Yano EM, Martin JL. Insomnia precipitating events among Women
Veterans: the impact of traumatic and nontraumatic events on sleep and mental health symp-
toms. Behav Sleep Med. 2020;19(5):672–88.
12. Singareddy R, Vgontzas AN, Fernandez-Mendoza J, et al. Risk factors for incident chronic
insomnia: a general population prospective study. Sleep Med. 2012;13(4):346–53.
13. Levenson JC, Benca RM, Rumble ME. Sleep related cognitions in individuals with symp-
toms of insomnia and depression. J Clin Sleep Med. 2015;11(8):847–54.
14. Morgenthaler T, Kramer M, Alessi C, et al. Amer ican academy of sleep medicine. Practice
parameters for the psychological and behavioral treatment of insomnia: an update. An ameri-
can academy of sleep medicine report. Sleep. 2006;29(11):1415.
15. Miller CB, Espie CA, Epstein DR, et al. The evidence base of sleep restriction therapy for
treating insomnia disorder. Sleep Med Rev. 2014;18(5):415–24.
16. Embry DD, Biglan A. Evidence-based kernels: fundamental units of behavioral influence.
Clin Child Fam Psychol Rev. 2008;11(3):75–113.
17. Bootzin RR, Epstein D, Wood JM. Stimulus control instructions. In: Case studies in insom-
nia. Boston: Springer; 1991. p. 19–28.
18. Bootzin RR. Stimulus control treatment for insomnia. Proc Am Psychol Assoc. 1972;7:395–6.
19. Sharma MP, Andrade C. Behavioral interventions for insomnia: theory and practice. Indian J
Psychiatry. 2012;54(4):359.
20. Cohen JS, Edmunds JM, Brodman DM, Benjamin CL, Kendall PC. Using self-monitoring:
implementation of collaborative empiricism in cognitive-behavioral therapy. Cogn Behav
Pract. 2013;20(4):419–28.
21. Spielman AJ, Saskin P, Thorpy MJ. Treatment of chronic insomnia by restriction of time in
bed. Sleep. 1987;10(1):45–56.
22. Manber R. Cognitive behavioral therapy for insomnia guide to overcoming your insomnia.
In: Affairs USDoV, ed. Washington, D.C. 2010.
23. Stepanski EJ, Wyatt JK. Use of sleep hygiene in the treatment of insomnia. Sleep Med Rev.
2003;7(3):215–25.
24. Chung K-F, Lee C-T, Yeung W-F, Chan M-S, Chung EW-Y, Lin W-L. Sleep hygiene edu-
cation as a treatment of insomnia: a systematic review and meta-analysis. Fam Pract.
2018;35(4):365–75.
25. Davison GC. Systematic desensitization as a counterconditioning process. J Abnorm Psychol.
1968;73(2):91.
26. Tsai H, Kuo TB, Lee GS, Yang CC. Efficacy of paced breathing for insomnia: enhances vagal
activity and improves sleep quality. Psychophysiology. 2015;52(3):388–96.
27. Alexandru BV, Róbert B, Viorel L, Vasile B. Treating primary insomnia: a comparative
study of self-help methods and progressive muscle relaxation. J Evid Based Psychother.
2009;9(1):67.
28. Taylor DJ, Pruiksma KE. Cognitive and behavioural therapy for insomnia (CBT-I) in psychi-
atric populations: a systematic review. Int Rev Psychiatry. 2014;26(2):205–13.
29. Beck AT. Cognitive therapy: past, present, and future. J Consult Clin Psychol. 1993;61(2):194.
30. Carey TA, Mullan RJ. What is Socratic questioning? Psychoth: Theory Res Pract Train.
2004;41(3):217.
31. Beck AT, Haigh EA. Advances in cognitive theory and therapy: the generic cognitive model.
Annu Rev Clin Psychol. 2014;10:1–24.
32. Wu JQ, Appleman ER, Salazar RD, Ong JC. Cognitive behavioral therapy for insomnia
comorbid with psychiatric and medical conditions: a meta-analysis. JAMA Intern Med.
2015;175(9):1461–72.
33. Okajima I, Komada Y, Inoue Y. A meta-analysis on the treatment effectiveness of cognitive
behavioral therapy for primary insomnia. Sleep Biol Rhythms. 2011;9(1):24–34.
34. Gehrman P, Shah MT, Miles A, Kuna S, Godleski L. Feasibility of group cognitive-
behavioral treatment of insomnia delivered by clinical video telehealth. Telemed e-Health.
2016;22(12):1041–6.
35. Koffel E, Bramoweth AD, Ulmer CS. Increasing access to and utilization of cognitive behav-
ioral therapy for insomnia (CBT-I): a narrative review. J Gen Intern Med. 2018;33(6):955–62.
36. Koffel EA, Koffel JB, Gehrman PR. A meta-analysis of group cognitive behavioral therapy
for insomnia. Sleep Med Rev. 2015;19:6–16.
37. Espie CA, MacMahon KM, Kelly H-L, et al. Randomized clinical effectiveness trial of nurse-
administered small-group cognitive behavior therapy for persistent insomnia in general prac-
tice. Sleep. 2007;30(5):574–84.
38. Gehrman P, Gunter P, Findley J, et al. Randomized noninferiority trial of telehealth delivery
of cognitive behavioral treatment of insomnia compared to in-person care. J Clin Psychiatry.
2021;82(5):20m13723.
39. Arnedt JT, Conroy DA, Mooney A, Furgal A, Sen A, Eisenberg D. Telemedicine versus face-
to-face delivery of cognitive behavioral therapy for insomnia: a randomized controlled non-
inferiority trial. Sleep. 2021;44(1):zsaa136.
40. Ulmer C, Bosworth H, Voils C, et al. 0403 Tele-self CBTI: provider supported self-
management cognitive behavioral therapy for insomnia. Sleep. 2018;41:A153.
41. Kuhn E, Weiss BJ, Taylor KL, et al. CBT-I coach: a description and clinician percep-
tions of a mobile app for cognitive behavioral therapy for insomnia. J Clin Sleep Med.
2016;12(4):597–606.
42. Batterham PJ, Christensen H, Mackinnon AJ, et al. Trajectories of change and long-term
outcomes in a randomised controlled trial of internet-based insomnia treatment to prevent
depression. BJPsych Open. 2017;3(5):228–35.
43. Espie CA, Kyle SD, Williams C, et al. A randomized, placebo-controlled trial of online cog-
nitive behavioral therapy for chronic insomnia disorder delivered via an automated media-
rich web application. Sleep. 2012;35(6):769–81.
44. Ritterband LM, Thorndike FP, Ingersoll KS, et al. Effect of a web-based cognitive behavior
therapy for insomnia intervention with 1-year follow-up: a randomized clinical trial. JAMA
Psychiat. 2017;74(1):68–75.
45. Lancee J, van Straten A, Morina N, Kaldo V, Kamphuis JH. Guided online or face-to-face
cognitive behavioral treatment for insomnia: a randomized wait-list controlled trial. Sleep.
2016;39(1):183–91.
46. Miller KE, Kuhn E, Owen JE, et al. Clinician perceptions related to the use of the CBT-I
coach mobile app. Behav Sleep Med. 2019;17(4):481–91.
47. Koffel E, Kuhn E, Petsoulis N, et al. A randomized controlled pilot study of CBT-I Coach:
feasibility, acceptability, and potential impact of a mobile phone application for patients in
cognitive behavioral therapy for insomnia. Health Informatics J. 2018;24(1):3–13.
48. Germain A, Moul DE, Franzen PL, et al. Effects of a brief behavioral treatment for late-life
insomnia: preliminary findings. J Clin Sleep Med. 2006;2(04):407–8.
49. Buysse DJ, Germain A, Moul DE, et al. Efficacy of brief behavioral treatment for chronic
insomnia in older adults. Arch Intern Med. 2011;171(10):887–95.
50. Troxel WM, Germain A, Buysse DJ. Clinical management of insomnia with brief behavioral
treatment (BBTI). Behav Sleep Med. 2012;10(4):266–79.
51. Bramoweth AD, Lederer LG, Youk AO, Germain A, Chinman MJ. Brief behavioral treatment
for insomnia vs. cognitive behavioral therapy for insomnia: results of a randomized noninfe-
riority clinical trial among veterans. Behav Ther. 2020;51(4):535–47.
52. Lichstein K, Durrence H, Taylor D, Bush A, Riedel B. Quantitative criteria for insomnia.
Behav Res Ther. 2003;41(4):427–45.
53. Morin CM, Jarrin DC, Ivers H, Mérette C, LeBlanc M, Savard J. Incidence, persistence, and
remission rates of insomnia over 5 years. JAMA Netw Open. 2020;3(11):–e2018782.
54. van der Zweerde T, Bisdounis L, Kyle SD, Lancee J, van Straten A. Cognitive behavioral
therapy for insomnia: a meta-analysis of long-term effects in controlled studies. Sleep Med
Rev. 2019;48:101208.
55. Espie CA, Inglis SJ, Tessier S, Harvey L. The clinical effectiveness of cognitive behaviour
therapy for chronic insomnia: implementation and evaluation of a sleep clinic in general
medical practice. Behav Res Ther. 2001;39(1):45–60.
56. Morgan K, Thompson J, Dixon S, Tomeny M, Mathers N. Predicting longer-term outcomes
following psychological treatment for hypnotic-dependent chronic insomnia. J Psychosom
Res. 2003;54(1):21–9.
57. Matthews EE, Arnedt JT, McCarthy MS, Cuddihy LJ, Aloia MS. Adherence to cognitive
behavioral therapy for insomnia: a systematic review. Sleep Med Rev. 2013;17(6):453–64.
58. Kabat-Zinn J. Wherever you go, there you are: mindfulness meditation in everyday life.
Hachette Books; 2009.
59. Keng S-L, Smoski MJ, Robins CJ. Effects of mindfulness on psychological health: a review
of empirical studies. Clin Psychol Rev. 2011;31(6):1041–56.
60. Ong JC, Ulmer CS, Manber R. Improving sleep with mindfulness and acceptance: a metacog-
nitive model of insomnia. Behav Res Ther. 2012;50(11):651–60.
61. Ong JC, Shapiro SL, Manber R. Combining mindfulness meditation with cognitive-behavior
therapy for insomnia: a treatment-development study. Behav Ther. 2008;39(2):171–82.
62. Ong JC, Manber R, Segal Z, Xia Y, Shapiro S, Wyatt JK. A randomized controlled trial of
mindfulness meditation for chronic insomnia. Sleep. 2014;37(9):1553–63.
63. Hayes SC, Strosahl KD, Bunting K, Twohig M, Wilson KG. What is acceptance and com-
mitment therapy? In: A practical guide to acceptance and commitment therapy. New York:
Springer; 2004. p. 3–29.
64. Hayes SC, Luoma JB, Bond FW, Masuda A, Lillis J. Acceptance and commitment therapy:
model, processes and outcomes. Behav Res Ther. 2006;44(1):1–25.
65. Jiménez FJR. Acceptance and commitment therapy versus traditional cognitive behavioral
therapy: a systematic review and meta-analysis of current empirical evidence. Int J Psychol
Psychol Ther. 2012;12(3):333–58.
66. David D, Cristea I, Hofmann SG. Why cognitive behavioral therapy is the current gold stan-
dard of psychotherapy. Front Psych. 2018;9:4.
67. Ruiz FJ. A review of Acceptance and Commitment Therapy (ACT) empirical evidence: cor-
relational, experimental psychopathology, component and outcome studies. Int J Psychol
Psychol Ther. 2010;10(1):125–62.
68. A-tjak JG, Davis ML, Morina N, Powers MB, Smits JA, Emmelkamp PM. A meta-analysis of
the efficacy of acceptance and commitment therapy for clinically relevant mental and physi-
cal health problems. Psychother Psychosom. 2015;84(1):30–6.
69. Salari N, Khazaie H, Hosseinian-Far A, et al. The effect of acceptance and commitment
therapy on insomnia and sleep quality: a systematic review. BMC Neurol. 2020;20(1):1–18.
70. Fiorentino L, Martin JL, Alessi CA. The ABCs of insomnia (ABC-I): an acceptance commit-
ment therapy (ACT)-based insomnia treatment development study: pilot results and future
directions. In: Sleep medicine and mental health. Cham: Springer; 2020. p. 85–100.
71. Dalrymple KL, Fiorentino L, Politi MC, Posner D. Incorporating principles from acceptance
and commitment therapy into cognitive-behavioral therapy for insomnia: a case example. J
Contemp Psychother. 2010;40(4):209–17.
72. Barbini B, Bertelli S, Colombo C, Smeraldi E. Sleep loss, a possible factor in augmenting
manic episode. Psychiatry Res. 1996;65(2):121–5.
73. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony,
and regulation. Am J Psychiatr. 2008;165(7):820–9.
74. Sweetman A, Lack L, Lambert S, Gradisar M, Harris J. Does comorbid obstructive sleep
apnea impair the effectiveness of cognitive and behavioral therapy for insomnia? Sleep Med.
2017;39:38–46.
75. Einollahi B, Izadianmehr N. Restless leg syndrome: a neglected diagnosis. Nephro-urology
Monthly. 2014;6(5):e22009.
76. Sweetman A, Lack L, Catcheside PG, et al. Cognitive and behavioral therapy for insomnia
increases the use of continuous positive airway pressure therapy in obstructive sleep apnea
participants with comorbid insomnia: a randomized clinical trial. Sleep. 2019;42(12):zsz178.
77. Woznica AA, Carney CE, Kuo JR, Moss TG. The insomnia and suicide link: toward an
enhanced understanding of this relationship. Sleep Med Rev. 2015;22:37–46.
78. Pigeon WR, Pinquart M, Conner K. Meta-analysis of sleep disturbance and suicidal thoughts
and behaviors. J Clin Psychiatry. 2012;73(9):0.
79. Bishop TM, Walsh PG, Ashrafioun L, Lavigne JE, Pigeon WR. Sleep, suicide behaviors, and
the protective role of sleep medicine. Sleep Med. 2020;66:264–70.
80. Trockel M, Karlin BE, Taylor CB, Brown GK, Manber R. Effects of cognitive behavioral
therapy for insomnia on suicidal ideation in veterans. Sleep. 2015;38(2):259–65.
81. Khurshid KA. Comorbid insomnia and psychiatric disorders: an update. Innov Clin Neurosci.
2018;15(3–4):28.
82. McCurry SM, Song Y, Martin JL. Sleep in caregivers: what we know and what we need to
learn. Curr Opin Psychiatry. 2015;28(6):497–503.
83. Husak AJ, Bair MJ. Chronic pain and sleep disturbances: a pragmatic review of their relation-
ships, comorbidities, and treatments. Pain Med. 2020;21(6):1142–52.
84. Guthrie KA, Larson JC, Ensrud KE, et al. Effects of pharmacologic and nonpharmacologic
interventions on insomnia symptoms and self-reported sleep quality in women with hot
flashes: a pooled analysis of individual participant data from four MsFLASH trials. Sleep.
2018;41(1):zsx190.
85. Miller KE, Brownlow JA, Gehrman PR. Sleep in PTSD: treatment approaches and outcomes.
Curr Opin Psychol. 2020;34:12–7.
86. Mysliwiec V, Martin JL, Ulmer CS, et al. The management of chronic insomnia dis-
order and obstructive sleep apnea: synopsis of the 2019 U.S. Department of Veterans
Affairs and U.S. Department of Defense Clinical Practice Guidelines. Ann Intern Med.
2020;172(5):325–36.
87. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for
the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep
Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(2):307–49.
88. Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies
for late life insomnia: a randomized controlled trial. JAMA. 1999;281(11):991–9.
89. Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW. Cognitive behavioral therapy and phar-
macotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern
Med. 2004;164(17):1888–96.
90. Buscemi N, Vandermeer B, Friesen C, et al. The efficacy and safety of drug treatments for
chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med. 2007;22:1335–50.
91. Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of insomnia in adults: a
systematic review and meta-analysis. Sleep Med. 2014;15(4):385–92.
92. Kishi T, Nomura I, Matsuda Y, et al. Lemborexant vs suvorexant for insomnia: a systematic
review and network meta-analysis. J Psychiatr Res. 2020;128:68–74.
93. Yi XY, Ni SF, Ghadami MR, et al. Trazodone for the treatment of insomnia: a meta-analysis
of randomized placebo-controlled trials. Sleep Med. 2018;45:25–32.
94. Rojas-Fernandez CH, Chen Y. Use of ultra-low-dose (≤6 mg) doxepin for treatment of
insomnia in older people. Can Pharm J (Ott). 2014;147(5):281–9.
95. Anderson SL, Vande Griend JP. Quetiapine for insomnia: a review of the literature. Am J
Health Syst Pharm. 2014;71(5):394–402.
96. Leach MJ, Page AT. Herbal medicine for insomnia: a systematic review and meta-analysis.
Sleep Med Rev. 2015;24:1–12.
97. Low TL, Choo FN, Tan SM. The efficacy of melatonin and melatonin agonists in insomnia –
an umbrella review. J Psychiatr Res. 2020;121:10–23.
98. Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched
cohort study. BMJ Open. 2012;2(1):e000850.
99. Linnet K, Sigurdsson JA, Tomasdottir MO, Sigurdsson EL, Gudmundsson LS. Association
between prescription of hypnotics/anxiolytics and mortality in multimorbid and
non-multimorbid patients: a longitudinal cohort study in primary care. BMJ Open.
2019;9(12):e033545.
100. Calhoun SL, Fernandez-Mendoza J, Vgontzas AN, Liao D, Bixler EO. Prevalence of insom-
nia symptoms in a general population sample of young children and preadolescents: gender
effects. Sleep Med. 2014;15(1):91–5.
101. Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model for clinical practice.
J Gen Intern Med. 2012;27(10):1361–7.
102. Culver NC, Song Y, McGowan SK, et al. Acceptability of medication and nonmedication
treatment for insomnia among female veterans: effects of age, insomnia severity, and psychi-
atric symptoms. Clin Ther. 2016;38(11):2373–85.
103. Gutner CA, Pedersen ER, Drummond SP. Going direct to the consumer: examining treat-
ment preferences for veterans with insomnia, PTSD, and depression. Psychiatry Res.
2018;263:108–14.
104. United States Food and Drug Administration. Sleep Disorder (Sedative-Hypnotic) Drug
Information (https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-
providers/sleep-disorder-sedative-hypnotic-druginformation). https://www.fda.gov/drugs/
postmarket-drug-safety-information-patients-and-providers/sleep-disorder-sedativehyp-
notic-drug-information. Published 2019. Updated 4/30/2019. Accessed 9/8/2021.
Chapter 14
Circadian Rhythm Sleep-Wake Disorders
Mia Y. Bothwell and Sabra M. Abbott
Keywords Circadian · Light · Melatonin · Sleep · Delayed sleep-wake phase ·

Advanced sleep-wake phase · Non-24 · Irregular · Shift work · Jet lag
Introduction
All life forms have intrinsic daily rhythms in cellular activity, physiology, and
behavior. These self-sustained biological rhythms are near-24-hour oscillations that
allow organisms to coordinate their internal processes to anticipate the environment
so that physiological functions occur at the appropriate times. Misalignment of the
internal circadian clock with the external 24-hour day-night cycle and/or social
behavior can lead to sleep disturbances, daytime impairments, mood disturbances,
and increase the risk for chronic disease [1–3].
Circadian properties are determined by both genetic and environmental influ-
ences. On a molecular level, circadian rhythms are generated by a transcriptional-
translational feedback loop of clock genes and proteins. At its core, the molecular
clock consists of a heterodimeric complex of proteins of the genes CLOCK and
BMAL1, which positively regulate the expression of Period (PER 1,2,3) and
Cryptochrome (CRY 1, 2) genes which, in turn, form their own transcription repres-
sor complex to inhibit the activity of CLOCK and BMAL1. This feedback loop is
further regulated by kinases like casein kinase 1 (CK1) which contribute to time-
keeping through the destabilization of PER proteins [4]. The cycle takes
M. Y. Bothwell
University of Illinois at Urbana-Champaign Medical Scholars Program, Champaign, IL, USA
S. M. Abbott (*)
Northwestern University Feinberg School of Medicine, Department of Neurology,
Chicago, IL, USA
e-mail: sabra.abbott@northwestern.edu

298 M. Y. Bothwell and S. M. Abbott
approximately 24 hours to complete, and disruptions to this molecular system can

alter the period and amplitude of circadian rhythms.
On an organismal level, the mammalian circadian system is organized hierarchi-
cally. The suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock
that not only organizes and synchronizes peripheral clocks to other tissues but also
to the 24-hour external environment [5–7]. If humans are isolated from all environ-
mental time cues, their intrinsic circadian rhythms will “free run” with a period
slightly longer than 24 hours. In sighted people, the average circadian period is
24.18 hours [8]. Thus, synchronization of the endogenous circadian system to the
24-hour day requires frequent adjustments in response to time cues (zeitgebers) in a
process known as entrainment. Light is the most powerful zeitgeber, but a number
of external stimuli such as food availability, exercise, social activity, and internal
stimuli such as melatonin secretion can also influence this process [9].
Photic information is conveyed from the eyes by melanopsin-expressing intrinsi-
cally photosensitive retinal ganglion cells (ipRGCs) that send projections to the
SCN via the retinohypothalamic tract [10, 11]. The timing of light exposure is an
important aspect of the entrainment process, producing shifts of the circadian
rhythm, as demonstrated by the phase response curve (Fig. 14.1). Light exposure in
the first half of the night before the nadir of core body temperature will delay circa-
dian timing. Light exposure in the latter half/early morning will advance circadian
timing [12]. The magnitude of phase shifting in response to light depends on the
time of exposure, intensity, and wavelength as ipRGCs are most sensitive to short-
wavelength light [10]. Although light is the strongest signal, non-photic cues can
also regulate circadian rhythm timing. Melatonin is a hormone secreted by the
pineal gland and regulated by the SCN to be released in a circadian pattern, with
endogenous levels rising at night and declining before morning [13]. Opposite of
the light exposure phase response curve, administration of exogenous melatonin at
night will advance the circadian rhythm, and melatonin given in the early morning
will delay the rhythm [14].
Fig. 14.1 Phase-response

Advances
curve to light and

melatonin. Circadian time 2 Light
Phase Shift (hours)
0 = time of temperature
nadir. (Reprinted with Melatonin
permission from Essentials
of Sleep Medicine (first 0
edition))
Delays
–2
–12 –8 –4 0 4 8 12
Circadian Time
14 Circadian Rhythm Sleep-Wake Disorders 299
One of the many patterns generated by the circadian system is a rhythm in sleep/
wake timing. The current understanding of sleep timing and regulation lies within
the two-process model of continuous interaction between circadian rhythmicity
(Process C) and sleep homeostasis (Process S) proposed more than three decades
ago [15, 16]. Process S represents the homeostatic sleep drive and accumulates dur-
ing wakefulness and declines during sleep. Process C is the endogenous biological
rhythm oscillating between day and night in response to external time cues to
oppose and balance the homeostatic drive to facilitate wakefulness during the day
and continuous sleep during the night [17].
Circadian rhythm sleep-wake disorders (CRSWDs) arise from disruption of the
circadian system or mismatch between the external sleep/wake schedule and the
intrinsic circadian rhythm. This chapter focuses on the diagnosis and treatment of
CRSWDs as well as providing a general overview of each disorder. The International
Classification of Sleep Disorders (ICSD-3) describes six CRSWD subtypes: delayed
sleep-wake phase disorder (DSWPD), advanced sleep-wake phase disorder
(ASWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), irregular sleep-
wake rhythm disorder (ISWRD), shift work disorder, and jet lag disorder. DSWPD,
ASWPD, N24SWD, and ISWRD are considered intrinsic circadian disorders,
resulting from physiologic circadian disruption or misalignment. Shift work and jet
lag disorders are considered extrinsic circadian disorders because they result from
misalignment secondary to externally imposed schedules. Per ICSD-3 diagnostic
criteria, CRSWDs must meet the following three requirements: A) Sleep complaint
is chronic and primarily due to misalignment between endogenous circadian
rhythm, sleep-wake schedule, and/or social schedule. B) Circadian rhythm disrup-
tion leads to symptoms of insomnia, excessive sleepiness, or both. C) Symptoms
cause clinically significant distress or impairment in functioning [18]. Each CRSWD
has an additional set of specific diagnostic criteria that must be met. Assessment of
sleep-wake patterns and endogenous circadian timing is important for the accurate
diagnosis and treatment of CRSWDs. Sleep logs and actigraphy are essential tools
for diagnosis, and measurement of circadian phase markers such as melatonin
rhythms can provide additional useful information for diagnosis and treatment.
Effective treatment often requires a multimodal and individualized approach of stra-
tegically timed light exposure and/or melatonin as well as behavioral modification
aimed to adjust circadian misalignment.
Delayed Sleep-Wake Phase Disorder
Delayed Sleep-Wake Phase Disorder (DSWPD) is the most commonly diagnosed

CRSWD and can be challenging to differentiate from sleep-onset insomnia. It was
first described in 1981 by Weitzman et al. and is characterized by sleep-wake timing
that is significantly delayed compared to a conventional schedule [19]. These indi-
viduals have circadian rhythms that are entrained to 24 hours but are out of phase
with the environment. Symptoms manifest as difficulty initiating sleep with delayed
sleep onset and excessive daytime sleepiness. It typically presents in adolescence

and persists into adulthood [18].
Prevalence
The prevalence of DSWPD has not been well-documented and is estimated between
0.1 and 9% depending on the population sampled and diagnostic criteria used. An
early Norwegian study among adults aged 18–67 calculated a prevalence of 0.17%
[20]. A study of New Zealand adults aged 20–59 estimated prevalence between
1.51% and 8.90% depending on the definition used [21]. The prevalence of delayed
sleep phase is estimated to be between 3.3% and 8.4% in the adolescent population
[22, 23]. DSWPD is extremely rare in older adults as circadian timing advances
with age [24]. Approximately 10% of patients presenting with insomnia have
DSWPD, and a detailed sleep history is important to differentiate the two [18].
Pathophysiology
The etiology of DSWPD is unclear, and the pathophysiology may be multifactorial

and include biological, psychological, behavioral, and genetic elements. Several
possible mechanisms include differences in properties of the circadian oscillator,
altered homeostatic regulation of sleep, increased sensitivity to light, and genetics.
Intrinsic circadian timing plays an important role in sleep-timing preference
[25]. A prolonged circadian period (tau) has been found in those with evening pref-
erence, indicating a longer amount of time to complete the circadian cycle which
can contribute to a delay in circadian phase [25–27]. Multiple studies have found
delays in circadian timing in patients with DSWPD compared to normal sleepers as
evidenced by delays in physiologic markers of circadian phase such as body tem-
perature and melatonin rhythms [28–31]. In addition to circadian dysfunction, there
may be a difference in homeostatic sleep mechanisms in these patients. Studies have
found that those with DSWPD are less able to accumulate compensatory sleep drive
than controls and are slower to wake [30, 32]. Environmental factors also contribute
to the pathogenesis of DSWPD. Patients are exposed to more light at night and less
light in the morning, which may perpetuate the delayed sleep/wake timing [33].
There is also evidence that they are more sensitive to light and have altered circa-
dian phase shifting with larger delays in response to light exposure [34, 35]. A
recent study showed that patients with DSWPD had decreased exposure to light
during the phase advancing window, increasing the tendency to delay [36].
While there are multiple genetic variations that shorten the circadian period
linked to a familial type of Advanced Sleep-Wake Phase Disorder (FASPD), the
genetic component of DSWPD is less clear. Twin studies indicate there is a strong
hereditary influence on chronotype, and the heritability of bedtime preference is
estimated to be approximately 50% [37–39]. A UK study found that a four-repeat

allele length polymorphism in Per3 is associated with DSWPD, while the five-
repeat allele is linked to morning preference [40]. However, a South American study
showed the opposite effect linking the five-repeat allele to DSWPD and speculate
the difference may be due to variables related to latitude such as day length and
temperature [41]. A familial form of DSWPD has been identified with a gain-of-
function mutation of the CRY1 gene resulting in lengthened circadian period and
inheritance of DSWPD in an autosomal dominant pattern. This allele has a fre-
quency between 0.1% and 0.6% [42]. Most recently a study of Japanese patients has
shown that a low-frequency missense variant in PER2 within the CRY-binding
domain is associated with DSWPD [43].
Clinical Features
DSWPD is characterized by a persistent inability to fall asleep until late in the eve-
ning and excessive sleep inertia (difficulty waking) in the morning. These patients
have great difficulty adhering to conventional sleep-wake schedules and typically
follow a sleep-wake schedule delayed by more than 2 hours [44]. Typical bedtimes
range from 2:00 AM to 6:00 AM or even later. Patients frequently have complaints
of insomnia, morning drowsiness, and tend to be more alert in the evening [19].
When patients can set their own schedules, such as during weekends or on vacation,
they no longer have difficulty sleeping or waking but will prefer a later schedule.
This is a fundamental feature that differentiates DSWPD from sleep-onset insomnia.
Diagnosis
The ICSD-3 requires five essential diagnostic criteria that must be met to be diag-
nosed with true DSWPD: (A) significant delay in sleep phase that manifests as an
inability to fall asleep and difficulty waking in relation to a desired or required time;
(B) symptoms are present for at least 3 months; (C) patients experience improved
sleep quality and duration for age when allowed to dictate their own schedule and
will exhibit a delayed sleep-wake pattern; (D) sleep log and/or actigraphy for at
least 7 days (preferably 14 days) including school/work days and free days that
demonstrate a delayed sleep-wake pattern; (E) sleep disturbance is not better
explained by other causes of insomnia and daytime sleepiness such as another sleep
disorder, psychiatric disorder, or medical disorder [18].
Clinical assessment should involve a detailed sleep history and include informa-
tion regarding the patient’s sleep-wake schedule on work/school days as well as free
days and their preferred schedule if given the opportunity to choose. To aid in the
diagnosis, obtain sleep logs for at least 7–14 days, with wrist actigraphy if possible.
Measurement of circadian phase biomarkers such as salivary dim light melatonin
onset (DLMO) is helpful to confirm intrinsic circadian timing and can be used to
time treatments. However, it is important to note that not all patients with clinically
diagnosed DSWPD will have delayed DLMO. In an Australian study of 182 DSWPD
patients sampled, 57% had delayed DLMO occurring at or after desired bedtime, and
43% did not show misaligned timing of melatonin rhythm with DLMO occurring
before desired bedtime [45]. The Morningness-Eveningness Questionnaire is a self-
assessment of the patient’s preferred sleep-wake and activity timing and can provide
a reasonable estimate of chronotype and demonstrate an evening preference [46].
Polysomnography is not indicated for diagnosis and should demonstrate normal
sleep architecture other than possible prolonged sleep onset latency and decreased
duration if conducted during typical laboratory times [47]. Insomnia may co-occur
with DSWPD secondary to conditioned arousal from time spent in bed unable to fall
asleep at standard bedtimes [48]. Comorbid psychiatric disorders are common, and
a thorough mental health history should be obtained [45]. Diagnosis of DSWPDs
should be made only after the exclusion of other sleep disorders, psychiatric disor-
ders, or medical disorders that can lead to the presenting sleep disturbance.
Treatment
Treatment of DSWPD is primarily focused on advancing the patient’s biological

clock to better align with their imposed environment. Current treatment primarily
relies on a combination of appropriately timed melatonin and bright light therapy.
Shortly after the discovery of DSWPD, chronotherapy was developed as a therapeu-
tic technique by progressively delaying sleep time further until the sleep period
circles around the clock and reaches the desired bedtime [49]. However, caution is
advised, as there have been some reports of adult patients who subsequently devel-
oped a non-24-hour sleep-wake pattern after treatment [50]. Chronotherapy is not
currently a recommended treatment per the most recent American Academy of
Sleep Medicine (AASM) guidelines as there have been insufficient published trials
showing efficacy. Sleep-promoting agents and wakefulness-promoting agents are
also not currently recommended for DSWPD, as there is little data showing effi-
cacy [44].
The mainstay of DSWPD treatment is strategically timed administration of
exogenous melatonin in the evening as recommended by AASM guidelines [44].
Low doses (0.5–3 mg) of melatonin are most effective with less concern for the
residual elevation of melatonin, causing further phase delay [51, 52]. A recent ran-
domized, placebo-controlled, double-blind trial of 0.5 mg melatonin taken 1 hour
before the desired bedtime resulted in an average sleep onset advance of 34 min in
patients diagnosed with DSWPD [53]. The magnitude of the phase advance response
is dependent upon the timing of melatonin administration, and maximum advances
occurred at 2 to 4 hours before DLMO, making the ideal time for melatonin 5 to
6 hours before habitual bedtime [48, 54].
Although there is no specific AASM recommendation for timed light therapy for
adults, morning light can provide an additional benefit in entrainment when admin-
istered at the optimal time for phase advance. A combination of bright light therapy
and melatonin is often used in the clinical setting. It is imperative for light therapy
to be administered at the correct time to avoid further phase delay. To appropriately
phase advance the patient, bright light should be delivered after the nadir of core
body temperature (referred to as CBTmin), which occurs approximately 2 to 3 hours
before habitual wake time [55, 56]. Exposure to light before the CBTmin can cause
further delay and evening light should be restricted. Combination therapy of low
dose melatonin (0.5–3 mg) 5 to 6 hours before bedtime and bright light (>5000 lux)
for 30 min to 2 hours on awakening with a gradually advancing schedule results in
greater long-term phase-advancing capacity than either alone [48, 57–59]. Large-
scale randomized trials are still needed to fully determine the efficacy of combined
light and melatonin.
Advanced Sleep-Wake Phase Disorder
Advanced Sleep-Wake Phase Disorder (ASWPD) is characterized by sleep-wake

timing that is advanced in relation to conventional schedules. These individuals
typically present with an earlier natural sleep phase than the general population with
earlier bedtime and wake-up time. There is also a familial subtype of ASWPD in
which a strong family history of advanced sleep phase is present, and multiple caus-
ative mutations have been identified [60–62].
Prevalence
There are few population studies on the prevalence of ASWPD, and true ASWPD
by stringent diagnostic criteria is thought to be rare. Of 10,000 randomly sampled
Norwegian adults aged 18–67 who received screening questionnaires, there were
zero cases of ASWPD detected [20]. A sample of 9100 New Zealand adults aged
20–59 was surveyed, and the calculated prevalence of ASPWD ranged from 0.25%
to 7.12% depending on the definition used, with a higher prevalence in older adults
[21]. A recent study of 2422 new patients presenting to a North American sleep
center over 10 years calculated an advanced sleep phase (ASP) prevalence of
0.33%, familial ASP prevalence of 0.21%, and estimated prevalence of ASPWD by
strict definition of chronic circadian dysfunction to be at least 0.04%. Most cases
presenting in young people were due to familial ASP [63]. One possible explana-
tion for the low prevalence of ASPWD may be that it is minimally disruptive, or
even advantageous, to daily life and affected individuals are less likely to seek
medical attention.
Pathophysiology
There is a strong genetic component to ASWPD, and those with reports of advanced
sleep phase in a first-degree relative can be considered to have a familial form [64]. The
first report of a familial subtype was in 1999 when three families were identified with
members experiencing significant phase advances of almost 4 hours in sleep-wake,
melatonin, and temperature rhythms inherited in an autosomal dominant pattern [60].
One family was found to have a missense mutation in the PER2 gene, which disrupts
the casein kinase Iε (CKIε) binding region, resulting in a shortened endogenous circa-
dian period [62]. Multiple additional mutations have been identified in CKIδ, CRY2,
PER3, and TIMELESS [61, 65–67]. Additional mechanisms include dysregulated phase
resetting in response to light with a blunted phase-delay response to evening light [67].
Clinical Features
Patients with ASWPD usually present with an advance of sleep-wake schedule by

at least 2 hours in relation to desired or required times [44]. These individuals usu-
ally have difficulty staying awake between 6:00 PM and 9:00 PM and wake up
between 2:00 AM and 5:00 AM with complaints of excessive late afternoon/early
evening sleepiness and morning insomnia [48]. They also may experience chronic
sleep loss due to early morning awakenings and sleep maintenance insomnia
(ICSD-3). When patients are allowed to set their own sleep-wake schedule, they
experience good age-appropriate sleep quality and quantity and will prefer an early
schedule. The onset of ASWPD usually occurs later in life and is more common in
older adults due to age-related advancing of circadian timing. However, familial
types typically present with earlier age of onset.
Diagnosis
The diagnostic process of ASWPD is similar to that of DSWPD. The ICSD-3 requires
five essential criteria: (A) significant advance in sleep phase episode that manifests as
an inability to stay awake and inability to remain asleep until desired or required con-
ventional bedtime and wake-up time; (B) symptoms are present for at least 3 months;
(C) patients experience improved sleep quality and duration for age when allowed to
dictate their own schedule and will exhibit an advanced sleep-wake pattern; (D) sleep
log and/or actigraphy for at least 7 days (preferably 14 days) including school/work
days and free days that demonstrate an advanced sleep-wake pattern; (E) sleep distur-
bance is not better explained by other causes of insomnia and daytime sleepiness such
as another sleep disorder, psychiatric disorder, or medical disorder [18].
Clinical assessment should involve a detailed sleep history, including the patient’s
sleep-wake schedule on work/school days as well as free/vacation days and their
preferred schedule if given the opportunity to choose. Diagnosis can be made based
on sleep logs and actigraphy data, if feasible, for at least 7–14 days. Circadian phase
biomarkers such as DLMO should demonstrate an advanced phase, and standard-
ized chronotype questionnaires such as the Morningness-Eveningness Questionnaire
should show a morning preference. These tools can be helpful in diagnosis and
treatment. Diagnosis of ASWPD must be made only after the exclusion of other
causes of sleep disruption, such as major depressive disorder.
Treatment
The primary goal of treatment is to delay the circadian clock to the desired schedule.
The AASM practice guidelines recommend light therapy as treatment. Bright light
before the nadir of core body temperature results in a delay of circadian phase, and
several studies have shown some efficacy with evening light treatment. In an early
study, exposure to bright white light (2500 lux) for two consecutive nights in nine
patients with early morning insomnia resulted in 1 to 2-hour delays in circadian
biomarkers including melatonin and temperature [68]. Similarly, treatment of 24
patients with 2500 lux light for 4 hours between 8:00 PM and 9:00 PM on two con-
secutive nights resulted in average phase delays of 2 hours [69]. It is important to
note that patients in these cohorts were not formally diagnosed with ASWPD. A
study testing exposure to bright white light (4000 lux) against dim red light control
(50 lux) for 2 hours before habitual bedtime in older subjects meeting ICSD criteria
for ASWPD resulted in a delay in wake time of 1 hour and improved sleep effi-
ciency and sleep time [70]. Per AASM guidelines, the largest phase-delay effects
were achieved after a 12-day treatment of 2 hours of bright, broad-spectrum light
(4000 lux) between 20:00 and 23:00, before habitual bedtime [44].
Exogenous melatonin administered in the morning results in circadian phase
delay, and low dose melatonin upon early morning awakening can be considered as
an option [71]. However, there has been no evidence demonstrating its efficacy and
administration of melatonin in the morning may cause drowsiness. Therefore,
morning melatonin is not currently recommended by the AASM [44]. One case
study reported a patient with ASWPD who responded to chronotherapy with sched-
uled bedtime and wake time advancing 3 hours every 2 days until goal bedtime was
reached [72]. There have been no further investigations of the efficacy of chrono-
therapy to date, and it is currently not a recommended treatment [44].
Non-24-Hour Sleep-Wake Disorder
The human circadian pacemaker has an average endogenous period of slightly lon-
ger than 24 hours at approximately 24.18 hours, and entrainment of the endogenous
clock to the 24-hour day-night cycle requires daily tuning to environmental cues [8].
Non-24-hour sleep-wake rhythm disorder (N24SWD) is characterized by cycles
that are typically longer than 24 hours and are not synchronized to the environment,
leading to a daily drift of progressively delayed sleep-wake timing. Symptoms are
often cyclical as they resolve during the time that the individual’s sleep-wake sched-
ule lines up with the 24-hour environment before continuing to drift. N24SWD
primarily affects blind individuals with no light perception and, although rare, has
been reported in sighted patients as well.
Prevalence
N24SWD affects both blind and sighted patients. It is most common in those who
are blind due to a lack of external light signals and rare in sighted individuals. The
prevalence of N24SWD in either population has not been well studied. There is a
high frequency of sleep disturbances in individuals who are blind and can be as high
as 66% in those with complete loss of light perception [73]. In a study of 20 totally
blind subjects, approximately 50% were found to have free running endogenous
rhythms with a high incidence of N24SWD [74]. In a study of 127 blind female
subjects, 2/3 of those with no light perception were not entrained to the 24-hour
environmental cycle compared to 1/3 in those with some light perception [75]. In a
cohort of sighted patients with N24SWD, 63% developed symptoms during their
teenage years, and 72% were male [76].
Pathophysiology
The average endogenous circadian period in humans is slightly longer than 24 hours
and requires daily tuning in response to external cues to synchronize to the 24-hour
environmental cycle. The strongest of these external influences is light, but other
daily cues include food intake, social activity, and exercise. In blind patients who
have no photic input to the central circadian pacemaker, light signaling to the SCN
is disrupted, and the circadian phase resetting response to light is absent. Interestingly,
not all of those who are totally blind are free-running, and this is most strikingly
illustrated by evidence of some bilaterally enucleated subjects who are normally
entrained [77]. This is perhaps because these individuals have endogenous rhythms
that are closer to 24 hours to begin with or are more responsive to entrainment by
non-photic time cues [78].
The pathophysiology of N24SWD in sighted patients is less well understood and
likely multifactorial. In sighted patients with N24SWD subjected to a forced desyn-
chrony protocol (i.e. a reasearch protocol designed to uncouple sleep-wake timing
from circadian timing), it was found that they had significantly lengthened periods
with a mean melatonin rhythm of 24.48 ± 0.05 hours [79]. Many individuals ini-
tially present with complaints similar to that of DSWPD but eventually develop
N24SWD [76, 80]. There are reports of patients with DSWPD who subsequently
developed a non-24-hour pattern after chronotherapy [50]. There may also be a

decreased ability to suppress melatonin in response to bright light and blunted
plasma melatonin rhythm in sighted patients with N24SWD [81, 82]. This may be
due to decreased sensitivity to light, although it is unclear if phase shifting is affected
in these patients. Inappropriately timed light exposure may also contribute to the
development of a non-24-hour pattern. These patients often initiate sleep at a later
phase than normal patients and expose themselves to light at a time in the circadian
cycle that causes further phase delay.
Lastly, there are reports of N24SWD in the context of traumatic brain injury or
schizophrenia, suggesting congenital or acquired lesions that disrupt circadian
structures or pathways can contribute to the development of non-24-hour sleep/
wake patterns [83, 84]. No familial patterns have been observed in N24SWD, and
genetic associations have not been explored.
Clinical Features
Patients with N24SWD present with a progressive daily delay in the sleep-wake
pattern, often with complaints of nighttime insomnia and/or excessive daytime
sleepiness that alternate with periods of normal sleep. Symptomatic periods are
most severe when the intrinsic biological rhythm and the extrinsic 24-hour environ-
mental cycle are most out of phase, and sleep is occurring during the daytime. The
frequency and duration of symptomatic periods depend on the magnitude of the
daily delay. For example, a patient with an intrinsic period of closer to 25 hours
would have a greater magnitude of delay and experience more frequent symptoms
than a patient with an intrinsic period closer to 24 hours. These patients frequently
have severe social disruption and may not be able to complete school or hold down
a job. For most sighted patients, the average age of onset was in adolescence [76,
80]. These patients commonly start with a delayed sleep-wake phenotype and then
progress to a N24 pattern [80].
Diagnosis
The ICSD-3 requires four essential diagnostic criteria that must be met: (A) his-
tory of insomnia, excessive daytime sleepiness, or both, due to circadian mis-
alignment. Sleep disturbances alternate with asymptomatic episodes of normal
sleep. (B) Symptoms persist for at least 3 months. (C) Daily sleep log and actig-
raphy for at least 14 days (longer for blind individuals) demonstrating a sleep-
wake pattern that delays each day. The circadian period is longer than 24 hours.
(D) Sleep disturbance is not better explained by other causes of insomnia and
daytime sleepiness such as another sleep disorder, psychiatric disorder, or medi-
cal disorder [18].
Documentation of a non-24-hour sleep-wake pattern is essential for diagnosis.

Thus, sleep log and/or actigraphy must be adequately long to capture the progres-
sively delaying pattern and should be continued for at least 14 days. Circadian bio-
markers such as DLMO or the urinary melatonin metabolite 6-sulfatoxymelatonin
should be obtained at two time points 2–4 weeks apart (enough time for drift to be
apparent) to confirm a non-entrained rhythm. Chronotype questionnaires are less
helpful as sleep-wake preferences may vary depending on which stage of the cycle.
Treatment
Treatment varies depending on the underlying cause of the disorder with the com-
mon goal of entraining to a 24-hour cycle and maintenance of synchronization. For
blind individuals, strategically timed melatonin is the mainstay of treatment and has
been relatively well-studied [44]. The first demonstration of the efficacy of exoge-
nous melatonin was in blind subjects with N24SWD who received placebo or 5 mg
melatonin at 21:00 for 35–71 days. Four of the seven subjects receiving melatonin
exhibited shortening of circadian period similar to entrainment [85]. In a crossover
study with seven totally blind subjects with free-running rhythms given 10 mg mel-
atonin or placebo 1 hour before preferred bedtime, six of seven were entrained to
24-hr cycle with daily melatonin compared to zero entrained with placebo.
Entrainment persisted even once the daily dose was lowered to 0.5 mg [86].
Subsequent studies demonstrated that 0.5 mg melatonin was sufficient to initiate
synchronization and was as effective as higher doses at shortening the circadian
period [87, 88]. An alternative to melatonin, the selective melatonin receptor agonist
Tasimelteon is approved for the treatment of N24SWD by the Food and Drug
Administration. Two consecutive placebo-controlled trials in blind adults with
N24SWD showed daily administration 1 hour before target bedtime for 6 months
showed circadian entrainment and improved clinical outcome measures [89].
Treatment of sighted patients is less established and relies on a combination of
light and melatonin based on known phase response curves. The usage of melatonin
in the treatment of sighted patients has been demonstrated in several case reports
with the administration of evening low dose melatonin (0.5 mg) or high dose mela-
tonin (5 mg) with vitamin B12 showing evidence of entrainment [81, 90]. Morning
bright light therapy upon awakening has also been shown to be effective in restoring
a 24-hour rhythm [91, 92]. Combination therapy with bright light upon awakening
and 2 mg melatonin 2 to 3 hours before habitual bedtime or 3 mg 1 hour before
bedtime successfully entrained the rhythm with a delayed phase [93, 94]. A recent
case series demonstrated a combination treatment algorithm of bright light and mel-
atonin initiated when the predicted bedtime aligns with the target bedtime. Treatment
consisted of low dose melatonin (0.5–1 mg) given 2 hours before predicted bedtime
and bright light therapy (10,000 lux) given for 1 hour after predicted wake time. The
goal was to maintain timing, rather than inducing large phase shifts, to achieve tar-
get sleep-wake timing [80].
Irregular Sleep-Wake Rhythm Disorder
Irregular sleep-wake rhythm disorder (ISWRD) is characterized by the lack of a

clearly discernable circadian pattern in sleep-wake behavior. This typically mani-
fests as chronic complaints of fragmented periods of sleep that occur both during
the day and night with no major sleep episode. ISWRD is more commonly
observed in adults with neurodegenerative disorders or children with developmen-
tal delays.
Prevalence
The exact prevalence of ISWRD is unknown, but is generally considered to be rare

and mostly observed in those with neurodevelopmental or neurodegenerative disor-
ders. It is more common in older adults, as the incidence of dementia increases [24].
There have been no reports of gender differences in ISWRD.
Pathophysiology
The pathogenesis of ISWRD is not entirely understood and is likely multifactorial.

It may depend on the underlying neuropathological cause of sleep disruption associ-
ated with the patient. Those affected include older patients with neurodegenerative
diseases, such as Alzheimer’s, adults with psychiatric disorders including schizo-
phrenia, and children with neurodevelopmental disorders such as Angelman syn-
drome, Smith-Magenis syndrome, and Autism spectrum disorder [48]. One
important underlying causative factor is thought to be the degeneration or disruption
of SCN neurons in the circadian system. Disruptive lesions can be congenital or
result from neurodegeneration or traumatic injury. This is supported by SCN abla-
tion studies in the diurnal squirrel monkey, which resulted in the fragmentation of
sleep, similar to an irregular sleep-wake pattern [95].
In the older adult population, insufficient exposure to entrainment cues such as
light can contribute to the development of ISWRD. Older adults are exposed to
significantly less environmental bright light relative to healthy younger adults.
Those who are institutionalized are exposed to even less light overall. Older patients
are also at risk of decreased transmission of light to the retina due to age-related
changes such as cataracts, glaucoma, macular degeneration, and diabetic retinopa-
thy [96]. In Alzheimer’s disease, there is evidence of a reduction in numbers of
vasopressin-expressing neurons in the SCN as well as an age-related decrease in
melatonin secretion that can contribute to the loss of cohesive rhythms [97].
Furthermore, sleep abnormalities may precede dementia and may be an early sign
of neurodegeneration as well as accelerate pathology [98].
Clinical Features
ISWRD typically presents as a lack of a discernable circadian sleep-wake rhythm in

which the patient sleeps in multiple short bursts lasting less than 4 hours throughout
the day and night. ICSD-3 diagnostic criteria require at least three short sleep epi-
sodes with no extended sleep period during the 24-hour cycle. The longest sleep
episode usually occurs between 2 and 6 AM with multiple naps throughout the day.
However, total sleep time over 24 hours is typically appropriate for age [99]. Patients
or their caretakers may report chronic symptoms of sleep maintenance insomnia,
excessive daytime sleepiness, or both. ISWRD is more common in the setting of
neurodegenerative disorders, neurodevelopmental disorders, and psychiatric disor-
ders and can be quite challenging for caregivers.
Diagnosis
Per ICSD-3, four diagnostic criteria must be met to be diagnosed with ISWRD: (A)
chronic or recurrent pattern of irregular sleep and wake periods throughout the
24-hour day with symptoms of insomnia during normal sleep period at nighttime,
excessive sleepiness or napping during the daytime, or both. (B) Symptoms present
for at least 3 months. (C) Sleep log and/or actigraphy for at least 7 days (preferably
14 days) showing no extended sleep period and at least 3 irregular sleep episodes
during a 24-hour period. (D) Sleep disturbance is not better explained by other
causes of insomnia and daytime sleepiness such as another sleep disorder, poor
sleep hygiene, psychiatric disorder, or medical disorder [18].
Clinical assessment should involve a detailed sleep history, and sleep logs should
be obtained for at least 7–14 days and with wrist actigraphy, if available. Actigraphy
may show low amplitude activity rhythms and at least three short sleep episodes
throughout the day and night in a 24-hour period [48]. Caregivers may also provide
valuable information regarding sleep-wake timing if the patient is unable to give
accurate information. Polysomnography is not required for diagnosis. Measurement
of circadian biomarkers such as melatonin and core body temperature may reveal
loss of circadian rhythmicity or a low amplitude rhythm [18].
Treatment
The goal of ISWRD treatment is to consolidate sleep and enhance circadian entrain-
ment to the day/night cycle. Treatment is multimodal and includes light therapy,
exogenous melatonin, and behavioral interventions. The AASM practice guidelines
recommend bright light therapy for the treatment of ISWRD in older adults with
dementia. In early trials, patients with dementia treated with 2 hours of 3000–5000
lux broad-spectrum light each morning for 4 weeks consolidated nocturnal sleep,
decreased daytime napping, and improved behavioral symptoms [100]. Bright light
exposure of 2500 lux for 2 hours in either morning or evening is beneficial in
patients with dementia and resulted in increased consolidated sleep [101]. Exogenous
melatonin alone is not recommended in older patients with dementia due to the lack
of evidence for efficacy and possible exacerbation of mood symptoms but may be
effective in combination with light [44]. A randomized study of assisted living facil-
ities with common areas lit with bright white broad-spectrum light (1000 lux) or
dim light (300 lux) with evening melatonin (2.5 mg) or placebo found that a combi-
nation of bright light and melatonin led to improved sleep efficiency, nocturnal rest-
lessness, and less aggressive behavior [102]. For adults with dementia, a
non-pharmacological mixed modality approach consisting of morning bright light
exposure (>10,000 lux), daytime physical activity, minimizing noise and light at
night, and a structured bedtime routine was effective in reducing nighttime awaken-
ings and improving daytime sleepiness [48, 103, 104]. The AASM currently does
not recommend the use of sleep-promoting medications for older patients with
dementia due to the high potential for adverse effects [44].
In children with neurodevelopmental delay and sleep disturbances, bright light
exposure of a minimum of 4000 lux resulted in normalization of sleep in some of
the children treated [105]. In a randomized controlled trial of children with autism
spectrum disorder and sleep disturbances, 2 mg–10 mg of melatonin 30–40 min
before bedtime improved sleep latency and total sleep time by 45 min compared to
placebo [106].
Shift Work Disorder
Shift work disorder (SWD) is a consequence of shift work that prevents individuals
from adhering to a normal sleep-wake schedule. Shifts outside of the traditional
9-to-5 workday may require the worker to sleep during the day and be awake at the
times of night typically reserved for sleep. Some workers may have trouble adapting
to this schedule, leading to chronic circadian misalignment and impairments in
sleep and wakefulness with significant negative consequences impacting health and
quality of life. Shift workers suffer increased rates of cancer, higher incidence of
cardiovascular and metabolic disorders, and are at a significantly higher risk for
psychiatric disorders [107, 108]. Other adverse consequences of SWD include
increased risk of workplace injuries and errors as well as auto accidents, which
incur a high societal cost.
Prevalence
Recent calculations approximate that 15–30% of the European and American work-
force are shift workers [107]. An estimated 20% of US workers are engaged in shift
work, and the numbers are rising in an increasingly 24/7 global economy [109].
While some workers may be able to adapt to their schedules, others experience
chronic sleep disturbance and impaired function. Data obtained from the US
National Health and Nutrition Examination Survey estimated a 62% prevalence of
short sleep duration (< 7 hours/day) and 31% prevalence of poor sleep quality
among night-shift workers with impaired activities of daily living (ADL) score and
insomnia in 36% [110]. In a study of 2570 US workers, the prevalence of SWD
meeting ICSD diagnostic criteria was estimated to be 10% in night and rotating shift
workers [111].
Pathophysiology
Shift workers live within the confines of an imposed schedule that conflicts with
their endogenous circadian rhythm and the external environment. Shift schedules
vary depending on industry, and overnight work is especially common in service
and healthcare occupations. Common examples include night shifts, early morning
shifts, evening shifts, rotating shifts, on-call overnight duty, and extended shifts of
24 hours or longer [18]. There is wide variability in the adaptability of shift workers
to their schedules. It is not completely clear why some people are more affected
than others, but individuals do vary in their sleep requirements and preferences for
timing. For example, those with evening-oriented chronotype may prefer night
shifts and be more challenged by early morning shifts, and those with morning
chronotypes may be more challenged by night shifts. Age may be a risk factor for
SWD, as young people are able to recover more quickly from shifts [112]. Other
factors that can influence tolerance of shift work include sex, health status, and
lifestyle choices [113]. The type of shift may contribute to the development of
SWD. Rapidly rotating shift rotations are associated with a greater reduction in total
sleep time compared to slowly rotating or permanent shifts [114]. There may also
be a genetic predisposition for excessive sleepiness in some shift workers. Shift
workers who reported insomnia and sleepiness during wake hours were found to be
more likely to carry a long polymorphism of PER3 than those who were less
sleepy [115].
Clinical Features
Shift work disorder is characterized by insomnia, excessive sleepiness, or both, as a

consequence of shift work with hours that interfere with conventional sleep times.
Patients experience chronically decreased total sleep time due to sleep disruption
and may report worsening function during waking hours. The effects of chronic
sleep deprivation compounded with circadian misalignment leave many shift work-
ers vulnerable to depression, anxiety, chronic fatigue, substance use, and cognitive
deficits [116]. Symptoms usually only last for the duration of the shift work, but
some sleep difficulties may persist as shift work can be a precipitant of insomnia in
certain individuals [117].
Diagnosis
The ICSD-3 requires the four following criteria must be met to be diagnosed with
shift work disorder: (A) symptoms of insomnia and/or excessive sleepiness, or both,
accompanied by decreased total sleep time associated with a work schedule that
overlaps with the usual time for sleep. (B) Symptoms have been present and associ-
ated with shift work schedule for at least 3 months. (C) Sleep log and wrist actigra-
phy (preferably with light exposure measurement) for at least 14 days (including
work and free days) demonstrate a disturbed sleep/wake pattern. (D) Sleep distur-
bance is not better explained by other causes of insomnia and excessive sleepiness
such as another sleep disorder, poor sleep hygiene, psychiatric disorder, or medical
disorder [18].
Diagnosis is made based primarily on history. Clinical assessment should involve
a detailed sleep history, including sleep schedule and habits before and after the
initiation of shift work. Work history should be obtained that includes occupation
with a detailed work schedule, and sleep patterns should be assessed for working
and non-working periods. Cognitive difficulties, performance deficits, and safety
concerns are important to identify as there is an increased risk of fatigue-related
motor vehicle accidents in shift workers [118, 119]. It is imperative to assess safety
risks such as excessive sleepiness while driving or operating machinery. The
Epworth Sleepiness Scale is a validated and commonly used method to assess sleep-
iness during waking hours. Polysomnography is not required for diagnosis but can
be helpful if there is a need to rule out other causes of poor sleep, such as sleep apnea.
Treatment
The goal of SWD treatment is to improve sleep quality and reduce wake-time sleep-
iness. A multifaceted approach is most effective in addressing symptoms and pro-
moting stable circadian entrainment, and should be tailored to the patient’s individual
needs and circumstance.
Non-pharmacological approaches aim to maintain circadian alignment and
include keeping a comfortable sleeping environment, adhering to a regular sleep/
wake and dietary schedule, scheduled napping, and strategic light exposure. There
is strong evidence for napping before or during a night shift, which has been shown
to improve performance and decrease accidents [120–122]. Appropriately timed
light may be effective in targeting circadian misalignment and aid in adaptation to
shift work schedules. Several studies have shown that exposure to bright light
(2000–12,000 lux) administered in constant or intermittent schedules for various
durations before or during the first half of night shift was effective in improving
alertness and tolerance of night shift [123, 124]. Avoidance of light at times that
may interfere with sleep is also an important part of optimizing entrainment to night
shifts. Patients can reduce bright light exposure in the morning, for example, on the
drive home, with dark sunglasses [47]. Exogenous melatonin can be used to enhance
daytime sleep. A meta-analysis found that administration of 1–10 mg of melatonin
before bedtime is associated with increased daytime sleep duration in those who
work night shifts but does not affect sleep latency time [125].
Wake-promoting agents that increase alertness may be prescribed to improve
function during work hours. Modafinil and armodafinil are FDA approved for the
treatment of excessive wake time sleepiness with modest improvement. In random-
ized trials of patients with SWD, 150 mg armodafinil taken 30–60 min before the
start of the night shift improved work shift sleepiness compared with placebo
regardless of shift duration [126–128]. Treatment with 200 mg modafinil before the
start of night shift is more effective in reducing sleepiness than a placebo [129, 130].
Caffeine can also be an effective agent for improving alertness during work hours
and has significantly fewer side effects than stimulant-type medications [109].
For patients who have trouble initiating daytime sleep, short-acting hypnotics
may be used to treat insomnia and promote sleep at the desired time [109].
Benzodiazepine and non-benzodiazepine hypnotics have been found to be effective
in inducing sleep in the setting of chronic insomnia, although with a risk of signifi-
cant side effects such as dependence, withdrawal, and rebound insomnia [130, 131].
Short-acting hypnotics such as zolpidem and intermediate-acting benzodiazepines
such as triazolam have been shown to increase daytime sleep in shift workers [132,
133]. However, these medications do not address circadian misalignment and may
have serious side effects. There is evidence that suggest matching individual
employee chronotypes to shift schedules reduces circadian disruption and improves
sleep and general wellbeing [134]. However, this may not be practical in most work
environments but should be taken into consideration, if feasible. When possible,
pharmacologic agents should be used in combination with non-pharmacologic ther-
apy, and good sleep hygiene should be a key element of any treatment regimen.
Lastly, all patients should be educated on the dangers of fatigue and drowsiness
while driving and should be counseled on how to recognize when they are unable to
operate a vehicle.
Jet Lag Disorder
Jet lag disorder (JLD) is characterized by temporary symptoms of insomnia and/or

excessive daytime sleepiness, with a decrease in total sleep time as a consequence
of circadian misalignment associated with air travel across at least two time zones.
Under these circumstances, the circadian system is not given enough time to catch
up to the current time zone, and there is a lag in the entrainment of the intrinsic
rhythms relative to the new environment. Although JLD is generally self-limited, it
can be extremely disruptive to travelers, and severe symptoms warrant treatment.
Treatment and prevention of jet lag are of particular interest to professional athletes,
business travelers, and the military.
Prevalence
The prevalence of JLD is unknown but likely affects many people, considering the
large proportion of the population who engage in air travel globally. International
and frequent travelers are especially vulnerable, especially if crossing five or more
time zones [135]. All age groups and genders are at risk for jet lag. Some studies
suggest that middle-aged and older individuals are more prone to having symptoms
and take a longer time to recuperate [24, 136] while others have found older subjects
were less likely to experience jet lag and fatigue [137]. More studies are needed to
better establish a relationship between age and jet lag.
Pathophysiology
The pathophysiology of JLD is relatively straightforward. Insomnia and daytime

somnolence are caused by a misalignment between the endogenous circadian
rhythm, homeostatic sleep drive, and local sleep-wake schedule caused by the rapid
changing of time zones. A period of desynchrony persists until the circadian system
is re-entrained. Symptom severity and duration are dependent on the number of time
zones crossed, the direction of the time change, the extent of travel-related sleep
deprivation, and individual differences in circadian adaptability [138]. Because the
human endogenous rhythm is longer than 24 hours, it is easier for the circadian
system to phase delay than to advance. Thus, individuals are more likely to experi-
ence jet lag and take longer to resynchronize with eastward travel due to the require-
ment to advance rather than delay the body’s intrinsic rhythm [18].
Clinical Features
Patients suffering from jet lag usually present with symptoms of insomnia and day-
time drowsiness with impaired functioning within a day or two of air travel across
at least two time zones. Many may also experience fatigue, headaches, irritability,
cognitive difficulties, and gastrointestinal dysfunction such as indigestion, appetite
changes, and inconsistent bowel function [139]. Eastward travel is associated with
sleep onset difficulty as the traveler’s biological time is behind the local time.
Westward travel is associated with daytime and early evening sleepiness as the trav-
eler’s biological time is ahead of the local time. Symptoms tend to be more severe
going from West to East and are typically compounded by general fatigue and stress
caused by travel [18]. Unlike typical travel fatigue, jet lag symptoms typically do
not resolve after a good night’s sleep and can take several days to re-adjust.
Diagnosis
The ICSD-3 requires three essential diagnostic criteria that must be met: (A) com-
plaint of insomnia and/or excessive daytime sleepiness, accompanied by reduced
total sleep time in the setting of air travel across at least two time zones. (B) Presence
of associated impairment of daytime function, fatigue, or somatic symptoms such as
gastrointestinal disturbance within one to two days after travel. (C) Sleep distur-
bance is not better explained by other causes of insomnia and daytime somnolence
such as another sleep disorder, psychiatric disorder, or medical disorder [18].
The diagnosis can be made based on sleep and travel history alone, and labora-
tory testing is usually not indicated. However, a thorough history and physical exam
may help exclude underlying sleep or medical conditions, especially in the setting
of gastrointestinal complaints. In some cases of international travel across multiple
time zones, prophylactic treatment can be initiated before travel to blunt the effects
of jet lag, and a diagnosis will not be required.
Treatment
Treatment for JLD differs for eastward or westward travel but has a shared focus on
reducing symptoms of insomnia and excessive sleepiness as well as speeding up the
adjustment process. Therapy is tailored to facilitate phase advances for travel east-
ward and delays for travel westward. Treatment for international trips across mul-
tiple time zones may begin before travel to shift the patient’s schedule preemptively
or after travel to accelerate entrainment.
For eastbound travel, a combination of timed morning bright light, evening low
dose melatonin, and gradually advancing sleep scheduling starting 3 days before the
day of travel can be employed to phase advance the circadian clock preemptively.
Both light and melatonin have advancing effects when used alone and can be used
together with an additive effect [140]. In one study, continuous bright light (>3000
lux) for 3 hours each day for 3 days was sufficient to produce a 2-hour phase advance
[141]. Another found that four 30 min pulses of 5000 lux light alternating with
30 min ambient light produced phase advances of 1 hour per day with the addition
of 0.5–3.0 mg melatonin 5 hours before bedtime [142, 143]. As sitting in front of
bright light for an extended period of time can be difficult, a study determined that
a single 30 min exposure of 5000 lux light with 0.5 mg melatonin 5 hours before
bedtime produced phase advances of similar magnitude as longer light treatments
(approximately 2 hours) [59]. If treatment is initiated after travel, melatonin can
decrease the effects of jet lag and is recommended for travelers crossing five or
more time zones. A comprehensive meta-analysis found melatonin doses ranging
from 0.5 mg to 5 mg taken near target bedtime are similarly effective, but higher
doses had greater sleep-inducing effects [144]. There are fewer studies pertaining to
westbound travel, and it is much easier to phase delay than to advance. Maximizing
evening light exposure and avoiding morning light may be useful in facilitating
phase delay [145]. Administration of morning melatonin could help delay timing,
but its hypnotic effects may cause daytime drowsiness.
If travel is short (2 days or less), the sleep/wake schedule can be kept unchanged,
and short-term use of hypnotics or wake-enhancing agents such as caffeine can be
considered for the alleviation of symptoms, as circadian realignment may not be
necessary or practical [109]. These agents can be used for symptom relief for more
extended travel as well, but it should be kept in mind that they do not address the
underlying circadian desynchrony.
Conclusion
The circadian system regulates and synchronizes many important physiologic func-
tions, including the sleep/wake cycle. CRSWDs arise as a consequence of the mis-
alignment between the endogenous rhythm and the external environment. This may
result from biological modifications within the circadian system or from behavioral
and societal pressure that imposes a mismatched schedule. In an increasingly global-
ized 24-hour economy in which people are surrounded by artificial lighting and bright
screens, it is more important than ever to recognize the importance of circadian disor-
ders. Early identification and treatment are important in prevention of the negative
health impacts of chronic circadian misalignment and improving patient quality
of life.
Key Summary Points

1. The primary circadian pacemaker is located in the suprachiasmatic nucleus
in the hypothalamus.
2. Most humans have an endogenous circadian period that is slightly longer
than 24 hours.
3. Light is the strongest regulator of the mammalian circadian clock, and
timed light exposure can be used to either advance or delay circa-
dian timing.
4. Other non-photic time cues such as melatonin, activity, and food timing
provide weaker time signals than light, but can also be used to adjust cir-
cadian timing.
5. Circadian rhythm sleep-wake disorders result when the endogenous circa-
dian clock is misaligned with the external environment. This can occur
either secondary to endogenous differences in circadian timing creating
misalignment with the external environment (DSWPD, ASWPD,
N24SWD, and ISWRD) or because of extrinsic factors requiring an indi-
vidual to be awake during their biological night (SWD and JLD).
References
1. Menet JS, Rosbash M. When brain clocks lose track of time: cause or consequence of neu-
ropsychiatric disorders. Curr Opin Neurobiol. 2011;21(6):849–57. https://doi.org/10.1016/j.
conb.2011.06.008.
2. Abbott SM, Malkani RG, Zee PC. Circadian disruption and human health: a bidirectional
relationship. Eur J Neurosci. 2020;51(1):567–83. https://doi.org/10.1111/ejn.14298.
3. Foster RG. Sleep, circadian rhythms and health. Interface Focus. 2020;10(3):20190098.
https://doi.org/10.1098/rsfs.2019.0098.
4. Ko CH, Takahashi JS. Molecular components of the mammalian circadian clock. Hum Mol
genet. 2006;15(2):R271–7. https://doi.org/10.1093/hmg/ddl207.
5. Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm follow-
ing suprachiasmatic lesions in the rat. Brain Res. 1972;42(1):201–6. https://doi.
org/10.1016/0006-8993(72)90054-6.
6. 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):1583–6.
https://doi.org/10.1073/pnas.69.6.1583.
7. Lehman MN, Silver R, Gladstone WR, Kahn RM, Gibson M, Bittman EL. Circadian rhyth-
micity restored by neural transplant. Immunocytochemical characterization of the graft and
its integration with the host brain. J Neurosci. 1987;7(6):1626–38.
8. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW, Ronda JM,
Silva EJ, Allan JS, Emens JS, Dijk DJ, Kronauer RE. Stability, precision, and near-24-hour
period of the human circadian pacemaker. Science. 1999;284(5423):2177–81. https://doi.
org/10.1126/science.284.5423.2177.
9. Golombek DA, Rosenstein RE. Physiology of circadian entrainment. Physiol Rev.
2010;90(3):1063–102. https://doi.org/10.1152/physrev.00009.2009.
10. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the
circadian clock. Science. 2002;295(5557):1070–3. https://doi.org/10.1126/science.1067262.
11. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing reti-
nal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science.
2002;295(5557):1065–70. https://doi.org/10.1126/science.1069609.
12. Czeisler CA, Allan JS, Strogatz SH, Ronda JM, Sanchez R, Rios CD, Freitag WO, Richardson
GS, Kronauer RE. Bright light resets the human circadian pacemaker independent of the
timing of the sleep-wake cycle. Science. 1986;233(4764):667–71. https://doi.org/10.1126/
science.3726555.
13. Benloucif S, Guico MJ, Reid KJ, Wolfe LF, L'Hermite-Baleriaux M, Zee PC. Stability of
melatonin and temperature as circadian phase markers and their relation to sleep times in
humans. J Biol Rhythm. 2005;20(2):178–88. https://doi.org/10.1177/0748730404273983.
14. Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milli-
grams of melatonin in humans. J Physiol. 2008;586(2):639–47. https://doi.org/10.1113/
jphysiol.2007.143180.
15. Borbely AA. A two process model of sleep regulation. Hum Neurobiol. 1982;1(3):195–204.
16. Daan S, Beersma DG, Borbely AA. Timing of human sleep: recovery process gated by a
circadian pacemaker. Am J Phys. 1984;246(2 Pt 2):R161–83. https://doi.org/10.1152/
ajpregu.1984.246.2.R161.
17. Borbely AA, Daan S, Wirz-Justice A, Deboer T. The two-process model of sleep regulation:
a reappraisal. J Sleep Res. 2016;25(2):131–43. https://doi.org/10.1111/jsr.12371.
18. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifi-
cations. Chest. 2014;146(5):1387–94. https://doi.org/10.1378/chest.14-0970.
19. Weitzman ED, Czeisler CA, Coleman RM, Spielman AJ, Zimmerman JC, Dement W,
Richardson G, Pollak CP. Delayed sleep phase syndrome. A chronobiological disorder with
sleep-onset insomnia. Arch Gen Psychiatry. 1981;38(7):737–46. https://doi.org/10.1001/
archpsyc.1981.01780320017001.
20. Schrader H, Bovim G, Sand T. The prevalence of delayed and advanced sleep phase syn-
dromes. J Sleep Res. 1993;2(1):51–5. https://doi.org/10.1111/j.1365-2869.1993.tb00061.x.
21. Paine SJ, Fink J, Gander PH, Warman GR. Identifying advanced and delayed sleep phase
disorders in the general population: a national survey of New Zealand adults. Chronobiol Int.
2014;31(5):627–36. https://doi.org/10.3109/07420528.2014.885036.
22. Saxvig IW, Pallesen S, Wilhelmsen-Langeland A, Molde H, Bjorvatn B. Prevalence and cor-
relates of delayed sleep phase in high school students. Sleep Med. 2012;13(2):193–9. https://
doi.org/10.1016/j.sleep.2011.10.024.
23. Sivertsen B, Pallesen S, Stormark KM, Boe T, Lundervold AJ, Hysing M. Delayed sleep
phase syndrome in adolescents: prevalence and correlates in a large population based study.
BMC Public Health. 2013;13:1163. https://doi.org/10.1186/1471-2458-13-1163.
24. Kim JH, Duffy JF. Circadian rhythm sleep-wake disorders in older adults. Sleep Med Clin.
2018;13(1):39–50. https://doi.org/10.1016/j.jsmc.2017.09.004.
25. Duffy JF, Rimmer DW, Czeisler CA. Association of intrinsic circadian period with
morningness- eveningness, usual wake time, and circadian phase. Behav Neurosci.
2001;115(4):895–9. https://doi.org/10.1037//0735-7044.115.4.895.
26. Emens JS, Yuhas K, Rough J, Kochar N, Peters D, Lewy AJ. Phase angle of entrainment in
morning- and evening-types under naturalistic conditions. Chronobiol Int. 2009;26(3):474–93.
https://doi.org/10.1080/07420520902821077.
27. Lazar AS, Santhi N, Hasan S, Lo JC, Johnston JD, Von Schantz M, Archer SN, Dijk
DJ. Circadian period and the timing of melatonin onset in men and women: predictors of
sleep during the weekend and in the laboratory. J Sleep Res. 2013;22(2):155–9. https://doi.
org/10.1111/jsr.12001.
28. Ozaki S, Uchiyama M, Shirakawa S, Okawa M. Prolonged interval from body temperature
nadir to sleep offset in patients with delayed sleep phase syndrome. Sleep. 1996;19(1):36–40.
29. Shibui K, Uchiyama M, Okawa M. Melatonin rhythms in delayed sleep phase syndrome. J
Biol Rhythm. 1999;14(1):72–6. https://doi.org/10.1177/074873049901400110.
30. Uchiyama M, Okawa M, Shibui K, Kim K, Tagaya H, Kudo Y, Kamei Y, Hayakawa T, Urata
J, Takahashi K. Altered phase relation between sleep timing and core body temperature
rhythm in delayed sleep phase syndrome and non-24-hour sleep-wake syndrome in humans.
Neurosci Lett. 2000;294(2):101–4. https://doi.org/10.1016/s0304-3940(00)01551-2.
31. Wyatt JK, Stepanski EJ, Kirkby J. Circadian phase in delayed sleep phase syndrome: predic-
tors and temporal stability across multiple assessments. Sleep. 2006;29(8):1075–80. https://
doi.org/10.1093/sleep/29.8.1075.
32. Uchiyama M, Okawa M, Shibui K, Liu X, Hayakawa T, Kamei Y, Takahashi K. Poor com-
pensatory function for sleep loss as a pathogenic factor in patients with delayed sleep phase
syndrome. Sleep. 2000;23(4):553–8.
33. Joo EY, Abbott SM, Reid KJ, Wu D, Kang J, Wilson J, Zee PC. Timing of light exposure
and activity in adults with delayed sleep-wake phase disorder. Sleep Med. 2017;32:259–65.
https://doi.org/10.1016/j.sleep.2016.09.009.
34. Aoki H, Ozeki Y, Yamada N. Hypersensitivity of melatonin suppression in response to light
in patients with delayed sleep phase syndrome. Chronobiol Int. 2001;18(2):263–71. https://
doi.org/10.1081/cbi-100103190.
35. Watson LA, Phillips AJK, Hosken IT, McGlashan EM, Anderson C, Lack LC, Lockley SW,
Rajaratnam SMW, Cain SW. Increased sensitivity of the circadian system to light in delayed
sleep-wake phase disorder. J Physiol. 2018;596(24):6249–61. https://doi.org/10.1113/
JP275917.
36. Wilson J, Reid KJ, Braun RI, Abbott SM, Zee PC. Habitual light exposure relative to circadian
timing in delayed sleep-wake phase disorder. Sleep. 2018;41(11) https://doi.org/10.1093/
sleep/zsy166.
37. Heath AC, Kendler KS, Eaves LJ, Martin NG. Evidence for genetic influences on sleep
disturbance and sleep pattern in twins. Sleep. 1990;13(4):318–35. https://doi.org/10.1093/
sleep/13.4.318.
38. Hur YM. Stability of genetic influence on morningness-eveningness: a cross-sectional

examination of south Korean twins from preadolescence to young adulthood. J Sleep Res.
2007;16(1):17–23. https://doi.org/10.1111/j.1365-2869.2007.00562.x.
39. Koskenvuo M, Hublin C, Partinen M, Heikkila K, Kaprio J. Heritability of diurnal type:
a nationwide study of 8753 adult twin pairs. J Sleep Res. 2007;16(2):156–62. https://doi.
org/10.1111/j.1365-2869.2007.00580.x.
40. Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, von Schantz M. A
length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syn-
drome and extreme diurnal preference. Sleep. 2003;26(4):413–5. https://doi.org/10.1093/
sleep/26.4.413.
41. Pereira DS, Tufik S, Louzada FM, Benedito-Silva AA, Lopez AR, Lemos NA, Korczak AL,
D'Almeida V, Pedrazzoli M. Association of the length polymorphism in the human Per3
gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? Sleep.
2005;28(1):29–32.
42. Patke A, Murphy PJ, Onat OE, Krieger AC, Ozcelik T, Campbell SS, Young MW. Mutation
of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell.
2017;169(2):203–215 e213. https://doi.org/10.1016/j.cell.2017.03.027.
43. Miyagawa T, Hida A, Shimada M, Uehara C, Nishino Y, Kadotani H, Uchiyama M, Ebisawa
T, Inoue Y, Kamei Y, Tokunaga K, Mishima K, Honda M. A missense variant in PER2 is
associated with delayed sleep-wake phase disorder in a Japanese population. J Hum Genet.
2019;64(12):1219–25. https://doi.org/10.1038/s10038-019-0665-6.
44. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM (2015) Clinical
Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders:
Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder
(DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-
Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of sleep
medicine clinical practice guideline. J Clin Sleep Med 11 (10):1199–1236. doi:https://doi.
org/10.5664/jcsm.5100.
45. Murray JM, Sletten TL, Magee M, Gordon C, Lovato N, Bartlett DJ, Kennaway DJ, Lack
LC, Grunstein RR, Lockley SW, Rajaratnam SM, Delayed Sleep on Melatonin Study
G. Prevalence of circadian misalignment and its association with depressive symptoms in
delayed sleep phase disorder. Sleep. 2017;40(1) https://doi.org/10.1093/sleep/zsw002.
46. Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness
in human circadian rhythms. Int J Chronobiol. 1976;4(2):97–110.
47. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP Jr, Vitiello MV, Zhdanova IV,
American Academy of Sleep M. Circadian rhythm sleep disorders: part II, advanced sleep
phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake
rhythm. An American Academy of sleep medicine review. Sleep. 2007;30(11):1484–501.
https://doi.org/10.1093/sleep/30.11.1484.
48. Abbott SM, Reid KJ, Zee PC. Circadian rhythm sleep-wake disorders. Psychiatr Clin North
Am. 2015;38(4):805–23. https://doi.org/10.1016/j.psc.2015.07.012.
49. Czeisler CA, Richardson GS, Coleman RM, Zimmerman JC, Moore-Ede MC, Dement WC,
Weitzman ED. Chronotherapy: resetting the circadian clocks of patients with delayed sleep
phase insomnia. Sleep. 1981;4(1):1–21. https://doi.org/10.1093/sleep/4.1.1.
50. Oren DA, Wehr TA. Hypernyctohemeral syndrome after chronotherapy for delayed
sleep phase syndrome. N Engl J Med. 1992;327(24):1762. https://doi.org/10.1056/
NEJM199212103272417.
51. van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed
sleep phase disorder: a meta-analysis. Sleep. 2010;33(12):1605–14. https://doi.org/10.1093/
sleep/33.12.1605.
52. Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC. Phase-dependent treatment
of delayed sleep phase syndrome with melatonin. Sleep. 2005;28(10):1271–8. https://doi.
org/10.1093/sleep/28.10.1271.
53. Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, Gwini SM,
Bartlett DJ, Lockley SW, Lack LC, Grunstein RR, Rajaratnam SMW, Delayed Sleep on
Melatonin Study G. Efficacy of melatonin with behavioural sleep-wake scheduling for
delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med.
2018;15(6):e1002587. https://doi.org/10.1371/journal.pmed.1002587.
54. Burgess HJ, Swanson GR, Keshavarzian A. Endogenous melatonin profiles in asymptom-
atic inflammatory bowel disease. Scand J Gastroenterol. 2010;45(6):759–61. https://doi.
org/10.3109/00365521003749818.
55. Rosenthal NE, Joseph-Vanderpool JR, Levendosky AA, Johnston SH, Allen R, Kelly KA,
Souetre E, Schultz PM, Starz KE. Phase-shifting effects of bright morning light as treatment
for delayed sleep phase syndrome. Sleep. 1990;13(4):354–61.
56. Minors DS, Waterhouse JM, Wirz-Justice A. A human phase-response curve to light.
Neurosci Lett. 1991;133(1):36–40. https://doi.org/10.1016/0304-3940(91)90051-t.
57. Burke TM, Markwald RR, Chinoy ED, Snider JA, Bessman SC, Jung CM, Wright KP Jr.
Combination of light and melatonin time cues for phase advancing the human circadian
clock. Sleep. 2013;36(11):1617–24. https://doi.org/10.5665/sleep.3110.
58. Wilhelmsen-Langeland A, Saxvig IW, Pallesen S, Nordhus IH, Vedaa O, Lundervold AJ,
Bjorvatn B. A randomized controlled trial with bright light and melatonin for the treatment
of delayed sleep phase disorder: effects on subjective and objective sleepiness and cognitive
function. J Biol Rhythm. 2013;28(5):306–21. https://doi.org/10.1177/0748730413500126.
59. Crowley SJ, Eastman CI. Phase advancing human circadian rhythms with morning bright
light, afternoon melatonin, and gradually shifted sleep: can we reduce morning bright-light
duration? Sleep Med. 2015;16(2):288–97. https://doi.org/10.1016/j.sleep.2014.12.004.
60. Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L,
Ptacek LJ. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant
in humans. Nat Med. 1999;5(9):1062–5. https://doi.org/10.1038/12502.
61. Kurien P, Hsu PK, Leon J, Wu D, McMahon T, Shi G, Xu Y, Lipzen A, Pennacchio LA,
Jones CR, Fu YH, Ptacek LJ. TIMELESS mutation alters phase responsiveness and causes
advanced sleep phase. Proc Natl Acad Sci U S A. 2019;116(24):12045–53. https://doi.
org/10.1073/pnas.1819110116.
62. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH. An hPer2
phosphorylation site mutation in familial advanced sleep phase syndrome. Science.
2001;291(5506):1040–3. https://doi.org/10.1126/science.1057499.
63. Curtis BJ, Ashbrook LH, Young T, Finn LA, Fu YH, Ptacek LJ, Jones CR. Extreme morn-
ing chronotypes are often familial and not exceedingly rare: the estimated prevalence of
advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disor-
der in a sleep clinic population. Sleep. 2019;42(10) https://doi.org/10.1093/sleep/zsz148.
64. Ashbrook LH, Krystal AD, Fu YH, Ptacek LJ. Genetics of the human circadian clock and
sleep homeostat. Neuropsychopharmacology. 2020;45(1):45–54. https://doi.org/10.1038/
s41386-019-0476-7.
65. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptacek LJ, Fu
YH. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase
syndrome. Nature. 2005;434(7033):640–4. https://doi.org/10.1038/nature03453.
66. Zhang L, Hirano A, Hsu PK, Jones CR, Sakai N, Okuro M, McMahon T, Yamazaki M, Xu Y,
Saigoh N, Saigoh K, Lin ST, Kaasik K, Nishino S, Ptacek LJ, Fu YH. A PERIOD3 variant
causes a circadian phenotype and is associated with a seasonal mood trait. Proc Natl Acad Sci
U S A. 2016;113(11):E1536–44. https://doi.org/10.1073/pnas.1600039113.
67. Hirano A, Shi G, Jones CR, Lipzen A, Pennacchio LA, Xu Y, Hallows WC, McMahon T,
Yamazaki M, Ptacek LJ, Fu YH. A Cryptochrome 2 mutation yields advanced sleep phase in
humans. Elife. 2016;5 https://doi.org/10.7554/eLife.16695.
68. Lack L, Wright H. The effect of evening bright light in delaying the circadian rhythms and
lengthening the sleep of early morning awakening insomniacs. Sleep. 1993;16(5):436–43.
69. Lack L, Wright H, Kemp K, Gibbon S. The treatment of early-morning awakening insom-
nia with 2 evenings of bright light. Sleep. 2005;28(5):616–23. https://doi.org/10.1093/
sleep/28.5.616.
70. Campbell SS, Dawson D, Anderson MW. Alleviation of sleep maintenance insomnia
with timed exposure to bright light. J Am Geriatr Soc. 1993;41(8):829–36. https://doi.
org/10.1111/j.1532-5415.1993.tb06179.x.
71. Lewy AJ, Bauer VK, Ahmed S, Thomas KH, Cutler NL, Singer CM, Moffit MT, Sack RL. 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. https://doi.org/10.3109/07420529808998671.
72. Moldofsky H, Musisi S, Phillipson EA. Treatment of a case of advanced sleep phase syn-
drome by phase advance chronotherapy. Sleep. 1986;9(1):61–5. https://doi.org/10.1093/
sleep/9.1.61.
73. Tabandeh H, Lockley SW, Buttery R, Skene DJ, Defrance R, Arendt J, Bird AC. Disturbance
of sleep in blindness. Am J Ophthalmol. 1998;126(5):707–12. https://doi.org/10.1016/
s0002-9394(98)00133-0.
74. Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormali-
ties in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab.
1992;75(1):127–34. https://doi.org/10.1210/jcem.75.1.1619000.
75. Flynn-Evans EE, Tabandeh H, Skene DJ, Lockley SW. Circadian rhythm disorders and mela-
tonin production in 127 blind women with and without light perception. J Biol Rhythm.
2014;29(3):215–24. https://doi.org/10.1177/0748730414536852.
76. Hayakawa T, Uchiyama M, Kamei Y, Shibui K, Tagaya H, Asada T, Okawa M, Urata J,
Takahashi K. Clinical analyses of sighted patients with non-24-hour sleep-wake syn-
drome: a study of 57 consecutively diagnosed cases. Sleep. 2005;28(8):945–52. https://doi.
org/10.1093/sleep/28.8.945.
77. Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R. Relationship between
melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab. 1997;82(11):3763–70.
https://doi.org/10.1210/jcem.82.11.4355.
78. Emens JS, Lewy AJ, Lefler BJ, Sack RL. Relative coordination to unknown "weak zeit-
gebers" in free-running blind individuals. J Biol Rhythm. 2005;20(2):159–67. https://doi.
org/10.1177/0748730404273294.
79. Kitamura S, Hida A, Enomoto M, Watanabe M, Katayose Y, Nozaki K, Aritake S, Higuchi S,
Moriguchi Y, Kamei Y, Mishima K. Intrinsic circadian period of sighted patients with circa-
dian rhythm sleep disorder, free-running type. Biol Psychiatry. 2013;73(1):63–9. https://doi.
org/10.1016/j.biopsych.2012.06.027.
80. Malkani RG, Abbott SM, Reid KJ, Zee PC. Diagnostic and treatment challenges of sighted
Non-24-hour sleep-wake disorder. J Clin Sleep Med. 2018;14(4):603–13. https://doi.
org/10.5664/jcsm.7054.
81. McArthur AJ, Lewy AJ, Sack RL. Non-24-hour sleep-wake syndrome in a sighted man:
circadian rhythm studies and efficacy of melatonin treatment. Sleep. 1996;19(7):544–53.
82. Nakamura K, Hashimoto S, Honma S, Honma K. Daily melatonin intake resets circadian
rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal
melatonin rise. Psychiatry Clin Neurosci. 1997;51(3):121–7. https://doi.org/10.1111/j.1440-
1819.1997.tb02373.x.
83. Boivin DB, James FO, Santo JB, Caliyurt O, Chalk C. Non-24-hour sleep-wake syndrome
following a car accident. Neurology. 2003;60(11):1841–3. https://doi.org/10.1212/01.
wnl.0000061482.24750.7c.
84. Wulff K, Dijk DJ, Middleton B, Foster RG, Joyce EM. Sleep and circadian rhythm dis-
ruption in schizophrenia. Br J Psychiatry. 2012;200(4):308–16. https://doi.org/10.1192/bjp.
bp.111.096321.
85. Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. Melatonin administration can
entrain the free-running circadian system of blind subjects. J Endocrinol. 2000;164(1):R1–6.
https://doi.org/10.1677/joe.0.164r001.
86. Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms
by melatonin in blind people. N Engl J Med. 2000;343(15):1070–7. https://doi.org/10.1056/
NEJM200010123431503.
87. Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires ML, Sack RL. Capturing the cir-
cadian rhythms of free-running blind people with 0.5 mg melatonin. Brain Res.
2001;918(1–2):96–100. https://doi.org/10.1016/s0006-8993(01)02964-x.
88. Hack LM, Lockley SW, Arendt J, Skene DJ. The effects of low-dose 0.5-mg melatonin on the
free-running circadian rhythms of blind subjects. J Biol Rhythm. 2003;18(5):420–9. https://
doi.org/10.1177/0748730403256796.
89. Lockley SW, Dressman MA, Licamele L, Xiao C, Fisher DM, Flynn-Evans EE, Hull JT,
Torres R, Lavedan C, Polymeropoulos MH. Tasimelteon for non-24-hour sleep-wake dis-
order in totally blind people (SET and RESET): two multicentre, randomised, double-
masked, placebo-controlled phase 3 trials. Lancet. 2015;386(10005):1754–64. https://doi.
org/10.1016/S0140-6736(15)60031-9.
90. Tomoda A, Miike T, Uezono K, Kawasaki T. A school refusal case with biological rhythm
disturbance and melatonin therapy. Brain and Development. 1994;16(1):71–6. https://doi.
org/10.1016/0387-7604(94)90117-1.
91. Hoban TM, Sack RL, Lewy AJ, Miller LS, Singer CM. Entrainment of a free-
running human with bright light? Chronobiol Int. 1989;6(4):347–53. https://doi.
org/10.3109/07420528909056941.
92. Oren DA, Giesen HA, Wehr TA. Restoration of detectable melatonin after entrainment to
a 24-hour schedule in a 'free-running' man. Psychoneuroendocrinology. 1997;22(1):39–52.
https://doi.org/10.1016/s0306-4530(96)00038-8.
93. Brown MA, Quan SF, Eichling PS. Circadian rhythm sleep disorder, free-running type
in a sighted male with severe depression, anxiety, and agoraphobia. J Clin Sleep Med.
2011;7(1):93–4.
94. Kuzniar TJ, Kovacevic-Ristanovic R, Nierodzik CL, Smith LC. Free-running (non-entrained
to 24-h period) circadian sleep disorder in a patient with obstructive sleep apnea, delayed
sleep phase tendency, and lack of social interaction. Sleep Breath. 2012;16(2):313–5. https://
doi.org/10.1007/s11325-011-0535-8.
95. Edgar DM, Miller JD, Prosser RA, Dean RR, Dement WC. Serotonin and the mammalian
circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists. J Biol
Rhythm. 1993;8(1):17–31. https://doi.org/10.1177/074873049300800102.
96. Van Someren EJ, Riemersma RF, Swaab DF. Functional plasticity of the circadian timing
system in old age: light exposure. Prog Brain Res. 2002;138:205–31. https://doi.org/10.1016/
S0079-6123(02)38080-4.
97. Swaab DF, Dubelaar EJ, Hofman MA, Scherder EJ, van Someren EJ, Verwer RW. Brain
aging and Alzheimer's disease; use it or lose it. Prog Brain Res. 2002;138:343–73. https://doi.
org/10.1016/S0079-6123(02)38086-5.
98. Havekes R, Heckman PRA, Wams EJ, Stasiukonyte N, Meerlo P, Eisel ULM. Alzheimer's dis-
ease pathogenesis: the role of disturbed sleep in attenuated brain plasticity and neurodegener-
ative processes. Cell Signal. 2019;64:109420. https://doi.org/10.1016/j.cellsig.2019.109420.
99. Zee PC, Vitiello MV. Circadian rhythm sleep disorder: irregular sleep wake rhythm type.
Sleep Med Clin. 2009;4(2):213–8. https://doi.org/10.1016/j.jsmc.2009.01.009.
100. Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Morning bright light
therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatr
Scand. 1994;89(1):1–7. https://doi.org/10.1111/j.1600-0447.1994.tb01477.x.
101. Ancoli-Israel S, Gehrman P, Martin JL, Shochat T, Marler M, Corey-Bloom J, Levi
L. Increased light exposure consolidates sleep and strengthens circadian rhythms in severe
Alzheimer's disease patients. Behav Sleep Med. 2003;1(1):22–36. https://doi.org/10.1207/

S15402010BSM0101_4.
102. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren
EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly res-
idents of group care facilities: a randomized controlled trial. JAMA. 2008;299(22):2642–55.
https://doi.org/10.1001/jama.299.22.2642.
103. McCurry SM, Gibbons LE, Logsdon RG, Vitiello MV, Teri L. Nighttime insomnia treat-
ment and education for Alzheimer's disease: a randomized, controlled trial. J Am Geriatr Soc.
2005;53(5):793–802. https://doi.org/10.1111/j.1532-5415.2005.53252.x.
104. Alessi CA, Martin JL, Webber AP, Cynthia Kim E, Harker JO, Josephson KR. Randomized,
controlled trial of a nonpharmacological intervention to improve abnormal sleep/wake
patterns in nursing home residents. J Am Geriatr Soc. 2005;53(5):803–10. https://doi.
org/10.1111/j.1532-5415.2005.53251.x.
105. Guilleminault C, McCann CC, Quera-Salva M, Cetel M. Light therapy as treatment of
dyschronosis in brain impaired children. Eur J Pediatr. 1993;152(9):754–9. https://doi.
org/10.1007/BF01953995.
106. Wright B, Sims D, Smart S, Alwazeer A, Alderson-Day B, Allgar V, Whitton C, Tomlinson
H, Bennett S, Jardine J, McCaffrey N, Leyland C, Jakeman C, Miles J. Melatonin versus
placebo in children with autism spectrum conditions and severe sleep problems not amenable
to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev
Disord. 2011;41(2):175–84. https://doi.org/10.1007/s10803-010-1036-5.
107. Cheng P, Drake CL. Psychological impact of shift Work. Curr Sleep Med Rep.
2018;4(2):104–9.
108. Brown JP, Martin D, Nagaria Z, Verceles AC, Jobe SL, Wickwire EM. Mental health con-
sequences of shift Work: an updated review. Curr Psychiatry Rep. 2020;22(2):7. https://doi.
org/10.1007/s11920-020-1131-z.
109. Morgenthaler T, Alessi C, Friedman L, Owens J, Kapur V, Boehlecke B, Brown T, Chesson
A Jr, Coleman J, Lee-Chiong T, Pancer J, Swick TJ, Standards of Practice C, American
Academy of Sleep M. Practice parameters for the use of actigraphy in the assessment of sleep
and sleep disorders: an update for 2007. Sleep. 2007;30(4):519–29. https://doi.org/10.1093/
sleep/30.4.519.
110. Yong LC, Li J, Calvert GM. Sleep-related problems in the US working population: preva-
lence and association with shiftwork status. Occup Environ Med. 2017;74(2):93–104. https://
doi.org/10.1136/oemed-2016-103638.
111. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence
and consequences beyond that of symptomatic day workers. Sleep. 2004;27(8):1453–62.
112. Harma MI, Hakola T, Akerstedt T, Laitinen JT. Age and adjustment to night work. Occup
Environ Med. 1994;51(8):568–73. https://doi.org/10.1136/oem.51.8.568.
113. Ritonja J, Aronson KJ, Matthews RW, Boivin DB, Kantermann T. Working time society
consensus statements: individual differences in shift work tolerance and recommendations
for research and practice. Ind Health. 2019;57(2):201–12. https://doi.org/10.2486/ind-
health.SW-5.
114. Pilcher JJ, Lambert BJ, Huffcutt AI. Differential effects of permanent and rotating shifts on
self-report sleep length: a meta-analytic review. Sleep. 2000;23(2):155–63.
115. Gumenyuk V, Belcher R, Drake CL, Roth T. Differential sleep, sleepiness, and neurophysiol-
ogy in the insomnia phenotypes of shift work disorder. Sleep. 2015;38(1):119–26. https://doi.
org/10.5665/sleep.4336.
116. Zee PC, Attarian H, Videnovic A. Circadian rhythm abnormalities. Continuum
(Minneap Minn). 2013;19(1 Sleep Disorders):132–47. https://doi.org/10.1212/01.
CON.0000427209.21177.aa.
117. Booker LA, Magee M, Rajaratnam SMW, Sletten TL, Howard ME. Individual vulner-
ability to insomnia, excessive sleepiness and shift work disorder amongst healthcare shift
workers. A systematic review. Sleep Med Rev. 2018;41:220–33. https://doi.org/10.1016/j.

smrv.2018.03.005.
118. Barger LK, Cade BE, Ayas NT, Cronin JW, Rosner B, Speizer FE, Czeisler CA, Harvard
Work Hours H, Safety G. Extended work shifts and the risk of motor vehicle crashes among
interns. N Engl J Med. 2005;352(2):125–34. https://doi.org/10.1056/NEJMoa041401.
119. Ftouni S, Sletten TL, Howard M, Anderson C, Lenne MG, Lockley SW, Rajaratnam
SM. Objective and subjective measures of sleepiness, and their associations with on-road driv-
ing events in shift workers. J Sleep Res. 2013;22(1):58–69. https://doi.org/10.1111/j.1365-
2869.2012.01038.x.
120. Purnell MT, Feyer AM, Herbison GP. The impact of a nap opportunity during the night shift
on the performance and alertness of 12-h shift workers. J Sleep Res. 2002;11(3):219–27.
https://doi.org/10.1046/j.1365-2869.2002.00309.x.
121. Garbarino S, Mascialino B, Penco MA, Squarcia S, De Carli F, Nobili L, Beelke M, Cuomo
G, Ferrillo F. Professional shift-work drivers who adopt prophylactic naps can reduce the risk
of car accidents during night work. Sleep. 2004;27(7):1295–302. https://doi.org/10.1093/
sleep/27.7.1295.
122. Schweitzer PK, Randazzo AC, Stone K, Erman M, Walsh JK. Laboratory and field studies
of naps and caffeine as practical countermeasures for sleep-wake problems associated with
night work. Sleep. 2006;29(1):39–50. https://doi.org/10.1093/sleep/29.1.39.
123. Burgess HJ, Sharkey KM, Eastman CI. Bright light, dark and melatonin can promote circa-
dian adaptation in night shift workers. Sleep Med Rev. 2002;6(5):407–20.
124. Lowden A, Ozturk G, Reynolds A, Bjorvatn B. Working time society consensus statements:
evidence based interventions using light to improve circadian adaptation to working hours.
Ind Health. 2019;57(2):213–27. https://doi.org/10.2486/indhealth.SW-9.
125. Liira J, Verbeek J, Ruotsalainen J. Pharmacological interventions for sleepiness and sleep
disturbances caused by shift work. JAMA. 2015;313(9):961–2. https://doi.org/10.1001/
jama.2014.18422.
126. Czeisler CA, Walsh JK, Wesnes KA, Arora S, Roth T. Armodafinil for treatment of excessive
sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin
Proc. 2009;84(11):958–72. https://doi.org/10.1016/S0025-6196(11)60666-6.
127. Erman MK, Seiden DJ, Yang R, Dammerman R. Efficacy and tolerability of armodafinil:
effect on clinical condition late in the shift and overall functioning of patients with excessive
sleepiness associated with shift work disorder. J Occup Environ Med. 2011;53(12):1460–5.
https://doi.org/10.1097/JOM.0b013e318237a17e.
128. Drake C, Gumenyuk V, Roth T, Howard R. Effects of armodafinil on simulated driving
and alertness in shift work disorder. Sleep. 2014;37(12):1987–94. https://doi.org/10.5665/
sleep.4256.
129. Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, Arora S, Schwartz JR,
Niebler GE, Dinges DF, Group USMiSWSDS. Modafinil for excessive sleepiness associated
with shift-work sleep disorder. N Engl J Med. 2005;353(5):476–86. https://doi.org/10.1056/
NEJMoa041292.
130. Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN. Effectiveness of
non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submit-
ted to the Food and Drug Administration. BMJ. 2012;345:e8343. https://doi.org/10.1136/
bmj.e8343.
131. Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, Klassen TP, Witmans
M. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of
RCTs. J Gen Intern Med. 2007;22(9):1335–50. https://doi.org/10.1007/s11606-007-0251-z.
132. Walsh JK, Schweitzer PK, Anch AM, Muehlbach MJ, Jenkins NA, Dickins QS. Sleepiness/
alertness on a simulated night shift following sleep at home with triazolam. Sleep.
1991;14(2):140–6.
133. Balkin TJ, O'Donnell VM, Wesensten N, McCann U, Belenky G. Comparison of the day-
time sleep and performance effects of zolpidem versus triazolam. Psychopharmacology.
1992;107(1):83–8. https://doi.org/10.1007/BF02244970.
134. Vetter C, Fischer D, Matera JL, Roenneberg T. Aligning work and circadian time in shift
workers improves sleep and reduces circadian disruption. Curr Biol. 2015;25(7):907–11.
https://doi.org/10.1016/j.cub.2015.01.064.
135. Herxheimer A. Jet lag. BMJ Clin Evid. 2014;2014
136. Moline ML, Pollak CP, Monk TH, Lester LS, Wagner DR, Zendell SM, Graeber RC,
Salter CA, Hirsch E. Age-related differences in recovery from simulated jet lag. Sleep.
1992;15(1):28–40. https://doi.org/10.1093/sleep/15.1.28.
137. Waterhouse J, Edwards B, Nevill A, Carvalho S, Atkinson G, Buckley P, Reilly T, Godfrey
R, Ramsay R. Identifying some determinants of "jet lag" and its symptoms: a study of
athletes and other travellers. Br J Sports Med. 2002;36(1):54–60. https://doi.org/10.1136/
bjsm.36.1.54.
138. Sack RL. The pathophysiology of jet lag. Travel Med Infect Dis. 2009;7(2):102–10. https://
doi.org/10.1016/j.tmaid.2009.01.006.
139. Waterhouse J, Reilly T, Atkinson G, Edwards B. Jet lag: trends and coping strategies. Lancet.
2007;369(9567):1117–29. https://doi.org/10.1016/S0140-6736(07)60529-7.
140. Paul MA, Gray GW, Lieberman HR, Love RJ, Miller JC, Trouborst M, Arendt J. Phase
advance with separate and combined melatonin and light treatment. Psychopharmacology.
2011;214(2):515–23. https://doi.org/10.1007/s00213-010-2059-5.
141. Burgess HJ, Crowley SJ, Gazda CJ, Fogg LF, Eastman CI. Preflight adjustment to eastward
travel: 3 days of advancing sleep with and without morning bright light. J Biol Rhythm.
2003;18(4):318–28. https://doi.org/10.1177/0748730403253585.
142. Eastman CI, Gazda CJ, Burgess HJ, Crowley SJ, Fogg LF. Advancing circadian rhythms
before eastward flight: a strategy to prevent or reduce jet lag. Sleep. 2005;28(1):33–44.
143. Revell VL, Burgess HJ, Gazda CJ, Smith MR, Fogg LF, Eastman CI. Advancing human
circadian rhythms with afternoon melatonin and morning intermittent bright light. J Clin
Endocrinol Metab. 2006;91(1):54–9. https://doi.org/10.1210/jc.2005-1009.
144. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane
Database Syst Rev. 2002;2:CD001520. https://doi.org/10.1002/14651858.CD001520.
145. Lu Z, Klein-Cardena K, Lee S, Antonsen TM, Girvan M, Ott E. Resynchronization of circa-
dian oscillators and the east-west asymmetry of jet-lag. Chaos. 2016;26(9):094811. https://
doi.org/10.1063/1.4954275.
Chapter 15
Narcolepsy and Idiopathic Hypersomnia
Imran Ahmed and Michael Thorpy
Keywords Narcolepsy · Idiopathic hypersomnia · Symptoms · Epidemiology

Pathophysiology · Diagnosis · Differential · Pediatric · Treatment
Introduction
Narcolepsy was originally described by Gelineau in 1880 as a disorder involving

excessive sleepiness and sleep attacks associated with a variety of emotional states.
He also described episodes of falls or “astasia” which was later termed cataplexy.
Our understanding of narcolepsy has since advanced. In the 1950s sleep onset REM
periods were identified as a prominent feature in narcolepsy. In the latter part of the
1900s, the discovery of the association between narcolepsy and the Human
Leukocyte antigens (HLA) DRB1*1501/DRB1*1503 and with DQB1*0602 sug-
gested an autoimmune process. Also, the discovery by two independent groups in
2005 of a reduction in the neuropeptide, hypocretin/orexin, is now strongly believed
to be responsible for many of the symptoms of narcolepsy. Around 2010, our under-
standing of the genetic factors and environmental factors (e.g., vaccines, infections)
associated with narcolepsy has given us a window into the pathophysiology of the
disorder.
Additionally, in 2013, the International Classification of Sleep Disorders, third
edition (ICSD-3), categorized narcolepsy into two different types: narcolepsy type
1 and narcolepsy type 2 based on cataplexy and the deficiency, or non-deficiency, of
hypocretin/orexin, respectively. The terms that classified narcolepsy based on the
presence or absence of cataplexy, as used by the International Classification of
I. Ahmed (*) · M. Thorpy

Sleep-Wake Disorders Center, Montefiore Medical Center, and Albert Einstein College of
Medicine, Bronx, NY, USA
e-mail: iahmed@montefiore.org

328 I. Ahmed and M. Thorpy
Sleep Disorders, second edition, were deemed inappropriate as some patients with-
out cataplexy will also have low cerebrospinal fluid hypocretin levels.
The term “idiopathic hypersomnia” was first used in 1976 by Bedrich Roth to
describe a disorder with both a monosymptomatic and a polysymptomatic form.
The monosymptomatic form exhibits only EDS, whereas the polysymptomatic
form manifests not only symptoms of EDS but also a long duration of the major
sleep period and a prominent sleep inertia upon awakening. Accordingly, in 2005,
the ICSD-2 classified idiopathic hypersomnia into two types, one associated with a
prolonged sleep episode at night, which was called idiopathic hypersomnia with
long sleep time, and another that has a normal duration of sleep at night called idio-
pathic hypersomnia without long sleep time. The ICSD-3 eliminated the division of
the idiopathic hypersomnia’s classification based on the sleep duration because of
the lack of validity for such a division based on sleep duration and classifies it only
as idiopathic hypersomnia.
Clinical Features
Narcolepsy
Narcolepsy is described as a syndrome consisting of EDS (including periods of

irresistible sleep), cataplexy, sleep paralysis, and hypnagogic hallucinations; addi-
tional features include frequent and vivid dreams, automatic behaviors, and frag-
mented or disrupted nighttime sleep. The effects of narcolepsy can be considered a
manifestation of REM sleep dissociation, with features of REM sleep that intrude
into sleep and wakefulness.
Narcolepsy typically begins with the symptom of excessive sleepiness, and other
symptoms of variable severity can develop slowly, suddenly, or not at all.
Occasionally, cataplexy can develop first and then later be followed by the develop-
ment of excessive sleepiness; this is especially true in children, where sleepiness is
disguised as behavioral abnormalities [1]. Narcolepsy patients often have an irre-
sistible urge to sleep, which often occurs at inopportune times whether it is during
monotonous sedentary tasks or while performing mentally or physically demanding
activities. For instance, they can fall asleep while eating, while sitting at a meeting,
during phone conversations, during sexual intercourse, or while driving a car. These
sleep episodes occur about 3–5 times/day in most patients and usually vary from a
few minutes to several hours in duration [2]. Patients often report that after these
sleep episodes or after taking scheduled naps, they wake up feeling refreshed and
may not feel sleepy again for up to a few hours later; however, there are also many
patients who indicate persistent (although perhaps somewhat improved) sleepiness
despite taking these naps. Patients can also experience microsleep events, which are
seconds or less of sleep that intrude into the waking state. Patients are not aware of
the microsleep episodes and continue the activities they were performing. It is likely
15 Narcolepsy and Idiopathic Hypersomnia 329
that such episodes are at least partially associated with patients’ complaints of dif-
ficulty concentrating, inattention, or memory impairment.
In children, it is difficult to identify classic narcolepsy symptoms since many are
not able to provide an accurate history of cataplexy, sleep-related hallucinations, or
sleep paralysis. Sleepiness may also manifest as behavioral problems (e.g., irritabil-
ity, hyperactivity), decreased performance, inattentiveness, lack of energy, or bizarre
hallucinations that makes it even more difficult to diagnose narcolepsy. Furthermore,
when excessive sleepiness is present, it can often be mistaken for normal behaviors
in children of preschool age, as they usually take habitual naps. Occasionally in
school-aged children, excessive sleepiness can be identified when there is a reap-
pearance of daytime naps in a child who had previously discontinued regular nap-
ping [3].
Cataplexy is the most specific symptom of narcolepsy consisting of an abrupt,
bilateral (occasionally unilateral) loss of skeletal muscle tone; it is associated with
narcolepsy type 1. It is usually triggered by the occurrence of sudden emotion such
as laughter or humorous experiences; sometimes even the memory of a humorous
event can precipitate an attack. Other triggers for cataplexy include anger, embar-
rassment, surprise, stress, or even sexual arousal [4]. During a cataplexy attack,
which can last up to several minutes, the patient is unable to move; however, the
diaphragm and ocular muscles are unaffected. During this time, the patient remains
awake, aware of their surroundings and able to remember the details of the event
and comments or questions that were made to them. If the attack is prolonged, how-
ever, sleep can follow. More commonly, attacks of cataplexy are partial, affecting
only certain muscle groups, such as the arms, neck, or face. During partial cataplexy
attacks, the jaw may sag, the head can droop, and speech may become garbled [5].
Deep tendon reflexes are usually absent during generalized cataplexy episodes;
however, they have been reported to be persistent during partial attacks [6]. In chil-
dren, atypical manifestations of cataplexy can include blurred vision, irregular
breathing, sudden loss of smiling, or “semipermanent eyelid and jaw weakness.”
Additionally, children’s cataplexy may also manifest as subtle and unusual facial
expressions or choreic-like movements which are not seen in adults [7, 8].
Sleep-related hallucinations, sleep paralysis, and automatic behaviors are com-
mon manifestations of many disorders that disrupt/fragment sleep and cause exces-
sive sleepiness, including narcolepsy and idiopathic hypersomnia [9]. Similar to
cataplexy, patients with sleep paralysis experience a brief loss of voluntary muscle
control with an inability to move or speak, but retain awareness during the event.
Unlike cataplexy, these episodes are not provoked by intense emotion or stress. The
phenomena usually occur during sleep–wake transitions and are often associated
with fearful sleep-related hallucinations, hypnopompic or hypnagogic. They are
intense dream-like states that occur when falling asleep (hypnagogic) or when wak-
ing from sleep (hypnopompic) [10]. The events typically remit on their own within
1–10 min, but can also be terminated when someone touches the patient [10].
The sleep-related hallucinations can also occur independently of the sleep paral-
ysis episodes and are usually visual or auditory and occasionally involve other
senses, e.g., tactile or vestibular. They are occasionally pleasant, but quite often
frightening or disturbing to the patient. The visual hallucinations can consist of

simple forms, such as circles or multi-sided geometric figures or can be more intri-
cate such as animals or people. Similarly, the auditory hallucinations can manifest
as simple sounds, such as knocking on a door or a phone ring, or more complex
tunes, such as a musical composition. Less often, patients report hallucinations such
as smelling a scent/odor, or having a sense that one is falling, or feeling that some-
one or something is touching them.
Automatic behavior is the performance of simple or complex routine tasks by
individuals who remain unaware of the activity. These behaviors range from activi-
ties such as talking on the phone or writing to walking, cooking, or driving. Some
patients report that they have ordered items through the phone, or cooked a meal,
and did not remember doing so. Some also report driving home from work and not
realizing how they got there. The personal and public hazards of such behaviors are
self-evident.
In addition to episodes of EDS, narcolepsy patients also report difficulty in main-
taining sleep at night due to a dysfunction of central sleep regulation which causes
frequent transitions between sleep and wakefulness throughout the entire 24-h cycle.
Typically they can fall asleep quickly but report frequent nocturnal awakenings and
occasionally indicate that they do not sleep for long periods during the night.
Idiopathic Hypersomnia
Similar to narcolepsy, patients with idiopathic hypersomnia also can have symp-
toms of excessive sleepiness. As mentioned earlier, it is no longer differentiated into
subtypes based on sleep duration. It is characterized either by excessive sleep that
usually is at least 11 hours in duration, but typically 12–14 hours, or daytime sleepi-
ness with a mean sleep latency of less than or equal to 8 minutes with less than 2
sleep onset REM periods on a multiple sleep latency test (MSLT).
There is typically severe or prolonged sleep inertia with difficulty waking up that
is often associated with irritability, automatic behaviors, and confusion. This sleep
drunkenness is similar to the confusion and behaviors a normal person may experi-
ence if abruptly awoken from deep sleep. Patients are confused upon awakening and
are unable to perform tasks or react appropriately [9, 11]. Accordingly, these patients
also experience difficulty waking up in the morning and at the end of naps. They
often never feel fully alert, even after their prolonged sleep period. They often
require multiple alarm clocks to awaken in the morning or after naps, but usually
end up becoming dependent on other people to awaken them. The naps are often
irresistible, prolonged (up to 3–4 hours in duration) and unrefreshing [3, 9, 11].
In a report by Bassetti and Aldrich in 1997 [11], some patients with idiopathic
hypersomnia were noted to have orthostatic hypotension, headaches, as well as cold
hands and feet (Raynaud’s type phenomena). A more recent study suggests that
patients may have parasympathetic dysfunction during sleep and wake with altered
autonomic responses to arousals [12]. Similar to narcolepsy (and sleep deprivation),
other associated features in idiopathic hypersomnia include sleep-related hallucina-

tions and sleep paralysis that are present in patients to a variable degree. Additionally,
overnight polysomnograms may also demonstrate a high sleep efficiency (≥90%) [3].
Epidemiology
Narcolepsy
Due to the overlap of clinical symptoms and polysomnographic/multiple sleep

latency test (MSLT) features with other conditions such as depression, other sleep
disorders, or even with normal individuals, it is difficult to make an accurate assess-
ment of the true prevalence of narcolepsy. It is estimated that less than 50% of
patients with narcolepsy have been diagnosed [13, 14]. Nevertheless, narcolepsy
has been documented to begin at any age from infancy (rarely) to as late as old age,
with a median age of 16 years but most commonly within the first two decades of
life. Narcolepsy type 1 affects both men and women equally (perhaps a slight pre-
ponderance for males) with an approximate prevalence of 1 in 2000 people (0.05%)
in the United States [15], less in Israel, and more in Japan.
There appears to be a genetic, racial, and ethnic predisposition for the develop-
ment of narcolepsy [16]. The risk of a first-degree relative developing narcolepsy
with cataplexy is approximately 1–2%, which is prominently higher than that esti-
mated for the general population [17]. In addition, the HLA subtypes DR2
(DRB1*1501) and DQ (DQB1*0602) have also been found to be closely associated
with narcolepsy. The HLA marker, DQB1*0602, has a prevalence ranging from 85
to 95% in patients with narcolepsy with cataplexy and about 40% in patients with
narcolepsy without cataplexy vs. about 26% in the general population [18]. A review
of the literature indicates that the prevalence of narcolepsy/cataplexy ranges from a
low of 0.002% among Israeli Jews to a high of 0.15% among the Japanese general
population. More recently, a general population study with a representative sample
of over 18,000 subjects in five European countries estimated a prevalence of
0.047% [3].
The prevalence of cataplexy among patients with narcolepsy varies widely with
estimates ranging from 60 to 90% [19]. Patients with cataplexy generally report that
this symptom remains persistent with only minor fluctuations in severity; however,
the severity and frequency of attacks may vary widely and range from occasional to
multiple attacks daily. A few patients have reported spontaneous remission of cata-
plexy attacks. It has been suggested that a decline in cataplexy over time represents
the ability of patients to adapt to their illness and learning to avoid those situations
where cataplexy is most likely to occur.
The prevalence of narcolepsy type 2, on the other hand, is more uncertain. It is
estimated that up to 36% of clinics’ narcolepsy population have “narcolepsy with-
out cataplexy.” The ambiguity is at least partially attributed to population-based
studies using MSLT diagnostic criteria for narcolepsy without the clinical symptom
of cataplexy; these studies included individuals with sleep deprivation, shift work
disorders, and even sleep apnea that likely contributed to false positive diagnoses
[3]. It should be noted that the true prevalence of narcolepsy type 1 and narcolepsy
type 2 are unknown as most epidemiologic studies were done prior to the publica-
tion of the ICSD 3.
More challenging than assessing the prevalence of narcolepsy is that of determining

the prevalence of idiopathic hypersomnia. The reported prevalence in clinic popula-
tions when compared to narcolepsy patients widely varies depending upon the lit-
erature reviewed [7, 20–22]. At least part of the difficulty in determining idiopathic
hypersomnia’s prevalence is due to its nosological ambiguity. There has also been a
propensity to label all difficult-to-classify cases of EDS as idiopathic hypersomnia
[23]. Similar to narcolepsy type 1 and narcolepsy type 2, since the ICSD-3 classifi-
cation scheme was developed, there have not been any systematic prevalence stud-
ies for idiopathic hypersomnia. Accordingly, it is safe to say that the true prevalence
of idiopathic hypersomnia is unknown. What we do know is that there appears to be
a female predominance [24] with the age of onset ranging from birth to early adult-
hood [25]. Some earlier studies also suggest an autosomal dominant mode of inheri-
tance [26].
Pathophysiology
Narcolepsy
The discovery of the neuropeptide hypocretin [27, 28] has greatly enhanced our
understanding of the pathophysiology of narcolepsy. It is thought that a deficiency
of this arousal system (and perhaps other yet unknown arousal systems), rather than
an overactivity of the sleep systems, underlies the pathogenesis of the symptoms in
narcolepsy [29]. Hypocretin-containing neurons are located in the perifornical and
lateral hypothalamus where they project widely to communicate with numerous
brain nuclei including those responsible for the regulation of sleep, alertness, and
muscle tone. Evidence suggests that most cases of narcolepsy are associated with
loss of or partial loss of hypocretin-containing hypothalamic neurons and the devel-
opment of cataplexy occurs when hypocretin is absent or nearly absent. Thannickal
et al. [30] and Mignot et al. [31] reported an 85–95% loss of hypocretin-containing
neurons in narcolepsy with cataplexy patients that corresponded to the finding of
low or undetectable concentrations (≤110 pg/mL) of hypocretin in the cerebrospi-
nal fluid (CSF) of these patients. Thannickal et al. [32] later found a loss of about a
third of the hypothalamic hypocretin-containing cells in one patient with narcolepsy
without cataplexy. An autoimmune process may be responsible for the loss of the
hypocretin neurons; however, antibodies to hypocretin and hypocretin receptors
have not been found [33–36].
As mentioned earlier, there is a higher occurrence of HLA DQB1*0602 in nar-
colepsy patients than in the general population. It is suspected that patients with this
HLA marker (and likely other non-HLA genes associated with immune regulation
or other currently unknown genetic links) may possess a genetic susceptibility for
some event (e.g., environmental influences) that leads to the development of narco-
lepsy. This HLA association suggests a T-cell mediated autoimmunity. Researchers
found a significant correlation between the degree of excessive sleepiness and the
presence of activated T-cells in the central nervous system of narcolepsy type 1,
narcolepsy type 2, and idiopathic hypersomnia patients lending further support to
evidence of T-cell mediated autoimmunity [37].
Several studies have shown increased cases of narcolepsy in children and adoles-
cents in relation to swine influenza A (H1N1). In Europe, the Pandemrix vaccina-
tion induced narcolepsy in patients who carried the HLA allele DQB1*0602, while
in China infection with the virus was associated with the development of narcolepsy
[38]. As mentioned above, polymorphisms in other non-HLA genes that may affect
immune regulatory function are likely present as well. For example, the non-coding
RNA gene GDNF-A51 was also significantly associated with the development of
narcolepsy in the patients given the Pandemrix vaccination [39].
Environmental factors such as infections [40, 41], head trauma [42], neurotoxic
metals, combustion smoke [43], or even a change in sleeping habits [41] have been
associated with the onset of narcolepsy. While it is not known exactly how these
environmental elements result in neurodegeneration of hypocretin neurons, Mori
[43, 44] suggested these agents may cause release of proinflammatory cytokines in
the olfactory bulb resulting in a breakdown of the blood-brain barrier; subsequently,
this allows autoimmune cells access to the hypocretin neurons in the hypothalamus,
which results in its degeneration.
Supporting evidence for the autoimmune etiology hypothesis continues to grow.
Increased antistreptococcal antibodies were reported in patients with recent onset of
narcolepsy, suggesting streptococcal infections may be an inciting event that is ini-
tiating an autoimmune process [40, 45]. Hallmayer et al. [46] also found a strong
association between narcolepsy and a polymorphism in the T-cell receptor alpha
locus (another indication that an autoimmune process has a role). Earlier in 2010,
elevated Tribbles homolog 2 (Trib2) specific antibody levels were discovered in
16%–26% of patients with narcolepsy. Trib2 was previously known as an autoanti-
gen in autoimmune uveitis; it has been identified in hypocretin neurons of a trans-
genic mouse model. In narcolepsy patients, titers of Trib2-specific antibodies were
highest soon after narcolepsy onset and then decreased within the first 3 years of the
disorder and finally stabilized at levels much higher than that of controls (normal
controls and patients with idiopathic hypersomnia, multiple sclerosis, or other
inflammatory neurologic disorders). Intracerebroventricular administration of
immunoglobulin-G purified from anti-trib2 positive narcolepsy patients in subjects
caused degeneration of hypocretin neurons [47, 48]. This finding provided support
for an autoimmune etiology for narcolepsy; however, additional work by Tanaka S

et al. in 2017 suggested that the anti-TRIB2 antibody seen in narcolepsy patients
was a result rather than the cause of hypocretin cell degeneration [48].
In comparison to narcolepsy, less is known about the pathophysiology of idiopathic

hypersomnia. One possible reason for this is that there are no specific criteria, clini-
cal or polysomnographic, that is pathognomonic or even partially characteristic of
the disorder, such as cataplexy or sleep onset REM periods in narcolepsy. There is
no clear association with CSF hypocretin levels [49] as in narcolepsy. Although
there appears to be a strong genetic component suggested by the high proportion of
familial cases, no associated genes have been identified. Studies with HLAs have
also found no connection [11].
Some studies suggested that dopamine and certain monoamine metabolites had
a role in the etiology of idiopathic hypersomnia [50–53], but further studies have
been inconclusive [3]. In some idiopathic hypersomnia patients, an endogenous
hypnotic peptide stimulating GABA receptors during wakefulness is suspected to
be at least partially etiologic [54]. Autoimmunity has also been suggested as etio-
logic in idiopathic hypersomnia [37]. Further studies to assess the validity of these
hypotheses need to be done.
There is a possible common pathway between the pathophysiology of narco-
lepsy and idiopathic hypersomnia. A low CSF histamine level has been identified in
both these disorders and has not been seen in patients with excessive sleepiness due
to sleep apnea [55, 56]. Accordingly, it is hypothesized that low histamine may be
specific to hypersomnias of central origin [56]; however, a more recent study failed
to demonstrate this deficiency [57]. In addition, since idiopathic hypersomnia hypo-
cretin levels are normal, it has been suggested that factors other than hypocretin
deficiency are the cause of these low histamine levels. Further research still needs to
be done to validate this hypothesis and to better understand the role of histamine in
these disorders.
Diagnosis
Narcolepsy
There are three main types of narcolepsy: narcolepsy type 1, NT1, narcolepsy type
2, NT2, and secondary narcolepsy (Table 15.1). Narcolepsy type 1 is defined as
excessive sleepiness that occurs for at least 3 months and is associated with definite
cataplexy and/or a low CSF hypocretin level (≤110 pg/mL or one third of mean
Table 15.1 Diagnostic criteria for narcolepsy

Narcolepsy type 1
1. At least 3 months of excessive daytime sleepiness (EDS) as well as item 2 and/or item 3
below are present
2A. Cataplexy is present
2B. On a polysomnogram (PSG) followed by a multiple sleep latency test (MSLT):
(a) The PSG rules out other causes of disrupted nocturnal sleep and demonstrates at least
7 h of sleep
(b) The MSLT should show a sleep latency of ≤8 min and two or more sleep onset REM
periods; if the PSG has a sleep onset REM period (i.e., within 15 minutes of sleep
onset), then only 1 SOREMP is needed on the MSLT study.
3. A cerebrospinal fluid (CSF) hypocretin-1 level ≤110 pg/mL or < 1/3 of normal control values
Narcolepsy type 2
1. At least 3 months of EDS
2. Cataplexy is absent; however, questionable or atypical cataplexy-like episodes can be present
3. On a PSG followed by a MSLT:
(a) The PSG rules out other causes of disrupted nocturnal sleep and demonstrate at least 7 h
of sleep
(b) The MSLT should show a sleep latency of ≤8 min and two or more sleep onset REM
periods; if the PSG has a sleep onset REM period (i.e., within 15 minutes of sleep onset),
then only 1 SOREMP is needed on the MSLT study.
4. CSF hypocretin-1 levels must be either unknown or ≥110 pg/mL (or 1/3 of normal control
values)
5. The EDS or MSLT findings cannot be better explained by other causes, e.g., other sleep
disorders, medication effect, or sleep deprivation
Adapted from American Academy of Sleep Medicine [3]
normal control values) [27]. In the presence of cataplexy, if CSF hypocretin level is
unknown or ≥ 110 pg/ml, then a polysomnography followed by a MSLT is needed
[58]. The polysomnography should confirm at least 7 h of sleep and exclude other
sleep disorders that could account for the symptoms, such as obstructive sleep apnea
syndrome. It usually demonstrates a short sleep latency and fragmented nocturnal
sleep and may show increased stage 1 sleep and early REM sleep onset [59]. The
MSLT should exhibit two or more sleep onset REM periods (SOREMP) with a
mean sleep latency of ≤8 min [3]. If a sleep onset REM period occurs during the
preceding polysomnogram (i.e., within 15 minutes of sleep onset), then only one
SOREMP is needed in the MSLT [3]. Accordingly, a patient with hypersomnia
without cataplexy can still meet criteria for a diagnosis of NT1 if CSF hypocretin
levels are reduced as described above. Alternatively, a patient with hypersomnia
with cataplexy can meet criteria for a diagnosis of NT1 if CSF hypocretin levels are
“normal.”
Patients with NT2 either do not have cataplexy or have atypical cataplexy-like
events. The PSG followed by an MSLT should demonstrate features similar to that
of NT1 as described above, and their CSF hypocretin-1 levels should be ≤110 pg/
mL or one third of mean normal control values if measured [21, 27]. Other disorders
that can explain the EDS and/or MSLT findings must be ruled out prior to making a
diagnosis of NT2.
Secondary narcolepsy is classified as a subtype of NT1 and NT2 in the ICSD 3,

namely, as narcolepsy type 1 due to a medical condition and narcolepsy type 2 due
to a medical condition. Secondary narcolepsy can potentially occur after any lesion
affecting the hypothalamus, including but not limited to tumors, autoimmune disor-
ders, paraneoplastic disorders, sarcoidosis, multiple sclerosis, Parkinson’s disease,
or head trauma [3]. This condition is given the diagnosis of NT1 due to a medical
condition or NT2 due to a medical condition, if the criteria for NT1 or NT2 are met,
respectively, and is attributable to another medical disorder.
Similar to adults, the diagnosis of NT1 can be made in children if excessive sleep-
iness and definite cataplexy is present and the MSLT is diagnostic or if CSF hypo-
cretin-1 deficiency is present. However, as mentioned earlier, it is difficult to identify
classic narcolepsy symptoms in children. Additionally, normal values on sleep stud-
ies, especially for MSLTs, have not been standardized in subjects younger than
6 years of age and results should be interpreted with care. Carskadon [60] suggested
using a child’s Tanner stage of sexual development to compare sleep study results to
normal values of nocturnal total sleep time, daytime sleep latency, and daytime REM
sleep latency as these are closely linked to the Tanner stages. A more recent study
showed that a MSLT with at least 2 SOREMPs and a mean sleep latency of ≤8.2 min-
utes was a reliable marker for the diagnosis of NT1 in the pediatric population [61].
Nevertheless, if the MSLT results are equivocal and there is still a high clinical sus-
picion for narcolepsy, a repeat study is warranted after a period of time.
Children with NT2 present similarly to those with NT1 except they do not have
cataplexy and CSF hypocretin levels if measured are in the normal range.
Occasionally, cataplexy may develop after the presenting symptom of excessive
sleepiness. In this situation, the patient (typically a child, but also can be an adult)
is given the diagnosis of NT2 until the onset of cataplexy at which time the diagno-
sis is changed to NT1.
As suggested earlier, HLA testing (in a child or adult) is not a useful screening
or diagnostic tool; however, it might be useful in atypical narcolepsy with cataplexy
presentations. A negative test should encourage the physician to make certain that
other sleep disorders are excluded before assigning a diagnosis of NT1 narcolepsy.
In order to make the diagnosis of idiopathic hypersomnia (Table 15.2), the associ-
ated excessive sleepiness, similar to narcolepsy, needs to occur almost daily for at
least 3 months and cataplexy is not present. There is often difficulty awaking from
the sleep period including any naps. Polysomnography should rule out other causes
of excessive sleepiness (e.g., sleep apnea), and a MSLT performed following the
nocturnal polysomnography should show a mean sleep latency of ≤8 min with less
than two sleep onset REM periods. If the preceding PSG has a SOREMP (i.e.,
within the initial 15 minutes of the study), then the MSLT should not have any
SOREMPs [3]. Awaking patients with idiopathic hypersomnia in the morning
Table 15.2 Diagnostic criteria for idiopathic hypersomnia

Idiopathic hypersomnia
1. At least 3 months of EDS
2. Cataplexy is not present
3. The MSLT should show a sleep latency of ≤8 min and less than two sleep onset REM
periods; if the preceding PSG has a sleep onset REM period (i.e., within 15 minutes of sleep
onset), then there should not be a SOREMP on the MSLT.
4. If the mean sleep latency on the MSLT is >8 min, then a total sleep time of at least
11 hrs/24 hr. period should be demonstrated either with a 24 hr. polysomnogram or by wrist
actigraphy and sleep log (averaged over at least 7 days)
5. Insufficient sleep syndrome should be ruled out
6. Other sleep, medical, or psychiatric disorders or medications/drugs should not better explain
the EDS and/or MSLT findings
Adapted from American Academy of Sleep Medicine [3]
following an overnight polysomnogram to do a MSLT does not allow for the docu-
mentation of a prolonged sleep time. Additionally, the mean sleep latency on the
MSLT may not always be diagnostic, and the short naps scheduled every 2 h do not
allow for the demonstration of prolonged unrefreshing naps. Therefore, as an alter-
native to the MSLT showing a mean sleep latency of ≤8 min, the typical nocturnal
sleep duration of at least 11 hours can be demonstrated with a 24 hr. polysomno-
graphic recording or by wrist actigraphy and sleep logs over at least 7 days.
Insufficient sleep syndrome and other sleep disorders should also be ruled out [3].
Similar to adults, before a diagnosis of idiopathic hypersomnia is made in chil-
dren, other sleep disorders, especially insufficient sleep syndrome, and use of recre-
ational drugs should be ruled out. If the sleep duration criteria is being used to
diagnose idiopathic hypersomnia in the pediatric population, age appropriate nor-
mal values for total sleep time should be taken into account. A repeat MSLT study
should be considered in patients diagnosed with idiopathic hypersomnia after a cer-
tain time interval, because SOREMPs may develop overtime in narcolepsy. If 2 or
more SOREMP are present in the repeat PSG/MSLT study, then the patient should
be reclassified as having NT2.
It is evident by many experts that the current diagnostic criteria have its limita-
tions. It relies on ancillary testing such as the MSLT that is not well validated in all
patient populations and is relatively nonspecific. The stability of repeated MSLT
results is also in question with one study showing only 10–20% of patients with a
positive initial MSLT being positive after the test was repeated in 4 years [62].
Additionally, although validated, the method for measurement of CSF hypocretin
levels has some issues [63–65]. Sakai et al. showed that the typical method of hypo-
cretin measurement actually measures hypocretin-1 metabolites believed to be inac-
tive. Therefore, while standard testing would demonstrate deficiency of
“hypocretin-1” in some NT1 patients, an alternative method of testing which mea-
sures the true active hypocretin-1 protein can actually demonstrate some degree of
deficiency in NT1 and NT2 patients that were found to have no deficiency when
tested with standard techniques [64].
Accordingly, it stands to reason that diagnostic tools utilizing other markers to

aid in the diagnosis of narcolepsy are needed. For instance, Stephansen et al. dem-
onstrated that a combination of a more thorough evaluation of the overnight poly-
somnogram and HLA testing yielded a high sensitivity and specificity for NT1
diagnosis. A PSG analysis revealing unusual sleep stage overlap alone achieved a
sensitivity of 91% and specificity of 96%, and when combined with testing showing
HLA-DQB1*0602, the specificity increased to 99% [66]. Identification of REM
sleep without atonia (in at least 8% of stage REM sleep epochs) in the pediatric
population has demonstrated high specificity for the diagnosis of narcolepsy [67].
Additionally, Murer et al. verified that sleep stage analysis with better characteriza-
tion of REM sleep duration and sleep stage sequence during the PSG contributed to
a higher MSLT specificity for narcolepsy [68].
Other features in patients with narcolepsy have been identified, and future tools
utilizing these findings may aid in diagnosing narcolepsy or differentiating it from
other hypersomnias. For instance, the frequency and distribution of eye movements
during various sleep stages throughout the night as well as while awake was shown
to be significantly different in NT1 patients compared to clinical controls as well as
NT2 patients [69]. Furthermore, heart rate variability abnormalities during stage
NREM 2 and non-dipping blood pressure patterns were found to be more prevalent
in NT1 patients compared to control groups [70, 71]. Additionally, certain neuro-
anatomical correlates on neuroimaging studies may also contribute to diagnosing
narcolepsy and other hypersomnias [72].
Excessive sleepiness is common to many sleep disorders, besides narcolepsy and

idiopathic hypersomnia, and can also be a normal phenomenon in certain circum-
stances (e.g., sleep deprivation). Some of these sleep disorders can be differentiated
from narcolepsy or idiopathic hypersomnia by history. For instance, identification
of a disruptive environmental feature during sleep may lead one to the diagnosis of
an environmental sleep disorder. A history of sleeping less than expected from age-
adjusted normative data or having a sleep period that is delayed, advanced, or irreg-
ular would suggest behaviorally induced, insufficient sleep syndrome or a circadian
rhythm disorder, respectively. A description of normal sleep between episodes of
hypersomnia can suggest a diagnosis of recurrent hypersomnia. Certain psychiatric
disorders (e.g., depression or substance abuse) can also be responsible for excessive
sleepiness and are identifiable on history.
Narcolepsy is commonly comorbid with several medical and psychiatric disor-
ders that can not only cause a misdiagnosis but can complicate narcolepsy treat-
ment. Cardiac, mental, neurologic, gastrointestinal, renal, and pulmonary disorders
are more common in narcolepsy [73]. Cardiac disorders can complicate therapy as
some narcolepsy medications can cause cardiac arrhythmias or exacerbate fluid
retention and add to hypertension or heart failure. Of the mental disorders,
depression and anxiety are particularly prevalent and are common causes of delay
in narcolepsy diagnosis. Anxiety disorders can contribute to stimulant medication
failure due to exacerbating adverse effects [74]. In addition, concurrent sleep disor-
ders, such as obstructive sleep apnea syndrome, sleep deprivation, restless legs syn-
drome, and circadian rhythm disorders, can contribute to, or mask, a narcolepsy
diagnosis.
Disorders that cause excessive sleepiness cannot always be identified by history
alone; additional studies to differentiate them from narcolepsy and idiopathic hyper-
somnia are often required. A polysomnogram will help identify sleep disordered
breathing. Imaging studies may discover the presence of a brain tumor or stroke
(although other findings on exam are also usually present). Blood work or CSF
analysis can help identify metabolic abnormalities or encephalitis as a cause of
sleepiness. There was a case report by Maestri et al. [75] on a patient that was diag-
nosed with idiopathic hypersomnia but after further evaluation was found to have an
insulinoma. After management of the insulinoma, his symptoms of excessive sleep-
iness resolved. Another report by Shinno et al. [76] identified a patient with idio-
pathic hypersomnia who was subsequently found to have subclinical hypothyroidism;
after management with levothyroxine his sleepiness improved.
History and additional laboratory studies are also useful in ruling out disorders
that can mimic cataplexy. Transient weakness episodes can represent transient isch-
emic attacks (TIAs) if there is no history of an association with emotion or if there
is a history of vascular risk factors and/or stroke. Seizures, syncope, and brainstem
or diencephalic tumors can look like cataplexy; a positive EEG may suggest sei-
zures; imaging studies can help identify tumors; and a history of loss of conscious-
ness may help differentiate syncope or seizures from cataplexy.
Excessive Sleepiness Due to Head Trauma
Sleep disturbances, including excessive sleepiness, can occur as a result of trau-

matic brain injury (TBI); accordingly, TBI should be considered in the differential
diagnosis of excessive sleepiness. Some researchers contend that the excessive
sleepiness is due to the increased prevalence of obstructive sleep apnea and periodic
limb movement disorder that is seen in TBI patients [77]. In addition, changes in
nocturnal sleep pattern seen in TBI patients are similar to those of depressed
patients, namely, increased nighttime awakenings and longer sleep onset latency
[78]. It is speculated that the sleepiness is due in part to this disturbed nocturnal
sleep and that treatment of concomitant mood disorders may improve the sleepiness
in the TBI patients; however, further research needs to be done in this area.
Hypothalamic damage, not necessarily visible on imaging studies, may be
responsible for the excessive sleepiness that is seen in many TBI patients. The
ICSD-3 classified this group of TBI patients under several separate subtypes: NT1
or NT2 due to a medical condition and hypersomnia due to a medical condition
(posttraumatic hypersomnia subtype). A 2007 study found that the CSF
hypocretin-1 levels were decreased in these TBI patients, and a follow-up study in
2009 demonstrated the number of hypocretin neurons in the hypothalamus was sig-
nificantly reduced [79, 80]. The loss of hypocretin is likely the etiology underlying
TBI associated with narcolepsy and possibly post-traumatic hypersomnia.
Treatment
There is no known cure for either narcolepsy or idiopathic hypersomnia; however,

with respect to idiopathic hypersomnia, there are reports of spontaneous remission
[25]. For those with persistent disease, treatment is targeted at symptom manage-
ment. Even with optimum management, the EDS in narcolepsy and idiopathic
hypersomnia patients, and the cataplexy in narcolepsy patients, are seldom com-
pletely controlled.
Nonpharmacologic Management
Nonpharmacologic management should be initiated in all patients. Patient educa-

tion is an important component of any treatment plan. Good sleep habits with avoid-
ance of sleep deprivation and/or irregular sleep patterns should be emphasized. In
narcolepsy patients, the scheduling of short naps (15–20 min) 2–3 times/day can
help control EDS and improve alertness, but this is impractical in many settings.
Napping, in contrast, is not recommended for management of sleepiness in patients
with idiopathic hypersomnia as it usually does not help and may result in unpleasant
sleep inertia. Patients and family members should also be warned about the poten-
tial dangers of sleepiness relative to driving and/or in other hazardous settings.
Typically, lifestyle changes alone are not enough to adequately control the symp-
toms of either narcolepsy or idiopathic hypersomnia; most patients require lifelong
medication.
harmacologic Management of Symptoms Common to Both

P
Narcolepsy and Idiopathic Hypersomnia
Pharmacological management of EDS, with a few exceptions, is similar in both

narcolepsy and idiopathic hypersomnia; however, it should be noted that random-
ized, double-blind, placebo-controlled clinical trials have not been done on idio-
pathic hypersomnia patients. Stimulants, such as methylphenidate or
dextroamphetamine, have previously been used as first-line therapy. This transi-
tioned to the use of modafinil and armodafinil as first-line treatment for most patients
[81, 82], and more recently a newer agent, solriamfetol, might be the next agent that
will gain acceptance as initial therapy for EDS treatment. Most clinical studies of
stimulant medications report objective improvements in sleepiness in 65–85% of
subjects.
Common adverse effects associated with stimulants include nervousness, head-
aches, irritability, tremor, insomnia, anorexia, gastrointestinal upset, and cardiovas-
cular stimulation [83]. The development of drug tolerance or addiction can also
occur; however, this risk is thought to be less than in other patient groups.
Modafinil is generally well tolerated, with headache and nausea being the most
common side effects. Rarely, severe rashes and allergic reactions can occur.
Modafinil also increases the metabolism of ethinylestradiol which lessens the effi-
cacy of oral contraceptive agents. Armodafinil is the long-acting dextro-enantiomer
component of racemic modafinil, which has equal amounts of S- and R-modafinil.
It has a similar therapeutic and side effect profile to racemic modafinil, but with the
advantage of having a longer elimination half-life (t ½) (3–4 h for S-modafinil vs.
10–15 h for armodafinil) [84]. Although comparative studies have not been done in
narcolepsy or idiopathic hypersomnia, armodafinil has been shown to be effective
and produce longer wakefulness than racemic modafinil in patients with sleepiness
due to acute sleep loss [85].
Sodium oxybate, the sodium salt of gamma-hydroxybutyrate (GHB), an endog-
enous substance in the brain, is an effective medication in the treatment of daytime
sleepiness cataplexy and sleep disruption in narcolepsy [81, 86, 87] and perhaps
also the sleep-related hallucinations and sleep paralysis episodes prominent in this
disorder. It is currently being studied in patients with idiopathic hypersomnia.
Sodium oxybate’s adverse effects include nausea (19%), dizziness (18% incidence),
headache (18%), nasopharyngitis (6%), somnolence (6%), vomiting (8%), and uri-
nary incontinence (6%) with most described as mild or moderate in severity.
Dizziness, nausea, vomiting, and enuresis may be dose related [88].
Pitolisant is a medication that acts as an antagonist/inverse agonist on the hista-
mine 3 receptors which results in increase of brain histamine levels that subsequently
help maintain wakefulness. The more common adverse reactions include headaches,
insomnia, nausea, and anxiety. Caution needs to be taken in patients at cardiac risk
for prolonged QTc. As with modafinil, pitolisant also increases the metabolism of
ethinylestradiol and therefore will lessen oral contraceptive efficacy. Although
pitolisant does not currently have an FDA-approved indication to treat cataplexy,
studies have also shown improvement in this symptom in treated NT1 patients [89,
90]. Alternative forms of H3 receptor inverse agonists are in investigation.
Solriamfetol works by inhibiting reuptake of both dopamine and norepinephrine.
It has a similar adverse reaction profile to other medications with headache being
most common followed by nausea, decreased appetite, nasopharyngitis, dry mouth,
and anxiety. With its relatively unique mechanism of action, efficacy, and side effect
profile, it has been increasingly used as first- or second-line therapy for the treat-
ment of EDS [91]. It has an FDA-approved indication for the treatment of EDS in
patients with narcolepsy.
Currently, sodium oxybate, amphetamines, methylphenidate, modafinil,
armodafinil, solriamfetol, and pitolisant are the only medications FDA approved in
the United States for the treatment of EDS in narcolepsy. Alterations of gamma
amino butyric acid (GABA) levels in the brain with GABA-A receptor agonists
(e.g., clarithromycin and flumazenil) have shown some efficacy in the treatment of
EDS in narcolepsy patients [92]. Medications targeting the hypocretin receptors for
the treatment of EDS are in development. One such medication currently undergo-
ing clinical trials is TAK-994, which is a hypocretin-2 receptor selective agonist that
has shown promise in preliminary studies. Other medications under investigation
include a low sodium formulation of oxybate, and a new drug application (NDA)
has been submitted for approval by the FDA. A long-acting, once-nightly formula-
tion of sodium oxybate has been studied, and an NDA is about to be submitted.
Reboxetine, a norepinephrine reuptake inhibitor, is currently undergoing evaluation
in narcolepsy. Other medications have been reported to have beneficial results, but
little data is available [93]. All medications are used “off-label” for the management
of excessive sleepiness due to idiopathic hypersomnia.
harmacologic Management of Symptoms Specific

P
to Narcolepsy
Cataplexy
Although treatment of sleepiness can have a mild beneficial effect on cataplexy,

most wake-promoting agents/stimulants do not provide sufficient relief from cata-
plexy. Pitolisant, as mentioned earlier, has been shown to improve both EDS and
cataplexy symptoms in patients with narcolepsy. Most medications used for the
treatment of cataplexy have REM sleep suppressant properties and/or increase
aminergic (mainly by blocking the norepinephrine (NE) transporter) activity [94].
Tricyclic antidepressants (TCAs), serotonin reuptake inhibitors, and NE reuptake
inhibitors have demonstrated benefit in animal studies (which is believed to be a
function of the NE reuptake inhibition). Sodium oxybate is highly efficacious for
the treatment of cataplexy in narcolepsy and, as of the writing of this chapter,
remains the only FDA-approved medication for its management.
Several small open-label studies and several decades of use have demonstrated
that the TCAs desmethylimipramine, protriptyline, imipramine, and desipramine
have beneficial anticataplectic effects [95]; however, clomipramine remains the
most widely used. Adverse events commonly associated with TCA therapy include
nausea, anorexia, dry mouth, urinary retention, and tachycardia. Men may encoun-
ter decreased libido, impotency, or delayed ejaculation. An unusual property of
TCAs is the rebound cataplexy phenomenon that occurs upon abrupt discontinua-
tion of TCA therapy. When severe, this is known as status cataplecticus and can be
disabling for several days [96].
Similar to TCAs, the SSRIs including fluvoxamine, zimeldine, femoxetine, par-
oxetine, and fluoxetine have all demonstrated anticataplectic activity; however,
fluoxetine appears to be the most commonly used of the SSRIs for the treatment of
cataplexy [97]. As a class, the SSRIs are generally less efficacious than TCAs; how-
ever, they have a better safety profile and are better tolerated than the older antide-
pressants. Reported adverse events include headache, nausea, weight gain, dry
mouth, and delayed ejaculation [97]. Other antidepressant medications have also
been found to have some anticataplectic activity; these include monoamine oxidase
inhibitors such as phenelzine and selegiline as well as other atypical antidepressants
with pronounced NE reuptake inhibition, such as venlafaxine and atomoxetine.
Given the evidence supporting an autoimmune etiology of narcolepsy, intrave-
nous immunoglobulin therapy (IVIG) has been used for the treatment of narcolepsy.
Unfortunately, the studies evaluating its use are limited, and the few case reports
have yielded conflicting results. Currently, it is not considered a valid treatment
option [98].
Fragmented Nocturnal Sleep
As mentioned earlier, sodium oxybate taken at bedtime and again during the night
increases slow wave sleep, decreases light sleep (stage N1 sleep), and decreases the
number of arousals. REM sleep is initially increased, but then decreases after
increasing dose and duration of therapy [87].
Other medications have also been tried in the management of the fragmented
sleep of narcoleptics. A study evaluating 0.25 mg of triazolam taken at bedtime
showed improved sleep efficiency and overall sleep quality, but had no beneficial
effect on daytime sleepiness [99]. Unlike the GABA-A receptor agonists mentioned
earlier, baclofen is actually a GABA B receptor agonist that has shown some effi-
cacy in the treatment of EDS as well as sleep fragmentation in adolescent narco-
lepsy. Morse et al. described five patients that failed treatment with traditional
narcolepsy medications, but reported subjective improvement in sleep maintenance
and daytime sleepiness. Accordingly, baclofen may be an effective treatment option
in narcolepsy that warrants further study [100]. Other medications such as zolpi-
dem, eszopiclone, or clonazepam have been used with varying success in some
patients (personal experience and conversations with other sleep medicine physi-
cians). For symptoms of sleep paralysis and hypnagogic hallucinations, TCAs,
other REM suppressant medications, and sodium oxybate have been successful.
Conclusion
Narcolepsy and idiopathic hypersomnia are primary central hypersomnias character-

ized by either EDS or prolonged nocturnal sleep. Whereas cataplexy is pathogno-
monic for narcolepsy, there is no pathognomonic symptom for idiopathic hypersomnia.
Narcolepsy is believed to be due to a deficiency in hypocretin-producing neurons in
the lateral hypothalamus, possibly as a result of an autoimmune disorder. The
pathophysiology of idiopathic hypersomnia is currently unknown. The diagnosis is

currently made by a combination of appropriate clinical symptoms, polysomnogra-
phy followed by an MSLT and/or CSF hypocretin-1 testing. There are both nonphar-
macologic and symptom directed pharmacologic treatments using medications
targeting monoaminergic or GABA receptors. New formulations of oxybate and
orexin receptor agonists are under investigation, as well as alternative NERIs and
histaminergic medications. The effective pharmacologic management of narcolepsy
is becoming a reality, although the treatment options are many and medication com-
binations are usually required for optimal management of cataplexy and excessive
sleepiness.
Summary of Keypoints
• Narcolepsy is a syndrome consisting of EDS, cataplexy, sleep paralysis,
and hypnagogic hallucinations. Additional features include automatic
behaviors and fragmented or disrupted nighttime sleep.
• Classic narcolepsy symptoms are difficult to identify in children as sleepi-
ness may manifest as inattentiveness, lack of energy, behavioral problems,
or decreased performance.
• Cataplexy is the most specific symptom of narcolepsy consisting of an
abrupt, bilateral loss of skeletal muscle tone, triggered by sudden emotion
such as laughter. Cataplexy is seen in 60–90% of patients with narcolepsy.
• Poor nighttime sleep is also common in narcolepsy, due to a dysfunction of
central sleep regulation which causes frequent transitions between sleep
and wakefulness throughout the entire 24-h cycle.
• Most cases of NT1 are associated with reduced or absent csf hypocretin;
cases of NT2 may be caused by a partial loss of hypocretin-containing
hypothalamic neurons.
• Sleep disturbances, including excessive sleepiness, may occur following
TBI. It is important to consider TBI among the causes of EDS.
• Appropriate sleep hygiene is critically important in patients with narco-
lepsy or idiopathic hypersomnia. Short naps (15–20 min) 2–3 times/day
can help control sleepiness in narcolepsy and improve alertness. However,
scheduled naps are not recommended in idiopathic hypersomnia.
• Alerting medications are the mainstay of management of daytime sleepi-
ness in patients with narcolepsy or idiopathic hypersomnia, with most
clinical studies reporting objective improvements in sleepiness in 65–85%
of subjects. Cataplexy can be effectively treated with oxybate, H3 receptor
inverse agonists, or NERIs.
• New formulations of current medications and orexin receptor agonists are
currently under investigation and hold promise of greatly improving patient
management.
References
1. Nevsimalova S. Narcolepsy in childhood. Sleep Med Rev. 2009;13(2):169–80.

2. Roth B. Narcolepsy and hypersomnia. Basel: Karger; 1980. p. 66–77.
Darien: American Academy of Sleep Medicine; 2014.
4. Krahn LE, Lymp JF, Moore WR, Slocumb N, Silber MH. Characterizing the emotions that
trigger cataplexy. J Neuropsychiatry Clin Neurosci. 2005;17:45–50.
5. Overeem S, Mignot E, van Dijk JG, et al. Narcolepsy: clinical features, new pathological
insights, and future perspectives. J Clin Neurophysiol. 2001;18:78–105.
6. Barateau L, Pizza F, Lopez R, et al. Persistence of deep-tendon reflexes during partial cata-
plexy. Sleep Med. 2018;45:80–2.
7. Serra L, Montagna P, Mignot E, et al. Cataplexy features in childhood narcolepsy. Mov
Disord. 2008;23(6):858–65.
8. Plazzi G, Clawges HM, Owens J. Clinical characteristics and burden of illness in pediatric
patients with narcolepsy. Pediatr Neurol. 2018;85:21–32.
9. Vernet C, Arnulf I. Idiopathic hypersomnia with and without long sleep time: a controlled
series of 75 patients. Sleep. 2009;32:753–9.
10. Guilleminault C, Fromherz S. Narcolepsy: diagnosis and management. In: Kryger MH,
Roth TA, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia: WB
Saunders; 2005. p. 780.
11. Bassetti C, Aldrich MS. Idiopathic hypersomnia: a series of 42 patients. Brain.
1997;120(8):1423–35.
12. Sforza E, Roche F, Barthelemy JC, et al. Diurnal and nocturnal cardiovascular variability and
heart rate arousal response in idiopathic hypersomnia. Sleep Med. 2016;24:131–6.
13. Mayer G, Kesper K, Peter H, Ploch T, Leinweber T, et al. Comorbidity in narcoleptic patients.
Dtsch Med Wochenschr. 2002;127(38):1942–6. German.
14. Kryger MH, Walid R, Manfreda J. Diagnoses received by narcolepsy patients in the year prior
to diagnosis by a sleep specialist. Sleep. 2002;25(1):36–41.
15. Ohayon MM, Ferini-Strambi L, Plazzi G, et al. Frequency of narcolepsy symptoms and
other sleep disorders in narcoleptic patients and their first-degree relatives. J Sleep Res.
2005;14(4):437–45.
16. Ohayon MM, Ferini-Strambi L, Plazzi G, et al. How age influences the expression of narco-
lepsy. J Psychosom Res. 2005;59(6):399–405.
17. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(2 Suppl 1):S16–22.
18. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of
narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686–99.
19. Silber MH, Krahn LE, Olson EJ, et al. The epidemiology of narcolepsy in Olmsted County,
Minnesota: a population-based study. Sleep. 2002;25(2):197–202.
20. Vignatelli L, d’Alessandro R, Mosconi P, et al. Health-related quality of life in Italian patients
with narcolepsy: the SF-36 health survey. Sleep Med. 2004;5:467–75.
21. Heier MS, Evsiukova T, Vilming S, et al. CSF hypocretin-1 levels and clinical profiles in
narcolepsy and idiopathic CNS hypersomnia in Norway. Sleep. 2007;30:969–73.
22. Dauvilliers Y, Paquereau J, Bastuji H, et al. Psychological health in central hypersomnias: the
French Harmony Study. J Neurol Neurosurg Psychiatry. 2009;80:636–41.
23. Billiard M, Dauvilliers Y. Idiopathic hypersomnia. Sleep Med Rev. 2001;5(5):349–58.
24. Aldrich MS. The clinical spectrum of narcolepsy and idiopathic hypersomnia. Neurology.
1996;46:393–401.
25. Anderson KN, Pilsworth S, Sharples LD, et al. Idiopathic hypersomnia: a study of 77 cases.
Sleep. 2007;30:1274–81.
26. Billiard M, Merle C, Carlander B, et al. Idiopathic hypersomnia. Psychiatry Clin Neurosci.
1998;52(2):125–9.
27. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy.
Lancet. 2000;355:39–40.
28. Zeitzer JM, Nishino S, Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and
related therapeutic interventions. Trends Pharmacol Sci. 2006;27(7):368–74.
29. Barateau L, Lopez R, Dauvilliers Y. Clinical neurophysiology of CNS hypersomnias. Handb
Clin Neurol. 2019;161:353–67.
30. Thannickal TC, Moore RY, Niehus R, et al. Reduced number of hypocretin neurons in human
narcolepsy. Neuron. 2000;27:469–74.
31. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measure-
ment in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553–62.
32. Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narco-
lepsy without cataplexy. Sleep. 2009;32(8):993–8.
33. Scammell TE. The frustrating and mostly fruitless search for an autoimmune cause of narco-
lepsy. Sleep. 2006;29(5):601–2.
34. Black JL III. Narcolepsy: a review of evidence for autoimmune diathesis. Int Rev Psychiatry.
2005;17(6):461–9.
35. Dauvilliers Y, Tafti M. Molecular genetics and treatment of narcolepsy. Ann Med.
2006;38(4):252–62.
36. Tanaka S, Honda Y, Inoue Y, et al. Detection of autoantibodies against hypocretin, hcrtrl, and
hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep. 2006;29(5):633–8.
37. Lippert J, Young P, Gross C, et al. Specific T-celll activation in peripheral blood and cerebro-
spinal fluid in central disorders of hypersomnolence. Sleep. 2019;1:42(2).
38. Dye TJ, Gurbani N, Simakajornboon N. Epidemiology and pathophysiology of childhood
narcolepsy. Paediatr Respir Rev. 2018;25:14–8.
39. Halberg P, Smedje H, Eriksson N, et al. Pandemrix-induced narcolepsy is associated with
genes related to immunity and neuronal survival. EBioMedicine. 2019;40:595–604.
40. Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with
recent narcolepsy onset. Sleep. 2009;32(8):979–83.
41. Picchioni D, Hope CR, Harsh JR. A case-control study of the environmental risk factors for
narcolepsy. Neuroepidemiology. 2007;29(3–4):185–92.
42. Castriotta RJ, Wilde MC, Lai JM, et al. Prevalence and consequences of sleep disorders in
traumatic brain injury. J Clin Sleep Med. 2007;3(4):349–56.
43. Mori I. The olfactory bulb: A link between environmental agents and narcolepsy,from the
standpoint of autoimmune etiology. Med Hypothesis. 2019;131:109294.
44. Mori I. The olfactory bulb: a link between environmental agents and narcolepsy. Med
Hypothesis. 2019;126:66–8.
45. Longstreth WT Jr, Ton TG, Koepsell TD. Narcolepsy and streptococcal infections. Sleep.
2009;32(12):1548.
46. Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the T-cell receptor
alpha locus. Nat Genet. 2009;41:708–11.
47. Cvetkovic V, Bayer L, Dorsaz S, et al. Tribbles homolog 2 as an autoantigen in human narco-
lepsy. J Clin Invest. 2010;120:713–9.
48. Tanaka S, Honda Y, Honda M, et al. Anti-Tribbles Pseudokinase 2 (TRIB2)-immunization
modulates hypocretin/orexin neuronal functions. Sleep. 2017;40(1). https://doi.org/10.1093/
sleep/zsw036.
49. Dauvilliers Y, Baumann CR, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy,
Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol
Neurosurg Psychiatry. 2003;74:1667–73.
50. Montplaisir J, de Champlain J, Young SN, et al. Narcolepsy and idiopathic hypersomnia:
biogenic amines and related compounds in CSF. Neurology. 1982;32:1299–302.
51. Faull KF, Guilleminault C, Berger PA, et al. Cerebrospinal fluid monoamine metabolites in
narcolepsy and hypersomnia. Ann Neurol. 1983;13:258–63.
52. Faull KF, Thiemann S, King RJ, et al. Monoamine interactions in narcolepsy and hypersom-
nia: a preliminary report. Sleep. 1986;9:246–9.
53. Bassetti CL, Khatami R, Poryazova R, et al. Idiopathic hypersomnia: a dopaminergic disor-
der. Sleep. 2009;32:A248–9.
54. Arnulf I, Leu-Semenescu S, Dodet P. Precision medicine for idiopathic hypersomnia. Sleep
Med Clin. 2019;14(3):333–50.
55. Nishino S, Sakurai E, Nevsimalova S, et al. Decreased CSF histamine in narcolepsy with and
without low CSF hypocretin-1 in comparison to healthy controls. Sleep. 2009;32:175–80.
56. Kanbayashi T, Kodama T, Kondo H, et al. CSF histamine contents in narcolepsy, idiopathic
hypersomnia and obstructive sleep apnea syndrome. Sleep. 2009;32:181–7.
57. Dauvilliers Y, Delallee N, Jaussent I, et al. Normal cerebrospinal fluid histamine and tele-
methylhistamine levels in hypersomnia conditions. Sleep. 2012;35:1359–66.
58. Rack M, Davis J, Roffwarg HP, et al. The multiple sleep latency test in the diagnosis of nar-
colepsy. Am J Psychiatry. 2005;162(11):2198–9.
59. Ferri R, Franceschini C, Zucconi M, et al. Sleep polygraphic study of children and adoles-
cents with narcolepsy/cataplexy. Dev Neuropsychol. 2009;34(5):523–38.
60. Carskadon MA. The second decade. In: Guilleminault C, editor. Sleeping and waking disor-
ders: indications and techniques. Menlo Park: Addison-Wesley; 1982. p. 99–125.
61. Pizza F, Barateau L, Jaussent I, et al. Validation of multiple sleep latency test for the diagnosis
of pediatric narcolepsy type 1. Neurology. 2019;93(11):e1034–44.
62. Mayer G, Lammers GJ. The MSLT: more objections than benefits as a diagnostic gold stan-
dard? Sleep. 2014;37:1027–8.
63. Baumann CR. Bassetti CI Hypocretin (orexins) and sleep-wakedisorders. Lancet Neurol.
2005;10:673–82.
64. Sakai N, Matsumura M, Lin L, et al. HLPC analysis of CSF hypocretin-1 in type 1 and 2
narcolepsy. Sci Rep. 2019;9:477.
65. Basseti CL, Adamantidis A, Burdakov D, et al. Narcolepsy - clinical spectrum, aetiopatho-
physiology, diagnosis and treatment. Nat Rev Neurol. 2019;15(9):519–39.
66. Stephansen JB, Olesen AN, Olsen M, et al. Neural network analysis of sleep stages enables
efficient diagnosis of narcolepsy. Nat Commun. 2018;9(1):5229.
67. Bin-Hasan S, Videnovic A, Maski K. Nocturnal REM sleep without atonia is a diagnostic
biomarker of pediatric narcolepsy. J Clin Sleep Med. 2018;14(2):245–52.
68. Murer T, Imbach LL, Hackius M, et al. OptimizingMSLT specificity in narcolepsy with cata-
plexy. Sleep. 2017;1:40(12).
69. Chritensen JAE, Kempfner L, Leonthin HL, et al. Novel method for evaluation ofeye move-
ments in patients with narcolepsy. Sleep Med. 2017;33:171–80.
70. Aslan S, Erbil N, Tezer FI. Heart rate variability during nocturnal sleep and daytime naps in
patients with narcolepsy type 1 and type 2. J Clin Neurophysiol. 2019;36(2):104–11.
71. Sieminski M, Chwojnicki K, Sarkanen T, et al. The relationship between orexin levels and
blood pressure changes in patients with narcolepsy. PLoS One. 2017;12(10):e0185975.
72. Hong SB. Neuroimaging of narcolepsy and Kleine-Levin syndrome. Sleep Med Clin.
2017;12(3):359–68.
73. Black J, Reaven NL, Funk SE. Medical comorbidity in narcolepsy: findings from the burden
of narcolepsy disease (BOND) study. Sleep Med. 2017;33:13–8.
74. Ruoff CM, Reaven NL, Funk SE. High rates of psychiatric comorbidity in narcolepsy: find-
ings from the burden of narcolepsy Dise ofase (BOND) study of 9312 patients in the United
States. J Clin Psychiatry. 2017;78(2):171–6.
75. Maestri M, Monzani F, Bonanni E, et al. Insulinoma presenting as idiopathic hypersomnia.
Neurol Sci. 2010;31(3):349–52.
76. Shinno H, Inami Y, Inagaki T, et al. Successful treatment with levothyroxine for idio-
pathic hypersomnia patients with subclinical hypothyroidism. Gen Hosp Psychiatry.
2009;31(2):190–3.
77. Masel BE, Scheibel RS, Kimbark T, et al. Excessive daytime sleepiness in adults with brain
injuries. Arch Phys Med Rehabil. 2001;82(11):1526–32.
78. Dl P, Ponsford JL, Rajaratnam SM, et al. Self reported changes to nighttime sleep after trau-
matic brain injury. Arch Phys Med Rehabil. 2006;87(2):278–85.
79. Baumann CR, Werth E, Stocker R, et al. Sleep-wake disturbances 6 months after traumatic
brain injury: a prospective study. Brain. 2007;130(Pt 7):1873–83.
80. Baumann CR, Bassetti CL, Valko PO, et al. Loss of hypocretin (orexin) neurons with trau-
matic brain injury. Ann Neurol. 2009;66(4):555–9.
81. Black J, Guilleminault C. Medications for the treatment of narcolepsy. Expert Opin Emerg
Drugs. 2001;6(2):239–47.
82. Didato G, Nobili L. Treatment of narcolepsy. Expert Rev Neurother. 2009;9(6):897–910.
83. Mitler MM, Hayduk R. Benefits and risks of pharmacotherapy for narcolepsy. Drug Saf.
2002;25:791–809.
84. Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treat-
ment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin.
2006;22(4):761–74.
85. Dinges DF, Arora S, Darwish M, et al. Pharmacodynamic effects on alertness of single doses
of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res
Opin. 2006;22(1):159–67.
86. U.S. Xyrem® International Study Group. A double blind placebo controlled study demon-
strates sodium oxybate is effective for the treatment of excessive sleepiness in narcolepsy. J
Clin Sleep Med. 2005;1(4):391–7.
87. U.S. Xyrem® Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy
for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004;5:119–23.
88. Xyrem® Product Information, Orphan Medical, Inc.
89. Li S, Yang J. Pitolisant for treating patients with narcolepsy. Expert Rev Clin Pharmacol.
2020;13(2):79–84.
90. Dauvilliers Y, Arnulf I, Szakacs Z, et al. Long-term Use of Pitolisant to Treat Patients with
Narcolepsy: Harmony III Study. Sleep. 2019;42(11):zsz174.
91. Thorpy MJ, Shapiro C, Mayer G, et al. A randomized study of solriamfetol for excessive
daytime sleepiness in narcolepsy. Ann Neurol. 2019;85(3):359–70.
92. Abad VC. Guilleminault. New developments in the management of narcolepsy. Nat Sci
Sleep. 2017;9:39–57.
93. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narco-
lepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705–11.
94. Guilleminault C, Raynal D, Takahashi S, et al. Evaluation of short-term and long-term treat-
ment of the narcolepsy syndrome with clomipramine hydrochloride. Acta Neurol Scand.
1976;54:71–87.
95. Houghton WC, Scammell TE, Thorpy M. Pharmacotherapy for cataplexy. Sleep Med Rev.
2004;8:355–66.
96. Martinez-Rodriguez J, Iranzo A, Santamaria J, et al. Status cataplecticus induced by abrupt
withdrawal of clomipramine. Neurologia. 2002;17:113–6.
97. Frey J, Darbonne C. Fluoxetine suppresses human cataplexy: a pilot study. Neurology.
1994;44:707–9.
98. Ruppert E, Zagalaa H, Chambe J, et al. Intravenous immunoglobulin therapy administered
early after narcolepsy type 1 onset in three patients evaluated by clinical and polysomno-
graphic follow-up. Behav Neurol. 2018;2018:1671–2.
99. Thorpy MJ, Snyder M, Aloe FS, et al. Short-term triazolam use improves nocturnal sleep of
narcoleptics. Sleep. 1992;15(3):212–6.
100. Morse AM, Kelly-Pieper K, Kothare SV. Management of excessive daytime sleepiness in
narcolepsy with baclofen. Pediatr Neurol. 2019;93:39–42.
Chapter 16
Non-REM Parasomnias
Nathan A. Walker and Bradley V. Vaughn
Keywords Parasomnia · Disorders of arousal · Sleepwalking · Sleep terror

Confusional arousal REM sleep behavior disorder · Sleep-related eating disorder
Exploding head syndrome
Introduction
Parasomnias are defined as “undesirable physical events or experiences that occur

during entry into sleep, within sleep, or during arousal from sleep” [1]. As part of a
larger collection of nocturnal events, parasomnias are included in the pathologies
that produce behaviors and occurrences at night. Many envision these events as
entertaining stories from family or roommates, or may be thought of as strange
inexplicable incidents. The clinical symptoms of parasomnias include complex pur-
poseful movements, unusual behaviors, perceptions, or emotional experiences.
Many of the parasomnias are very common in the general population, especially in
children. Although the majority of parasomnias are not harmful, injuries, sleep dis-
ruption, and psychosocial impairment can result from the events, and these events
provide the opportunity to diagnose underlying sleep disorders or medical issues
that may provoke the events. Therefore, it is useful to know the symptoms, clinical
associations, and treatment options to guide patients.
In early nomenclature, parasomnias were categorized based upon the most prom-
inent behavior. Some remnants of this convention still exist in terms such as sleep-
walking and sleep-related eating. However, as we have furthered our understanding
of the neuronal circuits determining the states of sleep and wake, we have grouped
events toward the originating sleep-wake state while acknowledging pathologies
N. A. Walker · B. V. Vaughn (*)

Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
e-mail: vaughnb@neurology.unc.edu

350 N. A. Walker and B. V. Vaughn
that are held in common [1]. The brain’s three distinct states of wake and NREM
and REM sleep allow us to understand the starting physiological state that provides
the substrate for some of these parasomnias. Thus parasomnias may be associated
with NREM sleep, REM sleep, or the transitions between wake and sleep as a plat-
form which demonstrates the underlying pathology. The current categorization in
the International Classification of Sleep Disorders third edition (ICSD 3) divides the
parasomnias into four main categories: NREM-related parasomnias, REM-related
parasomnias, other parasomnias, and normal variants (Table 16.1). This context
includes consideration of the drivers for the parasomnias as well as how to separate
mimics that may present with similar behaviors.
This classification scheme also allows us to ultimately move toward a classifica-
tion structure more aligned with physiology and subsequently underlying pathol-
ogy. Several parasomnias represent a mixture of states [2]. This model is best
demonstrated when considering the non-REM sleep-related parasomnias, disorders
of arousals. The disorders of arousals (sleep terrors, sleepwalking, and confusional
arousals) are associated with a mixture of features of NREM sleep with some wake-
like behaviors. These disorders represent a continuum of complex behaviors that
share features of NREM sleep, such as minimal cognitive functioning and amnesia
for the events, with features of the awake state such as complex motor patterns and
eyes open (Table 16.2) [1]. Commonly these events are triggered by stimuli during
deeper NREM sleep and involve a variety of nonstereotyped behaviors. One REM-
related parasomnia, recurrent isolated sleep paralysis, also represents a mixture of
wake and REM sleep. Although many times associated with narcolepsy, these
Table 16.1 Outline of parasomnias
1. Non-REM parasomnias
(a) Disorders of arousal
(i) Confusional arousals
(ii) Sleepwalking
(iii) Sleep terrors
(b) Sleep-related eating disorder
2. REM-related parasomnias
(a) REM sleep behavior disorder
(b) Recurrent isolated sleep paralysis
(c) Nightmare disorder
3. Other parasomnias
(a) Exploding head syndrome
(b) Sleep-related hallucinations
(c) Sleep enuresis
(d) Parasomnia due to a medical disorder
(e) Parasomnia due to a medication or substance
(f) Parasomnia, unspecified
4. Isolated symptoms and normal variants
(a) Sleep talking
Table 16.2 Distinguishing features of nocturnal events. Reprinted with permission from Bradley Vaughn
Recurrent
Sleep-related REM sleep behavior isolated sleep Exploding head Psychogenic Nocturnal
Feature Disorders of arousal eating disorder disorder paralysis syndrome events seizures
Behavior Confused; Eating Sometimes combative Episodes of Painless sensation Variable Dependent on the
semipurposeful typically with eyes closed inability to of explosion inside portion of brain
movement with eyes high-calorie move the head involved
open foods; eyes
open
16 Non-REM Parasomnias
Age of onset Childhood and Variable Older adult Variable Adult Adolescence Variable
adolescence to adulthood
Time of First third of night First half of During REM Typically on Usually near sleep Anytime Anytime
occurrence night awakening onset but can be
variable
Frequency of Less than one per Variable Multiple per night Variable less Rare Variable Frontal
events night than weekly seizures—
multiple per
night
Duration Minutes Minutes Seconds to minute Seconds to Seconds Variable Usually under
minutes minutes or 3 minutes
longer
Memory of event Usually none Usually none Dream recall Yes Yes None Usually none
or limited
Eyes open or Eyes open Eyes open Eyes closed Eyes closed Eyes closed but Variable Variable
closed immediately open
following the event
Stereotypical No No No No Similar sensation No Yes
movements
Polysomnogram Arousals from slow Arousal from Excessive Arousal from Usually occurs in Occur from Potentially
findings wave sleep NREM sleep electromyogram tone REM sleep light sleep awake state epileptiform
during REM sleep activity
351
events in isolation are related to the intrusion of REM sleep-related paralysis into
wakefulness [3, 4]. Other REM sleep parasomnias such as nightmare disorder and
REM sleep behavior disorder are confined to the state. The latter is an example of
neurological impairment of the circuitry that produces the REM sleep associated
paralysis [5]. This disorder represents an example of how sleep dedicated neural
circuitry may be uniquely more vulnerable to specific types of degeneration
or injury.
Many of the “other parasomnias” represent events that occur during the transi-
tion between wake and sleep (Table 16.1). Some sensory events such as exploding
head syndrome and sleep-related hallucinations are events that may occur as the
patient enters light sleep, but may also occur upon awakening. Additionally, in this
group are parasomnias that occur across the spectrum of sleep states or represent a
loss of sleep-wake state distinction.
The goal of this chapter is to review the variety of disorders classified as para-
somnias. This chapter provides a framework for parasomnias and outlines an over-
arching approach to patients with nocturnal events. The text reviews the known
pathology and the possible drivers for the parasomnias as well as describes mimics
that may present with similar behaviors. The challenge for the ardent clinician is to
utilize historical and physical examination clues with the appropriate investigative
tools to discern the underlying causes and propose appropriate therapy to improve
the patient’s condition.
Non-REM Related Parasomnias
As the name implicates, non-rapid eye movement (NREM) sleep-related parasom-

nias are parasomnia events that arise from NREM sleep. This group includes the
disorders of arousal and sleep-related eating disorder. As a whole, the episodes may
include a variety of complex movements that range a variety of basic behaviors.
These parasomnias are classically thought of as partial triggered awakenings with
retention of some features of sleep. Each of these disorders has their own criteria for
diagnosis and unique features.
Disorders of Arousal
The International Classification of Sleep Disorders, 3rd edition (ICSD-3) defines

disorders of arousal by specific universal features and then specific findings for the
subdivisions of confusional arousals, and sleepwalking and sleep terrors. The disor-
ders of arousal (DOA), as a group, have several common manifestations that define
the cluster, while each also has unique features in behavior that allow their distinc-
tion. For the group of DOA, the ICSD-3 requires several features to be present to
qualify as a DOA (Table 16.3).
16 Non-REM Parasomnias 353
Table 16.3 Features of disorders of arousal (adapted from ICSD-3)

1. Recurrent episodes of incomplete awakening from sleep
2. Inappropriate or absent responsiveness to intervention from observers or from others
attempting to redirect the person during the episode
3. Limited or no associated cognition or dream imagery
4. Partial or complete amnesia for the episode
5. The disturbance is not better explained by other medical, psychiatric or sleep conditions or
medications, or substance use
Furthermore, these three diagnoses share clinical features that help clinicians
identify these as NREM sleep events. The majority of events occur in the first third
of sleep and are relatively brief. Most of the events in disorders of arousal last for
30 seconds to a few minutes, but some may last up to 30 minutes. Many times,
patients have their eyes open but have a glassy confused stare. They may be partially
reactive to the environment and even may appear disoriented for several minutes
following the events. During the events, patients lack higher cognitive processing
and appear to be functioning unconsciously. These patients are difficult to awaken
from the events, and stimulation may result in the patients becoming agitated.
Following the event patients may have partial or total amnesia, although adults are
more likely to remember portions of the episodes. These disorders are most com-
mon in children and typically improve with age. Males and females are equally
represented in disorders of arousal, and family history of events is in nearly two
thirds of carefully screened cases.
Pathology
The vast majority of patients with disorder of arousal are neurologically and psy-
chologically normal. When examining the sleep physiology in these patients, the
studies show relatively normal sleep architecture. On sleep studies the onset of
NREM parasomnia is an abrupt arousal, usually from stage N3 sleep with the
patients having a dull confused look on video. Some studies have shown increased
spontaneous awakening or arousals from slow wave sleep, and some investigators
have found increased runs of hypersynchronous delta waves just prior to events [6,
7]. These studies have suggested increased slow wave activity and slow oscillations
in EEG patterns prior to sleepwalking events. These findings suggest that the
pathology is related to incomplete switching of deeper NREM sleep to wake.
Examination of the gross structure of the brain shows little differences between
patients and control subjects. However, Heidbreder reported that subjects with
NREM parasomnias had smaller gray volume of the dorsal posterior cingulate
when compared to nonparasomnia controls using magnetic resonance imaging
(MRI) and diffusion tensor imaging (DTI) [8]. Further studies using depth EEG
electrode recordings showed that disorder of arousal events activated the motor and
central cingulate cortex while deactivating the hippocampal and association
cortices [9, 10]. This activation pattern of cingulate motor area while deactivation
of other association cortices was seen using Single-Photon Emission Computed
Tomography (SPECT) when tracer was injected during a sleepwalking episode
[11]. Furthermore, studies of network function related to frontal inhibition elicited
by transcranial magnetic stimulation (TMS) showed that sleepwalkers have an
impaired efficiency of inhibitory circuits [12]. Based on their results, the authors
postulated that sleepwalkers have a dysfunction of both GABA-A and cholinergic
pathways leading to an inability to maintain slow wave sleep and suppress partial
arousals in sleep. As part of testing this functional inhibition, another study of
sleepwalkers showed they had greater impairment of inhibitory control resulting in
increased errors on Stroop Color Word Test and errors of commission on Continuous
Performance Test following 25 hours of sleep deprivation [13]. These studies
appear to suggest that the typical processes that inhibit specific portions of the
subclinical arousals are not sufficient in suppressing these partial arousals. Thus
patients with disorders of arousal are more vulnerable to activity that produces
arousals from NREM sleep.
Associated Conditions
Disorders of arousal have been reported with a variety of medical disorders includ-
ing endocrinological, vascular, neurological, and sleep disorders. Case reports of
new onset DOA have described right thalamic lesion, breathing disorder with Chiari
I malformation, hyperthyroidism, and diabetes [14–16]. Historically, disorders of
arousal were thought to be associated with depression and anxiety. However, more
recent studies show no relationship of these disorders to psychopathology [17, 18].
One caveat is that sleep terrors in children do not usually present with psychopa-
thology, but it may play a larger role in adults with sleep terrors [19].
The most common sleep disorder associated with NREM parasomnias is obstruc-
tive sleep apnea. Several studies have suggested the link of breathing disorders
increasing the frequency of disorder of arousal events. Goodwin found that children
with even mild upper airways disturbance were significantly more likely to have
parasomnia events than those without any disturbance [20]. Similarly in adults,
Lundetræ reported that sleepwalking has a higher prevalence in patients with severe
OSA than those with mild OSA [21]. These reports highlight that disorders of
arousal events may signal the presence of other sleep disorders and that patients
with NREM parasomnias may benefit from investigation and treatment of these
disorders.
Some disorder of arousal events appear to be elicited by specific medications.
Medications such as antidepressants, antipsychotic agents, beta blockers, and
GABA modulators have been reported as possible agents that can trigger events. Of
these, the most well recognized are the short-acting hypnotic agents, such as zolpi-
dem or sodium oxybate. These medications are linked to increase frequency of
sleepwalking and confusional arousal events. This association raises the possible
question that the mechanism is impairment of arousal circuitry caused by the medi-
cation [22].
Diagnosis
The gold standard for making the diagnosis of DOA is capturing an event arising
from NREM sleep on polysomnography (PSG). This finding helps elucidate the key
features of a mixture of wake and NREM sleep (Fig. 16.1). This testing also can
shed some light if the patient is having other sleep issues, such as sleep apnea, that
may be provoking the nocturnal events. Fois showed, in a study of 124 subjects, that
PSG confirmed parasomnia diagnosis in up to 60% of their study group [23]. PSG
was also helpful in identifying other diagnoses that may mimic the parasomnia.
Video PSG can capture the events in detail, and these events may show a spectrum
of behaviors from appearing awake and confused to non-agitated motor activity to
events with extreme emotional distress. These events typically arise from stage N3
sleep but less commonly occur from N2 sleep. Although recording spontaneous
Fig. 16.1 This figure shows a standard polysomnogram during a confusional arousal in a 7-year-
old boy. The patient is with eyes open during the event and has a confused look on his face.
(Reprinted with permission from Bradley Vaughn MD)
parasomnia activity during PSG is uncommon, Pilon tested a technique that pro-
voked events in nearly all of their subjects [24]. In their protocol, subjects with a
history of sleepwalking were kept awake through the night and then allowed to
sleep during the day. Once the subjects entered stage N3, an auditory stimulus was
introduced to cause an arousal. Nearly all of the patients had a subsequent event.
This study has yet to be repeated, but offers a possibility of a higher yield of events.
Management
Management of patients with disorders of arousal focuses on three major areas:

safety, decreasing the frequency of events, and determining the possibility of other
underlying provocative factors. The clinician initially needs to assess the possibility
of harm from the events to the patient or family members. Many patients may have
events without leaving the bed and have little chance of harm. For these patients
reassurance is an important component in the treatment plan. For all cases, the
patients and their families should be counselled on a safe sleeping environment and
how to safely interact with the patient when they are having an event. For those at
risk, placing the bed on the floor, securing windows and doors, and eliminating any
access to sharp or dangerous objects are key. For some patients having their bed-
room on the first floor to avoid falling or the use of door alarms is helpful.
Management may also focus on the predisposing, priming, and precipitating fac-
tors of what is called the three P model of NREM parasomnias [25]. The predisposing
factors such as genetics, thus understanding family history, may help families be
aware of the risks. Priming factors include medication that may increase the arousal
threshold, e.g., Z-drugs; sleep deprivation which can increase the amount of SWS and
increase arousal threshold; or substances that may increase arousals, caffeine or alco-
hol. Precipitating factors can include pain, a sleeping environment unconducive to
sleep, and a myriad of other sleep disorders. Therefore, targeting good sleep hygiene,
avoidance of priming substances/situations, and precipitating factors are useful tac-
tics to reduce events. Tracking the frequency of events on a calendar may help iden-
tify patterns that lead to clues of provoking agents, as well as response to therapies.
Patients and their families may look for sources of arousals to reduce, such as
environmental noise or stimuli as well as keeping a regular sleep schedule and avoid-
ing sleep deprivation. Anticipatory awakening therapy is one behavioral therapy that
is shown to be successful in children in reducing the frequency of events [26]. For this
therapy the patient is allowed to go to sleep but awoken anywhere from 10 to 30 min-
utes prior to the typical time of the event. This is repeated for 2–3 weeks, and then the
patient is assessed for further events. If the patient does resume having events, another
round of awakenings can be performed. For a small minority of patients, medication
is needed. Due to a lack of case control studies or randomized control trials, recom-
mendations at times can be contradictory. Clinically, patients appear to respond to
agents such as clonazepam or longer-acting benzodiazepines. In one series of 69
patients treated with these agents, 86% showed improvement [27]. Several case
reports have suggested response to imipramine, trazadone, or paroxetine [28–30].
Confusional Arousals
Confusional arousals are the events of disorder of arousal in which the patient nei-
ther shows a prominent fear reaction nor ambulates. This diagnosis can include a
wide variety of behaviors that range from mild sitting with a confused look to com-
plex actions appearing to meet a variety of basic needs. Patients may engage in a
range of emotions from amorous to aggressive outbursts, and behaviors can include
a variety of common everyday activities to more intrusive events including eating
and sexual behaviors.
Clinical Presentation
Confusional arousals are one of the disorders of arousal from NREM sleep [1].
Patients appear to be both asleep and awake. As the name implies, the patient
appears very confused. The patient is typically in bed, and the event commonly
involves the patient sitting upright with their eyes open and looking around. The
patient is often unresponsive or poorly responsive to questions or commands, and
some sleep talking may occur. The events are associated with partial or total amne-
sia and typically last only a few minutes with the person returning to sleep.
Confusional arousals occur in the first third of the night, predominantly from N3 or
slow wave sleep (SWS), when SWS is most likely to occur.
Epidemiology
Confusional arousals are more common in children than adults. Although these
events are nearly ubiquitous in children under the age of 3 years, the events are
noted to occur in 20–50% of preschool to school aged children [2]. These events are
present in up to 1–4% of young adults and as possibly as high as 7% in older adults
[26, 31]. The true incidence in all age groups is likely higher due to lack of reporting
and/or observation of events.
Pathophysiology
It is thought that confusional arousals and the other disorders of arousal (sleepwalk-
ing and night terrors) are due to a dissociation between the wake state and NREM
sleep. There is an incomplete arousal from NREM sleep that tends to occur in the
first third of the night when SWS predominates. However, 20% of cases may occur
from N2 or Stage 2 sleep [31, 32]. The preponderance of NREM parasomnias in
children may be due to the increased amounts of SWS as compared to adults.
Arousal thresholds are also at their highest during SWS. Substances or scenarios
that increase the arousal threshold can increase the likelihood of disorders of arousal,
such as sleep aides and sleep deprivation, respectively [31]. Conversely, agents that
increase arousals, such as a noisy sleeping environment or sleep apnea, can increase
the occurrence of NREM-related parasomnias [32]. There is a strong genetic com-
ponent to confusional arousals and the other disorders of arousals as there is usually
a strong family history [31, 33].
Diagnosis
Currently, the diagnosis of confusional arousals is based on the clinical history. The
ICSD-3 sets the specific characteristics for the diagnosis of confusional arousals as
disorders of arousal:
1. The disorder meets the general criteria for NREM disorder of arousal.
2. The episodes are characterized by mental confusion or confused behavior that
occurs while in bed.
3. An absence of terror or ambulation out of the bed.
The criteria specific for confusional arousal help differentiate these events from
sleepwalking and sleep terrors. Video polysomnography (VPSG) is used for the
diagnosis of confusional arousals when there is concern for the patient harming
themselves or others or the other disorder of arousals except to differentiate from
other disorders, i.e., seizures, in complex cases or to diagnose concomitant disor-
ders, such as sleep apnea [1, 2, 33].
Treatment
Confusional arousals are usually self-resolving and usually resolve by adolescence.

In children with little risk of harm, parents should be offered reassurance. Parents and
bed partners should be counseled not to attempt to wake the patient during these
events as it can result in worsening the confusion, increased agitation or aggressive-
ness, and prolonging the event. Treatment should focus on the priming and precipitat-
ing factors of the three P model (predisposing, priming and precipitating) of NREM
parasomnias. Priming factors such as avoidance of actions such as sleep deprivation
that increase the amount of slow wave sleep, and avoidance of substances that may
increase arousals, such as caffeine or alcohol. Precipitating factors also need evalua-
tion; thus the patient should be asked about things that cause arousals such as environ-
mental noise and light as well as other symptoms suggestive of other sleep disorders.
Therefore, targeting good sleep hygiene, avoidance of priming substances/situations,
and precipitating factors are useful tactics to reduce events [2, 25, 33]. In the event
that episodes are persistent despite the above or that the severity of the events is plac-
ing the patient or others at risk of harm, pharmacologic treatment may be necessary.
Clonazepam is the medication with the most evidence for use, but melatonin, antide-
pressants, and even the hypnotic z-drugs have been used with reported effect [33].
Sleepwalking (Also Known as Somnambulism)
Sleepwalking or somnambulism is another disorder or arousal from NREM sleep. It

is characterized by an incomplete arousal from NREM sleep with complex behavior
and ambulation out of the bed. These events may go unnoticed as the sleepwalker
may return to bed unnoticed and therefore not be reported. The main adverse out-
come from sleepwalking is injury to the patient or others. Patients have limited
ability to respond to the environment and thus are at risk for injury. As with other
disorders of arousal, they occur mostly in children and usually improve with age;
however onset in adulthood likely points to prior sleepwalking history or another
underlying sleep disorder.
Sleepwalking usually starts like a confusional arousal with the patient sitting up
confused; however, unlike confusional arousal the patient gets out of bed. The
events can be more complex than simple wandering about and involve opening
locked doors or windows, dressing, and even urinating in inappropriate places. The
episodes can end with the patient back in bed without reaching conscious aware-
ness, or it may end suddenly in an inappropriate place, such as outdoors in inclem-
ent weather. Patients may have limited or no memory or vague dream like mentation
of the event. Most events are relatively brief, but some patients have events that last
several minutes [1, 2].
Epidemiology
Like the other disorders of arousal, sleepwalking is more common in children. The
peak incidence is in the pre-teen to early teen years, 10–13, and resolves by adoles-
cence in 75% of people. The lifetime prevalence is estimated to be between 22 and
29% [2, 34]. In roughly 13% of adults sleepwalking develops de novo, and the
overall prevalence in adults is 4% [34]. Most adults with sleepwalking have a his-
tory of sleepwalking as children, and the de novo cases are most often associated
with medications and neurodegenerative disorders [35].
Pathophysiology/Etiology
The basic pathophysiology of sleepwalking like other disorders of arousal is related

to incomplete arousal from SWS. The patient has both features of being asleep and
awake that evoke motor central pattern generators for complex motor behaviors.
Several studies have shown that different brain regions have dissociative activity,
that is, certain regions showing activity consistent with the waking state and others
with activity consistent with the sleep state [10, 36]. Like the other disorders of
arousal, there is a strong family history pointing to a genetic underpinning. There
has been identification of chromosome 20q12-q13 as a possible locus as well as high
frequency in patients with the HLA-DQB1 05:01 allele [2, 32]. Sleepwalking can be
precipitated by increased arousals from SWS such as in the case of OSA, or it can
be primed in the case of sleep deprivation. There are numerous reports of medica-
tions associated with somnambulism, particularly the z-drugs (zolpidem, zaleplon),
but also for antidepressants of all classes, antipsychotics, and beta-blockers [22].
Diagnosis
The ICSD-3 criteria for sleepwalking include that the disorder meets the general
criteria for a disorder of arousal and that the patient has events that are associated
with ambulation or other complex behaviors out of bed. The ICDS-3 requires the
following to establish the diagnosis:
1. The disorder meets the general criteria for NREM disorder of arousal.
2. The arousals are associated with ambulation and other complex behaviors
out of bed.
The diagnosis of sleepwalking can usually be diagnosed based on clinical his-
tory, but since the patient is at inherent risk of harm by virtue of leaving the bed,
video PSG is an important component of the evaluation. Patients need evaluation to
determine if the events appear to be occurring from NREM sleep as well as other
possible provoking factors such as sleep apnea.
Treatment
For most patients, therapy can focus on non-pharmacologic avenues unless the
patient is at significant risk for harm. Reassurances should be given to parents that
sleepwalking is not a sign of developmental disability nor other mental issues. The
sleep environment should be made safe for the sleepwalker by removing sharp
objects and sharp-edged furniture, locking doors and windows, and bed alarms.
Parents and bed partners should be advised not to attempt to wake the patient as this
can result in prolongation of the event, aggressive or violent behavior, or running
away potentially causing harm to self and others. Additionally, efforts should be
directed at avoiding or targeting priming and precipitating factors, such as sleep
deprivation, sedative hypnotics, other sleep disorders, anxiety, etc. In the majority
of childhood cases, sleepwalking is self-resolving, but adults may frequently need
further intervention. Melatonin and clonazepam may be options [2, 6, 25, 33].
Sleep Terrors (Also Known as Night Terrors or

Pavor Nocturnum)
Sleep terrors are the most dramatic of the disorders of arousal from NREM sleep.
They often start with a piercing scream followed by consolable fear. These events
are very impressive to the observer, but have little impact on the patient. Like the
other disorders of arousal, they usually occur in the first part of the night and are
more common in children. Sleep terrors resolve with age and rarely occur
after age 7.
Sleep terrors start abruptly, usually with an intense terrified scream, associated
with intense fear and significant sympathetic outlay of the autonomic system. The
patient can be found profusely diaphoretic with tachycardia, mydriasis, and tachy-
pnea. The patient will be inconsolable and attempts to calm the patient can pro-
long the event. The patient is poorly responsive to observers and the environment
but may look around or reach around. The episodes usually only last a few min-
utes, and then the patient will spontaneously return back to sleep. There is no
memory for the event, and if the patient does wake at the end of the event, there is
usually only a vague remembrance of fear, but no accompanying dream imagery
[2, 31–33].
Epidemiology
Sleep terrors are more common in preschool children with 20–40% of children
younger than 3 years experiencing an event and reduces to less than 14% of school
aged children [37]. It is rare for adults, but prevalence has been reported to be
around 2.7% [2].
Etiology/Pathophysiology
Sleep terrors occur from an incomplete arousal from SWS as with the other
disorders of arousals above. The exact cause is unknown, but a strong genetic
component is suspected based on strong family histories in patients and concor-
dance twin studies. Patients have been shown to have more fragmented N3
sleep [2].
Diagnosis
The diagnosis can be made by clinical history. The key is related to the piercing
scream at the beginning of the event. The ICSD-3 requires the following items to
establish the diagnosis [1]:
1. The disorder must meet the general criteria for NREM disorders of arousal.
2. The events are characterized by episodes of abrupt terror, typically beginning
with an alarming vocalization such as a frightening scream.
3. The events also have accompanying features of intense fear and signs of auto-
nomic arousal, including mydriasis, tachycardia, tachypnea, and diaphoresis
during an episode.
Sleep terrors can be distinguished from nightmares as night terrors tend occur in
the first third of the night, when N3 is most prevalent, and there is lack of memory
for the event and the patient is difficult to arouse. By contrast, nightmares occur
from REM sleep, and the patient is not confused and is easily arousable. There is
also story-like recall in the case of nightmares, whereas night terrors are only asso-
ciated with vague, fragmented memory if any [2, 37].
Treatment
Sleep terrors are very dramatic and patients must first be protected from harming
themselves or others. Typically the patients are trying to escape and may even fling
themselves out of windows. The environment must be made safe from potential
hazards, and windows need to be blocked. Other means are locks on doors or noti-
fication alarms to avoid the patient leaving the house. Treatment should be focused
on addressing predisposing factors as mentioned above and examination for other
sleep and medical disorders such as sleep apnea that need treatment. Some have
recommended that anticipatory awakening therapy can be helpful in this population.
For this therapy the patient is awakened roughly 10–30 minutes prior to the usual
event time each night for 2 weeks, then allowed to sleep to see if the events resume.
The process can be repeated; however this should only be performed once other
disorders such as sleep apnea have been ruled out. In cases that are refractory to the
nonpharmacologic interventions or there is risk of harm to self or others, clonaze-
pam or tricyclic antidepressants have been used [2, 25, 33].
Sleep-Related Eating Disorder
Sleep-related eating disorder is characterized by patients having repeated bouts of

eating while in a partial sleep state. Unlike the other NREM parasomnias, sleep-
related eating disorder is not considered one of the disorders of arousal as discussed
above. However, SRED has similar characteristics including occurring from NREM
sleep and is also associated with incomplete arousal. The eating occurs after sleep
onset has occurred and needs to be distinguished from nocturnal eating syndrome
(NES) as discussed below.
This condition is characterized by recurrent eating episodes that occur after an arousal
from sleep. During these events patients may consume unusual to bizarre foods
including raw meats, cake batter, and frozen foods to inedible non-foodstuffs like
buttered cigarettes to toxins such as cleaning liquids. In addition to ingesting harmful
foods or substances, there is risk of harm from improperly attempting to prepare
foods [38–41]. The person with sleep-related eating disorder (SRED) has partial or
total amnesia for the event. The events occur almost nightly. Occurring during NREM
sleep they tend to occur in the first half of the night. SRED is, not surprisingly, associ-
ated with weight gain and morning anorexia, but also injury from eating toxic sub-
stances or inedible items. These types of events also raise several issues beyond being
unusual stories, and a complete evaluation is vital for the patients’ well being.
Epidemiology
The prevalence of SRED is estimated at 1–4.6% in the general population [38–40].

However Winkelman found up to 17% in patients with other eating disorders and
that these symptoms are more common in those patients who have been hospitalized
for eating disorders than the general population [42]. Sleep-related eating disorder
appears to have a peak incidence in young adulthood and is more common in
females than males. Santin, who examined a Chilean population, described a peak
age of diagnosis around 39 years, but symptoms starting on average 8 years prior to
diagnosis [43]. Concomitant sleep disorders are present in up to 80% of patients
with SRED [38].
A familial relationship has been shown in 5–26% of patients [38]. This may be in
part related to the possible relationship to the DOA for some of these patients; how-
ever, other contributors such as eating disorders also appear to run in families. Thus
the pathophysiology is not known, but it is surmised that arousals from NREM sleep
may result in varying levels of consciousness resulting in SRED in susceptible indi-
viduals. The strongest association is with other eating disorders, and this may have
a relationship to the underlying focus on food and eating. There is also an associa-
tion with restless leg syndrome, suggesting a possible dopaminergic pathway
involving the reward system of the mesolimbic region. Some medications such as
zolpidem are associated with episodes of sleep-related eating, and there is also an
association with many psychoactive drugs. Sedative hypnotics, antidepressants, and
antipsychotics have all been associated with SRED [38, 40, 41].
There is a high rate of psychiatric comorbidity and SRED as well. In the original
description of SRED over 40% of the patients had a coexisting mood disorder [41].
The rate of depression has been reported at 37% and 18% for anxiety disorder. The rate
of substance abuse is also high at 24% [38]. Daytime eating disorders, i.e., anorexia
and bulimia, also have a high association with SRED. The frequent co-occurrence of
SRED and psychiatric illness suggests a similar underlying pathology [41].
Diagnosis
The diagnosis of SRED is typically based upon the clinical features presented at the
initial history and physical examination. The key element is to have a reliable wit-
ness of the events describe the features of several events. The ICSD-3 sets four cri-
teria for diagnosing SRED. These include:
1. Recurrent episodes of dysfunctional eating occurring after an arousal from sleep
2. The presence of one of the following: ingestion of odd or peculiar foodstuffs or
combinations or inedible or toxic substances, injuries sustained by or potentially
injurious behavior when getting food or in the preparation of food that is sleep
related, and adverse health consequences, e.g., weight gain or diabetes
3. Partial or complete amnesia for the event
4. And finally that the above is not better explained by some other disorder, sub-
stance, or medication
Although the presence of SRED can usually be diagnosed based on the clinical
history, the clinician needs to have a high suspicion for other sleep, neurological, or
psychiatric disorders. If the episodes are stereotypic or other sleep disorders are
considered in the differential, then the VPSG should be performed. During this
study, the usual foods that the patient tends to eat during SRED should be available
in the room during the overnight study [38].
–– SRED needs to be distinguished from another form of abnormal nighttime eating

disorder. Nocturnal eating syndrome (NES) is defined differently depending on
the literature, but key distinctions are the level of consciousness, timing of eat-
ing, and frequency of comorbid sleep disorders [41]. Nocturnal eating syndrome
has similar features of eating during the night, but, as opposed to SRED, these
patients are fully conscious during the nocturnal eating. In addition, nighttime
eating very often occurs prior to sleep onset as NES is actually a circadian phase
delay in the eating schedule. Finally, SRED is more associated with other sleep
disorders, e.g., sleep apnea, than patients with NES [38, 41]. There is, however,
considerable overlap in other features of NES and SRED. NES can also be
accompanied by an eating episode after arousal from sleep. In addition, affective
disorders are also highly associated with NES as with SRED [38]. The astute
clinician may be able to delineate the two disorders by careful history; however
the diagnosis of NES should be on the differential with any sleep disturbance
accompanied by eating. On PSG studies of NES eating was accompanied by full
consciousness and no other sleep disorders were described, save for decreased
total sleep time and sleep efficiency [38].
Treatment
In general most treatments of SRED are anecdotal reports. If a patient started the
sleep-related eating events with the initiation of a medication such as a short-acting
hypnotic, then the hypnotic should be discontinued. Similarly good sleep hygiene
and avoidance of initiating or provoking factors are a foundation point for therapy.
Pharmacologic treatment includes pramipexole which showed some modest effec-
tiveness in a small placebo controlled trial [40]. Another trial has shown the anti-
epileptic medication topiramate to be effective as well. Case reports have shown the
SSRIs fluvoxamine, paroxetine, and fluoxetine to be successful [38, 40]. Treatment
should also be aimed at any sleep disruptors, including other sleep disorders that
may arouse the patient from NREM.
REM-Related Parasomnias
REM sleep is characterized by relative atonia of the voluntary muscles, rapid eye move-
ments, and vivid dream mentation. Portions of these characteristics are key in the
description of REM-related parasomnias as a group of parasomnias that, obviously,
arise out of REM sleep. These disorders share many of the characteristics of REM but
represent a variety of underlying pathologies. The disorders can be an intrusion of
REM sleep into wake, such as sleep paralysis, demonstrate a vulnerable neurocircuitry
as in REM sleep behavior disorder, or an over expression of emotion into the state such
as in nightmare disorder. Arising from REM sleep these parasomnias tend to occur in
the second half of the night. They affect both children and adults, and in the case of
REM behavior disorder can be a sign of or precursor to a neurodegenerative disorder.
REM Sleep Behavior Disorder
REM sleep behavior disorder (RBD) is characterized by the loss of the usual paraly-
sis during REM sleep resulting in the patient acting out their dreams. These events
are often violent resulting in injury of the patient as well as the bed partner. RBD
has a high association with a group of neurodegenerative disorders and can precede
the hallmark clinical characteristics by years.
RBD is a parasomnia that is characterized by abnormal behaviors occurring during

REM sleep. Due to the loss of the muscle atonia that normally accompanies REM
sleep, the affected sleeper has motor responses correlating to dream imagery. In
general RBD manifests as dream enactment, resulting in thrashing, slapping, or
kicking of the extremities and even yelling [44–47]. Self-injury is a common occur-
rence and a little over 60% of patients injuring a bed partner [44]. The usual dream
semiology involves predominantly defensive types of events in which the patient is
being attacked or threatened by animals or intruders or has to defend in a sport. The
resulting behaviors are the result of attempts at self-defense or the defense of others.
The patient usually wakes at the end of the dream and can recall the dream content
that parallels the observed behavior while asleep.
Epidemiology
The prevalence of RBD in the general population has been reported to be from 0.38
to roughly 2% [47]. However, the prevalence has been suggested to be as high as
5–13% of adults aged 60–99 [46]. The disorder is thought to be more common in
men than women, yet some of this may be related to reporting bias. In younger onset
patients, those under 50 years old, men and women are equal [46].
The exact mechanisms underlying RBD appear to be related to impairment of the

pathway that induces atonia during REM sleep. This syndrome can be created in
animal models by lesions involving the REM atonia pathways, suggesting involve-
ment of the REM sleep control centers located in the pons and medulla. The result-
ing dysfunction results in loss of the normal atonia associated with REM sleep [45].
Although several reports show that lesions in the pons, midbrain, and medulla can
elicit RBD, in older adults there is a high association with RBD, and a group of
neurodegenerative disorders called alpha-synucleinopathies. This group is named
for the protein that can be found intracellularly in these disorders. The alpha-
synucleinopathies include Parkinson’s disease (PD), multiple system atrophy
(MSA), and dementia with Lewy bodies (DLB). RBD is considered a predictor for
future conversion to one of the above disorders. Indeed RBD may precede pheno-
conversion to one of the alpha-synucleinopathies by decades. The risk of conversion
over 2–5 years is roughly 15–35% and after 25 years is over 90% [45]. Many medi-
cations have been associated with RBD as well. SSRIs and SNRIs are well known
to cause REM sleep without atonia (RSWA) and are associated with RBD. Up to
15% of patients taking SSRIs have been shown to have RSWA [18]. In younger
patients with the onset of RBD, narcolepsy may be a key driver. As with other par-
tial induction of the REM sleep state in narcolepsy, RBD can occur with the same
violent behaviors [48].
Diagnosis
The diagnosis of RBD requires two major features, the presence of dream enact-
ment and the loss of REM sleep-related atonia. The ICSD-3 requires the following
features to make the diagnosis of RBD:
A. A. Repeated episodes of sleep-related complex motor behaviors and/or
vocalization.
B. The behaviors are documented on polysomnography to arise during REM sleep
or, based on the description of the events including dream enactment, they are
presumed to occur during REM sleep.
C. Polysomnographic recording demonstrates the loss of REM sleep atonia.
D. The disturbance is not better explained by another sleep or mental disorder,
medication, or substance.
Thus unlike the NREM-related parasomnias, the diagnosis of RBD requires a poly-
somnogram to document the loss of atonia in REM sleep (Fig. 16.2). The loss of ato-
nia is best demonstrated with recording EMG activity from all four extremities. Events
do not need to be captured during the recording; however, the diagnosis can be made
either with a clinical history consistent with RBD and the findings of REM sleep with-
out atonia on polysomnogram. If there is no history of dream enactment, the diagnosis
can be made by capturing an episode of complex behavior or vocalizations during
REM on the study. RBD should be distinguished from other diseases that have vivid
dreams with dream enactment, such as PTSD and obstructive sleep apnea [46].
Clinical Approach
For patients suspected of having RBD, historical features of dream enactment

with clear description of the events are key. These events should vary in their
content but may center around the theme of defending. For patients over 55 years,
clinicians should ask about the other non-motor signs of alpha-synucleinopathies
such as constipation, loss of smell, or orthostatic hypotension. These features
may co-exist with the RBD events and precede other manifestations by years.
Similarly, a detailed neurological exam is essential to evaluate for other neuro-
logical features. Since RBD can be related to other processes impairing the atonia
pathways, patients should also be evaluated for possible underlying structural
causes of RBD such as stroke, demyelinating lesions, or tumors and undergo
brain imaging.
Fig. 16.2 This polysomnogram is a representative sample of loss of atonia during REM sleep.
Note that the submental EMG does not have a high amount of AMG activity but the extremities are
noted to demonstrate significant muscle activity. (a) This tracing is from a 76-year-old man with
multiple system atrophy and history of violent dream enactment. (b) It is from a 65-year-old
female who was not being evaluated for parasomnia and had incidental sudden movement of her
arm and leg during REM sleep and noted dreaming she was shooing a cat off the bed. The patient
later admitted to multiple events of dream enactment
Treatment
Patients should be counseled on bedroom safety to prevent injury. This includes

removal of furniture near the bed, placing the mattress on the floor, and removal of
weapons from the bedroom. The patient or the bed partner should be advised to
sleep in another bed or another room to prevent injury to others. Any OSA, if pres-
ent, should be treated as this may reduce incidence of events [45, 46]. The mainstay
of pharmacologic treatment is melatonin and clonazepam. Melatonin of 3–15 mg
dosed at bedtime has been shown in trials to reduce the incidence and severity of
events. In addition, clonazepam 0.25–2.0 mg at bedtime can be used as well.
However, the cautious use of clonazepam is advised in patients with dementia, gait
difficulties, and OSA as the medication can worsen these conditions [44–47].
Recurrent Isolated Sleep Paralysis
Recurrent isolated sleep paralysis is the phenomenon of the inability to move any
part of the body during the sleep-wake transition or vice versa. These events leave a
lasting impression upon the subject that can be remembered for decades. The events
typically occur upon awakening but may be related to going to sleep. Although
events are fairly uncommon, the events are noted to be described across a variety of
cultures and given sacred explanations.
Sleep paralysis is the phenomenon of the inability to move the limbs, head, or trunk
at the onset of sleep or upon awakening. The episodes only last a few seconds to
minutes and resolve abruptly. Respiratory muscles are not affected, and the patient
is usually fully conscious of their environment. The episodes are frequently accom-
panied by an overwhelming sense of impending doom or hallucinations of someone
or thing in the room, a sense of pressure as if someone sitting on their chest, and a
sense of fear or distress [3, 49–51]. Patients remember these events for decades with
unusual clarity.
Epidemiology
Sleep paralysis is fairly uncommon in the full-blown events; however partial events
may have a lifetime prevalence as high as 7.6% in the general population. Events
appear to be more prevalent in students with history of sleep deprivation and circa-
dian rhythm phase shifts ranging up to 28% in selected series, and almost 32% of
patients with psychiatric illness [49]. Women are slightly more likely to experience
sleep paralysis than men.
Sleep paralysis is thought to be a mixture of states with elements of REM invading

the waking state. Risk factors for experiencing sleep paralysis include sleep depri-
vation, sleep disruption, or shifts in circadian rhythm. Shift workers are noted to
experience sleep paralysis more commonly. Sleep paralysis is also more likely to
occur when sleeping in the supine position. Psychiatric illness has also been reported
to be a risk factor for sleep paralysis [3, 49–51].
Diagnosis
Recurrent isolated sleep paralysis is diagnosed by the clinical history and requires
that the episodes cause significant distress including fear of sleep and/or the bed-
time/bedroom. The ICSD-3 requires the following criteria to establish the diagnosis:
1. Recurrent episodes of inability to move the trunk and all of the limbs at sleep
onset or upon awakening from sleep.
2. Each of the individual episodes should last seconds to a few minutes.
3. The episodes cause significant distress which can include bedtime anxiety or fear.
4. The disturbance is not better explained by another sleep disorder (especially
narcolepsy), mental or medical disorder, or medication, or substance use.
As noted in the criteria, recurrent isolated sleep paralysis should not be diag-
nosed in a patient with symptoms consistent with narcolepsy. The patient with sleep
paralysis will not have daytime sleepiness nor cataplexy [1, 51]. VPSG does not
need to be performed unless an underlying sleep disorder is suspected; however
rarely an event can be captured during a recording (Fig. 16.3).
Treatment
For the most part, patients do not need to be treated for recurrent isolated sleep
paralysis as the majority do not have significant distress associated with the events.
The pharmacologic treatment is based on treatment for narcolepsy. SSRIs and tricy-
clic antidepressants have been used to effectively treat sleep paralysis, presumably
for their REM suppressant effects [51].
Nightmare Disorder
Nightmare disorder involves recurrent frightening dreams that cause the patient
anxiety or daytime distress. There is a high association with psychiatric illness,
particularly PTSD. Nightmares are common and affect both children and adults.
They are often associated with awakening and, unlike night terrors, are associated
Fig. 16.3 This is the tracing of a 27-year-old male with recurrent episodes of sleep paralysis, who
woke after this epoch, that he was having one of his events of paralysis. He noted a visual halluci-
nation of a small older man sitting on his chest. The epoch shows typical features of REM sleep.
(Reprinted with permission from Bradley Vaughn)
with complete recall and quick orientation to full consciousness. Nightmare disor-
der, however, results in daytime sequelae, which is what distinguishes it from the
general occurrence of nightmares.
Nightmare disorder consists of repeated episodes of nightmares that cause clinically

significant impairment in social, occupational, or other important areas of function-
ing. When the patient wakes from the nightmare, they are immediately oriented and
alert, and there is recall of the dream imagery. Nightmares are defined as dysphoric
dreams and usually involve threat of harm to the person [1]. The nightmares are
associated with negative emotions, most commonly fear. The nightmares can be
idiopathic or post-traumatic. Idiopathic nightmares are more imaginative and do not
have a traumatic content. Post-traumatic nightmares usually involve the direct rep-
lication of the traumatic event or contain material that is symbolically related to the
trauma [52, 53].
Epidemiology
Occasional nightmares are relatively common in the general population, and

approximately 3–8% of adults report recurrent nightmares. Although more common
in childhood roughly 7–11%, the rate increases to 15 to as high as 67% of adult
patients with psychiatric illness. Men and women appear to be equally affected, but
the overall prevalence of nightmare disorder is unclear.
Nightmares by themselves usually occur in relationship to either an experience of

the day, such as a horror movie, or related to a substance consumed – such as alco-
hol. Nightmare disorder, however, is associated with psychopathologies, particu-
larly PTSD, and personality characteristics. Some medications that affect serotonin,
norepinephrine, GABA, histamine, acetylcholine, and dopamine are associated
with nightmares. The withdrawal of REM suppressant medication is also associated
with nightmares [1, 52]. Dream generation is thought to be a process of brain regions
and mechanisms independent of REM generation. Nightmare disorder has been
proposed to be due to a two-factor process of hyperarousal and impaired fear extinc-
tion. Hyperarousal is a hallmark of not only insomnia but PTSD in which 80% of
patients report nightmares [53, 54].
Diagnosis
Diagnosis is usually established by clinical history. Nightmares should be distin-

guished from night terrors as discussed above. The ICSD-3 requires the following
for the diagnosis:
1. Recurrent extremely dysphoric, distressing well-remembered dreams that usu-
ally involve threats to survival, security, or physical integrity.
2. Upon awakening from the nightmare, the person quickly becomes oriented
and alert.
3. When awakening from the nightmare, the person has clinically significant dis-
tress or impairment in social, occupational, or other important areas of function-
ing as indicated by the report of at least one of the following:
• Mood disturbance (e.g., persistence of nightmare affect, anxiety, dysphoria)
• Sleep resistance (e.g., bedtime anxiety, fear of sleep/subsequent nightmares)
• Cognitive impairments (e.g., intrusive nightmare imagery, impaired concen-
tration, or memory)
• Negative impact on caregiver or family functioning (e.g., nighttime disruption)
• Behavioral problems (e.g., bedtime avoidance, fear of the dark)
• Daytime sleepiness
• Fatigue or low energy
• Impaired occupational or educational function
• Impaired Interpersonal/Social Function
When considering this diagnosis, the key is to have a clear description of the
nightmare events, and also the key features of the sequelae during wake. The later
part is what distinguishes nightmare disorder, from the occasional disturbing
dream. Many times patients may not spontaneously disclose the impairment in
social, occupational, or other important areas as they have not drawn the connec-
tion. Thus further questioning may be needed.
Treatment
Non-pharmacologic treatment consists of image rehearsal therapy (IRT), cognitive

behavioral therapy (CBT), lucid dreaming therapy, and hypnosis, among others
[52]. IRT is part of the recommended guidelines and appears to be successful in
patients with history of trauma. IRT consists of changing dream content by recreat-
ing the dream with positive images and rehearsing the dream for 10–20 minutes
daily while awake. Several RCTs have shown efficacy of IRT in the treatment of
nightmare disorder with reduction in nightmare frequency [52, 53]. Pharmacologic
treatment of nightmare disorder is based on studies of their efficacy in treating
PTSD-associated nightmares. Prazosin was initially thought to reduce the recur-
rence of nightmares but has mixed results in larger trials [55]. Other commonly
used medications in this instance include the atypical antipsychotics, clonidine,
cyproheptadine, trazodone, tricyclic antidepressants, and clonazepam with mixed
results [52].
Other Parasomnias
Other parasomnias include a collection of disorders that are either related to

sleep-wake transitions, or have no clear tie to a particular sleep stage. Some of
these are very specific phenomena, while others are more general catch-all
disorders. Each has specific criteria to help the clinician distinguish the
syndromes.
Exploding Head Syndrome
Exploding head syndrome is named due to the phenomenon of the sudden sensation
of an explosion or loud noise going off in the head. This usually occurs at sleep
onset, but can occur upon awakening. The person usually has an abrupt arousal
immediately after the event, which is brief, and is accompanied by a sense of fright,
but is not accompanied or associated with any significant pain [1, 56]. The preva-
lence is not well known due to the transient nature of the phenomenon and due to
underreporting and under recognition. However, prevalence has been reported to be
roughly 11% in the general population. Individuals may only have one episode in a
lifetime or may have clusters of events over a night or more. The most common
concern for a patient is bleeding or a tumor. Treatment is focused on reassurance as
the condition is benign and usually self-limiting. In the instances that exploding
head syndrome is recurrent or results in distress for the patient, medications may be
tried. Several medications, such as clonazepam, clomipramine, and topiramate,
have had varying success [57, 58].
Sleep-Related Hallucinations
Hypnic hallucinations are dreamlike imagery that occur during the wake-sleep
transition or vice versa. Hypnopompic hallucinations occur on the transition from
sleep to wake, and hypnogogic hallucinations occur at the onset of sleep and are
thought to be the intrusion of REM into the wake state [59–61]. The hallucinations
are most often visual, but can be auditory or tactile. Though hypnic hallucinations
occur commonly in narcolepsy, they can occur independent of any other disorder
and are common in the general population. Hypnogogic hallucinations are more
common than hypnopompic, with a reported prevalence of 37% and 12.5%,
respectively [62]. Sleep-related hallucinations are associated with sleep problems,
such as insomnia or poor sleep/wake schedules. Treatment is not usually necessary
as the episodes are short-lived and benign. Most individuals are aware that the
images are not real, but they can be distressing [59–61]. Treatment with benzodi-
azepines and tricyclics has been unsuccessful, but there are reports of success with
melatonin [59].
Sleep Enuresis or Nocturnal Enuresis
Sleep enuresis is the phenomenon of involuntary voiding during sleep in a patient

that is older than 5, occurring at least 2 nights a week, for at least 3 months.
Sleep enuresis or nocturnal bedwetting is delineated into primary and secondary
nocturnal enuresis, wherein primary there has never been dry periods of at least
6 months and in secondary forms the patient had previously been dry. Though
there is a common symptomatology of wetting the bed a night, the two have
distinct etiologies [1]. The prevalence is between 6 and 10% by age 7, which
then decreases to 2% and less than 2% in teenagers and adults, respectively. The
pathophysiology of nocturnal enuresis is thought to involve nocturnal polyuria,
decreased bladder storage ability, and poor arousal [63]. Primary nocturnal
enuresis is usually considered a disorder of acquired developmental skills, and
therefore there is a range of ages when these skills are acquired. However, in
secondary nocturnal enuresis it can be caused by a number of problems, includ-
ing diabetes, urinary tract infections, urinary tract malformations, and psychoso-
cial factors [1, 64]. In addition, there is a high rate of sleep disordered breathing
associated with nocturnal enuresis, being reported in 8–47% of cases. Diagnosis
involves a careful history, and it is important to distinguish between primary and
secondary enuresis as further workup is warranted in the latter. The mainstay of
treatment in primary enuresis is bed alarms. In secondary enuresis the underly-
ing cause should be investigated and treatment targeted based on the underlying
pathology. In suspected cases of sleep apnea, a PSG may need to be performed
[63–65].
Approach to Distinguishing Nocturnal Events
The goal of any evaluation of a patient with nocturnal events is to prevent harm to
the patient or others. For this the clinician should focus the initial consultation upon
answering the following questions: (1) Is the patient at risk potential for harm or
causing harming to someone else? (2) What may be driving the appearance of these
events? (3) Are these events indicating another underlying disorder?
In general, an astute clinician can differentiate parasomnias by looking for key
distinguishing features (Table 16.2). The key for any evaluation of nocturnal events
is a thorough history and excellent physical exam. Although these are foundational,
the underpinning of the evaluation is based on a clear description of the events from
witnesses who can give an accurate testimony of the behaviors. Key historical fea-
tures such as time of night, duration, frequency of occurrence, behavioral character-
istics with each event, eyes open or closed, memory recall, age of onset, and family
history of nocturnal events may help differentiate these disorders [66]. The physi-
cian should also search for factors that precipitate parasomnias such as poor sleep
environment, improper sleep hygiene, sleep deprivation, circadian rhythm abnor-
malities, other sleep disorders, medical issues, fever or other illnesses, emotional
stress, medication use, and ingestion of alcohol or sedatives before sleep onset [22,
67–69]. Additional search for other neurological symptoms such as decrease sense
of smell, constipation, or other autonomic issues may give clues to REM sleep
behavior disorder [46]. Similarly, features suggesting cognitive decline in adult may
provide the opening for further investigation of encephalopathic processes or
dementia [69].
Further testing may be indicated for patients with parasomnia. Key features may
elucidate the need for further study in the sleep lab (Table 16.4). Polysomnographic
recording can also provide important information in determining the etiology of the
nocturnal events, with the goal of capturing the physiology of each sleep state and
to evaluate the possibility of other contributing sleep disorders. Overnight polysom-
nography is necessary if the history is atypical, sleepiness is significant, other sleep
disorders are suspected, or the patient is at risk for harming themselves or others
Table 16.4 Indications for polysomnography in patients with nocturnal events. Reprinted with
permission from Bradley Vaughn
Unusual or atypical presentation for a parasomnia (time of night, behavioral description)

Events injurious or with significant risk for injury
Significant disturbance to patient’s home life
Unusual age of onset
Events stereotyped or repetitive
High frequency of the events
Patient has excessive daytime sleepiness or complaints of insomnia
Complaints suggestive of sleep apnea, periodic limb movements, or other sleep disorders
[70]. Studies should include complete respiratory monitoring, time-synchronized

video monitoring, additional electromyographic recording from all four limbs, a
complete set of cephalic electrodes, and ability to extensively review the electroen-
cephalogram [5, 71, 72]. Incorporation of a full 10- to 20-electrode array and ability
to view the tracing at 10 second windows is necessary in evaluating for seizures and
the differentiation of the epileptiform discharges from potential normal variants or
artifacts [73].
Parasomnias may be distinguished using key features. The challenge for the
ardent clinician is to utilize historical and physical examination clues and appropri-
ate diagnostic tools to distinguish the underlying causes and propose directed ther-
apy to improve the patient’s condition.
References
Darien, IL: American Academy of Sleep Medicine, 2014.
2. Provini F, Tinuper P, Bisulli F, Lugaresi E. Arousal disorders. Sleep Med. 2011;12(Suppl
2):S22–6. https://doi.org/10.1016/j.sleep.2011.10.007.
3. Denis D, French CC, Gregory AM. A systematic review of variables associated with sleep
paralysis. Sleep Med Rev. 2018;38:141–57. PMID: 28735779. https://doi.org/10.1016/j.
smrv.2017.05.005.
4. Stefani A, Holzknecht E, Högl B. Clinical neurophysiology of REM parasomnias. Handb Clin
Neurol. 2019;161:381–96.
5. Gieselmann A, Ait Aoudia M, Carr M, Germain A, Gorzka R, Holzinger B, Kleim B, Krakow
B, Kunze AE, Lancee J, Nadorff MR, Nielsen T, Riemann D, Sandahl H, Schlarb AA, Schmid
C, Schredl M, Spoormaker VI, Steil R, van Schagen AM, Wittmann L, Zschoche M, Pietrowsky
R. Aetiology and treatment of nightmare disorder: state of the art and future perspectives. J
Sleep Res. 2019;28:e12820.
6. Gaudreau H, Joncas S, Zadra A, Montplaisir J. Dynamics of slow-wave activity during the
NREM sleep of sleepwalkers and control subjects. Sleep. 2000;23:755–60.
7. Desjardins M, Carrier J, Lina J, et al. EEG functional connectivity prior to sleepwalking: evi-
dence of interplay between sleep and wakefulness. Sleep. 2017;40:zsx024.
8. Heidbreder A, Stefani A, Brandauer E, et al. Gray matter abnormalities of the dorsal posterior
cingulate in sleep walking. Sleep Med. 2017;36:152–5.
9. Gibbs SA, Proserpio P, Terzaghi M, et al. Sleep-related epileptic behaviors and non-REM-
related parasomnias: insights from stereo-EEG. Sleep Med Rev. 2016;25:4–20.
10. Januszko P, Niemcewicz S, Gajda T, et al. Sleepwalking episodes are preceded by arousal-
related activation in the cingulate motor area: EEG current density imaging. Clin Neurophysiol.
2016;127(1):530–6.
11. Bassetti C, Vella S, Donati F, et al. SPECT during sleepwalking. Lancet.
2000;356(9228):484–5.
12. Oliviero A, Della Marca G, Tonali PA, et al. Functional involvement of cerebral cortex in adult
sleepwalking. J Neurol. 2007;254(8):1066–72.
13. Labelle MA, Dang-Vu TT, Petit D, Desautels A, Montplaisir J, Zadra A. Sleep depriva-
tion impairs inhibitory control during wakefulness in adult sleepwalkers. J Sleep Res.
2015;24:658–65.
14. Di Gennaro G, Autret A, Mascia A, et al. Night terrors associated with thalamic lesion. Clin
Neurophysiol. 2004;115(11):2489–92.
15. Daftary AS, Walker JM, Farney RJ. NREM sleep parasomnia associated with Chiari I malfor-
mation. J Clin Sleep Med. 2011;7(5):526–9.
16. Giuliano L, Fatuzzo D, Mainieri G, La Vignera S, Sofia V, Zappia M. Adult-onset sleepwalking
secondary to hyperthyroidism: polygraphic evidence. J Clin Sleep Med. 2018;14(2):285–7.
17. Labelle M, Desautels A, Montplaisir J, Zadra A. Psychopathologic correlates of adult sleep-
walking. Sleep Med. 2013;14:1348–55.
18. Ohayon MM, Guilleminault C, Priest RG. Night terrors, sleepwalking, and confusional arous-
als in the general population: their frequency and relationship to other sleep and mental disor-
ders. J Clin Psychiatry. 1999;60:268–76.
19. Howell MJ. Parasomnias: an updated review. Neurotherapeutics. 2012;9(4):753–75.
20. Goodwin JL, Kaemingk KL, Fregosi RF, et al. Parasomnias and sleep disordered breathing
in Caucasian and Hispanic children – the Tucson children’s assessment of sleep apnea study.
BMC Med. 2004;2:14.
21. Lundetræ RS, Saxvig IW, Pallesen S, Aurlien H, Lehmann S, Bjorvatn B. Prevalence of para-
somnias in patients with obstructive sleep apnea. A registry-based cross-sectional study. Front
Psychol. 2018;9:1140.
22. Stallman HM, Kohler M, White J. Medication induced sleepwalking: a systematic review. Sleep
Med Rev. 2018;37:105–13. PMID: 28363449. https://doi.org/10.1016/j.smrv.2017.01.005.
23. Fois C, Wright MA, Sechi GP, et al. The utility of polysomnography for the diagnosis of
NREM parasomnias: an observational study over 4 years of clinical practice. J Neurol.
2015;262(2):385–93.
24. Pilon M, Montplaisir J, Zadra A. Precipitating factors of somnambulism: impact of sleep depri-
vation and forced arousals. Neurology. 2008;70(24):2274–5.
25. Pressman MR. Factors that predispose, prime and precipitate NREM parasomnias in adults:
clinical and forensic implications. Sleep Med Rev. 2007;11(1):5–30.
26. Attarian H. Treatment options for parasomnias. Neurol Clin. 2010;28(4):1089–106.
27. Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of injuri-
ous parasomnias and other disorders of disrupted nocturnal sleep in 170 adults. Am J Med.
1996;100(3):333–7.
28. Cooper AJ. Treatment of coexistent night-terrors and somnambulism in adults with imipra-
mine and diazepam. J Clin Psychiatry. 1987;48:209–10.
29. Balon R. Sleep terror disorder and insomnia treated with trazodone: a case report. Ann Clin
Psychiatry. 1994;6:161–3.
30. Wilson SJ, Lillywhite AR, Potokar JP, et al. Adult night terrors and paroxetine. Lancet.
1997;350:185.
31. Ekambaram V, Maski K. Non-rapid eye movement arousal parasomnias in children. Pediatr
Ann. 2017;46(9):e327–31. https://doi.org/10.3928/19382359-20170814-01.
32. Castelnovo A, Lopez R, Proserpio P, Nobili L, Dauvilliers Y. NREM sleep parasomnias
as disorders of sleep-state dissociation. Nat Rev Neurol. 2018;14(8):470–81. https://doi.
org/10.1038/s41582-018-0030-y.
33. Drakatos P, Leschziner G. Diagnosis and management of nonrapid eye movement-parasomnias.
Curr Opin Pulm Med. 2019;25(6):629–35. https://doi.org/10.1097/MCP.0000000000000619.
34. Bargiotas P, Arnet I, Frei M, Baumann CR, Schindler K, Bassetti CL. Demographic, clinical
and polysomnographic characteristics of childhood- and adult-onset sleepwalking in adults.
Eur Neurol. 2017;78(5–6):307–11. https://doi.org/10.1159/000481685.
35. Stallman HM, Kohler M. Prevalence of sleepwalking: a systematic review and meta-analysis.
PLoS One. 2016;11(11):e0164769. Published 2016 Nov 10. https://doi.org/10.1371/journal.
pone.0164769.
36. Baldini T, Loddo G, Sessagesimi E, et al. Clinical features and pathophysiology of disorders
of arousal in adults: a window into the sleeping brain. Front Neurol. 2019;10:526. Published
2019 May 17. https://doi.org/10.3389/fneur.2019.00526.
37. Ellington E. It's not a nightmare: understanding sleep terrors. J Psychosoc Nurs Ment Health
Serv. 2018;56(8):11–4. https://doi.org/10.3928/02793695-20180723-03.
38. Auger RR. Sleep-related eating disorders. Psychiatry (Edgmont). 2006;3(11):64–70.

39. Komada Y, Takaesu Y, Matsui K, et al. Comparison of clinical features between primary and
drug-induced sleep-related eating disorder. Neuropsychiatr Dis Treat. 2016;12:1275–80.
Published 2016 May 26. https://doi.org/10.2147/NDT.S107462.
40. Chiaro G, Caletti MT, Provini F. Treatment of sleep-related eating disorder. Curr Treat Options
Neurol. 2015;17(8):361. https://doi.org/10.1007/s11940-015-0361-6.
41. Inoue Y. Sleep-related eating disorder and its associated conditions. Psychiatry Clin Neurosci.
2015;69(6):309–20. https://doi.org/10.1111/pcn.12263.
42. Winkelman JW, Herzog DB, Fava M. The prevalence of sleep-related eating disorder in psy-
chiatric and non-psychiatric populations. Psychol Med. 1999;29:1461–6.
43. Santin J, Mery V, Elso MJ, Retamal E, Torres C, Ivelic J, Godoy J. Sleep-related eating disor-
der: a descriptive study in Chilean patients. Sleep Med. 2014;15(2):163–7.
44. McGrane IR, Leung JG, St Louis EK, Boeve BF. Melatonin therapy for REM sleep behavior
disorder: a critical review of evidence. Sleep Med. 2015;16(1):19–26. https://doi.org/10.1016/j.
sleep.2014.09.011.
45. Barone DA, Henchcliffe C. Rapid eye movement sleep behavior disorder and the link to
alpha-synucleinopathies. Clin Neurophysiol. 2018;129(8):1551–64. https://doi.org/10.1016/j.
clinph.2018.05.003.
46. St Louis EK, Boeve BF. REM sleep behavior disorder: diagnosis, clinical implications,
and future directions. Mayo Clin Proc. 2017;92(11):1723–36. https://doi.org/10.1016/j.
mayocp.2017.09.007.
47. Porter VR, Avidan AY. Clinical overview of REM sleep behavior disorder. Semin Neurol.
2017;37(4):461–70. https://doi.org/10.1055/s-0037-1605595.
48. Zhou J, Zhang J, Du L, Li Z, Li Y, Lei F, Wing YK, Kushida CA, Zhou D, Tang X. Characteristics
of early- and late-onset rapid eye movement sleep behavior disorder in China: a case-control
study. Sleep Med. 2014;15(6):654–60.
49. Sharpless BA, Kliková M. Clinical features of isolated sleep paralysis. Sleep Med.
2019;58:102–6. https://doi.org/10.1016/j.sleep.2019.03.007.
50. Ramos DF, Magalhães J, Santos P, Vale J, Santos MI. Recurrent sleep paralysis – fear of
sleeping. Rev Paul Pediatr. 2019;38:e2018226. Published 2019 Nov 25. https://doi.
org/10.1590/1984-0462/2020/38/2018226.
51. Sharpless BA. A clinician’s guide to recurrent isolated sleep paralysis. Neuropsychiatr Dis
Treat. 2016;12:1761–7. Published 2016 Jul 19. https://doi.org/10.2147/NDT.S100307.
52. Morgenthaler TI, Auerbach S, Casey KR, et al. Position paper for the treatment of nightmare
disorder in adults: an american academy of sleep medicine position paper. J Clin Sleep Med.
2018;14(6):1041–55. Published 2018 Jun 15. https://doi.org/10.5664/jcsm.7178.
53. Gieselmann A, Ait Aoudia M, Carr M, et al. Aetiology and treatment of nightmare dis-
order: state of the art and future perspectives. J Sleep Res. 2019;28(4):e12820. https://doi.
org/10.1111/jsr.12820.
54. Simor P, Blaskovich B. The pathophysiology of nightmare disorder: signs of impaired
sleep regulation and hyperarousal. J Sleep Res. 2019;28(6):e12867. https://doi.org/10.1111/
jsr.12867.
55. Rubin ML, Copeland LA, Kroll-Desrosiers AR, Knittel AG. Demographic variation in the use
of prazosin for treatment of sleep disturbance in combat veterans with PTSD. Psychopharmacol
Bull. 2020;50:26–35.
56. Ceriani CEJ, Nahas SJ. Exploding head syndrome: a review. Curr Pain Headache Rep.
2018;22(10):63. Published 2018 Jul 30. https://doi.org/10.1007/s11916-018-0717-1.
57. Sharpless BA. Exploding head syndrome. Sleep Med Rev. 2014;18(6):489–93. https://doi.
org/10.1016/j.smrv.2014.03.001.
58. Palikh GM, Vaughn BV. Topiramate responsive exploding head syndrome. J Clin Sleep Med.
2010;6:382–3.
59. Lysenko L, Bhat S. Melatonin-responsive complex nocturnal visual hallucinations. J Clin
Sleep Med. 2018;14(4):687–91. Published 2018 Apr 15. https://doi.org/10.5664/jcsm.7074.
60. Silber MH, Hansen MR, Girish M. Complex nocturnal visual hallucinations. Sleep Med.
2005;6(4):363–6. https://doi.org/10.1016/j.sleep.2005.03.002.
61. Mishra BR, Sarkar S, Mishra S, Mishra A, Praharaj SK, Nizamie SH. Isolated nocturnal audi-
tory hallucinations: a case report. Gen Hosp Psychiatry. 2011;33(5) https://doi.org/10.1016/j.
genhosppsych.2011.04.008.
62. Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucina-
tions: pathological phenomena? Br J Psychiatry. 1996;169(4):459–67. https://doi.org/10.1192/
bjp.169.4.459.
63. Harari MD. Nocturnal enuresis. J Paediatr Child Health. 2013;49(4):264–71. https://doi.
org/10.1111/j.1440-1754.2012.02506.x.
64. Graham KM, Levy JB. Enuresis [published correction appears in Pediatr Rev. 2009
Sep;30(9):369]. Pediatr Rev. 2009;30(5):165–73. https://doi.org/10.1542/pir.30-5-165.
65. Kuwertz-Bröking E, von Gontard A. Clinical management of nocturnal enuresis. Pediatr
Nephrol. 2018;33(7):1145–54. https://doi.org/10.1007/s00467-017-3778-1.
66. Singh S, Kaur H, Singh S, Khawaja I. Parasomnias: a comprehensive review. Cureus.
2018;10:e3807. PMID: 30868021.
67. Pressman M, Mahowald M, Schenck C, et al. Alcohol-induced sleepwalking or confusional
arousal as a defense to criminal behavior: a review of scientific evidence, methods and forensic
considerations. J Sleep Rev. 2007;16:198–212.
68. Papadimitriou GN, Linkowski P. Sleep disturbance in anxiety disorders. Int Rev Psychiatry.
2005;17:229–36.
69. Khachiyants N, Trinkle D, Son SJ, Kim KY. Sundown syndrome in persons with dementia: an
update. Psychiatry Investig. 2011;8:275–87.
70. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for
polysomnography and related procedures: an update for 2005. Sleep. 2005;28:499–521.
71. Schenck CH, Boyd JL, Mahowald MW. A parasomnia overlap disorder involving sleepwalk-
ing, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed
cases. Sleep. 1997;20:972–81.
72. Proserpio P, Loddo G, Zubler F, Ferini-Strambi L, Licchetta L, Bisulli F, Tinuper P, Agostoni
EC, Bassetti C, Tassi L, Menghi V, Provini F, Nobili L. Polysomnographic features differenti-
ating disorder of arousals from sleep-related hypermotor epilepsy. Sleep. 2019;42(12):zsz166.
73. Foldvary N, Caruso AC, Mascha E, et al. Identifying montages that best detect electrographic
seizure activity during polysomnography. Sleep. 2000;23:221–9.
Chapter 17
Rapid Eye Movement Parasomnias
Jordan Taylor Standlee and Margaret A. Kay-Stacey
Keywords REM parasomnias · REM sleep behavior disorder · Recurrent isolated

sleep paralysis · Nightmare disorder
Definition
REM Sleep Behavior Disorder (RBD) is clinically defined as having all of the fol-
lowing: (A) repeated sleep-related vocalizations and/or complex motor behaviors,
(B) the episodes are documented to occur in REM sleep either based on PSG or
clinical history, (C) PSG demonstrates REM sleep without atonia (RSWA), and (D)
the episodes are not better explained by an alternative disorder [1– 3].
Clinical Features
The usual presentation of RBD is dramatic, aggressive physical activity during

sleep. Patients may punch, kick, scream, curse, or even run or fall out of bed. It is
not uncommon for these activities to be associated with injury to the individuals and
bed partners, or to damage to objects around the bedroom. The movements tend to
be brief and can appear purposeful to observers. Bruises, fractures, and even legal
issues can result from these activities. In contrast to NREM parasomnias, it is
J. T. Standlee · M. A. Kay-Stacey (*)

Northwestern University Feinberg School of Medicine, Department of Neurology,
Chicago, IL, USA
e-mail: Jordan.standlee@northwestern.edu; Margaret-stacey@northwestern.edu

382 J. T. Standlee and M. A. Kay-Stacey
uncommon for the behaviors to be elaborate or involve leaving the room, though
relatively complex behaviors have occasionally been described in children and teen-
agers, and in non-Western populations [4, 5]. When questioned afterward, patients
report vivid dreams that commonly obtain life-threatening, action-filled content. As
a distinction from a confusional arousal, the patient will rapidly reorient upon awak-
ening and have clear recollection of dream content. There is usually no associated
daytime somnolence. As is true with all REM-related conditions, they are much
more common in the middle or latter third of the night, though this may not be the
case in patients with narcolepsy, as those patients often have REM abnormally early
within a sleep period. Frequency of events can be quiet variable, ranging from mul-
tiple events per night to one every few months. The onset of symptoms tends to be
gradual and slowly progressive, with usually a long lag between initial symptom
onset and diagnosis. When asked in retrospect, patients often report a gradual pro-
drome of limb jerking, teeth grinding, or sleep talking for years prior to RBD diag-
nosis [3, 6–9].
As will be discussed below, there is a strong association between idiopathic RBD
and alpha-synucleinopathies, and RBD is often one of the cardinal prodromal symp-
toms portending later neurodegeneration. As such, at the point where patients are
diagnosed with RBD, they often have other signs of early alpha-synucleinopathies:
loss of olfaction, chronic constipation, autonomic dysfunction (particularly ortho-
stasis), and impaired visuospatial abilities [2, 10–13].
Risk Factors
There is a clear association between RBD and neurodegenerative diseases, particu-

larly alpha-synucleinopathies (idiopathic Parkinson disease, dementia with Lewy
bodies, multiple system atrophy), though a huge range of other non-synuclein
degenerative diseases have been implicated including tauopathies like Alzheimer
disease, frontotemporal dementia, and progressive supranuclear palsy; Huntington
disease; amyotrophic lateral sclerosis; myotonic dystrophy; paraneoplastic and
autoimmune encephalitides; and spinal cerebellar ataxia [2, 3, 14–17]. Given the
association of RBD with neurodegenerative disease, it is unsurprising that the stron-
gest risk factor for RBD is older age, particularly age greater than 50 [3], and the
median age of diagnosis is 60–70 years old [18]. However, the absence of a comor-
bid neurodegenerative syndrome should not rule out clinical suspicion for RBD,
since RBD tends to be part of the initial prodrome of the syndrome and can precede
development of further symptoms by up to 50 years [19]. Often, the only comorbid
symptoms are anosmia and constipation which, together with RBD, make up the
classic prodrome for alpha-synucleinopathies. A 2019 meta-analysis found that
among patients diagnosed with RBD, at 5-year follow-up, a third (33.5%) had
developed a neurodegenerative disorder, whereas by 14-year follow-up, nearly
everyone (96.6%) had developed one [20]. This finding speaks to both the robust
17 Rapid Eye Movement Parasomnias 383
association between RBD and neurodegenerative diseases, as well as the relatively

long lag time that can separate the two.
Male sex is another very strong risk factor, though the mechanism for this is
unknown [3]. Some case series report a male-female prevalence of 9:1, though this
is likely inflated due to both the fact that women generally express less injurious
dream enactment behaviors, which makes them less likely to seek medical attention,
and that older women often outlive their spouses and therefore do not have a bed
partner to report their symptoms [21]. Other risk factors include the presence of
comorbid psychiatric conditions and antidepressant use, especially in cases where
RBD has a relatively rapid onset [22–24]. Antidepressants of nearly all categories
have been observed to acutely precipitate or exacerbate RBD episodes, including
SSRIs, SNRIs, tricyclic acids (TCAs), monoamine oxidase inhibitors (MAOIs), and
mirtazapine, though notably this has not been seen with bupropion [3, 23, 25, 26].
Further medications which have been implicated include beta-blockers and selegi-
line, and anticholinesterase inhibitors [3]. PTSD has an association with RBD,
though it is more commonly associated with a different REM parasomnia, night-
mare disorder, as discussed in section “Nightmare Disorder”. There is also a clear
association with narcolepsy, primarily narcolepsy type 1 [27]. Up to 50% of patients
with narcolepsy type 1 may demonstrate RBD, though the mechanism for this is
distinct from other causes of RBD, as discussed below. Unfortunately, treatments
aimed at reducing cataplexy in narcolepsy patients, such as TCAs or SNRIs, may
exacerbate RBD symptoms. While patients commonly report dreams with aggres-
sive content, in waking life there is no clear association with aggressive personality
traits; therefore, no particular personality traits are thought to impart risk [28–30].
Traumatic brain injury is a risk factor for all types of parasomnia (both NREM and
REM), with one study estimating new onset of RBD in 8% of TBI patients [31].
Family history is also a risk factor, with one study showing that among patients with
confirmed idiopathic RBD, 14% had a close family member with a history of dream
enactment [32]. Tobacco smokers are also more likely to develop RBD, both among
those with Parkinson disease and among the general population [33, 34].
Pathophysiology
While numerous distinct neurodegenerative diseases have all been associated with
RBD, the underlying pathophysiology connecting them appears to be disruption of
the dopaminergic and noradrenergic pathways through the pons, striatum, and fron-
tal lobes, as demonstrated by functional neuroimaging [3, 20, 35–42]. These path-
ways are integral to normal sleep physiology, involving the usual paralysis of
skeletal muscles during REM sleep. Alpha-synucleinopathies tend to target these
pontine nuclei of sleep early-on, which explains their strong association with
RBD. The exception to this physiology is in narcolepsy, where orexin deficiency
from the hypothalamus is the culprit, leading to destabilization of sleep architecture.
Epidemiology
Prevalence of RBD in the general population is thought to range from 0.5% to 1%,
though some studies estimate a higher prevalence in the elderly population, around
2% [3, 43, 44]. As discussed above, it is more common in elderly males, though it
has been reported in women, children, and teenagers.
Diagnostic Workup
In-laboratory video polysomnography (PSG) demonstrating REM sleep without

atonia (RSWA) is required for a diagnosis of RBD; this entails capturing REM sleep
with simultaneous capturing of excessive EMG activity on chin or limb leads. When
RSWA occurs in the setting of a clinical complaint of dream enactment, then the
diagnosis of RBD can be made. Practically speaking, when setting up for an RSWA
screen, EMG leads should be placed on upper and lower limbs as well as the chin in
order to increase sensitivity for muscle activity. RSWA tends to occur in all REM
periods throughout the night, though it is often most prominent in latter portions of
the night, when REM sleep is more emphasized. Home sleep apnea testing is not a
useful screen for this condition, as the lack of sleep stage identification prevents an
evaluation of RSWA.
Though there is a strong association between RBD and neurodegenerative dis-
eases, identification of such processes is not necessary for a diagnosis of RBD. As
such, it is not required to send diagnostic tests such as a dopamine transport scan
(DAT) or a neuropsychological battery to evaluate for neurodegeneration, though
these tests could be considered as part of a patient’s larger multidisciplinary care
plan, and would generally be coordinated by a neurologist.
The presence of significant autonomic activation such as tachycardia during a
behavioral episode should raise a diagnostic red flag because while this does not
rule out RBD, it is uncommon in this condition whereas it is quite common in the
NREM parasomnias associated with arousals. Also, in RBD, general sleep architec-
ture is preserved between wake, NREM, and REM stages, which differentiates it
from status dissociatus (as discussed in 17.1.9).
Other conditions that can manifest as dramatic sleep-related behaviors are NREM
parasomnias such as sleepwalking and sleep terrors, sleep-related hypermotor epi-
lepsy (SHE), rhythmic movement disorders, and OSA.
To distinguish REM from NREM parasomnias, PSG and clinical history can be
used to elucidate the stage of sleep associated with the behavior. Often the dramatic
behavior itself is not captured on a single night PSG, so clinical history is relied on
to clarify how early in the sleep cycle the behavior emerges. Typically, NREM para-
somnias occur within the first one-third of the night, and REM parasomnias occur
in the latter two-thirds of the night [3]. Further, RBD is characterized by rapid alert-
ness and orientation, whereas NREM parasomnias may have a prolonged period of
confusion [45]. Individuals with RBD tend to report vivid dream content, whereas
those with NREM parasomnias have at most a fragmentary, limited recall of dream
content. Vocalizations can be seen in both RBD and NREM parasomnias, but those
due to RBD are often loud and feature expletives or aggressive content, whereas
NREM vocalizations more often resemble usual conversation, though this can be
seen in REM as well [45]. NREM parasomnias tend to present in childhood or
young adulthood, whereas REM parasomnias traditionally present in older age,
though as discussed above, there are exceptions in both directions [3].
Sleep-related hypermotor epilepsy (SHE), formerly known as Nocturnal Frontal
Lobe Epilepsy (NFLE), is characterized by recurrent motor behaviors arising from
sleep which can sometimes by dramatic or injurious in nature, similar to RBD. A
key feature to screen for, especially from bed partners who can better describe the
specific motions being performed, is whether the behaviors are stereotyped, as RBD
tends to involve a range of vocalizations and actions, whereas epilepsy-induced
behaviors tend to be a very stereotyped action or set of actions which can occur
more than a dozen times throughout the night [46, 47].
Rhythmic movement disorder tends to be seen in childhood and only rarely
occurs in adults. It consists of rhythmic movement of large muscle groups, such as
body rocking or head-banging during sleep. These movements often occur in devel-
opmentally normal children and do not cause harm or distress to the affected indi-
viduals. When seen in adults, it may be related to other underlying sleep disorders
such as restless leg syndrome or obstructive sleep apnea.
Periodic limb movements of sleep (PLMS), while also consisting of movements
during sleep, are differentiated from RBD in that they predominantly occur during
NREM and often consist of a stereotyped triple flexion of a leg (hip flexion, knee
flexion, ankle dorsiflexion) that can occur frequently through the night around once
per minute [3]. These movements do not have an association with dream content.
Untreated obstructive sleep apnea (OSA) should be considered in any case of
parasomnia, given that it is a common condition that causes fractured sleep, which
can provoke parasomnias. Pseudo-RBD, as it is known, occurs when a patient with
sleep apnea presents with symptoms of RBD. However, the RSWA and dream
enactment are secondary to apneas and hypopneas disrupting REM sleep. Treatment
of OSA with CPAP or other therapies leads to resolution of the RBD symptoms [2].
Treatment
The predominant goal of all treatment strategies is to prevent injury by reducing the
burden of behavioral events.
First, clinicians should screen for any factors that may have provoked secondary
RBD and address those triggers. For instance, in cases of OSA-provoked parasom-
nias, appropriately treating the OSA generally resolves the symptoms [48, 49].
Further, if a medication, such as an antidepressant, is thought to be contributing,
then that medication should be discontinued if possible.
Second, if no provoking factor is identified, then the patient is considered to have
idiopathic primary RBD and warrants symptomatic treatment. Pharmacotherapy is
a mainstay of treatment, though optimizing the sleeping environment to minimize
injuries and property damage should also be part of treatment. For example, walls
should be padded, dangerous or breakable objects should be moved away from the
bed, and bed partners may be counseled to sleep in a separate bed. The primary
pharmacologic agents are melatonin and clonazepam [50, 51]. Both medications
have shown efficacy in reducing or eliminating RBD. Many clinicians prefer mela-
tonin as an initial agent given its favorable side effect profile, especially since clon-
azepam’s sedating properties can predispose elderly patients to falls, particularly
those with dementia or gait disorders, which is a large portion of the RBD popula-
tion [51]. There has never been a head-to-head trial between these agents, but clon-
azepam may be more likely to eliminate symptoms than melatonin, so it is a
reasonable second-line agent if patients do not respond to an adequate melatonin
trial (3–15 mg of melatonin).
Other medications which have some evidence suggesting their efficacy toward
RBD include “z-drugs” such as zopiclone, benzodiazepines other than clonazepam,
acetylcholinesterase inhibitors such as donepezil and rivastigmine, carbamazepine,
sodium oxybate, clozapine, pramipexole, levodopa, and paroxetine. Many of these
drugs have only been studied in case reports or limited populations and are rarely
used. However, they could be considered when both melatonin and clonazepam
have been ineffective.
Subtypes
Status Dissociatus
Status dissociatus is a subtype of RBD where the individual expresses clinical

behaviors suggestive of classic RBD (e.g., aggressive dream enactment), but on
PSG, there is a lack of identifiable sleep stages. The PSG has a mixture of markers
for wakefulness, NREM, and REM, without a clear delineation between these
stages. Even more than in classical RBD, individuals with status dissociatus are
often interpreted by observers to be awake when engaging in dream enactment
behaviors, and these individuals may often be confused about whether they are
awake or asleep [3]. If this condition is accompanied by generalized motor overac-
tivity during wakefulness, loss of slow wave sleep, and sympathetic overactivation,
then this would be consistent with a syndrome called “agrypnia excitata” and raises
concern for an autoimmune/paraneoplastic encephalitis, delirium tremens, or fatal

familial insomnia [3]. The prevalence of this subtype is unknown.
Parasomnia Overlap
Parasomnia overlap disorder refers to patients who meet clinical criteria for RBD
and, in addition, have an NREM-related parasomnia or rhythmic movement disor-
der. Unlike isolated RBD, overlap syndrome is much more common in younger
ages, often beginning during childhood and adolescence, though any age range
could be affected. The associated pathophysiology is not as clear as with isolated
RBD, and many diverse causes have been implicated, including pharmacotherapies,
substance use, various psychiatric disorders, multiple sclerosis, narcolepsy, and
traumatic brain injury [3]. As with status dissociatus, the prevalence is unknown.
While this disorder may sound like status dissociatus in that REM and NREM con-
ditions are blended, parasomnia overlap disorder does not feature involvement of
the awake state, and affected individuals do not report confusion about whether they
are awake, asleep, or dreaming.
Recurrent Isolated Sleep Paralysis
Definition
Recurrent isolated sleep paralysis is defined as (A) a recurrent inability to move the
trunk and all limbs at onset or offset of sleep, (B) the episodes last seconds to min-
utes, (C) the episodes cause distress, and (D) the episodes are not better explained
by a different medical condition [3].
Clinical Features
Recurrent isolated sleep paralysis is a recurrent distressing sensation of an inability

to move one’s body while transitioning to or from sleep [52, 53]. While it is benign,
it can be associated with significant anxiety during and after an episode. Affected
individuals are unable to speak or move, though they are fully conscious. Respiratory
muscles are unaffected. These episodes tend to resolve spontaneously within a short
period, usually seconds though it can last up to a few minutes, and sometimes an
episode can be ended early if an observer speaks to or touches the patient. These
episodes are not classified as a disease unless they are associated with significant
distress to the patient, such as inducing bedtime anxiety or fear of sleep.
Hallucinations often occur, including visual, auditory, or tactile hallucinations such
as a sensation of a creature sitting on the individual’s chest. The condition often

presents in adolescence, with mean age of onset 14–17 years old, and most episodes
occur in patient’s teens and 20s [3].
Risk Factors
A familial form of sleep paralysis has been reported in two families, suggesting that
underlying genetics may play a role; however, most cases do not have a clear famil-
ial component. Male and female sexes appear to have equal risk. As with all para-
somnias, sleep deprivation and irregular sleep cycles are risk factors [54]. Patients
who sleep supine appear to be at higher risk, though the mechanism for this is not
understood. One case has been reported of isolated sleep paralysis induced by the
abrupt withdrawal of bupropion [55]. As with all parasomnias, psychiatric disease
is a risk factor [24].
Pathophysiology
Like narcolepsy, isolated sleep paralysis is thought to occur from a state dissocia-
tion, with the normal expected REM paralysis of skeletal muscles continuing abnor-
mally into wakefulness. Brainstem systems that control serotonin, norepinephrine,
and acetylcholine appear to be affected. Individuals who are sensitive to sleep dis-
ruptions may be particularly vulnerable, and abrupt awakenings from REM may
produce an episode [3].
Epidemiology
There are limited global data on the prevalence of recurrent isolated sleep paralysis,
partially due to the various definitions that have been used. When examining for
single occurrences of isolated sleep paralysis, prevalence may range from 5% to
40% [3, 56].
Diagnostic Workup
A polysomnogram (PSG) is not required for diagnosis, and subjective history can be
sufficient. A PSG may be supportive if it demonstrates REM atonia on EMG leads
that persists into wakefulness.
The primary disease to consider is narcolepsy, which also often includes sleep
paralysis episodes and hypnagogic and/or hypnopompic hallucinations. However,
the prominent features of narcolepsy are extreme daytime somnolence and reduced
mean sleep latency time, whereas these features are absent from recurrent isolated
sleep paralysis. Another related phenomenon, cataplexy, also involves REM atonia
invading the awake state, though it occurs during full wakefulness rather than at
periods of transition to and from sleep; cataplexy also tends to be triggered by
intense emotions, whereas sleep paralysis does not. Similar to cataplexy, atonic
seizures can involve preserved consciousness with inability to move limbs, but
atonic seizures occur during wakefulness rather than only at times of sleep transition.
Periodic paralysis syndromes may resemble isolated sleep paralysis in that the
affected individual is conscious but unable to move the body. These episodes may
occur during wakefulness or at periods of sleep transition; if the latter is the case,
the primary way to differentiate these syndromes from isolated sleep paralysis is
that periodic paralysis lasts for hours rather than seconds. Periodic paralysis is also
less likely to affect bulbar muscles the way sleep paralysis can. These periodic
paralysis syndromes include a hypokalemic, hyperkalemic, and thyrotoxic form,
and involve mutations in skeletal muscle ions channels. Paralysis attacks can be
precipitated by a large intake of carbohydrates, excessive exercise, or alcohol intake.
Most cases of periodic paralysis are hereditary with an autosomal dominant inheri-
tance [57].
Treatment
If sleep deprivation is thought to be a provoking factor, then that component can be

addressed, such as avoiding shift work, addressing jet lag, or other general sleep
hygiene components. Further pharmacotherapy options include tricyclic antidepres-
sants (e.g., imipramine and clomipramine) or SSRIs (e.g., fluoxetine or escitalo-
pram), all of which are thought to work by suppressing REM [58, 59].
Nightmare Disorder
Definition
Nightmare disorder is defined as (A) repeated, extended, well-remembered dreams

associated with intensely unpleasant emotions, (B) rapid, full alertness on awaken-
ing, and (C) associated distress or impairment in functioning [3].
Clinical Features
Nightmares entail a realistic and vivid dream sequence that tends to become increas-
ingly frightening, though other negative emotions can be predominant such as
anger, disgust, guilt, or embarrassment. There is often a theme of imminent bodily
harm, though this is not universally true. On awakening, affected individuals are
quickly oriented, and can vividly recall dream content. There is often difficulty
returning to sleep after an episode, and individuals may note signs of increased
sympathetic activity such as rapid heart rate or piloerection. These episodes tend to
occur in the latter third of a sleep session, as this is when REM sleep is most promi-
nent. Nightmares associated with PTSD may be more variable in their timing within
a sleep cycle, and can occur at sleep onset or from NREM sleep [3].
While occasional nightmares are quite common among the general population, a
diagnosis of nightmare disorder is only made if these occurrences are persistent and
affect a person’s daily functioning. Distress can be manifested by any of the follow-
ing: mood disturbances, sleep resistance, cognitive impairment such as concentra-
tion difficulties, negative impact on family functioning, behavioral disturbances,
daytime somnolence, low energy, impairment in one’s education or occupation, or
impaired social function [3].
Risk Factors
The greatest risk factor for nightmare disorder is exposure to severe psychosocial
stressors. This is particularly true in children, though in all age groups there is an
association between physical or sexual abuse and nightmares. Trauma often pre-
cedes the onset of nightmares, though there may be a prolonged delay prior to night-
mare onset. In acute stress disorder, symptoms occur immediately after a trauma,
whereas in posttraumatic stress disorder, symptoms may arise more than a month
after the event [3, 60].
Individuals who had recurrent nightmares as children are more likely to report
recurrent nightmares as an adult, suggesting that predisposition to nightmares may
be a component of one’s personality traits. Twin studies also demonstrate that there
are genetic predispositions to nightmares, analogous to the pattern seen with NREM
parasomnias such as sleepwalking and sleep talking [61].
Nightmares can be induced by pharmaceuticals that affect neurotransmitter con-
centrations and function, particularly for serotonin, dopamine, and norepinephrine
[62, 63]. Medications of interest include antidepressants of all classes; antihyperten-
sive agents including beta-blockers and calcium channel blockers; dopaminergic
drugs including levodopa and methylphenidate; atypical antipsychotics including
risperidone and olanzapine; sedatives including alcohol and barbiturates (particu-
larly withdrawal from these); acetylcholinesterase inhibitors, including donepezil
and rivastigmine; and varenicline, which is a nicotinic acetylcholine receptor
antagonist. Another class of implicated medications is antimicrobials (e.g., cipro-

floxacin, ganciclovir, and mefloquine) which, in contrast to the above list, are
thought to act via modulation of cytokines that are involved in sleep such as IL-1B
and TNF-alpha. Implicated medical conditions include hypoglycemia induced by
nocturnal insulin use [64], as well as all mood disorders including major depression,
bipolar affective disorder, and schizoaffective disorder [24, 65]. As with all para-
somnias, sleep deprivation and OSA can be a predisposing factor [66].
Pathophysiology
The pathophysiology of nightmares is not known.
Epidemiology
Occasional nightmares occur in 60–75% of children, and in most cases these night-
mares are sporadic. Only in a small minority of children are nightmares frequent
and extensive, occurring in 1–5% of children [3]. Among the general population,
2–8% report distress related to nightmares, and the age most likely to be affected is
between 6 and 10 years old [67–69]. However, the incidence is increased among
adults with psychopathology, most notable among those with PTSD where 80%
report recurrent nightmares.
Diagnostic Workup
Patient history is sufficient for diagnosis of nightmare disorder, and further PSG
evaluation is not required [70]. However, it may be considered if during the patients’
nightmares they perform actions that either cause harm to self or others, or are
highly stereotyped in nature, as this would raise clinical suspicion for other condi-
tions, as described below.
The main conditions to distinguish from nightmare disorder are sleep terrors, noc-
turnal panic attacks, seizures, RBD, and sleep paralysis.
Sleep terrors also involve an awakening from sleep with appearance of distress.
However, with sleep terrors there is a prominent component of confusion and dis-
orientation, which is not seen with nightmares. Further, in sleep terrors there is a
lack of recall of dream content, whereas dream recall tends to be vivid with night-
mares. Prominent autonomic activity (e.g., diaphoresis, pupillary dilatation) is more
common with sleep terrors than nightmares. As sleep terrors arise from NREM
sleep, they tend to occur earlier in the night, while nightmares occur later in the
night. Similarly, nocturnal panic attacks tend to arise from NREM sleep, occurring
earlier in the night and are not typically associated with vivid dream content.
Nocturnal seizures can, in rare cases, present only with recurrent nightmares
[71]. These can be difficult to distinguish from true nightmares by history, though
suspicion should be raised in patients with underlying cerebral disease or a history
of epilepsy. Nightmares from epilepsy are more likely to resemble classic temporal
lobe auras, such as déjà vu or intense panic without any associated dream content to
induce the fear. These episodes come from NREM sleep rather than true REM sleep.
A PSG, preferably with an extended EEG montage, is required to capture and prove
that episodes are epileptic in nature.
REM sleep behavior disorder (RBD), as discussed in section “REM Sleep
Behavior DisorderS30”, involves involuntary acting out of dream content, much of
which tends to involve frightening and life-threatening situations. While the dream
content can be analogous between these two conditions, nightmare disorder does
not involve any physical action, movement, or injury, so the presence of these would
be strongly suggestive of RBD. RBD is most common in older age, whereas night-
mare disorder is most common in childhood, though there are exceptions in both
directions, as discussed above.
Sleep paralysis, whether occurring as part of isolated recurrent sleep paralysis
(see section “Recurrent Isolated Sleep Paralysis”) or narcolepsy, occurs at periods
of transition to or from sleep and can often be associated with anxiety during the
episode. Hallucinations commonly co-occur and can be disturbing in nature. While
nightmares can occasionally involve an inability to move or speak, a recurrent expe-
rience of total paralysis with simultaneous wakefulness is much more suggestive of
sleep paralysis.
Treatment
Nightmares on their own do not necessitate treatment, as they can often be self-
limited. In particular, nightmares occurring in the context of recent bereavement
tend to resolve over time [72]. For those patients who do require treatment, the next
step is to address general sleep hygiene and any predisposing medications or medi-
cal conditions. When this approach is insufficient, then a choice or combination
between cognitive behavioral therapy (CBT) and pharmacotherapy can be
employed [73].
CBT interventions for nightmare disorder emphasize stress management and
repeated exposures [74]. As with other forms of CBT, it consists of a limited set of
therapy sessions, aimed at addressing the maladaptive thoughts, emotions, and
behaviors that disrupt patients’ lives. One option is image rehearsal therapy, where
patients recall the nightmare while awake, write down its details including emo-
tional content, modify the story to have a more positive ending, and then rehearse
the new narrative with the goal of replacing the nightmare if the dream recurs [73,
75, 76]. Another option is lucid dreaming treatment, where the patient is taught to
identify that they are dreaming during a nightmare and then actively change the end-
ing of the nightmare to a positive one [77]. Hypnosis has also been shown in small
case studies to be effective in decreasing nightmare frequency [78]. Finally, sys-
temic desensitization, where patients are gradually exposed to cues associated with
their nightmares and taught stress management techniques, can be used [79].
The best-studied pharmacotherapy option is prazosin, which is a centrally active
alpha1-adrenergic antagonist, and has been well-described to be effective in both
PTSD and other nightmare disorders [73, 80–83]. It is thought to act via blunting of
the sympathetic arousal state associated with nightmares. The only other medica-
tions recommended by the American Academy of Sleep Medicine (AASM) are tri-
azepam and nitrazolam [84]. If these medications are ineffective or not tolerated,
then there are many other options, which have primarily been studied in the context
of PTSD nightmares: topiramate [85, 86], trazodone [87], risperidone [87], gaba-
pentin [73, 88], olanzapine [89, 90], clonidine [73], aripiprazole [84], cyprohepta-
dine [84], phenelzine [84], tricyclic antidepressants [84], and synthetic cannabinoids
[91, 92]. Two medications which the AASM specifically recommends against using
are venlafaxine and clonazepam, as the limited studies looking at these two have
shown no efficacy [84]. Once a patient has attained prolonged relief from night-
mares, pharmacotherapy can be tapered off.
References
1. Gagnon J-F, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eye-movement sleep

behaviour disorder and neurodegenerative diseases. Lancet Neurol. 2006;5(5):424–32.
2. Boeve B. Updated review of the core features, the REM sleep behavior disorder-
neurodegenerative disease association, evolving concepts, controversies, and future directions.
Ann N Y Acad Sci. 2010;1184:15–54.
3. Sateia MJ. International classification of sleep disorders. Chest. 2014;146(5):1387–94.
4. Stores G. Rapid eye movement sleep behaviour disorder in children and adolescents. Dev Med
Child Neurol. 2008;50(10):728–32.
5. Lin FC, Lai CL, Huang P, Liu CK, Hsu CY. The rapid-eye-movement sleep behavior disorder
in Chinese-Taiwanese patients. Psychiatry Clin Neurosci. 2009;63(4):557–62.
6. Tachibana N, Yamanaka K, Kaji R, Nagamine T, Watatani K, Kimura J, et al. Sleep brux-
ism as a manifestation of subclinical rapid eye movement sleep behavior disorder. Sleep.
1994;17(6):555–8.
7. Abe S, Gagnon J-F, Montplaisir JY, Postuma RB, Rompré PH, Huynh NT, et al. Sleep bruxism
and oromandibular myoclonus in rapid eye movement sleep behavior disorder: a preliminary
report. Sleep Med. 2013;14(10):1024–30.
8. Covassin N, Neikrug AB, Liu L, Corey-Bloom J, Loredo JS, Palmer BW, et al. Clinical
correlates of periodic limb movements in sleep in Parkinson's disease. J Neurol Sci.
2012;316(1–2):131–6.
9. Fantini M, Michaud M, Gosselin N, Lavigne G, Montplaisir J. Periodic leg movements

in REM sleep behavior disorder and related autonomic and EEG activation. Neurology.
2002;59(12):1889–94.
10. Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY. Olfaction and color vision
identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann
Neurol. 2011;69(5):811–8.
11. Fantini ML, Farini E, Ortelli P, Zucconi M, Manconi M, Cappa S, et al. Longitudinal study of
cognitive function in idiopathic REM sleep behavior disorder. Sleep. 2011;34(5):619–25.
12. Kawamura M, Sugimoto A, Kobayakawa M, Tsuruya N. Neurological disease and facial rec-
ognition. Brain Nerve. 2012;64(7):799–813.
13. Génier Marchand D, Postuma RB, Escudier F, De Roy J, Pelletier A, Montplaisir J, et al. How
does dementia with Lewy bodies start? prodromal cognitive changes in REM sleep behavior
disorder. Ann Neurol. 2018;83(5):1016–26.
14. Coco DL, Cupidi C, Mattaliano A, Baiamonte V, Realmuto S, Cannizzaro E. REM sleep
behavior disorder in a patient with frontotemporal dementia. Neurol Sci. 2012;33(2):371–3.
15. Chokroverty S, Bhat S, Rosen D, Farheen A. REM behavior disorder in myotonic dystrophy
type 2. Neurology. 2012;78(24):2004.
16. Ebben MR, Shahbazi M, Lange DJ, Krieger AC. REM behavior disorder associated with
familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012;13(5):473–4.
17. Nomura T, Inoue Y, Takigawa H, Nakashima K. Comparison of REM sleep behaviour disorder
variables between patients with progressive supranuclear palsy and those with Parkinson’s
disease. Parkinsonism Relat Disord. 2012;18(4):394–6.
18. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demographic,
clinical and laboratory findings in 93 cases. Brain. 2000;123(2):331–9.
19. Claassen D, Josephs KA, Ahlskog J, Silber M, Tippmann-Peikert M, Boeve BF. REM sleep
behavior disorder preceding other aspects of synucleinopathies by up to half a century.
Neurology. 2010;75(6):494–9.
20. Galbiati A, Verga L, Giora E, Zucconi M, Ferini-Strambi L. The risk of neurodegeneration in
REM sleep behavior disorder: a systematic review and meta-analysis of longitudinal studies.
Sleep Med Rev. 2019;43:37–46.
21. Bodkin CL, Schenck CH. Rapid eye movement sleep behavior disorder in women: relevance
to general and specialty medical practice. J Women's Health. 2009;18(12):1955–63.
22. Teman PT, Tippmann-Peikert M, Silber MH, Slocumb NL, Auger RR. Idiopathic rapid-eye-
movement sleep disorder: associations with antidepressants, psychiatric diagnoses, and other
factors, in relation to age of onset. Sleep Med. 2009;10(1):60–5.
23. Schenck CH, Mahowald MW, Kim SW, O'Connor KA, Hurwitz TD. Prominent eye move-
ments during NREM sleep and REM sleep behavior disorder associated with fluoxetine treat-
ment of depression and obsessive-compulsive disorder. Sleep. 1992;15(3):226–35.
24. Waters F, Moretto U, Dang-Vu TT. Psychiatric illness and parasomnias: a systematic review.
Curr Psychiatry Rep. 2017;19(7):37.
25. Hoque R, Chesson AL Jr. Pharmacologically induced/exacerbated restless legs syndrome, peri-
odic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: litera-
ture review, qualitative scoring, and comparative analysis. J Clin Sleep Med. 2010;6(01):79–83.
26. Frauscher B, Jennum P, Ju Y-ES, Postuma RB, Arnulf I, De Cock VC, et al. Comorbidity
and medication in REM sleep behavior disorder: a multicenter case-control study. Neurology.
2014;82(12):1076–9.
27. Nightingale S, Orgill J, Ebrahim I, De Lacy S, Agrawal S, Williams A. The association between
narcolepsy and REM behavior disorder (RBD). Sleep Med. 2005;6(3):253–8.
28. Fantini ML, Corona A, Clerici S, Ferini-Strambi L. Aggressive dream content without daytime
aggressiveness in REM sleep behavior disorder. Neurology. 2005;65(7):1010–5.
29. D’Agostino A, Manni R, Limosani I, Terzaghi M, Cavallotti S, Scarone S. Challenging the
myth of REM sleep behavior disorder: no evidence of heightened aggressiveness in dreams.
Sleep Med. 2012;13(6):714–9.
30. Sasai T, Inoue Y, Matsuura M. Do patients with rapid eye movement sleep behavior disorder
have a disease-specific personality? Parkinsonism Relat Disord. 2012;18(5):616–8.
31. Verma A, Anand V, Verma NP. Sleep disorders in chronic traumatic brain injury. J Clin Sleep
Med. 2007;3(04):357–62.
32. Dauvilliers Y, Postuma RB, Ferini-Strambi L, Arnulf I, Högl B, Manni R, et al. Family his-
tory of idiopathic REM behavior disorder: a multicenter case-control study. Neurology.
2013;80(24):2233–5.
33. Jacobs ML, Dauvilliers Y, St Louis EK, McCarter SJ, Romenets SR, Pelletier A, et al. Risk
factor profile in Parkinson’s disease subtype with REM sleep behavior disorder. J Parkinsons
Dis. 2016;6(1):231–7.
34. Yao C, Fereshtehnejad S-M, Keezer MR, Wolfson C, Pelletier A, Postuma RB. Risk factors
for possible REM sleep behavior disorder: a CLSA population-based cohort study. Neurology.
2019;92(5):e475–e85.
35. Postuma R, Gagnon J, Vendette M, Fantini M, Massicotte-Marquez J, Montplaisir
J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disor-
der. Neurology. 2009;72(15):1296–300.
36. Iranzo A, Santamaria J, Tolosa E. The clinical and pathophysiological relevance of REM sleep
behavior disorder in neurodegenerative diseases. Sleep Med Rev. 2009;13(6):385–401.
37. Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, et al.
Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-
movement sleep behaviour disorder: an observational cohort study. Lancet Neurol.
2013;12(5):443–53.
38. Heller J, Brcina N, Dogan I, Holtbernd F, Romanzetti S, Schulz JB, et al. Brain imaging
findings in idiopathic REM sleep behavior disorder (RBD)–a systematic review on potential
biomarkers for neurodegeneration. Sleep Med Rev. 2017;34:23–33.
39. Eisensehr I, Linke R, Tatsch K, Kharraz B, Gildehaus JF, Wetter CT, et al. Increased mus-
cle activity during rapid eye movement sleep correlates with decrease of striatal presynap-
tic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically
manifest idiopathic REM sleep behavior disorder, Parkinson's disease, and controls. Sleep.
2003;26(5):507–12.
40. Albin R, Koeppe R, Chervin R, Consens F, Wernette K, Frey K, et al. Decreased striatal dopa-
minergic innervation in REM sleep behavior disorder. Neurology. 2000;55(9):1410–2.
41. Gilman S, Koeppe R, Chervin R, Consens F, Little R, An H, et al. REM sleep behavior disorder
is related to striatal monoaminergic deficit in MSA. Neurology. 2003;61(1):29–34.
42. Shirakawa SI, Takeuchi N, Uchimura N, Ohyama T, Maeda H, Abe T, et al. Study of image
findings in rapid eye movement sleep behavioural disorder. Psychiatry Clin Neurosci.
2002;56(3):291–2.
43. Haba-Rubio J, Frauscher B, Marques-Vidal P, Toriel J, Tobback N, Andries D, et al. Prevalence
and determinants of rapid eye movement sleep behavior disorder in the general population.
Sleep. 2018;41(2):zsx197.
44. Kang S-H, Yoon I-Y, Lee SD, Han JW, Kim TH, Kim KW. REM sleep behavior disorder in the
Korean elderly population: prevalence and clinical characteristics. Sleep. 2013;36(8):1147–52.
45. Howell MJ. Parasomnias: an updated review. Neurotherapeutics. 2012;9(4):753–75.
46. Tinuper P, Bisulli F. From nocturnal frontal lobe epilepsy to sleep-related hypermotor epi-
lepsy: a 35-year diagnostic challenge. Seizure. 2017;44:87–92.
47. Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. Nocturnal frontal lobe epilepsy:
a clinical and polygraphic overview of 100 consecutive cases. Brain. 1999;122(6):1017–31.
48. Henriques-Filho PSA, Pratesi R. Sleep apnea and REM sleep behavior disorder in patients
with Chiari malformations. Arq Neuropsiquiatr. 2008;66(2B):344–9.
49. Iranzo A, Santamaría J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep
behavior disorder. Sleep. 2005;28(2):203–6.
50. Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melato-
nin in REM sleep behaviour disorder. J Sleep Res. 2010;19(4):591–6.
51. Zak RS, Maganti RK, Auerbach SH, Casey KR, Chowdhuri S, Karippot A, et al. Best prac-
tice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med.
2010;6(01):85–95.
52. Goode GB. Sleep paralysis. Arch Neurol. 1962;6(3):228–34.
53. Sharpless BA. A clinician’s guide to recurrent isolated sleep paralysis. Neuropsychiatr Dis
Treat. 2016;12:1761.
54. Takeuchi T, Miyasita A, Sasaki Y, Inugami M, Fukuda K. Isolated sleep paralysis elicited by
sleep interruption. Sleep. 1992;15(3):217–25.
55. Bieber ED, Bieber DA, Romanowicz M, Voort JLV, Kolla BP, McKean AJ. Recurrent iso-
lated sleep paralysis following bupropion cessation: a case report. J Clin Psychopharmacol.
2019;39(4):407–9.
56. Ohayon MM, Zulley J, Guilleminault C, Smirne S. Prevalence and pathologic associations of
sleep paralysis in the general population. Neurology. 1999;52(6):1194.
57. Fontaine B, Lapie P, Plassart E, Tabti N, Nicole S, Reboul J, et al. Periodic paralysis and
voltage-gated ion channels. Kidney Int. 1996;49(1):9–18.
58. Mitler MM, Hajdukovic R, Erman M, Koziol JA. Narcolepsy. J Clin Neurophysiol.
1990;7(1):93.
59. Hintze JP, Gault D. Escitalopram for recurrent isolated sleep paralysis. J Sleep Res.
2020;29:e13027.
60. Lavie P. Sleep disturbances in the wake of traumatic events. N Engl J Med. 2001;345(25):
1825–32.
61. Hublin C, Kaprio J, Partinen M, Koskenvuo M. Nightmares: familial aggregation and
association with psychiatric disorders in a nationwide twin cohort. Am J Med Genet.
1999;88(4):329–36.
62. Pagel J, Helfter P. Drug induced nightmares—an etiology based review. Hum Psychopharmacol
Clin Exp. 2003;18(1):59–67.
63. Foral P, Knezevich J, Dewan N, Malesker M. Medication-induced sleep disturbances. Consult
Pharm. 2011;26(6):414–25.
64. Allen KV, Frier BM. Nocturnal hypoglycemia: clinical manifestations and therapeutic strate-
gies toward prevention. Endocr Pract. 2003;9(6):530–43.
65. Beauchemin KM, Hays P. Dreaming away depression: the role of REM sleep and dreaming in
affective disorders. J Affect Disord. 1996;41(2):125–33.
66. Schredl M, Schmitt J, Hein G, Schmoll T, Eller S, Haaf J. Nightmares and oxygen desaturations:
is sleep apnea related to heightened nightmare frequency? Sleep Breath. 2006;10(4):203–9.
67. Levin R, Fireman G. Nightmare prevalence, nightmare distress, and self-reported psychologi-
cal disturbance. Sleep. 2002;25(2):205–12.
68. Zadra A, Donderi D. Nightmares and bad dreams: their prevalence and relationship to well-
being. J Abnorm Psychol. 2000;109(2):273.
69. Gauchat A, Seguin J, Zadra A. Prevalence and correlates of disturbed dreaming in children.
Pathol Biol. 2014;62(5):311–8.
70. Boursoulian LJ, Schenck CH, Mahowald MW, Lagrange AH. Differentiating parasomnias
from nocturnal seizures. J Clin Sleep Med. 2012;8(01):108–12.
71. Silvestri R, Bromfield E. Recurrent nightmares and disorders of arousal in temporal lobe epi-
lepsy. Brain Res Bull. 2004;63(5):369–76.
72. Wright ST, Kerr CW, Doroszczuk NM, Kuszczak SM, Hang PC, Luczkiewicz DL. The impact
of dreams of the deceased on bereavement: A survey of hospice caregivers. Am J Hosp Palliat
Med. 2014;31(2):132–8.
73. Zak RS, Auerbach SH, Casey KR, Chowdhuri S, Karippot A, Maganti RK, et al. Best practice
guide for the treatment of nightmare disorder in adults. J Clin Sleep Med. 2010;6(04):389–401.
74. Lancee J, Spoormaker VI, Krakow B, van den Bout J. A systematic review of cognitive-
behavioral treatment for nightmares: toward a well-established treatment. J Clin Sleep Med.
2008;4(05):475–80.
75. Seda G, Sanchez-Ortuno MM, Welsh CH, Halbower AC, Edinger JD. Comparative meta-
analysis of prazosin and imagery rehearsal therapy for nightmare frequency, sleep quality, and
posttraumatic stress. J Clin Sleep Med. 2015;11(01):11–22.
76. Krakow B, Hollifield M, Johnston L, Koss M, Schrader R, Warner TD, et al. Imagery rehearsal
therapy for chronic nightmares in sexual assault survivors with posttraumatic stress disorder: a
randomized controlled trial. JAMA. 2001;286(5):537–45.
77. Spoormaker VI, Van Den Bout J. Lucid dreaming treatment for nightmares: a pilot study.
Psychother Psychosom. 2006;75(6):389–94.
78. Committee SP, Aurora RN, Zak RS, Auerbach SH, Casey KR, Chowdhuri S, et al. Best practice
guide for the treatment of nightmare disorder in adults. J Clin Sleep Med. 2010;6(4):389–401.
79. Grandi S, Fabbri S, Panattoni N, Gonnella E, Marks I. Self-exposure treatment of recur-
rent nightmares: waiting-list-controlled trial and 4-year follow-up. Psychother Psychosom.
2006;75(6):384–8.
80. Daly CM, Doyle ME, Radkind M, Raskind E, Daniels C. Clinical case series: the use of prazo-
sin for combat-related recurrent nightmares among Operation Iraqi Freedom combat veterans.
Mil Med. 2005;170(6):513–5.
81. Miller LJ. Prazosin for the treatment of posttraumatic stress disorder sleep disturbances.
Pharmacotherapy. 2008;28(5):656–66.
82. Taylor F, Raskind MA. The α1-adrenergic antagonist prazosin improves sleep and nightmares
in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol. 2002;22(1):82–5.
83. Taylor HR, Freeman MK, Cates ME. Prazosin for treatment of nightmares related to posttrau-
matic stress disorder. Am J Health Syst Pharm. 2008;65(8):716–22.
84. Morgenthaler TI, Auerbach S, Casey KR, Kristo D, Maganti R, Ramar K, et al. Position paper
for the treatment of nightmare disorder in adults: an American Academy of Sleep Medicine
position paper. J Clin Sleep Med. 2018;14(6):1041.
85. Nadorff MR, Lambdin KK, Germain A. Pharmacological and non-pharmacological treatments
for nightmare disorder. Int Rev Psychiatry. 2014;26(2):225–36.
86. Aalbersberg C, Mulder J. Topiramate for the treatment of post traumatic stress disorder. A case
study. Tijdschr Psychiatr. 2006;48(6):487–91.
87. Nielsen T, Levin R. Nightmares: a new neurocognitive model. Sleep Med Rev.
2007;11(4):295–310.
88. Hamner MB, Brodrick PS, Labbate LA. Gabapentin in PTSD: a retrospective, clinical series
of adjunctive therapy. Ann Clin Psychiatry. 2001;13(3):141–6.
89. Detweiler MB, Pagadala B, Candelario J, Boyle JS, Detweiler JG, Lutgens BW. Treatment
of post-traumatic stress disorder nightmares at a veterans affairs medical center. J Clin Med.
2016;5(12):117.
90. Jakovljević M, Šagud M, Mihaljević-Peleš A. Olanzapine in the treatment-resistant, combat-
related PTSD–a series of case reports. Acta Psychiatr Scand. 2003;107(5):394–6.
91. Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a synthetic cannabinoid,
in the treatment of PTSD-associated nightmares: a preliminary randomized, double-blind,
placebo-controlled cross-over design study. Psychoneuroendocrinology. 2015;51:585–8.
92. Fraser GA. The use of a synthetic cannabinoid in the management of treatment-resistant night-
mares in posttraumatic stress disorder (PTSD). CNS Neurosci Ther. 2009;15(1):84–8.
Chapter 18
Movement Disorders
Salam Zeineddine and Nidhi S. Undevia
Keywords Sleep-related movement disorders · Restless legs syndrome · Periodic

limb movement disorder · Sleep-related leg cramps · Sleep-related bruxism ·
Sleep-related rhythmic movement disorder
Introduction
Sleep-related movement disorders are conditions that are characterized by simple,

usually stereotyped, movements that disturb sleep or its onset, such as RLS. The
Third Edition of the International Classification of Sleep Disorders (ICSD-3)
includes restless legs syndrome (RLS), periodic limb movement disorder (PLMD),
sleep-related leg cramps, sleep-related bruxism and sleep-related rhythmic move-
ment disorder (RMD). Propriospinal myoclonus at sleep onset, sleep-related move-
ment disorder due to a medical disorder, and sleep-related movement disorder due
to a medication or substance are also included under this heading [1] (Table 18.1).
RLS is classified within this group of disorders due to its close association with
PLMD. Movement alone is not sufficient for the diagnosis of a sleep-related move-
ment disorder as an associated sleep disturbance or an impairment of daytime func-
tioning is required. Daytime impairment can affect any important area of functioning
S. Zeineddine
Department of Medicine, John D. Dingell VA Medical Center and Wayne State University
School of Medicine, Detroit, MI, USA
N. S. Undevia (*)
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Loyola Center
for Sleep Disorders, Loyola University Medical Center, Maywood, IL, USA
e-mail: nundevia@lumc.edu

400 S. Zeineddine and N. S. Undevia
Table 18.1 Sleep-related movement disorders

Restless legs syndrome
Periodic limb movement disorder
Sleep-related leg cramps
Sleep-related bruxism
Sleep-related rhythmic movement disorder
Propriospinal myoclonus at sleep onset
Sleep-related movement disorder due to a medical disorder
Sleep-related movement disorder due to a medication or substance
such as mental, physical, social, behavioral, educational, or others. Each of these

topics will be discussed in this chapter.
Restless Legs Syndrome
RLS is a sensorimotor disorder characterized by a distressing urge to move the legs

and sometimes other parts of the body such as the arms. The British physician Sir
Thomas Willis first described RLS in the seventeenth century by these very descrip-
tive words “Wherefore to some, when being abed they betake themselves to sleep,
presently in the arms and legs, leapings and contractions of the tendons, and so great
a restlessness and tossings of their members ensue that the diseased are no more
able to sleep than if they were in a place of the greatest torture” [2]. The first signifi-
cant clinical review was carried out by the Swedish neurologist Karl-Axel Ekbom
in the 1940s who also coined the term “restless legs” [3]. The severity of RLS can
vary from mild with only occasional symptoms to daily severe symptoms that can
have a profound effect on sleep and daytime functioning. The pathophysiology of
RLS is incompletely understood, but probably results from derangements in iron
and dopamine metabolism and has a genetic component [4–6].
Demographics
The prevalence of RLS varies from region to region; in Europe, South and North
America, and the Indian subcontinent, it is estimated to be 4–10% of the adult popu-
lation, while in Japan, Korea, and China, for example, it is 0.6, 0.9, and 1.6%,
respectively [7–9]. In the United States, it is believed to affect more than ten million
adults. The 2005 National Sleep Foundation Poll reported RLS symptoms in 8% of
men and 11% of women [10]. Women and older adults appear to be at increased risk
[11]. The prevalence of RLS in women is roughly twice that reported in men [12].
A population survey study reported that the prevalence of symptoms of RLS was
18 Movement Disorders 401
3% between the ages of 18 and 29 years, 10% between the ages of 30 and 79 years,
and 19% in persons older than 80 years of age [13].
Diagnosis
RLS diagnosis is based on clinical grounds and no laboratory study reliably identi-
fies RLS. It does not require a polysomnogram (PSG) unless an additional sleep
disorder is thought to be present. The diagnosis of RLS in adults according to
ICSD-3 requires the following: (a) The patient reports an urge to move the legs,
usually accompanied or caused by uncomfortable and unpleasant sensation in the
legs. (b) The urge to move or the unpleasant sensations begin or worsen during
periods of rest or inactivity such as lying or sitting. (c) The urge to move or the
unpleasant sensations are partially or totally relieved by movement, such as walking
or stretching, at least as long as the activity continues. (d) The urge to move or the
unpleasant sensations are worse, or only occur, in the evening or night. (e) The con-
dition is not better explained by another current sleep disorder, medical or neuro-
logical disorder, mental disorder, medication use, or substance use disorder. (f) The
symptoms cause concern, distress, sleep disturbance, or impairment in daytime
functionning [1] (Table 18.2). Separate diagnostic criteria have been developed for
cognitively impaired adults and young children (age 2–12 years) who have diffi-
culty in reporting these symptoms.
Associated Features
There are several supportive clinical features which, while not required, may assist
in diagnosis. These include a response to dopaminergic agents, the presence of peri-
odic leg movements (PLMs) on diagnostic polysomnography (PSG), and a positive
family history for RLS. PLMs may occur in sleep (PLMS) and resting wakefulness
(PLMW). PLMS ≥5/hour is a highly sensitive marker for RLS, occurring in 80–90%
of patients, but has low specificity as it is also frequently associated with narcolepsy,
rapid eye movement behavioral disorder (RBD), and even healthy individuals, nota-
bly the elderly [14, 15]. PLMW may be noted during the wake time on standard
Table 18.2 Diagnostic criteria for restless legs syndrome (RLS)

Uncomfortable sensation in the legs associated with an urge to move
Symptoms are worse at rest
Symptoms are temporarily relieved by movement
Symptoms are worse or only occur at night
The condition is not better explained by another disorder
Symptoms cause concern, distress, sleep disturbance, or impairment in daytime functioning
PSG recorded 1 hour before the usual bedtime while the patient is upright in bed
with stretched-out legs (Suggested Immobilization Test – SIT). A rate greater than
40 PLMW/hour supports the diagnosis of RLS [1]. RLS is associated with PLMW
in ≈ 1/3 of patients [14]. The frequency of RLS among first-degree relatives of
people with RLS is 3–5 times greater than in people without RLS [16]. There is a
negative impact of RLS symptoms on sleep including reports of disrupted sleep, an
inability to fall asleep, and insufficient hours of sleep [11]. Sleep disruption has also
been associated with negative effects on cognitive function in patients with RLS
[17]. Onset occurs at all ages from early childhood to late adult life with a mean age
of onset between the third and fifth decade [18]. In children RLS may be misdiag-
nosed as “growing pains” or attention deficit hyperactivity disorder (ADHD). Two
age-of-onset phenotypes for RLS have been described. Early-onset RLS usually
starts before the age of 45 years with intermittent symptoms and progresses slowly.
Late-onset RLS is usually either stable at onset or rapidly progresses over 5 years to
a stable pattern. Patients may describe the symptoms as creeping, crawling, pulling,
aching, prickling, or tingling. RLS can occur unilaterally or bilaterally in the lower
extremities. About half (48.7%) of patients with RLS complain of restlessness in the
arms as well. However, every patient who had arm restlessness also had leg restless-
ness. In most mild cases or RLS, symptoms are localized to the lower extremities,
and only with increased severity do they also affect the arms and other parts of the
body [19]. Peak intensity of RLS symptoms is on the falling phase of the core tem-
perature cycle suggesting that RLS is related to the circadian rhythm [20].
The differential diagnosis of RLS includes neuropathic paresthesias, positional dis-

comfort, akathisia, sleep starts (hypnic jerks), PLMD, sleep-related leg cramps,
habitual foot tapping, and pain from other conditions. RLS can be distinguished
from positional discomfort as the discomfort is resolved with change of body posi-
tion without the need for continued movement and an urge to move the legs is not
present. Akathisia involves a generalized need to move the body and often in asso-
ciation with neuroleptic medication. Akathisia sufferers frequently report an inner
sense of restlessness rather than leg discomfort and lack the circadian pattern char-
acteristic of RLS. Sleep starts produce brief body movements during the transition
from wake to sleep, and an urge to move is not present. PLMD is a disorder that is
only present during sleep without the essential diagnostic features of RLS. Sleep-
related leg cramps are painful sensations caused by sudden and intense involuntary
contractions of muscles and require stretching the legs to relieve symptoms rather
than movement alone. Patients also describe hardening of the leg muscles that is not
typical of RLS. Residual pain is also usually present with sleep-related leg cramps.
Pain may be worse at rest but does not include an urge to move the legs. The pres-
ence of pain does not exclude a diagnosis or RLS as some patients report their RLS
symptoms as pain; however, the additional characteristic features must also be
present. Habitual foot tapping is easily differentiated from RLS but the absence of
nocturnal predominance of symptoms except when exacerbated by alcohol or medi-
cations taken in the evening.
Primary Versus Secondary Factors
RLS can be classified as primary or secondary. The majority of cases of primary

RLS are hereditary (autosomal dominant) with possible loci on chromosomes 12,
14, and 9. Onset of symptoms before the age of 40 years indicates an increased risk
of RLS occurrence in the family. Physical and neurologic examinations are normal
in the majority of primary RLS cases [21]. A number of secondary causes can con-
tribute to RLS and can be expected to improve when the other disorders are treated.
Iron deficiency has been associated with RLS. Pathologic studies suggest decreased
iron and ferritin in the substantia nigra of RLS patients [22]. Low serum ferritin
levels (< 45 μg/l) correlate significantly with increased RLS symptoms and with
decreased sleep efficiency. A significant correlation to serum iron levels has not
been found [23, 24]. Studies suggest disordered transport of iron from the periphery
to the central nervous system [25]. The most commonly reported neurologic cause
of secondary RLS is peripheral neuropathy [21]. Uremia associated with renal fail-
ure has also been identified as a cause of RLS. A 2008 study found that as many as
58.3% of dialysis patients have RLS [26]. Renal transplantation, unlike dialysis,
causes significant or complete resolution of RLS symptoms [27]. Ekbom made the
first observation that there is a high prevalence of RLS in pregnancy. In a study of
642 pregnant women, 26% were found to be affected by RLS during pregnancy.
RLS was strongly associated with the third trimester [12]. A recent study in a French
population of women in their third trimester of pregnancy found that 32% were
affected by RLS. RLS disappeared after delivery in 64.8% of the women [28]. In a
study of 184 narcolepsy with cataplexy patients, RLS was found to be significantly
more prevalent compared to controls (14.7% vs. 3%). In this population, RLS
symptoms occurred more than 10 years after narcolepsy onset and were less familial
and, in contrast to idiopathic RLS, not more prevalent in women [29]. Transient
RLS has been described in those undergoing spinal anesthesia [30]. Other second-
ary causes of RLS include myelopathy, Parkinson’s disease, and diabetes.
Medications may also precipitate RLS symptoms. Common medications which can
precipitate RLS include those with dopamine receptor-blocking properties (sedat-
ing antihistamines, antipsychotics, and antinausea drugs) and those with serotonin-
promoting activity (most antidepressants with the exception of bupropion, with its
dopamine-promoting properties). There is limited or contradictory evidence for caf-
feine, tobacco, and alcohol as aggravating factors for RLS [31–33]. Multimorbidity
was shown to be a strong risk factor for RLS in two independent German cohort
studies indicating that the severity of underlying morbidity is a stronger risk factor
for RLS than any specific single disease. Furthermore, the association was stronger
with incident than with preexisting RLS, suggesting that RLS developed subse-
quently to preexisting comorbid diseases [34].
Management
The first step in managing RLS is performing a medication review. Medications that
can precipitate or worsen RLS should be discontinued if possible. Secondary causes
should undergo evaluation and treatment as this may resolve or improve symptoms.
Patients with iron deficiency will benefit from iron replacement therapy to target
ferritin levels ≥75 μg/l [35]. Intravenous (IV) iron may be considered when oral
iron is not appropriate provided ferritin ≤100 μg/l. IV iron, unlike oral iron whose
absorption in the gastrointestinal tract is highly variable, helps to achieve higher
levels of peripheral iron required to increase cerebral iron levels. Vitamin C may
enhance oral iron absorption. Non-pharmacologic treatments include improving
sleep hygiene, warm baths, leg massage, and acupuncture. Only one study assessed
the effect of a 12-week moderate-intensity aerobic and resistance exercise program
and found 39% improvement in symptoms with a ceiling effect after 6 weeks [36].
Two studies, to date, have investigated the effectiveness of sequential compression
devices for the treatment of RLS [37, 38]. In a prospective, randomized, double-
blinded, sham-controlled trial, there was significant improvement in RLS severity
and quality of life measures in those using the sequential compression device com-
pared to the sham devices. Complete relief occurred in one-third of the therapeutic
group in this study [38]. There has been one case reporting the improvement in RLS
symptoms with a 4-week near-infrared light therapy [39]. A subsequent study by the
same group, with 34 volunteers, reported significant improvement in RLS symp-
toms in the near-infrared light treatment group compared to the control group [40].
More research is necessary to investigate these and other potential non-pharmacologic
therapies.
Pharmacologic treatment of RLS consists of four classes of medications which
include dopaminergic agents, anticonvulsants, benzodiazepines, and opioids though
other agents have been used (Table 18.3). An evidence-based review produced by a
task force commissioned by the Movement Disorder Society concluded that
levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin were
efficacious for the treatment of RLS, while rotigotine, bromocriptine, oxycodone,
carbamazepine, valproic acid, and clonidine were likely efficacious [41]. Levodopa/
benserazide or levodopa/carbidopa at dosages of 100/25 to 200/50 mg is considered
efficacious for the treatment of RLS. The side-effect profile of levodopa is favor-
able; however treatment carries the highest incidence of augmentation among all
dopamine agonists; hence levodopa is used mainly to treat intermittent RLS [42].
The dopamine agonists ropinirole and pramipexole are FDA approved for the treat-
ment of RLS. Ropinirole (0.25–4 mg, mean 2 mg) and pramipexole (0.75 mg) are
efficacious for treating RLS in patients with moderate to severe symptoms. Several
studies have demonstrated the effectiveness of the rotigotine transdermal patch for
Table 18.3 Treatment for RLS

Non-pharmacological treatments
Improved sleep hygiene
Exercise
Massage
Acupuncture
Sequential compression devices
Near-infrared light
Pharmacological treatments
Dopaminergic agents
Antiepileptics
Benzodiazepines
Opioids
Iron
treatment of RLS including a randomized, double-blinded, placebo-controlled trial

including 505 participants with moderate to severe RLS [43–47]. Ergot-derived
dopamine agonists, including bromocriptine, pergolide, and cabergoline, require
special monitoring due to increased incidence of cardiac valvular fibrosis and other
fibrotic side effects. While efficacious, these agents are rarely used currently.
Augmentation is the main side effect of long-term dopaminergic treatment of RLS
and is characterized by an earlier onset of symptoms (≥ 4 hours) or a shorter time
advance (2–4 hours) along with other required features such as an overall increase
in severity of symptoms, a faster onset of symptoms at rest, and extension of the
symptoms to other body parts, notably the upper extremities. A paradoxical response
to dopaminergic agonists (worsening of symptoms with dosage increase and vice
versa) constitutes an alternative diagnostic criterion [48, 49]. Mild cases may be
followed with either a trial of judicious dose increase or dividing the dose and ear-
lier dose administration, while in more severe cases, a complete change in treatment
is indicated [49]. Ferritin may play a role as a biomarker for patients likely to
develop augmentation [50], and treatment with oral/intravenous iron should be
strongly considered in combination with other measures if ferritin levels <50–75 μg/l.
Side effects of dopaminergic agents include excessive daytime sleepiness, nausea,
vomiting, hallucinations, and insomnia. Dopaminergic therapy for RLS has also
been associated with impulse control behaviors such as compulsive gambling and
shopping. Antiepileptics used in the treatment of RLS include carbamazepine, gab-
apentin, pregabalin, and lamotrigine. Antiepileptics may be considered first-line
therapy in those with concomitant neuropathy or painful leg symptoms. Gabapentin
has been reported to be as effective as ropinirole in improving the sensorimotor
symptoms in idiopathic RLS [51]. Pregabalin also has been demonstrated to improve
RLS symptoms in double-blinded, placebo-controlled trial [52, 53]. Of the benzo-
diazepines, clonazepam is the best documented for treatment of RLS. Side effects
of these agents include sleepiness and tolerance. Opioids are used in the treatment
of RLS; however at sufficient analgesic doses, they cause a series of minor and
major adverse effects including sedation, fatigue, and constipation. Short-acting
agents including hydrocodone, oxycodone, and codeine may be used for intermit-
tent or nightly symptoms. Tramadol has also been used. For more severe symptoms,
low dose of longer-acting opioids such as oxycodone and methadone is usually very
effective and safe in appropriate patients.
Periodic Limb Movement Disorder
Initially termed “nocturnal myoclonus” by the English neurologist Charles P

Symonds in 1953, the term periodic movements in sleep was suggested by Coleman
in 1980 [54, 55]. PLMD is characterized by periodic episodes of repetitive, highly
stereotyped, limb movements that occur during sleep (PLMS) and by clinical sleep
disturbance that cannot be accounted for by another primary sleep disorder. PLMS
typically involve the extension of the big toe, often in combination with partial flex-
ion of the ankle, the knee, and sometimes the hip. Similar movements can occur in
the upper limb. They can occur individually in association with arousals or awaken-
ings from sleep. PLMS may occur unilaterally, alternate between legs, or occur
simultaneously in both legs. Significant night-to-night variability may be present.
Demographics
In a study of randomly selected community-dwelling persons 65 years and older,

the prevalence rate of PLMS was 45% [56]. Considerable clinical evidence suggests
that although PLMS are common, the diagnosis of PLMD is extremely rare in adults
and is best thought of as a diagnosis of elimination.
Diagnosis
The diagnosis of PLMD in adults according to the ICSD-3 requires the following:
(a) Polysomnography demonstrates repetitive, highly stereotyped, limb movements
that are 0.5–5 seconds in duration, of amplitude greater than or equal to 25% of toe
dorsiflexion during calibration, in a sequence of four or more movements, and sepa-
rated by an interval of more than 5 seconds and less than 90 seconds. (b) The PLMS
index exceeds 5/hour in children and 15/hour in most adult cases. (c) There is clini-
cal sleep disturbance or a complaint of daytime fatigue. (d) The PLMS are not better
explained by another current sleep disorder, medical or neurological disorder, men-
tal disorder, medication use, or substance use disorder [1] (Table 18.4).
Table 18.4 Diagnostic criteria for periodic limb movement disorder (PLMD)
Polysomnography demonstrates repetitive, highly stereotyped, limb movements
The periodic limb movement index exceeds 15/hour in most adult cases
Clinical sleep disturbance or daytime fatigue
Limb movements during sleep are not better explained by another disorder
Associated Features
Patients often report history of sleep onset or maintenance problems, unrefreshing

sleep, or excessive daytime hypersomnolence or fatigue. However, the presence of
insomnia or hypersomnia with PLMS is insufficient to diagnose PLMD, as in most
cases, the sleep disturbance is better explained by another underlying sleep disorder.
In that case, PLMS are solely noted as polysomnographic findings. PLMS have been
associated with a number of sleep disorders including narcolepsy, RBD, and sleep
apnea as well as with a number of neurologic disorders. PSG is necessary to exclude
sleep-related breathing disorders as the cause of the PLMS. Bed partner observations
of leg movements may help in the clinical evaluation of PLMS. PLMD cannot be
diagnosed if sleep disruption of the bed partner is the only complaint. PLMS should
also be distinguished from other movements such as change in body position, stretch-
ing, or leg cramps. Movements are reported as an index of the number of leg move-
ments per hour of sleep called the PLM index. PLMS may produce no change in the
EEG or associated arousal or may be associated with K complexes, K alpha com-
plexes, alpha activity, or other evidence of arousal. In a study of 23 patients with
PLMs and/or RLS, 60% of PLMS were associated with microarousals, 4% were
associated with slow-wave activity, and 36% showed no electroencephalographic
changes. There was a prevalence of leg movements with microarousals in stage N1
and N2 sleep, while PLMS without microarousals were prevalent in slow-wave
sleep [57].
PLMS are usually absent during rapid eye movement (REM) sleep. Two types of
PLMS have been described. Type I has a peak frequency between midnight and
3 a.m. followed by a decrease in late morning hours and is seen in those with RLS
and idiopathic PLMS. In Type II, leg movements are more evenly distributed
throughout the night and are associated with sleep-related breathing disorders,
RBD, and narcolepsy.
The differential diagnosis includes sleep starts, normal phasic REM activity, and
fragmentary myoclonus. Sleep starts are limited to the transition from wakefulness
to sleep and are shorter than PLMS. Normal phasic REM activity is usually associ-
ated with bursts of rapid eye movements and does not have the periodicity of
PLMS. Fragmentary myoclonus activity is briefer and is primarily an EMG diagno-

sis with little or no visible movement.
Management
Similar to management of RLS, an investigation to identify secondary causes of

PLMD is recommended. Consideration should be given to discontinuing medica-
tions that may contribute to PLMD. The decision to treat PLMD should be based on
signs of EEG arousal, disturbed nocturnal sleep, or associated daytime mental or
functional impairment. Medication treatment is similar to that of RLS and includes
dopaminergic agents, anticonvulsants, benzodiazepines, and opioids. Given that
many patients may not be aware of PLMS, assessment of response to therapy is
dependent on improvement in sleep quality and daytime symptoms, including
fatigue. In some instances, PSG performed on treatment is required to assess
response to therapy.
Sleep-Related Leg Cramps
Sleep-related leg cramps are painful sensations caused by sudden and intense invol-
untary contractions of muscles or muscle groups, usually in the calf or small mus-
cles of the foot and occurring during the sleep period. The lay term is “Charley
horse.” These episodes may last up to a few minutes, awaken the patient, and inter-
rupt sleep.
Diagnosis
The diagnosis of sleep-related leg cramps according to ICSD-3 requires the follow-
ing: (a) A painful sensation in the leg or foot is associated with sudden muscle hard-
ness or tightness indicating a strong muscle contraction. (b) The painful muscle
contraction in the legs or feet occurs during the sleep period, although they may
arise from either wakefulness or sleep. (c) The pain is relieved by forceful stretching
of the affected muscles, releasing the contraction [1] (Table 18.5).
Table 18.5 Diagnostic criteria for sleep-related leg cramps

Painful sensation in the leg or foot associated with strong muscle contraction
Painful muscle contraction occurs during the sleep period
Pain is relieved by forceful stretching of the affected muscles
Demographics
Sleep-related leg cramps appear to occur at any age but are more common and fre-
quent in the elderly. In an epidemiologic study in children, an overall incidence of
7.3% was reported [58]. In a general practice-based study of 233 people older than
age 60, almost one-third had cramps during the previous 2 months, and this increased
to one-half in those older than 80. In addition, 40% had cramps more than 3 times a
week and 6% reported daily cramps [59]. A study of outpatient veterans found that
56% reported leg cramps [60]. Sleep-related leg cramps may appear or worsen dur-
ing pregnancy and were reported in 75% of women in their third trimester in a study
of 12 women [61].
The differential diagnosis of sleep-related leg cramps includes muscle strain, dysto-
nia, claudication, RLS, PLMS, and nocturnal myoclonus. The pain associated with
muscle strain is often associated with overuse or injury and does not usually occur
only at night. The pain associated with claudication is usually relieved by rest. RLS
involves an urge to move the legs with temporary relief with movement and does not
require stretching of the muscle. PLMS occur during sleep and are not associated
with pain or muscle hardening. Muscle cramps may also be a feature of a number of
other neurologic conditions; however these cramps are not usually restricted to
nighttime or the legs alone.
Associated Features
During the cramp the muscles are firm and tender. Tenderness and discomfort in the
muscle may persist for several hours after the cramping. Delayed sleep onset and
awakenings from sleep are often present with persistent discomfort delaying return
to sleep. Patients may need to get out of bed to stand and stretch to alleviate symp-
toms. Sleep-related leg cramps are not sleep-stage specific as they may occur in any
sleep stage. Although sleep-related leg cramps are idiopathic in most individuals, a
large number of potential contributing factors have been reported. Medications that
have been reported to cause leg cramps include diuretics, nifedipine, statins,
β-agonists, steroids, morphine, cimetidine, penicillamine, and lithium. Medical
conditions associated with sleep-related leg cramps include uremia, diabetes, thy-
roid disease, hypoparathyroidism, hypomagnesemia, hypocalcemia, hyponatremia,
and hypokalemia. Additional predisposing factors include vigorous exercise during
the day, oral contraceptive use, peripheral vascular disease, and dehydration. PSG is
not routinely recommended for the evaluation of sleep-related leg cramps, but may
show bursts of increased electromyographic activity over the affected area.
Treatment
A careful history to identify and treat any precipitating factors is important in

patients with sleep-related leg cramps. Patients should be reassured regarding the
benign nature of the disease. Adjustment of possible contributing medications
should be considered. Cramps, once present, can be aborted by forcible dorsiflexion
of the foot with the knee extended. This is often discovered by patients while deal-
ing with cramps acutely at night and may be all that is required when sleep-related
leg cramps are infrequent. Passive massage or stretching may also help. However,
research data on the efficacy of stretching exercises are contradictory. A randomized
controlled trial of 80 adults above 55 years found that stretching of the calves and
hamstrings before sleep effectively reduced the frequency and severity of leg
cramps, while a previous trial found this treatment to be ineffective [62].
Pharmacological treatment of leg cramps may be necessary when symptoms are
severe and frequent. A number of treatments have been investigated. Quinine, an
alkaloid agent, reduces the excitability of the motor end plate to nerve stimulation
and increases the refractory period of skeletal muscle contraction. It has been used
with great efficacy to treat leg cramps since 1940 though there were significant
concerns regarding the risk/benefit ratio with this drug [63, 64]. In 1995, the FDA
concluded that the risks of quinine outweighed any possible benefit and ordered a
stop to the marketing of quinine for off-label use for prevention or treatment of
sleep-related leg cramps. Quinine-induced thrombocytopenia and hypersensitivity
reactions are among the most serious complications of quinine. Naftidrofuryl oxa-
late, a vasodilator, significantly reduced the frequency of cramps and increased the
number of cram-free days by a third in a double-blind, placebo-controlled trial in 14
patients [65]. Orphenadrine citrate, an anticholinergic, reduced the frequency of leg
cramps by a third in the majority of patients in a double-blind crossover trial [66].
Verapamil at 120 mg given at bedtime for 8 weeks resulted in an improvement in
cramp symptoms in seven out of eight patients during an uncontrolled study [67].
Magnesium was effective in treating sleep-related leg cramps in pregnant women in
several double-blind, randomized, placebo-controlled studies [68–70]; however, no
significant effect was seen in the study of nonpregnant adults [71–73]. It was sug-
gested that possible underlying pregnancy-induced magnesium deficiency may
have led to positive results in pregnant patients and measurements of baseline and
posttreatment serum magnesium in all patients should be conducted to highlight
that finding. Vitamin E use yielded conflicting results among two randomized
blinded studies [74, 75]. In the only randomized, double-blind, placebo-controlled
study evaluating the efficacy of vitamin B complex capsules, 86% of the patients
had prominent remission of leg cramps at 3 months compared to placebo [76].
Several studies have demonstrated the effectiveness of gabapentin in the treatment
of leg cramps in those with neurologic conditions though its usefulness in idiopathic
leg cramps remains unclear [77, 78]. The effectiveness of lidocaine injection at the
gastrocnemius trigger point and botulinum injection into calf muscles for treatment
of sleep-related leg cramps has also been reported [79, 80]. Finally, continuous
positive airway pressure (CPAP) cured leg cramps in patients in a report of four
patients with comorbid obstructive sleep apnea (OSA) [81]. More research in this
area is needed.
Sleep-Related Bruxism
One of the first reports of bruxism was from Black in 1886; however, the term brux-
ism was introduced by Miller in 1938 [82, 83]. Sleep-related bruxism is an oral
activity characterized by grinding or clenching of the teeth during sleep usually
associated with sleep arousals. Jaw activity during sleep includes tonic contractions
and rhythmic masticatory muscle activity (RMMA) that occurs at about 1 Hz.
Teeth-grinding sounds occur when these contractions are strong during sleep and
are present in about 20% of episodes [84].
Demographics
Bruxism has the highest prevalence in childhood which decreases with increasing
age. One study reported an overall prevalence of 8% with a frequency of 13% in
those 18–29 years of age and only 3% in older individuals [85]. No gender differ-
ences have been found [86]. A familial pattern is seen in approximately 20–35% of
patients [87]. Moderate to severe tooth wear and jaw discomfort is seen in about
5–10% of the population [84].
Diagnosis
The diagnosis of sleep-related bruxism according to the ICSD-3 requires the fol-
lowing: (a) The patient reports or is aware of tooth-grinding sounds or tooth clench-
ing during sleep. (b) One or more of the following are present: abnormal wear of the
teeth, transient morning jaw muscle discomfort, fatigue or pain, and/or jaw locking
[1] (Table 18.6). Although PSG is not required for diagnosis, bruxism is ideally
recorded via the masseter EMG showing characteristic RMMA either a phasic pat-
tern of activity at 1 Hz frequency lasting 0.25–2 s, sustained tonic activity lasting
longer than 2 s, or a mixed pattern. Simultaneous audiovisual recording increases
diagnostic reliability distinguishing between RMMA episodes and orofacial and
other muscular activities that occur during sleep (swallowing, sleep talking, etc.).
The RMMA episodes are associated with sleep arousal and are preceded by signs of
increased autonomic activity (such as increased heart rate). PSG will also assess
comorbid sleep disorders that may worsen bruxism such as OSA or RBD [88].
Sleep-related bruxism must be distinguished from other nocturnal faciomandibular

activities including idiopathic myoclonus, RBD, parasomnias such as night terrors
and confusional arousals, and dyskinetic jaw movements persisting in sleep. Very
rarely, nocturnal partial or complex seizures may present as isolated bruxism.
Associated Features
Sleep-related bruxism can lead to abnormal wear of the teeth, tooth pain, jaw mus-
cle pain, or temporal headache. Fractured teeth and buccal lacerations and temporo-
mandibular joint pain can also occur as a consequence. Sleep disruption is also
prevalent. Over time, hypertrophy of the masseter and other facial muscles can
develop. Sleep bruxism has been attributed to several etiologies though the theory
that malocclusion was the cause has fallen out of favor. Presumed mechanisms
include sleep arousal, autonomic sympathetic cardiac activation, genetic predisposi-
tion, psychological components, and comorbidities such as sleep-disordered breath-
ing and acid reflux. Medications such as selective serotonin reuptake inhibitors
(SSRI) and amphetamines have been associated with bruxism. Bruxism is fre-
quently associated with Down’s syndrome, autism, and ADHD [89, 90]. Although
bruxism can occur during any sleep stage, including REM sleep, it is most often
seen during arousals from stage N1 and N2 sleep.
Management
Therapies for sleep-related bruxism can be divided into orthodontic, behavioral, and
pharmacologic. Non-pharmacological treatments include occlusal bite splints that
are extensively used in clinical practice to provide protection against tooth damage,
although there is a lack of evidence to support their role in halting bruxism [88].
Furthermore, side effects of such treatment include changes in dental occlusion,
dental hypersensitiveness, and worsening of orofacial pain and SDB by reducing the
intraoral cavity space [91]. Patients should be followed by a dentist who can
Table 18.6 Diagnostic criteria for sleep-related bruxism

Tooth-grinding sounds or tooth clenching during sleep
One or more of the following are present: abnormal wear of the teeth, jaw muscle discomfort,
fatigue or pain, and jaw lock upon awakening
monitor dental wear. Excessively worn teeth may need to be crowned. OSA is a risk
factor for sleep-related bruxism, and successful treatment of sleep-disordered
breathing may eliminate bruxism during sleep [92]. Psychological counseling may
be helpful in stress-related cases of bruxism. Albeit, there is little evidence to sup-
port the use of antidepressants to treat bruxism. Amitriptyline (a tricyclic antide-
pressant) was found to be ineffective, and SSRI worsened bruxism in some reports
[93, 94]. Benzodiazepines and muscle relaxants may be necessary in more severe
cases though they may contribute to daytime sleepiness. Randomized, controlled,
and double-blinded studies investigating the pharmacologic therapies for sleep-
related bruxism are lacking. Other medications that have been reported to be used
for bruxism include propranolol, l-dopa, pergolide, bromocriptine, clonidine, and
gabapentin [95–99]. A recent systematic review of four randomized controlled trials
assessing the effect of botulinum toxin in the treatment of bruxism concluded that
botulinum toxin injection in the masseter muscles resulted in a significant reduction
of the frequency and severity of bruxism episodes, as well as pain intensity and
improved patients’ quality of life. In addition, doses <100 IU are safe and effective
treatment with a low risk of adverse side effects. Therefore the authors recom-
mended botulinum toxin in patients with severe bruxism who did not respond to
conventional therapy [100].
Sleep-Related Rhythmic Movement Disorder
Described in 1905 by Zappert as “jactatio capitis nocturna” and independently by

Cruchet as “rhythmie du sommeil,” the term “rhythmic movement disorder” was
adopted by the ICSD in 1990. RMD is characterized by repetitive, stereotyped, and
rhythmic motor behaviors that occur predominantly during drowsiness or sleep and
involve large muscle groups. Initially classified as a sleep-wake transition disorder,
the revised ICSD reclassified RMD under the heading of sleep-related movement
disorders. Sleep-related rhythmic movements are normal in children, and a disorder
should be diagnosed when significant consequences are present. RMD is typically
seen in infants and children. Body rocking, head banging, and head rolling are sub-
types of RMD. Combined types may also be observed.
Demographics
RMD is most commonly observed in children. The incidence of RMD is 66% in

9-month-old infants and decreases to 8% in 4-year-olds [101]. In one study, head
banging persisted beyond the age of 4 in 30% of patients but usually ended by age 10
Table 18.7 Diagnostic criteria for sleep-related rhythmic movement disorder (RMD)
Repetitive, stereotyped, and rhythmic motor behaviors
Involving large muscle groups
Movements are predominantly sleep related or occur near nap or bedtime
A significant complaint such as interference with sleep, significant impairment in daytime
function, or self-inflicted bodily injury is present
Rhythmic movements are not better explained by another disorder
[102]. Though most common in children, RMD has also been reported in adolescents
and adults. When observed in older children and adults, there have been conflicting
reports regarding persistent RMD and its association with neurodevelopmental and
psychiatric disorders as cases in adults of normal intelligence have been reported
[103–105]. Therefore, there is insufficient evidence to fully understand the true natu-
ral history of the condition. No sex differences have been found in patients with RMD.
Diagnosis
RMD can be recognized by its characteristic clinical features. However, in some

instances PSG may be useful. The diagnosis of RMD according to the ICSD-3
requires the following: (a) The patient exhibits repetitive, stereotyped, and rhythmic
motor behaviors involving large muscle groups. (b) The movements are predomi-
nantly sleep related, occurring near nap or bedtime or when the individual appears
drowsy or asleep. (c) The behaviors result in a significant complaint as manifest by
at least one of the following: interference with normal sleep, significant impairment
in daytime function, or self-inflicted bodily injury or likelihood of injury if preven-
tive measures are not used. (d) The rhythmic movements are not better explained by
another movement disorder or epilepsy [1] (Table 18.7).
Associated Features
While PSG have shown rhythmic movements to occur most often in stage N1 and
N2 sleep, there have been reports of RMD in REM (24%) [104, 106, 107]. In the
case of RMD occurring in REM sleep, concurrent RBD has not been reported
[104, 107, 108]. Exclusively REM-RMD occurs more frequently in adults. The
most common subtypes of RMD are body rocking (19.1%), head banging (5.1%),
and head rolling (6.3%). Body rolling, head rolling, and leg banging subtypes have
also been described. As noted previously patients may also have combinations of
the noted subtypes. Sleep is not fragmented by RMD and sleep stages do not
usually change as a result of movement. RMD does not usually interrupt sleep and
patients have minimal recall. A review of ten subjects with RMD persisting beyond
5 years of age found a strong association with ADHD [104]. Several studies have
reported RMD in adults with OSA with RMD initiated by arousals at the termina-
tion of the apneas. Improvement in RMD was noted with treatment of OSA with
CPAP [109–111]. PSG is useful to uncover RMD aggravated by another sleep
disorder, such as OSA, RBD, and RLS. On PSG the frequency of movements
ranges from 0.5 to 2 Hz.
The clinical history of RMD is usually clear though the differential diagnosis of
RMD includes RLS and sleep-related epilepsy. In contrast to RLS, the movements
of RMD are continuous for short periods of time rather than periodic jerking.
Electroencephalographic studies are normal between RMD episodes in most indi-
viduals. Polysomnographic findings of RMD may be confused with bruxism, thumb
sucking, and rhythmic sucking of the lips or a pacifier. RMD should also be distin-
guished from akathisia which is not sleep related and involves a feeling of general-
ized restlessness.
Treatment
For the majority of RMD patients, no treatment other than reassurance is required.
Parents should be advised that neurologic damage is unlikely and that the child will
outgrow the problem. RMD has rarely been associated with head injury, carotid
artery dissection, and ocular injury [112–114]. In cases where there is concern
regarding serious injury, treatment is warranted. There is a lack of systematic stud-
ies assessing the risk of injury or daytime consequences of RMD and clinical trials
evaluating its treatment. Contemporary management of RMD is guided by clinical
experience and reports of case studies. Hypnosis was reported as an effective treat-
ment in a 26-year-old woman with body rocking since infancy [115]. Other treat-
ments that have been used include behavioral interventions [116]. Almost complete
resolution of rhythmic movements was noted in six children with 3 weeks of con-
trolled sleep restriction with hypnotic administration in the first week [117].
Tricyclic antidepressants have also been used to treat RMD. One study documented
failure of doxepin, amitriptyline, and imipramine, while another reported success
with imipramine [118, 119] . In one report citalopram at a dose of 20 mg was
effective in eliminating head banging in a 5-year-old with ADHD [120]. Several

studies have demonstrated the utility of low-dose clonazepam. Clonazepam at a
starting dose of 0.5 mg was not sufficient to decrease the intensity or frequency of
events, but 1 mg was found to be effective [121, 122]. The use of the dopamine
antagonists haloperidol and pimozide decreased the intensity and duration of head
punching in a 17-year-old boy [123].
Propriospinal Myoclonus at Sleep Onset
Propriospinal myoclonus at sleep onset (PSM) was first described in 1997 in

three patients with jerks occurring only during relaxed wakefulness preceding
sleep and at the sleep-wake transition (N1 sleep) and quickly disappears when
N2 sets in [124–126]. Few reports showed persistence of jerks during sleep
[127, 128]. Myoclonus is termed “propriospinal” when it doesn’t remain
restricted to its segmental origin and it propagates along the spinal cord with a
slow conduction velocity. PSM usually originates from the thoracoabdominal
myelomere and less often from cervical ones. It provokes spontaneous and
repetitive flexion of the trunk and neck. Less frequently an extension pattern has
been reported.
Finally, a striking shift came with the first description of a case of functional
(psychogenic) PSM and with the paper by Kang and Shon reporting that the typical
pattern of PSM may be mimicked voluntary by healthy volunteers [129, 130].
Afterward, a number of cohorts with functional PSM have been described and so
far, and more than 50% of all the reported cases of PSM appear to be functional
[131]. Hence, our current knowledge of PSM presents heterogeneous features that
are difficult to disentangle.
Diagnosis
PSM was previously classified among the “isolated symptoms, apparently normal
variants and unresolved issues.” ICSD-3 reclassified PSM at sleep onset among the
“sleep-related movement disorders” since it is very rarely associated with spinal
injury or disease and most patients with this disorder have a normal spinal MRI. Its
diagnosis compromises a combination of all the following criteria: (a) A complaint
of sudden jerks, mainly of the abdomen, trunk, and neck. (b) The jerks appear dur-
ing relaxed wakefulness and during sleep-wake transition. (c) The jerks disappear
upon mental activation and with onset of stable sleep. (d) The jerks are so bother-
some, and they preclude sleep onset. (e) The disorder is not better explained by
another sleep, mental, medical, or neurological disorder, as well as by a medication
or substance use disorder [1] (Table 18.8).
Table 18.8 Diagnostic criteria for propriospinal myoclonus at sleep onset

Sudden jerks, mainly of the abdomen, trunk, and neck
The jerks appear during relaxed wakefulness and during sleep-wake transition
The jerks disappear upon mental activation and with onset of stable sleep
The jerks are so bothersome, and they preclude sleep onset
The disorder is not better explained by another sleep, mental, medical, or neurological disorder,
as well as by a medication or substance use disorder
Demographics
Epidemiologic data are lacking. PSM appears to be typical of middle-aged subjects

and extremely rare in children [131]. PSM is considered position dependent, with
worsening in the supine position in >50% of the cases. In at least one-third of the
cases, the movements are stimulus-sensitive.
Associated Features
PSM appears to be idiopathic in around 80% of cases. Etiology is postulated to

involve a functional abnormality of the spinal generator with afferent stimuli from
the distal part of the spinal cord triggering hyperexcitability of the myoclonic vol-
leys [131]. The remainder consists of “symptomatic forms” that include a wide
range of organic lesions of the spine or other central nervous system levels and
medical conditions such as herpes zoster, Lyme disease, hepatitis C, myasthenia
gravis, breast cancer, and Escherichia coli infection. Isolated reports associated the
development of PSM with use of certain drugs such as interferon-alpha, intrathecal
bupivacaine, ciprofloxacin, and cannabis; however, causality remains to be proven
[132–136]. Sleep-onset insomnia is a common and peculiar feature of PSM. The
movements disappear once stable sleep is reached but may reappear during arous-
als or awakenings with similar features. Patients may develop a fear of falling
asleep, anxiety, and depression. PSM has also been described in association with
RLS [137]. Remarkably, in those patients PSM coexisted with prominent PLM
during relaxed wakefulness and significant restlessness and leg discomfort, typi-
cal of RLS.
The sleep-wake transition stage appears to act as a pacemaker for many sleep-related
movement disorders besides PSM, such as hypnic jerks and restless legs syndrome
(RLS). Hypnic jerks similarity to PSM might be the caudal propagation from facial
and cervical muscles but is easily differentiated given the absence of periodicity and
slow propagation velocity. Hypnic jerks do not typically cause sleep-onset insomnia, a
hallmark feature of PSM. PLMS generally spare the trunk and abdomen and are longer
in duration. RLS is differentiated from PSM given associated prominent leg discom-
fort. Functional (psychogenic) PSM mimics a typical PSM presentation in healthy
adults; however the muscle recruitment pattern and the spread velocity differ [130].
Associated psychological disturbances as well as intraindividual variability over time
are also common features on functional PSM. Differentiating PSM and tic disorders
should also be taken into account. The “tic-like” myoclonus with jerks, involving the
trunk and arms, if present, lacks the positional triggering (supine position) and is not
usually limited to the trunk. Finally, epileptic myoclonus is not confined to relaxed
wakefulness, and electroencephalography may show epileptic discharges.
Treatment
There are no current guidelines for idiopathic PSM treatment. Treatment of under-
lying condition is mainstay of symptomatic PSM management, even if this doesn’t
lead to a complete PSM resolution in most cases [131]. For example, almost com-
plete resolution of PSM anterior cervical discectomy with fusion significantly
improved PSM in a patient with cord compression in the absence of myelopathy
[138]. Clonazepam at doses 0.5–2 mg given at bedtime to 65 patients was an effec-
tive treatment in 52% of patients [139]. Anecdotal use of other medical treatments
that were sporadically effective in some cases include valproate, SSRI, zonisamide,
and intrathecal infusion of baclofen [131, 140–142]. A case study of a 62-year-old
male patient with comorbid PSM at sleep onset and OSA reported that CPAP
decreased the frequency of the events [143].
Sleep-Related Movement Disorder Due to a Medical Disorder
The ICSD-3 intends this diagnosis for sleep-related movement disorders due to an
underlying medical or neurological condition that does not meet criteria for another
specific movement disorder. Often, this is a transient diagnosis until the underlying
medical or neurological condition is fully diagnosed, and therefore the latter will
take precedence in terms of the final diagnosis.
Diagnosis
According to ICSD-3, all the three following criteria must be met for diagnosis: (a)
The patient manifests sleep-related movements that disturb sleep or its onset. (b)
The movement disorder occurs as a consequence of a significant underlying medical
or neurological condition. (c) The symptoms are not better explained by another
sleep-related movement disorder, other sleep or mental disorder, or substance use
[1] (Table 18.9).
leep-Related Movement Disorder Due to a Medication

S
or Substance
The ICSD-3 intends this diagnosis for sleep-related movement disorder due to a
medication or substance that does not meet criteria for another specific movement
disorder. Since movement abnormalities during sleep or wake is a common and
often anticipated complication of multiple medications or substances, the clinician
must not resort to this diagnosis unless the sleep-related aspects of the abnormal
movements are the focus of independent clinical attention.
Diagnosis
According to ICSD-3, all the three following criteria must be met for diagnosis: (a)
The patient manifests sleep-related movements that disturb sleep or its onset. (b)
The movement disorder occurs as a consequence of a current medication or sub-
stance use or withdrawal from a wake-promoting medication or substance. (c) The
symptoms are not better explained by another sleep-related movement disorder
and other untreated sleep, medical, neurological, or mental disorder [1]
(Table 18.10).
Table 18.9 Diagnostic criteria for sleep-related movement disorder due to a medical disorder
The patient manifests sleep-related movements that disturb sleep or its onset
The movement disorder occurs as a consequence of a significant underlying medical or
neurological condition
The symptoms are not better explained by another sleep-related movement disorder, other sleep
or mental disorder, or substance use
Table 18.10 Diagnostic criteria for sleep-related movement disorder due to a medication or
substance
The patient manifests sleep-related movements that disturb sleep or its onset
The movement disorder occurs as a consequence of a current medication or substance use or
withdrawal from a wake-promoting medication or substance
The symptoms are not better explained by another sleep-related movement disorder and other
untreated sleep, medical, neurological, or mental disorder
Conclusion
Sleep-related movement disorders include a varied group of diseases which are

quite prevalent and can cause significant sleep disturbance and impairment in day-
time functioning and compromise quality of life. These disorders are frequently
encountered yet may be confused or misdiagnosed by healthcare professionals.
Increasing awareness of these conditions is necessary to allow for prompt identifica-
tion and management as this can significantly improve quality of life.
Summary of Keypoints
• Restless legs syndrome (RLS) is a common sensorimotor disorder charac-
terized by a distressing urge to move the legs and sometimes other parts of
the body such as the arms. RLS affects approximately 10% of US adults.
Difficulty falling asleep may frequently be associated with moderate to
severe RLS.
• The diagnosis of RLS is based on clinical criteria and does not require a
polysomnogram unless an additional sleep disorder is suspected.
• The majority of cases of primary RLS are hereditary (autosomal domi-
nant). Causes of secondary RLS include iron deficiency, peripheral neu-
ropathy, uremia associated with renal failure, and pregnancy. Common
medications which can precipitate RLS include tricyclic antidepressants,
SSRI, lithium, antihistamines, and dopamine antagonists. RLS affects
approximately 10% of US adults.
• RLS diagnostic criteria:
1. Uncomfortable sensation in the legs associated with an urge to move.
2. Symptoms are worse at rest.
3. Symptoms are temporarily relieved by movement.
4. Symptoms are worse or only occur at night.
• Medications that can worsen RLS should be discontinued, and secondary
causes should be evaluated and treated.
• Management strategy consists of discontinuation of medications that can
worsen RLS, treatment of secondary causes of RLS such as iron deficiency,
conservative treatment, and pharmacologic treatment. Four classes of med-
ications have been used for the treatment of RLS, including dopaminergic
agents, anticonvulsants, benzodiazepines, and opioids.
• Periodic limb movement disorder (PLMD) is a sleep disorder character-
ized by rhythmic movements of the limbs during sleep, involving the legs,
but upper extremity movements may also occur. Movements tend to cluster
in episodes that last anywhere from a few minutes to several hours.
• The causes of PLMD are unknown. However, people with a variety of
medical problems, including Parkinson’s disease and narcolepsy, may
have frequent periodic limb movements in sleep. PLMD may be caused by

medications, most notably antidepressants. Periodic leg movements
(PLMs) occur in at least 85% of people with RLS. PLMS are not usually
seen in REM sleep.
• Rhythmic movement disorder (RMD) occurs mainly in infants and chil-
dren, and it is usually a benign condition that does not require intervention.
• Propriospinal myoclonus at sleep onset (PSM) is a rare disorder, mostly
idiopathic, that causes severe sleep-onset insomnia. There are no current
guidelines for treatment of PSM.
References
1. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd

edition. Darien, IL.: American Academy of Sleep Medicine; 2014.
2. Willis T. The London practice of physick: or the whole practical part of physick contained
in the works of Dr. Willis. Faithfully made English, and printed together for the publick
good. 1685.
3. Ekbom K-A FH. Restless legs, a clinical study of a hitherto overlooked disease in the legs
characterized by peculiar paresthesia (“anxietas tibiarum”), pain and weakness and occur-
ring in two main forms, asthenia crurum paraesthetica and asthenia crurum dolorosa. A short
review of paresthesias in general. Stockholm. 1945.
4. Allen RP, Barker PB, Wehrl FW, Song HK, Earley CJ. MRI measurement of brain iron in
patients with restless legs syndrome. Neurology. 2001;56(2):263–5.
5. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless legs syndrome:
18F-dopa and 11C-raclopride PET studies. Neurology. 1999;52(5):932–7.
6. Winkelmann J, Wetter TC, Collado-Seidel V, et al. Clinical characteristics and frequency of the
hereditary restless legs syndrome in a population of 300 patients. Sleep. 2000;23(5):597–602.
7. Chen NH, Chuang LP, Yang CT, et al. The prevalence of restless legs syndrome in Taiwanese
adults. Psychiatry Clin Neurosci. 2010;64(2):170–8.
8. Cho SJ, Hong JP, Hahm BJ, et al. Restless legs syndrome in a community sample of Korean
adults: prevalence, impact on quality of life, and association with DSM-IV psychiatric disor-
ders. Sleep. 2009;32(8):1069–76.
9. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome.
Sleep Med. 2004;5(3):293–9.
10. Phillips B, Hening W, Britz P, Mannino D. Prevalence and correlates of restless legs syn-
drome: results from the 2005 National Sleep Foundation Poll. Chest. 2006;129(1):76–80.
11. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact:
REST general population study. Arch Intern Med. 2005;165(11):1286–92.
12. Manconi M, Ulfberg J, Berger K, et al. When gender matters: restless legs syndrome. Report
of the "RLS and woman" workshop endorsed by the European RLS Study Group. Sleep Med
Rev. 2012;16(4):297–307.
13. Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs
symptoms in adults. Arch Intern Med. 2000;160(14):2137–41.
14. Ferri R, Manconi M, Plazzi G, et al. Leg movements during wakefulness in restless legs
syndrome: time structure and relationships with periodic leg movements during sleep. Sleep
Med. 2012;13(5):529–35.
15. Montplaisir J, Lapierre O, Warnes H, Pelletier G. The treatment of the restless leg syndrome
with or without periodic leg movements in sleep. Sleep. 1992;15(5):391–5.
16. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special
considerations, and epidemiology. A report from the restless legs syndrome diagnosis and
epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4(2):101–19.
17. Pearson VE, Allen RP, Dean T, Gamaldo CE, Lesage SR, Earley CJ. Cognitive deficits asso-
ciated with restless legs syndrome (RLS). Sleep Med. 2006;7(1):25–30.
18. Gonzalez-Latapi P, Malkani R. Update on restless legs syndrome: from mechanisms to treat-
ment. Curr Neurol Neurosci Rep. 2019;19(8):54.
19. Michaud M, Chabli A, Lavigne G, Montplaisir J. Arm restlessness in patients with restless
legs syndrome. Mov Disord. 2000;15(2):289–93.
20. Trenkwalder C, Hening WA, Walters AS, Campbell SS, Rahman K, Chokroverty S. Circadian
rhythm of periodic limb movements and sensory symptoms of restless legs syndrome. Mov
Disord. 1999;14(1):102–10.
21. Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology.
1996;47(6):1435–41.
22. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired
brain iron acquisition in restless legs syndrome. Neurology. 2003;61(3):304–9.
23. O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age
Ageing. 1994;23(3):200–3.
24. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep.
1998;21(4):371–7.
25. Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferritin and transferrin
levels in restless legs syndrome. J Sleep Res. 2005;14(1):43–7.
26. Enomoto M, Inoue Y, Namba K, Munezawa T, Matsuura M. Clinical characteristics of rest-
less legs syndrome in end-stage renal failure and idiopathic RLS patients. Mov Disord.
2008;23(6):811–6; quiz 926
27. Chrastina M, Martinkova J, Minar M, Zilinska Z, Valkovic P, Breza J. Impact of kidney trans-
plantation on restless legs syndrome. Bratisl Lek Listy. 2015;116(7):404–7.
28. Neau JP, Marion P, Mathis S, et al. Restless legs syndrome and pregnancy: follow-up of preg-
nant women before and after delivery. Eur Neurol. 2010;64(6):361–6.
29. Plazzi G, Ferri R, Antelmi E, et al. Restless legs syndrome is frequent in narcolepsy with
cataplexy patients. Sleep. 2010;33(5):689–94.
30. Hogl B, Frauscher B, Seppi K, Ulmer H, Poewe W. Transient restless legs syndrome after
spinal anesthesia: a prospective study. Neurology. 2002;59(11):1705–7.
31. Duz OA, Yilmaz NH, Olmuscelik O. Restless legs syndrome in aircrew. Aerosp Med Hum
Perform. 2019;90(11):934–7.
32. Hadjigeorgiou GM, Stefanidis I, Dardiotis E, et al. Low RLS prevalence and awareness in
Central Greece: an epidemiological survey. Eur J Neurol. 2007;14(11):1275–80.
33. Oksenberg A. Alleviation of severe restless legs syndrome (RLS) symptoms by cigarette
smoking. J Clin Sleep Med. 2010;6(5):489–90.
34. Szentkiralyi A, Volzke H, Hoffmann W, Trenkwalder C, Berger K. Multimorbidity and the risk
of restless legs syndrome in 2 prospective cohort studies. Neurology. 2014;82(22):2026–33.
35. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice
guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults
and children: an IRLSSG task force report. Sleep Med. 2018;41:27–44.
36. Aukerman MM, Aukerman D, Bayard M, Tudiver F, Thorp L, Bailey B. Exercise and restless
legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2006;19(5):487–93.
37. Eliasson AH, Lettieri CJ. Sequential compression devices for treatment of restless legs syn-
drome. Medicine (Baltimore). 2007;86(6):317–23.
38. Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for rest-
less legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest.
2009;135(1):74–80.
39. Mitchell UH. Use of near-infrared light to reduce symptoms associated with restless legs
syndrome in a woman: a case report. J Med Case Rep. 2010;4:286.
40. Mitchell UH, Myrer JW, Johnson AW, Hilton SC. Restless legs syndrome and near-infrared
light: an alternative treatment option. Physiother Theory Pract. 2011;27(5):345–51.
41. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syn-
drome: an evidence- based review and implications for clinical practice. Mov Disord.
2008;23(16):2267–302.
42. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa.
Sleep. 1996;19(3):205–13.
43. Hening WA, Allen RP, Ondo WG, et al. Rotigotine improves restless legs syndrome: a
6-month randomized, double-blind, placebo-controlled trial in the United States. Mov
Disord. 2010;25(11):1675–83.
44. Oertel WH, Benes H, Garcia-Borreguero D, et al. Efficacy of rotigotine transdermal system
in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week
dose-finding trial in Europe. Sleep Med. 2008;9(3):228–39.
45. Oertel WH, Benes H, Garcia-Borreguero D, et al. One year open-label safety and efficacy
trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syn-
drome. Sleep Med. 2008;9(8):865–73.
46. Stiasny-Kolster K, Kohnen R, Schollmayer E, Moller JC, Oertel WH, Rotigotine Sp 666
Study G. Patch application of the dopamine agonist rotigotine to patients with moderate to
advanced stages of restless legs syndrome: a double-blind, placebo-controlled pilot study.
2004;19(12):1432–8.
47. Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-
severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet
Neurol. 2008;7(7):595–604.
48. Garcia-Borreguero D, Allen RP, Kohnen R, et al. Diagnostic standards for dopaminergic
augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-
International Restless Legs Syndrome Study Group consensus conference at the Max Planck
Institute. Sleep Med. 2007;8(5):520–30.
49. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment
of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic
augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.
Sleep Med. 2016;21:1–11.
50. Trenkwalder C, Hogl B, Benes H, Kohnen R. Augmentation in restless legs syndrome is
associated with low ferritin. Sleep Med. 2008;9(5):572–4.
51. Happe S, Sauter C, Klosch G, Saletu B, Zeitlhofer J. Gabapentin versus ropinirole in the
treatment of idiopathic restless legs syndrome. Neuropsychobiology. 2003;48(2):82–6.
52. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of
pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512–9.
53. Garcia-Borreguero D, Larrosa O, Williams AM, et al. Treatment of restless legs syndrome with
pregabalin: a double-blind, placebo-controlled study. Neurology. 2010;74(23):1897–904.
54. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclo-
nus): relation to sleep disorders. Ann Neurol. 1980;8(4):416–21.
55. Symonds CP. Nocturnal myoclonus. J Neurol Neurosurg Psychiatry. 1953;16(3):166–71.
56. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Periodic limb move-
ments in sleep in community-dwelling elderly. Sleep. 1991;14(6):496–500.
57. Sforza E, Jouny C, Ibanez V. Time course of arousal response during periodic leg movements
in patients with periodic leg movements and restless legs syndrome. Clin Neurophysiol.
2003;114(6):1116–24.
58. Leung AK, Wong BE, Chan PY, Cho HY. Nocturnal leg cramps in children: incidence and
clinical characteristics. J Natl Med Assoc. 1999;91(6):329–32.
59. Naylor JR, Young JB. A general population survey of rest cramps. Age Ageing.
1994;23(5):418–20.
60. Haskell SG, Fiebach NH. Clinical epidemiology of nocturnal leg cramps in male veterans.
Am J Med Sci. 1997;313(4):210–4.
61. Hertz G, Fast A, Feinsilver SH, Albertario CL, Schulman H, Fein AM. Sleep in normal late
pregnancy. Sleep. 1992;15(3):246–51.
62. Hallegraeff JM, van der Schans CP, de Ruiter R, de Greef MH. Stretching before sleep
reduces the frequency and severity of nocturnal leg cramps in older adults: a randomised
trial. J Physiother. 2012;58(1):17–22.
63. Jansen PH, Veenhuizen KC, Wesseling AI, de Boo T, Verbeek AL. Randomised controlled
trial of hydroquinine in muscle cramps. Lancet. 1997;349(9051):528–32.
64. Moss HK, Herrmann LG. Night cramps in human extremities; a clinical study of the physi-
ologic action of quinine and prostigmine upon the spontaneous contractions of resting mus-
cles. Am Heart J. 1948;35(3):403–8.
65. Young JB, Connolly MJ. Naftidrofuryl treatment for rest cramp. Postgrad Med
J. 1993;69(814):624–6.
66. Popkin RJ. Orphenadrine citrate (Norflex) for the treatment of “restless legs” and related
syndromes. J Am Geriatr Soc. 1971;19(1):76–9.
67. Baltodano N, Gallo BV, Weidler DJ. Verapamil vs quinine in recumbent nocturnal leg cramps
in the elderly. Arch Intern Med. 1988;148(9):1969–70.
68. Dahle LO, Berg G, Hammar M, Hurtig M, Larsson L. The effect of oral magnesium substitu-
tion on pregnancy-induced leg cramps. Am J Obstet Gynecol. 1995;173(1):175–80.
69. Nygaard IH, Valbo A, Pethick SV, Bohmer T. Does oral magnesium substitution relieve
pregnancy-induced leg cramps? Eur J Obstet Gynecol Reprod Biol. 2008;141(1):23–6.
70. Supakatisant C, Phupong V. Oral magnesium for relief in pregnancy-induced leg cramps: a
randomised controlled trial. Matern Child Nutr. 2015;11(2):139–45.
71. Frusso R, Zarate M, Augustovski F, Rubinstein A. Magnesium for the treatment of nocturnal
leg cramps: a crossover randomized trial. J Fam Pract. 1999;48(11):868–71.
72. Garrison SR, Birmingham CL, Koehler BE, McCollom RA, Khan KM. The effect of mag-
nesium infusion on rest cramps: randomized controlled trial. J Gerontol A Biol Sci Med Sci.
2011;66(6):661–6.
73. Roffe C, Sills S, Crome P, Jones P. Randomised, cross-over, placebo controlled trial of
magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit.
2002;8(5):CR326–30.
74. Connolly PS, Shirley EA, Wasson JH, Nierenberg DW. Treatment of nocturnal leg cramps. A
crossover trial of quinine vs vitamin E. Arch Intern Med. 1992;152(9):1877–80.
75. Roca AO, Jarjoura D, Blend D, et al. Dialysis leg cramps. Efficacy of quinine versus vitamin
E. ASAIO J. 1992;38(3):M481–5.
76. Chan P, Huang TY, Chen YJ, Huang WP, Liu YC. Randomized, double-blind, placebo-
controlled study of the safety and efficacy of vitamin B complex in the treatment of nocturnal
leg cramps in elderly patients with hypertension. J Clin Pharmacol. 1998;38(12):1151–4.
77. Mueller ME, Gruenthal M, Olson WL, Olson WH. Gabapentin for relief of upper motor
neuron symptoms in multiple sclerosis. Arch Phys Med Rehabil. 1997;78(5):521–4.
78. Serrao M, Rossi P, Cardinali P, Valente G, Parisi L, Pierelli F. Gabapentin treatment for mus-
cle cramps: an open-label trial. Clin Neuropharmacol. 2000;23(1):45–9.
79. Bertolasi L, Priori A, Tomelleri G, et al. Botulinum toxin treatment of muscle cramps: a clini-
cal and neurophysiological study. Ann Neurol. 1997;41(2):181–6.
80. Prateepavanich P, Kupniratsaikul V, Charoensak T. The relationship between myofascial
trigger points of gastrocnemius muscle and nocturnal calf cramps. J Med Assoc Thail.
1999;82(5):451–9.
81. Westwood AJ, Spector AR, Auerbach SH. CPAP treats muscle cramps in patients with
obstructive sleep apnea. J Clin Sleep Med. 2014;10(6):691–2.
82. SC M. Textbook of periodontia (oral medicine). Philadelphia: P. Blakiston’s Son; 1938.
83. WF L. The American system of dentistry, in treatises by various authors. Philadelphia: Lea
Brothers; 1886.
84. Rugh JD, Harlan J. Nocturnal bruxism and temporomandibular disorders. Adv Neurol.
1988;49:329–41.
85. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and asso-
ciation among Canadians. Sleep. 1994;17(8):739–43.
86. Bader G, Lavigne G. Sleep bruxism; an overview of an oromandibular sleep movement dis-
order. REVIEW ARTICLE. Sleep Med Rev. 2000;4(1):27–43.
87. Abe K, Shimakawa M. Genetic and developmental aspects of sleeptalking and teeth-grinding.
Acta Paedopsychiatr. 1966;33(11):339–44.
88. Carra MC, Huynh N, Lavigne G. Sleep bruxism: a comprehensive overview for the dental
clinician interested in sleep medicine. Dent Clin N Am. 2012;56(2):387–413.
89. DeMattei R, Cuvo A, Maurizio S. Oral assessment of children with an autism spectrum dis-
order. J Dent Hyg. 2007;81(3):65.
90. Ghanizadeh A. ADHD, bruxism and psychiatric disorders: does bruxism increase the chance
of a comorbid psychiatric disorder in children with ADHD and their parents? Sleep Breath.
2008;12(4):375–80.
91. Gagnon Y, Mayer P, Morisson F, Rompre PH, Lavigne GJ. Aggravation of respiratory dis-
turbances by the use of an occlusal splint in apneic patients: a pilot study. Int J Prosthodont.
2004;17(4):447–53.
92. Oksenberg A, Arons E. Sleep bruxism related to obstructive sleep apnea: the effect of con-
tinuous positive airway pressure. Sleep Med. 2002;3(6):513–5.
93. Ellison JM, Stanziani P. SSRI-associated nocturnal bruxism in four patients. J Clin Psychiatry.
1993;54(11):432–4.
94. Raigrodski AJ, Christensen LV, Mohamed SE, Gardiner DM. The effect of four-week admin-
istration of amitriptyline on sleep bruxism. A double-blind crossover clinical study. Cranio.
2001;19(1):21–5.
95. Amir I, Hermesh H, Gavish A. Bruxism secondary to antipsychotic drug exposure: a positive
response to propranolol. Clin Neuropharmacol. 1997;20(1):86–9.
96. Lobbezoo F, Lavigne GJ, Tanguay R, Montplaisir JY. The effect of catecholamine precursor
L-dopa on sleep bruxism: a controlled clinical trial. Mov Disord. 1997;12(1):73–8.
97. Sjoholm TT, Lehtinen I, Piha SJ. The effect of propranolol on sleep bruxism: hypothetical
considerations based on a case study. Clin Auton Res. 1996;6(1):37–40.
98. Van der Zaag J, Lobbezoo F, Van der Avoort PG, Wicks DJ, Hamburger HL, Naeije M. Effects
of pergolide on severe sleep bruxism in a patient experiencing oral implant failure. J Oral
Rehabil. 2007;34(5):317–22.
99. Huynh N, Lavigne GJ, Lanfranchi PA, Montplaisir JY, de Champlain J. The effect of 2 sym-
patholytic medications--propranolol and clonidine--on sleep bruxism: experimental random-
ized controlled studies. Sleep. 2006;29(3):307–16.
100. Fernandez-Nunez T, Amghar-Maach S, Gay-Escoda C. Efficacy of botulinum toxin in the
treatment of bruxism: systematic review. Med Oral Patol Oral Cir Bucal. 2019;24(4):e416–24.
101. Klackenberg G. A prospective longitudinal study of children. Data on psychic health and
development up to 8 years of age. Acta Paediatr Scand Suppl. 1971;224:1–239.
102. Kravitz H, Rosenthal V, Teplitz Z, Murphy JB, Lesser RE. A study of head-banging in infants
and children. Dis Nerv Syst. 1960;21:203–8.
103. Happe S, Ludemann P, Ringelstein EB. Persistence of rhythmic movement disorder beyond
childhood: a videotape demonstration. Mov Disord. 2000;15(6):1296–8.
104. Stepanova I, Nevsimalova S, Hanusova J. Rhythmic movement disorder in sleep persisting
into childhood and adulthood. Sleep. 2005;28(7):851–7.
105. Gwyther ARM, Walters AS, Hill CM. Rhythmic movement disorder in childhood: an integra-
tive review. Sleep Med Rev. 2017;35:62–75.
106. Kaneda R, Furuta H, Kazuto K, Arayama K, Sano J, Koshino Y. An unusual case of rhythmic
movement disorder. Psychiatry Clin Neurosci. 2000;54(3):348–9.
107. Kohyama J, Matsukura F, Kimura K, Tachibana N. Rhythmic movement disorder: polysom-
nographic study and summary of reported cases. Brain and Development. 2002;24(1):33–8.
108. Kempenaers C, Bouillon E, Mendlewicz J. A rhythmic movement disorder in REM sleep: a
case report. Sleep. 1994;17(3):274–9.
109. Chirakalwasan N, Hassan F, Kaplish N, Fetterolf J, Chervin RD. Near resolution of sleep
related rhythmic movement disorder after CPAP for OSA. Sleep Med. 2009;10(4):497–500.
110. Gharagozlou P, Seyffert M, Santos R, Chokroverty S. Rhythmic movement disorder associ-
ated with respiratory arousals and improved by CPAP titration in a patient with restless legs
syndrome and sleep apnea. Sleep Med. 2009;10(4):501–3.
111. Mayer G, Wilde-Frenz J, Kurella B. Sleep related rhythmic movement disorder revisited. J
Sleep Res. 2007;16(1):110–6.
112. Jackson MA, Hughes RC, Ward SP, McInnes EG. "Headbanging" and carotid dissection. Br
Med J (Clin Res Ed). 1983;287(6401):1262.
113. Mackenzie JM. "Headbanging" and fatal subdural haemorrhage. Lancet.
1991;338(8780):1457–8.
114. Noel LP, Clarke WN. Self-inflicted ocular injuries in children. Am J Ophthalmol.
1982;94(5):630–3.
115. Rosenberg C. Elimination of a rhythmic movement disorder with hypnosis--a case report.
Sleep. 1995;18(7):608–9.
116. Ross RR. Treatment of nocturnal headbanging by behavior modification techniques: a case
report. Behav Res Ther. 1971;9(2):151–4.
117. Etzioni T, Katz N, Hering E, Ravid S, Pillar G. Controlled sleep restriction for rhythmic
movement disorder. J Pediatr. 2005;147(3):393–5.
118. Drake ME Jr. Jactatio nocturna after head injury. Neurology. 1986;36(6):867–8.
119. Regestein QR, Hartmann E, Reich P. Single case study. A head movement disorder occurring
in dreaming sleep. J Nerv Ment Dis. 1977;164(6):432–6.
120. Vogel W, Stein DJ. Citalopram for head-banging. J Am Acad Child Adolesc Psychiatry.
2000;39(5):544–5.
121. Chisholm T, Morehouse RL. Adult headbanging: sleep studies and treatment. Sleep.
1996;19(4):343–6.
122. Manni R, Tartara A. Clonazepam treatment of rhythmic movement disorders. Sleep.
1997;20(9):812.
123. Lee SK. A case with dopamine-antagonist responsive repetitive head punching as rhythmic
movement disorder during sleep. J Epilepsy Res. 2013;3(2):74–5.
124. Khoo SM, Tan JH, Shi DX, Jamil HK, Rajendran N, Lim TK. Propriospinal myoclonus at
sleep onset causing severe insomnia: a polysomnographic and electromyographic analysis.
Sleep Med. 2009;10(6):686–8.
125. Montagna P, Provini F, Plazzi G, Liguori R, Lugaresi E. Propriospinal myoclonus upon relax-
ation and drowsiness: a cause of severe insomnia. Mov Disord. 1997;12(1):66–72.
126. Oguri T, Hisatomi K, Kawashima S, Ueki Y, Tachibana N, Matsukawa N. Postsurgical pro-
priospinal myoclonus emerging at wake to sleep transition. Sleep Med. 2014;15(1):152–4.
127. Brown P, Thompson PD, Rothwell JC, Day BL, Marsden CD. Axial myoclonus of proprio-
spinal origin. Brain. 1991;114(Pt 1A):197–214.
128. Manconi M, Sferrazza B, Iannaccone S, Massimo A, Zucconi M, Ferini-Strambi L. Case
of symptomatic propriospinal myoclonus evolving toward acute "myoclonic status". Mov
Disord. 2005;20(12):1646–50.
129. Kang SY, Sohn YH. Electromyography patterns of propriospinal myoclonus can be mim-
icked voluntarily. Mov Disord. 2006;21(8):1241–4.
130. Williams DR, Cowey M, Tuck K, Day B. Psychogenic propriospinal myoclonus. Mov
Disord. 2008;23(9):1312–3.
131. Antelmi E, Provini F. Propriospinal myoclonus: the spectrum of clinical and neurophysi-
ological phenotypes. Sleep Med Rev. 2015;22:54–63.
132. Abrao J, Bianco Mde P, Roma W, Krippa JE, Hallak JE. Spinal myoclonus after subarachnoid
anesthesia with bupivacaine. Rev Bras Anestesiol. 2011;61(5):619–23, 339-640
133. Benatru I, Thobois S, Andre-Obadia N, et al. Atypical propriospinal myoclonus with possible
relationship to alpha interferon therapy. Mov Disord. 2003;18(12):1564–8.
134. Lozsadi DA, Forster A, Fletcher NA. Cannabis-induced propriospinal myoclonus. Mov
Disord. 2004;19(6):708–9.
135. Post B, Koelman JH, Tijssen MA. Propriospinal myoclonus after treatment with ciprofloxa-
cin. Mov Disord. 2004;19(5):595–7.
136. Zamidei L, Bandini M, Michelagnoli G, Campostrini R, Consales G. Propriospinal myoc-
lonus following intrathecal bupivacaine in hip surgery: a case report. Minerva Anestesiol.
2010;76(4):290–3.
137. Vetrugno R, Provini F, Plazzi G, Cortelli P, Montagna P. Propriospinal myoclonus: a motor
phenomenon found in restless legs syndrome different from periodic limb movements during
sleep. Mov Disord. 2005;20(10):1323–9.
138. Shprecher D, Silberstein H, Kurlan R. Propriospinal myoclonus due to cord compression in
the absence of myelopathy. Mov Disord. 2010;25(8):1100–1.
139. van der Salm SM, Erro R, Cordivari C, et al. Propriospinal myoclonus: clinical reappraisal
and review of literature. Neurology. 2014;83(20):1862–70.
140. Fouillet N, Wiart L, Arne P, Alaoui P, Petit H, Barat M. Propriospinal myoclonus in tet-
raplegic patients: clinical, electrophysiological and therapeutic aspects. Paraplegia.
1995;33(11):678–81.
141. Roze E, Bounolleau P, Ducreux D, et al. Propriospinal myoclonus revisited: clinical, neuro-
physiologic, and neuroradiologic findings. Neurology. 2009;72(15):1301–9.
142. Wong SH, Selvan A, White RP. Propriospinal myoclonus associated with fragile-X-
premutation and response to selective serotonin reuptake inhibitor. Parkinsonism Relat
Disord. 2011;17(7):573–4.
143. Okura M, Tanaka M, Sugita H, Taniguchi M, Ohi M. Obstructive sleep apnea syndrome
aggravated propriospinal myoclonus at sleep onset. Sleep Med. 2012;13(1):111–4.
Part IV
Sleep in Special Conditions
Chapter 19
Sleep in Critical Illness
Michael T. Y. Lam, Atul Malhotra, Jamie Nicole LaBuzetta,

and Biren B. Kamdar
Keywords Critical illness · Sleep · Circadian rhythms · Delirium

Sleep fragmentation · Sleep disruption · Sleep deprivation · Intensive care unit
The importance of sleep to overall wellness and physiological homeostasis has

been increasingly appreciated. For critically ill patients in the intensive care unit
(ICU) setting, physiological disruptions are common, highlighting sleep as an
important factor in this vulnerable population. In this chapter, we review existing
literature on sleep in the ICU and provide ideas for future research. After providing
an overview of sleep in healthy and critically ill patients, we review tools to mea-
sure sleep and causes of sleep disruption in the ICU. We also highlight the impact
of sleep disruption on two systems that are essential to recovery: the immune sys-
tem and brain.
M. T. Y. Lam · A. Malhotra
Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine
and Physiology, University of California San Diego Health, La Jolla, CA, USA
J. N. LaBuzetta
Department of Neurosciences, Division of Neurocritical Care, University of California San
Diego Health, La Jolla, CA, USA
B. B. Kamdar (*)
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine,
University of California San Diego Health, La Jolla, CA, USA
e-mail: kamdar@ucsd.edu

432 M. T. Y. Lam et al.
Sleep Patterns in the ICU
Sleep in Healthy Adults
An understanding of sleep in healthy adults (summarized in greater detail in other

chapters of this book) is necessary to appreciate the sleep experienced by criti-
cally ill patients. In healthy adults, sleep architecture—as measured using poly-
somnography (PSG)—is divided into non-rapid eye movement (NREM) sleep,
comprised of N1 (2–5% of total sleep time), N2 (45–55%), and N3 (3–15%), and
REM (20–25%). Sleep onset usually occurs within 10–20 minutes, and the first
REM period usually begins 90–120 minutes into sleep. In healthy adults, total
consolidated nightly sleep time is usually 7–9 hours. Arousals occur roughly ten
times per hour (even in normal individuals), although higher figures have been
reported [1–3].
The drive to sleep is primarily governed by two factors: homeostatic and cir-
cadian. The homeostatic drive refers to the impact of antecedent sleep depriva-
tion on the urge to sleep, i.e., the longer an individual is awake, the more tired
they get and more pressure to sleep. The circadian drive is based on an endoge-
nous body clock, which increases or decreases the propensity to sleep during the
24-hour day.
The importance of circadian rhythms has been well established in health and
in disease, as the circadian system—consisting of a central oscillator and periph-
eral “clocks”—can affect cells in nearly every vital organ system [4]. The clinical
relevance of the circadian system is represented by the disproportionate number
of myocardial infarctions and ischemic strokes that occur in the morning and
asthma flares that occur at night [5–7]. Sleep-wake coordination, rest-activity
maintenance, light-dark exposure, feeding timing, and social interactions follow
a circadian pattern and are modifiable factors for circadian rhythm align-
ment [8, 9].
Sleep in Critically Ill Patients
In contrast to healthy adults, sleep in critically ill patients is characterized by low

total sleep time (~5 hr) and interruption of the normal diurnal pattern, with approxi-
mately 50% of sleep occurring during daytime hours [10–14]. Critically ill patients
undergoing polysomnography (PSG) have been shown to experience mostly N1 and
N2 sleep, with notably reduced or absent slow-wave sleep (N3) and REM (Fig. 19.1)
[10–14]. Sleep in the ICU is also severely fragmented, with frequent interruptions
and arousals resulting in discrete and frequent sleep episodes [10–14]. This sleep
fragmentation was highlighted in a landmark study demonstrating that critically ill
patients undergoing PSG experienced 41 ± 28 sleep episodes each day, with each
episode averaging 15 ± 9 minutes [15].
19 Sleep in Critical Illness 433
Fig. 19.1 Sleep patterns in critically ill patients, as recorded using polysomnography, as com-
pared to a healthy adult. Gray areas represent sleep and white areas represent wakefulness; notable
in critically ill patients is the lack of consolidated sleep, N3 and REM. ICU intensive care unit,
REM rapid eye movement. (From Knauert, with permission [14])
Sleep Measurement in the ICU
Large-scale, accurate measurement of sleep in the ICU setting is challenging and

represents a key barrier to efforts aimed at building knowledge in this area.
Nevertheless, sleep measurement in the ICU is a topic of great interest motivating
many prior and ongoing investigations.
Polysomnography
In the ICU setting, PSG is cumbersome and expensive; furthermore, it is not feasi-
ble to perform for longer than 24 hours [13]. Additionally, interpretation of the PSG
differs substantially when comparing prototypical critically ill patients with com-
munity-dwelling adults [16]. For example, while N2 sleep is characterized by sleep
spindles, benzodiazepines—sedative medications commonly used in the ICU—can
produce spindles on EEG that are qualitatively similar but functionally different
than those occurring during natural sleep. Thus, the N2 designation in the ICU can
be problematic due to its inability to discriminate between natural and benzodiaze-
pine-induced N2. Similarly, N3 (slow-wave) sleep is characterized by delta activity,
a brain wave pattern also resembling that seen in ICU patients experiencing enceph-
alopathy, i.e., diffuse slowing [14, 17, 18]. Finally, submentalis electromyography
(EMG), which is commonly used for sleep staging (e.g., REM vs. NREM), can be
affected in the ICU setting by paralytics or comorbidities.
While ICU-based efforts to define new criteria for sleep staging of PSG record-
ings are ongoing, no major consensus has been reached [16]. As a result, efforts to
evaluate the effectiveness of sleep interventions remain hampered by difficulties in
assessing sleep, e.g., scoring sleep according to conventional methods.
Actigraphy
Actigraphy involves accelerometry, often via a wristwatch-like device, to evaluate

cycles of rest and activity. A decades-old technology, actigraphy has received recent
attention for large-scale use in the ICU since it is inexpensive and well tolerated and
can wirelessly capture continuous rest-activity data across daytime and nighttime
periods [19–21]. Moreover, as demonstrated in nursing home and ICU survivor
populations, actigraphic rest-activity data can be used to approximate circadian
rhythm alignment [22, 23]. Despite these strengths, actigraphy is challenging in the
ICU as critically ill patients are mostly inactive, resulting in overestimation of sleep
using traditional scoring algorithms [19, 20, 24]. Moreover, actigraphy-based activ-
ity monitoring can be confounded by common ICU factors such as sedating medica-
tions, delirium, and staff interventions such as turning and bathing. Nevertheless,
actigraphy is a promising method for capturing rest-activity rhythms in critically ill
patients, especially if ICU-specific scoring algorithms are developed.
Subjective Measures
Subjective measurement of sleep is a practical, low-cost option for evaluating sleep

at a large scale in the ICU. Currently, the Richards-Campbell Sleep Questionnaire
(RCSQ), which involves a 5-item visual analogue scale (VAS), and the Verran/
Snyder-Halpern Sleep Scale [25, 26]—which involves a 14-item VAS—represent
the most commonly used sleep questionnaires in the ICU [27–32]. The RCSQ is the
only instrument validated against PSG [26, 33]. While easy to collect and inexpen-
sive to use in the ICU setting, subjective instruments have inherent limitations,
including recall bias and fatigue across repeated assessments. Notably, ICU staff
may complete subjective instruments for patients with altered cognition and/or con-
sciousness [28, 34, 35]; however these ratings tend to be overestimated [36].
Whether by observation or validated instruments, subjective sleep measurement in
the ICU must be performed with caution.
Causes of Sleep Disruption in the ICU
The nature of the ICU environment could be described as a “constant routine” in

which noise, light, and biological stress occur 24/7. As such, critically ill patients
are felt to experience substantial circadian rhythm disruption, but data are sparse to
support the presence of circadian misalignment or the therapeutic benefits of circa-
dian rhythm entrainment in the ICU [4, 8, 9, 37, 38]. Several factors can contribute
to disrupted sleep in critically ill patients, many of which are modifiable (Fig. 19.2).
In theory, modulation of ambient light and noise, timing of food and medication
administration (e.g., melatonin, ramelteon), as well as adjusting mechanical ventila-
tion could influence sleep-wake rhythms highlighting these factors as potential tar-
gets for ICU-based interventions aimed at improving clinical outcomes [18, 39].
Noise
Noise, defined as an unpleasant, unwanted, and/or disruptive sound, is common in

the ICU setting [40, 41]. Noises produced by people (e.g., staff, visitors), machines
(e.g., ventilator alarms, IV pumps), or objects (e.g., doors, squeaky shoes) can
Patient factors
Sleep disorders and disordered
breathing
Medications and illicit substances
Pre-existing conditions and genetics
Increased age
Environmental factors Critical illness Care-related factors
Ambient sound Pain Frequent examinations
Changes in sound level (e.g. Ventilator dyssynchrony
beeping monitor) Continuous sedation
Unnatural timing and/or quality (especially benzodiazepine
of light Sleep disruption in administration)
Temperature the ICU Medication administration
Unfamiliarity Patient hygiene
Other interactions (e.g. lab
draws)
Neurocognitive
Short-term outcomes Long-term
Agitation Cognitive Dysfunction
Delirium PTSD, depression, anxiety
Disordered Sleep
Increased mortality and morbidity
Fig. 19.2 Causes and consequences of sleep disruption in the ICU

disrupt sleep [42, 43]. In the ICU, noise levels range from 55 to 65 dB [15, 44–46]
but often exceed 80 dB, a level sufficient for sleep arousal [47]. In comparison, the
Environmental Protection Agency recommends hospital noise levels average less
than 35–45 dB during the day and 30–35 dB at night [48]. Some data suggest that
absolute noise levels are less critical than sound-level changes [49]. Abrupt changes
in noise level—for example, an IV pump alarming in an otherwise quiet room—are
common in the ICU and may disrupt sleep more than constant background sounds.
Additionally, recent studies have shown that the majority of noise in the ICU origi-
nates from sources near the ears of the patient and is often due to staff conversations
and nonessential alarms [42, 43]. As patients and survivors consistently report noise
as a disruptive factor needing improvement [18, 50], efforts are needed to identify
and minimize noise in the ICU.
Light
Despite suboptimal day-night light exposure in the ICU setting, critically ill patients
generally report light to be less disruptive than other factors such as noise and care-
based interactions [28, 51]. Nevertheless, mistimed, excessive, or inadequate envi-
ronmental light exposure can affect sleep-wake rhythms. As described above and in
other chapters, sleep-wake rhythms follow a circadian pattern, with the suprachias-
matic nucleus (SCN) acting as a central 24-hour pacemaker. Light represents the
strongest zeitgeber (environmental cues that entrain the central clock) for sleep-
wake rhythms by regulating melatonin secretion from the SCN. Typically, retinal
receptors receive early morning light, which signal the SCN to suppress melatonin
secretion from the pineal gland. Melatonin levels accumulate in the early evening to
promote sleep.
When compared to indoor light (~1000 lux), subjects exposed to natural light
(>4000 lux) over longer durations have been shown to exhibit improved melatonin
and sleep-wake rhythms [52]. Unfortunately, in the ICU setting, light levels range
from 30 to 165 lux during the day, below the level needed to inhibit melatonin, and
can rise as high as 1445 lux at night, above the level needed to suppress melatonin
release [49, 53–57]. Light levels during bedside procedures have been shown to
reach 10,000 lux [56]. Interestingly, independent of light exposure, impaired mela-
tonin secretion has been observed in patients with sepsis [58] and delirium [59, 60],
highlighting bright light exposure as a potentially important intervention in criti-
cally ill patients [56]. Additionally, melatonin and melatonin-receptor agonists are
receiving attention as part of ICU-based sleep-wake improvement efforts [61–66].
Care-Related Interactions
While vigilant monitoring is required in the ICU setting, in some circumstances

excessive or poorly timed staff interactions can be deleterious. For example, hourly
assessments may capture signs of deterioration early in an ICU course, but may
disrupt sleep once a patient achieves clinical stability. When surveyed, ICU patients
report blood draws, vital signs, and nurse visits among the most disruptive factors,
along with radiographs, baths, wound care, and suctioning and non-care-related
interactions from family and visitors.
When quantified, ICU patients can experience up to 8 care-related interactions
per hour while sleeping [67] and 50 across the night shift [68, 69]. When evaluated
against PSG in one study, one out of every five interactions resulted in a sleep
arousal or awakening [12]. Hence, efforts to improve sleep should involve individu-
alization of bedside interactions, consideration of nondisruptive technologies (e.g.,
devices with outside-of-the-room alarms and controls), and bundling of care [70,
71]. Vital to such efforts is multidisciplinary and staff engagement to develop inter-
ventions to minimize interactions and to evaluate their feasibility [72].
Medications
Via mechanisms including sympathetic activation, deliriogenicity, and drug-drug

interactions, nearly every medication administered in the ICU can disrupt patient
sleep (Table 19.1). Notably, chronotherapy—treatments provided in the context of
the body clock—is gaining interest, as data suggest that the timing of treatment may
impact the safety and efficacy of various treatments [73]. For example, inhaled ste-
roid use at 3 pm has been shown to have similar efficacy to more frequent dosing
[74]. Additionally, chemotherapy may be safer and more effective when adminis-
tered at specific times [75]. Understanding and optimizing the timing of medica-
tions in critically ill patients represents a compelling area of research, along with
other common ICU practices such as enteral feeding and mechanical ventilation.
Mechanical Ventilation
While mechanical ventilation (MV) is a cornerstone of critical care, inappropriate

patient-ventilator interactions can result in profound sleep disruption. In general,
patients receiving mechanical ventilation report worse sleep quality compared to
those not receiving MV, for various reasons including patient-ventilator dyssyn-
chrony, endotracheal tube discomfort, alarms, and ventilator-related care interac-
tions (i.e., suctioning) [51, 76, 77]. Additionally, small studies in patients receiving
MV suggest that spontaneous modes such as pressure support (PSV) may inhibit
sleep by inducing central apneas from intermittent bursts of excessive support [78].
Controlled modes of ventilation, such as volume control (VC), pressure control
(PC), and proportional assist ventilation (PAV), may be better for sleep, in particular
PAV via matching of driving pressure with patient effort [79]. However, one study
involving clinician-adjusted PSV [80] and another involving addition of dead space
to the ventilator circuit in patients receiving PSV [81] demonstrated improvement in
central apneas and associated sleep disruption as compared to PSV alone, suggest-
ing that individualized instead of “one size fits all” approaches are vital for
Table 19.1 Commonly used ICU medications and their effect on sleep
Medication class Mechanism of action Effect on sleep
Sedative
Benzodiazepines GABA receptor agonist ↓W, ↑TST, ↓N3, ↓REM,
↓SL
Dexmedetomidine α2-Agonist ↑N3, ↓SL, ↓REM, ↑N2
with spindles, ↑SE
Propofol GABA receptor agonist ↑TST, ↓SL, ↓W, ↓REM
Nonbenzodiazepine hypnotics GABA receptor agonist ↓N2, ↑TST, ↓N3, ↑↓REM,
↓SL, ↓W
Analgesic
Opioids μ-Receptor agonist ↓TST, ↓N3, ↓REM, ↑W
Antipsychotic
Haloperidol Dopamine-receptor antagonist ↑TST, ↑N3, ↑SE, ↓SL, ↓W
Olanzapine 5HT2-, D2-receptor antagonist ↑TST, ↑N3, ↑SE, ↓SL, ↓W
Trazodone SSRI, 5HT1a/1c/2-receptor ↑N3, ↑↓REM,? ↑SE, ↓SL
antagonist, H1-receptor antagonist
Antihistamine
Diphenhydramine H1-receptor antagonist ?↑N3, ↓REM,? ↑SE, ↓SL
Melatonin and melatonin-
receptor agonist
Ramelteon Melatonin 1 and 2 receptor agonist ↑TST, ↓SL, ↑SE
Immunosuppressant
Corticosteroids Decreased melatonin secretion ↑W, ↓N3, ↓REM,
insomnia
Tacrolimus Calcineurin inhibitor Insomnia
Cyclosporine Inhibits production and release of Insomnia
IL-2
Cardiovascular
Norepinephrine/epinephrine α- and β-receptor agonist ↓N3, ↓REM, insomnia
Dopamine D2-, β1-, α1-receptor agonist ↓N3, ↓REM, insomnia
Phenylephrine α1-Receptor agonist ↓N3, ↓REM
β-Blockers CNS β-receptor antagonist ↑W, ↓REM, nightmares,
insomnia
Amiodarone Various pathways Nightmares
Clonidine α2-Agonist ↓REM
Antimicrobial
Fluoroquinolones GABA type A receptor inhibition Insomnia
Abbreviations: ICU intensive care unit, GABA gamma-aminobutyric acid, W wake, TST total sleep
time, N2 deeper sleep, N3 restorative/slow-wave sleep, REM rapid eye movement sleep, SL sleep
latency, SE sleep efficiency, SSRI selective serotonin reuptake inhibitor, CNS central nervous sys-
tem, W wake
optimizing sleep quality. Other strategies to improve sleep quality could include
adjusting positive end-expiratory pressure (PEEP) to lessen respiratory effort for
patients with auto-PEEP, increasing the inspiratory flow rate in the setting of air
hunger, shortening inspiratory time to prevent double triggering, and minimizing

sleep-disrupting sedative medications. Additionally, modes such as neurally
adjusted ventilator assist (NAVA), which involves neuromechanical coupling to pro-
mote patient-ventilator synchrony, may also be considered [82]. While the 2018
Clinical Practice Guidelines for Pain, Agitation/Sedation, Delirium, Immobility,
and Sleep Disruption (PADIS) conditionally recommend controlled ventilation
modes for sleep at night, large multi-site studies are needed to fill substantial knowl-
edge gaps [83].
Sleep, Immunity, and Cognition in Critically Ill Patients
Sleep disruption can have a profound effect on nearly every major organ system,
thus impeding recovery for critically ill patients (Fig. 19.3). The SARS-CoV-2
(COVID-19) pandemic has increased attention toward critical care, specifically
highlighting the poor sleep patients experience in the ICU setting [84] and its pos-
sible association with immune dysfunction [85] and—in the context of delirium and
dementia—cognitive dysfunction [86, 87]. As a summary of the multi-organ effects
of sleep disruption would be beyond the scope of this chapter, this section instead
will focus specifically on the role of sleep disruption on immune and cognition
function in critically ill patients.
Neurological
• Depressed mood Inflammation Æ Sleep homeostasis
• Circadian dysrhythmia
• ↓ cognitive processing (e.g. ICU-related inflammation
memory) • Pathogens exposure
• Delirium • Infection and sepsis
• Tissue injury
Pulmonary Altered inflammatory mediators
• ↓ ventilatory response to Cardiovascular
• IL1β
hypercapnia & hypoxemia • ↑ blood pressure • TNFα
• ↑ upper airway • ↑ blood pressure • Prostagladins
collapsibility leading to variability
more apneic events • Long-term: ↑ Altered sleep physiology
• ↓ inspiratory muscle cardiovascular morbidity • ↑ Somnolence
endurance • ↓ Sleep efficiency
• ∆ NREM
Metabolic & endocrine • ↓ REM
• Impaired fasting glucose Immune
• Temperature
dysregulation Sleep disruption Æ Immune function
• ↓ growth hormone surge
• Shift in cortisol peak ICU-related and chronic sleep disruption
• ↑ norepinephrine • Acute sleep deprivation
Gastrointestinal • Chronic sleep insufficiency Antibody
production
• Possible bacterial overgrowth Immune dysfunction
Musculoskeletal • Microinflammation → GI
symptoms • ↑ Susceptibility to infection
• Hyperalgesia • Altered adaptive immune
• ↑ risk of injury response (e.g. vaccination)
• Altered circulating cytokine levels
(IL6, IL1β)
• Altered peripheral immune cell
composition and functions
Fig. 19.3 The effect of disrupted sleep on major organ systems, with a focus on the relationship
of poor sleep, immunity, and inflammation. (Adapted from Chang et al. [146])
Sleep and Immunity
Adequate sleep is critical to immune function (Fig. 19.3). Outside of the ICU, clini-
cians and researchers observed the development of respiratory infections as a con-
sequence of sleep deprivation, which has more recently been supported by
high-quality studies. First, a rhinovirus inoculation study in healthy human volun-
teers observed a higher rate of infection in subjects obtaining 7 hours or less of
sleep, as compared to rested controls [88]. Second, in large epidemiological cohorts,
reported sleep duration of 5 hours—as compared to matched controls obtaining
7–8 hours of sleep—has been associated with an increased incidence of pneumonia
[89] and upper respiratory tract infections [90]. Third, in response to influenza [91,
92] and hepatitis vaccination [93, 94], a slowed peak in antibody levels has been
noted in those who are sleep deprived as compared to those obtaining adequate
sleep. The findings may suggest an adequate but delayed antigenic response due to
sleep deprivation. Lastly, acute sleep deprivation in healthy individuals alters circu-
lating cytokine levels [95] and the transcriptome relevant to immune function in
blood cells [96, 97]. While these studies suggest that sleep disruption may alter
humoral and cellular immunity, other studies suggest that chronic sleep disruption
may exacerbate inflammatory states such as atherosclerosis [98–100], metabolic
syndrome [101–105], stroke [106, 107], and tumor immunity [108, 109] (Fig. 19.3).
Reciprocally, infection also has an important relationship with sleep. Somnolence
is a cardinal symptom of infection, and sleep is therefore considered an acute-phase
compensatory response. In animal models, viral and bacterial infections, as well as
the inoculation of pathogenic components (e.g., muramyl peptide, lipopolysaccha-
ride), are sufficient to alter sleep [110]. In a series of studies in healthy volunteers,
low doses of systemic endotoxin resulted in changes in sleep patterns on PSG, pro-
longing NREM sleep while suppressing REM sleep [111]. Moreover, sleep is
altered differentially depending on the timing and dosing of a septic challenge
[112], highlighting the complex relationship between acute inflammation and sleep.
Indeed, the effect of sepsis on sleep architecture is likely influenced by a complex
combination of factors, including cytokines IL (interleukin)-1β, TNF (tumor necro-
sis factor)-α, and prostaglandins [95].
In the ICU setting, the relationship between sleep disruption and immune func-
tion is unclear and complicated by the ubiquity of sleep disruption and infection in
critically ill patients. Research in animals has contributed valuable knowledge in
this area. Sleep-deprived mice have a higher mortality after a septic challenge as
compared to non-sleep-deprived controls [113–115], an observation that could be
attributed to impaired pathogen clearance [114]. Furthermore, as the somnogenic
effect of sepsis depends on a neuronal-specific isoform of IL1 receptor accessory
protein, mice deficient of this gene lacked the sleep response when given a septic
challenge with influenza and experienced higher mortality than controls [116].
Moreover, animals invariably died after 6–8 weeks of chronic total sleep deprivation
[117] and showed signs of bacterial infection before death [118]. While these stud-
ies support the notion of compromised microbial defense as a consequence of sleep
deprivation, the levels of sleep deprivation and stress imposed by these models may
not generalize to critically ill patients. Last, it is unclear whether acute-on-chronic
sleep disruption predisposes critically ill patients to a hyper-inflammatory state.
Overall, the collective body of research provides a biological plausibility for the
sleep-immunity association, particularly in critically ill patients who experience
sepsis as a common cause of mortality [119–121]. Sepsis survivors have poor long-
term prognosis, with infection as the most common reason for rehospitalization
[122]. For critically ill patients, an intact immune system may play a vital role in
noninfectious processes such as wound healing and tissue repair (e.g., after trauma,
surgery, or acute myocardial infarction). Understanding the sleep-immune axis in
the critically ill is of paramount importance. The awareness to improve sleep may
have an immediate implication in immune-related ICU outcomes (e.g., enhanced
pathogen clearance and improved recovery from sepsis) as well as long-term conse-
quences (e.g., mounting an adequate adaptive immune response for a robust acquired
immunity).
Sleep Disruption and Cognition
A comprehensive pathophysiological review of the relationship between sleep,

delirium, and cognition is outside the scope of this chapter, but briefly is believed to
include common pathophysiologic pathways, mechanisms, and neurotransmitters
[34, 123]. Sleep disruption likely plays a role in the development of delirium, and
vice versa, though a causal relationship has not been established [124, 125].
Approximately one-third of critically ill patients experience delirium, including up
to 80% of those receiving mechanical ventilation [123]. Patients experiencing delir-
ium are at high risk of devastating outcomes, including longer duration of mechani-
cal ventilation and prolonged ICU and hospital length of stay [126]. Over the past
decade, increased attention has been paid to the long-term sequelae of ICU delir-
ium, in particular its association with severe and disabling long-term neurocognitive
impairments [127–129]. Another study observed an eightfold increase in develop-
ing dementia for elderly (>85-year-old) patients who developed delirium during
their hospital stay [130].
Risk factors for delirium in the ICU include critical illness, older age, preexisting
cognitive impairments, and genetic predisposition [123]. Disrupted sleep has
received particular attention as a modifiable risk factor for delirium in the ICU and
is supported by observational studies demonstrating increased mental status change
frequency among critically ill patients experiencing more sleep interruptions [131]
and higher delirium incidence after thoracic surgery in patients reporting sleep
deprivation [132]. More objectively, a study involving PSG in mechanically venti-
lated patients demonstrated a higher rate of incident delirium in patients with REM
suppression [133].
The interaction between pharmacological agents and delirium has been studied
extensively, with benzodiazepine infusions being identified consistently as a risk
factor for delirium development [125, 134–138]. Several studies have examined
strategies to prevent or treat delirium, with inconclusive results [83]. Antipsychotics
are traditionally administered off-label for delirium, but have not been shown to be
effective in large studies [139, 140]. Dexmedetomidine has been a subject of inter-
est as it has a favorable deliriogenicity profile [141, 142] and may act via the ven-
trolateral preoptic nucleus of the hypothalamus [143], thus promoting biological
sleep rather than sedation seen with benzodiazepines and propofol. However, a
large, randomized control trial did not show any major benefits of dexmedetomidine
when compared with usual care [144]. Thus, strategies to address delirium have
largely focused on non-pharmacological strategies such as sleep promotion and
early mobility and, from a pharmacological perspective, avoidance of deliriogenic
medications such as benzodiazepines (Table 19.2) [72, 83]. As sleep-focused
improvement efforts have been shown to reduce delirium in ICU settings [28, 29],
design and implementation of larger interventions is a high priority [145], in large
part due to heightened awareness of delirium and its associated short- and long-term
consequences [83].
Future Directions
This chapter highlights the important intersection between sleep and critical illness
and reviews some of the short- and long-term consequences when sleep is disrupted
during critical illness. However, a dearth of data highlights the vast array of research
opportunities in the area. Further research is needed to evaluate the role of ICU-
related sleep disruption on clinically important patient outcomes, in particular on
immunity and cognition. Circadian rhythms are also gaining attention in the ICU, in
particular in the context of balancing the provision of potentially lifesaving treat-
ments while minimizing the short- and long-term impairments imposed by critical
illness itself. While multicomponent bundled interventions are recommended for all
critically ill patients, the ideal strategy to optimize sleep and associated outcomes
remains unknown and represents a complex and fascinating topic of future
investigation.
Music
Massage
Ear Plugs
Eye Mask
Behavioral
Acupressure
White Noise
Intervention
Modification
Aromatherapy
Foot reflexology
(e.g. quiet time,
Guided Imagery
clustering of care)
(men)
sound
Impact
↓ Anxiety
↓ Waking
↓ Delirium
↓ Sedative use
and/or noise
↑ Sleep quality
↑ Sleep quality
↑ Sleep quality
↑ Sleep quality
↑ Sleep quality
No improvement
↑ Sleep quality
↓ Ambient light
↑ Subjective sleep
↓ Average peak
↑ Sleep efficiency
Kahn et al [n= all ICU staff] (147)

Olson et al [n=239] (148)
Monsen and Edell-Gustafsson [n=23] (149)
Dennis et al [n=50] (55)
Li et al [n=55] (30)
Faraklas et al [n=130] (150)
Maidl et al [n=129] (151)
Foster and Kelly [n=32] (152)
Hansen et al [n=37] (153)
Walder et al [n=17] (154)
Kamdar et al [n=300] (28)
Table 19.2 Interventions to promote sleep in the ICU setting
Patel et al [n=338] (29)

Boyko et al [n=17] (155)
Haddock [n=18] (156)
Scotto et al [n=88] (31)
Neyse et al [n=60] (157)
Van Rompaey et al [n=136] (158)
Richardson at al [n=64] (159)
Ryu et al [58] (160)
Jones and Dawson [n=100] (161)
Le Guen et al [n=41] (162)
Yazdannik et al [n=50] (32)
Dave et al [n=50] (163)
Mashayekhi et al [n=90] (164)
Bajwa et al [n=100] (165)
Hu et al [n=45] (166)
Babaii [n=60] (167)
Mashayekhi et al [n=60] (168)
Daneshmandi et al [n=60] (169)
Richardson [n=36] (170)
Chlan et al [n=373] (171)
Su et al [n=28] (172)
Gragert [n=40] (173)
Williamson [n=60] (174)
Afshar et al [n=60] (175)
Richards [n=69] (27)
Nerbass et al [n=57] (176)
Oshvandi et al [n=60] (177)
Shinde and Anjum [n=60] (178)
Hsu et al [n=60] (179)
Moeini et al [n=64] (180)
Cho et al [56] (181)
Hajibagheri et al [60] (182)
Karadag et a [n=60] (183)
Cho et al [n=60] (184)
Chen et al [85] (185)
Bagheri-Nesami et al [n=90] (186)
Rahmani et al [n=140] (187)
Acknowledgments Dr. Malhotra is funded by the NIH. He reports income related to medical
education from LivaNova and Equillium and serves on a DSMB for Corvus. ResMed provided a
philanthropic donation to UC San Diego. Dr. Kamdar is supported by a Paul B. Beeson Career
Development Award through the National Institutes of Health/National Institute on Aging (K76
AG059936).
Dr. Lam is supported by the Academic Sleep Pulmonary Integrated Research/Clinical
Fellowship through the American Thoracic Society and by the NIH (5T32HL134632-04).
References
1. Mathur R, Douglas NJ. Frequency of EEG arousals from nocturnal sleep in normal subjects.
Sleep. 1995;18(5):330–3.
2. Boselli M, Parrino L, Smerieri A, Terzano MG. Effect of age on EEG arousals in normal
sleep. Sleep. 1998;21(4):351–7.
3. Bonnet MH, Arand DL. EEG arousal norms by age. J Clin Sleep Med. 2007;3(3):271–4.
4. Oldham MA, Lee HB, Desan PH. Circadian rhythm disruption in the critically ill: an oppor-
tunity for improving outcomes. Crit Care Med. 2016;44(1):207–17.
5. Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke.
1998;29(5):992–6.
6. Martin RJ. Nocturnal asthma: circadian rhythms and therapeutic interventions. Am Rev
Respir Dis. 1993;147(6 Pt 2):S25–8.
7. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, et al. Circadian
variation in the frequency of onset of acute myocardial infarction. N Engl J Med.
1985;313(21):1315–22.
8. Brainard J, Gobel M, Bartels K, Scott B, Koeppen M, Eckle T. Circadian rhythms in anes-
thesia and critical care medicine: potential importance of circadian disruptions. Semin
Cardiothorac Vasc Anesth. 2015;19(1):49–60.
9. McKenna H, Reiss I, Martin D. The significance of circadian rhythms and dysrhythmias in
critical illness. J Intensive Care Soc. 2017;18(2):121–9.
10. Hilton BA. Quantity and quality of patients’ sleep and sleep-disturbing factors in a respira-
tory intensive care unit. J Adv Nurs. 1976;1(6):453–68.
11. Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic record-
ing of sleep in nine patients receiving postoperative care. Br Med J. 1985;290(6474):1029–32.
12. Gabor JY, Cooper AB, Crombach SA, Lee B, Kadikar N, Bettger HE, et al. Contribution of
the intensive care unit environment to sleep disruption in mechanically ventilated patients
and healthy subjects. Am J Respir Crit Care Med. 2003;167(5):708–15.
13. Knauert MP, Yaggi HK, Redeker NS, Murphy TE, Araujo KL, Pisani MA. Feasibility
study of unattended polysomnography in medical intensive care unit patients. Heart Lung.
2014;43(5):445–52.
14. Knauert MP, Malik V, Kamdar BB. Sleep and sleep disordered breathing in hospitalized
patients. Semin Respir Crit Care Med. 2014;35(5):582–92.
15. Freedman NS, Gazendam J, Levan L, Pack AI, Schwab RJ. Abnormal sleep/wake cycles and
the effect of environmental noise on sleep disruption in the intensive care unit. Am J Respir
Crit Care Med. 2001;163(2):451–7.
16. Watson PL, Pandharipande P, Gehlbach BK, Thompson JL, Shintani AK, Dittus BS, et al.
Atypical sleep in ventilated patients: empirical electroencephalography findings and the path
toward revised ICU sleep scoring criteria. Crit Care Med. 2013;41(8):1958–67.
17. King LM, Bailey KB, Kamdar BB. Promoting sleep in critically ill patients. Nurs Crit Care.
2015;10(3):37–43.
18. Kamdar BB, Needham DM, Collop NA. Sleep deprivation in critical illness: its role in physi-
cal and psychological recovery. J Intensive Care Med. 2012;27(2):97–111.
19. Schwab KE, To AQ, Chang J, Ronish B, Needham DM, Martin JL, et al. Actigraphy to mea-
sure physical activity in the intensive care unit: a systematic review. J Intensive Care Med.
2019;35(11):1323–31. https://doi.org/10.1177/0885066619863654.
20. Schwab KE, Ronish B, Needham DM, To AQ, Martin JL, Kamdar BB. Actigraphy
to evaluate sleep in the intensive care unit. A systematic review. Ann Am Thorac Soc.
2018;15(9):1075–82.
21. Kamdar BB, Kadden DJ, Vangala S, Elashoff DA, Ong MK, Martin JL, et al. Feasibility
of continuous actigraphy in patients in a medical intensive care unit. Am J Crit Care.
2017;26(4):329–35.
22. Martin J, Marler M, Shochat T, Ancoli-Israel S. Circadian rhythms of agitation in institution-
alized patients with Alzheimer’s disease. Chronobiol Int. 2000;17(3):405–18.
23. Yang P-L, Ward TM, Burr RL, Kapur VK, McCurry SM, Vitiello MV, et al. Sleep and circa-
dian rhythms in survivors of acute respiratory failure. Front Neurol. 2020;11:94.
24. Gupta P, Martin JL, Needham DM, Vangala S, Colantuoni E, Kamdar BB. Use of actig-
raphy to characterize inactivity and activity in patients in a medical ICU. Heart Lung.
2020;49(4):398–406.
25. Snyder-Halpern R, Verran JA. Instrumentation to describe subjective sleep characteristics in
healthy subjects. Res Nurs Health. 1987;10(3):155–63.
26. Shahid A, Wilkinson K, Marcu S, Shapiro C. Verran and Snyder-Halpern sleep scale (VSH).
In: Shahid A, Wilkinson K, Marcu S, Shapiro CM, editors. STOP, THAT and one hundred
other sleep scales. New York: Springer; 2012. p. 397–8.
27. Richards KC. Effect of a back massage and relaxation intervention on sleep in critically ill
patients. Am J Crit Care. 1998;7(4):288–99.
28. Kamdar BB, King LM, Collop NA, Sakamuri S, Colantuoni E, Neufeld KJ, et al. The effect
of a quality improvement intervention on perceived sleep quality and cognition in a medical
ICU. Crit Care Med. 2013;41(3):800–9.
29. Patel J, Baldwin J, Bunting P, Laha S. The effect of a multicomponent multidisciplinary
bundle of interventions on sleep and delirium in medical and surgical intensive care patients.
Anaesthesia. 2014;69(6):540–9.
30. Li SY, Wang TJ, Vivienne Wu SF, Liang SY, Tung HH. Efficacy of controlling night-time
noise and activities to improve patients’ sleep quality in a surgical intensive care unit. J Clin
Nurs. 2011;20(3–4):396–407.
31. Scotto CJ, McClusky C, Spillan S, Kimmel J. Earplugs improve patients’ subjective experi-
ence of sleep in critical care. Nurs Crit Care. 2009;14(4):180–4.
32. Yazdannik AR, Zareie A, Hasanpour M, Kashefi P. The effect of earplugs and eye mask
on patients’ perceived sleep quality in intensive care unit. Iran J Nurs Midwifery Res.
2014;19(6):673–8.
33. Shahid A, Wilkinson K, Marcu S, Shapiro C. Richards–Campbell sleep questionnaire
(RCSQ). In: Shahid A, Wilkinson K, Marcu S, Shapiro CM, editors. STOP, THAT and one
hundred other sleep scales. New York: Springer; 2012. p. 299–302.
34. Figueroa-Ramos MI, Arroyo-Novoa CM, Lee KA, Padilla G, Puntillo KA. Sleep and
delirium in ICU patients: a review of mechanisms and manifestations. Intensive Care Med.
2009;35(5):781–95.
35. Nicolas A, Aizpitarte E, Iruarrizaga A, Vazquez M, Margall A, Asiain C. Perception of night-
time sleep by surgical patients in an intensive care unit. Nurs Crit Care. 2008;13(1):25–33.
36. Kamdar BB, Shah PA, King LM, Kho ME, Zhou X, Colantuoni E, et al. Patient-nurse inter-
rater reliability and agreement of the Richards-Campbell sleep questionnaire. Am J Crit Care.
2012;21(4):261–9.
37. Engwall M, Fridh I, Johansson L, Bergbom I, Lindahl B. Lighting, sleep and circadian rhythm:
an intervention study in the intensive care unit. Intensive Crit Care Nurs. 2015;31(6):325–35.
38. Simons KS, Laheij RJ, van den Boogaard M, Moviat MA, Paling AJ, Polderman FN, et al.
Dynamic light application therapy to reduce the incidence and duration of delirium in
intensive-care patients: a randomised controlled trial. Lancet Respir Med. 2016;4(3):194–202.
39. Dorsch JJ, Martin JL, Malhotra A, Owens RL, Kamdar BB. Sleep in the intensive care unit:
strategies for improvement. Semin Respir Crit Care Med. 2019;40(5):614–28.
40. Kamdar BB, Simons KS, Spronk PE. Can ICUs create more sleep by creating less noise?
Intensive Care Med. 2020;46(3):498–500.
41. Kamdar BB, Martin JL, Needham DM. Noise and light pollution in the hospital: a call for
action. J Hosp Med. 2017;12(10):861–2.
42. Darbyshire JL, Muller-Trapet M, Cheer J, Fazi FM, Young JD. Mapping sources of noise in
an intensive care unit. Anaesthesia. 2019;74(8):1018–25.
43. Park M, Kohlrausch A, de Bruijn W, de Jager P, Simons K. Analysis of the soundscape
in an intensive care unit based on the annotation of an audio recording. J Acoust Soc Am.
2014;135(4):1875–86.
44. Elbaz M, Leger D, Sauvet F, Champigneulle B, Rio S, Strauss M, et al. Sound level intensity
severely disrupts sleep in ventilated ICU patients throughout a 24-h period: a preliminary
24-h study of sleep stages and associated sound levels. Ann Intensive Care. 2017;7(1):25.
45. Tainter CR, Levine AR, Quraishi SA, Butterly AD, Stahl DL, Eikermann M, et al. Noise
levels in surgical ICUs are consistently above recommended standards. Crit Care Med.
2016;44(1):147–52.
46. Darbyshire JL, Young JD. An investigation of sound levels on intensive care units with refer-
ence to the WHO guidelines. Crit Care. 2013;17(5):R187.
47. Gardner G, Collins C, Osborne S, Henderson A, Eastwood M. Creating a therapeutic environ-
ment: a non-randomised controlled trial of a quiet time intervention for patients in acute care.
Int J Nurs Stud. 2009;46(6):778–86.
48. Horsten S, Reinke L, Absalom AR, Tulleken JE. Systematic review of the effects of
intensive-care-unit noise on sleep of healthy subjects and the critically ill. Br J Anaesth.
2018;120(3):443–52.
49. Jaiswal SJ, Garcia S, Owens RL. Sound and light levels are similarly disruptive in ICU and
non-ICU wards. J Hosp Med. 2017;12(10):798–804.
50. Jha AK, Orav EJ, Zheng J, Epstein AM. Patients’ perception of hospital care in the United
States. N Engl J Med. 2008;359(18):1921–31.
51. Freedman NS, Kotzer N, Schwab RJ. Patient perception of sleep quality and etiology of sleep
disruption in the intensive care unit. Am J Respir Crit Care Med. 1999;159(4 Pt 1):1155–62.
52. Wright KP Jr, McHill AW, Birks BR, Griffin BR, Rusterholz T, Chinoy ED. Entrainment of
the human circadian clock to the natural light-dark cycle. Curr Biol. 2013;23(16):1554–8.
53. Voigt LP, Reynolds K, Mehryar M, Chan WS, Kostelecky N, Pastores SM, et al. Monitoring
sound and light continuously in an intensive care unit patient room: a pilot study. J Crit Care.
2017;39:36–9.
54. Fan EP, Abbott SM, Reid KJ, Zee PC, Maas MB. Abnormal environmental light exposure in
the intensive care environment. J Crit Care. 2017;40:11–4.
55. Dennis CM, Lee R, Woodard EK, Szalaj JJ, Walker CA. Benefits of quiet time for neuro-
intensive care patients. J Neurosci Nurs. 2010;42(4):217–24.
56. Verceles AC, Liu X, Terrin ML, Scharf SM, Shanholtz C, Harris A, et al. Ambient light levels
and critical care outcomes. J Crit Care. 2013;28(1):110.e1–8.
57. Meyer TJ, Eveloff SE, Bauer MS, Schwartz WA, Hill NS, Millman RP. Adverse environmen-
tal conditions in the respiratory and medical ICU settings. Chest. 1994;105(4):1211–6.
58. Mundigler G, Delle-Karth G, Koreny M, Zehetgruber M, Steindl-Munda P, Marktl W, et al.
Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe
sepsis. Crit Care Med. 2002;30(3):536.
59. Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma
melatonin concentration in postoperative critically ill patients: its association with delirium.
J Crit Care. 2013;28(3):236–42.
60. Miyazaki T, Kuwano H, Kato H, Ando H, Kimura H, Inose T, et al. Correlation between
serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagec-
tomy. Surgery. 2003;133(0039-6060; 0039-6060; 6):662.
61. Mo Y, Scheer CE, Abdallah GT. Emerging role of melatonin and melatonin receptor agonists
in sleep and delirium in intensive care unit patients. J Intensive Care Med. 2016;31(7):451–5.
62. Shilo L, Dagan Y, Smorjik Y, Weinberg U, Dolev S, Komptel B, et al. Effect of melatonin on
sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int. 2000;17(1):71–6.
63. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in criti-
cally ill patients: encouraging results from a small randomised controlled trial. Crit Care.
2008;12(2):R52.
64. Ibrahim MG, Bellomo R, Hart GK, Norman TR, Goldsmith D, Bates S, et al. A double-
blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised
patients. Crit Care Resusc. 2006;8(3):187–91.
65. Jaiswal SJ, Vyas AD, Heisel AJ, Ackula H, Aggarwal A, Kim NH, et al. Ramelteon for pre-
vention of postoperative delirium: a randomized controlled trial in patients undergoing elec-
tive pulmonary thromboendarterectomy. Crit Care Med. 2019;47(12):1751–8.
66. Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, et al. Preventive effects of ramelt-
eon on delirium: a randomized placebo-controlled trial. JAMA Psychiat. 2014;71(4):397–403.
67. Malik V, Parthasarathy S. Sleep in intensive care units. Curr Resp Care Rep. 2014;3(2):35–41.
68. Tamburri LM, DiBrienza R, Zozula R, Redeker NS. Nocturnal care interactions with patients
in critical care units. Am J Crit Care. 2004;13(2):102–12; quiz 14–5.
69. Celik S, Oztekin D, Akyolcu N, Issever H. Sleep disturbance: the patient care activities
applied at the night shift in the intensive care unit. J Clin Nurs. 2005;14(1):102.
70. Kamdar BB, Kamdar BB, Needham DM. Bundling sleep promotion with delirium preven-
tion: ready for prime time? Anaesthesia. 2014;69(6):527–31.
71. Kamdar BB, Yang J, King LM, Neufeld KJ, Bienvenu OJ, Rowden AM, et al. Developing,
implementing, and evaluating a multifaceted quality improvement intervention to promote
sleep in an ICU. Am J Med Qual. 2014;29(6):546–54.
72. Kamdar BB, Martin JL, Needham DM, Ong MK. Promoting sleep to improve delirium in the
ICU. Crit Care Med. 2016;44(12):2290–1.
73. Smolensky MH, Hermida RC, Reinberg A, Sackett-Lundeen L, Portaluppi F. Circadian dis-
ruption: new clinical perspective of disease pathology and basis for chronotherapeutic inter-
vention. Chronobiol Int. 2016;33(8):1101–19.
74. Song J-U, Park HK, Lee J. Impact of dosage timing of once-daily inhaled corticoste-
roids in asthma: a systematic review and meta-analysis. Ann Allergy Asthma Immunol.
2018;120(5):512–9.
75. Ozturk N, Ozturk D, Kavakli IH, Okyar A. Molecular aspects of circadian pharmacology and
relevance for cancer chronotherapy. Int J Mol Sci. 2017;18(10):2168.
76. Cooper AB, Thornley KS, Young GB, Slutsky AS, Stewart TE, Hanly PJ. Sleep in critically
ill patients requiring mechanical ventilation. Chest. 2000;117(3):809–18.
77. Hardin KA, Seyal M, Stewart T, Bonekat HW. Sleep in critically ill chemically paralyzed
patients requiring mechanical ventilation. Chest. 2006;129(0012-3692; 0012-3692; 6):1468.
78. Poongkunran C, John SG, Kannan AS, Shetty S, Bime C, Parthasarathy S. A meta-analysis
of sleep-promoting interventions during critical illness. Am J Med. 2015;128(10):1126–37.
79. Bosma K, Ferreyra G, Ambrogio C, Pasero D, Mirabella L, Braghiroli A, et al. Patient-
ventilator interaction and sleep in mechanically ventilated patients: pressure support versus
proportional assist ventilation. Crit Care Med. 2007;35(4):1048.
80. Cabello B, Thille AW, Drouot X, Galia F, Mancebo J, d’Ortho MP, et al. Sleep quality in
mechanically ventilated patients: comparison of three ventilatory modes. Crit Care Med.
2008;36(6):1749.
81. Parthasarathy S, Tobin MJ. Effect of ventilator mode on sleep quality in critically ill patients.
Am J Respir Crit Care Med. 2002;166(1073-449; 1073-449; 11):1423.
82. Delisle S, Ouellet P, Bellemare P, Tetrault JP, Arsenault P. Sleep quality in mechanically
ventilated patients: comparison between NAVA and PSV modes. Ann Intensive Care.
2011;1(1):42.
83. Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, et al.
Clinical practice guidelines for the prevention and management of pain, agitation/seda-
tion, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med.
2018;46(9):e825–e73.
84. Cardinali DP, Brown GM, Reiter RJ, Pandi-Perumal SR. Elderly as a high-risk group during
COVID-19 pandemic: effect of circadian misalignment, sleep dysregulation and melatonin
administration. Sleep Vigil. 2020;4:81–7.
85. Zhang J, Xu D, Xie B, Zhang Y, Huang H, Liu H, et al. Poor-sleep is associated with slow
recovery from lymphopenia and an increased need for ICU care in hospitalized patients with
COVID-19: a retrospective cohort study. Brain Behav Immun. 2020;88:50–8.
86. Zambrelli E, Canevini M, Gambini O, D’Agostino A. Delirium and sleep disturbances in
COVID–19: a possible role for melatonin in hospitalized patients? Sleep Med. 2020;70:111.
87. LaHue SC, Douglas VC, Miller BL. The one-two punch of delirium and dementia during the
COVID-19 pandemic and beyond. Front Neurol. 2020;11:1409.
88. Cohen S, Doyle WJ, Alper CM, Janicki-Deverts D, Turner RB. Sleep habits and susceptibility
to the common cold. Arch Intern Med. 2009;169(1):62–7.
89. Patel SR, Malhotra A, Gao X, Hu FB, Neuman MI, Fawzi WW. A prospective study of sleep
duration and pneumonia risk in women. Sleep. 2012;35(1):97–101.
90. Prather AA, Leung CW. Association of insufficient sleep with respiratory infection among
adults in the United States. JAMA Intern Med. 2016;176(6):850–2.
91. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immuniza-
tion. JAMA. 2002;288(12):1471–2.
92. Benedict C, Brytting M, Markstrom A, Broman JE, Schioth HB. Acute sleep deprivation has
no lasting effects on the human antibody titer response following a novel influenza A H1N1
virus vaccination. BMC Immunol. 2012;13:1.
93. Lange T, Perras B, Fehm HL, Born J. Sleep enhances the human antibody response to hepa-
titis A vaccination. Psychosom Med. 2003;65(5):831–5.
94. Lange T, Dimitrov S, Bollinger T, Diekelmann S, Born J. Sleep after vaccination boosts
immunological memory. J Immunol. 2011;187(1):283–90.
95. Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiol
Rev. 2019;99(3):1325–80.
96. Möller-Levet CS, Archer SN, Bucca G, Laing EE, Slak A, Kabiljo R, et al. Effects of insuf-
ficient sleep on circadian rhythmicity and expression amplitude of the human blood transcrip-
tome. Proc Natl Acad Sci U S A. 2013;110(12):E1132–41.
97. Foo JC, Trautmann N, Sticht C, Treutlein J, Frank J, Streit F, et al. Longitudinal transcriptome-
wide gene expression analysis of sleep deprivation treatment shows involvement of circadian
genes and immune pathways. Transl Psychiatry. 2019;9(1):343.
98. Aggarwal B, Makarem N, Shah R, Emin M, Wei Y, St-Onge MP, et al. Effects of inadequate
sleep on blood pressure and endothelial inflammation in women: findings from the American
Heart Association go red for women strategically focused research network. J Am Heart
Assoc. 2018;7(12):e008590.
99. Dominguez F, Fuster V, Fernandez-Alvira JM, Fernandez-Friera L, Lopez-Melgar B, Blanco-
Rojo R, et al. Association of sleep duration and quality with subclinical atherosclerosis. J Am
Coll Cardiol. 2019;73(2):134–44.
100. McAlpine CS, Kiss MG, Rattik S, He S, Vassalli A, Valet C, et al. Sleep modulates haemato-
poiesis and protects against atherosclerosis. Nature. 2019;566(7744):383–7.
101. Bakker JP, Weng J, Wang R, Redline S, Punjabi NM, Patel SR. Associations between obstruc-
tive sleep apnea, sleep duration, and abnormal fasting glucose. The multi-ethnic study of
atherosclerosis. Am J Respir Crit Care Med. 2015;192(6):745–53.
102. Tanno S, Tanigawa T, Saito I, Nishida W, Maruyama K, Eguchi E, et al. Sleep-related
intermittent hypoxemia and glucose intolerance: a community-based study. Sleep Med.
2014;15(10):1212–8.
103. Stamatakis KA, Punjabi NM. Effects of sleep fragmentation on glucose metabolism in nor-
mal subjects. Chest. 2010;137(1):95–101.
104. Wang Y, Carreras A, Lee S, Hakim F, Zhang SX, Nair D, et al. Chronic sleep fragmentation
promotes obesity in young adult mice. Obesity. 2013;22(3):758–62.
105. Poroyko VA, Carreras A, Khalyfa A, Khalyfa AA, Leone V, Peris E, et al. Chronic sleep dis-
ruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin
resistance in mice. Sci Rep. 2016;6(1):35405.
106. Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O’Connor GT, Resnick HE, et al. Obstructive
sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care
Med. 2010;182(2):269–77.
apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–41.
108. Hakim F, Wang Y, Zhang SXL, Zheng J, Yolcu ES, Carreras A, et al. Fragmented sleep accel-
erates tumor growth and progression through recruitment of tumor-associated macrophages
and TLR4 signaling. Cancer Res. 2014;74(5):1329–37.
109. Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farré R. Sleep-disordered breathing and
cancer mortality. Am J Respir Crit Care Med. 2012;186(2):190–4.
110. Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin
Immunol. 2005;116(6):1188–98.
111. Pollmächer T, Schreiber W, Gudewill S, Vedder H, Fassbender K, Wiedemann K, et al.
Influence of endotoxin on nocturnal sleep in humans. Am J Phys. 1993;264(6 Pt 2):R1077–83.
112. Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, et al. Dose-
dependent effects of endotoxin on human sleep. Am J Phys Regul Integr Comp Phys.
2000;278(4):R947–55.
113. Friese RS, Bruns B, Sinton CM. Sleep deprivation after septic insult increases mortality inde-
pendent of age. J Trauma. 2009;66(1):50–4.
114. Lungato L, Gazarini ML, Paredes-Gamero EJ, Tufik S, D’Almeida V. Paradoxical sleep depri-
vation impairs mouse survival after infection with malaria parasites. Malar J. 2015;14:183.
115. Chou KT, Cheng SC, Huang SF, Perng DW, Chang SC, Chen YM, et al. Impact of intermit-
tent hypoxia on sepsis outcomes in a murine model. Sci Rep. 2019;9(1):12900.
116. Davis CJ, Dunbrasky D, Oonk M, Taishi P, Opp MR, Krueger JM. The neuron-specific inter-
leukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to
influenza viral challenge in mice. Brain Behav Immun. 2015;47(C):35–43.
117. Rechtschaffen A, Bergmann BM. Sleep deprivation in the rat: an update of the 1989 paper.
Sleep. 2002;25(1):18–24.
118. Everson CA, Toth LA. Systemic bacterial invasion induced by sleep deprivation. Am J
Physiol Regul Integr Comp Physiol. 2000;278(4):R905–16.
119. Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, et al. Hospital deaths in
patients with sepsis from 2 independent cohorts. JAMA. 2014;312(1):90–2.
120. Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P, et al.
Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates
and limitations. Am J Respir Crit Care Med. 2016;193(3):259–72.
121. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global,
regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global
Burden of Disease Study. Lancet (London, England). 2020;395(10219):200–11.
122. Shankar-Hari M, Rubenfeld GD. Understanding long-term outcomes following sepsis: impli-
cations and challenges. Curr Infect Dis Rep. 2016;18(11):37.
123. Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, et al. Delirium.
Nat Rev Dis Primers. 2020;6(1):90.
124. Kamdar BB, Knauert MP, Jones SF, Parsons EC, Parthasarathy S, Pisani MA, et al.
Perceptions and practices regarding sleep in the intensive care unit. A survey of 1,223 critical
care providers. Ann Am Thorac Soc. 2016;13(8):1370–7.
125. Kamdar BB, Niessen T, Colantuoni E, King LM, Neufeld KJ, Bienvenu OJ, et al. Delirium
transitions in the medical ICU: exploring the role of sleep quality and other factors. Crit Care
Med. 2015;43(1):135–41.
126. Salluh JIF, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, et al. Outcome of
delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015;350:h2538.
127. Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, et al. The
association between brain volumes, delirium duration, and cognitive outcomes in intensive
care unit survivors: the VISIONS cohort magnetic resonance imaging study*. Crit Care Med.
2012;40(7):2022–32.
128. Morandi A, Rogers BP, Gunther ML, Merkle K, Pandharipande P, Girard TD, et al. The
relationship between delirium duration, white matter integrity, and cognitive impairment in
intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS pro-
spective cohort magnetic resonance imaging study*. Crit Care Med. 2012;40(7):2182–9.
129. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-
term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306–16.
130. Davis DH, Muniz Terrera G, Keage H, Rahkonen T, Oinas M, Matthews FE, et al. Delirium
is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain.
2012;135(Pt 9):2809–16.
131. Helton MC, Gordon SH, Nunnery SL. The correlation between sleep deprivation and the
intensive care unit syndrome. Heart Lung. 1980;9(3):464.
132. Yildizeli B, Ozyurtkan MO, Batirel HF, Kuscu K, Bekiroglu N, Yuksel M. Factors associated
with postoperative delirium after thoracic surgery. Ann Thorac Surg. 2005;79(3):1004.
133. Trompeo AC, Vidi Y, Locane MD, Braghiroli A, Mascia L, Bosma K, et al. Sleep distur-
bances in the critically ill patients: role of delirium and sedative agents. Minerva Anestesiol.
2011;77(6):604–12.
134. Lonardo NW, Mone MC, Nirula R, Kimball EJ, Ludwig K, Zhou X, et al. Propofol is associ-
ated with favorable outcomes compared with benzodiazepines in ventilated intensive care
unit patients. Am J Respir Crit Care Med. 2014;189(11):1383–94.
135. Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, et al. Lorazepam
is an independent risk factor for transitioning to delirium in intensive care unit patients.
Anesthesiology. 2006;104(1):21–6.
136. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the
neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit
Care Clin. 2008;24(4):789–856, ix.
137. Pandharipande P, Cotton BA, Shintani A, Thompson J, Pun BT, Morris JA Jr, et al. Prevalence
and risk factors for development of delirium in surgical and trauma intensive care unit
patients. J Trauma. 2008;65(1):34.
138. McPherson JA, Wagner CE, Boehm LM, Hall JD, Johnson DC, Miller LR, et al. Delirium in
the cardiovascular ICU: exploring modifiable risk factors. Crit Care Med. 2013;41(2):405–13.
139. Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, et al. Haloperidol and
ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379(26):2506–16.
140. Van Den Boogaard M, Slooter AJ, Brüggemann RJ, Schoonhoven L, Beishuizen A,
Vermeijden JW, et al. Effect of haloperidol on survival among critically ill adults with a high
risk of delirium: the REDUCE randomized clinical trial. JAMA. 2018;319(7):680–90.
141. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al. Effect of sedation
with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated
patients: the MENDS randomized controlled trial. JAMA. 2007;298(22):2644.
142. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al.
Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.
JAMA. 2009;301(5):489.
143. Nelson Laura E, Lu J, Guo T, Saper Clifford B, Franks Nicholas P, Maze M. The
α2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting
pathway to exert its sedative effects. Anesthesiology. 2003;98(2):428–36.
144. Shehabi Y, Howe BD, Bellomo R, Arabi YM, Bailey M, Bass FE, et al. Early sedation with
dexmedetomidine in critically ill patients. N Engl J Med. 2019;380(26):2506–17.
145. Pandharipande PP, Ely EW, Arora RC, Balas MC, Boustani MA, La Calle GH, et al. The
intensive care delirium research agenda: a multinational, interprofessional perspective.
Intensive Care Med. 2017;43(9):1329–39.
146. Chang VA, Owens RL, LaBuzetta JN. Impact of sleep deprivation in the neurological inten-
sive care unit: a narrative review. Neurocrit Care. 2020;32(2):596–608.
147. Kahn DM, Cook TE, Carlisle CC, Nelson DL, Kramer NR, Millman RP. Identification
and modification of environmental noise in an ICU setting. Chest. 1998;114(0012-3692;
0012-3692; 2):535.
148. Olson DM, Borel CO, Laskowitz DT, Moore DT, McConnell ES. Quiet time: a nursing inter-
vention to promote sleep in neurocritical care units. Am J Crit Care. 2001;10(2):74–8.
149. Monsen MG, Edell-Gustafsson UM. Noise and sleep disturbance factors before and after
implementation of a behavioural modification programme. Intensive Crit Care Nurs.
2005;21(4):208.
150. Faraklas I, Holt B, Tran S, Lin H, Saffle J, Cochran A. Impact of a nursing-driven sleep
hygiene protocol on sleep quality. J Burn Care Res. 2013;34(2):249–54.
151. Maidl CA, Leske JS, Garcia AE. The influence of “quiet time” for patients in critical care.
Clin Nurs Res. 2014;23(5):544–59.
152. Foster J, Kelly M. A pilot study to test the feasibility of a nonpharmacologic interven-
tion for the prevention of delirium in the medical intensive care unit. Clin Nurse Spec.
2013;27(5):231–8.
153. Hansen IP, Langhorn L, Dreyer P. Effects of music during daytime rest in the intensive care
unit. Nurs Crit Care. 2018;23(4):207–13.
154. Walder B, Francioli D, Meyer JJ, Lancon M, Romand JA. Effects of guidelines implementa-
tion in a surgical intensive care unit to control nighttime light and noise levels. Crit Care Med.
2000;28(7):2242–7.
155. Boyko Y, Jennum P, Nikolic M, Holst R, Oerding H, Toft P. Sleep in intensive care unit: the
role of environment. J Crit Care. 2017;37:99–105.
156. Haddock J. Reducing the effects of noise in hospital. Nurs Stand. 1994;8(43):25–8.
157. Neyse F, Daneshmandi M, Sadeghi Sharme M, Ebadi A. The effect of earplugs on sleep qual-
ity in patients with acute coronary syndrome. Iran J Crit Care Nurs. 2011;4(3):127–34.
158. Van Rompaey B, Elseviers MM, Van Drom W, Fromont V, Jorens PG. The effect of earplugs
during the night on the onset of delirium and sleep perception: a randomized controlled trial
in intensive care patients. Crit Care. 2012;16(3):R73.
159. Richardson A, Allsop M, Coghill E, Turnock C. Earplugs and eye masks: do they improve
critical care patients’ sleep? Nurs Crit Care. 2007;12(6):278.
160. Ryu MJ, Park JS, Park H. Effect of sleep-inducing music on sleep in persons with per-
cutaneous transluminal coronary angiography in the cardiac care unit. J Clin Nurs.
2012;21(5–6):728–35.
161. Jones C, Dawson D. Eye masks and earplugs improve patient’s perception of sleep. Nurs Crit
Care. 2012;17(5):247–54.
162. Le Guen M, Nicolas-Robin A, Lebard C, Arnulf I, Langeron O. Earplugs and eye masks vs
routine care prevent sleep impairment in post-anaesthesia care unit: a randomized study. Br J
Anaesth. 2014;112(1):89–95.
163. Dave K, Qureshi A, Gopichandran L. Effects of earplugs and eye masks on perceived qual-
ity of sleep during night among patients in intensive care units. Int J Sci Res (Ahmedabad).
2015;5(3):319–22.
164. Mashayekhi F, Rafiei H, Arab M, Abazari F, Ranjbar HJ. The effect of sleep quality on
patients in a coronary care unit. Br J Cardiac Nurs. 2013;8(9):443–7.
165. Bajwa N, Saini P, Kaur H, Kalra S, Kaur J. Effect of ear plugs and eye mask on sleep among
ICU patients: a randomized control trial. Int J Curr Res. 2015;7(12):23741–5.
166. Hu RF, Jiang XY, Hegadoren KM, Zhang YH. Effects of earplugs and eye masks combined
with relaxing music on sleep, melatonin and cortisol levels in ICU patients: a randomized
controlled trial. Crit Care. 2015;19:115.
167. Babaii A, Adib-Hajbaghery M, Hajibagheri A. Effect of using eye mask on sleep quality in
cardiac patients: a randomized controlled trial. Nurs Midwifery Stud. 2015;4(4):e28332.
168. Mashayekhi F, Pilevarzadeh M, Amiri M, Rafiei H. The effect of eye mask on sleep quality in
patients of coronary care unit o efeito da mascara de olhos na qualidade de sono em pacientes
em uma unidade coronariana. Sleep Sci. 2013;6(3):108–11.
169. Daneshmandi M, Neiseh F, SadeghiShermeh M, Ebadi A. Effect of eye mask on sleep quality
in patients with acute coronary syndrome. J Caring Sci. 2012;1(3):135–43.
170. Richardson S. Effects of relaxation and imagery on the sleep of critically ill adults. Dimens
Crit Care Nurs. 2003;22(4):182–90.
171. Chlan LL, Weinert CR, Heiderscheit A, Tracy MF, Skaar DJ, Guttormson JL, et al.
Effects of patient-directed music intervention on anxiety and sedative exposure in criti-
cally ill patients receiving mechanical ventilatory support: a randomized clinical trial.
JAMA. 2013;309(22):2335–44.
172. Su CP, Lai HL, Chang ET, Yiin LM, Perng SJ, Chen PW. A randomized controlled trial of
the effects of listening to non-commercial music on quality of nocturnal sleep and relaxation
indices in patients in medical intensive care unit. J Adv Nurs. 2013;69(6):1377–89.
173. Gragert MD. The use of a masking signal to enhance the sleep of men and women 65 years
of age and older in the critical care environment: University of Texas at Austin; 1991.
174. Williamson JW. The effects of ocean sounds on sleep after coronary artery bypass graft sur-
gery. Am J Crit Care. 1992;1(1):91.
175. Farokhnezhad Afshar P, Bahramnezhad F, Asgari P, Shiri M. Effect of white noise on sleep in
patients admitted to a coronary care. J Caring Sci. 2016;5(2):103–9.
176. Nerbass FB, Feltrim MI, Souza SA, Ykeda DS, Lorenzi-Filho G. Effects of massage
therapy on sleep quality after coronary artery bypass graft surgery. Clinics (Sao Paulo).
2010;65(11):1105–10.
177. Oshvandi K, ABDI S, Karampourian A, Moghimbaghi A, Homayounfar S. The effect of foot
massage on quality of sleep in ischemic heart disease patients hospitalized in CCU. 2014.
178. Shinde MB, Anjum S. Effectiveness of slow back massage on quality of sleep among ICU
patent’s. Int J Sci Res. 2014;3(3):292–8.
179. Hsu WC, Guo SE, Chang CH. Back massage intervention for improving health and sleep
quality among intensive care unit patients. Nurs Crit Care. 2019;24(5):313–9.
180. Moeini M, Khadibi M, Bekhradi R, Mahmoudian SA, Nazari F. Effect of aromatherapy on
the quality of sleep in ischemic heart disease patients hospitalized in intensive care units of
heart hospitals of the Isfahan University of Medical Sciences. Iran J Nurs Midwifery Res.
2010;15(4):234–9.
181. Cho M-Y, Min ES, Hur M-H, Lee MS. Effects of aromatherapy on the anxiety, vital signs,
and sleep quality of percutaneous coronary intervention patients in intensive care units. Evid
Based Complement Alternat Med. 2013;2013:381381.
182. Hajibagheri A, Babaii A, Adib-Hajbaghery M. Effect of Rosa damascene aromatherapy on
sleep quality in cardiac patients: a randomized controlled trial. Complement Ther Clin Pract.
2014;20(3):159–63.
183. Karadag E, Samancioglu S, Ozden D, Bakir E. Effects of aromatherapy on sleep quality and
anxiety of patients. Nurs Crit Care. 2017;22(2):105–12.
184. Cho EH, Lee MY, Hur MH. The effects of aromatherapy on intensive care unit patients’ stress
and sleep quality: a nonrandomised controlled trial. Evid Based Complement Alternat Med.
2017;2017:2856592.
185. Chen JH, Chao YH, Lu SF, Shiung TF, Chao YF. The effectiveness of valerian acupressure on
the sleep of ICU patients: a randomized clinical trial. Int J Nurs Stud. 2012;49(8):913–20.
186. Bagheri-Nesami M, Gorji MA, Rezaie S, Pouresmail Z, Cherati JY. Effect of acupressure
with valerian oil 2.5% on the quality and quantity of sleep in patients with acute coronary
syndrome in a cardiac intensive care unit. J Tradit Complement Med. 2015;5(4):241–7.
187. Rahmani A, Naseri M, Salaree MM, Nehrir B. Comparing the effect of foot reflexology mas-
sage, foot bath and their combination on quality of sleep in patients with acute coronary
syndrome. J Caring Sci. 2016;5(4):299–306.
Chapter 20
Sleep in Hospitalized Patients
Nancy H. Stewart and Vineet M. Arora
Keywords Sleep · Hospital · ICU · Medical care
Abbreviations
ACOVE-3 Assessing Care of Vulnerable Elders-3
AGS American Geriatrics Society
CABG Coronary artery bypass graft
CPAP Continuous positive airway pressure
EEG Electroencephalogram
HELP Hospital Elder Life Program
ICU Intensive care unit
NICU Neuro-intensive care unit
OSA Obstructive sleep apnea
RCT Randomized controlled trial
REM Rapid eye movement
SIESTA Sleep for Inpatients: Empowering Staff to Act
Sleep Loss in Adults
Over 70 million Americans suffer from a chronic disorder of sleep, which adversely
affects their health [1]. It is estimated by the National Academy of Medicine that
hundreds of billions of dollars per year are spent caring for patients with sleep dis-
orders [1]. Regardless of this, a staggering number of patients suffering from sleep
N. H. Stewart
Department of Medicine, University of Kansas Medical Center, Kansas City, KS, USA
V. M. Arora (*)
Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA
e-mail: varora@uchicago.edu

454 N. H. Stewart and V. M. Arora
disorders remain undiagnosed. Nearly half of the general population (30–48%)

report difficulty initiating or maintaining sleep [2]. Awareness of diagnoses and
treatment of sleep disorders among healthcare professionals and the public remain
very low. The lack of awareness among the general public results from the absence
of sleep awareness in public health education programs [1]. This in turn causes
patients to be hesitant to discuss sleep issues with their healthcare providers.
Sleep is considered a protector of the normal brain activity and strikes a balance
between the various functions of the central nervous system [3]. Shortened sleep
duration is characterized on polysomnography with decreased stage N3 sleep, and
chronic sleep loss can demonstrate a greater percentage of rapid eye movement
sleep [4]. Interestingly, effects of health conditions can also be noted on polysom-
nography [5].
Sleep Loss in Older Adults
Although sleep architecture changes as one ages, there is not a decreased need for
sleep, and sleep disturbance is not an inherent aspect of the aging process [6]. Sleep
disturbance is common in aging adults, not due to aging, in fact due to comorbidi-
ties and psychosocial and polypharmacy factors that elderly often face [6]. A multi-
disciplinary approach to care is encouraged with these patients [6]. Sleep
disturbances in older adults are reported more frequently later in life, among
females, among those with physical disabilities, among those experiencing psychi-
atric health concerns [7].
Health Effects of Sleep Loss in Hospitalized Patients
Unfortunately, the patients most at risk for poor, non-restorative sleep are often also
acutely ill and hospitalized, when they need sleep to recover from their acute illness.
Predictors of poor inpatient sleep quality include decreased sleep duration, increased
nighttime awakenings, younger age, and female [8]. Acute sleep loss in the hospital
has been associated with poor patient outcomes, including cardiometabolic effects
such as high blood pressure, hyperglycemia, as well as delirium [9–11]. In-hospital
acute sleep loss is implicated by Krumholz as a factor in “post-hospital syndrome”
development, an acquired condition of vulnerability and increased risk of hospital
readmission for diseases unrelated to their index admission [12]. Although studies
of long-term consequences of acute sleep loss are lacking, in-hospital sleep loss was
implicated as a potential mediator of post-hospital syndrome.
Prior research has demonstrated in-hospital sleep loss is associated with worse
psychological and cardiometabolic outcomes [11]. Up to 40 percent of hospitalized
medical patients without a diagnosed sleep disorder are at high risk for sleep apnea
[13]. Although patients experience acute in-hospital sleep loss, one would expect
20 Sleep in Hospitalized Patients 455
sleep to improve on discharge, yet sleep loss does not recover in the week following
discharge [14]. The time spent in-hospital provides an opportunity not only to opti-
mize the sleep environment for patients but also to screen patients for undiagnosed
sleep disorders and reduce unnecessary admissions [15].
Barriers to Healthy Sleep in Hospitalized Patients
Despite a paucity of literature regarding sleep loss in hospitalized patients, multiple

factors have been noted to affect the sleep of patients while they are hospitalized. To
understand factors affecting sleep while hospitalized, it is imperative to first under-
stand the effects that hospitalization has upon sleep. Several laboratory and epide-
miological studies suggest sleep deprivation in itself can lead to a variety of intrinsic
physiologic health consequences (i.e., delirium development and metabolic
derangements in blood sugar and blood pressure) [16–19]. Interestingly, these
health consequences are also known complications of hospitalization in patients.
[20, 21] In addition to the health consequences linked to sleep deprivation during
hospitalization (delirium, hyperglycemia, and hypertension), these health condi-
tions are often associated with administration of medications and increased dosages
of medications to ameliorate or control the condition: antipsychotics for delirium,
insulin for hyperglycemia, and antihypertensives to enable blood pressure control.
As such, a significant number of these medications may be continued on after
patient discharge, which subsequently can result in downstream patient harm (i.e.,
polypharmacy, hypoglycemia, and hypotension) [22]. Sleep loss can also impair
recovery during hospitalization due to daytime fatigue and excessive daytime sleep-
iness, hindering participation in recovery activities such as physical or occupational
therapy, as well as participation in important healthcare discussions (i.e., informed
consent, understanding medication changes, discussion discharge/follow-up plans)
[23, 24]. Decreased daytime physical activity is a known contributor to functional
decline, an unfortunate consequence of hospitalization for older adults. In addition,
adults who are less empowered and informed regarding their hospital care are more
likely to experience readmission [25].
Medical Care Interruptions
Obtaining a good night of sleep is not an easy task during hospitalization. Many
factors can lead to sleep disruptions, including environmental factors (e.g., noise),
medical care factors (e.g., medication distribution, vital sign checks, phlebotomy),
and patient factors (e.g., pain, anxiety). Hospitalized patients report difficulty with
sleep initiation and sleep maintenance, decreased sleep quality, and increased day-
time sleepiness [26]. Frequent awakenings by members of the care team represent
a significant barrier to sleep in the hospital setting. One study on patients in the
neuro-intensive care unit (NICU) demonstrated that although hourly neurological

exams may be beneficial in the acute phase of a neurological injury, surprisingly,
prolonged use of these exams was associated with a 75% increase in development
of delirium [27]. Patients awakened often may be unable to complete an entire sleep
cycle and may struggle with falling back to sleep, leading to deprivation of slow-
wave sleep, e.g., stage 3 sleep, and rapid eye movement (REM) sleep (e.g., “dream”
sleep). Routine night awakenings by care team members are often to complete day-
time tasks requested by clinicians, such as vital signs or blood draws [28, 29].
Environmental Factors Disrupting Sleep
Sounds within the walls of the hospital are more than an irritation [32]. The audi-
tory environment in the hospital should complement high standards of compas-
sionate patient care. Failure to provide patients with quiet hospital rooms affects
clinical patient outcomes through multiple mechanisms. Increased noise within the
hospital affects clinical outcomes through increased physiological and stress
responses, medical errors, sleep disturbances, and interference with privacy prac-
tices [33, 34]. While the United States Environmental Protection Agency recom-
mends a maximum noise level of 45 decibels (dB) throughout the day and 35 dB at
night, most hospitals have noise levels ranging from 50 to 70 dB during the day-
time and averaging just under 70 dB (67 dB) at nighttime [35]. Regrettably, this
data demonstrates only 62% of Americans report their hospital rooms “always
quiet” at night, which is one of the worst performing patient experience measures
in the entire Hospital Consumer Assessment of Healthcare Providers and Systems
Survey. Moreover, patients staying in the loudest rooms reportedly get significantly
less sleep [36]. In addition, the elimination of diurnal light-dark cycles in hospital
environments can result in disruption of circadian rhythm and entrainment of
sleep [12].
Patient Factors Influencing Sleep
Conditions such as multiple comorbidities, anxiety, and depression often associated

with acute and chronic illness and repeated hospitalizations and contribute to dimin-
ished sleep among hospitalized inpatients [30]. Studies show poor self-rated health
and presence of chronic conditions (cardiovascular disease, lung disease, gastro-
esophageal reflux disease, and arthritis) are all associated with increased complaints
of poor sleep [7]. Pain is also a frequently reported factor causing sleep disruptions
and nighttime awakenings [31].
Prevalence of Sleep Disorders Among Hospitalized Patients
Hospitalization represents a “missed opportunity” to screen patients for sleep dis-

orders. The high prevalence of untreated sleep disorders may often complicate or
worsen patients’ underlying conditions. For instance, two in every five patients
older than age 50 screened at high risk for having obstructive sleep apnea (OSA)
and were also found to have worse in-hospital sleep quality and quantity [37]. In
addition, in a small single-center study of hospitalized patients, up to 80% screened
high risk for OSA using the STOP-BANG questionnaire [38]. Despite a high prev-
alence, few had been evaluated with a sleep study, diagnosed with OSA, or were
receiving treatment with continuous positive airway pressure (CPAP) therapy,
which is known to improve quality of life and reduce complications [39, 40]. The
prevalence of insomnia is also increased, with several studies finding nearly two
out of every five patients screen positive for insomnia [41, 42]. Another study of
hospitalized patients noted half of inpatients reported chronic sleep complaints,
and nearly one-third of patients screened positive for insomnia, yet no mention of
sleep complaints was found in the hospital admission documentation [43].
Additionally, even if sleep disorders are suspected or recognized during hospital-
ization, therapy is frequently unavailable or suboptimal. For example, in a nation-
ally representative sample of nearly 300,000 discharges of patients with OSA from
nonfederal acute care hospitals in the United States, only 5.8% of patients were
documented to have received CPAP therapy [44]. Given that sleep disorders can
exacerbate cardiopulmonary health conditions and may actually result in heart
failure or chronic obstructive pulmonary disease (COPD) exacerbations, it is cru-
cial to recognize sleep disorders as an underlying health condition [45–48]. Certain
inpatient diagnoses, such as acute stroke and heart failure, are associated with a
higher prevalence of sleep-disordered breathing, poor outcomes, and even death
[49–56]. Moreover, treatment of OSA with CPAP therapy in patients with acute
stroke, systolic heart failure, or COPD improves outcomes and decreases readmis-
sion rates [40, 57–60]. The presence of a highly treatable disease and a very preva-
lent disorder such as sleep-disordered breathing warrants early recognition and
treatment.
Perhaps most concerning is that acute sleep loss in the hospital may precipitate
insomnia, leading to chronic insomnia after discharge. [61] This is particularly con-
cerning given the association of chronic insomnia and poor long-term health conse-
quences [62]. Early recognition of insomnia is imperative [62]. Lastly, poor
self-reported sleep quality predicts 1-year mortality among adults who received
inpatient rehabilitation [63]. In a similar study among geriatric hospitalized patients,
observed sleep disturbances determined by hourly observations were associated
with higher mortality at 2 years [64].
Interventions to Improve Sleep in Hospitalized Patients
Interventions to improve sleep in hospitalized patients can be categorized in two

categories: pharmacologic and nonpharmacologic. While hospitalized patients
often request pharmacological sleep aids, they are generally not recommended for
first-line therapy [65]. It determined that a pharmacologic sleep aid would be of
benefit to the patient; general consensus is that the choice of sleep aid should be
customized based on patient needs and comorbidity profile to minimize any poten-
tial drug side effect and ultimate polypharmacy.
Pharmacologic
Melatonin
If a pharmacologic sleep aid is deemed necessary, melatonin may be an appropriate

first-line treatment due to its minimal side effect profile and low likelihood of poten-
tial drug-drug interactions, as well as its ability to improve circadian rhythm distur-
bances [66, 67]. Small randomized studies done in simulated sleep environments,
hospitalized patients, and intensive care unit (ICU) patients note improved sleep
duration (by polysomnography) and improved sleep quality (by actigraphy) when
initiating 1 mg to 5 mg of melatonin at nighttime [68–70]. Although rates of mela-
tonin usage in hospitalized patients have increased, no dosing standard exists [71].
The typical dose used during initiation of melatonin for a hospitalized patient is
1 mg to 5 mg at night, usually dispensed between 2100 and 2200, depending on
patient sleep habits, and should be given 30 minutes prior to the desired bedtime.
Notably, melatonin given nightly to hospitalized patients over age 65 did not pre-
vent delirium.
Sleep Initiation and Sleep Maintenance Aids
Sleep aids are generally not recommended. In a single-center retrospective study in

2014 determined over a 2-month period, 26.2% of patients received a sleep aid, with
trazodone being the most commonly prescribed sleep aid medication 30.4% of the
time [72]. In a 2005 meta-analysis by Glass et al., risks and benefits of sedative hyp-
notic utilization in patients over age 60 found a statistically significant improvement
in sleep quality and sleep quantity with sedative use compared to use of placebo,
although the magnitude of the effect was small and the patient risk was great (e.g.,
falls and cognitive impairment) [73]. Notably, while four classes of medications for
insomnia have been FDA approved (benzodiazepines, non-benzodiazepines, mela-
tonin receptor agonists, and benzodiazepine receptor agonist hypnotics (“Z drugs”)),
three of these are also found on the Beers Criteria list from the American Geriatrics
Society (AGS) of medications to avoid in the elderly population (benzodiazepines,

non-benzodiazepines, benzodiazepine receptor agonist hypnotics) [74, 75].
Nonpharmacologic Interventions
Nonpharmacologic therapies are the first line of therapy for sleep disturbances in
the hospital setting. There is great interest in evidence-based interventions that dem-
onstrate improvement in sleep and related outcomes among hospitalized patients,
yet data are limited. To this end, two relevant symptomatic reviews have summa-
rized extant evidence. A Cochrane review in 2015 on improving sleep in the ICU
setting evaluated multiple points of potential interventions including type of ventila-
tor used, eye masks used in collaboration with ear plugs, relaxation therapy, sleep-
inducing music, aromatherapy, foot baths, acupressure, and visit times for family
members of the hospitalized patient, yet the evidence was low [76]. In 2014 the
Journal of General Internal Medicine found only 13 intervention studies, 4 of which
were randomized controlled trials [77]. Despite the limited evidence, some data
existed for improving sleep quality, interventions to improve sleep hygiene, inter-
ventions to reduce nighttime interruptions, and daytime bright light exposure [77].
These nonpharmacologic interventions are discussed in more detail below.
Relaxation Techniques
Despite the low level of evidence and limited data, several methods of relaxation tech-
niques have been suggested. A systematic review in 2014 by Tamrat et al. in the Journal
of General Internal Medicine evaluated four randomized controlled trials (RCT) on
relaxation techniques and found a 0–28% improvement of overall sleep quality [77].
Soden et al. evaluated the use of aromatherapy, aromatherapy and massage, or
usual care and found no difference between groups [78]. In a pilot study by Toth et al.
on the effect of guided imagery for 20 minutes daily compared to solitary activity of
choice, no difference was noted between groups [79]. Finally, a study randomizing
patients postcoronary artery bypass graft (CABG) to a music intervention involving
a soothing music video, 30 minutes of rest, or 30 minutes of music via headphones
demonstrated a 28% improvement in self-reported sleep quality in those patients that
received the soothing music video when compared to the control group [80].
Bright Light Therapy
Several small studies have been performed evaluating the impact of bright light
therapy on sleep. Three studies investigated bright light therapy (3000–5000 lux)
use during daytime hours. Wakmurua et al. exposed seven older (mean age 67)
hospitalized patients to 5 hours of bright light therapy during daytime hours (1000
to 1500) and noted a 7% increase in total sleep duration in the intervention arm [81].
This study also noted increased “immobile minutes” via wrist Actiwatch, suggest-
ing illuminating conditions for elder hospitalized patients may improve nocturnal
sleep [81]. A study by Mishima et al. in hospitalized dementia patients exposed to
bright light therapy between 0900 and 1100 for 4 weeks found an improvement in
average sleep time in the patients in the intervention arm [82]. Twenty-seven patients
with Alzheimer-type dementia were treated with bright light therapy in the morning
for 4 consecutive weeks and noted to have an increase in total nighttime sleep time
[83]. In a 2018 systematic review of the effects of bright light therapy on sleep,
mood, and cognition in Alzheimer’s patients, 32 studies were evaluated based on the
United States Preventive Services Task Force Guidelines, and although the results
were mixed, a trend toward benefit was noted [84].
Noise Reduction
Uncontrolled in-hospital noise can have a negative physiological and psychological

effect on patients and care staff. A quality improvement study in 2018 by McGough
et al. described the implementation and improvement in noise perception using a
“Quiet Time Bundle” on four different progressive care units [85]. Another study
performed on a medical-surgical unit demonstrated an overwhelmingly favorable
response from staff and patients following the implementation of a “Quiet Time
Noise Reduction” program [86]. Due to the increased number of monitors and acu-
ity, modalities for noise reduction in the intensive care unit have been evaluated.
These approaches include the use of eye masks in conjunction with ear plugs [87],
the use of “white noise” also known as sound masking [88, 89],and the installation
of soundproof ceiling materials [90]. Sound absorbing modalities are relatively
effective at noise reduction, whereas sound masking modalities appear to be the
most effective at actually improving sleep [91].
Sleep Hygiene
Promoting good sleep hygiene during hospitalization can be challenging. Gathecha

et al. described a nurse-delivered sleep-promoting intervention augmented by sleep
hygiene education in the Journal of Hospital Medicine as an opportunity for
improvement [92]. A randomized controlled trial by Lareau et al. in geriatric hospi-
talized patients evaluated a nighttime intervention of minimizing patient contact,
clustering nursing care, as well as decreasing sounds and lights, as compared to
usual care. The group found that intervention was associated with a decrease in the
use of sleep aid medications and a 7% improvement in sleep quality [93]. Another
study evaluated a sleep hygiene program in hospitalized psychiatric patients. The
intervention in this study by Edinger et al. included the standardization of wake and
sleep times and the removal of the opportunity for daytime napping [94]. This inter-
vention was associated with an increase of 18 minutes in total sleep time; however
neither sleep quality nor significant testing was discussed [94].
Reduction of Nighttime Interruptions
The goal of reducing nighttime interruptions of patient sleep during hospitalized

patient sleep may seem ambitious, yet as the most cited nighttime disruption, action
is warranted [95]. For example, many nighttime disruptions in the intensive care
unit could be safely omitted or clustered, noted Le et al. [96] A recent study evaluat-
ing nearly 3500 patients determined that passive vital sign monitoring and reduction
in nighttime noise ultimately led to a decreased hospital length of stay and an
increase in patient self-reported emotional and mental health [97]. Future studies
are needed to best determine methods to implement reductions in nighttime interac-
tions, which in turn improves hospital sleep, enhancing quality and safety.
Sleep Education and Empowerment
Improving patient knowledge and education on health and disease is essential. In a

recent randomized controlled trial, non-ICU patients who received sleep-enhancing
tools (a white noise machine, ear plugs, and an eye mask) along with sleep educa-
tion reported decreased sleep impairment and less fatigue than those who received
only the sleep-enhancing tool kit [98].
Multifaceted Protocols
The “Somerville” multifaceted protocol implemented several components for sleep

improvement. These components included an 8-hour quiet time, “lights off” lullaby,
staff-monitored noise control, and avoidance of staff disruptions for routine vitals
and medications. The study investigators reported fewer patients reporting night-
time disruptions and fewer patients requesting sleep aid/sedatives [99]. Another
multifaceted protocol program of electronic health record reminders and nursing
“nudges,” “Sleep for Inpatients: Empowering Staff to Act (SIESTA),” demonstrated
that a unit-based nursing empowerment approach was associated with fewer night-
time hospital room entries and overall improved patient experiences [28]. Finally,
the Hospital Elder Life Program (HELP) designed in 1999 by SK Inouye was suc-
cessfully implemented across 200 German hospitals [100]. This protocol consisted
of multiple strategies to aid in delirium prevention in hospitalized elderly including
(re)orientation, cognitive activation, mobilization, meal companionship, and non-

pharmacological sleep promotion [100].
Pain and Sleep
Pain should be evaluated frequently on every patient during hospitalization. It is not

only a barrier to hospital discharge, but its management is a quality of care issue
[101]. Optimal treatment of pain is recommended, as pain can interfere with falling
asleep and with the ability to participate in recovery activities during hospitalization
[102, 103]. Pharmacologic and nonpharmacologic management options should be
evaluated for treatment of pain [103].
leep in Hospitalized Patients with Underlying Disorders

S
of Mental Health
Associations between sleep health and mental health are many, yet knowledge of
this association is lacking [104]. Among patients hospitalized with depressive dis-
order, 25–40% report almost always having daytime sleepiness, and a more indi-
vidualized sleep-wake schedule should be applied in these patients [105]. In a small
study of inpatients hospitalized with moderate-to-severe depression undergoing
chronotherapy, a significant number of patients (>40%) reported a significant
improvement in their depressive symptoms [106].
Hospitalized Older Adults
Predisposing factors and precipitating factors play a role in delirium development in

hospitalized older patients [20]. Sleep loss in hospitalized older adults can slow
recovery during hospitalization due to fatigue and excessive daytime sleepiness,
which leads to decreased participation in recovery activities such as participation
with therapy and in important healthcare discussions and decisions with social work
and case management [22, 23]. Coaching and empowerment of hospitalized older
adults and their caregivers to confirm their needs are met during transitions of care
may reduce rates of rehospitalization [24].
Moreover, sleep deprivation has been associated with a variety of significant
outcomes of relevance to hospitalized older adults as they recover from acute ill-
ness. In addition to delirium, sleep loss has been associated with other health condi-
tions often seen in the elderly population, such as falls. For example, one study by
Stone et al. noted women with shorter sleep duration (< 7 hours) or lower sleep
efficiency (<70%), as determined by wrist actigraphy, were more likely to suffer

from falls in the subsequent year compared to women with normal sleep duration
and sleep efficiency [107]. Additionally, sleep deprivation has also been associated
with impaired immune function in healthy humans as well as animals, which most
certainly has implications for hospitalized older adults [108]. Scientists have also
noted genes in Drosophila flies – which promote increased sleep – in turn promote
survival following infection [109, 110]. Sleep disturbances in hospitalized elderly
patients are associated with increased mortality at 2 years [63]. As previously noted,
the AGS has recommended against certain medications to aid in sleep initiation and
maintenance in the hospitalized elderly due to increased risk of falls and cognitive
impairment, specifically benzodiazepines and non-benzodiazepines. Melatonin
remains the sleep aid of choice in this patient population. The Assessing Care of
Vulnerable Elders-3 (ACOVE-3) program utilizes quality metrics to assess and pro-
mote best practices of elder care [111]. Medications such as anticholinergics
(including antihistamines) should be avoided [75]. Other medications frequently
utilized to aid in sleep, but not recommended, in the elderly population such as
antihistamines, oral decongestants (pseudoephedrine and ephedrine), and stimu-
lants (amphetamine and methylphenidate) make insomnia worse, are associated
with anticholinergic side effects, and are not recommended in the elder population
[75, 103].
Sleep in the Intensive Care Unit (ICU)
A study in the ICU found that 51% of noise was modifiable, while patients report
staff conversations as well as television noise as the most irritating disturbances
[112]. In addition, this noise was notable and found to interfere with sleep as seen
on electroencephalogram (EEG) recordings [112]. Light disruptions of the circa-
dian rhythm are particularly problematic in the ICU setting. Due to continued expo-
sure of differing levels of light in the ICU, melatonin secretion patterns are atypical,
and in turn the circadian rhythms of these patients are markedly abnormal [113,
114]. Modifiable factors in the ICU which lead to sleep disturbances are best dealt
with from a multidisciplinary approach involving multiple ICU stakeholders [115].
Assess and Treat Underlying Sleep Disorders
Several studies have shown that early recognition and treatment of sleep disorders
in hospitalized patients is associated with improved outcomes. To illustrate, in a
small study by Konikkara, patients hospitalized with a COPD exacerbation were
screened for sleep apnea, and if positive, CPAP therapy was initiated. Patients with
COPD and OSA overlap disease that were adherent to CPAP therapy were noted to
demonstrate a reduction in 6-month hospital readmission rates and emergency room
visits [46]. In another study of hospitalized patients with congestive heart failure,
those patients compliant with CPAP for a minimum of 4 hours for 70% of the nights
in the month (Medicare PAP compliance guidelines) had fewer hospital readmis-
sions when compared to those patients who were not compliant with their CPAP
therapy following hospital discharge [116]. To that end, in another study involving
early diagnosis of sleep-disordered breathing utilizing portable sleep study equip-
ment, patients hospitalized with cardiac disease demonstrated significantly lower
hospital readmission rates and decreased emergency department visits in those
adherent with PAP therapy [117]. Initiation of CPAP therapy for patients with OSA
is associated with decreased hospital readmissions [116].
Conclusions
Hospitalization is a period of acute illness and multifactorial acute sleep depriva-

tion. Sleep deprivation in hospitalized patients can be related to patient factors,
environmental factors, as well as medical interventions. Sleep loss in the hospital is
also associated with poor health outcomes, including an increased risk of delirium
and cardiometabolic derangements. Both pharmacologic and nonpharmacologic
interventions have shown promise in improving sleep loss in patients while hospi-
talized. Awareness and consideration of implicit sleep loss in hospitalization is war-
ranted, and implementation of treatment measures is justified.
References
1. Institute of Medicine (US) Committee on Sleep Medicine and Research. In: Colten HR,
Altevogt BM, editors. Sleep disorders and sleep deprivation: an unmet public health problem.
Washington DC: National Academies Press (US); 2006. Accessed 13 June 2020. http://www.
ncbi.nlm.nih.gov/books/NBK19960/.
2. Ohayon MM. Epidemiological overview of sleep disorders in the general population.
Published online 2011. Accessed 13 June 2020. https://doi.org/10.17241/smr.2011.2.1.1
3. Guyton AC, Hall JE. States of brain activity-sleep, brain waves, epilepsy, psychoses. In:
Textbook of medical physiology. 13th ed. Mississippi: Elsevier Saunders; 2011. p. 763–72.
4. Åkerstedt T, Lekander M, Nilsonne G, et al. Effects of late-night short-sleep on in-home
polysomnography: relation to adult age and sex. J Sleep Res. 2018;27(4):e12626. https://doi.
org/10.1111/jsr.12626.
5. Miner B, Kryger MH. Sleep in the aging population. Sleep Med Clin. 2017;12(1):31–8.
https://doi.org/10.1016/j.jsmc.2016.10.008.
6. Blazer DG, Hays JC, Foley DJ. Sleep complaints in older adults: a racial comparison. J Gerontol
A Biol Sci Med Sci. 1995;50(5):M280–4. https://doi.org/10.1093/gerona/50a.5.m280.
7. Sorensen, RT, Bergholt, MD, Herning, M, Noiesen, E, Szots K, Harboe, G, Troosborg, I,
Konradsen, H. To sleep or not to sleep during hospitalisation - a mixed-method study of
patient reported sleep quality and the experience of sleeping poorly during hospitalisation.
Published online 2018.
8. Pilkington S. Causes and consequences of sleep deprivation in hospitalised patients. Nurs

Stand. 2013;27(49):35–42. https://doi.org/10.7748/ns2013.08.27.49.35.e7649.
9. DePietro RH, Knutson KL, Spampinato L, et al. Association between inpatient sleep loss
and hyperglycemia of hospitalization. Diabetes Care. 2017;40(2):188–93. https://doi.
org/10.2337/dc16-1683.
10. Arora VM, Chang KL, Fazal AZ, et al. Objective sleep duration and quality in hos-
pitalized older adults: associations with blood pressure and mood. J Am Geriatr Soc.
2011;59(11):2185–6. https://doi.org/10.1111/j.1532-5415.2011.03644.x.
11. Krumholz HM. Post-hospital syndrome--an acquired, transient condition of generalized risk.
N Engl J Med. 2013;368(2):100–2. https://doi.org/10.1056/NEJMp1212324.
12. Shear TC, Balachandran JS, Mokhlesi B, et al. Risk of sleep apnea in hospitalized older
patients. J Clin Sleep Med. 2014;10(10):1061–6. https://doi.org/10.5664/jcsm.4098.
13. Shah MS, Spampinato LM, Beveridge C, Meltzer DO, Arora VM. Quantifying post hospital
syndrome: sleeping longer and physically stronger?. Abstracted presented at the Society of
Hospital Medicine Annual Meeting, 2016, March 6–9, San Diego, Calif. Abstract 340. J Hosp
Med. 11(1). https://shmabstracts.org/abstract/quantifying-post-hospital-syndrome-sleeping-
longer-and-physically-stronger/. June 13th 2020.
14. Sharma S. Hospital sleep medicine: the elephant in the room? J Clin Sleep Med.
2014;10(10):1067–8. https://doi.org/10.5664/jcsm.4100.
15. Knutson KL, Spiegel K, Penev P, Van Cauter E. The metabolic consequences of sleep depri-
vation. Sleep Med Rev. 2007;11(3):163–78. https://doi.org/10.1016/j.smrv.2007.01.002.
16. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine func-
tion. Lancet. 1999;354(9188):1435–9. https://doi.org/10.1016/S0140-6736(99)01376-8.
17. Meisinger C, Heier M, Loewel H, MONICA/KORA Augsburg Cohort Study. Sleep distur-
bance as a predictor of type 2 diabetes mellitus in men and women from the general popula-
tion. Diabetologia. 2005;48(2):235–41. https://doi.org/10.1007/s00125-004-1634-x.
18. Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of
type 2 diabetes. Diabetes Care. 2006;29(3):657–61. https://doi.org/10.2337/diacare.29.03.06.
dc05-0879.
19. Inzucchi SE. Clinical practice. Management of hyperglycemia in the hospital setting. N Engl
J Med. 2006;355(18):1903–11. https://doi.org/10.1056/NEJMcp060094.
20. Inouye SK. Prevention of delirium in hospitalized older patients: risk factors
and targeted intervention strategies. Ann Med. 2000;32(4):257–63. https://doi.
org/10.3109/07853890009011770.
21. Bell CM, Fischer HD, Gill SS, et al. Initiation of benzodiazepines in the elderly after hospital-
ization. J Gen Intern Med. 2007;22(7):1024–9. https://doi.org/10.1007/s11606-007-0194-4.
22. Ancoli-Israel S, Cooke JR. Prevalence and comorbidity of insomnia and effect on func-
tioning in elderly populations. J Am Geriatr Soc. 2005;53(7 Suppl):S264–71. https://doi.
org/10.1111/j.1532-5415.2005.53392.x.
23. Gooneratne NS, Weaver TE, Cater JR, et al. Functional outcomes of excessive daytime sleep-
iness in older adults. J Am Geriatr Soc. 2003;51(5):642–9. https://doi.org/10.1034/j.1600-05
79.2003.00208.x.
24. Coleman EA, Parry C, Chalmers S, Min S-J. The care transitions intervention: results of a
randomized controlled trial. Arch Intern Med. 2006;166(17):1822–8. https://doi.org/10.1001/
archinte.166.17.1822.
25. Redeker NS. Sleep in acute care settings: an integrative review. J Nurs Scholarsh.
2000;32(1):31–8. https://doi.org/10.1111/j.1547-5069.2000.00031.x.
26. McLaughlin DC, Hartjes TM, Freeman WD. Sleep deprivation in neurointensive care
unit patients from serial neurological checks: how much is too much? J Neurosci Nurs.
2018;50(4):205–10. https://doi.org/10.1097/JNN.0000000000000378.
27. Grossman MN, Anderson SL, Worku A, et al. Awakenings? patient and hospital staff per-
ceptions of nighttime disruptions and their effect on patient sleep. J Clin Sleep Med.
2017;13(2):301–6. https://doi.org/10.5664/jcsm.6468.
28. Arora VM, Machado N, Anderson SL, et al. Effectiveness of SIESTA on Objective and
Subjective Metrics of Nighttime Hospital Sleep Disruptors. J Hosp Med. 2019;14(1):38–41.
https://doi.org/10.12788/jhm.3091.
29. Hoffman S. Sleep in the older adult: implications for nurses (CE). Geriatr Nurs.
2003;24(4):210–4; quiz 215-216. https://doi.org/10.1016/s0197-4572(03)00213-1.
30. Ersser S, Wiles A, Taylor H, Wade S, Walsh R, Bentley T. The sleep of older people in hos-
pital and nursing homes. J Clin Nurs. 1999;8(4):360–8. https://doi.org/10.1046/j.1365-2702.
1999.00267.x.
31. Hospital Compare. U.S. Department of Health and Human Services. Available at: https://
www.medicare.gov/hospitalcompare/search.html.
32. Buxton OM, Ellenbogen JM, Wang W, et al. Sleep disruption due to hospital noises: a pro-
spective evaluation. Ann Intern Med. 2012;157(3):170–9. https://doi.org/10.7326/0003-4819-
157-3-201208070-00472.
33. Pope DS, Miller-Klein ET. Acoustic assessment of speech privacy curtains in two nursing
units. Noise Health. 2016;18(80):26–35. https://doi.org/10.4103/1463-1741.174377.
34. Tullmann DF, Dracup K. Creating a healing environment for elders. AACN Clin Issues.
2000;11(1):34–50; quiz 153-154. https://doi.org/10.1097/00044067-200002000-00006.
35. Yoder JC, Staisiunas PG, Meltzer DO, Knutson KL, Arora VM. Noise and sleep among adult
medical inpatients: far from a quiet night. Arch Intern Med. 2012;172(1):68–70. https://doi.
org/10.1001/archinternmed.2011.603.
36. Monk TH, Buysse DJ, Billy BD, Kennedy KS, Kupfer DJ. The effects on human sleep
and circadian rhythms of 17 days of continuous bedrest in the absence of daylight. Sleep.
1997;20(10):858–64. https://doi.org/10.1093/sleep/20.10.858.
37. Kumar S, McElligott D, Goyal A, Baugh M, Ionita RN. Risk of obstructive sleep apnea
(OSA) in hospitalized patients. Chest. 2010;138(4):supp 779A. Available at: https://journal.
chestnet.org/article/S0012-3692(16)42455-4/abstract. Presented at the:
38. Javaheri S, Caref EB, Chen E, Tong KB, Abraham WT. Sleep apnea testing and outcomes in
a large cohort of Medicare beneficiaries with newly diagnosed heart failure. Am J Respir Crit
Care Med. 2011;183(4):539–46. https://doi.org/10.1164/rccm.201003-0406OC.
39. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive air-
way pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med.
2003;348(13):1233–41. https://doi.org/10.1056/NEJMoa022479.
40. Kokras N, Kouzoupis AV, Paparrigopoulos T, et al. Predicting insomnia in medical
wards: the effect of anxiety, depression and admission diagnosis. Gen Hosp Psychiatry.
2011;33(1):78–81. https://doi.org/10.1016/j.genhosppsych.2010.12.003.
41. Isaia G, Corsinovi L, Bo M, et al. Insomnia among hospitalized elderly patients: prevalence,
clinical characteristics and risk factors. Arch Gerontol Geriatr. 2011;52(2):133–7. https://doi.
org/10.1016/j.archger.2010.03.001.
42. Meissner HH, Riemer A, Santiago SM, Stein M, Goldman MD, Williams AJ. Failure
of physician documentation of sleep complaints in hospitalized patients. West J Med.
1998;169(3):146–9.
43. Spurr KF, Graven MA, Gilbert RW. Prevalence of unspecified sleep apnea and the use of con-
tinuous positive airway pressure in hospitalized patients, 2004 National Hospital Discharge
Survey. Sleep Breath. 2008;12(3):229–34. https://doi.org/10.1007/s11325-007-0166-2.
44. Gay PC. Sleep and sleep-disordered breathing in the hospitalized patient. Respir Care.
2010;55(9):1240–54.
45. Shorofsky M, Bourbeau J, Kimoff J, et al. Impaired sleep quality in COPD is associated with
exacerbations: The CanCOLD Cohort Study. Chest. Published online 28 May 2019. https://
doi.org/10.1016/j.chest.2019.04.132.
46. Konikkara J, Tavella R, Willes L, Kavuru M, Sharma S. Early recognition of obstructive sleep
apnea in patients hospitalized with COPD exacerbation is associated with reduced readmis-
sion. Hosp Pract. 2016;44(1):41–7. https://doi.org/10.1080/21548331.2016.1134268.
47. Kendzerska T, Leung RS, Aaron SD, Ayas N, Sandoz JS, Gershon AS. Cardiovascular out-
comes and all-cause mortality in patients with obstructive sleep apnea and chronic obstruc-
tive pulmonary disease (overlap syndrome). Ann Am Thorac Soc. 2019;16(1):71–81. https://
doi.org/10.1513/AnnalsATS.201802-136OC.
48. Mohsenin V, Valor R. Sleep apnea in patients with hemispheric stroke. Arch Phys Med
Rehabil. 1995;76(1):71–6. https://doi.org/10.1016/s0003-9993(95)80046-8.
49. Harbison J, Ford GA, James OFW, Gibson GJ. Sleep-disordered breathing following acute
stroke. QJM. 2002;95(11):741–7. https://doi.org/10.1093/qjmed/95.11.741.
50. Brown DL, Shafie-Khorassani F, Kim S, et al. Sleep-disordered breathing is associ-
ated with recurrent ischemic stroke. Stroke. 2019;50(3):571–6. https://doi.org/10.1161/
STROKEAHA.118.023807.
51. Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128
patients. Sleep. 1999;22(2):217–23. https://doi.org/10.1093/sleep/22.2.217.
52. Wu Z, Chen F, Yu F, Wang Y, Guo Z. A meta-analysis of obstructive sleep apnea in patients
with cerebrovascular disease. Sleep Breath. 2018;22(3):729–42. https://doi.org/10.1007/
s11325-017-1604-4.
apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–41. https://doi.
org/10.1056/NEJMoa043104.
54. Good DC, Henkle JQ, Gelber D, Welsh J, Verhulst S. Sleep-disordered breathing and poor
functional outcome after stroke. Stroke. 1996;27(2):252–9. https://doi.org/10.1161/01.
str.27.2.252.
55. Oldenburg O, Lamp B, Faber L, Teschler H, Horstkotte D, Töpfer V. Sleep-disordered breath-
ing in patients with symptomatic heart failure: a contemporary study of prevalence in and
characteristics of 700 patients. Eur J Heart Fail. 2007;9(3):251–7. https://doi.org/10.1016/j.
ejheart.2006.08.003.
56. Bravata DM, Concato J, Fried T, et al. Continuous positive airway pressure: evaluation of a
novel therapy for patients with acute ischemic stroke. Sleep. 2011;34(9):1271–7. https://doi.
org/10.5665/SLEEP.1254.
57. Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled
trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J
Respir Crit Care Med. 2004;169(3):361–6. https://doi.org/10.1164/rccm.200306-752OC.
58. Truong KK, De Jardin R, Massoudi N, Hashemzadeh M, Jafari B. Nonadherence to CPAP
associated with increased 30-day hospital readmissions. J Clin Sleep Med. 2018;14(2):183–9.
https://doi.org/10.5664/jcsm.6928.
59. Scalzitti NJ, O’Connor PD, Nielsen SW, et al. Obstructive sleep apnea is an independent risk
factor for hospital readmission. J Clin Sleep Med. 2018;14(5):753–8. https://doi.org/10.5664/
jcsm.7098.
60. Griffiths MF, Peerson A. Risk factors for chronic insomnia following hospitalization. J Adv
Nurs. 2005;49(3):245–53. https://doi.org/10.1111/j.1365-2648.2004.03283.x.
61. Morin CM, Benca R. Chronic insomnia. Lancet. 2012;379(9821):1129–41. https://doi.
org/10.1016/S0140-6736(11)60750-2.
62. Martin JL, Fiorentino L, Jouldjian S, Mitchell M, Josephson KR, Alessi CA. Poor self-
reported sleep quality predicts mortality within one year of inpatient post-acute rehabilitation
among older adults. Sleep. 2011;34(12):1715–21. https://doi.org/10.5665/sleep.1444.
63. Manabe K, Matsui T, Yamaya M, et al. Sleep patterns and mortality among elderly patients in
a geriatric hospital. Gerontology. 2000;46(6):318–22. https://doi.org/10.1159/000022184.
64. Lenhart SE, Buysse DJ. Treatment of insomnia in hospitalized patients. Ann Pharmacother.
2001;35(11):1449–57. https://doi.org/10.1345/aph.1A040.
65. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a
meta-analysis. Sleep Med Rev. 2005;9(1):41–50. https://doi.org/10.1016/j.smrv.2004.06.004.
66. Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treat-
ment for age-related insomnia. J Clin Endocrinol Metab. 2001;86(10):4727–30. https://doi.
org/10.1210/jcem.86.10.7901.
67. Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with
insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry. 2001;62(1):41–5.
https://doi.org/10.4088/jcp.v62n0109.
68. Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD inten-
sive care patients: a pilot study. Chronobiol Int. 2000;17(1):71–6. https://doi.org/10.1081/
cbi-100101033.
69. Huang H-W, Zheng B-L, Jiang L, et al. Effect of oral melatonin and wearing earplugs and
eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit envi-
ronment: which might be a more promising strategy for ICU sleep deprivation? Crit Care.
2015;19:124. https://doi.org/10.1186/s13054-015-0842-8.
70. MacMillan TE, Lui P, Wu RC, Cavalcanti RB. Melatonin Increasingly Used in Hospitalized
Patients. J Hosp Med. 2020;15(6):349–51. https://doi.org/10.12788/jhm.3408.
71. Jaiswal SJ, McCarthy TJ, Wineinger NE, et al. Melatonin and Sleep in Preventing Hospitalized
Delirium: A Randomized Clinical Trial. Am J Med. 2018;131(9):1110–1117.e4. https://doi.
org/10.1016/j.amjmed.2018.04.009.
72. Gillis CM, Poyant JO, Degrado JR, Ye L, Anger KE, Owens RL. Inpatient pharmacological
sleep aid utilization is common at a tertiary medical center. J Hosp Med. 2014;9(10):652–7.
with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331(7526):1169. https://doi.
org/10.1136/bmj.38623.768588.47.
74. Young JS, Bourgeois JA, Hilty DM, Hardin KA. Sleep in hospitalized medical patients,
part 2: behavioral and pharmacological management of sleep disturbances. J Hosp Med.
2009;4(1):50–9. https://doi.org/10.1002/jhm.397.
75. By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American
Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate
Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674–94. https://doi.
org/10.1111/jgs.15767.
76. Hu R-F, Jiang X-Y, Chen J, et al. Non-pharmacological interventions for sleep promotion
in the intensive care unit. Cochrane Database Syst Rev. 2015;10:CD008808. https://doi.
org/10.1002/14651858.CD008808.pub2.
77. Tamrat R, Huynh-Le M-P, Goyal M. Non-pharmacologic interventions to improve the sleep
of hospitalized patients: a systematic review. J Gen Intern Med. 2014;29(5):788–95. https://
doi.org/10.1007/s11606-013-2640-9.
78. Soden K, Vincent K, Craske S, Lucas C, Ashley S. A randomized controlled trial of aroma-
therapy massage in a hospice setting. Palliat Med. 2004;18(2):87–92. https://doi.org/10.119
1/0269216304pm874oa.
79. Toth M, Wolsko PM, Foreman J, et al. A pilot study for a randomized, controlled trial on
the effect of guided imagery in hospitalized medical patients. J Altern Complement Med.
2007;13(2):194–7. https://doi.org/10.1089/acm.2006.6117.
80. Zimmerman L, Nieveen J, Barnason S, Schmaderer M. The effects of music interventions on
postoperative pain and sleep in coronary artery bypass graft (CABG) patients. Sch Inq Nurs
Pract. 1996;10(2):153–70; discussion 171-174.
81. Wakamura T, Tokura H. Influence of bright light during daytime on sleep parameters in hos-
pitalized elderly patients. J Physiol Anthropol Appl Hum Sci. 2001;20(6):345–51. https://doi.
org/10.2114/jpa.20.345.
82. Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Morning bright light
therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatr
Scand. 1994;89(1):1–7. https://doi.org/10.1111/j.1600-0447.1994.tb01477.x.
83. Yamadera H, Ito T, Suzuki H, Asayama K, Ito R, Endo S. Effects of bright light on cognitive
and sleep-wake (circadian) rhythm disturbances in Alzheimer-type dementia. Psychiatry Clin
Neurosci. 2000;54(3):352–3. https://doi.org/10.1046/j.1440-1819.2000.00711.x.
84. Mitolo M, Tonon C, La Morgia C, Testa C, Carelli V, Lodi R. Effects of light treatment on
sleep, cognition, mood, and behavior in Alzheimer’s disease: a systematic review. Dement
Geriatr Cogn Disord. 2018;46(5–6):371–84. https://doi.org/10.1159/000494921.
85. McGough NNH, Keane T, Uppal A, et al. Noise reduction in progressive care units. J Nurs
Care Qual. 2018;33(2):166–72. https://doi.org/10.1097/NCQ.0000000000000275.
86. Applebaum D, Calo O, Neville K. Implementation of quiet time for noise reduction
on a medical-surgical unit. J Nurs Adm. 2016;46(12):669–74. https://doi.org/10.1097/
NNA.0000000000000424.
87. Richardson A, Allsop M, Coghill E, Turnock C. Earplugs and eye masks: do they improve crit-
ical care patients’ sleep? Nurs Crit Care. 2007;12(6):278–86. https://doi.org/10.1111/j.1478-
5153.2007.00243.x.
88. Gragert MD. The Use of Masking Signal to Enhance Sleep of Men and Women 65 Years of
Age and Older in the Critical Care Environment. Austin: The University of Texas; 1990.
89. Stanchina ML, Abu-Hijleh M, Chaudhry BK, Carlisle CC, Millman RP. The influence of
white noise on sleep in subjects exposed to ICU noise. Sleep Med. 2005;6(5):423–8. https://
doi.org/10.1016/j.sleep.2004.12.004.
90. Blomkvist V, Eriksen CA, Theorell T, Ulrich R, Rasmanis G. Acoustics and psychosocial
environment in intensive coronary care. Occup Environ Med. 2005;62(3):e1. https://doi.
org/10.1136/oem.2004.017632.
91. Xie H, Kang J, Mills GH. Clinical review: the impact of noise on patients’ sleep and the
effectiveness of noise reduction strategies in intensive care units. Crit Care. 2009;13(2):208.
https://doi.org/10.1186/cc7154.
92. Gathecha E, Rios R, Buenaver LF, Landis R, Howell E, Wright S. Pilot study aiming to sup-
port sleep quality and duration during hospitalizations. J Hosp Med. 2016;11(7):467–72.
93. Lareau R, Benson L, Watcharotone K, Manguba G. Examining the feasibility of implement-
ing specific nursing interventions to promote sleep in hospitalized elderly patients. Geriatr
Nurs. 2008;29(3):197–206. https://doi.org/10.1016/j.gerinurse.2007.10.020.
94. Edinger JD, Lipper S, Wheeler B. Hospital ward policy and patients’ sleep patterns: A mul-
tiple baseline study. Rehabil Psychol. 34(1):43. Published online 1989.
95. Freedman NS, Kotzer N, Schwab RJ. Patient perception of sleep quality and etiology of sleep
disruption in the intensive care unit. Am J Respir Crit Care Med. 1999;159(4 Pt 1):1155–62.
https://doi.org/10.1164/ajrccm.159.4.9806141.
96. Le A, Friese RS, Hsu C-H, Wynne JL, Rhee P, O’Keeffe T. Sleep disruptions and nocturnal
nursing interactions in the intensive care unit. J Surg Res. 2012;177(2):310–4. https://doi.
org/10.1016/j.jss.2012.05.038.
97. Milani RV, Bober RM, Lavie CJ, Wilt JK, Milani AR, White CJ. Reducing hospital toxic-
ity: impact on patient outcomes. Am J Med. 2018;131(8):961–6. https://doi.org/10.1016/j.
amjmed.2018.04.013.
98. Farrehi PM, Clore KR, Scott JR, Vanini G, Clauw DJ. Efficacy of Sleep Tool Education
During Hospitalization: A Randomized Controlled Trial. Am J Med. 2016;129(12):1329.
e9–1329.e17. https://doi.org/10.1016/j.amjmed.2016.08.001.
99. Bartick MC, Thai X, Schmidt T, Altaye A, Solet JM. Decrease in as-needed sedative use
by limiting nighttime sleep disruptions from hospital staff. J Hosp Med. 2010;5(3):E20–4.
100. Singler K, Thomas C. HELP - Hospital Elder Life Program - multimodal delirium pre-
vention in elderly patients. Internist (Berl). 2017;58(2):125–31. https://doi.org/10.1007/
s00108-016-0181-0.
101. Carr ECJ, Meredith P, Chumbley G, Killen R, Prytherch DR, Smith GB. Pain: a quality of
care issue during patients’ admission to hospital. J Adv Nurs. 2014;70(6):1391–403. https://
doi.org/10.1111/jan.12301.
102. Li JMW. Pain management in the hospitalized patient. Med Clin North Am. 2008;
92(2):371–85, ix. https://doi.org/10.1016/j.mcna.2007.11.003.
103. Martin JL, Fung CH. Quality indicators for the care of sleep disorders in vulnerable elders.
J Am Geriatr Soc. 2007;55(Suppl 2):S424–30. https://doi.org/10.1111/j.1532-5415.2007.
01351.x.
104. Kragh M, Møller DN, Wihlborg CS, et al. Experiences of wake and light therapy in patients
with depression: a qualitative study. Int J Ment Health Nurs. 2017;26(2):170–80. https://doi.
org/10.1111/inm.12264.
105. Müller MJ, Olschinski C, Kundermann B, Cabanel N. Sleep duration of inpatients with a
depressive disorder: associations with age, subjective sleep quality, and cognitive complaints.
Arch Psychiatr Nurs. 2017;31(1):77–82. https://doi.org/10.1016/j.apnu.2016.08.008.
106. Kragh M, Larsen ER, Martiny K, et al. Predictors of response to combined wake and light ther-
apy in treatment-resistant inpatients with depression. Chronobiol Int. 2018;35(9):1209–20.
https://doi.org/10.1080/07420528.2018.1468341.
107. Stone KL, Ancoli-Israel S, Blackwell T, et al. Actigraphy-measured sleep characteristics
and risk of falls in older women. Arch Intern Med. 2008;168(16):1768–75. https://doi.
org/10.1001/archinte.168.16.1768.
108. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immuniza-
tion. JAMA. 2002;288(12):1471–2. https://doi.org/10.1001/jama.288.12.1471-a.
109. Toda H, Williams JA, Gulledge M, Sehgal A. A sleep-inducing gene, nemuri, links sleep and
immune function in drosophila. Science. 2019;363(6426):509–15. https://doi.org/10.1126/
science.aat1650.
110. Kuo T-H, Williams JA. Increased sleep promotes survival during a bacterial infection in dro-
sophila. Sleep. 2014;37(6):1077–86, 1086A-1086D. https://doi.org/10.5665/sleep.3764.
111. Sinvani L, Kozikowski A, Smilios C, et al. Implementing ACOVE Quality Indicators as
an Intervention Checklist to Improve Care for Hospitalized Older Adults. J Hosp Med.
2017;12(7):517–22. https://doi.org/10.12788/jhm.2765.
112. Kahn DM, Cook TE, Carlisle CC, Nelson DL, Kramer NR, Millman RP. Identification and
modification of environmental noise in an ICU setting. Chest. 1998;114(2):535–40. https://
doi.org/10.1378/chest.114.2.535.
113. Shilo L, Dagan Y, Smorjik Y, et al. Patients in the intensive care unit suffer from severe
lack of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci.
1999;317(5):278–81. https://doi.org/10.1097/00000441-199905000-00002.
114. Pisani MA, Friese RS, Gehlbach BK, Schwab RJ, Weinhouse GL, Jones SF. Sleep in the
intensive care unit. Am J Respir Crit Care Med. 2015;191(7):731–8. https://doi.org/10.1164/
rccm.201411-2099CI.
115. Knauert MP, Haspel JA, Pisani MA. Sleep loss and circadian rhythm disruption in the intensive
care unit. Clin Chest Med. 2015;36(3):419–29. https://doi.org/10.1016/j.ccm.2015.05.008.
116. Sharma S, Mather P, Gupta A, et al. Effect of early intervention with positive airway pres-
sure therapy for sleep disordered breathing on six-month readmission rates in hospitalized
patients with heart failure. Am J Cardiol. 2016;117(6):940–5. https://doi.org/10.1016/j.
amjcard.2015.12.032.
117. Kauta SR, Keenan BT, Goldberg L, Schwab RJ. Diagnosis and treatment of sleep disordered
breathing in hospitalized cardiac patients: a reduction in 30-day hospital readmission rates. J
Clin Sleep Med. 2014;10(10):1051–9. https://doi.org/10.5664/jcsm.4096.
Chapter 21
Sleep in Pregnancy
Louise M. O’Brien
Keywords Pittsburgh Sleep Quality Index (PSQI) · Unrefreshed sleep · Sleep in

mid-pregnancy · Sleep-disordered breathing (SDB) · RLS during pregnancy ·
Insufficient Sleep
Introduction
During pregnancy, a life stage during which there are significant hormonal, ana-
tomic, physiological, and psychological changes, women experience unique chal-
lenges with sleep. Pregnancy can exacerbate preexisting sleep problems as well as
cause the emergence of new ones. The impact of sleep deficiency – which includes
insufficient sleep, poorly timed sleep, and clinical sleep disorders – is observed not
only on the individual but also on the offspring, with potentially long-lasting
implications.
Sleep in Normal Pregnancy
Due to physiological and hormonal changes related to pregnancy, most women

experience changes in sleep [1]. In the first trimester, common complaints include
daytime sleepiness and fatigue with many women reporting daytime naps. Sleep
quality and slow-wave sleep (SWS) typically decrease compared to prepregnancy
L. M. O’Brien (*)
Division of Sleep Medicine, Department of Neurology, Michigan Medicine,
Ann Arbor, MI, USA
Department of Obstetrics & Gynecology, Michigan Medicine, Ann Arbor, MI, USA
e-mail: louiseo@med.umich.edu

472 L. M. O’Brien
or the nonpregnant state [1, 2] but improve in the second trimester, along with
improvements in daytime sleepiness and fatigue [2–5]. Toward the end of the sec-
ond trimester and into the third trimester, snoring is common along with restless
legs and increased awakenings [6]. Indeed, in the third trimester, the vast majority
of women endorse sleep deficiencies with insomnia symptoms, sleep-disordered
breathing (SDB), frequent awakenings [2, 5, 7, 8], and increased napping [5, 7–9],
with consequentially more light sleep [10, 11].
Insufficient Sleep
Although there are no guidelines specific to pregnant women, the National Sleep
Foundation (www.sleepfoundation.org) recommends that adults obtain 7–9 hours of
sleep per night, with <6 hours per night considered insufficient [12]. Nonetheless,
definition of short sleep is likely dependent on the method of assessment, and short
sleep in pregnancy has been suggested as being <7 hours if reported subjectively
and <6 hours if data are collected objectively [13]. Individual studies differ in the
definition of short sleep, which can range anywhere from 5 to 8 hours depending on
the study and thus makes comparisons challenging. Regardless, insufficient sleep
has been linked with poor cardiometabolic health in nonpregnant populations [14],
and accumulating evidence, as discussed below, suggests that these findings are
similar in pregnancy.
With regard to maternal health, few studies have specifically investigated the
relationships between sleep duration and blood pressure in pregnancy. In a self-
report study, Williams et al. found that both maternally reported short sleep duration
(defined as ≤6 hours) and long sleep duration (defined as at least 9 hours) in early
pregnancy were both associated with increases in systolic and diastolic blood pres-
sure in the third trimester [15]. In particular, a report of <5 hours’ sleep was found
to have a particularly high odds of preeclampsia (aOR 9.5, 95%CI 1.8–49.4),
although sleeping more than 10 hours did not show an increase in preeclampsia:
aOR 2.5 (95%CI 0.7–8.2) [15]. Conversely, results from an actigraphy-based study
in over 700 women found no relationship between short sleep duration (defined as
<7 hours) and a diagnosis of hypertension [16]. Recently, Tang et al. have demon-
strated that in the first trimester, both systolic and diastolic blood pressure was lower
in women who slept longer; in longitudinal analyses across pregnancy, women with
longer sleep durations had lower systolic blood pressure [17].
Associations between sleep duration and gestational diabetes (GDM) have been
studied more than maternal blood pressure. A large study of >1200 women found
that GDM risk was increased among those who slept ≤4 hours per night when com-
pared to those sleeping at least 9 hours per night, with a relative risk (RR) of 5.6
(95%CI 1.3–23.7) [18]. Sleep duration has been reported to have a “J”-shaped asso-
ciation with GDM; in over 900 women, with sleep durations of ≥9 hours and
<7 hours, the odds for GDM were 1.2 (95%CI 1.0–1.4) and 1.4 (95%CI 0.9–2.1),
respectively, although the proportion of women in the short sleep category was
21 Sleep in Pregnancy 473
small [19]. In a cohort of over 600 multiethnic Asian women, those who reported
sleeping less than 6 hours per night had the highest frequency of GDM compared to
those who slept 7–8 hours per night (27.3% vs. 16.8%), and fasting glucose levels
were observed to decrease linearly with increasing sleep duration [20]. However,
after accounting for other covariates, no relationship with sleep duration and glu-
cose levels was evident. Associations between sleep duration and GDM have been
reported to differ by prepregnancy obesity status. Findings from the multi-site Fetal
Growth Study of approximately 2500 women [21] found that the association
between maternal sleep duration and GDM was only significant among nonobese
women, with a twofold higher increased risk of GDM in women who reported more
or less than 8–9 hours. The highest adjusted relative risk for GDM (aRR 2.5, 95%CI
1.27–5.0) was observed among nonobese women who slept 5–6 hours in the second
trimester. Specifically, in women who slept <7 hours, the risk for GDM was more
than twice that of women who slept 8–9 (aRR 2.5, 95%CI 1.2–5.1), with long sleep-
ers (at least 10 hours) who rarely or never napped having the highest risk of GDM
(aRR 3.1, 95%CI 1.0–9.2) [21]. Napping appears to modify the sleep-GDM asso-
ciation with a significant association among women who rarely or never napped in
the second trimester. Recent work in Chinese pregnant women supports these find-
ings; the influence of shorter nighttime sleep duration on GDM was found to be
weaker in women with more napping, and midday napping reduced the risk of
GDM among women with insufficient sleep [22].
Objective data from 782 women with actigraphy also supports that sleep dura-
tion <7 hours per night is associated with an increased risk of GDM (aOR 2.2,
95%CI 1.1–4.5) [16]. Furthermore, an individual patient data (IPD) meta-analysis
has demonstrated that pregnant women who slept <6–7 hours were at higher odds
of GDM compared to those without short sleep: aOR 1.7 (95%CI, 1.2–2.3) [23]. In
addition, compared to sleeping >6.25 hours, women who slept ≤6.25 hours had
higher 1-hour glucose levels and an increased odds of GDM, aOR 2.8 (95%CI
1.3–6.4) [23]. Taken together, both subjective and objective data suggest that sleep-
ing less than 7 hours in early-mid-pregnancy is associated with an approximate
twofold increased risk for the development of GDM, with extremes of sleep (e.g.,
less than 4 hours or greater than 10 hours) possibly associated with even higher risks.
While short sleep duration in pregnancy has been linked with poor maternal out-
comes, fewer studies have focused on fetal outcomes. Similar to the studies
described above, those focused on sleep duration and fetal outcomes have inconsis-
tent definitions of short sleep, ranging from between <4 hours and <8 hours per
night. Fetal growth has been investigated in a few studies of maternal sleep duration.
In a study of almost 1100 women, no differences in birth weight or being born small
for gestational age (SGA; <10th percentile) were found in women who self-reported
less than 5 hours of sleep per night [24]. Similarly, Howe et al. [25] found no differ-
ences in birth weight or percentile in infants born to women reporting sleep <6 hours
per night. However, both SGA <5th percentile and low birth weight have been
linked with sleeping less than 8 hours per night, with odds ratios of 2.2 and 2.8,
respectively [26, 27]. In a prospective study of 32 depressed and 136 nondepressed
pregnant women, it was only the depressed women who reported fewer than 7 hours
474 L. M. O’Brien
of sleep at 30 weeks’ gestation that had smaller babies than women who reported
more than 9 hours’ sleep [13].
Nonetheless, it should be noted that cross-sectional studies have limitations
when measuring fetal outcomes. Insults in early pregnancy may influence subse-
quent fetal growth, which is not captured with cross-sectional designs. Longitudinal
studies are therefore critical to investigate the impacts of maternal sleep on fetal
health. For example, in 1500 women who were assessed at several times across
pregnancy, those sleeping at least 9 hours per night hours before the 17- and 28-week
assessments had mean birth weights 74 g and 60 g higher, respectively, compared to
other women, and a linear trend was evident at 17 weeks [28]. In contrast, cross-
sectional studies of those sleeping more than 9 hours per night find no association
with a single measure of birth weight [25]. In a large cohort of over 3500 women,
those who slept <7 hours in early pregnancy, compared to those who slept 8–9 hours,
had a shorter birth length by 2.4 mm and a 42.7 g reduction in birth weight. The risk
of low birth weight increased 83% and the risk of SGA increased 56% in women
sleeping <7 hours [29]. More recently, a Brazilian study reported first-trimester
24-hour sleep duration and its change throughout pregnancy were inversely associ-
ated with birth weight such that women with greater decreases in sleep duration
gave birth to infants with lower birth weight z-scores [30]. These findings were only
in nulliparous women and no associations were detected in multiparous women. In
a large study of women who had delivered at full term, no association between sleep
durations in the second trimester was found with SGA [31]. A recent study in which
subjective and objective sleep measures were collected in 166 low-risk women
found that shorter self-reported sleep duration (but not actigraphy-assessed dura-
tion) was associated with shorter gestational age [32]. The authors posited that in
otherwise healthy women, there appears to be minimal evidence that sleep measures
in early gestation impact pregnancy outcomes. Despite this, findings of recent meta-
analyses suggest that women with the shortest sleep duration have an increased rela-
tive risk of preterm birth compared to women with the longest sleep durations
(RR1.23, 95%CI 1.01–1.50) [33] although findings are unclear in regard to whether
short – or long – sleep duration impacts fetal growth as the adjusted odds ratios for
SGA and large for gestational age (LGA) were found to be 1.3 “(95%CI 0.9–2.0)
and 1.5 (95%CI 0.7–2.8) [34]. However, it should be noted that both of the latter
meta-analyses included cross-sectional studies as well as longitudinal ones.
Sleep Quality
The National Women’s Sleep Poll (www.sleepfoundation.org) found that 30% of

pregnant women rarely/never get a good night’s sleep, which is twice as many as
nonpregnant women who endorsed the same question. Reasons for this include
increased need to urinate, difficulty finding comfortable sleeping positions, and
body aches [35]. Prevalence estimates of poor sleep quality in pregnancy, as mea-
sured by the Pittsburgh Sleep Quality Index (PSQI) [36] with a score of at least 5,
range from 29% to 76% [5, 37], with a recent meta-analysis from over 11,000 preg-
nant women suggesting that the frequency of poor sleep quality is approximately
45% [38]. Indeed, waking up feeling unrefreshed is a very common complaint in
pregnancy with most women endorsing unrefreshing sleep [5]. Parity and gesta-
tional age appear to play a role in reported sleep quality, with nulliparous women
reporting worse sleep quality compared to multiparous women [39] and better sleep
quality in early pregnancy compared to late pregnancy [38]. Unsurprisingly, poor
sleep quality is also common in depressed women [13].
Several studies have suggested that poor sleep quality may impact blood pres-
sure. In a study of 161 pregnant women that utilized sleep diaries and actigraphy,
latency to sleep onset and wake after sleep onset – which are two measures of sleep
continuity – were associated with higher blood pressures, despite accounting for
covariates including BMI [40]. In a Japanese cohort, an increase in morning systolic
blood pressure from the first to the third trimester was larger in women with poor
sleep quality than in those with good sleep quality (7.1 ± 7.0 mmHg vs.
3.0 ± 5.6 mmHg, p < 0.01), suggesting that sleep quality early in pregnancy may
contribute to a rise in systolic blood pressure in late pregnancy [41]. Similarly, a
mixed model analysis of over 900 pregnant women in Singapore demonstrated an
overall positive association between sleep quality, as measured by the PSQI score,
and diastolic blood pressure [17]. In the latter study, overall poor sleep during preg-
nancy was also found to be associated with a higher uterine artery pulsatility index
(an increased resistance to blood flow and thus increased risk for hypertension).
However, it is possible that the influence of poor sleep and hypertension may be
bidirectional. In a small cross-sectional study of 56 women with gestational hyper-
tension and GDM, higher PSQI scores continued to worsen throughout pregnancy,
and the authors suggested that the presence of hypertension may increase maternal
stress and subsequently affect sleep [42].
In a multiethnic cohort of Asian women, Cai et al. reported that poor sleep qual-
ity – again measured by the PSQI – was independently associated with an increased
risk of GDM with an adjusted odds ratio of 1.75 (95%CI 1.11–2.76) [20], similar to
the findings in Chinese women [19]. However, other studies using the same measure
of sleep quality have not supported these findings [43, 44]. In addition to the PSQI,
sleep quality has also been investigated via a single self-reported question item
although findings are inconsistent. Some studies have not found associations with
GDM [45, 46], while two very large studies (over 4000 and 12,000 women, respec-
tively) did find that poor sleep quality increased the odds of GDM 60–70% even
after adjusting for other covariates [19, 47]. Indeed, a recent systematic review of
sleep quality and GDM risk reported that subjectively measured poor sleep quality
was associated with a higher risk for GDM (pooled OR 1.43; 95%CI, 1.16–1.77),
but little evidence was found for associations when using objective measures [48].
It should be noted that the latter objectively measured studies were quite small and
measure different aspects of sleep such as continuity or efficiency as opposed to
self-report of perceived sleep quality, which is what is captured subjectively.
In recent years, data on poor sleep quality and fetal outcomes have begun to
emerge. There appears to be little impact for maternal poor sleep quality on fetal
476 L. M. O’Brien
growth [25, 43, 49] although one study reported lower birth weight in babies born
to women with very high PSQI scores (greater than 18) compared to those with
lower PSQI scores [50]. Women with “unrefreshed sleep” have been reported to be
more likely to deliver babies with a birth weight of at least 3.5 kg compared to those
who report refreshed sleep: 26% vs. 14%, p < 0.03 [51]. Nonetheless, a recent sys-
tematic review found that current evidence does not support differences in birth
weight or fetal growth with poor maternal sleep quality [34]. It should be noted
however that most studies have relatively small sample sizes which is particularly
challenging when the exposure is a subjective measure.
Several studies have investigated associations between poor sleep quality and
preterm birth; some have found no relationship [49, 52], while others have reported
higher frequencies of preterm birth in women with poor sleep quality [53–55].
Interestingly, Blair et al. demonstrated that the odds of preterm birth were tenfold
higher in African American women with poor sleep quality compared to those with-
out, a finding that was not replicated in European women [54]. While data suggest
a potential association between poor sleep quality and preterm birth, there is wide
variability in sample sizes, differing study designs (such as preterm birth as an
exposure in some studies and an outcome in others), and differing definitions of
poor sleep quality which make it difficult to draw firm conclusions [34]. However,
in studies that have measured sleep in mid-pregnancy, poor sleep quality was dem-
onstrated to increase the odds for preterm birth in several studies in the United
States, China, and Japan [53–57], with risk estimates being two-to fivefold higher
for preterm birth. In a very recent meta-analysis, the pooled relative risk for preterm
birth was 1.54 (95%CI 1.18–2.01) [33]. It is thus plausible that the impact of dis-
turbed sleep on fetal outcome may begin in early pregnancy and that longitudinal
studies are necessary for fully delineate any associations. Indeed, it has been sug-
gested that disturbed sleep during early pregnancy may contribute to an increased
inflammatory response or decreased uterine blood flow that could disrupt the nor-
mal remodeling of maternal blood vessels that perfuse the placenta and thus could
subsequently result in poor pregnancy outcomes [58].
Insomnia
Insomnia, defined as difficulty falling asleep, staying asleep, or poor sleep quality,
is one of the most common sleep complaints in pregnancy. The prevalence of insom-
nia disorder and clinically significant insomnia symptoms are much greater in preg-
nant women relative to the general population of women of childbearing age with
60% of pregnant women meeting criteria compared to only 11% of nonpregnant
women [59]. The prevalence of insomnia symptoms also increases across preg-
nancy from 6.1% pregestation, 44.2% in the first trimester, and 46.3% in the second
trimester to a peak of 63.7% in the third trimester [60]. Physiological and psycho-
social changes that occur during the perinatal period contribute to the development
and maintenance of insomnia within the framework of the diathesis-stress model of
chronic insomnia, which identifies predisposing factors, precipitating events, and

perpetuating factors (i.e., Spielman’s “Three P Model” [61]) as critical to the evolu-
tion of insomnia into chronicity across time. Pregnant women experience more cog-
nitive hyperarousal [62] than nonpregnant women who appear more likely to engage
in nocturnal rumination (i.e., repetitive negative thinking at night) [63], possibly
related to hormonal influences [64]. Insomnia symptoms are highly associated with
PSQI scores, and the increased prevalence of poor sleep quality during pregnancy
may indicate an increase in insomnia symptoms [38].
While insomnia in pregnancy is well-known to have strong associations with
depressive symptomatology [65] and has been associated with higher blood pres-
sures in the nonpregnant population [66], there is a dearth of data regarding its
relationship with maternal and fetal outcomes. A study of 370 women found that
presence of insomnia was associated with abnormalities of maternal body composi-
tion (increased weight and arm circumference) [67]. In pregnant women who were
screened for insomnia as well as habitual snoring, only those with comorbid insom-
nia and habitual snoring had an increased odds for gestational hypertension (OR
3.6, 95%CI 1.1–11.7), but isolated insomnia had no association [68]. The same
study also demonstrated that isolated insomnia increased the odds for babies being
born large for gestational age even after adjustment for confounders. An observa-
tional study of approximately three million women reported that a diagnosis of
insomnia was associated with a 30% in the odds of preterm birth [69]. Furthermore,
women with a recorded insomnia diagnosis were almost twice as likely to deliver
before 34 weeks’ gestation (OR 1.7, 95% CI 1.1–2.6) compared to women without
a sleep disorder diagnosis, and the risk was highest for preterm premature rupture of
membranes at less than 34 weeks (OR 4.1, 95% CI 2.0–8.3). It should be noted
insomnia is often discussed in the context of poor sleep quality and insufficient
sleep, both of which have been associated with poor pregnancy outcomes [9], but
studies focused on insomnia and pregnancy outcomes are lacking.
Sleep-Disordered Breathing
Sleep-disordered breathing (SDB) is common in pregnancy with up to 35% of

women reporting habitual snoring by the third trimester [70]. However, the fre-
quency of objectively measured SDB is somewhat less common, with approxi-
mately 3% of women in early pregnancy and 8% by mid-pregnancy having an
apnea-hypopnea index of at least 5 [71]. Unsurprisingly, women with higher BMIs
are more likely to have SDB [72, 73]. Furthermore, in women with hypertensive
disorders of pregnancy, both symptoms of SDB and objectively defined SDB are
much more common, with as many as 85% of hypertensive women endorsing habit-
ual snoring and approximately 50% having underlying SDB [74–76].
A robust literature demonstrates strong associations between maternal SDB and
gestational hypertension/preeclampsia, regardless of whether SDB is symptom-
based or objectively measured [70, 71, 77, 78]. Furthermore, the timing of SDB
478 L. M. O’Brien
onset is important; it has been shown that pregnancy-onset SDB may drive the rela-
tionship with maternal hypertension [70]. In a systematic review and meta-analysis,
SDB during pregnancy has been related to a twofold increased risk of gestational
hypertension/preeclampsia [77]. The NuMoM2b study, a large cohort of women
who underwent home sleep testing during pregnancy, found that the presence of
SDB (defined as an AHI ≥5) was associated with a twofold increase in odds for the
development of preeclampsia [71]. Of note, in the latter study, the adjusted odds
ratio for hypertensive disorders with early pregnancy SDB did not reach statistical
significance, but SDB in mid-pregnancy was statistically significant: aOR 1.7 (95%
CI 1.2–2.5). This supports prior reports using subjective symptoms of SDB that tim-
ing of SDB is important [70]. While obesity is common in pregnant women, it does
not completely explain the higher odds of hypertension in women with SDB; appli-
cation of causal mediation has demonstrated that the presence of new-onset mater-
nal SDB accounts for 15% of the relationship between BMI and hypertension [79].
In addition to gestational hypertension/preeclampsia, there is an increasing lit-
erature that demonstrates associations between SDB and GDM. Several cohort
studies utilizing retrospective and prospective data all found increased odds
(approximately two- to fivefold) for GDM or impaired glucose tolerance in women
with SDB symptoms [18, 56, 78, 80, 81]. Similar findings were reported when using
a population-based study of ICD-9 codes to identify SDB up to a year prior to deliv-
ery [82], as did a national cohort of over 1.5 million women [83]. Moreover, in the
NuMoM2b study of over 3000 women with objective sleep measures, women with
an AHI ≥5 in early pregnancy had an aOR of 3.45 (95%CI 2.0–6.2) for the develop-
ment of GDM [71]. Meta-analyses also support these findings [84, 85]. One study
compared lean women (BMI < 25 kg/m2) to overweight women (BMI ≥ 25 kg/m2)
and found that lean women who snored had double the odds for GDM compared to
lean non-snorers, with overweight snoring women having the highest odds, at 5.0
(95%CU 2.7–9.3) [81].
While robust associations between SDB and maternal outcomes have been
reported as described above, associations with fetal outcomes are not as strong.
Although associations between maternal SDB and fetal well-being were first
reported in 1978 [86], it was not until recently that work became focused in this
area. In 2000 the first study of pregnant women with SDB suggested that habitual
snoring was associated with infants born SGA [87]. However, data are conflicting,
and several studies fail to find associations between SDB symptoms and birth
weight or birth centile [25, 88–92]. In those studies that do find a relationship, SDB
appears to be associated with both SGA and LGA. Some have reported SGA/growth
restriction with odds ratios or relative risks of between 1.7 and 3.5 [24, 87, 93],
while others have reported LGA with very similar relative risks of 1.7–2.6 [94–96].
Timing of onset of maternal SDB symptoms may also be relevant to fetal outcomes
as only chronic habitual snoring but not pregnancy-onset snoring appears associated
with SGA <10th percentile (aOR 1.7, 95% CI 1.0–2.7) [93]. Of note, studies that
found an approximate twofold increase in LGA used the Berlin Questionnaire [94–
98], which performs poorly in pregnancy [99], likely because it includes obesity in
the scoring paradigm which may drive the relationship with poor outcomes [100].
In support of this, a study stratified by BMI found that the association with high
birth weight in snoring women was only present in those with a BMI >30 kg/m2
[96]. Further, when prepregnancy BMI is accounted for, the apparent association
with abnormal glucose levels disappears [70]. Further research is needed to tease
out the contributions of SDB and obesity to fetal growth.
Symptom-based studies are also conflicting with regard to associations with pre-
term birth. Several cross-sectional and cohort studies find no associations between
snoring and preterm birth [24, 89, 95, 101, 102], although gasping has been associ-
ated with preterm birth with an odds of 1.8 (95% CI 1.1–3.2) [78] and witnessed
apnea has demonstrated more than double an increased risk of preterm birth (aRR
2.6, 95%CI 1.2–5.2) [95]. Maternal snoring may also play a role in gestational
length; deliveries before 38 weeks’ gestation occurred among 25% of women with
chronic, frequent-loud snoring, and women with the latter symptom had an increased
hazard ratio for delivery of 1.60 (95% CI 1.04, 2.45) as well as a higher frequency
of delivery prior to both 37 and 39 weeks’ gestation compared with non-snorers
(45% vs. 33% and 19% vs. 9%, respectively) [103].
Similar to the data for subjective SDB measures, most objective SDB assess-
ments do not demonstrate differences in birth weight or percentile [104–107].
However, in 230 women who underwent polysomnography, a two- to threefold
increase in SGA has been reported, with higher odds for SGA in those with more
severe sleep disturbance [108]. Conversely, in 155 healthy Israeli women without
comorbidities, SDB has been associated with LGA (aOR 5.1, 95%CI 1.3–20.1)
[109]. Population-based studies of diagnostic codes have yielded inconsistent
results with reports of SDB being associated with SGA [82], LGA [110], or no dif-
ference [73]. Large population-based studies are challenging to interpret because
the true prevalence of SDB is not known nor is the proportion of women who receive
and appropriately use treatment interventions. One further consideration in studies
of fetal growth is that a single measure after delivery may not reflect the true pattern
of fetal growth. Fetuses of women with SDB have been reported to demonstrate a
fall in growth percentile between 32 weeks and delivery [106], while a causal rela-
tionship between maternal SDB and fetal growth is suggested by a study which
showed a fall in fetal growth percentiles across the third trimester in women with
untreated SDB, with no such slowing in growth in women treated with positive
airway pressure [111]. A recent meta-analysis has demonstrated that both SDB
symptoms and objective measures of SDB are independently associated with growth
abnormalities, both SGA and LGA with similar pooled odds ratios of approximately
1.3–1.6 [34]. While these findings may appear counterintuitive, it is plausible that
the underlying mechanisms of SDB may differentially affect fetal growth such that
hypertension and its associated sympathetic activation may be associated with fetal
growth restriction, while a poor metabolic environment may be more likely to be
related to macrosomia.
In studies using clinical diagnoses of SDB, an increase in early preterm birth
(<32 weeks) as well as an increase in delivery prior to 37 weeks has been reported
in women with SDB compared to both obese women and to normal-weight women
[112], with the presence of SDB doubling the odds for preterm birth. Small
480 L. M. O’Brien
prospective studies, however, have generally found no differences in preterm birth

whether that be defined as <32 weeks [72], <34 weeks [105], or <37 weeks [72,
108]. Nonetheless, rather than preterm birth as a dichotomous outcome, some stud-
ies have reported gestational length as a continuous variable although findings are
mixed. Some do not support a difference in gestational length [104, 113], while oth-
ers suggest a slightly shorter gestation in women with OSA [106]. Data from large
population-based data sets do however appear to support a link [73, 82, 110, 114]
with about a twofold increase in odds in earlier delivery.
Restless Leg Syndrome
Symptoms of restless leg syndrome (RLS) increase as pregnancy progresses, peak-

ing in third trimester and resolving a few days before delivery [115–118]. A recent
meta-analysis [119] reported that the frequency of RLS increases across the first,
second, and third trimesters of pregnancy, with 8%, 16%, and 22% of women,
respectively, reporting RLS symptoms, with a large decrease in frequency to 4%
after delivery. RLS symptoms are associated with shorter total sleep time, more dif-
ficulty initiating and maintaining sleep, and more daytime sleepiness compared to
pregnant women without RLS [115, 116, 118, 120]. In extreme cases, symptoms are
so disturbing that evening relaxation and falling asleep is almost impossible and
creates a high risk for depression [120, 121]. The prevalence of RLS is approxi-
mately two- to threefold higher in pregnant women compared to nonpregnant
women [116], at about 3–36% [115, 116, 122]. In a prospective study of 1428
women, prepregnancy RLS was found to be a risk factor for both prenatal and post-
natal depression, while no added risk was seen in those with new-onset RLS during
pregnancy [121]. Moreover, RLS has been linked with poor sleep quality, poor day-
time function, and excessive daytime sleepiness although it should be noted that
despite the high frequency of RLS in pregnancy, there is little evidence to suggest
an association with birth outcomes [122–124]. However, in a study that used a sur-
rogate measure of RLS (“jumpy or jerky leg movements”), having such movements
“always” was associated with an increased incidence of preterm birth and a lower
birth weight [125].
Mechanisms for Cardiovascular Morbidity
The mechanisms of sleep disruption – especially SDB – that affect cardiovascular

morbidity in nonpregnant adults are remarkably similar to the biological pathways
for preeclampsia and include sympathetic activation, oxidative stress, inflammation,
and endothelial dysfunction [126, 127]. In SDB, increased sympathetic activation is
propagated by frequent arousals and repetitive apneas; the surges in sympathetic
activity ultimately result in elevated nocturnal and daytime blood pressures, a key
factor in the pathogenesis of cardiovascular morbidity [128]. In pregnancy, sympa-

thetic overactivity is one of the hallmarks of preeclampsia [129]. Furthermore, epi-
sodes of intermittent hypoxia and reoxygenation are involved in the generation of
reactive oxygen species and reduction in the levels of circulating antioxidants. The
subsequent imbalance leads to oxidative stress which plays a central role in endo-
thelial damage and ultimately hypertension [130]. It has been postulated that condi-
tions of chronic sleep loss in pregnancy, such as insufficient sleep, insomnia, and
poor sleep quality, could lead to sustained overload of the stress system, which may
in turn impair the HPA axis and the proinflammatory system, leading to poor preg-
nancy outcomes [9, 127].
Treatment Interventions
Treatment intervention trials for sleep disturbance in pregnancy are limited. For
pregnant women with SDB, small studies and case reports show that use of positive
airway pressure is safe and appears to improve maternal blood pressure and insulin
secretion, extend time in utero, and improve markers of maternal and fetal well-
being [131–136]. For insomnia, cognitive behavioral therapy (CBTI) is efficacious
during pregnancy [137, 138]. A 5-week CBTI program for pregnant women demon-
strated significant reductions in insomnia symptoms and increases in subjective
sleep quality as well as less time in bed, shorter sleep-onset latency, increased sleep
efficiency, and increased subjective total sleep time. Importantly, symptoms of
depression, pregnancy-specific anxiety, and fatigue all decreased over the course of
treatment [138]. Moreover, since access to trained clinicians can be challenging to
many women, delivery of digital CBTI online has also been shown to improve sleep
onset and maintenance symptoms as well as sleep duration [139]. Importantly,
CBTI during pregnancy appears to protect against sleep loss after childbirth. Support
for other therapies to improve sleep quality such as yoga/mindfulness, relaxation,
herbal therapies, and acupuncture has also been reported (see Bacaro [140] for a
review). However, whether these interventions translate to improvements in fetal
outcomes is yet to be tested. Effective treatments, either via therapies such as posi-
tive airway pressure for SDB or behavioral strategies to promote good hygiene,
should be aggressively pursued in order to reduce the short- and long-term burden
of the consequences of sleep deficiency during pregnancy.
Circadian Rhythm Disruption
The majority of studies of circadian rhythms focus on nonpregnant individuals with

shift work and find associations with poor health outcomes, especially obesity and
type 2 diabetes mellitus [141, 142]. Although an emerging area of investigation in
pregnant women, circadian rhythm disruption has been associated with poorer
482 L. M. O’Brien
fertility and early pregnancy loss via alterations in circadian rhythm-regulating gene
expression [143]. Indeed, shift work has been reported to increase the risk of mis-
carriage [144–146]. However, data on circadian disruption and its relationship with
pregnancy outcomes is scarce. Recently, a large multicenter study of over 7000
women found that those who self-reported a late sleep midpoint (>5 am) in early
pregnancy – as a marker of circadian misalignment – had an aOR of 1.67 (95% CI
1.17–2.38) for GDM [147] and an aOR of 1.39 (95%CI 1.08–1.80) for preterm birth
[148]. Similar findings were reported by the same group using a sub-cohort of
women with actigraphic measures, with a later sleep midpoint being associated with
an increased odds for GDM (aOR 2.58, 95%CI 1.24–5.36) [16] although the asso-
ciations between later sleep midpoint and preterm birth were not quite significant in
this smaller sample (aOR 1.68, 95%CI 0.88–3.20) [148].
Analysis of 24-hour rest-activity and saliva cortisol rhythms across the second
and third trimester of gestation has shown that more robust activity rhythms are
associated with more robust cortisol rhythms and suggest that more irregular sleep-
activity rhythms may be associated with earlier gestational age [149]. Furthermore,
women diagnosed with gestational-related disease (hypertension, gestational diabe-
tes mellitus, and/or preeclampsia) showed a trend for higher cortisol levels [149],
which is consistent with the relationship of hypercortisolism with gestational diabe-
tes [150]. In light of these emerging findings, there is an urgent need to explore the
impact of disrupted circadian rhythms among the pregnant women and their off-
spring. To that end, a large study in Malaysia is underway to investigate the role of
circadian rhythms, activity, and nutrition during pregnancy on birth outcomes and
infant growth [151].
Maternal Sleep Position
In recent years, data from several countries have shown that self-reported maternal
supine going-to-sleep position is a significant risk factor for late-gestation stillbirth
(stillbirth at 28 weeks’ gestation or more). Report of supine sleep position is three-
to eightfold higher in women who experience a late stillbirth [101, 152–155] with
an individual patient data analysis showing a 2.6-fold increased odds [156]. While
it has long been recognized that posture in pregnancy – particularly during labor –
has a profound impact on maternal hemodynamics, few people have extrapolated
these practices to how a pregnant woman sleeps. In the supine position, the inferior
vena cava is compressed, with subsequent reduced blood flow and a reduction in
cardiac output [157]. Even in healthy late-gestation pregnancies, maternal position
results in an approximate 6% reduction in oxygen delivery to the fetus and 11%
reduction in fetal umbilical venous blood flow [158]. Maternal supine position has
been demonstrated to induce fetal quiescence [159], an oxygen conserving state
observed during periods of fetal hypoxia, and a small cross-sectional study has sug-
gested that maternal supine sleep was linked to a fivefold increase in low birth
weight [101], a finding that was confirmed in a large individual patient data analysis
of 1760 women and which found a threefold increase in small for gestational age
[160]. Taken together, these findings provide evidence of biological plausibility in
the relationship of supine sleep to late-gestation stillbirth. Unlike the studies that
have used self-report of going-to-sleep position mentioned above, a study of home
sleep testing found no association between sleep position prior to 30 weeks’ gesta-
tion and stillbirth [161]. However, the latter study was conducted at a much earlier
gestational age than other studies [101, 152–156], and this suggests that the heavier
gravid uterus later in the third trimester likely conveys the risk. Other sleep behav-
iors such as long sleep duration, non-restless sleep, and not waking in the night have
also been associated with late stillbirth [162], which raises the question of whether
long periods of undisturbed sleep increase the risk of late fetal demise. Data are
lacking on how the neuroendocrine and autonomic system pathways are regulated
in pregnant women during sleep, and this is a fertile area for investigation.
Since most pregnant women spend at least some time in the supine position
[163], supine sleep is a potentially modifiable risk factor which could prevent up to
10% of late stillbirths [154, 164]. While there is no intervention study adequately
powered to investigate whether reduction in supine sleep translates to fewer still-
births, several recent studies have shown promise in the ability to reduce time spent
in the supine position without impacting sleep quality or duration [165–167] and
even suggest that fetal heart rate decelerations can be reduced and infant birth
weight may be increased [165, 167]. Work is ongoing in this area.
Summary
In summary, pregnancy is a vulnerable period for sleep disturbance and confers

significant impact to both maternal and fetal health. Clinicians caring for pregnant
women should be mindful of the accumulating evidence, and identification of sleep
disturbance and clinical sleep disorders should be prioritized. Effective therapies to
reduce the public health burden of sleep deficiencies are urgently needed since preg-
nancy offers a window of opportunity to improve long-term health outcomes for
both mothers and their babies.
References
1. Lee KA, Zaffke ME, McEnany G. Parity and sleep patterns during and after pregnancy.
Obstet Gynecol. 2000;95(1):14–8. PubMed PMID: 10636494.
2. Hedman C, Pohjasvaara T, Tolonen U, Suhonen-Malm AS, Myllyla VV. Effects of pregnancy
on mothers’ sleep. Sleep Med. 2002;3(1):37–42. PubMed PMID: 14592252.
3. Facco FL, Kramer J, Ho KH, Zee PC, Grobman WA. Sleep disturbances in pregnancy. Obstet
Gynecol. 2010;115(1):77–83. PubMed PMID: 20027038. Epub 2009/12/23.
4. Lee KA, Zaffke ME. Longitudinal changes in fatigue and energy during pregnancy and the
postpartum period. J Obstet Gynecol Neonatal Nurs. 1999;28(2):183–91.
484 L. M. O’Brien
5. Mindell JA, Cook RA, Nikolovski J. Sleep patterns and sleep disturbances across pregnancy.
Sleep Med. 2015;16(4):483–8. PubMed PMID: 25666847. Epub 2015/02/11.
6. Izci-Balserak B, Pien GW. The relationship and potential mechanistic pathways between
sleep disturbances and maternal hyperglycemia. Curr Diab Rep. 2014;14:459.
7. National Sleep Foundation. Women and sleep in America poll. Available at https://www.
sleepfoundation.org/professionals/sleep-america-polls/2007-women-and-sleep. Accessed 30
Oct 2019. Washington, DC, 2007.
8. Beebe KR, Gay CL, Richoux SE, Lee KA. Symptom experience in late pregnancy. J Obstet
Gynecol Neonatal Nurs. 2017;46(4):508–20. PubMed PMID: 28549613. Epub 2017/05/28.
9. Palagini L, Gemignani A, Banti S, Manconi M, Mauri M, Riemann D. Chronic sleep loss
during pregnancy as a determinant of stress: impact on pregnancy outcome. Sleep Med.
2014;15(8):853–9. PubMed PMID: 24994566. Epub 2014/07/06.
10. Izci-Balserak B, Keenan BT, Corbitt C, Staley B, Perlis M, Pien GW. Changes in sleep char-
acteristics and breathing parameters during sleep in early and late pregnancy. J Clin Sleep
Med. 2018;14(7):1161–8. PubMed PMID: 23354511. PMCID: PMC3696035.
11. Brunner DP, Munch M, Biedermann K, Huch R, Huch A, Borbely AA. Changes in sleep and
sleep electroencephalogram during pregnancy. Sleep. 1994;17(7):576–82.
12. Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O, DonCarlos L, et al. National Sleep
Foundation’s sleep time duration recommendations: methodology and results summary.
Sleep Health. 2015;1(1):40–3. PubMed PMID: 29073412.
13. Okun ML, Kline CE, Roberts JM, Wettlaufer B, Glover K, Hall M. Prevalence of sleep defi-
ciency in early gestation and its associations with stress and depressive symptoms. J Womens
Health (Larchmt). 2013;22(12):1028–37. PubMed PMID: 24117003. PMCID: PMC3852611.
Epub 2013/10/15.
14. Cappuccio FP, Miller MA. Sleep and cardio-metabolic disease. Curr Cardiol Rep.
2017;19(11):110. PubMed PMID: 28929340. PMCID: PMC5605599. Epub 2017/09/21.
15. Williams MA, Miller RS, Qiu C, Cripe SM, Gelaye B, Enquobahrie D. Associations of
early pregnancy sleep duration with trimester-specific blood pressures and hypertensive
disorders in pregnancy. Sleep. 2010;33(10):1363–71. PubMed PMID: 21061859. PMCID:
PMC2941423. Epub 2010/11/11.
16. Facco FL, Grobman WA, Reid KJ, Parker CB, Hunter SM, Silver RM, et al. Objectively mea-
sured short sleep duration and later sleep midpoint in pregnancy are associated with a higher
risk of gestational diabetes. Am J Obstet Gynecol. 2017;217(4):447 e1–e13. PubMed PMID:
28599896. PMCID: PMC5783638. Epub 2017/06/11.
17. Tang Y, Zhang J, Dai F, Razali NS, Tagore S, Chern B, et al. Poor sleep is associated with
higher blood pressure and uterine artery pulsatility index in pregnancy: a prospective cohort
study. BJOG. 2020. PubMed PMID: 33145901. Epub 2020/11/05.
18. Qiu C, Enquobahrie D, Frederick IO, Abetew D, Williams MA. Glucose intolerance and ges-
tational diabetes risk in relation to sleep duration and snoring during pregnancy: a pilot study.
BMC Womens Health. 2010;10:17. PubMed PMID: 20470416. PMCID: PMC2885310.
Epub 2010/05/18.
19. Wang H, Leng J, Li W, Wang L, Zhang C, Li W, et al. Sleep duration and quality, and risk of
gestational diabetes mellitus in pregnant Chinese women. Diabet Med. 2017;34(1):44–50.
PubMed PMID: 27154471. Epub 2016/05/08.
20. Cai S, Tan S, Gluckman PD, Godfrey KM, Saw SM, Teoh OH, et al. Sleep quality and noctur-
nal sleep duration in pregnancy and risk of gestational diabetes mellitus. Sleep. 2017;40(2).
PubMed PMID: 28364489. Epub 2017/04/02.
21. Buck Louis GM, Grewal J, Albert PS, Sciscione A, Wing DA, Grobman WA, et al. Racial/
ethnic standards for fetal growth: the NICHD Fetal Growth Studies. Am J Obstet Gynecol.
2015;213(4):449 e1–e41. PubMed PMID: 26410205. PMCID: PMC4584427.
22. Wang W, Li M, Huang T, Fu Q, Zou L, Song B, et al. Effect of nighttime sleep duration and
midday napping in early pregnancy on gestational diabetes mellitus. Sleep Breath. 2020.
PubMed PMID: 32266661. Epub 2020/04/09.
23. Reutrakul S, Anothaisintawee T, Herring SJ, Balserak BI, Marc I, Thakkinstian A. Short
sleep duration and hyperglycemia in pregnancy: aggregate and individual patient data meta-
analysis. Sleep Med Rev. 2017. PubMed PMID: 29103944.
24. Micheli K, Komninos I, Bagkeris E, Roumeliotaki T, Koutis A, Kogevinas M, et al. Sleep pat-
terns in late pregnancy and risk of preterm birth and fetal growth restriction. Epidemiology.
2011;22(5):738–44. PubMed PMID: 21734587. Epub 2011/07/08.
25. Howe LD, Signal TL, Paine SJ, Sweeney B, Priston M, Muller D, et al. Self-reported sleep in
late pregnancy in relation to birth size and fetal distress: the E Moe, Mama prospective cohort
study. BMJ Open. 2015;5(10):e008910. PubMed PMID: 26438138. PMCID: PMC4606387.
Epub 2015/10/07.
26. Abeysena C, Jayawardana P, DE A Seneviratne R. Maternal sleep deprivation is a risk factor
for small for gestational age: a cohort study. Aust N Z J Obstet Gynaecol. 2009;49(4):382–7.
PubMed PMID: 19694692. Epub 2009/08/22.
27. Abeysena C, Jayawardana P, Seneviratne RA. Effect of psychosocial stress and physical
activity on low birthweight: a cohort study. J Obstet Gynaecol Res. 2010;36(2):296–303.
PubMed PMID: 20492380. Epub 2010/05/25.
28. Rabkin CS, Anderson HR, Bland JM, Brooke OG, Chamberlain G, Peacock JL. Maternal
activity and birth weight: a prospective, population-based study. Am J Epidemiol.
1990;131(3):522–31. PubMed PMID: 2301361. Epub 1990/03/01.
29. Wang W, Zhong C, Zhang Y, Huang L, Chen X, Zhou X, et al. Shorter sleep duration in early
pregnancy is associated with birth length: a prospective cohort study in Wuhan, China. Sleep
Med. 2017;34:99–104. PubMed PMID: 28522106. Epub 2017/05/20.
30. Franco-Sena AB, Kahn LG, Farias DR, Ferreira AA, Eshriqui I, Figueiredo ACC, et al.
Sleep duration of 24 h is associated with birth weight in nulli- but not multiparous women.
Nutrition. 2018;55–56:91–8. PubMed PMID: 29980093. Epub 2018/07/07.
31. Morokuma S, Shimokawa M, Kato K, Sanefuji M, Shibata E, Tsuji M, et al. Maternal sleep
and small for gestational age infants in the Japan Environment and Children’s Study: a cohort
study. BMC Res Notes. 2017;10(1):394. PubMed PMID: 28800769. PMCID: PMC5553583.
Epub 2017/08/13.
32. Okun ML, Obetz V, Feliciano L. Sleep disturbance in early pregnancy, but not inflamma-
tory cytokines, may increase risk for adverse pregnancy outcomes. Int J Behav Med. 2020.
PubMed PMID: 32372169. Epub 2020/05/07.
33. Wang L, Jin F. Association between maternal sleep duration and quality, and the risk of pre-
term birth: a systematic review and meta-analysis of observational studies. BMC Pregnancy
Childbirth. 2020;20(1):125. PubMed PMID: 32093626. PMCID: PMC7041242. Epub
2020/02/26.
34. Warland J, Dorrian J, Morrison JL, O’Brien LM. Maternal sleep during pregnancy and
poor fetal outcomes: a scoping review of the literature with meta-analysis. Sleep Med Rev.
2018;41:197–219. PubMed PMID: 29910107. Epub 2018/06/19.
35. Mindell JA, Jacobson BJ. Sleep disturbances during pregnancy. J Obstet Gynecol Neonatal
Nurs. 2000;29(6):590–7. PubMed PMID: 11110329. Epub 2000/12/08.
36. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep
Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res.
1989;28(2):193–213. PubMed PMID: 2748771. Epub 1989/05/01.
37. Gelaye B, Barrios YV, Zhong QY, Rondon MB, Borba CP, Sanchez SE, et al. Association of
poor subjective sleep quality with suicidal ideation among pregnant Peruvian women. Gen
Hosp Psychiatry. 2015;37(5):441–7. PubMed PMID: 25983188. PMCID: PMC4558240.
Epub 2015/05/20.
38. Sedov ID, Cameron EE, Madigan S, Tomfohr-Madsen LM. Sleep quality during preg-
nancy: a meta-analysis. Sleep Med Rev. 2018;38:168–76. PubMed PMID: 28866020. Epub
2017/09/04.
39. Signal TL, Gander PH, Sangalli MR, Travier N, Firestone RT, Tuohy JF. Sleep duration
and quality in healthy nulliparous and multiparous women across pregnancy and post-
486 L. M. O’Brien
partum. Aust N Z J Obstet Gynaecol. 2007;47(1):16–22. PubMed PMID: 17261094. Epub

2007/01/31.
40. Haney A, Buysse DJ, Rosario BL, Chen YF, Okun ML. Sleep disturbance and cardiometa-
bolic risk factors in early pregnancy: a preliminary study. Sleep Med. 2014;15(4):444–50.
PubMed PMID: 24657205. PMCID: PMC4084505. Epub 2014/03/25.
41. Okada K, Saito I, Katada C, Tsujino T. Influence of quality of sleep in the first trimester on
blood pressure in the third trimester in primipara women. Blood Press. 2019;28(5):345–55.
PubMed PMID: 31266373. Epub 2019/07/04.
42. Hayase M, Shimada M, Seki H. Sleep quality and stress in women with pregnancy-induced
hypertension and gestational diabetes mellitus. Women. Birth. 2014;27(3):190–5. PubMed
PMID: 24881523. Epub 2014/06/03.
43. Sharma SK, Nehra A, Sinha S, Soneja M, Sunesh K, Sreenivas V, et al. Sleep disorders in
pregnancy and their association with pregnancy outcomes: a prospective observational study.
Sleep Breath. 2016;20(1):87–93. PubMed PMID: 25957617. Epub 2015/05/11.
44. Bisson M, Series F, Giguere Y, Pamidi S, Kimoff J, Weisnagel SJ, et al. Gestational diabe-
tes mellitus and sleep-disordered breathing. Obstet Gynecol. 2014;123(3):634–41. PubMed
PMID: 24499765. Epub 2014/02/07.
45. Xu X, Liu Y, Liu D, Li X, Rao Y, Sharma M, et al. Prevalence and determinants of gesta-
tional diabetes mellitus: a cross-sectional study in China. Int J Environ Res Public Health.
2017;14(12). PubMed PMID: 29292753. PMCID: PMC5750950. Epub 2018/01/03.
46. Ahmed AH, Hui S, Crodian J, Plaut K, Haas D, Zhang L, et al. Relationship between sleep
quality, depression symptoms, and blood glucose in pregnant women. West J Nurs Res.
2019;41(9):1222–40. PubMed PMID: 30406728. Epub 2018/11/09.
47. Zhong C, Chen R, Zhou X, Xu S, Li Q, Cui W, et al. Poor sleep during early pregnancy
increases subsequent risk of gestational diabetes mellitus. Sleep Med. 2018;46:20–5. PubMed
PMID: 29773207. Epub 2018/05/19.
48. Zhu B, Shi C, Park CG, Reutrakul S. Sleep quality and gestational diabetes in pregnant
women: a systematic review and meta-analysis. Sleep Med. 2020;67:47–55. PubMed PMID:
31911280. Epub 2020/01/09.
49. Hung HM, Ko SH, Chen CH. The association between prenatal sleep quality and obstetric
outcome. J Nurs Res. 2014;22(3):147–54. PubMed PMID: 25111108. Epub 2014/08/12.
50. Rajendiran S, Swetha Kumari A, Nimesh A, Soundararaghavan S, Ananthanarayanan PH,
Dhiman P. Markers of oxidative stress in pregnant women with sleep disturbances. Oman Med
J. 2015;30(4):264–9. PubMed PMID: 26366260. PMCID: PMC4561639. Epub 2015/09/15.
51. Zafarghandi N, Hadavand S, Davati A, Mohseni SM, Kimiaiimoghadam F, Torkestani F. The
effects of sleep quality and duration in late pregnancy on labor and fetal outcome. J Matern
Fetal Neonatal Med. 2012;25(5):535–7. PubMed PMID: 21827377. Epub 2011/08/11.
52. Strange LB, Parker KP, Moore ML, Strickland OL, Bliwise DL. Disturbed sleep and preterm
birth: a potential relationship? Clin Exp Obstet Gynecol. 2009;36(3):166–8. PubMed PMID:
19860360. Epub 2009/10/29.
53. Li R, Zhang J, Zhou R, Liu J, Dai Z, Liu D, et al. Sleep disturbances during pregnancy
are associated with cesarean delivery and preterm birth. J Matern Fetal Neonatal Med.
2017;30(6):733–8. PubMed PMID: 27125889. Epub 2016/04/30.
54. Blair LM, Porter K, Leblebicioglu B, Christian LM. Poor sleep quality and associated
inflammation predict preterm birth: heightened risk among African Americans. Sleep.
2015;38(8):1259–67. PubMed PMID: 25845693. PMCID: PMC4507731. Epub 2015/04/08.
55. Okun ML, Schetter CD, Glynn LM. Poor sleep quality is associated with preterm birth. Sleep.
56. Reutrakul S, Zaidi N, Wroblewski K, Kay HH, Ismail M, Ehrmann DA, et al. Sleep dis-
turbances and their relationship to glucose tolerance in pregnancy. Diabetes Care.
57. Ota H, Hasegawa J, Sekizawa A. Effect of sleep disorders on threatened premature delivery.
J Perinat Med. 2017;45(1):57–61. PubMed PMID: 27219094. Epub 2016/05/25.
58. Okun ML, Roberts JM, Marsland AL, Hall M. How disturbed sleep may be a risk factor
for adverse pregnancy outcomes. Obstet Gynecol Surv. 2009;64(4):273–80. PubMed PMID:
19296861. PMCID: PMC2880322. Epub 2009/03/20.
59. Sivertsen B, Hysing M, Dorheim SK, Eberhard-Gran M. Trajectories of maternal sleep prob-
lems before and after childbirth: a longitudinal population-based study. BMC Pregnancy
Childbirth. 2015;15:129. PubMed PMID: 26031504. PMCID: PMC4458335. Epub
2015/06/03.
60. Roman-Galvez RM, Amezcua-Prieto C, Salcedo-Bellido I, Martinez-Galiano JM, Khan KS,
Bueno-Cavanillas A. Factors associated with insomnia in pregnancy: a prospective cohort
study. Eur J Obstet Gynecol Reprod Biol. 2018;221:70–5. PubMed PMID: 29304393. Epub
2018/01/06.
Psychiatr Clin North Am. 1987;10(4):541–53. PubMed PMID: 3332317.
62. Michopoulos V, Rothbaum AO, Corwin E, Bradley B, Ressler KJ, Jovanovic
T. Psychophysiology and posttraumatic stress disorder symptom profile in pregnant African-
American women with trauma exposure. Arch Womens Ment Health. 2015;18(4):639–48.
PubMed PMID: 25278341. Epub 10/03. eng.
63. Kalmbach DA, Cheng P, Ong JC, Ciesla JA, Kingsberg SA, Sangha R, et al. Depression
and suicidal ideation in pregnancy: exploring relationships with insomnia, short sleep, and
nocturnal rumination. Sleep Med. 2020;65:62–73. PubMed PMID: 31710876. PMCID:
PMC6980654. Epub 2019/11/12. eng.
64. Soldin OP, Guo T, Weiderpass E, Tractenberg RE, Hilakivi-Clarke L, Soldin SJ. Steroid hor-
mone levels in pregnancy and 1 year postpartum using isotope dilution tandem mass spectrom-
etry. Fertil Steril. 2005;84(3):701–10. PubMed PMID: 16169406. PMCID: PMC3640374.
Epub 2005/09/20. eng.
65. Pauley AM, Moore GA, Mama SK, Molenaar P, Symons DD. Associations between prenatal
sleep and psychological health: a systematic review. J Clin Sleep Med. 2020;16(4):619–30.
66. Bathgate CJ, Fernandez-Mendoza J. Insomnia, short sleep duration, and high blood pressure:
recent evidence and future directions for the prevention and management of hypertension.
Curr Hypertens Rep. 2018;20(6):52. PubMed PMID: 29779139. Epub 2018/05/21.
67. Fernandez-Alonso AM, Trabalon-Pastor M, Chedraui P, Perez-Lopez FR. Factors related
to insomnia and sleepiness in the late third trimester of pregnancy. Arch Gynecol Obstet.
2012;286(1):55–61. PubMed PMID: 22331224. Epub 2012/02/15.
68. Okun ML, O’Brien LM. Concurrent insomnia and habitual snoring are associated with
adverse pregnancy outcomes. Sleep Med. 2018;46:12–9. PubMed PMID: 29773206. Epub
2018/05/19.
69. Felder JN, Baer RJ, Rand L, Jelliffe-Pawlowski LL, Prather AA. Sleep disorder diagnosis
during pregnancy and risk of preterm birth. Obstet Gynecol. 2017;130(3):573–81. PubMed
PMID: 28796676. Epub 2017/08/11.
70. O’Brien LM, Bullough AS, Owusu JT, Tremblay KA, Brincat CA, Chames MC, et al.
Pregnancy-onset habitual snoring, gestational hypertension, and preeclampsia: prospec-
tive cohort study. Am J Obstet Gynecol. 2012;207(6):487 e1–9. PubMed PMID: 22999158.
PMCID: PMC3505221. Epub 2012/09/25.
71. Facco FL, Parker CB, Reddy UM, Silver RM, Koch MA, Louis JM, et al. Association
between sleep-disordered breathing and hypertensive disorders of pregnancy and gestational
diabetes mellitus. Obstet Gynecol. 2017;129(1):31–41. PubMed PMID: 27926645. PMCID:
PMC5512455. Epub 2016/12/08.
72. Louis J, Auckley D, Miladinovic B, Shepherd A, Mencin P, Kumar D, et al. Perinatal out-
comes associated with obstructive sleep apnea in obese pregnant women. Obstet Gynecol.
488 L. M. O’Brien
73. Louis JM, Mogos MF, Salemi JL, Redline S, Salihu HM. Obstructive sleep apnea and
severe maternal-infant morbidity/mortality in the United States, 1998-2009. Sleep.
2014;37(5):843–9. PubMed PMID: 24790262. PMCID: PMC3985102.
74. Izci B, Martin SE, Dundas KC, Liston WA, Calder AA, Douglas NJ. Sleep complaints: snoring
and daytime sleepiness in pregnant and pre-eclamptic women. Sleep Med. 2005;6(2):163–9.
PubMed PMID: 15716220. Epub 2005/02/18.
75. O’Brien LM, Bullough AS, Chames MC, Shelgikar AV, Armitage R, Guilleminualt C, et al.
Hypertension, snoring, and obstructive sleep apnoea during pregnancy: a cohort study.
BJOG. 2014;121(13):1685–93. PubMed PMID: 24888772. PMCID: PMC4241143. Epub
2014/06/04.
76. Reid J, Skomro R, Cotton D, Ward H, Olatunbosun F, Gjevre J, et al. Pregnant women with
gestational hypertension may have a high frequency of sleep disordered breathing. Sleep.
77. Pamidi S, Pinto LM, Marc I, Benedetti A, Schwartzman K, Kimoff RJ. Maternal sleep-
disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis.
Am J Obstet Gynecol. 2014;210(1):52 e1–e14. PubMed PMID: 23911687. Epub 2013/08/06.
78. Bourjeily G, Raker CA, Chalhoub M, Miller MA. Pregnancy and fetal outcomes of symptoms
of sleep-disordered breathing. Eur Respir J. 2010;36(4):849–55. PubMed PMID: 20525714.
Epub 2010/06/08.
79. Dunietz GL, Shedden K, Lisabeth LD, Treadwell MC, O’Brien LM. Maternal weight, snoring,
and hypertension: potential pathways of associations. Am J Hypertens. 2018;31(10):1133–8.
80. Facco FL, Grobman WA, Kramer J, Ho KH, Zee PC. Self-reported short sleep duration
and frequent snoring in pregnancy: impact on glucose metabolism. Am J Obstet Gynecol.
2010;203(2):142 e1–5. PubMed PMID: 20510182. PMCID: PMC3178265. Epub 2010/06/01.
81. Qiu C, Lawrence W, Gelaye B, Stoner L, Frederick IO, Enquobahrie DA, et al. Risk of
glucose intolerance and gestational diabetes mellitus in relation to maternal habitual snor-
ing during early pregnancy. PLoS One. 2017;12(9):e0184966. PubMed PMID: 28926639.
PMCID: PMC5605003. Epub 2017/09/20.
82. Chen YH, Kang JH, Lin CC, Wang IT, Keller JJ, Lin HC. Obstructive sleep apnea and the
risk of adverse pregnancy outcomes. Am J Obstet Gynecol. 2012;206(2):136 e1–5. PubMed
PMID: 22000892. Epub 2011/10/18.
83. Bourjeily G, Danilack VA, Bublitz MH, Lipkind H, Muri J, Caldwell D, et al. Obstructive
sleep apnea in pregnancy is associated with adverse maternal outcomes: a national cohort.
Sleep Med. 2017;38:50–7. PubMed PMID: 29031756. PMCID: PMC5677512. Epub
2017/10/17.
84. Luque-Fernandez MA, Bain PA, Gelaye B, Redline S, Williams MA. Sleep-disordered
breathing and gestational diabetes mellitus: a meta-analysis of 9,795 participants enrolled
in epidemiological observational studies. Diabetes Care. 2013;36(10):3353–60. PubMed
PMID: 24065843. PMCID: PMC3781575. Epub 2013/09/26.
85. Li L, Zhao K, Hua J, Li S. Association between sleep-disordered breathing during pregnancy
and maternal and fetal outcomes: an updated systematic review and meta-analysis. Front
Neurol. 2018;9:91. PubMed PMID: 29892255. PMCID: PMC5985400. Epub 2018/06/13.
86. Joel-Cohen SJ, Schoenfeld A. Fetal response to periodic sleep apnea: a new syndrome in
obstetrics. Eur J Obstet Gynecol Reprod Biol. 1978;8(2):77–81. PubMed PMID: 45501.
87. Franklin KA, Holmgren PA, Jonsson F, Poromaa N, Stenlund H, Svanborg E. Snoring,
pregnancy- induced hypertension, and growth retardation of the fetus. Chest.
2000;117(1):137–41. PubMed PMID: 10631211. Epub 2000/01/13.
88. Ayrim A, Keskin EA, Ozol D, Onaran Y, Yiidirim Z, Kafali H. Influence of self-reported snor-
ing and witnessed sleep apnea on gestational hypertension and fetal outcome in pregnancy.
Arch Gynecol Obstet. 2011;283(2):195–9. PubMed PMID: 20033421. Epub 2009/12/25.
89. Koken G, Sahin FK, Cosar E, Saylan F, Yilmaz N, Altuntas I, et al. Oxidative stress markers
in pregnant women who snore and fetal outcome: a case control study. Acta Obstet Gynecol
Scand. 2007;86(11):1317–21. PubMed PMID: 17963059. Epub 2007/10/27.
90. Loube DI, Poceta JS, Morales MC, Peacock MD, Mitler MM. Self-reported snoring in preg-
nancy. Association with fetal outcome. Chest. 1996;109(4):885–9. PubMed PMID: 8635365.
91. Perez-Chada D, Videla AJ, O’Flaherty ME, Majul C, Catalini AM, Caballer CA, et al.
Snoring, witnessed sleep apnoeas and pregnancy-induced hypertension. Acta Obstet Gynecol
Scand. 2007;86(7):788–92. PubMed PMID: 17611822. Epub 2007/07/06.
92. Tauman R, Sivan Y, Katsav S, Greenfeld M, Many A. Maternal snoring during pregnancy is
not associated with fetal growth restriction. J Matern Fetal Neonatal Med. 2012;25(8):1283–6.
PubMed PMID: 21999115.
93. O’Brien LM, Bullough AS, Owusu JT, Tremblay KA, Brincat CA, Chames MC, et al. Snoring
during pregnancy and delivery outcomes: a cohort study. Sleep. 2013;36(11):1625–32.
94. Antony KM, Agrawal A, Arndt ME, Murphy AM, Alapat PM, Guntupalli KK, et al.
Association of adverse perinatal outcomes with screening measures of obstructive sleep
apnea. J Perinatol. 2014;34(6):441–8. PubMed PMID: 24603455. Epub 2014/03/08.
95. Ge X, Tao F, Huang K, Mao L, Huang S, Niu Y, et al. Maternal snoring may predict adverse
pregnancy outcomes: a cohort study in China. PLoS One. 2016;11(2):e0148732. PubMed
PMID: 26871434. PMCID: PMC4752474.
96. Olivarez SA, Ferres M, Antony K, Mattewal A, Maheshwari B, Sangi-Haghpeykar H,
et al. Obstructive sleep apnea screening in pregnancy, perinatal outcomes, and impact of
maternal obesity. Am J Perinatol. 2011;28(8):651–8. PubMed PMID: 21480159. PMCID:
PMC3966067. Epub 2011/04/12.
97. Higgins N, Leong E, Park CS, Facco FL, McCarthy RJ, Wong CA. The Berlin questionnaire
for assessment of sleep disordered breathing risk in parturients and non-pregnant women. Int
J Obstet Anesth. 2011;20(1):22–5. PubMed PMID: 21123046. Epub 2010/12/03.
98. Ko HS, Kim MY, Kim YH, Lee J, Park YG, Moon HB, et al. Obstructive sleep apnea
screening and perinatal outcomes in Korean pregnant women. Arch Gynecol Obstet.
2013;287(3):429–33. PubMed PMID: 23086136. Epub 2012/10/23.
99. Tantrakul V, Numthavaj P, Guilleminault C, McEvoy M, Panburana P, Khaing W, et al.
Performance of screening questionnaires for obstructive sleep apnea during pregnancy: a
systematic review and meta-analysis. Sleep Med Rev. 2017;36:96–106. PubMed PMID:
28007402.
100. O’Brien LR, Dunietz GL. The Berlin questionnaire in pregnancy predominantly identifies
obesity. J Clin Sleep Med. 2021;17(8):1553–61.
101. Owusu JT, Anderson FJ, Coleman J, Oppong S, Seffah JD, Aikins A, et al. Association of
maternal sleep practices with pre-eclampsia, low birth weight, and stillbirth among Ghanaian
women. Int J Gynaecol Obstet. 2013;121(3):261–5. PubMed PMID: 23507553. PMCID:
PMC3662549. Epub 2013/03/20.
102. Leung PL, Hui DS, Leung TN, Yuen PM, Lau TK. Sleep disturbances in Chinese pregnant
women. BJOG. 2005;112(11):1568–71. PubMed PMID: 16225581. Epub 2005/10/18.
103. Dunietz GL, Shedden K, Schisterman EF, Lisabeth LD, Treadwell MC, O’Brien
LM. Associations of snoring frequency and intensity in pregnancy with time-to-delivery.
Paediatr Perinat Epidemiol. 2018. PubMed PMID: 30266041.
104. Bassan H, Uliel-Sibony S, Katsav S, Farber M, Tauman R. Maternal sleep disordered breath-
ing and neonatal outcome. Isr Med Assoc J. 2016;18(1):45–8. PubMed PMID: 26964280.
Epub 2016/03/12.
105. Facco FL, Ouyang DW, Zee PC, Strohl AE, Gonzalez AB, Lim C, et al. Implications of sleep-
disordered breathing in pregnancy. Am J Obstet Gynecol. 2014;210(6):559 e1–6. PubMed
490 L. M. O’Brien
106. Fung AM, Wilson DL, Lappas M, Howard M, Barnes M, O’Donoghue F, et al. Effects of
maternal obstructive sleep apnoea on fetal growth: a prospective cohort study. PLoS One.
2013;8(7):e68057. PubMed PMID: 23894293. PMCID: PMC3722214. Epub 2013/07/31.
107. Sahin FK, Koken G, Cosar E, Saylan F, Fidan F, Yilmazer M, et al. Obstructive sleep apnea
in pregnancy and fetal outcome. Int J Gynaecol Obstet. 2008;100(2):141–6. PubMed PMID:
17976624. Epub 2007/11/03.
108. Pamidi S, Marc I, Simoneau G, Lavigne L, Olha A, Benedetti A, et al. Maternal sleep-
disordered breathing and the risk of delivering small for gestational age infants: a prospective
cohort study. Thorax. 2016;71(8):719–25. PubMed PMID: 27084956. Epub 2016/04/17.
109. Telerant A, Dunietz GL, Many A, Tauman R. Mild maternal obstructive sleep apnea in non-
obese pregnant women and accelerated fetal growth. Sci Rep. 2018;8(1):10768. PubMed
110. Bin YS, Cistulli PA, Ford JB. Population-based study of sleep apnea in pregnancy and mater-
nal and infant outcomes. J Clin Sleep Med. 2016;12(6):871–7. PubMed PMID: 27070246.
PMCID: PMC4877320. Epub 2016/04/14.
111. Kneitel AW, Treadwell MC, O’Brien LM. Effects of maternal obstructive sleep apnea on
fetal growth: a case-control study. J Perinatol. 2018;38(8):982–8. PubMed PMID: 29785058.
PMCID: PMC6092194. Epub 2018/05/23.
112. Louis JM, Auckley D, Sokol RJ, Mercer BM. Maternal and neonatal morbidities associated
with obstructive sleep apnea complicating pregnancy. Am J Obstet Gynecol. 2010;202(3):261
e1–5. PubMed PMID: 20005507.
113. Olivarez SA, Maheshwari B, McCarthy M, Zacharias N, van den Veyver I, Casturi L, et al.
Prospective trial on obstructive sleep apnea in pregnancy and fetal heart rate monitoring. Am
J Obstet Gynecol. 2010;202(6):552 e1–7. PubMed PMID: 20171603. Epub 2010/02/23.
114. Spence DL, Allen RC, Lutgendorf MA, Gary VR, Richard JD, Gonzalez SC. Association
of obstructive sleep apnea with adverse pregnancy-related outcomes in military hospitals.
Eur J Obstet Gynecol Reprod Biol. 2017;210:166–72. PubMed PMID: 28040612. Epub
2017/01/04.
115. Manconi M, Ulfberg J, Berger K, Ghorayeb I, Wesstrom J, Fulda S, et al. When gender
matters: restless legs syndrome. Report of the “RLS and woman” workshop endorsed by
the European RLS Study Group. Sleep Med Rev. 2012;16(4):297–307. PubMed PMID:
22075215. Epub 2011/11/15.
116. Srivanitchapoom P, Pandey S, Hallett M. Restless legs syndrome and pregnancy: a review.
Parkinsonism Relat Disord. 2014. PubMed PMID: 24768121. Epub 2014/04/29. Eng.
117. Hubner A, Krafft A, Gadient S. Characteristics and determinants of restless legs syndrome in
pregnancy: a prospective study. Neurology. 2013;80:738–42.
118. Lee KA, Zaffke ME, Baratte-Beebe K. Restless legs syndrome and sleep disturbance during
pregnancy: the role of folate and iron. J Womens Health Gend Based Med. 2001;10(4):335–41.
PubMed PMID: 11445024. Epub 2001/07/11.
119. Chen SJ, Shi L, Bao YP, Sun YK, Lin X, Que JY, et al. Prevalence of restless legs syndrome
during pregnancy: a systematic review and meta-analysis. Sleep Med Rev. 2018;40:43–54.
PubMed PMID: 29169861. Epub 2017/11/25.
120. Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, et al. Restless legs
syndrome and pregnancy. Neurology. 2004;63(6):1065–9.
121. Wesstrom J, Skalkidou A, Manconi M, Fulda S, Sundstrom-Poromaa I. Pre-pregnancy rest-
less legs syndrome (Willis-Ekbom disease) is associated with perinatal depression. J Clin
Sleep Med. 2014;10(5):527–33. PubMed PMID: 24812538. PMCID: PMC4013381. Epub
2014/05/09.
122. Dunietz GL, Lisabeth LD, Shedden K, Shamim-Uzzaman QA, Bullough AS, Chames MC,
et al. Restless legs syndrome and sleep-wake disturbances in pregnancy. J Clin Sleep Med.
123. Minar M, Habanova H, Rusnak I, Planck K, Valkovic P. Prevalence and impact of restless
legs syndrome in pregnancy. Neuro Endocrinol Lett. 2013;34(5):366–71. PubMed PMID:
23922045. Epub 2013/08/08.
124. Vahdat M, Sariri E, Miri S, Rohani M, Kashanian M, Sabet A, et al. Prevalence and associ-
ated features of restless legs syndrome in a population of Iranian women during pregnancy.
Int J Gynaecol Obstet. 2013;123(1):46–9. PubMed PMID: 23886452. Epub 2013/07/28.
125. Oyieng’o DO, Kirwa K, Tong I, Martin S, Antonio Rojas-Suarez J, Bourjeily G. Restless legs
symptoms and pregnancy and neonatal outcomes. Clin Ther. 2016;38(2):256–64. PubMed
126. Izci-Balserak B, Pien GW. Sleep-disordered breathing and pregnancy: potential mechanisms
and evidence for maternal and fetal morbidity. Curr Opin Pulm Med. 2010;16(6):574–82.
127. Chang JJ, Pien GW, Duntley SP, Macones GA. Sleep deprivation during pregnancy and
maternal and fetal outcomes: is there a relationship? Sleep Med Rev. 2010;14(2):107–14.
128. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-
disordered breathing, sleep apnea, and hypertension in a large community-based study.
Sleep Heart Health Study. JAMA. 2000;283(14):1829–36. PubMed PMID: 10770144. Epub
2000/04/19.
129. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsia -- a state of sym-
pathetic overactivity. N Engl J Med. 1996;335(20):1480–5. PubMed PMID: 8890098. Epub
1996/11/14.
130. Lavie L. Oxidative stress--a unifying paradigm in obstructive sleep apnea and comorbidities.
Prog Cardiovasc Dis. 2009;51(4):303–12. PubMed PMID: 19110132. Epub 2008/12/27.
131. Edwards N, Blyton DM, Kirjavainen T, Kesby GJ, Sullivan CE. Nasal continuous positive
airway pressure reduces sleep-induced blood pressure increments in preeclampsia. Am J
Respir Crit Care Med. 2000;162(1):252–7. PubMed PMID: 10903250. Epub 2000/07/21.
132. Guilleminault C, Palombini L, Poyares D, Takaoka S, Huynh NT, El-Sayed Y. Pre-eclampsia
and nasal CPAP: part 1. Early intervention with nasal CPAP in pregnant women with
risk-factors for pre-eclampsia: preliminary findings. Sleep Med. 2007;9(1):9–14. PubMed
PMID: 17644420. Epub 2007/07/24.
133. Poyares D, Guilleminault C, Hachul H, Fujita L, Takaoka S, Tufik S, et al. Pre-eclampsia and
nasal CPAP: part 2. Hypertension during pregnancy, chronic snoring, and early nasal CPAP
intervention. Sleep Med. 2007;9(1):15–21. PubMed PMID: 17644475. Epub 2007/07/24.
134. Chirakalwasan N, Amnakkittikul S, Wanitcharoenkul E, Charoensri S, Saetung S,
Chanprasertyothin S, et al. Continuous positive airway pressure therapy in gestational
diabetes with obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med.
135. Blyton DM, Skilton MR, Edwards N, Hennessy A, Celermajer DS, Sullivan CE. Treatment
of sleep disordered breathing reverses low fetal activity levels in preeclampsia. Sleep.
136. Whitehead C, Tong S, Wilson D, Howard M, Walker SP. Treatment of early-onset preeclamp-
sia with continuous positive airway pressure. Obstet Gynecol. 2015;125(5):1106–9. PubMed
PMID: 25774926. Epub 2015/03/17.
137. Manber R, Bei B, Simpson N, Asarnow L, Rangel E, Sit A, et al. Cognitive behavioral therapy
for prenatal insomnia: a randomized controlled trial. Obstet Gynecol. 2019;133(5):911–9.
138. Tomfohr-Madsen LM, Clayborne ZM, Rouleau CR, Campbell TS. Sleeping for two: an open-
pilot study of cognitive behavioral therapy for insomnia in pregnancy. Behav Sleep Med.
2017;15(5):377–93. PubMed PMID: 27124405. Epub 2016/04/29.
139. Kalmbach DA, Cheng P, O’Brien LM, Swanson LM, Sangha R, Sen S, et al. A randomized
controlled trial of digital cognitive behavioral therapy for insomnia in pregnant women. Sleep
Med. 2020;72:82–92. PubMed PMID: 32559716. Epub 2020/06/20.
492 L. M. O’Brien
140. Bacaro V, Benz F, Pappaccogli A, De Bartolo P, Johann AF, Palagini L, et al. Interventions
for sleep problems during pregnancy: a systematic review. Sleep Med Rev. 2020;50:101234.
PubMed PMID: 31801099. Epub 2019/12/05.
141. Hansen AB, Stayner L, Hansen J, Andersen ZJ. Night shift work and incidence of diabe-
tes in the Danish Nurse Cohort. Occup Environ Med. 2016;73(4):262–8. PubMed PMID:
26889020. Epub 2016/02/19.
142. Rosa D, Terzoni S, Dellafiore F, Destrebecq A. Systematic review of shift work and
nurses’ health. Occup Med (Lond). 2019;69(4):237–43. PubMed PMID: 31132107. Epub
2019/05/28.
143. Mills J, Kuohung W. Impact of circadian rhythms on female reproduction and infertility treat-
ment success. Curr Opin Endocrinol Diabetes Obes. 2019. PubMed PMID: 31644470. Epub
2019/10/24.
144. Grajewski B, Whelan EA, Lawson CC, Hein MJ, Waters MA, Anderson JL, et al. Miscarriage
among flight attendants. Epidemiology. 2015;26(2):192–203. PubMed PMID: 25563432.
PMCID: PMC4510952. Epub 2015/01/08.
145. Begtrup LM, Specht IO, Hammer PEC, Flachs EM, Garde AH, Hansen J, et al. Night work
and miscarriage: a Danish nationwide register-based cohort study. Occup Environ Med.
2019;76(5):302–8. PubMed PMID: 30910992. Epub 2019/03/27.
146. Lawson CC, Rocheleau CM, Whelan EA, Lividoti Hibert EN, Grajewski B, Spiegelman D,
et al. Occupational exposures among nurses and risk of spontaneous abortion. Am J Obstet
Gynecol. 2012;206(4):327 e1–8. PubMed PMID: 22304790. PMCID: PMC4572732. Epub
2012/02/07.
147. Facco FL, Parker CB, Hunter S, Reid KJ, Zee PC, Silver RM, et al. Association of adverse
pregnancy outcomes with self-reported measures of sleep duration and timing in women
who are nulliparous. J Clin Sleep Med. 2018;14(12):2047–56. PubMed PMID: 30518449.
PMCID: PMC6287730. Epub 2018/12/07.
148. Facco FL, Parker CB, Hunter S, Reid KJ, Zee PP, Silver RM, et al. Later sleep timing
is associated with an increased risk of preterm birth in nulliparous women. Am J Obstet
Gynecol MFM. 2019;1(4):100040. PubMed PMID: 33345835. PMCID: PMC7757682. Epub
2020/12/22.
149. Casey T, Sun H, Suarez-Trujillo A, Crodian J, Zhang L, Plaut K, et al. Pregnancy rest-activity
patterns are related to salivary cortisol rhythms and maternal-fetal health indicators in
women from a disadvantaged population. PLoS One. 2020;15(3):e0229567. PubMed PMID:
32126104. PMCID: PMC7053712. Epub 2020/03/04.
150. Ahmed SA, Shalayel MH. Role of cortisol in the deterioration of glucose tolerance in
Sudanese pregnant women. East Afr Med J. 1999;76(8):465–7. PubMed PMID: 10520355.
Epub 1999/10/16.
151. Kaur S, Teoh AN, Shukri NHM, Shafie SR, Bustami NA, Takahashi M, et al. Circadian
rhythm and its association with birth and infant outcomes: research protocol of a prospec-
tive cohort study. BMC Pregnancy Childbirth. 2020;20(1):96. PubMed PMID: 32046676.
PMCID: PMC7014629. Epub 2020/02/13.
152. Gordon A, Raynes-Greenow C, Bond D, Morris J, Rawlinson W, Jeffery H. Sleep position,
fetal growth restriction, and late-pregnancy stillbirth: the Sydney stillbirth study. Obstet
Gynecol. 2015;125(2):347–55. PubMed PMID: 25568999. Epub 2015/01/09.
153. Heazell A, Li M, Budd J, Thompson J, Stacey T, Cronin RS, et al. Association between
maternal sleep practices and late stillbirth - findings from a stillbirth case-control study.
BJOG. 2018;125(2):254–62. PubMed PMID: 29152887. PMCID: PMC5765411. Epub
2017/11/21.
154. McCowan LME, Thompson JMD, Cronin RS, Li M, Stacey T, Stone PR, et al. Going to sleep
in the supine position is a modifiable risk factor for late pregnancy stillbirth; findings from
the New Zealand multicentre stillbirth case-control study. PLoS One. 2017;12(6):e0179396.
155. Stacey T, Thompson JM, Mitchell EA, Ekeroma AJ, Zuccollo JM, McCowan
LM. Association between maternal sleep practices and risk of late stillbirth: a case-control
study. BMJ. 2011;342:d3403. PubMed PMID: 21673002. PMCID: PMC3114953. Epub
2011/06/16.
156. Cronin RS, Li M, Thompson JMD, Gordon A, Raynes-Greenow CH, Heazell AEP, et al. An
individual participant data meta-analysis of maternal going-to-sleep position, interactions
with fetal vulnerability, and the risk of late stillbirth. EClinicalMedicine. 2019;10:49–57.
157. Humphries A, Mirjalili SA, Tarr GP, Thompson JMD, Stone P. The effect of supine posi-
tioning on maternal hemodynamics during late pregnancy. J Matern Fetal Neonatal Med.
2019;32(23):3923–30. PubMed PMID: 29772936. Epub 2018/05/19.
158. Couper S, Clark A, Thompson JMD, Flouri D, Aughwane R, David AL, et al. The effects of
maternal position, in late gestation pregnancy, on placental blood flow and oxygenation: an
MRI study. J Physiol. 2020. PubMed PMID: 33369732. Epub 2020/12/29.
159. Stone PR, Burgess W, McIntyre J, Gunn AJ, Lear CA, Bennet L, et al. An investigation
of fetal behavioural states during maternal sleep in healthy late gestation pregnancy: an
observational study. J Physiol. 2017;595(24):7441–50. PubMed PMID: 29023736. PMCID:
PMC5730849. Epub 2017/10/13.
160. Anderson NH, Gordon A, Li M, Cronin RS, Thompson JMD, Raynes-Greenow CH, et al.
Association of supine going-to-sleep position in late pregnancy with reduced birth weight:
a secondary analysis of an individual participant data meta-analysis. JAMA Netw Open.
161. Silver RM, Hunter S, Reddy UM, Facco F, Gibbins KJ, Grobman WA, et al. Prospective
evaluation of maternal sleep position through 30 weeks of gestation and adverse pregnancy
outcomes. Obstet Gynecol. 2019;134(4):667–76. PubMed PMID: 31503146. PMCID:
PMC6768734. Epub 2019/09/11.
162. O’Brien LM, Warland J, Stacey T, Heazell AEP, Mitchell EA, Consortium S. Maternal
sleep practices and stillbirth: findings from an international case-control study. Birth.
2019;46(2):344–54. PubMed PMID: 30656734. Epub 2019/01/19.
163. O’Brien LM, Warland J. Typical sleep positions in pregnant women. Early Hum Dev.
164. Cronin RS, Chelimo C, Mitchell EA, Okesene-Gafa K, Thompson JMD, Taylor RS, et al.
Survey of maternal sleep practices in late pregnancy in a multi-ethnic sample in South
Auckland, New Zealand. BMC Pregnancy Childbirth. 2017;17(1):190. PubMed PMID:
28623890. PMCID: PMC5474014. Epub 2017/06/19.
165. Coleman J, Okere M, Seffah J, Kember A, O’Brien LM, Borazjani A, et al. The Ghana
PrenaBelt trial: a double-blind, sham-controlled, randomised clinical trial to evaluate the
effect of maternal positional therapy during third-trimester sleep on birth weight. BMJ Open.
166. Kember AJ, Scott HM, O’Brien LM, Borazjani A, Butler MB, Wells JH, et al. Modifying
maternal sleep position in the third trimester of pregnancy with positional therapy: a ran-
domised pilot trial. BMJ Open. 2018;8(8):e020256. PubMed PMID: 30158217. PMCID:
PMC6119420. Epub 2018/08/31.
167. Warland J, Dorrian J, Kember AJ, Phillips C, Borazjani A, Morrison JL, et al. Modifying
maternal sleep position in late pregnancy through positional therapy: a feasibility study. J
Clin Sleep Med. 2018;14(8):1387–97. PubMed PMID: 30092890. PMCID: PMC6086963.
Epub 2018/08/11.
Chapter 22
Sleep in Older Patients
Armand Michael Ryden and Cathy Alessi
Keywords Human sleep with aging · Central sleep apnea · REM sleep behavior
disorder · Behavioral therapies for insomnia · Syndromes of aging
Learning Points
1. There are well-established changes in sleep with aging, including worsen-
ing sleep fragmentation and decreasing slow-wave sleep.
2. Changes in sleep have been linked to the pathophysiology of Alzheimer’s
disease.
3. Sleep-disordered breathing is a common condition in older patients, with
a marked increase in central sleep apnea due to comorbidities.
4. Older patients, even those who have mild to moderate dementia, can ben-
efit from treatment of obstructive sleep apnea.
A. M. Ryden (*)
Pulmonary, Critical Care and Sleep Medicine Division, Veterans Affairs Greater Los Angeles
Healthcare System, Los Angeles, CA, USA
David Geffen School of Medicine at University of California, Los Angeles,
e-mail: armand.ryden@va.gov
C. Alessi
David Geffen School of Medicine at University of California, Los Angeles,
Geriatric Research, Education and Clinical Center, Veterans Affairs Greater Los Angeles
Healthcare System, Los Angeles, CA, USA
e-mail: Cathy.Alessi@va.gov

496 A. M. Ryden and C. Alessi
5. Behavioral therapies are first-line treatment for insomnia in all adults, par-
ticularly in those who are older.
6. Optimizing iron stores is a key first step in the treatment of restless legs
syndrome.
7. REM sleep behavior disorder is tied to the development of alpha-
synucleinopathy related neurodegenerative disorders, such as Parkinson’s
disease, Lewy body dementia, and multisystem atrophy.
Introduction
Sleep disorders in older adults offer unique challenges. With advancing age many
patients accrue increasing numbers of comorbidities. More than two-thirds of those
with multiple comorbidities report sleep problems. These problems can include dif-
ficulty falling asleep, difficulty staying asleep, or sleepiness during the day. This
chapter will explore age-related changes in sleep and the effects of sleep disorders
on selected syndromes of aging. It will also explore the epidemiology, clinical pre-
sentations, and management decisions that are unique to sleep disorders commonly
encountered in older adults.
Sleep and Aging
There is strong evidence that there are changes in sleep efficiency and sleep stage
architecture with aging. Advancing age is generally associated with advanced (i.e.,
earlier) sleep timing, longer sleep-onset latency, shorter sleep duration, increased
sleep fragmentation, and decreased slow-wave sleep [1]. The reduction in non-REM
stage 3 (N3) sleep with age is more prominent in men than women. It is less clear if
there are significant changes in REM sleep with aging. There is evidence that exces-
sive daytime sleepiness increases with aging. Naps, including unplanned naps, are
more frequent in older people. However, napping and excessive daytime sleepiness
are associated with comorbidities such as depression, pain, and nocturia [2]. Thus,
increased napping may not be a part of normal aging per se. Using the multiple
sleep latency test as a measure of sleep propensity in healthy subjects of different
ages showed that older adults (age 66–83 years) had a decreased sleep propensity,
possibly related to a weakened homeostatic drive to sleep [3]. It is reasonable to
conclude that excessive daytime sleepiness in older people may be due to comor-
bidities rather than being part of the natural aging process.
It is not clear whether changes in sleep with age are due to a decreased ability to
sleep or a decreased need to sleep. However, there are several lines of evidence that
suggest that short sleep duration and disturbed sleep are associated with adverse
22 Sleep in Older Patients 497
health and cognitive outcomes. Decreased sleep efficiency and higher amount of
wake after sleep onset have been associated with greater cognitive decline in older
people. There is emerging evidence that sleep disruption is associated with
β-amyloid (Aβ) protein accumulation and tau neurofibrillary tangles that are char-
acteristic of Alzheimer’s disease (AD). Experimental evidence in animal models
has shown that sleep plays a crucial role in the clearance of Aβ through the glym-
phatic system [4]. Aβ cerebrospinal fluid levels have been associated with poor
sleep efficiency and increased napping [5]. Excessive daytime sleepiness has been
longitudinally associated with the development of Aβ positivity [6, 7]. There is pre-
liminary evidence that acute sleep deprivation can increase Aβ deposition in healthy
adults [8]. These findings support a hypothesis that sleep disruption with aging may
lead to a decline in cognitive function by promoting the deposition of pathological
proteins. However, most of the data are still cross-sectional in nature. Since neuro-
nal systems in the brain crucial to sleep-wake homeostasis are impacted by deposi-
tion of these abnormal proteins, it is reasonable to conclude that these pathological
changes may be a cause of sleep disruption and excessive daytime sleepiness (EDS)
[1]. It is reasonable to conclude that there is likely a bidirectional relationship
between sleep disturbance and neurodegenerative disease.
Sleep and sleep disruption have an impact on the body as well as the brain.
Numerous prospective studies have shown a U-shaped relationship between sleep
duration and mortality, with both short and long sleep durations conferring an
increased risk of death [9]. Whether short or long sleep directly causes excess death
is difficult to prove given all of the potential confounders, despite attempts to math-
ematically control for known comorbidities. Sleep may be short or long due to
known or unknown health factors. However, there is strong evidence that sleep qual-
ity and quantity are associated with overall health. Changes in sleep stage distribu-
tion with age may contribute to the age-related changes in metabolism. N3 sleep is
associated with growth hormone secretion. The reduction in N3 sleep with aging
may be partly responsible for the decrease in growth hormone in older men [10].
Sleep deficiencies have also been linked to metabolic dysregulation that may con-
tribute to diseases that impact healthy aging such as obesity and diabetes [11].
Given the link between insufficient and fragmented sleep on quality of life and
health outcomes, there is a need for awareness, evaluation, and treatment of the
sleep disorders that commonly affect older adults.
Sleep-Disordered Breathing
Sleep-disordered breathing comprises both obstructive and central sleep apnea syn-
dromes. Obstructive sleep apnea (OSA) occurs when the airway is obstructed dur-
ing sleep, which is determined by the persistence of respiratory effort during the
apneas on a sleep study. If there are no detectable efforts during the apneas, the
disorder is classified as central sleep apnea (CSA) because there is a momentary
defect in the central control of breathing. Approximately 40% of adults who have
CSA have Cheyne-Stokes respiration (CSR), which is a periodic cycling between
hypoventilation and hyperventilation [12]. Congestive heart failure is the most com-
monly recognized cause of CSA and is associated with CSR. Other common causes
of CSA include cerebrovascular accidents, chronic kidney disease, atrial fibrillation,
and opioid use. OSA is by far the most common sleep-related breathing disorder;
however there can be overlap between obstructive and central sleep apnea. The con-
sequences of respiratory events during sleep include arousals from sleep and cycli-
cal drops in the blood oxygen level. This ultimately leads to sleep fragmentation and
nocturnal hypoxemia, which may lead to insomnia symptoms, excessive daytime
sleepiness and may have potential health consequences.
Many of the risk factors for OSA increase with age. Estimates of the prevalence
of OSA have varied widely and are dependent on the populations studied. Results
from a US cohort studied between 2007 and 2010 have estimated moderate to severe
OSA to occur in 6% of women and 13% of men between ages 30 and 70 years [13].
Evidence suggests that OSA is underdiagnosed in the general population, particu-
larly in women. Less is known about the epidemiology of OSA in an older popula-
tion; there is a suggestion that the risk of OSA increases with advancing age until
70 years after which there is a plateau [14]. Male gender is clearly a risk factor for
OSA. However, this gender gap lessens significantly after menopause in women.
The risk of having CSA also increases with older age. CSA has been found to be
2–3 times more common in people aged 65–90 than in those aged 39–64 years. This
is likely due to the increased prevalence of conditions associated with CSA such as
congestive heart failure, atrial fibrillation, chronic kidney disease, and chronic pain
syndromes treated with opioids [12]. For instance, it is estimated that upward of
50% of patients with stable heart failure have some form of sleep-disordered breath-
ing (SDB). The majority of these patients have a form of CSA; however, many have
OSA or a combination of the two disorders.
The major symptoms of OSA include excessive daytime sleepiness, sleep dis-
ruption, and snoring. The classic patient with OSA is an obese male with snoring,
gasping, and daytime sleepiness. However, these associations are less predictive in
an older population. Other important symptoms of SDB include nocturia, insomnia,
morning headaches, nocturnal confusion, and daytime impairments in mood and
cognition. Snoring is indicative of a partially collapsed airway and is a useful pre-
dictor of the presence of OSA or future development of the condition. The lack of
classic symptoms and findings should not preclude further evaluation for OSA, par-
ticularly in older patients.
The primary modalities for testing for OSA include an in-laboratory attended
polysomnogram (PSG) or a home sleep apnea test (HSAT). PSG is generally con-
sidered the gold standard for the diagnosis of OSA; however HSAT has been shown
to be a reasonable diagnostic modality in patients with symptoms suggestive of
moderate to severe OSA without significant comorbidities [15]. HSAT can be per-
formed at much lower costs than PSG, which can dramatically improve access to
OSA testing, and some patients may be more comfortable sleeping at home than in
a sleep laboratory. In an older population, there are concerns that the usability of the
HSAT equipment may be compromised by impairments in dexterity or cognition.

One study showed that self-assembled HSAT combined with symptoms was able to
accurately diagnose OSA in an older patient population [16]. A smaller study also
showed a high degree of correlation between HSAT and PSG in older patients [17].
However, HSAT in older populations appears to be an area that has been understudied.
Continuous positive airway pressure (CPAP) therapy is the gold standard treat-
ment for OSA. CPAP devices essentially use air to stent open the upper airway in
order to combat airway obstruction. The vast majority of trials of CPAP therapy
have focused on patients who are middle-aged. Only recently have there been ran-
domized controlled trials focused on CPAP therapy in older individuals. The
PREDICT trial comprised of 231 patients and found that CPAP improved subjective
sleepiness and was cost-effective in patients aged greater than 65 years [18]. A simi-
larly sized study in Spain among patients with severe OSA over the age of 70 years
found that CPAP improved quality of life, mood, and some indices of neurocogni-
tive function [19]. A smaller pilot study found that CPAP improved episodic and
short-term memory as well as executive functioning with a suggestion of increased
connectivity on neuroimaging [20]. A larger study to extrapolate these results to
moderate OSA failed to show the same neurocognitive benefits but did show that
sleepiness and quality of life were improved on CPAP in those older than 70 years
of age [21]. Observational studies have suggested that CPAP is well-tolerated and
may have a mortality benefit in older patients including in those over the age of 80
[22]. Studies on whether CPAP adherence is better or worse in an older population
have had mixed results, and any changes in CPAP adherence with age may be due
to factors other than advancing age [23]. CPAP has been found to be well-tolerated
and beneficial in patients with mild to moderate Alzheimer’s disease [24]. Age alone
should not be a barrier to the testing for and treatment of OSA. Even the presence
of dementia should not preclude using CPAP for OSA.
The impact of the treatment of OSA on cardiovascular outcomes has shown
mixed results, with observational studies generally showing benefit of CPAP in
reducing cerebrovascular events, while randomized controlled trials have largely
been negative. The observational studies have shown stronger links between OSA
and stroke than between OSA and coronary events [25]. It is hypothesized that those
with severe OSA who survive to older age may have ischemic preconditioning of
the heart protecting them to some extent from myocardial infarction. One large
randomized controlled trial of 2717 patients aged 45 to 75 years followed on aver-
age for 3.7 years showed no reduction in cardiovascular events with CPAP therapy
[26]. A meta-analysis of studies including this one also showed no cardiovascular
benefit in largely middle-aged patients [27]. The major limitation of these studies is
that adherence to CPAP was fairly low among participants. Furthermore, significant
excessive daytime somnolence was an exclusion criterion in many studies. In a pop-
ulation of older adults, the diagnosis and treatment of OSA may not be a potent
strategy to reduce cardiovascular events relative to other strategies, particularly in
the absence of excessive daytime sleepiness. However, in an individual who is
adherent to therapy, CPAP may confer some cardiovascular benefit although this
remains unproven.
Oral appliances that shift the jaw forward (mandibular advancement or mandibu-
lar repositioning devices) are a viable treatment alternative to positive airway pres-
sure for many patients with OSA. The principle behind this therapy is that moving
the jaw forward pulls the tongue away from the oropharynx, which may also benefi-
cially reconfigure the soft palate. The American Academy of Sleep Medicine rec-
ommends the use of oral appliances, rather than no treatment, for those who are
intolerant of CPAP therapy or who have a strong preference for an alternative to
PAP therapy [28]. It is generally thought that oral appliances are more effective in
those with mild OSA; however there is not strong data to support this assumption.
If adherence to oral appliance therapy were higher, this would mitigate the fact that
reduction in AHI is generally less than the reduction achieved with PAP. Oral appli-
ances generally require good dentition to hold the device in place, which would
present a barrier to use in individuals missing teeth or who require dentures. Oral
appliance therapy specifically in older patients has not been studied extensively.
One small postal study in older veterans showed that only one-third were confident
in the use of the device and felt that it was an effective treatment [29].
As previously discussed, CSA syndromes are increasingly common in older
patients. CSAs can sometimes be treated with CPAP, but more advanced bilevel
modalities such as adaptive servoventilation (ASV) are sometimes also used to treat
CSA. ASV treats CSA by increasing ventilatory support during hypopneas, breath-
ing for the patient during apneas, but decreasing ventilatory support during periods
of excessive ventilation. This helps “smooth out” the overall breathing pattern. The
SERVE-HF trial revealed significant safety concerns for the use of ASV in CSA
among patients with symptomatic heart failure and a reduced ejection fraction (EF)
(≤ 45%), where the ASV group had an increased all-cause and cardiac mortality
[30]. ASV is therefore not recommended to be used in the presence of reduced sys-
tolic function. It is still considered a therapeutic option in patients who have CSA
due to heart failure with a preserved EF or from other causes. A review looking at
the efficacy of ASV in older patients with central or combined central and obstruc-
tive sleep apnea in patients with preserved EF was only able to identify 6 studies
with sample sizes ranging from 45 to 126 patients and mean ages in the mid to late
60s [31]. These studies demonstrated an improvement in sleep-related symptoms
and daytime functional status. ASV use for CSA not due to heart failure does not
seem to have been systematically studied in older patients. In general, ASV is an
option in older patients with CSA who do not respond to CPAP alone; however
long-term benefits have not been established.
Insomnia
Insomnia is a highly prevalent sleep disorder with advanced age, affecting 30–48%
of older adults [32]. This high prevalence may be related to age-related changes in
sleep and the accumulation of comorbidities and medications with older age that are
associated with insomnia. In addition, the higher prevalence of insomnia in women
compared to men seen in younger adults appears to continue into old age, with a
meta-analysis showing that the greater relative risk of insomnia in women com-
pared with men increases with age, from 1.28 in young adults to 1.73 in those aged
65 years and older [33]. Several epidemiologic studies have linked sleep distur-
bances to worse health-related quality of life, nursing-home placement, and even
death in older people [32]. Late-life insomnia is often a chronic problem, and with-
out treatment, symptoms often persist for years.
Several age-related changes in sleep may contribute to insomnia in older adults.
Common changes include a decreased sleep efficiency (time spent asleep divided by
total time spent in bed), decreased total sleep time, and increased sleep latency (time
to fall asleep). An earlier bedtime and earlier morning awakening, more awaken-
ings, more total wakefulness during the night, and more daytime napping are also
common. As described above, older age, especially among men, is associated with
less N3 sleep, whereas the percentage of stages N1 and N2 increases with age [34].
Many age-related changes in sleep occur by middle age, with sleep parameters
remaining relatively stable among healthy people after age 60 [34]. There is some
question of the clinical significance of these age-related changes in sleep in healthy
people. For example, with sleep deprivation, older adults may actually show less
daytime sleepiness, less evidence of decline in performance measures, and a quicker
recovery than younger adults [35]. In studies comparing good sleepers with poor
sleepers, poor sleepers were found to take more medications, make more clinician
visits, and have poorer self-ratings of health, suggesting that some age-related
changes in sleep may reflect poor health, rather than aging per se.
Many comorbidities and medications are associated with insomnia in older
adults. Depression is perhaps the most common and strongly associated psychiatric
comorbidity associated with insomnia in older people [36]. Anxiety is also a com-
mon risk factor for developing insomnia. Many medical conditions that are common
in older adults also contribute to insomnia. For example, the prevalence of insomnia
is higher in individuals with hypertension, heart disease, arthritis, lung disease, gas-
trointestinal reflux, stroke, and neurodegenerative disorders. Symptoms such as
pain, paresthesia, cough, dyspnea, gastroesophageal reflux, and nocturia also con-
tribute to insomnia. Medications can also impair sleep or alter sleep architecture.
Sleep can be disturbed if stimulating medications (e.g., caffeine, sympathomimet-
ics, bronchodilators, activating psychiatric medications) are taken too near to bed-
time, and sedating medications taken during the daytime can lead to more daytime
sleeping and a decrease in nighttime sleep drive. Caregiving for others (such as
loved ones with dementia) is also a common factor contributing to insomnia in older
adults [37].
PSG is not routinely indicated in the evaluation of older patients presenting with
insomnia, unless another comorbid sleep condition is suspected or the patient has
not responded to first-line therapy for insomnia disorder [38]. Sleep diaries with
daily entries over 1 to 2 weeks can be very helpful in determining the severity of the
insomnia as well as identifying possible perpetuating factors such as extended day-
time napping or irregular bedtimes. Wrist actigraphy in conjunction with a sleep
diary can be used to obtain a more objective measure of the patient’s overall
sleep-wake pattern, and use of actigraphy has been recommended in patients with
insomnia when objective estimates of sleep parameters will aid clinical decision-
making [39]. Wrist actigraphy can also be used in identifying circadian rhythm
disorders and for use in nursing-home residents unable to complete detailed sleep
diaries and for whom other forms of sleep monitoring (e.g., PSG) can be difficult
to obtain.
Behavioral therapies, particularly cognitive-behavioral therapy for insomnia,
CBT-I, are recommended as first-line treatments for insomnia in all adults [40].
Evidence for use of behavioral treatments is particularly compelling in older adults
where the potential adverse effects of sedative-hypnotic medications are particu-
larly worrisome, such as increased risk of falls and fractures and increased risk of
cognitive decline. In addition to low likelihood of adverse effects, behavioral treat-
ments are preferred by most patients and have better long-term efficacy than seda-
tive-hypnotics [41]. Behavioral therapies for insomnia have also been demonstrated
to be effective in older adults with comorbid conditions, such as depression.
Several randomized trials and systematic reviews provide strong evidence for
CBT-I [38, 40, 42], including among older adults [43]. CBT-I may include stimulus
control, sleep restriction, and cognitive therapy, often with other components such
as sleep hygiene and relaxation techniques [44]. Stimulus control is designed to
break the negative associations patients have with their sleep environment, which
have come about from maladaptive behaviors. Examples of stimulus control include
using the bed for sleep or intercourse, only, and to only go to bed when tired enough
to fall asleep. Sleep restriction limits the amount of time the patient spends in bed,
usually guided by their actual sleep time from the sleep diary, to help the patient fall
asleep more quickly and have more consolidated sleep. Cognitive therapy addresses
the maladaptive thoughts or dysfunctional beliefs patients have about their sleep.
Sleep hygiene is also commonly provided, including education on general guide-
lines to maintain a healthy sleep-wake routine. Other components of CBT-I may
include various relaxation techniques, scheduled worry time during the day, and
other interventions. These components can be used with older adults, sometimes
with adaptations for safety, including developing alternatives to getting out of bed
at night for those at high risk for falls.
CBT-I has reliably been shown to improve sleep efficiency, decrease nighttime
wakefulness, and increase satisfaction with sleep [38, 40, 42]. In trials comparing
CBT-I with a prescription sedative-hypnotic agent, participants reported better
improvement in sleep and more satisfaction with the CBT-I therapy [45]. As noted
above, studies that compare CBT-I with pharmacologic therapy typically show that
the improvements with CBT-I are more sustained. In addition, newer delivery mod-
els that involve the use of the Internet and/or phone applications [46], nonspecialist
providers [43], and telehealth-based CBT-I have demonstrated evidence for effec-
tiveness, suggesting a variety of options may be used to provide this therapy to
older people.
Studies have found variable effects of bright light, either provided from natural
sunlight or light boxes, on insomnia symptoms in older adults [47, 48]. Effects of
bright light on circadian rhythm problems are more clearly established [49]. For
example, light therapy has been recommended in adults with an advanced sleep
phase and in older adults with dementia [49]. Evidence suggests that aerobic exer-
cise (combined with sleep hygiene education) improves sleep in older adults with
insomnia [50]. Tai chi has also been demonstrated to improve sleep quality in indi-
viduals with insomnia, including older adults [51].
In general, older adults are more likely than younger adults to experience adverse
side effects of sedative-hypnotics, such as an increased risk of falls and fractures,
and cognitive decline. In one meta-analysis of sedative-hypnotics in older adults
with insomnia, the number of individuals needed to treat for improved sleep quality
was more than twice as high as the number needed to harm for any adverse event,
suggesting these agents were more likely to cause harm than benefit [52]. If a
sedative-hypnotic is used in an older adult, the smallest dose of the agent with the
least risk of adverse events should be chosen for the shortest duration necessary.
Benzodiazepines bind nonselectively to the gamma-aminobutyric-acid-
benzodiazepine (GABA-A) receptor subunits, resulting in sedative, anxiolytic, and
amnestic effects. Temazepam, lorazepam, and estazolam are intermediate-acting
benzodiazepines that are most commonly used for insomnia; triazolam is a shorter-
acting agent that is also used for insomnia. Longer-acting benzodiazepines (e.g.,
flurazepam, quazepam) should not be used in older adults due to a long half-life that
can result in significant daytime effects. In addition to falls and fracture, other side
effects associated with benzodiazepines in older adults include confusion, rebound
insomnia, tolerance, and withdrawal symptoms on discontinuation [53]. There is
also evidence for an increased risk of pneumonia in older people with Alzheimer’s
disease [54]. These agents are all on the Beer’s list of potentially inappropriate
medications for older adults [55].
Nonbenzodiazepine-benzodiazepine receptor agonists (NBRAs, e.g., zolpidem,
zaleplon, eszopiclone) bind selectively to the GABA-type A receptors and generally
produce sedation and amnestic effects without the anxiolytic properties. These
agents likely have similar efficacy to benzodiazepines but with a somewhat better
side effect profile, in part due to their relatively short duration of action. Zolpidem
and zaleplon should only be taken immediately before bed because of their rapid
onset of action. Eszopiclone has a longer duration of action than the other NRBAs
and is better for sleep maintenance but may cause drowsiness in the morning.
Evidence suggests that the NBRAs also increase risk of falls and fractures in older
adults [56]. The emergence of complex sleep-related behaviors such as sleep driv-
ing and sleep eating that has been reported with NBRAs [57] has led to a black box
warning for these agents. NBRAs are also all included on the Beer’s list of poten-
tially inappropriate medications for older adults [55].
Melatonin receptor agonists (e.g., ramelteon) act at MT1/MT2 melatonin recep-
tors. Ramelteon has been shown to reduce self-reported sleep latency in older adults
[58], with few side effects, but somnolence, dizziness, headache, and fatigue can
occur. Evidence suggests ramelteon does not lead to significant rebound insomnia
or withdrawal effects [58].
Other agents are available for treatment of insomnia. The tricyclic antidepressant
doxepin is available in an ultralow-dose formulation (3–6 mg) that selectively
antagonizes H1 receptors, which is believed to have sleep-promoting effects. Data

suggest that this low-dose doxepin does not have more significant anticholinergic
side effects compared to placebo [59]. A newer class of medications that antagonize
the orexin system has been developed. These dual orexin receptor antagonists
include suvorexant and lemborexant. A trial of 277 participants with mild to moder-
ate probable Alzheimer’s disease showed an improvement in polysomnographic
total sleep time of 28 minutes with suvorexant. There were increases in daytime
sleepiness but no apparent changes in cognitive function testing [60]. Low-dose
trazodone has also been used for insomnia, with some evidence for effectiveness in
decreasing sleep latency and increasing sleep duration; the most common side
effects appear to be daytime sleepiness, headache, and orthostatic hypotension [61].
There is a lack of evidence to support use of atypical antipsychotics for insomnia in
the absence of other serious psychiatric illness and significant concern for harm [62].
Almost half of all older adults report the use of nonprescription over-the-counter
(OTC) sleeping agents, commonly sedating antihistamines, melatonin, or herbal
products. The sedating antihistamines (e.g., diphenhydramine) are the most com-
mon ingredients in OTC drugs marketed for sleep [63]. Diphenhydramine is sedat-
ing through its potent anticholinergic effect and tolerance to its sedating effect
develops rapidly. The long half-life of diphenhydramine may result in next-day
sedation. Side effects can be quite problematic in older adults (e.g., dry mouth, uri-
nary retention, delirium, decreased cognition, constipation, increased ocular pres-
sure), so diphenhydramine is not recommended for insomnia in older patients.
Other supplements are available OTC, such as melatonin and valerian, but recent
guidelines do not recommend use of these agents for insomnia [64].
Restless Legs Syndrome/Periodic Leg Movements
Restless legs syndrome (RLS) is defined by the urge to move one’s legs. The other
defining features of RLS are an improvement with movement, worsening with
relaxation, and an evening onset. More rarely RLS can also affect and may even be
limited to the arms. This urge to move is often described as an uncomfortable sensa-
tion in the limbs. The prevalence of RLS does increase with age with up to an 8%
prevalence in older patients [65]. A similar prevalence has been found in patients
with cognitive impairment and dementia [66]. The pathophysiology of RLS is
thought to involve low levels of iron stores in the brain. Increasing prevalence of
iron deficiency may in part explain why older patients have an increase in RLS
symptoms. Other comorbidities such as chronic kidney disease, neuropathy, and the
use of antidepressants and neuroleptics are also associated with RLS [67]. The
accrual of these comorbidities may explain why RLS is more common in older
patients. In older individuals it is difficult to distinguish “primary RLS,” i.e., RLS
without comorbidities, from comorbid RLS.
The diagnosis of RLS is made solely on clinical evaluation. The International

Classification of Sleep Disorders-Third Edition (ICSD-3) recommends that the
diagnosis be based on an urge to move the legs that worsens during rest, is at least
partially relieved by movement, and occurs most predominately in the evening [68].
The presence of periodic leg movements can help support the diagnosis of RLS. The
diagnosis is challenging in older patients due to the need to rule out other conditions
such as neuropathy and radiculopathy. Patients may attribute complaints about their
legs to leg cramps, edema, and arthritis which are all prevalent in older individuals.
Another challenge is that patients with significant cognitive impairment may have
difficulty describing their symptoms. It has been suggested that behaviors such as
rubbing or kneading the legs be considered as evidence for RLS in patients with
dementia. Excessive motor activity such as pacing, kicking, rubbing feet together,
foot tapping, and cycling movements can all be used as signs of RLS [69]. This
approach was used to create an instrument validated in cognitively intact patients
with and without RLS. Using iron deficiency, symptom of discomfort in legs and a
behavioral observational tool among other factors can be used to predict the pres-
ence of RLS [70].
The presence of RLS in older patients may adversely impact their quality of life.
The presence of RLS was found to be associated with a subsequent decline in physi-
cal function [71]. Severity of RLS has been linked to decreased quality of life
scores, including daily and social functioning [72]. Abnormal nocturnal behaviors
are a risk factor for the institutionalization of patients with dementia. It stands to
reason that a condition causing the urge to walk around at night could worsen such
behaviors and contribute to a risk of falls. Indeed, in 1 study in a sample of 59
patients, probable RLS was found to predict nocturnal agitation behaviors along
with OSA [73]. There has been a link between RLS symptoms in patients with
dementia and the presence of apathy, which is hypothesized as due to a common
problem in the dopaminergic system [74].
Periodic leg movements of sleep (PLMS) are stereotypical extensions of the
great toe with dorsiflexion of the ankle occasionally including flexions of the knee
and hip that occur repeatedly. PLMS have been shown to increase substantially with
age in healthy adults [75]. In healthy individuals it is controversial what the impact
of PLMS have on sleep. PLMS have been correlated with increased nocturnal blood
pressure, autonomic activity, and incident cardiovascular disease [76]. The diagno-
sis of periodic limb movement disorder (PLMD) requires a frequency of at least 15
leg movements per hour and that the patient have sleep disturbance or impaired
daytime functioning that is not better explained by another current sleep disorder
[68]. Therefore, patients who have RLS by definition cannot have PLMD. Also,
other medical or neurologic disorders have to be excluded as the cause of the
patients’ symptoms in order to make a PLMD diagnosis. Given that comorbidities
are common in older adults, it can be challenging to diagnose PLMD in this
population.
The treatments for RLS and PLMD are similar. The first step of therapy is to
ensure adequate iron stores. Iron supplementation should be given if the ferritin
level is below 75 ng/ml. Supplemental iron has been found to be an effective therapy
for RLS without significant adverse effects [77]. The mainstay of pharmacologic
therapy has traditionally been non-ergot dopamine agonists such as ropinirole and
pramipexole. These therapies have been effective for the treatment of RLS symp-
toms, but are not without potential side effects, such as sleep attacks and gastroin-
testinal side effects. The most worrisome side effects of these agents include
behavioral disinhibition such as impulsive gambling. It would stand to reason that
older adults may have more difficulty tolerating these agents. However, a study of
patients treated with this class of medication in those with Parkinson’s disease did
not find a significant difference in tolerability between older and younger patients,
with 90% tolerating this therapy [78]. Another potential adverse outcome stemming
from the use of dopaminergic therapy is the risk for augmentation, which is an ear-
lier timing of symptoms, spread of symptoms to previously unaffected limbs, and/
or increased intensity of symptoms. Augmentation is thought to occur at around 9%
per year among patients on pramipexole [79]. Many experts feel that this is an unac-
ceptable risk of augmentation and suggest that an alternative class of therapeutic
agents should be considered for first-line therapy.
The major alternative class of therapeutic agents are the alpha-2-delta calcium
channel ligands such as gabapentin and pregabalin. Of these agents only gabapentin
enacarbil is FDA approved for the treatment of RLS. There is strong evidence that
pregabalin is as effective as dopamine agonists and confers a decreased risk for
augmentation [80]. As with many drugs in older people, these agents should be used
with caution since there is significant variability in the pharmacokinetics of drugs
such as gabapentin, in part due to changes in renal function [81]. The accumulation
of these medications can theoretically cause somnolence, dizziness, and gastroin-
testinal disturbances. However, the safety and efficacy of these medications in an
older patient population for RLS have not been specifically studied.
Opioids can be an effective therapy for the treatment of refractory RLS [69].
However, this class of medications comes with significant safety concerns including
constipation, somnolence, impaired cognition, and a potential for drug overdose.
The American Geriatrics Society recommends avoidance of opioids in combination
with other central nervous system depressants in older adults and in those with a
history of falls [55].
Non-pharmacologic therapies should also be considered in the treatment of
RLS. The majority of non-pharmacologic advice is the recommendation that
patients avoid substances that provoke RLS symptoms. Such exacerbating factors
include antidepressants, alcohol, caffeine, and sleep deprivation. Alternative thera-
pies that include exercise, massage, transcutaneous stimulation, pneumatic com-
pression, and yoga have been shown to have benefit in low-quality studies [82].
Additional controlled trials on alternative or complementary therapies for RLS in
older adults are needed.
REM sleep behavior disorder (RBD) involves dream enactment behavior with a
failure to inhibit muscle tone as normally occurs during REM sleep. RBD can
potentially cause injury to the patient or a bed partner due to acting out dream
actions such as punching, kicking, or running while unconscious. The prevalence of
RBD in adults over the age of 40 has been estimated to be around 1% [83]. Clinical
samples of patients have shown that patients typically present for evaluation of
RBD in their mid-60s while having had approximately 5 years of symptoms [84].
Indeed, the prevalence of RBD was found to be 2% among those older than 60 years
[85]. Therefore, RBD is essentially a disease of aging.
This strong predilection for older adults is likely due to the connection of RBD
to neurodegenerative disorders of aging, in particular alpha-synucleinopathies [86].
There is a high prevalence of RBD in those with Parkinson’s disease, Lewy body
dementia, and multisystem atrophy. However, RBD may be a precursor to the devel-
opment of these disorders. Over the course of 15 to 20 years of observation, up to
90% of patients with RBD will ultimately develop a neurodegenerative disorder
associated with alpha-synuclein [87]. It is thought that this relationship is due to a
shared pathophysiology with early deposition of alpha-synuclein in areas of the
brain stem that inhibit muscle tone during REM sleep.
The diagnosis of RBD requires both a history of dream enactment and findings
of abnormally increased muscle tone during REM sleep during polysomnography
making it the only parasomnia that explicitly requires confirmatory findings on PSG
to make a diagnosis [67]. Conditions that confound the diagnosis of RBD are sig-
nificant sleep-disordered breathing and PTSD, which can both present with appar-
ent dream enactment behavior. There is some evidence that REM sleep tone is also
increased in sufferers of PTSD making the distinction diagnostically challenging.
There is also further evidence that the presence of PTSD may be a risk factor in the
development of RBD [88].
The primary goal of treating RBD is to avoid nocturnal injury and to prevent
sleep disruption. The first priority should be to ensure that the patient is sleeping
in a safe environment and that they are not a danger to themselves or others. The
two major pharmacological treatments of RBD are low-dose clonazepam and
melatonin. In older patients it is preferable to avoid benzodiazepines when pos-
sible making melatonin the primary first choice for therapy. There is evidence
from small randomized trials and two retrospective studies that melatonin reduces
both REM sleep without atonia and the clinical manifestations of RBD [89]. The
mechanism of action for melatonin in RBD is not known. Often very high doses
(up to 18 mg) of melatonin are sometimes required. Clonazepam also has evi-
dence from case series at improving RBD behaviors; however caution must be
used in those with dementia or gait instability [90]. A single-center retrospective
review of RBD patient experiences with melatonin and clonazepam showed that
both medications improved dream enactment behaviors. However, only melatonin

was associated with reduced injuries and falls, while clonazepam was associated
with increased adverse effects such as sleepiness, unsteadiness, dizziness, and
trouble thinking [91].
leep Disturbance among Residents in Long-Term

S
Care Settings
Sleep problems are common among older people in long-term care settings, such as
nursing homes (NHs) [92]. Many older NH residents have an irregular sleep-wake
rhythm, with fragmented nighttime sleep and excessive daytime napping [93]. In
addition to older age, other common factors associated with poor sleep in these resi-
dents include medical and psychiatric comorbidities, polypharmacy, a disruptive
nighttime environment, limited physical activity and lack of exposure to bright light
during the daytime, and increased time spent in bed during the day. Sleep distur-
bance in NH residents is associated with lower quality of life, less involvement in
social activities, and other adverse consequences. Evidence suggests that sleep dis-
turbance in NH residents is also associated with distress in NH staff, resident agita-
tion, and prescription of psychotropic medications [94]. In addition to identifying
and treating primary sleep disorders, the management of sleep disturbance in NH
residents usually requires a multidimensional treatment approach to improve the
nighttime sleeping environment and increase daytime physical activity (as appropri-
ate) as well as bright light exposure. A recent meta-analysis suggested the most
promising approaches were increased daytime light exposure, nighttime use of mel-
atonin, and acupressure [95]. Sedating medications may have limited benefit in
improving sleep of NH home residents, particularly given the complex factors in
metabolism of these drugs in frail older adults and adverse consequences, including
increased risk of hip fracture [96].
References
1. Mander BA, Winer JR, Walker MP. Sleep and Human Aging. Neuron. 2017;94(1):19–36.
2. Foley DJ, Vitiello MV, Bliwise DL, Ancoli-Israel S, Monjan AA, Walsh JK. Frequent nap-
ping is associated with excessive daytime sleepiness, depression, pain, and nocturia in older
adults: findings from the National Sleep Foundation '2003 sleep in America' poll. Am J Geriatr
Psychiatry. 2007;15(4):344–50.
3. Dijk DJ, Groeger JA, Stanley N, Deacon S. Age-related reduction in daytime sleep propensity
and nocturnal slow wave sleep. Sleep. 2010;33(2):211–23.
4. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clear-
ance from the adult brain. Science. 2013;342(6156):373–7.
5. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, et al. Sleep quality
and preclinical Alzheimer disease. JAMA Neurol. 2013;70(5):587–93.
6. Spira AP, An Y, Wu MN, Owusu JT, Simonsick EM, Bilgel M, et al. Excessive daytime sleepi-
ness and napping in cognitively normal adults: associations with subsequent amyloid deposi-
tion measured by PiB PET. Sleep. 2018;41(12).
7. Carvalho DZ, St Louis EK, Knopman DS, Boeve BF, Lowe VJ, Roberts RO, et al. Association
of Excessive Daytime Sleepiness with Longitudinal β-amyloid accumulation in elderly per-
sons without dementia. JAMA Neurol. 2018;75(6):672–80.
8. Shokri-Kojori E, Wang GJ, Wiers CE, Demiral SB, Guo M, Kim SW, et al. β-Amyloid accu-
mulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S
A. 2018;115(17):4483–8.
9. Kripke DF, Langer RD, Elliott JA, Klauber MR, Rex KM. Mortality related to actigraphic long
and short sleep. Sleep Med. 2011;12(1):28–33.
10. 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):861–8.
11. Van Cauter E, Spiegel K, Tasali E, Leproult R. Metabolic consequences of sleep and sleep loss.
Sleep Med. 2008;9(Suppl 1):S23–8.
12. Donovan LM, Kapur VK. Prevalence and characteristics of central compared to obstructive
sleep apnea: analyses from the sleep heart health study cohort. Sleep. 2016;39(7):1353–9.
13. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-
disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–14.
14. Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb DJ, et al. Predictors of sleep-
disordered breathing in community-dwelling adults: the sleep heart health study. Arch Intern
Med. 2002;162(8):893–900.
15. Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, et al. Clinical prac-
tice 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.
16. Morales CR, Hurley S, Wick LC, Staley B, Pack FM, Gooneratne NS, et al. In-home,
self-assembled sleep studies are useful in diagnosing sleep apnea in the elderly. Sleep.
2012;35(11):1491–501.
17. Polese JF, Santos-Silva R, de Oliveira Ferrari PM, Sartori DE, Tufik S, Bittencourt L. Is por-
table monitoring for diagnosing obstructive sleep apnea syndrome suitable in elderly popula-
tion? Sleep Breath. 2013;17(2):679–86.
18. McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, et al.
Continuous positive airway pressure in older people with obstructive sleep apnoea syn-
drome (PREDICT): a 12-month, multicentre, randomised trial. Lancet Respir Med.
2014;2(10):804–12.
19. Martínez-García M, Chiner E, Hernández L, Cortes JP, Catalán P, Ponce S, et al. Obstructive
sleep apnoea in the elderly: role of continuous positive airway pressure treatment. Eur Respir
J. 2015;46(1):142–51.
20. Dalmases M, Solé-Padullés C, Torres M, Embid C, Nuñez MD, Martínez-Garcia M, et al.
Effect of CPAP on cognition, brain function, and structure among elderly patients with OSA:
a randomized pilot study. Chest. 2015;148(5):1214–23.
21. Ponce S, Pastor E, Orosa B, Oscullo G, Catalán P, Martinez A, et al. The role of CPAP treat-
ment in elderly patients with moderate obstructive sleep apnoea: a multicentre randomised
controlled trial. Eur Respir J. 2019;54(2).
22. López-Padilla D, Alonso-Moralejo R, Martínez-García M, De la Torre CS. Díaz de Atauri
MJ. Continuous positive airway pressure and survival of very elderly persons with moderate to
severe obstructive sleep apnea. Sleep Med. 2016;19:23–9.
23. Sawyer AM, Gooneratne NS, Marcus CL, Ofer D, Richards KC, Weaver TE. A systematic
review of CPAP adherence across age groups: clinical and empiric insights for developing
CPAP adherence interventions. Sleep Med Rev. 2011;15(6):343–56.
24. Chong MS, Ayalon L, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, et al. Continuous
positive airway pressure reduces subjective daytime sleepiness in patients with mild to moder-
ate Alzheimer's disease with sleep disordered breathing. J Am Geriatr Soc. 2006;54(5):777–81.
25. Posadas T, Oscullo G, Zaldívar E, Garcia-Ortega A, Gómez-Olivas JD, Monteagudo M, et al.

Treatment with CPAP in elderly patients with obstructive sleep apnoea. J Clin Med. 2020;9(2).
26. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, et al. CPAP for prevention of car-
diovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10):919–31.
27. Yu J, Zhou Z, McEvoy RD, Anderson CS, Rodgers A, Perkovic V, et al. Association of Positive
Airway Pressure with Cardiovascular Events and Death in adults with sleep apnea: a system-
atic review and meta-analysis. JAMA. 2017;318(2):156–66.
28. Ramar K, Dort LC, Katz SG, Lettieri CJ, Harrod CG, Thomas SM, 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.
29. Carballo NJ, Alessi CA, Martin JL, Mitchell MN, Hays RD, Col N, et al. Perceived effective-
ness, self-efficacy, and social support for Oral appliance therapy among older veterans with
obstructive sleep apnea. Clin Ther. 2016;38(11):2407–15.
30. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d'Ortho MP, Erdmann E, et al.
Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med.
2015;373(12):1095–105.
31. Baniak LM, Chasens ER. Sleep disordered breathing in older adults with heart failure with
preserved ejection fraction. Geriatr Nurs. 2018;39(1):77–83.
32. Patel D, Steinberg J, Patel P. Insomnia in the elderly: a review. J Clin Sleep Med.
2018;14(6):1017–24.
33. Zhang B, Wing YK. Sex differences in insomnia: a meta-analysis. Sleep. 2006;29(1):85–93.
34. Edwards BA, O'Driscoll DM, Ali A, Jordan AS, Trinder J, Malhotra A. Aging and sleep: physi-
ology and pathophysiology. Semin Respir Crit Care Med. 2010;31(5):618–33.
35. Zitting KM, Münch MY, Cain SW, Wang W, Wong A, Ronda JM, et al. Young adults are more
vulnerable to chronic sleep deficiency and recurrent circadian disruption than older adults. Sci
Rep. 2018;8(1):11052.
36. Miner B, Gill TM, Yaggi HK, Redeker NS, Van Ness PH, Han L, et al. Insomnia in community-
living persons with advanced age. J Am Geriatr Soc. 2018;66(8):1592–7.
37. McCurry SM, Gibbons LE, Logsdon RG, Vitiello MV, Teri L. Insomnia in caregivers
of persons with dementia: who is at risk and what can be done about it? Sleep Med Clin.
2009;4(4):519–26.
38. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation
and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504.
39. Smith MT, McCrae CS, Cheung J, Martin JL, Harrod CG, Heald JL, et al. Use of Actigraphy
for the evaluation of sleep disorders and circadian rhythm sleep-wake disorders: an American
Academy of sleep medicine clinical practice guideline. J Clin Sleep Med. 2018;14(7):1231–7.
40. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Physicians CGCotACo.
Management of Chronic Insomnia Disorder in adults: a clinical practice guideline from the
American College of Physicians. Ann Intern Med. 2016;165(2):125–33.
41. Belanger L, LeBlanc M, Morin C. Cognitive behavioral therapy for insomnia in older adults.
Cognitive Behavioral Practice. 2012;19:101–15.
42. Morin CM, Bootzin RR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. Psychological
and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep.
2006;29(11):1398–414.
43. Alessi C, Martin JL, Fiorentino L, Fung CH, Dzierzewski JM, Rodriguez Tapia JC, et al.
Cognitive behavioral therapy for insomnia in older veterans using nonclinician sleep coaches:
randomized controlled trial. J Am Geriatr Soc. 2016;64(9):1830–8.
44. Morgenthaler T, Kramer M, Alessi C, Friedman L, Boehlecke B, Brown T, et al. Practice
parameters for the psychological and behavioral treatment of insomnia: an update. An
American academy of sleep medicine report. Sleep. 2006;29(11):1415–9.
45. Mitchell MD, Gehrman P, Perlis M, Umscheid CA. Comparative effectiveness of cognitive
behavioral therapy for insomnia: a systematic review. BMC Fam Pract. 2012;13:40.
46. Zachariae R, Lyby MS, Ritterband LM, O'Toole MS. Efficacy of internet-delivered cognitive-
behavioral therapy for insomnia - a systematic review and meta-analysis of randomized con-
trolled trials. Sleep Med Rev. 2016;30:1–10.
47. Friedman L, Zeitzer JM, Kushida C, Zhdanova I, Noda A, Lee T, et al. Scheduled bright light
for treatment of insomnia in older adults. J Am Geriatr Soc. 2009;57(3):441–52.
48. Gammack JK. Light therapy for insomnia in older adults. Clin Geriatr Med.
2008;24(1):139–49, viii.
49. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice
guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-
wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), Non-24-hour
sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD).
An update for 2015: An American Academy of sleep medicine clinical practice guideline. J
Clin Sleep Med. 2015;11(10):1199–236.
50. Reid KJ, Baron KG, Lu B, Naylor E, Wolfe L, Zee PC. Aerobic exercise improves self-reported
sleep and quality of life in older adults with insomnia. Sleep Med. 2010;11(9):934–40.
51. Raman G, Zhang Y, Minichiello VJ, D'Ambrosio CM, Wang C. Tai chi improves sleep quality
in healthy adults and patients with chronic conditions: a systematic review and meta-analysis.
J Sleep Disord Ther. 2013;2(6).
with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331(7526):1169.
53. McIntosh B, Clark M, Spry C. Benzodiazepines in older adults: a review of clinical effective-
ness, cost-effectiveness, and guidelines. 2011.
54. Taipale H, Tolppanen AM, Koponen M, Tanskanen A, Lavikainen P, Sund R, et al. Risk of
pneumonia associated with incident benzodiazepine use among community-dwelling adults
with Alzheimer disease. CMAJ. 2017;189(14):E519–E29.
55. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate
Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674–94.
56. Treves N, Perlman A, Kolenberg Geron L, Asaly A, Matok I. Z-drugs and risk for falls and frac-
tures in older adults-a systematic review and meta-analysis. Age Ageing. 2018;47(2):201–8.
57. Dolder CR, Nelson MH. Hypnosedative-induced complex behaviours: incidence, mechanisms
and management. CNS Drugs. 2008;22(12):1021–36.
58. Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P. Effects of ramelteon on patient-
reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006;7(4):312–8.
59. Rojas-Fernandez CH, Chen Y. Use of ultra-low-dose (≤6 mg) doxepin for treatment of insom-
nia in older people. Can Pharm J (Ott). 2014;147(5):281–9.
60. Herring WJ, Ceesay P, Snyder E, Bliwise D, Budd K, Hutzelmann J, et al. Polysomnographic
assessment of suvorexant in patients with probable Alzheimer's disease dementia and insom-
nia: a randomized trial. Alzheimers Dement. 2020;16(3):541–51.
61. Jaffer KY, Chang T, Vanle B, Dang J, Steiner AJ, Loera N, et al. Trazodone for insomnia: a
systematic review. Innov Clin Neurosci. 2017;14(7–8):24–34.
62. Thompson W, Quay TAW, Rojas-Fernandez C, Farrell B, Bjerre LM. Atypical antipsychotics
for insomnia: a systematic review. Sleep Med. 2016;22:13–7.
63. Abraham O, Schleiden L, Albert SM. Over-the-counter medications containing diphen-
hydramine and doxylamine used by older adults to improve sleep. Int J Clin Pharm.
2017;39(4):808–17.
64. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for
the pharmacologic treatment of chronic insomnia in adults: An American Academy of sleep
medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–49.
65. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs
syndrome prevalence and impact: REST general population study. Arch Intern Med.
2005;165(11):1286–92.
66. Guarnieri B, Adorni F, Musicco M, Appollonio I, Bonanni E, Caffarra P, et al. Prevalence of

sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian
clinical cross-sectional study on 431 patients. Dement Geriatr Cogn Disord. 2012;33(1):50–8.
67. Figorilli M, Puligheddu M, Ferri R. Restless legs syndrome/Willis-Ekbom disease and peri-
odic limb movements in sleep in the elderly with and without dementia. Sleep Med Clin.
2015;10(3):331–42, xiv-xv.
68. American Academy of Sleep Medicine. The international classification of sleep disorders -Third
Edition (ICSD-3). 2nd ed. Westchester, Ill: American Academy of Sleep Medicine; 2014. p.
xviii, 297.
69. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, et al. Restless
legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from
the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of
Health. Sleep Med. 2003;4(2):101–19.
70. Richards KC, Bost JE, Rogers VE, Hutchison LC, Beck CK, Bliwise DL, et al. Diagnostic
accuracy of behavioral, activity, ferritin, and clinical indicators of restless legs syndrome.
Sleep. 2015;38(3):371–80.
71. Zhang C, Li Y, Malhotra A, Ning Y, Gao X. Restless legs syndrome status as a predictor for
lower physical function. Neurology. 2014;82(14):1212–8.
72. Cuellar NG, Strumpf NE, Ratcliffe SJ. Symptoms of restless legs syndrome in older adults:
outcomes on sleep quality, sleepiness, fatigue, depression, and quality of life. J Am Geriatr
Soc. 2007;55(9):1387–92.
73. Rose KM, Beck C, Tsai PF, Liem PH, Davila DG, Kleban M, et al. Sleep disturbances and
nocturnal agitation behaviors in older adults with dementia. Sleep. 2011;34(6):779–86.
74. Talarico G, Canevelli M, Tosto G, Vanacore N, Letteri F, Prastaro M, et al. Restless legs syn-
drome in a group of patients with Alzheimer's disease. Am J Alzheimers Dis Other Dement.
2013;28(2):165–70.
75. Pennestri MH, Whittom S, Adam B, Petit D, Carrier J, Montplaisir J. PLMS and PLMW
in healthy subjects as a function of age: prevalence and interval distribution. Sleep.
2006;29(9):1183–7.
76. Koo BB, Blackwell T, Ancoli-Israel S, Stone KL, Stefanick ML, Redline S, et al. Association
of incident cardiovascular disease with periodic limb movements during sleep in older men:
outcomes of sleep disorders in older men (MrOS) study. Circulation. 2011;124(11):1223–31.
77. Trotti LM, Becker LA. Iron for the treatment of restless legs syndrome. Cochrane Database
Syst Rev. 2019;1:CD007834.
78. Rizos A, Sauerbier A, Falup-Pecurariu C, Odin P, Antonini A, Martinez-Martin P, et al.
Tolerability of non-ergot oral and transdermal dopamine agonists in younger and older
Parkinson's disease patients: an European multicentre survey. J Neural Transm (Vienna).
2020;127(6):875–9.
79. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine ago-
nists and methadone in the treatment of restless legs syndrome. Sleep Med. 2011;12(5):440–4.
80. Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, et al. Comparison of
pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370(7):621–31.
81. Conway JM, Eberly LE, Collins JF, Macias FM, Ramsay RE, Leppik IE, et al. Factors in vari-
ability of serial gabapentin concentrations in elderly patients with epilepsy. Pharmacotherapy.
2017;37(10):1197–203.
82. Xu XM, Liu Y, Jia SY, Dong MX, Cao D, Wei YD. Complementary and alternative thera-
pies for restless legs syndrome: an evidence-based systematic review. Sleep Med Rev.
2018;38:158–67.
83. Haba-Rubio J, Frauscher B, Marques-Vidal P, Toriel J, Tobback N, Andries D, et al. Prevalence
and determinants of rapid eye movement sleep behavior disorder in the general population.
Sleep. 2018;41(2).
84. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demographic,
clinical and laboratory findings in 93 cases. Brain. 2000;123(Pt 2):331–9.
85. Kang SH, Yoon IY, Lee SD, Han JW, Kim TH, Kim KW. REM sleep behavior disorder in the
Korean elderly population: prevalence and clinical characteristics. Sleep. 2013;36(8):1147–52.
86. Boeve BF, Silber MH, Ferman TJ, Lin SC, Benarroch EE, Schmeichel AM, et al.
Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder
with or without a coexisting neurologic disorder. Sleep Med. 2013;14(8):754–62.
87. Iranzo A, Fernández-Arcos A, Tolosa E, Serradell M, Molinuevo JL, Valldeoriola F, et al.
Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174
patients. PLoS One. 2014;9(2):e89741.
88. Elliott JE, Opel RA, Pleshakov D, Rachakonda T, Chau AQ, Weymann KB, et al. Posttraumatic
stress disorder increases the odds of REM sleep behavior disorder and other parasomnias in
Veterans with and without comorbid traumatic brain injury. Sleep. 2020;43(3).
89. McGrane IR, Leung JG, St Louis EK, Boeve BF. Melatonin therapy for REM sleep behavior
disorder: a critical review of evidence. Sleep Med. 2015;16(1):19–26.
90. Aurora RN, Zak RS, Maganti RK, Auerbach SH, Casey KR, Chowdhuri S, et al. Best prac-
tice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med.
2010;6(1):85–95.
91. McCarter SJ, Boswell CL, St Louis EK, Dueffert LG, Slocumb N, Boeve BF, et al. Treatment
outcomes in REM sleep behavior disorder. Sleep Med. 2013;14(3):237–42.
92. Zhu X, Hu Z, Nie Y, Zhu T, Chiwanda Kaminga A, Yu Y, et al. The prevalence of poor sleep
quality and associated risk factors among Chinese elderly adults in nursing homes: a cross-
sectional study. PLoS One. 2020;15(5):e0232834.
93. Martin JL, Webber AP, Alam T, Harker JO, Josephson KR, Alessi CA. Daytime sleeping,
sleep disturbance, and circadian rhythms in the nursing home. Am J Geriatr Psychiatry.
2006;14(2):121–9.
94. Webster L, Costafreda Gonzalez S, Stringer A, Lineham A, Budgett J, Kyle S, et al. Measuring
the prevalence of sleep disturbances in people with dementia living in care homes: a systematic
review and meta-analysis. Sleep. 2020;43(4).
95. Capezuti E, Sagha Zadeh R, Pain K, Basara A, Jiang NZ, Krieger AC. A systematic review of
non-pharmacological interventions to improve nighttime sleep among residents of long-term
care settings. BMC Geriatr. 2018;18(1):143.
96. Berry SD, Lee Y, Cai S, Dore DD. Nonbenzodiazepine sleep medication use and hip fractures
in nursing home residents. JAMA Intern Med. 2013;173(9):754–61.
Index
A B
Achondroplasia, 223 Behavioral therapies, 502
Actigraphy, 434 Benzodiazepine receptor agonists
Adaptive servoventilation (ASV), 500 (BZRAs), 287
Adenotonsillar hypertrophy, 218 Benzodiazepines (BDZs), 23, 24, 386
Adenotonsillectomy, 216–218 Benzodiazepines bind, 503
Advanced sleep-wake phase disorder Berlin questionnaire, 190
(ASWPD), 299, 303 Bilevel positive airway pressure
clinical features, 304 (BPAP), 131–133
diagnosis, 304–305 Board-Certified Sleep Medicine Physicians
pathophysiology, 304 (BCSMPs), 70
prevalence, 303 Brief behavioral treatment for insomnia
treatment, 305 (BBT-I), 282
Alpha-synucleinopathies, 382
Alzheimer’s disease, 382, 503
American Academy of Pediatrics (AAP), C
235, 236 Capnography, 200
American Academy of Sleep Medicine Carbamazepine, 386
(AASM), 155, 190, 238 Cardiovascular disease, 95–97
American Society of Anesthesiologists Cardiovascular function, 12
(ASA), 190 Cataplexy, 342–343
Amphetamines, 34, 35 Centers for Medicare and Medicaid Services
Angelman syndrome, 309 (CMS), 135
Antidepressants, 31, 32 Center-to-Home (C2H) telemedicine, 79
Antipsychotic agents, 32 Central hypoventilation syndromes, 227
Apnea hypopnea indices (AHI), 219 Central sleep apnea, 227
Apneic threshold, 150 breathing instability, 147
Apparent life-threatening event (ALTE), 234 categories, 148
Armodafinil, 36, 341 clinical features and diagnosis, 152, 153
Artificial intelligence (AI), 76, 77 hyperpnea, 146
Attention deficit hyperactivity disorder hyperventilation, 149
(ADHD), 402 hypocapnia, 145, 146
Autism spectrum disorder, 309 hypoventilation, 148, 149
Automatic behaviors, 329 ICSD-3, 148
Autotitrating positive airway pressure (APAP), loop gain, 147
123, 124 management

Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3
516 Index
pharmacologic therapy, 155 pathophysiology, 306–307

positive pressure therapy, 153–155 prevalence, 306
supplemental O2 and CO2, 155, 156 treatment, 308
TPNS, 156 retinohypothalamic tract, 298
pathophysiologic classification, 148 self-sustained biological rhythms, 297
risk factors shift work disorder (SWD), 299
age and gender, 150, 151 clinical features, 312–313
medical conditions, 151, 152 diagnosis, 313
sleep state, 150 pathophysiology, 312
short–term potentiation (STP), 146 prevalence, 311–312
ventilatory control, 147 treatment, 313–314
Cerebrovascular accident (CVA), 151 Circadian rhythms, 54, 55
Cervical spinal cord injury (C-SCI), 151 Cleft lip/palate, 222
Change from baseline (CFB), 30 Clinical video telehealth (CVT), 79
Cheyne–Stokes breathing pattern, 146, 155 Clonazepam, 386
Chiari I malformation, 230 Clozapine, 386
Chiari II malformation, 231 Cognitive behavioral therapy (CBT), 373, 481
Chicago criteria, 118 Cognitive behavioral therapy for insomnia
Chronic obstructive pulmonary disease (CBTi), 72, 260
(COPD), 457 Confusional arousals, 357, 358
Chronotype, 54, 55 Congenital central hypoventilation syndrome
Circadian properties, 297 (CCHS), 228, 229
Circadian rhythm sleep-wake disorders Continuous positive airway pressure (CPAP)
(CRSWDs) therapy, 129, 131–135, 146,
advanced sleep-wake phase 457, 499
disorder (ASWPD) COVID-19 pandemic, 70, 79, 80
clinical features, 304 Craniosynostosis, 222
diagnosis, 304–305 Critical illness
pathophysiology, 304 actigraphy, 434
prevalence, 303 care-related interactions, 436–439
treatment, 305 causes and consequences of, 435
delayed sleep-wake phase causes of sleep disruption, 435–439
disorder (DSWPD) critically Ill patients
clinical features, 301 sleep and immunity, 440–441
diagnosis, 301–302 sleep disruption and
pathophysiology, 300–301 cognition, 441–442
prevalence, 300 physiological disruptions, 431
treatment, 302–303 sleep in critically Ill patients, 432–433
ICSD-3 diagnostic criteria, 299 sleep in healthy adults, 432
intrinsic circadian rhythm, 299 sleep measurement, 433–434
irregular sleep-wake rhythm sleep patterns, 433
disorder (ISWRD)
clinical features, 310
diagnosis, 310 D
pathophysiology, 309 Daytime eating disorders, 364
prevalence, 309 Delayed sleep-wake phase disorder
treatment, 310–311 (DSWPD), 299
jet lag disorder (JLD), 299, 314–317 clinical features, 301
light exposure, 298 diagnosis, 301–302
non-24-hour sleep-wake rhythm disorder pathophysiology, 300–301
(N24SWD) prevalence, 300
clinical features, 307 treatment, 302–303
diagnosis, 307–308 Dementia with Lewy bodies (DLB), 366
Index 517
Dexmedetomidine, 442 Growth hormone secretion, 13

Diagnostic and statistical manual of mental
disorders fifth edition (DSM-5), 256
Disorders of arousal, 350, 352–354 H
Donepezil, 386 Home sleep apnea testing (HSAT), 77, 217
Dopamine transport scan (DAT), 384 Hospital Elder Life Program (HELP), 461
Down’s syndrome, 220 Hospitalized patients
Doxepin, 288 barriers to, 455
Dual orexin receptor antagonist agents bright light therapy, 459–460
(DORAs), 28, 30 continuous positive airway pressure
Duchenne muscular dystrophy (DMD), (CPAP) therapy, 463, 464
224, 225 disorders of mental health, 462
environmental factors, 456
health effects of, 454–455
E hospitalized older adults, 462–463
Endocrine function, 13 ICU, 463
Enzyme replacement therapy, 226 improving patient knowledge and
Epilepsy and vagal nerve stimulators, 226 education, 461
Epworth sleepiness scale (ESS), 35 interventions to improve sleep, 458
Excessive daytime sleepiness (EDS), 33 medical care interruptions, 455–456
Exogenous melatonin, 311 melatonin, 458
Exploding head syndrome, 352, 373 noise reduction, 460
nonpharmacologic therapies, 459
pain and sleep, 462
F patient factors influencing sleep, 456
Familial dysautonomia, 229, 230 prevalence of, 457
Follicular stimulating hormone (FHS), 13 reducing nighttime interruptions, 461
Fragmented nocturnal sleep, 343 relaxation techniques, 459
Future of sleep medicine sleep aids, 458
Board-Certified Sleep Medicine Physicians sleep hygiene, 460
(BCSMP), 70 sleep loss in adults, 453–454
development, 69 sleep loss in older adults, 454
patient-centered model “Somerville” multifaceted protocol, 461
American Academy of Sleep Medicine Human leukocyte antigens (HLA), 327
(AASM), 81 Huntington disease, 382
artificial intelligence/machine Hypercapnia, 7
learning, 76, 77 Hyperpnea, 146
existing paradigms, 71–73 Hyperventilation, 149
feasibility of communication, 79, 80 Hypnic hallucinations, 374
home sleep apnea testing (HSAT), 81 Hypocapnia, 7, 145, 146
positive airway pressure (PAP), 82 Hypoglossal nerve stimulation (HNS),
patient and provider portals, 77, 78 140, 141
project ECHO, 73–75 Hypoventilation, 148, 149
questionnaires, 75, 76 Hypoxic ventilatory responsiveness (HVR), 7
terminology, 78, 79
I
G ICU-related sleep disruption, see
γ(gamma)-aminobutyric acid (GABA), 22 Critical illness
Gastrointestinal function, 14 Idiopathic hypersomnia
Gestational diabetes (GDM), 472 cataplexy, 342–343
Ghrelin, 13 clinical features, 330, 331
Glycogen storage diseases, 225 diagnosis, 336–338
518 Index
differential diagnosis, 338–339 relaxation strategies, 279

epidemiology, 332 safety considerations, 284
fragmented nocturnal sleep, 343 self-guided formats, 281
head trauma and excessive sleep hygiene recommendations, 279
sleepiness, 339–340 sleep restriction, 278, 279
nonpharmacologic management, 340 stimulus control, 277, 278
pathophysiology, 334 symptoms, 253, 254
pharmacologic management of telehealth modalities, 280
symptoms, 340–342 “3-Ps” model, 277
Image rehearsal therapy (IRT), 373 treatment, 253, 268
Insomnia, 53, 54, 476, 477, 500–504 International Classification of Sleep Disorders
Insomnia disorder Third Edition (ICSD-3), 232, 256
acceptance and commitment therapy Intrinsic circadian timing, 300
(ACT), 283 Irregular sleep-wake rhythm disorder
adherence challenges, 282 (ISWRD), 299, 309
antidepressants, 287, 288 clinical features, 310
antipsychotics, 288 diagnosis, 310
behavioral treatments, 284, 285 pathophysiology, 309
brief behavioral treatment for Insomnia prevalence, 309
(BBT-I), 282 treatment, 310–311
benzodiazepine receptor agonists
(BZRAs), 287
clinical evaluation, 261–265 J
challenges in assessment, 259, 260 Jet lag disorder (JLD), 314–317
patient identification, 261
sleep diary, 265, 266
tools and questionnaires, 265 K
cognitive behavioral therapy for insomnia Kaplan–Meier event-free survival curves,
(CBT-I), 277 177, 178
cognitive techniques, 279–281
decision-making framework, 276
diagnosis, 256, 257, 259 L
diagnostic systems, 275 Laser-assisted uvuloplasty (LAUP), 139
differential diagnosis, 266, 267 Lemborexant, 28–31
DSM-5, 258–259 Leptin, 13
group format, 280 Loop gain concept, 147
ICSD-3, 258–259 Low-dose doxepin, 31
individual format, 280 Lucid dreaming therapy, 373
medical and mental health Luteinizing hormone (LH), 13
comorbidities, 276
medication treatments, 285, 286, 289
melatonin, 288 M
melatonin receptor agonists, 287 Machine learning (ML), 76, 77
mindfulness-based therapy, 283 Melatonin, 27, 28, 288, 458
non-BZRAs, 286, 287 Melatonin receptor agonists, 28, 287, 503
nutritional supplements, 288 Methylphenidate, 34, 35
orexin receptor antagonists, 287 Modafinil, 35, 36, 341
pathophysiology and Monoamine oxidase inhibitors (MAOIs), 383
neuropsychology, 254–256 Mucopolysaccharidosis, 225
physical and mental effects, 254 Multiple sleep latency testing (MSLT), 77,
precipitating factors, 277 124, 125
prevalence, 253, 276 Myotonic muscular dystrophy, 225
Index 519
N continuous positive airway pressure

Naftidrofuryl oxalate, 410 (CPAP), 129, 131–135
Narcolepsy critical closing pressure (Pcrit), 129–131
cataplexy, 342–343 diagnosis, 117
clinical features, 328–331 epidemiology, 93, 95, 188
diagnosis, 334–338 extubation, 197
differential diagnosis, 338–339 hypoglossal nerve stimulation (HNS),
epidemiology, 331–332 140, 141
and idiopathic hypersomnia, 327 in infants, 237, 238
nonpharmacologic management, 340 laboratory-based PSG, 217
pathophysiology, 332–334 laser-assisted uvuloplasty (LAUP), 139
pharmacologic management of management, 93
symptoms, 340–342 maxillomandibular advancement
National Sleep Foundation, 266 (MMA), 138
Neuromuscular disorders (NMDs), in medical, neurologic, and psychiatric
174–176, 224 disorders, 103–106
Nightmare disorder, 370 multiple sleep latency testing (MSLT),
NIH Consensus Conference on Infantile 124, 125
Apnea, 234 multilevel surgery, 139, 140
Nocturnal eating syndrome (NES), 363, 364 objectives measurements, 116
Nocturnal seizures, 392 office epidemiology, 98–100
Nonbenzodiazepine-benzodiazepine receptor oral appliances, 136
agonists (NBRAs), 503 overnight polysomnography
Nonbenzodiazepine receptor agonists (PSG), 118–120
(Non-BzRAs), 25–27, 286, 287 oximetry, 199
Nonpharmacologic management, 340 pathogenesis, 91
Nonpharmacologic therapies, 459, 506 pharyngeal collapsibility, 129
Non-rapid eye movement (NREM) sleep, 3, pharyngeal compliance, 130
5–7, 9, 12, 352 physical examination, 116, 117
Non-REM sleep related parasomnias, 350 pneumatic splint, 131
Non-24-hour sleep-wake rhythm disorder polysomnography (PSG)-confirmed
(N24SWD), 299, 305 OSA, 115
Norepinephrine (NE) reuptake inhibitors, 342 population epidemiology, 94–98
Normal sleep portable monitoring (PM), 120–123
cardiovascular function, 12 positional therapy, 137
control of breathing, 7 positive airway pressure (PAP) therapy,
endocrine function, 13 135, 194, 201, 204–206
gastrointestinal function, 14 post anesthesia care unit (PACU), 200–203
normal breathing and ventilation, 6, 7 postoperative monitoring, 198, 199
renal function, 14, 15 postoperative pain control, 197, 198
stages and architecture, 3–6 postoperative risks, 188, 189
upper-airway structure and function, 8–12 preoperative evaluation approach, 194
Normal sleep breathing, 164, 165 preoperative risk assessment and screening
NREM-related parasomnias, 350 protocols, 189, 190, 193, 194
presence and severity, 92
prevalence and epidemiology, 91,
O 92, 111–113
Obesity, 219 PSG vs. PM, 124
clinical diagnosis, 91 radiofrequency therapies, 139
clinical history, 114, 115 risk factors, 92, 113, 114, 188, 217
collapsible tube model, 130 sleep apnea clinical score (SACS), 192
common terminology, 112 sleep detection and gaps, 106
complications, 116 sleep medicine practices, 101, 102
520 Index
split night study, 120 definition, 349

sleep position treatment (SPT), 138 diagnosis, 355–356
STOP-bang questionnaire, 191, 192 disorders of arousal, 352, 353
STOP questionnaire, 191 exploding head syndrome, 373
symptoms, 91 historical and physical examination, 352
tennis ball technique (TBT), 137 hypnic hallucinations, 374
tracheal intubation, 195 indications for polysomnography, 368,
upper airway dynamics, 131 371, 375
Obesity hypoventilation syndrome (OHS), management of patients, 356
105, 133, 166, 167, 171–174 medical disorders, 354
Obstructive apnea systematic intervention nightmare disorder
strategy (OASIS) protocol, 201 clinical presentation, 371
Obstructive sleep apnea (OSA), 30, 52, 53, diagnosis, 372
457, 497 epidemiology, 371
adverse consequences, 217 etiology/pathophysiology, 372
American Society of Anesthesiologists’ treatment, 373
checklist, 191 nocturnal events, 351
anesthetics/anesthetic technique, 196 NREM sleep, 352
apnea hypopnea indices (AHI), 219 obstructive sleep apnea, 354
autotitrating positive airway pressure outline of, 350
(APAP), 123, 124 pathology, 353–354
Berlin questionnaire, 190 patient with nocturnal events, 375, 376
bilevel positive airway pressure (BPAP), perceptions or emotional experiences, 349
132, 133 primary nocturnal enuresis, 374
capnography, 200 recurrent isolated sleep paralysis, 369, 370
in children REM sleep behavior disorder
adult, or obese child/teen, 218 clinical approach, 367
and teens, 216–218 clinical presentation, 366
Obstructive sleep apnea hypopnea syndrome diagnosis, 367
(OSAHS), 91 epidemiology, 366
Older patients etiology/pathophysiology, 366–367
difficulty falling asleep, 496 treatment, 369
difficulty staying asleep, 496 sleep enuresis, 374
insomnia, 500–504 sleep related eating disorder, 349
long-term care settings, 508 clinical presentation, 363
REM sleep behavior disorder, 507 diagnosis of, 364, 365
restless leg syndrome (RLS), 504–506 epidemiology, 363
sleep and aging, 496–497 etiology/pathophysiology, 363–364
sleep-disordered breathing, 497–500 treatments of, 365
sleepiness, 496 sleep terrors
Opioids, 506 clincial presentation, 361
Orexin antagonists, 28–31 diagnosis, 362
Orexin receptor antagonists, 287 epidemiology, 361
Out-of-center (OOC) telemedicine, 79 etiology/pathophysiology, 361
treatment, 362
sleepwalking/somnambulism, 349
P clinical presentation, 359
Parasomnia overlap disorder, 387 diagnosis, 360
Parasomnias epidemiology, 359
beta blockers and GABA modulators, 354 NREM sleep, 359
complex purposeful movements, 349 pathophysiology/etiology, 359–360
confusional arousals, 357, 358 treatment, 360
deeper NREM sleep, 350 unusual behaviors, 349
Index 521
Parkinson’s disease (PD), 366, 403 Positive airway pressure (PAP) therapy, 77,
Periodic breathing, 233, 234 201, 204–206
Periodic leg movements (PLM), 401 Post-hospital syndrome, 454
Periodic limb movement disorder (PLMD), Prader-Willi syndrome, 220, 221
399, 406–408, 505 Pramipexole, 386
Periodic limb movements of sleep Pregnancy
(PLMS), 385 circadian rhythm disruption, 481–482
Pharmacology insomnia, 476, 477
development, 41, 42 insufficient sleep, 472–474
sleep-promoting drugs maternal sleep position, 482–483
antidepressants, 31, 32 normal pregnancy, 471–472
antipsychotic agents, 32 restless leg syndrome (RLS), 480, 481
benzodiazepines, 23, 24 sleep disordered breathing (SDB), 477–480
melatonin, 27, 28 sleep quality, 474–476
melatonin receptor agonists, 28 treatment intervention, 481
non-BzRAs, 25–27 Prolactin, 13
orexin antagonists, 28–31 Proportional assist ventilation (PAV), 437
OTC, 33 Propriospinal myoclonus at sleep onset
wake-promoting drugs, 34 (PSM), 416–418
amphetamines, 34, 35 PSG interpretation in pediatrics, 240–241
armodafinil, 36
methylphenidate, 34, 35
modafinil, 35, 36 Q
pitolisant, 40, 41 Quetiapine, 288
sodium oxybate, 37, 38 Quinine induced thrombocytopenia, 410
solriamfetol, 38–40
Pierre Robin sequence, 221
Pitolisant, 40, 41, 341 R
Pittsburgh sleep quality index (PSQI), 474 Ramelteon, 28
Polysomnographic recording, 375 Rapid eye movement behavioral disorder
Polysomnography, 433–434 (RBD), 352, 365, 381, 392,
Poor sleep health 401, 507
biological causes, 57, 58 Rapid eye movement (REM) parasomnias, 350
chronotype, 54, 55 nightmare disorder
circadian rhythms, 54, 55 clinical features, 390
growing evidence, 48 definition, 389
health consequences, 60, 61 diagnostic workup, 391
parameters, 48, 49 differential diagnosis, 391–392
pathogenesis, 47 epidemiology, 391
psychosocial causes pathophysiology, 391
behaviors, 59 risk factors, 390–391
beliefs and attitudes, 58, 59 treatment, 392–393
physical and environment recurrent isolated sleep paralysis
causes, 59, 60 clinical features, 387–388
social stressors, 58 definition, 387
sleep architecture, 55, 56 diagnostic workup, 388
sleep disorders, 52–54 differential diagnosis, 389
sleep disruptions, 48 epidemiology, 388
sleep duration, 50–52 pathophysiology, 388
sleep efficiency, 56 risk factors, 388
sleep health disparity, 49, 50 treatment, 389
sleep quality and sleepiness, 56, 57 sleep behavior disorder, 7, 10, 164, 456
522 Index
clinical features, 381–382 central control of breathing

definition, 381 abnormalities, 226, 227
diagnostic workup, 384 central hypoventilation
differential diagnosis, 384–385 syndromes, 227
epidemiology, 384 central sleep apnea, 227
parasomnia overlap disorder, 387 Chiari I malformation, 230
pathophysiology, 383 Chiari II malformation, 231
risk factors, 382–383 cleft lip/palate, 222
status dissociatus, 386 congenital central hypoventilation
treatment, 385–386 syndrome (CCHS), 228, 229
Rapid onset obesity with hypothalamic combination of factors, 219
dysfunction, hypoventilation, and CNS tumors, 231
autonomic dysregulation craniofacial abnormalities, 221
(ROHHAD), 229 craniosynostosis, 222
Recurrent isolated sleep paralysis, 369, 370 Down’s syndrome, 220
REM atonia pathways, 366 Duchenne muscular dystrophy (DMD),
Remote veteran apnea management platform 224, 225
(REVAMP), 78 enzyme replacement therapy, 226
REM sleep without atonia (RSWA), 367, 384 epilepsy and vagal nerve
Renal function, 14, 15 stimulators, 226
Restless leg syndrome (RLS), 399–406, 480, familial dysautonomia, 229, 230
481, 504–506 glycogen storage diseases, 225
Rett syndrome, 230 mucopolysaccharidosis, 225
Rhythmic movement disorder, 384, 385 myotonic muscular dystrophy, 225
Rivastigmine, 386 neuromuscular disease (NMD), 224
overview, 216
pediatric and adult presentation, 216
S Pierre Robin sequence, 221
Salivary dim light melatonin onset polysomnography and diagnostic
(DLMO), 301–302 testing, 238–240
Secondary narcolepsy, 336 Prader-Willi syndrome, 220, 221
Seep related eating, 349 respiratory-related hypoventilation, 216
Serotonin reuptake inhibitors, 342 Rett syndrome, 230
Shift work disorder (SWD), 311 ROHHAD, 229
clinical features, 312–313 sickle cell disease (SCD), 223
diagnosis, 313 skeletal dysplasias, 223
pathophysiology, 312 spinal muscular atrophy (SMA), 224
prevalence, 311–312 Treacher Collins syndrome, 222
treatment, 313–314 in infants
Short–term potentiation (STP), 146 apparent life-threatening event
Sickle cell disease (SCD), 223 (ALTE), 234
Single-photon emission computed tomography apnea of infancy, 234
(SPECT), 354 apnea of prematurity, 232, 233
Skeletal dysplasias, 223 BRUE, 235
Sleep aids, 458 clinical history and physical
Sleep apnea clinical score (SACS), 192 examination, 238
Sleep architecture, 55, 56 direct endoscopic visualization, 238
Sleep-disordered breathing (SDB), 104, 472, multiple factors, 232, 233
477–480, 497–500 non-surgical treatment options, 238
in children periodic breathing, 233, 234
accommodating in sleep laboratory, predisposing factors and medical
241, 242 conditions, 237
and acquisition, scoring, and reporting safe infant sleep, 236
respiratory parameters in sudden infant death syndrome
adults, 239 (SIDS), 236
Index 523
sudden unexpected infant death Social jetlag, 55

(SUID), 236 Society of Anesthesia and Sleep Medicine
Sleep efficiency, 56 (SASM), 190
Sleep enuresis, 374 Sodium oxybate (Xyrem®) (SXB), 37, 38,
Sleep health disparity, 50 341, 386
Sleep hypoventilation Solriamfetol, 38–40, 341
compensatory mechanisms, 164, 166 “Somerville” multifaceted protocol, 461
chronic obstructive pulmonary disease Spinal muscular atrophy (SMA), 224
(COPD), 176 Starling resistor model, 10, 11
daytime measures, 167–169 Status dissociatus, 386
neuromuscular disorders Sudden infant death syndrome (SIDS), 236
(NMDs), 174–176 Sudden unexpected infant death (SUID), 236
nocturnal monitoring, 169–171 Suprachiasmatic nucleus (SCN), 298
obesity hypoventilation syndrome Suvorexant, 28–31
(OHS), 171–174 Symptomless multi-variable apnea prediction
physiological changes, 163 index (sMVAP), 106
signs and symptoms, 163
symptoms, 168
Sleep paralysis, 329, 369 T
Sleep position treatment device (SPT), 138 Telehealth modalities, 280
Sleep quality and sleepiness, 56, 57 Temazepam, 503
Sleep related bruxism, 399, 411–413 Tennis ball technique (TBT), 137
Sleep related eating disorder (SRED), 363 Thoracoabdominal asynchrony, 232
Sleep related hallucinations, 329, 352, 374 Thyroid-stimulating hormone (TSH), 13
Sleep-related hypermotor epilepsy (SHE), Transcranial magnetic stimulation (TMS), 354
384, 385 Transient ischemic attacks (TIAs), 339
Sleep related leg cramps, 399, 408–410 Transvenous phrenic nerve stimulation
Sleep-related movement disorders (TPNS), 156
due to medical disorder, 418–419 Trazodone, 32
due to medication or substance, 419–420 Treacher Collins syndrome, 222
periodic limb movement disorder, 406–408 Treatment-emergent central sleep apnea
propriospinal myoclonus at sleep (TECSA), 152
onset, 416–418 Tricyclic antidepressants (TCAs), 342
restless legs syndrome
clinical features, 401, 402
demographics, 400–401 U
diagnosis, 401 Untreated obstructive sleep apnea (OSA), 385
differential diagnosis, 402 Uvulopalatopharyngoplasty (UPPP), 139
management, 404–406
primary vs. secondary factors, 403–404
treatment for, 405 V
rhythmic movement disorder, 413–416 VA-based program (VA-ECHO), 73
sleep related bruxism, 411–413 VA Puget sound health care system
sleep related leg cramps, 408–410 (VAPSHCS), 73
Sleep related rhythmic movement disorder Veteran Health Administration’s (VHA), 281
(RMD), 399, 413–416 Video polysomnography (VPSG), 358
Sleep terrors, 361
Sleep-wake schedule, 262
Sleep walking, 349 Z
Slow-wave sleep (SWS), 471 Zolipdem/sodium oxybate, 354
Smith-Magenis syndrome, 309 Zopiclone, 386

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Respiratory Medicine

Series Editors: Sharon I.S. Rounds · Anne Dixon · Lynn M. Schnapp

More information about this series at https://link.springer.com/bookseries/7665

Essentials of Sleep Medicine

ISSN 2197-7372 ISSN 2197-7380 (electronic)

© Springer Nature Switzerland AG 2022

Introduction to Sleep Medicine, in summary, is an extremely masterful and

November 8, 2021 Sonia Ancoli-Israel

Detroit, MI, USA M. Safwan Badr

Part I Introduction to Sleep Medicine

Part II Sleep Disordered Breathing

9 Sleep and Hypoventilation���������������������������������������������������������������������� 163

Part III Non-respiratory Sleep Disorders

Part IV Sleep in Special Conditions

Sabra M. Abbott Northwestern University Feinberg School of Medicine,

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of

Michael T. Y. Lam Department of Medicine, Division of Pulmonary, Critical

Nancy H. Stewart Department of Medicine, University of Kansas Medical Center,

James A. Rowley and M. Safwan Badr

Keywords NREM sleep · REM sleep · EEG · Upper airway resistance ·

Normal Sleep Stages and Architecture

J. A. Rowley (*) · M. S. Badr

© Springer Nature Switzerland AG 2022 3

a predominance of low amplitude activity in 4–7 Hz (often referred to as theta

Fig. 1.2 Representative hypnogram showing normal sleep architecture

Overall sleep architecture is dependent upon stage of development and aging

Breathing During Sleep: Ventilation and the Upper Airway

Summary of Normal Breathing and Ventilation During Sleep

Effect of Sleep on Control of Breathing

Chemoresponsiveness refers to changing ventilation in response to changes in

Before mechanical During mechanical After mechanical

Effect of Sleep on Upper-Airway Structure and Function

The evidence for increased upper-airway resistance during sleep is compelling,

PUS PDS PUS PDS

PUS>PDS > Pcrit c Flow-Limited Pcrit > PUS,PDS

PUS > Pcrit > PDS

Cardiovascular Function During Sleep

NREM sleep is characterized by autonomic stability, driven by increased vagal

Endocrine Function During Sleep

The levels of circulating endocrine hormones are generally influenced either by

Gastrointestinal Function During Sleep

Renal Function During Sleep

Urine formation decreases during sleep compared to wakefulness. Both glomerular

1. Silber MH, Ancoli-Israel S, Bonnet MH, Chokroverty S, Grigg-Damberger MM, Hirshkowitz

87. Brandenberger G, Charifi C, Muzet A, Saini J, Simon C, Follenius M. Renin as a biologi-

Janet H. Dailey and Susmita Chowdhuri

Keywords GABA γ(gamma)-aminobutyric acid · Histamine-3 inverse agonist ·

© Springer Nature Switzerland AG 2022 21

Overall, drugs that are agonistic to the sleep-promoting GABA (γ(gamma)-

Safety The pharmacokinetics and pharmacodynamics differences of BDZs can

Nonbenzodiazepine Receptor Agonists (Non-BzRAs)

The non-BzRAs have no anxiolytic, myorelaxant, and anticonvulsant properties but

Table 2.3 Characteristics of non-BzRAs [10, 76, 77]

Melatonin is a neurohormone of the pineal gland that is modulated by the suprachi-

Melatonin Receptor Agonist: Ramelteon

Ramelteon is a synthetic analog of melatonin. It is a melatonin receptor agonist and

Orexin Antagonists: Suvorexant and Lemborexant

Table 2.4 Characteristics of orexin antagonists in adultsa [19, 20]

Antidepressants Used Off-Label

Detroit, MI, USA M. Safwan Badr

Part I Introduction to Sleep Medicine

Part II Sleep Disordered Breathing

9 Sleep and Hypoventilation�� 163

Part III Non-respiratory Sleep Disorders

Part IV Sleep in Special Conditions

Normal Sleep Stages and Architecture

Breathing During Sleep: Ventilation and the Upper Airway

Summary of Normal Breathing and Ventilation During Sleep

Effect of Sleep on Control of Breathing

Effect of Sleep on Upper-Airway Structure and Function

Cardiovascular Function During Sleep

Endocrine Function During Sleep

Gastrointestinal Function During Sleep

Renal Function During Sleep

Nonbenzodiazepine Receptor Agonists (Non-BzRAs)

Melatonin Receptor Agonist: Ramelteon

Orexin Antagonists: Suvorexant and Lemborexant

Antidepressants Used Off-Label

Amphetamines and Methylphenidate

Modafinil and Armodafinil

Novel Drugs in Pipeline

Prevalence and Burden of Poor Sleep Health

Chronotype and Circadian Rhythms

Sleep Quality and Sleepiness

Causes of Poor Sleep Health

Physical and Built Environment Causes

Health Consequences of Poor Sleep Health

A Patient-Centered Model of Sleep Care

rimary Care and Broader Medical Community Collaboration

Non-Sleep Specialty Care Collaboration (Point B)

Development of Sound Screening Protocols (Point C)

Leverage Telemedicine (Point D)

Putting It All Together