Essential Sleep Medicine and Surgery 9781685072209, 9781685073893, 2021056216, 1685072208

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KJ LEE ESSENTIAL MEDICINE SERIES

ESSENTIAL SLEEP MEDICINE AND SURGERY

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KJ LEE ESSENTIAL MEDICINE SERIES K. J. LEE, MD, FACS - SERIES EDITOR-IN-CHIEF YALE UNIVERSITY SCHOOL OF MEDICINE QUINNIPIAC UNIVERSITY NETTER SCHOOL OF MEDICINE NEW HAVEN, CONNECTICUT, USA HOFSTRA UNIVERSITY ZUCKER SCHOOL OF MEDICINE HEMPSTEAD, NEW YORK, USA

Essential Sleep Medicine and Surgery Maria V. Suurna, Stacey L. Ishman (Editors) and Josephine H. Nguyen (Assistant Editor) 2022. ISBN: 978-1-68507-220-9 (Hardcover) 2022. ISBN: 978-1-68507-389-3 (e-book)

KJ LEE ESSENTIAL MEDICINE SERIES

ESSENTIAL SLEEP MEDICINE AND SURGERY

MARIA V. SUURNA STACEY L. ISHMAN EDITORS

JOSEPHINE H. NGUYEN ASSISTANT EDITOR

Copyright © 2022 by Nova Science Publishers, Inc. DOI: https://doi.org/10.52305/YFBM3093 All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470

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NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the Publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data Names: Suurna, Maria V., editor. | Ishman, Stacey L., editor. | Nguyen, Josephine H., assistant editor. | Lee, K. J. (Keat Jin), 1940- chief editor. Title: Essential sleep medicine and surgery / Maria V. Suurna, Department of Otolaryngology--Head and Neck Surgery, Weill Cornell Medicine, New York, New York, USA, editor, Stacey L. Ishman, Healthvine Health Network, Tristate Child Health Services, Department of Otolaryngolog--Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA, editor, Josephine H. Nguyen, Sacramento Ear, Nose, and Throat Surgical and Medical Group, Inc., Stockton, California, USA, assistant editor, K.J. Lee, Yale University School of Medicine, Quinnipiac University Netter School of Medicine, New Haven, Connecticut, USA; Hofstra University Zucker School of Medicine, Hempstead, New York, USA, chief editor. Description: New York : Nova Science Publishers, [2022] | Series: KJ Lee essential medicine series | Includes bibliographical references and index. | Identifiers: LCCN 2021056216 (print) | LCCN 2021056217 (ebook) | ISBN 9781685072209 (hardcover) | ISBN 9781685073893 (adobe pdf) Subjects: LCSH: Sleep disorders. | Surgery. Classification: LCC RC547 .E875 2022 (print) | LCC RC547 (ebook) | DDC 616.8/498--dc23/eng/20211129 LC record available at https://lccn.loc.gov/2021056216 LC ebook record available at https://lccn.loc.gov/2021056217

Published by Nova Science Publishers, Inc. † New York

Contents Foreword and Acknowledgment ........................................................................................... ix K. J. Lee Preface

...................................................................................................................... xi

Part I: Basics of Sleep Medicine............................................................................................. 1 Chapter 1

Normal Sleep and Its Variants.................................................................... 3 Swapan Dholakia and Nancy Collop

Chapter 2

Sleep Physiology ......................................................................................... 15 Meena Khan and Madelyn Rosenthal

Chapter 3

Classification of Sleep Disorders .............................................................. 27 Ofer Jacobowitz and Lee Shangold

Chapter 4

Sleep Evaluation ......................................................................................... 57 Tracey L. Stierer

Chapter 5

Sleep Deprivation and Sleep Hygiene....................................................... 67 Jennifer Rose V. Molano

Chapter 6

Sleep Pharmacology ................................................................................... 85 Kimberly Y. Kreitinger and Atul Malhotra

Chapter 7

Sleep in Women ........................................................................................ 107 Jessica A. Mong and Katie Kruk

Chapter 8

Sleep and Aging ........................................................................................ 127 Kathleen L. Yaremchuk and Andrea M. Plawecki

Chapter 9

Sleep and Medical Conditions................................................................. 145 Gerald D. Suh

Part II: Adult Sleep-Related Breathing Disorders ........................................................... 165 Chapter 10

Adult OSA Overview ............................................................................... 167 Yi Cai, Andrew N. Goldberg and Jolie L. Chang

Chapter 11

Pathogenesis and Endotypes of OSA ...................................................... 175 Luke D. J. Thomson, Caroline J. Beatty, Shane A. Landry and Bradley A. Edwards

vi

Contents

Chapter 12

Diagnosis and Assessment of Adult OSA ............................................... 193 Jason L. Yu, Erica R. Thaler and Richard J. Schwab

Chapter 13

Associated Health Risks of OSA ............................................................. 211 Josephine H. Nguyen

Chapter 14

Snoring ...................................................................................................... 219 Anders Sideris and Stuart Mackay

Chapter 15

Adult OSA Medical Management .......................................................... 239 Madeline Ravesloot and Julia Crawford

Chapter 16

PAP Treatment for OSA ......................................................................... 245 Jay T. Guevarra, Robert Hiensch and David M. Rapoport

Chapter 17

Oral Appliance Therapy for OSA .......................................................... 263 Ryan J. Soose and Nicole D. Chenet

Chapter 18

Surgery for OSA ...................................................................................... 283 Robert M. Frederick and M. Boyd Gillespie

Chapter 19

Peri-Operative Considerations in Sleep Surgery .................................. 299 Brian W. Rotenberg and Sarah Zahabi

Chapter 20

The Nose and Sleep Apnea ...................................................................... 313 Amrita Ray and Ashutosh Kacker

Chapter 21

Tonsillectomy and Palatal Surgery for OSA ......................................... 337 B. Tucker Woodson and Erin Harvey

Chapter 22

Surgery to Address the Tongue Base and Hypopharynx ..................... 349 Mark A. D’Agostino and Michael Hajek

Chapter 23

Skeletal Surgery for OSA ........................................................................ 373 Robson Capasso, Tahir Mirza and Badr Ibrahim

Chapter 24

Hypoglossal Nerve Stimulation for Treatment of OSA ........................ 395 Maurits Boon and Maria V. Suurna

Chapter 25

Bariatric Surgery for OSA ...................................................................... 411 Roberta Leu, Nikhila Raol and Kelli-Lee Harford

Chapter 26

Combination Therapy for OSA .............................................................. 423 Nithin S. Peddireddy, Jeffrey J. Stanley and Paul T. Hoff

Chapter 27

Central Sleep Apnea ................................................................................ 437 Shahrokh Javaheri and Robin Germany

Part III: Other Sleep Disorders ......................................................................................... 455 Chapter 28

Insomnia ................................................................................................... 457 Ashwin Anath, Karl Doghramji and Colin Huntley

Chapter 29

Central Disorders of Hypersomnolence ................................................. 465 Anne Marie Morse, Michael Strunc and Asim Roy

Contents

vii

Chapter 30

Circadian Rhythm Sleep-Wake Disorders............................................. 479 Bala S. C. Koritala, Marc D. Ruben and David F. Smith

Chapter 31

Parasomnias ............................................................................................. 499 Joshua Roland and Alon Y. Avidan

Chapter 32

Sleep-Related Movement Disorders ....................................................... 527 Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas

Part IV: Pediatric Sleep and Sleep Disorders ................................................................... 549 Chapter 33

Sleep in Children ...................................................................................... 551 Sally Ibrahim and Carol Rosen

Chapter 34

Sleep Related Breathing Disorders and Other Conditions in Children ................................................................................................ 567 Megan L. Durr, Christopher C. Xiao, Umakanth A. Katwa and Judith A. Owens

Chapter 35

Treatment of Pediatric OSA ................................................................... 587 Cristina Baldassari, Erin Kirkham and Derek Lam

Chapter 36

Pediatric OSA Treatment Beyond Tonsillectomy ................................. 601 Carol Li, Yann-Fuu Kou and Stacey L. Ishman

Part V

................................................................................................................... 621

Chapter 37

How to Set Up a Sleep Laboratory ......................................................... 623 Hannah N. Kuhar, Siobhan Kuhar and Gavin Setzen

Chapter 38

The Future of Sleep Medicine and Surgery and a Glossary of Acronyms.............................................................................. 635 Shi Nee Tan and K. J. Lee

Answers to Multiple Choice Questions.............................................................................. 659 About the Editors and Contributors ................................................................................. 665 Index

................................................................................................................... 679

FOREWORD AND ACKNOWLEDGMENT As the field of medicine has grown, more subspecialties have evolved and some subspecialties, like Sleep Medicine and Surgery, bring together different disciplines. I had the vision of creating a book for each subspecialty building from the formula and on the success of Essential Otolaryngology-Head and Neck Surgery, the inceptive book, which is in its 12th Edition, 48th year, and has been translated into several languages. It was cited as one of the most read texts in the field worldwide. Working with President Nadya S. Gotsiridze-Columbus, CEO of Nova Science Publishers, Inc., we developed K. J. Lee Essential Medicine Series, and Essential Sleep Medicine and Surgery is the first book in this series. After a national search, we were fortunate to have Dr. Maria Suurna and Dr. Stacey Ishman to be Editors of this book and Dr. Josephine Nguyen as Assistant Editor who worked with me diligently to articulate cogently and to present in an understandable, simple manner the ever-important Practice Guidelines. We commend the scholarly contents of the chapters’ contributing authors. We also appreciate the meticulous editorial assistance of Ms. Rachel Oaks-Leaf. It is with great pleasure and honor for me to say they all worked very hard and have done a superb job. I thank them all and kudos to them. Like the inceptive book, I have no doubt this book will find its way to libraries, to the reference sections of emergency rooms, urgent care centers, as well as the dorm rooms, apartments, and homes of medical students, residents, fellows, young attendings, physician assistants, nurse practitioners and others. In the near future, insurance companies and Medicare and Medicaid executives may also find it a must-read, especially the Practice Guidelines. This book is not only a great text and reference for medical professionals, but it can also be of value for people outside the medical field to understand key concepts in order to better communicate with providers.

K. J. Lee, MD, FACS, Editor-in-Chief KJ Lee Essential Medicine Series

PREFACE Awareness of the importance of sleep and sleep disorders has been increasing over the past several decades, and sleep medicine is constantly evolving as new treatments are pioneered. Poor sleep can have devastating effects on daily living and is associated with numerous health problems affecting a variety of systems. Because of this, sleep medicine is relevant across disciplines and an understanding of sleep disorders and their treatment is a critical aspect of medical training. Our aim with this textbook is to provide a broad overview and multidisciplinary perspective on sleep physiology and disorders from experts in Otolaryngology, Internal Medicine, Pediatrics, Anesthesia, Neurology, Family Medicine, Dentistry, Surgery and Psychiatry. The content of the book is intended to allow for trainees and experts alike to access the essential topics in sleep so as to enhance our understanding of sleep medicine in the above-mentioned fields as well as key partner specialties. We have presented comprehensive information in an easily digestible outline format to facilitate quick reference of key facts as well as to optimize the time it takes learn these varied topics. To this effect, each group of authors has graciously provided us with review questions that consolidate learned information from each chapter. Crucial information from the chapters has also been summarized as a group of practice guidelines to promote a clear understanding of the current evidence in sleep medicine. We would like to thank the authors for their exceptional work and perspectives. Their insight has informed, and continues to inform, our knowledge of sleep medicine and is an invaluable contribution to wellness and quality of life. We would like to acknowledge Rachel Oaks-Leaf who was instrumental in consolidating the authors’ work. It is our pleasure to serve as Editors for this Essential Sleep Medicine and Surgery textbook. It has been an incredible experience working with Dr. K.J. Lee. We are both immensely grateful to be a part of this project and hope that you appreciate it as much as we do.

Maria V. Suurna, MD Stacey L. Ishman, MD, MPH Editors

PART I: BASICS OF SLEEP MEDICINE

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 1

NORMAL SLEEP AND ITS VARIANTS Swapan Dholakia1,2,, MD and Nancy Collop3, MD 1

2

Atlanta VA Medical Center, Decatur, GA, USA Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA 3 Emory Sleep Center, Emory University, Atlanta, GA, USA

SLEEP DEFINITION 1. Sleep is a reversible state of behavioral quiescence and diminished responsiveness to external stimuli. It is usually accompanied by recumbent posture, eye closure and reduced or absent movements.

STATES OF EXISTENCE 1. Humans (and mammals in general) exist in 3 different states based on responsiveness to external stimuli, brain waves, eye movements and muscle tone: a. Wakefulness b. Rapid eye movement (REM) sleep c. Non-rapid eye movement (NREM) sleep. 2. Normally, features of one state of existence do not overlap with the other states. If this boundary between the states is lost, sleep disorders can arise.

SLEEP REQUIREMENTS 1. Based on recommendations from the American Academy of Sleep Medicine and Sleep Research Society, healthy adults need 7 or more hours of sleep on a consistent basis for optimal health.

4

Swapan Dholakia and Nancy Collop 2. Less than 7 hours of sleep is associated with diabetes, hypertension, heart disease, stroke, pain, impaired immune response, and motor vehicle accidents a. Unfortunately, about a third of the population in the United States does not consistently get the required amount of sleep. 3. Short sleepers: Adults who need less than 6 hours of sleep and have no sleep related symptoms a. Considered a normal variant. 4. Long sleepers: Adults who need more than 10 hours of sleep in 24 hours and develop excessive daytime sleepiness if unable to obtain the required amount of sleep. a. Considered a normal variant.

SLEEP ARCHITECTURE 1. Sleep is divided into different stages based on electroencephalography (EEG), electro-oculography (EOG) and electromyography (EMG) findings a. NREM sleep i. Divided into N1, N2 and N3 based on the depth of sleep and types of brain waves noted. b. REM sleep. i. Characterized by the presence of rapid eye movements and low or absent muscle tone recorded by EMG. 2. During polysomnography, the quantification of sleep stages occurs by scoring each 30 second period known as an epoch.

WAKEFULNESS (STAGE W) 1. Stage W. a. EEG i. Alpha rhythm, also known as the posterior dominant rhythm, seen best in the occipital leads. These waves are 8-13 Hz in frequency and are seen when the individual is awake but with eyes closed (Figure 1). Some individuals do not generate this posterior dominant rhythm. b. EOG i. May show reading eye movements, eye blinks or rapid eye movements. c. EMG. i. Shows normal or high chin muscle tone.

Normal Sleep and Its Variants

5

Figure 1. A 30 second epoch of polysomnography showing Stage W. Note the posterior dominant rhythm (alpha frequencies) for >50% of the epoch.

NREM SLEEP 1. In adults, sleep is entered through NREM sleep, usually beginning with N1 and then progressing to N2 and then deeper N3 sleep. This accounts for 75-80% of the total sleep time. 2. Stage N1: (Figure 2) a. EEG i. Replacement of the alpha rhythm by low-amplitude mixed frequency EEG ii. EEG shows theta frequencies of 4-7 Hz iii. Vertex sharp waves: These are sharp waves seen over the central head region, 500 msec. c. EMG i. Muscle tone is less than or equal to Stage W ii. Individual can be aroused easily. d. Comprises 2-5% of the total sleep time. i. Increased percentage of stage N1 is seen with disrupted sleep such as might be observed in obstructive sleep apnea.

6

Swapan Dholakia and Nancy Collop

Figure 2. A 30 second epoch of polysomnography showing Stage N1. Note the replacement of the posterior dominant rhythm with low-amplitude mixed frequency EEG for >50% of the epoch.

Figure 3. A 30 second epoch of polysomnography showing Stage N2. Note the K complex (arrow) and sleep spindles (circle).

3. Stage N2: (Figure 3) a. EEG i. Low-amplitude, mixed frequency brain waves ii. K complexes: Sharp waves with an initial upward deflection, ≥0.5 seconds in duration, seen over the frontal head regions and standing out from the background iii. Sleep Spindles: A train of sinusoidal waves with a frequency of 11-16 Hz (most commonly 12-14 Hz), seen over the central regions and ≥0.5 seconds in duration. These are generated from the reticular nucleus of the thalamus. b. EOG i. Infrequent eye movements. c. EMG i. Low muscle tone. d. Comprises 45-55% of the total sleep time.

Normal Sleep and Its Variants 4. Stage N3: (Figure 4). a. EEG i. Slow wave activity: Slow, high amplitude ≥ 75 microvolts delta waves with frequency of 0.5-2 Hz, seen in ≥ 20% of each 30 second epoch. b. EOG i. Infrequent eye movements. c. EMG ii. Low muscle tone. d. This stage is considered to be “deep sleep” and has the highest arousal threshold e. Comprises 10-20% of the total sleep time f. Also known as slow wave sleep g. Parasomnias such as sleepwalking and sleep terrors most commonly occur during this stage.

Figure 4. A 30 second epoch of polysomnography showing Stage N3. Note the high amplitude slow waves for ≥20% of the epoch.

REM SLEEP (STAGE R) 1. Stage R: (Figure 5) a. EEG i. Low-amplitude, mixed frequency brain waves ii. Sawtooth waves: A train of triangular, serrated waves, 2-6 Hz in frequency, seen over the central head area. b. EOG i. Rapid eye movements: Bursts of conjugate, sharply contoured eye movements seen in clusters or phases. The initial deflection is non-REM (NREM) > REM d. Alterations in upper airway function i. Decreased upper airway (UA) dilator muscle tone during NREM sleep compared to wake and further decreased in REM sleep ii. Decreased UA muscle tone leads to increased upper airway resistance

PHYSIOLOGICAL CHANGES DURING SLEEP 1. Cardiovascular physiology a. NREM sleep i. Increased parasympathetic activity ii. Decreased sympathetic activity b. REM sleep i. Marked increase in parasympathetic activity and decrease in sympathetic activity compared to NREM sleep ii. During phasic REM there are bursts of sympathetic activity  This can lead to fluctuation in blood pressure and heart rate leading to bradytachyarrhythmias c. Heart rate i. Heart rate slows down by 5-8% in NREM sleep. The heart rate slows down even more in REM sleep but becomes variable during phasic REM. d. Cardiac output i. Decreased during sleep e. Blood pressure (BP) i. Systolic blood pressure (SBP) decreases by 10-20% during NREM sleep ii. During REM sleep, blood pressure (BP) is variable but is about 5% higher compared to NREM sleep. BP rises around awakening. f. Peripheral vascular resistance i. Does not change much between wake and NREM sleep but does decrease during REM sleep due to vasodilation of the vasculature in the cutaneous, muscular and mesenteric vascular beds.

24

Meena Khan and Madelyn Rosenthal g. Cerebral blood flow (CBF) i. CBF and metabolism of glucose and oxygen decrease in NREM sleep but increase in REM sleep mainly in the hypothalamus and brainstem areas ii. The cerebral vasculature is autoregulated such that if SBP drops, cerebral blood vessels dilate to increase CBF. If SBP increases, cerebral vessels constrict. 2. Endocrine physiology a. The secretion of neuroendocrine hormones is mainly circadian or sleep related i. Circadian related secretion  Adrenocorticotrophic (ACTH)  Cortisol  Decreases at sleep onset, rises last part of sleep at night and then declines during the day  Melatonin  Secretion rises in the evening, with maximum values at 3-5 o’clock in the morning. Levels then decrease during the day.  The secretion of melatonin is inhibited by light ii. Sleep related secretion  Growth hormone (GH)  Largest amount of secretion is during slow wave sleep o This makes slow wave sleep particularly important for children’s growth  GH release declines with age  Thyroid stimulating hormone (TSH)  Peaks in the early evening, peaks right before sleep onset and declines during sleep  Prolactin  Increases during sleep and peaks in the early morning  Renin  Secretion level is high during NREM sleep and falls during REM sleep 3. Gastrointestinal physiology a. During sleep, swallowing is suppressed, esophageal motility is decreased, and the upper and lower esophageal sphincter pressure is decreased. These changes can lead to increased gastroesophageal reflux. b. Gastric acid secretion peaks at 10 pm-2 am c. There is decreased colonic motility during sleep as well as increased retrograde rectal motor activity. Anal canal pressure is high during sleep which prevents rectal contents from being released during sleep. 4. Immune function a. Sleep is important for immune function. Lack of sleep has been linked to decreased immune response. b. Cytokines interleukin (IL) IL- 1, IL-6 and tumor necrosis factor promote sleep

Sleep Physiology

25

c. Cytokines IL-4 and IL-10 decrease sleep 5. Thermoregulation a. Body temperature decreases during sleep. Lower body temperatures also promote sleep, in particular slow wave sleep. b. Thermoregulation does not occur during REM sleep, therefore one does not sweat during REM sleep c. The nadir of the body temperature occurs 2 hours one’s habitual wake time 6. Metabolic function a. Glucose metabolism i. Oral glucose is impaired in the evening and during the night. It then peaks in the morning. ii. Insulin sensitivity is impaired in the evening and insulin clearance is higher at night b. Lipid metabolism i. Mainly mediated by circadian rhythm ii. Peak lipid metabolite levels are reached by mid-morning to noon c. Energy expenditure i. Peaks morning to noon time

KEY CLINICAL POINTS 1. High-altitude travelers with underlying medical problems should undergo altitude simulation studies prior to traveling to evaluate the safety of current plans. Possible prophylactic medications and appropriate dose adjustments may be required. 2. Bright light exposure during the desired wake time and darkness during the desired sleep time will help set one’s circadian rhythm to the desired sleep-wake cycle. 3. Medications that enhance serotonin such as serotonin reuptake inhibitors (SSRIs) suppress REM sleep. 4. Slow wave sleep is important for children’s growth as this is when growth hormone is secreted. 5. Thermoregulation does not occur during REM sleep.

QUESTIONS 1. Which neurotransmitter acts to promote sleep? a. Galanin b. Histamine c. Acetylcholine d. Norepinephrine

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Meena Khan and Madelyn Rosenthal 2. Which is a REM on cell? a. Dorsal raphe nucleus b. Tuberomammillary nucleus c. Sublaterodorsal nucleus d. Lateral hypothalamus 3. What is the area of the brain that if affected will result in ataxic breathing? a. Dorsal respiratory group b. Pre-Botzinger Complex c. Dorsal raphe nucleus d. Pontine respiratory group 4. What are the correct changes to breathing during sleep? a. Set point for O2 decreases during sleep b. Response to increased PaCO2 increased in REM sleep compared to wake c. Minute ventilation increases compared to wake d. Set point for PaCO2 increases compared to wake 5. Which is the strongest zeitgeber for the circadian rhythm system? a. Meals b. Activity c. Light d. Sleep –wake timing

REFERENCES Avidan A Y. Review of Sleep Medicine. 4th ed. Elsevier; 2018. Broaddus, V C, et al. Textbook of Respiratory Medicine. 6th Ed. Elsevier; 2016. Douglas N J. Control of ventilation during sleep. Clin. Chest Med. 1985 Dec;6(4):563-75. Kryger, M, Roth, T, Dement W C. Principles and Practice of Sleep Medicine. Elsevier; 2017. Peever J, Fuller P M. The Biology of REM Sleep. Curr. Biol. 2017 Nov 20;27(22):R1237R1248. doi: 10.1016/j.cub.2017.10.026. Poggiogalle E, Jamshed H, Peterson C M. Circadian regulation of glucose, lipid, and energy metabolism in humans. Metabolism. 2018 Jul;84:11-27. doi: 10.1016/j.metabol.2017.11. 017. Rosenwasser A M, Turek F W. Neurobiology of Circadian Rhythm Regulation. Sleep Med. Clin. 2015 Dec;10(4):403-12. doi: 10.1016/j.jsmc.2015.08.003. Epub 2015 Sep 11. Saper, C B. The Neurobiology of Sleep. Continuum. 2013 Feb;19(1):19-31. doi: 10.1212/01. CON.0000427215.07715.73. Schwartz W, Klerman E. Circadian Neurobiology and the Physiologic Regulation of Sleep and Wakefulness. Neurol. Clin. 2019 Aug;(37): 475-486. doi: 10.1016/j.ncl.2019.03.001. West, J B. Respiratory physiology. William and Wilkins; 1990.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 3

CLASSIFICATION OF SLEEP DISORDERS Ofer Jacobowitz1,2, MD, PhD and Lee Shangold1, MD 1

Sleep, ENT, and Allergy Associates, Tarrytown, NY, USA Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

2

INTRODUCTION The average person spends approximately 1/3 of their life sleeping. Even though there is no clear-cut, simple answer to the question “why do we sleep?,” sleep is essential for many vital functions including development, memory, cardiovascular health, metabolism, brain homeostasis, modulation of immune responses, cognition, performance, and vigilance. This chapter will classify disorders of sleep. It is important to have a familiarity with sleep disorders to have the most positive impact on our “sleep” patients. There are 3 major classification systems for sleep disorders: 1. International Classification of Sleep Disorders (ICSD) a. Published by American Academy of Sleep Medicine b. 3rd edition, 2014 2. Diagnostic and Statistical Management of Mental Disorders (DSM) a. Published by American Psychiatric Association b. 5th edition, 2013 3. International Statistical Classification of Disease and Related Health Problems (ICD) a. Published by World Health Organization b. 10th edition is currently being used; its start date varied around the world. It will be replaced by ICD-11 in 2022 For this chapter, the ICSD-3 will be used as the main source of reference. It is dedicated to the classification of sleep disorders, the focus of this chapter. Of note, the diagnostic criteria listed for all of the sleep disorders also includes that the particular disturbance in question is not better explained by another sleep disorder, insufficient sleep, mental disorder, medical condition, medication, or substance use.

28

Ofer Jacobowitz and Lee Shangold

INSOMNIA 1. Diagnostic Criteria a. Difficulty falling asleep, difficulty maintaining sleep or waking up earlier than desired i. Alternatively, in pediatric patients, or older patients with a caregiver, resistance to going to bed or difficulty sleeping without parent or caregiver intervention b. Adequate opportunity for sleep in a comfortable environment c. A daytime consequence such as excessive daytime sleepiness, impaired functioning, mood disturbance, error/accident prone, concerns or dissatisfaction with sleep i. In pediatric patients, include behavioral issues, such as hyperactivity 2. Subtypes: a. Chronic insomnia disorder i. Sleep disturbance and associated daytime consequences occur at least three times per week for at least 3 months b. Short-term insomnia disorder i. Sleep disturbance and symptoms are present for < 3 months 3. Prevalence a. Insomnia is the most common sleep disorder. 10% of the population has chronic insomnia. Transient insomnia symptoms occur in ~30 to 35% of the population. b. Insomnia is more common in: i. Women ii. Older adults iii. Lower socioeconomic strata 4. Risk factors for developing insomnia a. Hyperarousal – increased level of alertness and anxiety and elevated heart rate and respiratory rate b. Certain personality traits, such as neuroticism, internalization and perfectionist traits c. Depression d. Posttraumatic-stress disorder e. Substance use and abuse f. Stressful life events, including work stress g. Chronic pain h. Cancer i. Coronary artery disease (CAD) j. Diabetes 5. Insomnia is a risk factor for a. Depression b. Anxiety c. Substance use and abuse d. Cardiovascular disease

Classification of Sleep Disorders e. f.

29

Suicide Diabetes

SLEEP RELATED BREATHING DISORDERS Obstructive Sleep Apnea Disorders 1. Obstructive Sleep Apnea, Adult a. Diagnostic Criteria i. Polysomnography (PSG) or home sleep apnea test (HSAT) has 15 respiratory events/hour (obstructive or mixed apneas, hypopneas, respiratory effort related arousals (RERAs)) ii. Or PSG or HSAT has 5 or more respiratory events /hour AND any of the below:  Sleepiness, fatigue, non-restorative sleep or insomnia  Patient reports awakening with breath holding, gasping, or choking  Observed habitual snoring or breathing interruption  Diagnosis of hypertension (HTN), mood disorder, coronary artery disease (CAD), non-insulin dependent diabetes mellitus (NIDDM), stroke, atrial fibrillation (Afib), congestive heart failure (CHF), cognitive dysfunction b. Prevalence (depends on hypopnea scoring criteria*) i. 3-7% in men, 2-5% in women have AHI > 5 with sleepiness ii. 24% in men and 9% in women have AHI > 5 iii. More common in  African Americans  Males (2:1) and post-menopausal women  Older adults c. Hypopneas can be defined by a 30 or 50% pressure signal drop minimum accompanied by a 3 or 4% oxygen desaturation minimum, or arousal. Center for Medicare and Medicaid Services (CMS) requires at least a 4% oxygen desaturation for hypopneas. d. Risk factors i. Obesity ii. Maxillary or mandibular hypoplasia iii. Adenotonsillar hypetrophy iv. Low neuromuscular tone (e.g., myotonic dystrophy) v. Alcohol or sedative intake, smoking vi. Nasal obstruction, rhinitis vii. Endocrine- menopause, hypothyroidism, acromegaly viii. Family history – first degree relative 2x risk ix. Post head and neck radiation therapy

30

Ofer Jacobowitz and Lee Shangold e.

Complications i. Cardiovascular disease (HTN, cerebrovascular accident (CVA), Afib, CHF, CAD) ii. Premature death iii. NIDDM iv. Depression v. Dementia vi. Cancer vii. Motor vehicle accidents 2. Obstructive Sleep Apnea, Pediatric (< 18 yo or < 13 yo as clinically applicable) a. Diagnostic Criteria (one or more) i. Snoring ii. Obstructed, labored or paradoxical breathing iii. Sleepiness, hyperactivity, behavioral or learning problems iv. Polysomnogram has 1 or more respiratory events /hour (obstructive or mixed apneas, hypopneas) or obstructive hypoventilation (≥ 25% with PaCO2 > 50 mmHg with snoring, flattening of the inspiratory nasal pressure, paradoxical thoracoabdominal motion) b. Prevalence i. 1-4% ii. M:F equal prevalence iii. More common in  Syndromic, craniofacial anomalies  Down’s  Cerebral Palsy (CP)  Gastroesophageal reflux disease (GERD)  Post pharyngeal flap for cleft  Mucopolysccharidoses, sickle cell disease c. Risk factors i. Obesity ii. Maxillary or mandibular hypoplasia iii. Adenotonsillar hypetrophy iv. Low neuromuscular tone v. Smoke exposure vi. Nasal obstruction, rhinitis vii. Family history d. Complications i. Poor academic performance, aggression, attention deficit disorder (ADD) ii. HTN, pulmonary HTN iii. Failure to thrive iv. Rarely, brain damage, seizures

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Central Sleep Apnea Disorders 1. Central Sleep Apnea with Cheyne-Stokes Breathing a. Diagnostic criteria (all needed) i. Sleepiness or insomnia or nonrestorative sleep or snoring or apnea symptoms in context of Afib, CHF or central neurological disorder ii. PSG shows 5 or more central apneas/hypopneas per hour of sleep AND central events are ≥ 50% of all apnea and hypopneas AND pattern of breathing is Cheyne-Stokes Breathing b. Risk factors i. Heart failure, stroke, age > 60 years, male (if with CHF) c. Complications: worsening of heart failure 2. Central Sleep Apnea due to medical disorder without Cheyne-Stokes Breathing a. Diagnostic criteria: (all needed) i. Sleepiness or insomnia or nonrestorative sleep or snoring or apnea symptoms ii. PSG shows 5 or more central apneas/hypopneas per hour of sleep AND central events are ≥ 50% of all apnea and hypopneas AND absence of Cheyne-Stokes Breathing iii. Occurs as a consequence of a medical disorder but not due to medication/substance use b. Risk factors i. Chiari malformations, stroke, brain neoplasms, multiple-system atrophy (MSA) or Shy Drager Syndrome c. Complications: sleep fragmentation 3. Central Sleep Apnea due to High Altitude Periodic Breathing a. Diagnostic criteria: (all needed) i. Sleepiness, insomnia, nonrestorative sleep, apnea, or morning headache symptoms ii. Attributable to high altitude periodic breathing OR, if PSG performed, there are 5 or more central apneas/hypopneas per hour of non-rapid eye movement (NREM) sleep b. Risk factors: Exposure to > 2500 meters above sea level, some may be sensitive at > 1500 meters c. Complications: sleep fragmentation, fatigue, sleepiness over 3 days to 2 weeks 4. Central Sleep Apnea due to medication or substance a. Diagnostic criteria: (all needed) i. Patient is taking an opioid or respiratory depressant medication ii. Sleepiness, insomnia, nonrestorative sleep, snoring, or apnea symptoms iii. PSG shows 5 or more central apneas/hypopneas per hour of sleep AND central events are≥ 50% of all apnea and hypopneas AND absence of Cheyne-Stokes Breathing iv. Occurs as a consequence of medication/substance use b. Risk factors: most commonly long-acting narcotic

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Ofer Jacobowitz and Lee Shangold

5.

6.

7.

8.

c. Complications: possibly, death Primary Central Sleep Apnea a. Diagnostic criteria: (all needed) i. Sleepiness, insomnia, nonrestorative sleep, snoring, or apnea symptoms (*children may be asymptomatic) ii. PSG shows 5 or more central apneas/hypopneas per hour of sleep AND central events are ≥ 50% of all apnea and hypopneas AND absence of Cheyne-Stokes Breathing iii. No evidence of daytime or nocturnal hypoventilation b. Risk factors: rare disorder, more common in men, middle age to elderly c. Complications: uncertain Primary Central Sleep Apnea of Infancy a. Diagnostic criteria: (all needed) i. Apnea or cyanosis are observed, OR central apnea documented ii. At least 37 weeks conceptional age iii. PSG or other monitor shows short recurrent central apneas of > 20 second duration or periodic breathing for ≥ 5% of sleep time. b. Risk factors: GERD, neurological d/o, medications, anesthesia, infection (Respiratory Syncytial Virus [RSV] most commonly), impaired oxygenation c. Complications: usually self-limited but may result in failure to thrive, or signal an underlying medical disorder Primary Central Sleep Apnea of Prematurity a. Diagnostic criteria: (all needed) i. Apnea or cyanosis are observed, OR central apnea, desaturation, bradycardia documented ii. < 37 weeks conceptional age iii. PSG or other monitor shows long recurrent central apneas of > 20 second duration or periodic breathing for ≥ 5% of sleep time b. Risk factors: developmental delay, thermal instability, GERD, neurological d/o, medications, anesthesia, infection (RSV, most commonly), impaired oxygenation c. Complications: usually self-limited but if persistent may be due to an underlying medical disorder Treatment-emergent Central Sleep Apnea a. Diagnostic criteria: (all needed) i. Diagnostic PSG shows 5 or more obstructive apneas/hypopneas/RERAs per hour of sleep ii. PSG during PAP titration shows resolution of obstructions with emergence of persistence of 5 or more central events /hour AND central events are ≥ 50% of all apnea and hypopneas iii. There is no other central sleep apnea disorder b. Risk factors: Presence of central events on diagnostic study c. Complications: sleep fragmentation, sleepiness. Often self-limited

Classification of Sleep Disorders

33

Sleep-Related Hypoventilation Disorders 1. Obesity Hypoventilation Syndrome a. Diagnostic criteria: (all needed) i. Hypoventilation during wakefulness, PaCO2 > 45 mm Hg by arterial PCO2, end-tidal PCO2 or transcutaneous PCO2 measurement ii. Obesity: > 30kg/m2; for children > 95th percentile for age and sex iii. Not primarily due to disorders involving the lung parenchyma, airway, pulmonary vasculature, chest wall, neuromuscular function, congenital disorder, idiopathic central alveolar hypoventilation, or medication/substance use b. Risk factors: obesity, obstructive sleep apnea c. Complications: pulmonary hypertension, heart failure, dysrhythmias, neurocognitive dysfunction, increased mortality 2. Congenital Central Alveolar Hypoventilation Syndrome a. Diagnostic criteria: i. Sleep-related hypoventilation PaCO2 > 45 mm Hg AND PHOX2B gene mutation  Wake PaCO2 may or may not be elevated b. Risk factors: congenital, sometimes familial. Occasionally presents in adults with respiratory failure post anesthesia c. Complications: Death from cor pulmonale, apneas, mental retardation if not treated with mechanical ventilation 3. Late-onset Central Alveolar Hypoventilation with hypothalamic dysfunction a. Diagnostic criteria (all needed) i. Sleep-related hypoventilation PaCO2 > 45 mm Hg ii. Absence of PHOX2B gene mutation iii. Presence of at least two of the following: obesity, hypothalamic endocrine disorder, severe emotional disturbance, tumor of neural origin b. Risk factors: hyperphagia, obesity c. Complications: Death from cor pulmonale or respiratory failure if not treated with mechanical ventilation 4. Idiopathic Central Alveolar Hypoventilation a. Diagnostic criteria: (all needed) i. Hypoventilation during sleep PaCO2 > 45 mm Hg ii. Not primarily due to disorders involving the lung parenchyma, airway, pulmonary vasculature, chest wall, neuromuscular function, congenital hypoventilation disorder, obesity b. Risk factors: idiopathic, central nervous system (CNS) depressants worsen condition c. Complications: pulmonary hypertension, heart failure, dysrhythmias, neurocognitive dysfunction 5. Sleep-related Hypoventilation due to a medical disorder a. Diagnostic criteria: (all needed) i. Hypoventilation during sleep PaCO2 > 45 mm Hg

34

Ofer Jacobowitz and Lee Shangold ii.

Due to disorders involving the lung parenchyma, airway, pulmonary vasculature, chest wall, neuromuscular function iii. Not due to congenital hypoventilation disorder, obesity hypoventilation, medication, or substance use b. Complications: neurocognitive dysfunction 6. Sleep-related Hypoventilation due to medication or substance a. Diagnostic criteria: (all needed) i. Hypoventilation during sleep PaCO2 > 45 mm Hg ii. Medication or substance intake that inhibits ventilatory drive or breathing iii. Not primarily due to disorders involving the lung parenchyma, airway, pulmonary vasculature, chest wall, neuromuscular function, congenital hypoventilation disorder, obesity hypoventilation b. Complications: pulmonary hypertension, heart failure, dysrhythmias, neurocognitive dysfunction, possibly increased mortality

Sleep-Related Hypoxemia Disorders 1. Diagnostic criteria: (all needed) a. PSG or HSAT or sleep oximetry shows SpO2 ≤ 88% (adults) or ≤ 90% (children) for ≥ 5 minutes b. Sleep-related hypoventilation is excluded and is not primarily due to other sleep-related breathing disorder 2. Risk factors: medical or neurological disorder 3. Complications: pulmonary hypertension, heart failure, neurocognitive dysfunction

Catathrenia 1. Diagnostic criteria: a. Groaning during prolonged expiration in sleep 2. Risk factors: unknown 3. Complications: unknown

CENTRAL DISORDERS OF HYPERSOMNOLENCE For diagnosis of certain hypersomnolence disorders, a Multiple Sleep Latency Test (MSLT) is needed. The MSLT consists of 4-5 naps during the day, on the morning following an overnight PSG. Each nap is 15 minutes, separated by 2 hours. The average sleep latency (time to achieve sleep) is assessed, and a mean sleep latency of > 10 minutes is normal. A mean sleep latency of < 8 minutes is consistent with hypersomnia. The presence of REM is also assessed. Having 2 or more Sleep onset REM periods (SOREMPs) in the 5 naps, or one during

Classification of Sleep Disorders

35

the 5 naps plus an early REM period at the preceding night’s polysomnogram, is considered abnormal. 1. Narcolepsy Type 1 (Narcolepsy with cataplexy) a. Disorder that occurs secondary to loss of hypocretin neuronal transmission b. Diagnostic Criteria i. At least 3 months of daily episodes of irrepressible need to sleep or lapses into sleep during “daytime” (sleep attacks) AND ii. (A or B) A. Cataplexy (brief, bilateral loss of muscle tone without loss of consciousness, often precipitated by emotion) AND on MSLT the sleep latency is ≤ 8 minutes and 2 or more SOREMPs are present B. Cerebrospinal fluid (CSF) hypocretin-1 level by immunoreactivity assay is ≤ 110 pg/mL or < 1/3 of mean values of normal in same assay iii. Common symptoms include sleep paralysis (inability to move on waking), hypnagogic hallucinations (vivid dream like experience just before sleep onset), fatigue, anxiety. Patients often feel more alert after a night’s sleep or naps. c. Risk Factors: obesity, DQB1*0602 HLA subtype, adolescence, or young adulthood i. May occur with head trauma, autoimmune or paraneoplastic disorders (with anti -Ma2 or antiaquaporin4 antibodies), hypothalamic disorders or tumors ii. Family history increases risk by 10-40 fold iii. Possibly associated with prior Strep infection identified by elevated anti-strep antibody level d. Complications: poor academic and social performance, sleep disruption, depression, motor vehicle accidents, loss of employment 2. Narcolepsy Type 2 (Narcolepsy Without Cataplexy) a. Associated with loss of hypocretin in a portion. Some may develop cataplexy later and be classified as type 1. b. Diagnostic Criteria (all needed) i. At least 3 months of daily episodes of irrepressible need to sleep or lapses into sleep during “daytime” (sleep attacks) ii. No Cataplexy (brief, bilateral loss of muscle tone without loss of consciousness, often precipitated by emotion) AND on MSLT the sleep latency is ≤ 8 minutes and 2 or more SOREMPs are present iii. CSF hypocretin-1 level by immunoreactivity assay is > 110 pg/mL or > 1/3rd of mean values of normal in same assay or not assayed iv. Not explained by another cause such as insufficient sleep, a sleep disorder, medication or substance use or withdrawal c. Common symptoms include sleep paralysis (inability to move on waking), hypnagogic hallucinations (vivid dream like experience just before sleep onset), fatigue, anxiety. Patients often feel more alert after a night’s sleep or naps

36

Ofer Jacobowitz and Lee Shangold d. Risk Factors: obesity, DQB1*0602 HLA subtype, adolescence, or young adulthood, prior viral infection i. May occur with head trauma, autoimmune or paraneoplastic disorders with anti-Ma2 or antiaquaporin4 antibodies, hypothalamic disorders or tumors, multiple sclerosis, Myotonic dystrophy, Parkinson disease, Prader Willi syndrome e. Complications: poor academic and social performance, sleep disruption, depression, motor vehicle accidents, loss of employment 3. Idiopathic Hypersomnia a. Diagnostic Criteria (all needed) i. At least 3 months of daily episodes of irrepressible need to sleep or lapses into sleep during “daytime” (sleep attacks)  Patients often report sleep inertia and do not feel more alert after naps ii. Absence of Cataplexy iii. In an MSLT, sleep latency is ≤ 8 minutes but < 2 SOREMPs are present iv. Total sleep time is ≥ 660 minutes by 24-hour polysomnography or by wrist actigraphy + sleep logs (averaged over at least 7 days with unrestricted sleep) v. Insufficient sleep is excluded  If needed, by increased time in bed at night, confirmed preferably by wrist actigraphy b. Risk Factors: unknown pathophysiology, but possibly may have a longer circadian rhythm i. Autonomic dysfunction is common, i.e., headaches, orthostatic intolerance, cold extremities ii. Family history present in 30% c. Complications: poor academic and social performance, loss of employment 4. Kleine-Levin Syndrome a. Possibly an autoimmune encephalitis (perivascular lymphocytic infiltrate) b. Diagnostic Criteria (all needed) i. At least 2 episodes of excessive sleepiness or sleep duration, lasting from 2 days to 5 weeks ii. Episodes occur usually more than annually and a least once in 18 months iii. Alertness, mood, cognitive function, behavior and mood are normal between episodes iv. During the episodes, the patient experiences any of the following: cognitive dysfunction, altered perception, eating disorder, disinhibited behavior c. Risk Factors: Birth and developmental problems, Jewish heritage, possible HLA DQB1*02, antecedent flu-like illness i. Family history present in 5% ii. Onset is usually in adolescence

Classification of Sleep Disorders

5.

6.

7.

8.

37

d. Complications: social problems, loss of employment, rarely accidents, memory loss Hypersomnia due to a medical disorder a. Diagnostic Criteria (all needed) i. At least 3 months of daily episodes of irrepressible need to sleep or lapses into sleep during daytime ii. Occurs secondary to a medical or neurological disorder iii. If a MSLT is obtained, sleep latency is ≤ 8 minutes but < 2 SOREMPs are present b. Risk Factors: Parkinson disease, traumatic brain injury, brain tumors or infections or neurodegenerative or vascular lesions, hypothyroidism, metabolic encephalopathy (i.e., hepatic), OSA despite adequate treatment, genetic disorders (Niemann Pick type C, Norrie disease, Prader Willi, Myotonic dystrophy, fragile X) c. Complications: dependent on etiology Hypersomnia due to a medication or substance use a. Diagnostic Criteria (all needed) i. Daily episodes of irrepressible need to sleep or lapses into sleep during the daytime ii. Occurs secondary to medication or substance use, or withdrawal from a medication b. Risk Factors: intake of drugs with sedative potential, substance abuse, stimulant medication withdrawal c. Complications: dependent on etiology Hypersomnia associated with a psychiatric disorder a. Diagnostic Criteria (all needed) i. At least 3 months of daily episodes of irrepressible need to sleep or lapses into sleep during the daytime ii. Occurs secondary to a psychiatric disorder b. Risk Factors: Mood disorders (major depression, atypical depression, bipolar, seasonal affective), conversion disorder, somatic symptom disorder c. Complications: poor academic and social performance, loss of employment Insufficient Sleep Syndrome a. Diagnostic Criteria (all needed) i. Daily episodes of irrepressible need to sleep or lapses into sleep during the daytime. For prepubertal age, behavioral anomalies present due to sleepiness ii. Sleep duration by history, logs or actigraphy is shorter than expected for age iii. Present for most days over 3 months iv. Patient shortens sleep duration using external means but sleeps longer when undisturbed, such as when on vacation v. Extending sleep time resolves the sleepiness symptoms b. Risk Factors: Common in adolescents, evening type (night owl) c. Complications: Poor academic and social performance, loss of employment, depression, drug abuse

38

Ofer Jacobowitz and Lee Shangold 9. Long Sleeper a. A normal variant of sleep, where the person sleeps about 10 hours or more per 24 hours or 2 hours more than normal for age with resultant normal daytime function. Work or school demands may often lead to shorter sleep duration during school or workdays and longer sleep on days off.

CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS 1. Delayed Sleep-Wake Phase Disorder a. Diagnostic Criteria (all needed) i. Delay in the phase of the main sleep episode in relation to desired or required sleep and wake-up times, evidenced by chronic/recurrent inability to fall asleep and difficulty awakening at desired or required time ii. Present for at least 3 months iii. Sleep quality and duration improve and are maintained when patients are permitted to sleep per their delayed phase schedule iv. Sleep logs or actigraphy for at least 1 week demonstrate delay in timing of habitual sleep period (days off must be included)  May also be confirmed by melatonin assays b. Risk Factors: Common in adolescents, those with mood disorders, Autism spectrum, ADHD. i. Family history present in ~40% c. Complications: Poor academic performance, depression, drug abuse 2. Advanced Sleep-Wake Disorder a. Diagnostic Criteria (all needed) i. Advance in the phase of the main sleep episode in relation to desired or required sleep and wake-up times, evidenced by chronic/recurrent inability to stay awake until desired/required bedtime and inability to stay asleep until desired/required to wake up ii. Present for at least 3 months iii. Sleep quality and duration improve and are maintained when patients are permitted to sleep per their advanced phase schedule iv. Sleep logs or actigraphy for at least 1 week demonstrate advance in timing of habitual sleep period (days off must be included)  May also be confirmed by melatonin assays b. Risk Factors: Common in middle to advanced age, children with autism. Circadian clock pathway mutations have also been described in familial form. c. Complications: Insomnia, drug abuse 3. Irregular Sleep-Wake Rhythm Disorder a. Diagnostic Criteria (all needed) i. Chronic/recurrent pattern of irregular sleep and wake episodes throughout the 24-hour period, with insomnia during the scheduled

Classification of Sleep Disorders

39

sleep period and excessive sleepiness during the scheduled wake period or both. ii. Present for at least 3 months iii. Sleep logs or actigraphy for at least 1 week demonstrate no major sleep period and 3 or more irregular sleep period in 24 hours (days off must be included) b. Risk Factors: Neurodegenerative disorders, i.e., dementia, children with developmental disorders (i.e., Angelman syndrome, autism, Smith-Magentis syndrome), poor sleep hygiene and lack of exposure to light, activity and social cues that entrain the circadian clock c. Complications: Disease-related, but may result in institutionalization, poor health 4. Non-24-Hour Sleep-Wake Rhythm Disorder a. Diagnostic Criteria (all needed) i. Insomnia, excessive sleepiness, or both, which alternate with asymptomatic periods due to circadian misalignment with the light-dark 24-hour cycle ii. Present for at least 3 months iii. Sleep logs or actigraphy for at least 1 week demonstrate pattern of sleep and wake times that typically delay each day and a period that is > 24 hours  May also be confirmed by melatonin assays b. Risk Factors: Present in > 50% of blind patients (failure of photic entrainment). Also reported in Rett syndrome, Angelman Syndrome, Autism. Delayed sleep wake phase disorder and decreased exposure to light may be risk factors. Unlikely familial. c. Complications: poor academic performance, depression, drug abuse 5. Shift Work Disorder a. Diagnostic Criteria (all needed) i. Insomnia, excessive sleepiness, or both, with a reduction in total sleep time, associated with a recurrent work schedule that overlaps the usual sleep period ii. Present for at least 3 months iii. Sleep logs or actigraphy for at least 1 week demonstrate pattern of disturbed sleep and wake times (days off must be included) b. Risk Factors: Circadian preference (chronotype), OSA, medical and psychiatric disorders and social pressure may worsen and predispose. c. Complications: accident risk, exacerbation of cardiovascular, gastrointestinal, metabolic, neoplastic, reproductive disorders and dysfunction 6. Jet Lag Disorder a. Diagnostic Criteria (all needed) i. Insomnia, excessive sleepiness, or both, with a reduction in total sleep time, associated with trans-meridian jet travel across at least 2 time zones ii. There is impairment of daytime function, malaise or somatic symptoms within 1-2 days of travel

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Ofer Jacobowitz and Lee Shangold b. Risk Factors: Eastward travel, number of time zones traversed, individual tolerance. c. Complications: neurocognitive dysfunction, performance of tasks that require vigilance, menstrual and reproductive dysfunction

PARASOMNIAS 1. A parasomnia is an experiential event that occurs while sleeping. It manifests as abnormal behavior in the context of sleeping. 2. Parasomnias can occur while falling asleep, sleeping or waking up from sleep 3. There are 3 states of being: a. Wake b. Non-REM (NREM) sleep – (stages N1, N2 and N3) c. Rapid Eye Movement (REM) sleep 4. Normally, we transition smoothly from wakefulness to NREM sleep and then into REM sleep a. With normal sleep architecture, we transition from NREM sleep to REM sleep 4 to 5 times during a typical night prior to awakening in the morning b. Parasomnias occur when there is overlap and parts of the central nervous system are in one state and parts are in another 5. The initial goal should be to prevent harm to the patient or someone else

Non-REM-Related Parasomnias 1. Disorders of Arousal (from NREM sleep) a. Diagnostic criteria i. Recurrent episodes of partial or incomplete awakening from NREM sleep ii. Inappropriate or absent responsiveness to efforts of others to intervene or redirect the affected person during episode iii. Limited or absent cognitive functioning or dream-like imagery iv. Partial or complete amnesia for the episode b. Usually occurs during the first third of the major sleep episode out of Stage N3 (slow wave) sleep, but terminates in either wakefulness or lighter NREM sleep (stage N1 or N2) c. The below three disorders need to meet all of the above diagnostic criteria for Disorders or Arousal from NREM sleep, in addition to their own specific criteria i. Confusional Arousals – “sleep inertia” or “sleep drunkenness”  Mental confusion or confused behavior while in bed  Absence of terror or ambulation out of bed ii. Sleepwalking  Arousals are associated with ambulation out of bed

Classification of Sleep Disorders

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iii. Sleep Terrors – a.k.a. night terrors  Arousals are characterized by episodes of abrupt terror, usually beginning with a frightening scream  Intense fear with dilated pupils, rapid heart rate, rapid breathing and/or sweating d. Essential Features i. Usually brief, but can last 30-40 minutes in some children ii. Difficult to awaken and, when awakened, usually confused iii. High-level cognitive functions such as attention, planning, social interaction and intent are absent iv. More common in children and usually resolve by puberty e. Demographics i. Confusional arousals  17.3% of children 3 to 13 years of age (most common in < 5 years of age) ii. Sleepwalking  ~1-17% in children; 4% in adults iii. Sleep terrors  1 to 6.5% of children; peak incidence 5 to 7 years of age  1% in adults f. Predisposing and precipitating factors i. Genetic predisposition (family history in 62-96% of people affected) ii. Anything that disrupts sleep can be a trigger such as OSA, telephone calls, messaging from electric devices iii. Can be provoked by sleep deprivation, emotional stress, hyperthyroidism, migraines, head injury, CVA, febrile illness, full bladder g. Onset, course and complications i. Serious or even lethal injuries can occur to patient or someone who disturbs patient with confusional arousal h. Pathology and pathophysiology i. Overwhelming majority of people with disorders of arousal do not have neurological or psychological pathology ii. Typically considered to be normal age-related sleep manifestations in children, not requiring specific intervention i. Differential diagnosis i. Seizures have stereotypical behavior and a higher frequency of events in a given night 2. Sleep Related Eating Disorder (SRED) a. Diagnostic criteria i. Recurrent episodes of dysfunctional eating that occur after an arousal during the main sleep period ii. Need at least one of the following in association with recurrent episodes of involuntary eating

42

Ofer Jacobowitz and Lee Shangold 

Eating of peculiar forms or combinations of food or inedible or toxic substances  Sleep related injuries or potentially injurious behaviors performed while in the pursuit of food or while cooking  Adverse health consequences from recurrent nocturnal eating iii. Partial or complete loss of conscious awareness during the eating episode, with subsequent impaired recall b. Demographics i. More common in females ii. Mean age of onset 22 to 39 years c. Predisposing and precipitation factors i. Frequently associated with sleepwalking ii. Associated with other sleep disorders including, RLS, PLMD, OSA, circadian rhythm sleep-wake disorders iii. Medication-induced SRED reported most commonly with zolpidem, but has been seen in association with a broad range of sedative hypnotics and anticholinergics d. Onset, Course and Complications i. Fires can occur when person with SRED begins to cook foods on the stove or in the oven, and then abandons them e. Differential Diagnosis i. Night eating syndrome – excessive eating between dinner and bedtime, as well as during full awakenings during the sleep period ii. Klein-Levin Syndrome (periodic hypersomnia) – can present with inappropriate nocturnal eating, but is predominant in adolescent males with periodic hypersomnia, hypersexuality and hyperphagia lasting days to weeks

REM-Related Parasomnias 1. REM Sleep Behavior Disorder (RBD) a. The physiologic hallmark of REM sleep is skeletal muscle atonia. That is, we are essentially paralyzed while we are in REM sleep. This allows us to dream without acting them out. The muscles that continue to function during REM sleep are the eyes (ergo, rapid eye movement (REM) sleep), the heart and the diaphragm. REM sleep generally encompasses ~20% of total sleep time. b. Diagnostic Criteria i. Repeated episodes of sleep related vocalization and/or complex motor behaviors ii. Behaviors are documented by PSG to occur during REM sleep or, based upon clinical history of dream enactment, are presumed to occur during REM sleep iii. PSG demonstrates REM sleep without atonia c. Essential Features

Classification of Sleep Disorders

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i. Acting out dreams that may cause injury to the person or bed partner ii. Person becomes rapidly alert and reports a dream with a coherent story after the episode. The dream action corresponds closely to observed sleep behaviors iii. Eyes usually remain closed during an RBD episode d. Demographics i. Male predominant ii. Usually emerges after 50 years of age iii. Prevalence is 0.4 to 0.8% (although ~9% in people 70-99 years of age) e. Predisposing and Precipitating Factors i. An underlying neurological disorder, particularly Parkinson disease (PD), MSA, dementia with Lewy bodies (DLB), narcolepsy or stroke ii. Medications iii. Antidepressants (but not bupropion), beta blockers, anticholinesterase inhibitors and selegiline iv. May be associated with post-traumatic stress disorder (PTSD) f. Onset, Course, and Complications i. Complications include sleep related injuries to self and/or bed partner ii. Delayed emergence of a neurodegenerative disorder, often more than a decade after the onset of idiopathic RBD is very common in men 50 years of age and older – PD, MSA and DLB iii. > 80% of idiopathic RBD converted to Parkinsonism/dementia iv. RBD is present in > 90% of people with MSA, ~50% DLB and up to 46% with PD g. Developmental Issue i. Can emerge in children, usually in association with narcolepsycataplexy, brainstem tumors, or antidepressant medications h. Pathology and Pathophysiology i. RBD is associated with neurodegenerative disorders, the synucleinopathies (PD, MSA and DLB) that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons, nerve fibers or glial cells. RBD is frequently an initial manifestation of a fully expressed synucleinopathy which will develop within 15 years of RBD diagnosis in the majority of patients. ii. RBD is strongly linked with narcolepsy type 1 and may be worsened by pharmacologic treatment of cataplexy with antidepressants iii. Pathophysiology – interruption of the REM atonia pathway and/or disinhibition of brainstem motor pattern generators i. Objective Findings i. PSG – excessive amount of sustained or intermittent loss of REM atonia and/or excessive phasic muscle twitch activity of the submental and/or limb electromyograms (EMGs) during REM sleep ii. ~ 75% of patients with RBD have periodic limb movements during NREM sleep

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Ofer Jacobowitz and Lee Shangold j.

Differential Diagnosis i. RBD is one of several disorders that can manifest as complex, injurious, and violent sleep related and dream-related behaviors in adults. Other disorders that can mimic RBD include sleepwalking, sleep terrors, OSA, nocturnal seizures, rhythmic movement disorders, sleep related dissociative disorders, frightening hypnopompic hallucinations, PTSD, nightmares, panic disorder and malingering 2. Recurrent Isolated Sleep Paralysis a. Diagnostic Criteria i. A recurrent inability to move the trunk and all of the limbs at sleep onset or upon awakening from sleep ii. Each episode last seconds to a few minutes iii. Episodes cause clinically significant distress including bedtime anxiety or fear of sleep b. Essential Features i. Inability to speak or to move the limbs, trunk or head ii. Consciousness is preserved, and full recall is present iii. Usually resolves spontaneously but can be aborted by sensory stimulation, such as being touched or spoken to, or by the patient making intense efforts to move c. Associated Features i. Hallucinations accompany paralysis in 25 to 75% of patients d. Demographics i. ~ 5% of the population ii. Mean age of onset is 14 to 17 years of age e. Predisposing and Precipitating Factors i. Sleep deprivation and an irregular sleep-wake schedule f. Familial Pattern i. Maternal form of transmission is postulated g. Onset, Course, and Complications i. Onset usually in adolescence ii. Most events occur in the 2nd and 3rd decades h. Pathology and Pathophysiology i. Sleep paralysis is an example of state dissociation with elements of REM sleep atonia persisting into wakefulness ii. Common in patients with narcolepsy, but frequently occurs in isolation in the general population i. Objective Findings i. PSG – persistence of REM-related EMG atonia into conscious wakefulness 3. Nightmare Disorder a. Diagnostic Criteria i. Repeated occurrences of extended, extremely dysphoric, and wellremembered dreams that usually involve threats to survival, security and physical integrity

Classification of Sleep Disorders

b.

c.

d.

e.

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ii. On awakening from the dysphoric dreams, the person rapidly becomes oriented and alert iii. The dream experience causes clinically significant distress or impairment in social, occupational, or other important areas of functioning as indicated by the report of at least one of the following:  Mood disturbance  Sleep resistance  Cognitive impairments  Negative impact on caregiver or family functioning  Behavior problems  Daytime sleepiness  Fatigue or low energy  Impaired occupational or educational function  Impaired interpersonal/social function Associated Features i. Post-awakening anxiety and difficulty returning to sleep may be present ii. Commonly seen in those who have been physically or sexually abused and in those suffering from PTSD Demographics i. Occasional nightmares, which does not constitute a nightmare disorder, occurs in 60 to 75% of children ii. Frequent nightmares – 1 to 5% of preadolescent children iii. General population – 2 to 8% Predisposing and Precipitating Factors i. Frequent nightmares are inversely correlated with measures of wellbeing ii. Associated with pharmacologic agents - mostly antidepressants, antihypertensives and dopamine-receptor agonists Onset, Course, and Complications i. Usually starts between 3 to 6 years of age ii. Peaks between 6 and 10 years of age and decreases thereafter

Other Parasomnias 1. Exploding Head Syndrome a. Diagnostic Criteria i. Complaint of sudden loud noise or sense of explosion in the head either at the wake-sleep transition or upon awakening during the night ii. Abrupt arousal following the event, often with a sense of fright iii. Not associated with significant complaints of pain b. Essential Features i. Many patients feel that they are having a stroke ii. Sensation lasts a few seconds and may recur

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Ofer Jacobowitz and Lee Shangold c.

Associated Features i. Flash of light may accompany the sound ii. Myoclonic jerk may sometimes occur d. Demographics i. More common in women than men ii. Median age of onset is 58 years e. Onset, Course, and Complications i. Benign course with no reported neurologic sequelae ii. Can lead to insomnia f. Pathology and Pathophysiology i. May be sensory variant of transient motor phenomenon of sleep starts or hypnic jerks occurring at the wake-sleep transition g. Objective Findings i. No epileptiform discharges accompany the event 2. Sleep Related Hallucinations a. Diagnostic Criteria i. Recurrent hallucinations just prior to sleep onset or upon awakening ii. Hallucinations are predominantly visual b. Essential Features i. Hypnagogic hallucinations – occur at sleep onset ii. Hypnopompic hallucinations – occur upon awakening in the morning iii. Complex nocturnal visual hallucinations  Usually occurs after a sudden awakening without recall of preceding dream  Complex, vivid, relatively immobile images or people or animals  May remain for minutes  Disappear if ambient illumination increased c. Clinical and Pathophysiological Subtypes i. Hypnagogic and hypnopompic hallucinations are common in narcolepsy and also occur as occasional phenomena in a high percentage of the general population ii. Complex nocturnal visual hallucinations are rare and occur in a setting of a range of neurologic and visual disorders d. Demographics i. Hypnagogic hallucinations – 25 to 37% of population ii. Hypnopompic hallucinations – 7 to 13% of population iii. More common in younger persons e. Predisposing and Precipitating Factors i. Associated with younger age, current drug use, past alcohol use, anxiety, mood disorders, sleep onset insomnia and perceived sleep insufficiency f. Pathology and Pathophysiology i. Dream ideation of REM sleep intruding into wakefulness ii. May be within the limits of normal sleep-wake transition

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g. Objective Findings i. Hypnagogic hallucinations – sleep onset REM period ii. Complex nocturnal visual hallucinations – onset from NREM sleep iii. MRI scans of brain, sleep study, electroencephalography (EEG) and neuropsychological testing warranted to identify underlying disorders 3. Sleep Enuresis (bedwetting) a. Diagnostic Criteria i. Patient is older than 5 years ii. Recurrent involuntary voiding during sleep, occurring at least twice a week iii. Condition has been present for at least 3 months  Primary – patient has never been consistently dry during sleep  Secondary - patient has previously been consistently dry during sleep for at least 6 months b. Essential Features i. Sleep enuresis is associated with difficulty arousing from sleep in response to an urge to urinate and may occur during any sleep stage. Sleep disorders that fragment sleep such as sleep apnea are associated with sleep enuresis, and treatment of these disorders may cure or reduce their incidence c. Associated Features i. If involuntary voiding is present during wakefulness, consider physiological etiology ii. Secondary sleep enuresis more common in children with recent psychosocial stress, such as parental divorce, physical or sexual abuse, or neglect iii. Chronic constipation and encopresis (fecal soiling) often occur in children with secondary sleep enuresis iv. In adults, sleep enuresis associated with diabetes, urinary tract infections, nocturnal epilepsy, CHF, OSA, depression, dementia v. Sleep related breathing disorders (SRBD) in 8 to 47% of children with enuresis, compared to overall prevalence of 1 to 2% d. Demographics i. 15 to 20% of 5-year-olds ii. 3 times more common in boys than girls iii. Older adults, more common in women than men e. Predisposing and Precipitating Factors i. “Deep sleepers” – high arousal threshold ii. 60% of patients with nocturnal enuresis and OSA cured after adenotonsillectomy f. Onset, Course, and Complications i. Primary complication of sleep enuresis is to the child’s self-esteem 4. Parasomnia Due to a Medical Disorder a. RBD is parasomnia most commonly associated with an underlying neurological condition

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Ofer Jacobowitz and Lee Shangold b. Complex nocturnal sleep related visual hallucinations can occur with neurological disorders such as narcolepsy, PD, DLB, visual loss (Charles Bonnet hallucinations), and midbrain and diencephalic pathology (peduncular hallucinosis) 5. Parasomnia Due to a Medication or Substance a. Essential feature is close temporal relationship between exposure to a drug, medication, or biological substance and the onset of signs and symptoms of a parasomnia. A likely causal relationship can be inferred if signs and symptoms of the parasomnia disappear when the drug or substance is withdrawn. b. NREM sleep parasomnias i. Zolpidem and sodium oxybate can cause sleepwalking, sleep-related eating disorder, sleep driving and sleep sex c. REM sleep parasomnias i. Antidepressants have been described to trigger RBD 6. Parasomnia, Unspecified a. Parasomnias that cannot be classified elsewhere or for cases in which the physician has a clinical suspicion of a parasomnia but is unable to establish a specific diagnosis 7. Isolated Symptoms and Normal Variants a. Sleep Talking i. Talking, with varying degrees of comprehensibility, during sleep ii. Can be idiopathic or associated with parasomnias such as RBD or disorders of arousal such as confusional arousal iii. May occur during REM or NREM sleep iv. Prevalence  Lifetime 66%  Current – in past 3 months – 17% v. Sleep talker is rarely aware of his or her sleep talking

SLEEP RELATED MOVEMENT DISORDERS Sleep related movement disorders are primarily characterized by relatively simple, usually stereotyped, movements that disturb sleep or its onset: a.

Different than parasomnias that involve complex behaviors, such as sleepwalking, sleep talking, RBD b. Nocturnal sleep disturbance or complaints of daytime sleepiness or fatigue are a prerequisite for a diagnosis of a sleep related movement disorder 1. Restless Legs Syndrome (RLS) – a.k.a. Willis-Ekbom disease (WED) asRLS term is thought not to encompass upper exteremity movements. Therefore, some use WED after those who defined the disease (Willis – 1672; Ekbom – 1945). a. Diagnostic Criteria

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i.

An urge to move the exteremities, usually accompanied by, or thought to be caused by, uncomfortable and unpleasant sensation in the exteremities. These symptoms must: ii. Begin or worsen during periods of rest or inactivity such as lying or sitting  Be partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; and  Occur exclusively or predominantly in the evening or night rather than during the day. iii. The above features are not solely accounted for as symptoms of another medical or behavioral condition (e.g., leg cramps, positional discomfort, myalgia, venous stasis, leg edema, arthritis, habitual foot tapping) iv. The symptoms of RLS cause concern, distress, sleep disturbance, or impairment in mental, physical, social, occupational, education, behavioral, or other important areas of functioning b. Essential Features i. ~21 to 57% of individuals with RLS describe some arm sensations c. Associated Features i. Disturbed sleep is a common, prominent, and distressing aspect of RLS ii. Periodic Limb Movements of Sleep (PLMS), a family history of RLS, and response to dopaminergic therapy are supportive of the diagnosis iii. Increased prevalence of mood and anxiety disorders in individuals with RLS. Treatment of RLS frequently improves depressive symptoms.  Increased rate of ADHD found in patients with RLS d. Demographics i. Clinically significant RLS – ~2.7% ii. Women > men e.

Predisposing and Precipitating Factors i. Family history of RLS, female sex, iron deficiency, pregnancy, chronic renal failure ii. Medications – sedating antihistamines, most antidepressants (except bupropion), dopamine receptor antagonists, possibly H-2 antagonists and proton pump inhibitors. f. Familial Patterns i. Early onset RLS is highly familial ii. Developmental Issues  ~ 70% of children with RLS demonstrate PLMS > 5/hour on sleep study g. Pathology and Pathophysiology i. Brain iron deficiency, CNS dopamine regulation, and genetics appear to be primary factors in the pathophysiology of RLS

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Ofer Jacobowitz and Lee Shangold h. Objective Findings i. 70 to 80% of patient with RLS will have PLMS > 5/hour ii. About 1/3 PLMS are associated with cortical arousals 2. Periodic Limb Movement Disorder (PLMD) a. Diagnostic Criteria i. PSG demonstrates PLMS (> 5/hour in children or > 15/hour in adults) ii. PLMS cause clinically significant sleep disturbance or impairment in mental, physical, social, occupational, educational, behavioral, or other important areas of functioning b. Essential Features i. Repetitive, highly stereotyped limb movements that occur during sleep, in conjunction with clinical sleep disturbance or fatigue that cannot be accounted for by another primary sleep disorder or other etiology ii. PLMS occur most frequently in the lower extremities. They typically involve extension of the big toe, often in combination with partial flexion of the ankle, the knee, and sometimes, the hip. Similar movements can occur in the upper limbs. iii. A clinical history of sleep onset problems, sleep maintenance problems, or unrefreshing sleep attributable to the PLMS is needed for diagnosis of PLMD c. Associated Features i. 26-64% of children with attention-deficit/hyperactivity disorder (ADHD) will have PLMS > 5/hour ii. Conversely, 44% of children with PLMS have symptoms of ADHD d. Demographics i. PLMS > 15/hour – 7.6% of 18 to 65-year-olds ii. PLMD is rare e. Predisposing and Precipitating Factors i. Positive family history of RLS, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, lithium, dopamine receptor antagonists, low brain iron, as reflected by serum ferritin level f. Pathology and Pathophysiology i. Dopaminergic impairment has been implicated in the pathophysiology of PLMS and PLMD ii. The autonomic arousals associated with PLMS are characterized by significant heart rate and blood pressure surges, a mechanism for possible increased cardiovascular and cerebrovascular disease risk g. Objective Findings i. PLMS can appear immediately with the onset of stage N1 sleep, are frequent during stage N2 sleep, decrease in frequency in stage N3, and are usually absent in REM sleep ii. PLMS typically occur in discrete episodes that last from a few minutes to an hour

Classification of Sleep Disorders iii.

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Specific scoring criteria for PLMS are described in the American Academy of Sleep Medicine Manual for Scoring of Sleep and Associated Events iv. The PLMS index is the number of periodic limb movements per hour of total sleep time, as determined by PSG 3. Sleep Related Leg Cramps a. Diagnostic Criteria i. A painful sensation in the leg or foot associated with sudden, involuntary muscle hardness or tightness, indicating a strong muscle contraction ii. The painful muscle contractions occur during the time in bed, although they may arise from either wakefulness or sleep iii. The pain is relieved by forceful stretching of the affected muscles, thus releasing the contraction b. Essential Features i. Usually in the calf or small muscle of the foot ii. The cramps can be relieved by strongly stretching the affected muscle and sometimes also by local massage, application of heat, or movement of the affected limb c. Demographics i. Common ii. Prevalence and frequency increases with age iii. 7% of children and adolescents iv. 33% of adults > 60 years of age v. 50% of adults > 80 years of age vi. 40% pregnant women d. Predisposing and Precipitating Factors i. Predisposing factors include diabetes, amyotrophic lateral sclerosis (ALS), cramp fasciculation syndrome, peripheral vascular disease (PVD), hypokalemia, hypocalcemia, hypomagnesemia, and metabolic disorders ii. Can be associated with prior vigorous exercise, prolonged standing at work, dehydration, fluid and electrolyte disturbance, endocrine disorders, neuromuscular disorders, disorders of reduced mobility, vascular disease, cirrhosis, and hemodialysis 4. Sleep Related Bruxism a. Diagnostic Criteria i. The presence of regular or frequent tooth grinding sounds occurring during sleep ii. The presence of one or more of the following clinical signs:  Abnormal tooth wear consistent with above reports of tooth grinding during sleep  Transient morning jaw muscle pain or fatigue; and/or temporal headache; and/or jaw locking upon awakening consistent with above reports of tooth grinding during sleep

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Ofer Jacobowitz and Lee Shangold b. Essential Features i. Can disturb bed partner ii. Jaw muscle pain, tenderness in the masseter and temporalis muscle regions, morning headaches, or fatigue can arise due to sleep related bruxism c. Associated Features i. Both children and adults with sleep related bruxism seem to have higher scores in stress, anxiety, and psychiatric scales compared to control individuals d. Clinical and Pathophysiological Subtypes i. Primary or idiopathic ii. Secondary  Medical disorders – OSA, PD, RBD, Down Syndrome, CP, mental retardation  Psychoactive medications, recreational drugs, caffeine, cigarettes e. Demographics i. 14 to 17% in childhood and decreases over the life span f. Precipitating Factors i. Anxiety related to current life events, tasks requiring high levels of performance, and repetitive tasks with short deadlines g. Onset, Course, and Complications i. Dental damage and abnormal tooth wear are the most frequent signs of the disorder ii. The natural course of this sleep disorder is benign. Further diagnostic investigations are recommended if sleep related bruxism is associated with other more severe sleep or medical disorders (e.g., SRBD, RBD, epilepsy). h. Pathology and Pathophysiology i. The majority of rhythmic masticatory muscle activity (RMMA) episodes during sleep (up to 80%) occur in association with sleep arousals. Sleep related bruxism episodes typically follow a clear arousal sequence, starting with increased sympathetic-cardiac activity and fast EEG waves in the minutes to seconds preceding the onset of an RMMA episode. The jaw muscle contractions are then followed by, or concomitant with, an increase in blood pressure and ventilation. 5. Sleep Related Rhythmic Movement Disorder (SRMD) a. Diagnostic Criteria i. The patient exhibits repetitive, stereotyped, and rhythmic motor behaviors involving large muscle groups ii. The movements are predominantly sleep related, occurring near nap or bedtime, or when the individual appears drowsy or asleep iii. The behaviors result in a significant complaint as manifest by at least 1 of the following:

Classification of Sleep Disorders   

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Interference with normal sleep Significant impairment in daytime function Self-inflicted bodily injury or likelihood of injury if preventative measures are not used  The rhythmic movements are not better explained by another movement disorder or epilepsy iv. When there are no clinical consequences of the rhythmic movements, the rhythmic movements are simply noted but the term rhythmic movement disorder is not employed b. Essential Features i. Occur predominantly during drowsiness or sleep ii. Typically seen in infants and children iii. Sleep related rhythmic movements should be considered only if the behaviors significantly interfere with normal sleep, cause significant impairment in daytime function, or result in self-inflicted bodily injury (or would result in injury if preventative measures are not used) c. Associated Features i. The vast majority of infants and children with SRMD are otherwise developmentally and intellectually normal d. Clinical and Pathophysiological Subtypes i. Body Rocking: the whole body is rocked while on the hands and knees ii. Head Banging: the head is forcibly moved, striking an object iii. Head Rolling: the head is moved laterally, typically while in a supine position iv. Other: includes body rolling, leg rolling, and leg banging v. Combined: involves 2 or more of the individual types e. Demographics i. 9 months of age – 59% ii. 18 months – 33% iii. 5 years – 5% f. Onset, Course, and Complications i. Typical cases in infants and toddlers pose little risk of serious injury ii. Under extraordinary circumstances, particularly in the developmentally disabled, injury to soft tissues or bone has been reported g. Differential Diagnosis i. Children with autism spectrum disorder often exhibit repetitive behaviors, but these movements typically occur during wakefulness and are not predominantly sleep related. Stereotypic movement disorder is a Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis that is typically seen with intellectual disability and is not predominantly sleep related.

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Ofer Jacobowitz and Lee Shangold 6. Benign Sleep Myoclonus of Infancy (BSMI) a. Diagnostic Criteria i. Observation of repetitive myoclonic jerks that involve the limbs, trunk, or whole body ii. The movements occur in early infancy, typically from birth to 6 months of age iii. The movements occur only during sleep iv. The movements stop abruptly and consistently when the infant is aroused b. Essential Features i. Benign and relatively rare ii. Commonly confused with epilepsy c. Onset, Course, and Complication i. Course is self-limited and benign d. Differential Diagnosis i. BSMI should be distinguished from myoclonic seizures. The absence of episodes while awake in infants with BSMI is the single most helpful clinical feature. In addition, BSMI will stop abruptly and consistently when the infant is aroused. 7. Propriospinal Myoclonus at Sleep Onset (PSM) a. Diagnostic Criteria i. The patient complains of sudden jerks, mainly of the abdomen, trunk, and neck ii. The jerks appear during relaxed wakefulness and drowsiness, as the patient attempts to fall asleep iii. The jerks disappear upon mental activation and with onset of a stable sleep stage iv. The jerks result in difficulty initiating sleep b. Associated Features i. PSM often is associated with severe sleep-onset insomnia due to the inability of the patient to fall asleep because of the recurrent disturbing muscular activity c. Demographics i. Rare ii. Affects adults, not children d. Onset, Course, and Complications i. PSM arises in adulthood and is usually a chronic, unremitting condition e. Differential Diagnosis i. Sleep starts (hypnic jerks) usually appear during the transition between wakefulness and sleep and during light NREM sleep, whereas PSM may sometimes be present during relaxed wakefulness 8. Sleep Related Movement Disorder Due to a Medical Disorder a. Diagnostic Criteria i. The patient manifests sleep related movements that disturb sleep or its onset

Classification of Sleep Disorders ii.

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The movement disorder occurs as a consequence of a significant underlying medical or neurological condition b. This diagnosis is intended for sleep related movement disorders due to an underlying medical or neurologic condition that does not meet criteria for another specific movement disorder 9. Sleep Related Movement Disorder Due to a Medication or Substance a. Diagnostic Criteria b. The patient manifests sleep related movements that disturb sleep or its onset c. The movement disorder occurs as a consequence of current medication or substance use or withdrawal from a wake-promoting medication or substance 10. Sleep Related Movement Disorder, Unspecified a. This diagnosis is assigned when patients have a sleep related movement disorder that cannot be classified elsewhere and is suspected of being associated with an underlying psychiatric condition. In some cases, this is a temporary diagnosis prior to establishment of an underlying psychiatric condition that may explain the sleep related movement. 11. Isolated Symptoms and Normal Variants a. Excessive Fragmentary Myoclonus (EFM) i. EFM is a largely incidental PSG finding on EMG, characterized by small movements of the corners of the mouth, fingers, or toes, or by no visible movement at all. The finding is associated with no known clinical consequence. ii. Patients usually are not aware of the twitch-like movements iii. EFM is a NREM phenomenon b. Hypnagogic Foot Tremor (HFT) and Alternating Leg Muscle Activation (ALMA) i. HFT is rhythmic movement of the feet or toes that occurs at the transition between wake and sleep or during light NREM sleep (stages N1 and N2) ii. ALMA consists of brief activation of the anterior tibialis in 1 leg in alternation with similar activation in the other leg during sleep or arousals from sleep iii. Most cases of HFT have been reported in persons with other sleep disorders, such as RLS or SRBDs iv. ALMA has been identified mainly in patients with SRBD or PLMS as well as patients on antidepressant medication c. Sleep Start (Hypnic Jerks) i. Sleep starts, also known as hypnic jerks, are sudden, brief, simultaneous contractions of the body or one or more body segments occurring at sleep onset ii. The motor activity is often associated with a sensory component, often an impression of falling or less commonly pain or tingling; auditory, such as banging, snapping or crackling noises; or visual, including flashing lights, hypnagogic dreams, or hallucinations

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Ofer Jacobowitz and Lee Shangold iii.

Excessive caffeine or stimulant intake, prior intense physical work or exercise, sleep deprivation, and emotional stress can increase the frequency and severity of sleep starts

QUESTIONS 1. Referable to gender, age and socioeconomic strata, insomnia is more common in: a. Male, younger adults, lower socioeconomic strata b. Female, older adults, higher socioeconomic strata c. Male, older adults, higher socioeconomic strata d. Female, older adults, lower socioeconomic strata e. Male, younger adults, higher socioeconomic strata 2. Which of the following is not a diagnostic criterion for pediatric obstructive sleep apnea a. Paradoxical breathing b. Hyperactivity c. Enuresis d. Obstructive hypoventilation e. AHI ≥ 1 3. For the diagnosis of Narcolepsy with Cataplexy, which of the following are not essential? a. On MSLT, Sleep latency ≤ 8 minutes b. On MSLT, 2 or more SOREMPs (Sleep Onset REM Periods) c. Hypocretin level in CSF ≤110 pg/mL d. Severe Sleepiness e. Sleep paralysis 4. Other than REM Sleep Behavior Disorder (RBD), which of the following parasomnias is considered a REM-related parasomnia: a. Exploding Head Syndrome b. Sleep Related Eating Disorder c. Sleepwalking d. Recurrent Isolated Sleep Paralysis e. Sleep Terrors 5. Which of the following is a true statement: a. Most people who have a history of Restless Legs Syndrome (RLS) will have an elevated Periodic Limb Movement Index (PLMI) on an in-lab sleep study b. Most people who have an elevated PLMI on an in-lab sleep study will have RLS upon questioning c. A and B are both true d. Neither A nor B are true

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 4

SLEEP EVALUATION Tracey L. Stierer, MD Departments of Anesthesiology and Critical Care Medicine, Neurology, Otolaryngology, Head and Neck Surgery, Johns Hopkins Medical Institution, Baltimore, MD, USA

HISTORY AND PHYSICAL EXAM 1. Patients referred for sleep evaluation due to suspected sleep apnea may present with a chief complaint of snoring, fatigue, restless sleep, and even insomnia a. Alternatively, they may be referred due to the presence of a condition thought to be the sequelae of untreated sleep disordered breathing such as uncontrolled hypertension (HTN), atrial fibrillation, congestive heart failure, or refractory depression 2. Regardless of the reason for referral, a thorough history and physical examination are key in determining appropriate testing and an accurate diagnosis 3. It is frequently helpful for a spouse, bed partner, or family member to provide their perspective of the patient’s sleep habits as well

ASSESSMENT OF SLEEP DISORDERED BREATHING (SDB) SIGNS AND SYMPTOMS 1. Symptoms: a. Excessive daytime somnolence b. Fatigue c. Insomnia d. Frequent nighttime awakening e. Nocturia f. Dry mouth g. Morning Headache

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Tracey L. Stierer

2.

3.

4.

5.

6.

7.

8.

h. Awakening gasping and choking i. Mood changes including depression, anxiety, and irritability j. Memory loss and impaired cognition Additional Pediatric Symptoms: a. Hyperactivity/Attention deficit b. Poor school performance Signs: a. Snoring b. Witnessed apneas c. HTN d. Touching tonsils e. Retrognathia f. Craniofacial anomalies g. Enlarged neck circumference i. 17 inches for males, > 16 inches for females h. Elevated body mass index (BMI) i. 35 kg/m2 i. Age greater than 50 years Additional Pediatric Signs: a. Difficulty awakening in the morning b. Heavy breathing or snorting c. Unusual sleeping positions d. Obesity or failure to thrive Assessment of sleepiness a. Patients may be unaware that the level of sleepiness that they are experiencing is not “normal” b. Screening tools and questionnaires can aid the patient in assessing their sleepiness Epworth Sleepiness Scale (ESS): a. Widely utilized in Sleep Medicine practices to assess subjective sleepiness b. The ESS is an 8-item self-administered questionnaire with each question describing a scenario in which a patient may fall asleep c. Patients rate their tendency to doze in each situation on a scale of 0 (no chance of dozing) to 3 (high chance of dozing) d. The total score is the sum of the 8-item scores and can range from 0 to 24 with a score greater than 10 indicating subjective sleepiness Berlin Questionnaire: a. The Berlin Questionnaire is a self-administered survey designed to identify patients at risk for obstructive sleep apnea (OSA) b. It consists of 10 questions in three categories related to the severity of snoring, frequency of daytime sleepiness, and presence of HTN or obesity (BMI higher than 30 kg/m2) c. High risk patients for OSA are those that score high risk in at least 2 of the three categories STOP Bang Questionnaire: Eight dichotomous (yes/no) questions related to the features of OSA—snoring, tiredness, observed apnea, high blood pressure, BMI

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greater than 35 kg/m2, age greater than 50 years, neck circumference greater than 16 inches for women, 17 inches for men, and male gender a. One point is assigned for each question answered “yes” b. Patients with a score of 0 to 2 are classified as low risk for moderate to severe OSA and patients who score 5-8 are high risk for moderate to severe OSA c. Patients with a score of 3 to 4 require further criteria in order to be classified, and a score of 2 may be at high risk if the patient has a BMI of > 35 kg/m2

POLYSOMNOGRAPHY FUNDAMENTALS AND INTERPRETATION 1. The polysomnogram (PSG) is a multi-parametric test used to diagnose the presence of sleep disorders and is the gold standard by which sleep apnea is diagnosed a. Performed in a laboratory setting designed to resemble a bedroom b. Technician in attendance c. Standard monitoring devices for a full montage PSG include (Figure 1): i. Electroencephalogram (EEG) ii. Electrooculogram (EOG) iii. Chin electromyogram (EMG) iv. Limb EMG

Figure 1. Channels recorded: Electrooculogram (EOG) from both eyes; Electromyogram (EMG) of chin (S) and leg (L), electroencephalogram (EEG) from standard locations C3-A2, C3-O1; electrocardiogram (ECG); oxygen saturation (SaO2); airflow (cannula and thermistor); respiratory effort (thoracic and abdomen). Stierer T, Punjab N. Anesthesiol Clin North Am. 2005 Sep.; 23(3):40520.

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Tracey L. Stierer v.

Nasal canula equipped with:  Pneumotach: measures nasal inspiratory airflow OR  Thermistor: measures nasal airflow temperature changes  Electrocardiogram (ECG)  Pulse oximetry  Respiratory inductance plethysmography (RIP) belts on abdomen and thorax  Optional:  Transcutaneous carbon dioxide (TcCO2)  End tidal carbon dioxide (ETCO2)  Continuous positive air pressure (CPAP) or Bilevel positive air pressure (BiPAP) 2. Results are scored and interpreted in accordance with the American Academy of Sleep Medicine Manual for the Scoring of Sleep and Associated Events (Figure 2)

Figure 2. Channels recorded: Electrooculogram (EOG) from both eyes; Electromyogram (EMG) of chin (S) and leg (L), electroencephalogram (EEG) from standard locations C3-A2, C3-O1; electrocardiogram (ECG); oxygen saturation (SaO2); airflow (cannula and thermistor); respiratory effort (thoracic and abdomen). Stierer T, Punjab N. Anesthesiol Clin North Am. 2005 Sep.; 23(3):40520.

a.

Respiratory events (adult): i. Apnea: absence of breath for ≥ 10 seconds duration ii. Hypopnea: decreased inspiratory flow for > 10 seconds duration associated with 4% or more decrease in oxyhemoglobin saturation iii. Respiratory effort related arousal (RERA): series of breaths with evidence of increasing effort or flattening of the nasal pressure

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waveform leading to a cortical arousal from sleep that does not otherwise meet criteria for scoring as an apnea or hypopnea. b. Apnea hypopnea index (AHI): i. Total sum of all apnea and hypopnea events recorded during study divided by the total sleep time:  AHI = Apneas + Hypopneas Total sleep time (hr) c. Respiratory disturbance index (RDI): i. Total sum of all apneas, hypopneas, and RERA events recorded during PSG divided by the total sleep time:  RDI = Apneas + Hypopneas + RERA’s Total sleep time (hr) d. AHI or RDI may be used to categorize the severity of sleep apnea (adult): i. Mild: ≥ 5 but < 15 events/hour ii. Moderate: ≥ 15 but < 30 events/hour iii. Severe: ≥ 30 events/hour 3. While an in-laboratory sleep study provides more physiologic data than most portable sleep monitors, some patients may experience anxiety and difficulty sleeping in an unfamiliar environment resulting in a non-diagnostic test

HOME SLEEP APNEA TESTING (HSAT) 1. Portable sleep testing equipment used to detect sleep disordered breathing in patients with a high pre-test probability of having the condition 2. Devices with limited channels may not be particularly useful for diagnosing other sleep related disorders 3. Although the devices are widely used to screen for OSA, home sleep tests (HST) tend to underrepresent the severity of sleep disordered breathing a. Less costly than in-laboratory PSG b. Enhanced convenience as patients can sleep in their own bed during the study and initiate the test with lights off at a time of their choice c. Three categories of portable monitors: (Type I is an in-laboratory attended PSG) i. Type II-unattended, must include a minimum of 7 channels including EEG ii. Type III-unattended, must include a minimum of 4 channels iii. Type IV-unattended, must include a minimum of 3 channels  Type III and IV devices are not capable of measuring sleep stages and are therefore have no role in the diagnosis of many other sleep related disorders or parasomnias 4. Not all patients are appropriate for HSAT. The following criteria are considered exclusionary criteria by most insurers for HSAT in a patient: a. Severe obesity (BMI > 45 kg/m2) b. Neuromuscular disease

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Tracey L. Stierer c. Seizure history d. Congestive heart failure – ejection fraction (EF) 65 years)

14-17 hours 12-15 hours 11-14 hours 10-13 hours 9-11 hours 8-10 hours 7-9 hours 7-8 hours

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Jennifer Molano Table 2. Age-appropriate sleep quality

Sleep latency Awakenings < 5 minutes Wake after sleep onset Sleep efficiency - Defined as total sleep time over time in bed Naps in a 24-hour period

Appropriate < 15-30 minutes for all age groups < 1 for toddlers to adults < 2 for older adults < 20 minutes for toddlers to adults < 30 minutes for older adults > 85% across all age groups

Inappropriate > 60 minutes for all age groups > 4 for all age groups

No naps for school-aged children and young adults 0-1 naps in teens

> 4 naps for all age groups > 2 naps for school aged children > 3 naps in teens and young adults Uncertain in adults/older adults > 100-120 minutes in teens, young adults and older adults > 3 days per week in school-aged children

Nap duration

< 20 minutes in teens

Nap frequency

0 naps per week in teens and young adults

< 65-75% across all age groups

2. Aberrations in sleep duration and/or sleep quality may lead to sleep deprivation 3. Guidelines for age-appropriate sleep duration and sleep quality times per the National Sleep Foundation are indicated in Tables 1 and 2.

SLEEP NEUROBIOLOGY: ESSENTIAL COMPONENTS OF OPTIMAL SLEEP HEALTH 1. The Sleep-wake cycle is driven by a. Homeostatic sleep drive b. Circadian rhythms c. Underlying neurotransmitter systems 2. Alterations in the homeostatic sleep drive, circadian rhythms, and/or neurotransmitter systems may contribute to sleep deprivation 3. A brief description of the neurobiology of sleep is included here. Further details are provided in Chapter 2 - Sleep Physiology.

Homeostatic Sleep Drive 1. Assuming adequate sleep duration and sleep quality, the homeostatic sleep drive, driven by adenosine, is lowest in the morning and increases during the waking hours to promote sleep at night 2. Daytime naps and late caffeine use can lower adenosine levels a. This can lead to partial sleep deprivation through difficulties initiating sleep or maintaining sleep

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Circadian Rhythms 1. Our circadian rhythms for alertness are highest during the waking hours and lowest at sleep onset a. Conducted by the suprachiasmatic nucleus in the hypothalamus b. Circadian rhythm is associated with the timing of multiple processes in the body, including sleep 2. Light entrains the circadian rhythm through pathways from the retinohypothalamic tract, the spinal cord, the superior cervical ganglion and finally the pineal gland to suppress melatonin a. Melatonin release is subsequently triggered by darkness, leading to the initiation of sleep 3. In addition to light, circadian rhythms also are entrained by multiple environmental factors such as exercise and eating habits a. Aberrations in these behaviors may contribute to sleep deprivation

Neurotransmitters Associated with Sleep and Wakefulness 1. Multiple neurotransmitters contribute to the sleep wake cycle, and medications that affect these neurotransmitter systems also may contribute to sleep deprivation 2. Wakefulness a. These neurotransmitters are activated during wakefulness: i. Monoaminergic neurotransmitters  Norepinephrine, serotonin, dopamine, and histamine ii. Acetylcholine 3. Non-Rapid Eye Movement (REM) sleep a. Gamma aminobutyric acid (GABA)-mediated projections from the ventral lateral preoptic nucleus in the hypothalamus promote sleep by inhibiting the wake-promoting neurotransmitters 4. REM sleep a. Monoaminergic neurotransmitters remain deactivated b. Acetylcholine becomes activated c. Glycine-mediated projections into the spinal cord also drive the muscle atonia during REM sleep 5. Sleep-wake stabilization a. The neuropeptide orexin stabilizes the sleep-wake circuitry towards wakefulness, and also enables the REM circuitry to remain off during wakefulness

TYPES OF SLEEP DEPRIVATION 1. Sleep deprivation can be defined as total sleep deprivation or partial sleep deprivation a. Since partial sleep deprivation is more common, this definition will be the primary focus for the rest of this book chapter

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Jennifer Molano 2. Total sleep deprivation a. Associated with complete lack of sleep for at least 24 hours 3. Partial sleep deprivation a. Sleep restriction or debt i. The most common type of partial sleep deprivation, often driven by lifestyle or societal demands ii. Also may be known as insufficient sleep time, an inadequate amount of sleep, or short sleep duration b. Changes in sleep architecture due to sleep restriction or sleep debt i. Sleep latency progressively shortens and daytime sleep propensity increases with sleep restriction on consecutive nights in a doseresponse relationship ii. Decreased time to N2 and REM sleep seen after multiple nights of 4 hours of sleep but no decrease in slow wave sleep in healthy adults c. Effects of recovery sleep on sleep architecture i. Recovery sleep may provide temporary relief for daytime sleepiness in the setting of inadequate sleep duration/sleep debt ii. More slow wave sleep is seen with the first night of recovery sleep after sleep deprivation iii. More REM sleep is seen after the second night of recovery sleep iv. The amount of sleep recovered is not proportional to the amount lost with sleep deprivation 4. Sleep fragmentation a. Associated with multiple awakenings during sleep which may or may not be noticed by an individual

CONSEQUENCES OF SLEEP DEPRIVATION 1. Sleep deprivation affects many domains a. Interindividual variability can occur in response to sleep deprivation and is influenced by both environmental and biological factors, such as epigenetic mechanisms 2. Socioeconomic impact a. Sleep deprivation is associated with the following socioeconomic consequences: i. Increased motor vehicle crashes, with 20% of all serious car crashes thought to be related to sleep deprivation ii. Increased work-related injuries iii. Increased falls in older adults iv. Billions of dollars of cost v. Increased health care utilization vi. Increased workplace absenteeism vii. Increased workplace accidents viii. Decreased work productivity

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3. Mortality risk a. Short sleep duration was associated with a 12% increased risk of mortality 4. Quality of life a. Sleep deprivation can lead to decreased quality of life 5. Cardiovascular risk a. Short sleep duration was associated with a 17% increased risk of hypertension, 16% increased risk for cardiovascular disease, and 26% increased risk for coronary heart disease b. Mechanisms driving this increased risk may be associated with increased inflammatory markers, such as C-reactive protein 6. Excessive daytime sleepiness a. Sleep duration of less than 6.75 hours a night had a 73% increased risk of falling asleep compared to those with > 7.5 hours of sleep b. Sleep restriction leads to increased sleep propensity during the waking hours in a linear/dose-response fashion c. Objective effects of chronic sleep restriction may be present based on psychomotor vigilance tasks i. People may underestimate their degree of subjective sleepiness, stating that they are only moderately sleepy d. Those with fewer than 7 hours of sleep at night also had an increased incidence in sleep-related crashes 7. Cognitive and behavioral effects a. Sleep deprivation can contribute to changes in the frontal-subcortical networks of cognition, contributing to difficulties with behavioral alertness, attention and executive functions such as decision-making skills b. Increased risk-taking and increased emotional dysregulation also may occur c. May be associated with maladaptive behaviors such as increased alcohol usage d. May contribute to increased anxiety, depression, and irritability - Example: Effects of sleep deprivation on physicians i. Acute sleep deprivation with on-call schedules and chronic sleep deprivation have been associated with mood impairments and decreased cognitive performance in residents ii. Sleep deprivation has also been associated with increased physician burnout, with 92% of sleep disorders underdiagnosed in physicians in one cross-sectional study iii. The effects of sleep deprivation on surgeon performance or dexterity need further study 8. Metabolic consequences a. Sleep deprivation can lead to weight gain i. Short sleep time is associated with a 38% increased risk for obesity compared normal sleeper b. Decreased leptin and increased ghrelin release can lead to increased subjective hunger and subsequent food consumption

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Short-term sleep restriction has been associated with decreased glucose tolerance, with meta-analyses showing a 37% increased risk for diabetes mellitus d. Short sleep time may contribute to childhood obesity

CAUSES OF SLEEP DEPRIVATION 1. Sleep deprivation often is multifactorial a. Some of these causes include environmental factors, behavioral influences, primary sleep disorders, circadian rhythm misalignment, underlying medical or psychiatric issues, and medications 2. Environmental factors and behavioral influences a. Environmental and behavioral factors may affect both the homeostatic sleep drive and circadian altering signal b. Work, school, social demands, psychosocial stressors, and/or technology and excessive screen time may lead to variability in sleep schedules c. Additional behavioral factors that may lead to sleep deprivation include prolonged naps during the day, prolonged time in bed, late caffeine use and/or evening alcohol consumption 3. Primary sleep disorders a. Behaviorally induced insufficient sleep syndrome i. Associated with voluntary, yet unintentional sleep deprivation ii. One does not have any issues initiating sleep or staying asleep but may not get enough sleep needed for optimal daytime alertness b. Sleep disordered breathing disorders i. Associated with intermittent decrements and/or cessation of breathing followed by oxyhemoglobin desaturations that can contribute to sleep deprivation through sleep fragmentation ii. Includes obstructive and central sleep apnea c. Insomnia i. Contributes to sleep deprivation due to prolonged sleep onset, sleep fragmentation and increased wakefulness after sleep onset d. Restless legs syndrome (RLS) i. Associated with an urge to move the legs at night that is worse at rest and better with movement, can interfere with sleep onset ii. Periodic limb movements of sleep, seen in 80-90% of those with RLS, can lead to sleep-fragmentation e. Parasomnias i. Includes non-REM parasomnias such as sleepwalking, sleep-talking, and confusional arousals and REM parasomnias such as nightmares and REM sleep behavior disorder ii. REM parasomnias may contribute to sleep deprivation if symptoms are distressing to the patient. Periodic limb movements of sleep also can be seen in those with REM sleep behavior disorder.

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Narcolepsy i. May be associated with cataplexy (type I) or without cataplexy (type 2) ii. Sleep disruption and fragmentation can be associated in 50% of those with type I narcolepsy g. Circadian rhythm disorders i. Includes delayed sleep phase disorder, advanced sleep phase disorder, irregular sleep wake cycles, shift work disorder, and jet lag ii. Sleep time ideally should match with one’s underlying circadian rhythm iii. Conditions associated with circadian misalignment such as delayed sleep phase or shift work can contribute to chronic sleep debt due to insufficient sleep or short sleep time if one needs to awaken during one’s natural sleep time 4. Medical issues a. Underlying medical issues such as gastroesophageal reflux disease, renal disease, chronic pain, asthma and neurological conditions such as dementia, among many others, may contribute to sleep fragmentation and poor sleep quality b. May have a bidirectional relationship with sleep - Example: Alzheimer’s Disease (AD) i. AD is a neurodegenerative condition whose initial clinical features are episodic memory loss ii. Pathologically, AD has a prodromal/pre-symptomatic phase associated with amyloid plaque deposition, which occurs ~15-20 years prior to the onset of cognitive symptoms and neurodegeneration due to tau-related neurofibrillary tangles iii. Insufficient sleep and reduced sleep efficiency have contributed to amyloid deposition in cognitively normal adults based on amyloid imaging and cerebrospinal fluid studies iv. Alterations in the suprachiasmatic nucleus and ventrolateral preoptic nucleus may contribute to sleep issues in those with AD 5. Psychiatric issues a. Psychiatric conditions such as depression and anxiety may contribute to insufficient sleep time and sleep debt due to prolonged sleep latency, increased arousals and/or early morning awakenings b. Post-traumatic stress disorder also can lead to sleep fragmentation due to increased arousals and nightmares 6. Medications and substances a. Multiple medications may contribute to sleep deprivation, including corticosteroids, cardiovascular medications, and others (such as those for renal failure, cancer, and rheumatologic/immunologic conditions) b. Beta-blockers and hemodialysis may decrease melatonin levels

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Antidepressants such as selective serotonin and norepinephrine reuptake inhibitors may have activating properties that may contribute to sleep fragmentation, worsen restless legs syndrome, or contribute to parasomnias such as nightmares and REM sleep behavior disorders i. e.g., fluoxetine and venlafaxine d. Donepezil for Alzheimer’s disease is an acetylcholinesterase inhibitor and increases acetylcholine, a wake-promoting neurotransmitter i. Dosing at nighttime may contribute to insomnia and nightmares e. Opioids may contribute to sleep fragmentation due to central sleep apnea f. Caffeine is an adenosine antagonist, leading to disrupted sleep or delays in sleep onset i. May also worsen RLS symptoms g. Alcohol may shorten sleep onset latency, but may cause sleep fragmentation towards the later part of the night i. It can worsen obstructive sleep apnea and trigger parasomnias h. Nicotine is activating and may contribute to sleep fragmentation and worsen obstructive sleep apnea

WORKUP FOR SLEEP DEPRIVATION 1. A comprehensive sleep history and evaluation is essential to determine possible causes and underlying reasons for sleep deprivation 2. Sleep history a. Obtaining a thorough sleep history can determine perceptions of sleep duration and sleep quality b. It is important to ask about a person’s sleep schedule during the week and the weekend since sleep duration may vary based on work, school, and home obligations c. Sleep schedule parameters i. Bedtime ii. Time to fall asleep iii. Number of nighttime awakenings iv. Time to fall back to sleep after a nighttime wakening v. Wake up time vi. Time out of bed vii. Number and duration of intentional and unintentional naps d. Environmental and behavioral factors i. Additional history should address environmental and behavioral factors that may contribute to sleep deprivation  Routines before bedtime  Psychosocial stressors  Alcohol consumption  Caffeine use, including latest time of usage during the day  Recreational drug use

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 Smoking and nicotine use  Use of electronic devices in bed and screen time  Timing of exercise and eating schedules 3. Screening for primary sleep disorders a. Screening of symptoms for specific primary sleep disorders is also needed b. Behaviorally induced insufficient sleep syndrome i. Symptoms include excessive daytime sleepiness due to insufficient sleep time, typically during the weekdays, with an extended sleep time during the weekend or holidays c. Sleep-disordered breathing i. Symptoms include snoring, witnessed apneas, morning headaches, excessive daytime sleepiness ii. Exam findings may include a crowded airway, retrognathia, an increased neck circumference, and obesity d. Insomnia i. Difficulty falling asleep, staying asleep, frequent nighttime awakenings, or early morning awakenings ii. May be multifactorial. An assessment of predisposing, precipitating, and perpetuating factors may inform potential contributing factors for insomnia. iii. Predisposing factors may include a family history of insomnia or predisposition for light sleep iv. Precipitating factors include potential triggers for insomnia such as a major stressful event v. Perpetuating factors include behaviors that may reinforce insomnia, such as a prolonged time in bed or late caffeine use e. Parasomnias i. Non-REM parasomnias include sleepwalking, sleep-talking, and confusional arousals ii. REM-related parasomnias include nightmares and REM sleep behavior disorder iii. Dream enactment behavior may indicate obstructive sleep apnea due to REM-related respiratory events or REM sleep behavior disorder f. Narcolepsy i. In addition to possible cataplexy, additional symptoms may include sleep paralysis and/or hypnagogic or hypnopompic hallucinations g. RLS i. Associated with an urge to move the legs at night, worse at rest, better with movement ii. May be associated with peripheral neuropathy or renal disease h. Circadian rhythm disorders i. Asking about one’s natural bedtime and wake-up time on the weekends and/or on vacation may determine if a circadian rhythm disorder is present

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Jennifer Molano ii. If a person is a shift worker, asking about their schedule while working versus non-working days may provide an indication of the variability of their sleep schedule 4. Additional sleep testing and evaluation a. Further testing may be indicated to evaluate a person’s sleep-wake cycle or to determine if a primary sleep condition is present b. Polysomnography i. Consider if obstructive sleep apneas, parasomnias, or periodic limb movements of sleep are suspected ii. Note that REM sleep without muscle atonia is needed to confirm the diagnosis of REM sleep behavior disorder in a person who presents with dream enactment behavior c. Sleep log i. Provides additional subjective information on a person’s sleep schedule d. Actigraphy i. Actigraphy is a wrist-worn device that approximates a person’s sleepwake cycle based on movement ii. In conjunction with sleep logs, can provide objective data on a person’s sleep schedule, can approximate one’s sleep duration and quality, and may also assist in determining if circadian misalignment is present e. Multiple sleep latency test i. A daytime sleep study performed after overnight polysomnography to evaluate for possible narcolepsy ii. Note that workup for narcolepsy requires the exclusion of other entities such as sleep deprivation due to insufficient sleep time and obstructive sleep apnea as the cause of excessive daytime sleepiness f. Lab work i. Iron studies and ferritin levels may be useful to evaluate for underlying causes of RLS

MANAGEMENT OF SLEEP DEPRIVATION 1. Management of sleep deprivation is associated with addressing the underlying causes, with the goal of optimizing sleep duration and sleep quality 2. Address primary sleep issues. Table 3 summarizes symptoms, evaluation, and management of the primary sleep disorders that may contribute to sleep fragmentation. A more comprehensive review is covered in subsequent chapters. 3. Address underlying medical and psychiatric issues a. Optimal treatment of underlying medical and psychiatric issues that may contribute to sleep deprivation is also recommended 4. Medications a. Adjust medications that may contribute to sleep issues

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Table 3. Sleep disorders Cause Behaviorally induced insufficient sleep syndrome Sleep disordered breathing

Insomnia

History - Excessive daytime sleepiness due to insufficient sleep time

Evaluation - Thorough sleep history

- Snoring, witnessed apneas, morning headaches, excessive daytime sleepiness - Review of opioid use for central sleep apnea - Assessment of alcohol consumption for obstructive sleep apnea - Subjective assessment of sleep duration and sleep quality - Predisposing, precipitating, and perpetuating factors for insomnia - Detailed medical, psychiatric, and substance use history

- Polysomnography

Circadian rhythm disorders

- Misalignment of sleep times and natural circadian rhythms

Restless legs syndrome

- Urge to move the legs Symptoms more prominent at night - Worse at rest - Better with movement - Sleepwalking - Sleep-talking - Dream enactment behaviors - Nightmares - Excessive daytime sleepiness - Cataplexy - Sleep paralysis - Hypnagogic hallucinations

Parasomnias

Narcolepsy

- Sleep logs - Actigraphy - Polysomnography can be considered if sleep-disordered breathing or parasomnias are suspected, or if the etiology is uncertain - Sleep logs - Actigraphy

- Iron studies and ferritin levels

- Polysomnography if REM sleep behavior disorder is suspected - Sleep logs +/actigraphy to ensure adequate sleep time - Polysomnography to exclude sleepdisordered breathing and/or periodic limb movements of sleep - Multiple sleep latency test

Management - Extend sleep time and encourage behaviors that optimize sleep duration - Positive airway pressure - Alternative treatments for obstructive sleep apnea Oral appliance therapy Surgical modifications Positional therapy for supinedependent obstructive sleep apnea - Cognitive behavioral therapy - Relaxation therapy - Stimulus control techniques - Pharmacological treatment ideally is for short term use only and should be used in conjunction with cognitive-behavioral therapy

- Timed melatonin and light therapy - Chronotherapy - For shift workers, a planned nap before the shift may be helpful -Wake promoting medications or caffeine may be helpful but should not be a substitute for sufficient sleep - Iron supplementation - Dopamine agonists - Alpha-delta ligands

- Safety precautions - Clonazepam - Melatonin for REM sleep behavior disorder - Wake-promoting medications - Sodium oxybate for type I narcolepsy - Selective serotonin reuptake inhibitors for cataplexy

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OPTIMIZING SLEEP HYGIENE 1. Managing sleep deprivation also requires optimizing sleep hygiene and behaviors to promote sleep a. Optimizing sleep hygiene provides a solid foundation to optimize the environmental and behavioral factors that can affect sleep, but should be used in conjunction with a comprehensive approach to the management of sleep deprivation b. Sleep hygiene guidelines should be tailored to the individual 2. Maintain a consistent sleep schedule a. Encouraging a consistent sleep schedule promotes regularity of the homeostatic sleep drive and circadian rhythms 3. Develop a bedtime routine a. Assists in preparing the brain for sleep 4. Optimize the bedroom environment for sleep a. The bedroom should be quiet and at a cool, comfortable temperature b. Keep the bedroom for sleep only i. Encourage people to get out of bed and do a non-activating activity if unable to fall asleep or stay asleep within 20 minutes 5. Limit naps a. Daytime naps can be a countermeasure to sleep restriction to improve daytime alertness and performance, but they should not be a substitute for adequate sleep at night b. Naps longer than 30 minutes may lead to sleep inertia c. Additionally, napping during the day decreases the homeostatic sleep drive and may make it more challenging to sleep at night d. Limit naps to no more than 30 minutes a day if absolutely necessary 6. Monitor caffeine use a. Caffeine is an adenosine antagonist with a half-life of 3-5 hours b. Caffeine-free beverages should be consumed in the late afternoon or beyond c. Note that decaffeinated beverages still have a small amount of caffeine and still may be stimulating for individuals 7. Monitor alcohol consumption a. Avoidance of alcohol in the evening 8. Encourage nicotine cessation a. Smoking can affect sleep, and smoking cessation is recommended for overall health benefits 9. Encourage exercise and good nutrition a. Exercise has been shown to improve sleep quality and sleep onset latency b. The timing of exercise may be important, since high intensity exercise before bedtime may increase cortisol levels and affect sleep c. Avoidance of a heavy meal before bedtime may assist with sleep

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CONCLUSION 1. Sleep deprivation, especially partial sleep deprivation due to inadequate sleep time or sleep fragmentation, is common 2. Sleep deprivation has significant socioeconomic, personal, and professional consequences 3. Management of sleep deprivation requires a comprehensive sleep evaluation that investigates the possible causes of sleep deprivation

KEY CLINICAL POINTS 1. The goal of treatment for sleep deprivation is optimizing age-appropriate sleep quality and sleep duration. 2. A comprehensive sleep evaluation should address the environmental factors, behavioral influences, primary sleep disorders including circadian misalignment, underlying medical or psychiatric issues, and/or medications that may be contributing to sleep deprivation. 3. Management of sleep deprivation should target the causes of sleep deprivation in an individual. 4. Addressing sleep hygiene focuses on the environmental and behavioral factors that may affect sleep. 5. Optimizing sleep hygiene should be used in conjunction with a comprehensive approach to the management of sleep deprivation.

QUESTIONS 1. Sleep deprivation can lead to which of the following metabolic changes? a. Decreased ghrelin and decreased leptin b. Decreased ghrelin and increased leptin c. Increased ghrelin and decreased leptin d. Increased ghrelin and increased leptin e. No changes in ghrelin or leptin levels. 2. Which of the following class of medications decrease melatonin levels? a. Acetylcholinesterase inhibitors b. Alcohol c. Beta-blockers d. Opioids e. Selective serotonin reuptake inhibitors

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Jennifer Molano 3. Which of the following changes occur after the second night of recovery sleep after sleep restriction? a. Increased arousals b. Increased N1 sleep c. Increased N2 sleep d. Increased N3 sleep e. Increased REM sleep 4. Caffeine can affect sleep by decreasing which of the following levels? a. Acetylcholine b. Adenosine c. GABA d. Serotonin e. Histamine 5. Sleep deprivation affects which of the following cognitive domains? a. Episodic memory b. Executive function c. Language d. Premorbid intelligence e. Visuospatial skills

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Sugden C, Athanasiou T, Darzi A. What are the effects of sleep deprivation and fatigue in surgical practice? Semin Thorac Cardiovasc Surg. 2012 Autumn;24(3):166-75. doi: 10.1053/j.semtcvs.2012.06.005. Van Cauter E, Spiegel K, Tasali E, Leproult R. Metabolic consequences of sleep and sleep loss. Sleep Med. 2008 Sep;9 Suppl 1(0 1):S23-8. doi: 10.1016/S1389-9457(08)70013-3. Vitale KC, Owens R, Hopkins SR, Malhotra A. Sleep Hygiene for Optimizing Recovery in Athletes: Review and Recommendations. Int J Sports Med. 2019 Aug;40(8):535-543. doi: 10.1055/a-0905-3103. Weaver MD, Robbins R, Quan SF, O'Brien CS, Viyaran NC, Czeisler CA, Barger LK. Association of Sleep Disorders With Physician Burnout. JAMA Netw Open. 2020 Oct 1;3(10):e2023256. doi: 10.1001/jamanetworkopen.2020.23256.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 6

SLEEP PHARMACOLOGY Kimberly Y. Kreitinger1, MD and Atul Malhotra2, MD 1

Division of Sleep Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA 2 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA

INSOMNIA Table 1. Sleep hygiene recommendations Keep a regular sleep schedule Optimize sleeping environment. Try to keep the area dark, cool, and quiet Avoid screen time and stimulating activities before bedtime Avoid excessive caffeine, nicotine, and alcohol Avoid long naps Keep active during the day but avoid vigorous exercise close to bedtime

1. Initial approach for insomnia a. Assess sleep hygiene factors (Table 1) b. Evaluate if patient may be a candidate for cognitive behavior or mindfulness-based theories for insomnia. Due to potential side effects of pharmacological treatment, behavior therapies are considered first-line treatment for chronic insomnia. 2. Benzodiazepines a. Mechanism of action (MOA): Modulates/enhances γ-aminobutyric acid type A (GABA-A) receptors via benzodiazepine receptors b. Used for sleep onset and sleep maintenance c. Decreases slow wave sleep d. Short-acting: Triazolam i. Used primarily for sleep onset given short half-life ii. Half-life: 2-5 hours

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Kimberly Y. Kreitinger and Atul Malhotra iii. Dose: 0.125-0.5 mg. Usual dose 0.25 mg. e. Intermediate-acting: Temazepam i. Half-life: 8-15 hours ii. Dose: 7.5-30 mg. Usual dose 15 mg. f. Long-acting: Flurazepam i. Half-life: 90-110 hours, longer for elderly patients ii. Dose: 15-30 mg g. Side effects i. Tolerance ii. Morning and daytime somnolence and cognitive/motor impairment especially with long-acting benzodiazepines iii. Increased risk of falls in elderly patients 3. Z-drugs a. MOA: Modulates/enhances GABA-A receptor via selective agonism at the benzodiazepine-1 receptor b. Used for sleep onset and sleep maintenance c. More preserved sleep architecture compared to benzodiazepines d. Food delays onset of action. Ideally, medication is taken before sleep on an empty stomach. e. Zaleplon i. Used primarily for sleep onset given short half-life ii. Half-life: 1 hour iii. Dose: 5-20 mg f. Zolpidem i. Comes in different preparations: tablet, controlled release (CR), sublingual (SL), and oral spray ii. Half-life: 2.5 hours. CR 3 hours. iii. Sublingual formulation has a faster onset of action iv. Dose: Tablet 5-10 mg. CR 6.25-12.5 mg. SL 1.75-3.5 mg and 5-10 mg. Oral spray 5 mg.  Men metabolize at twice the rate as women. Clearance also decreases with age. Start with lower doses in women and geriatric patients. g. Eszopiclone i. Half-life: 6 hours ii. Dose: 1-3 mg h. Side effects i. Complex sleep-related behaviors and parasomnia (e.g., sleep-driving, sleep-eating)  Seen mostly in zolpidem  Increased risk with concomitant alcohol or pre-existing parasomnia ii. Driving impairment  Seen with higher and later (middle of the night) doses of zolpidem

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iii. Zolpidem associated with increased risk of hip fractures in the elder iv. Eszopiclone associated with unpleasant/metallic taste (not related to taste of pill) 4. Melatonin agonist a. Ramelteon i. MOA: Agonist of melatonin MT1 and MT2 receptors i. Used for sleep onset insomnia ii. Low frequency of adverse events iii. Half-life: 2-5 hours iv. Dose: 8 mg 5. Orexin antagonist a. Suvorexant, Lemborexant i. MOA: Antagonist of orexin receptor OX1R and OX2R ii. Used for sleep onset and sleep maintenance iii. Suvorexant is FDA-approved for the use of insomnia in Alzheimer’s disease iv. Half-life: Suvorexant 12 hours. Lemborexant 17-19 hours. v. Dose: Suvorexant 10-20 mg. Lemborexant 5-10 mg. vi. Side effects: Daytime somnolence (dose-dependent) vii. Avoid use with inhibitors or inducers of CYP3A4 6. Sedating antidepressants a. Doxepin i. MOA: Histamine H1 receptor antagonist ii. Used for sleep maintenance iii. Half-life: 15-30 hours iv. Dose: 3-6 mg (Note: antidepressant dose is 100-300 mg) v. Side effects: Daytime somnolence, dry mouth, dizziness, abnormal dreams b. Trazodone i. MOA: Histamine H1, α2, and serotonin receptor antagonist ii. Not approved by the FDA for insomnia. Most frequently used “offlabeled” medication. iii. Increases slow wave sleep iv. Decreases sleep latency and early awakenings. Improves perceived sleep quality. v. Half-life: 5-9 hours vi. Dose: 25-100 mg vii. Side effects: Headache, daytime somnolence, QT prolongation, priapism (rate is between 1 in 1,000 and 1 in 10,000)

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CENTRAL HYPERSOMNIAS (NARCOLEPSY TYPE 1, NARCOLEPSY TYPE 2, IDIOPATHIC HYPERSOMNIA) 1. Pharmacological treatment targeted to symptoms of excessive daytime sleepiness, sleep fragmentation, and cataplexy 2. Sodium oxybate (gamma-hydroxybutyrate [GHB]) a. MOA: Activation of GABA-B receptors and GHB receptors b. Effective for narcolepsy type 1 for excessive daytime sleepiness, sleep fragmentation, and cataplexy c. Recently, low-sodium formulation given FDA-approved for idiopathic hypersomnia. First medication approved for this indication. d. Dose: Start with 2.25 g at bedtime and 2.25 g after 2-4 hours of sleep. Can increase up to 9 g in divided doses. e. Side effects: Nausea, enuresis, sleepwalking, sleep groaning, anxiety f. Should not be taken with alcohol or sedating medications g. Highly controlled due to potential for abuse (rape drug, recreational use) i. Distributed by one central pharmacy in the United States h. Tolerance does not develop with long-term use i. High sodium content. Use with caution in sensitive patients (e.g., patients with congestive heart failure) i. Low-sodium formulation (calcium, magnesium, potassium, and sodium oxybates) has 92% less sodium

EXCESSIVE DAYTIME SLEEPINESS IN CENTRAL HYPERSOMNIAS 1. Sodium oxybate improves excessive daytime sleepiness in central hypersomnias. Often the addition of a stimulant is needed for residual daytime sleepiness. 2. Stimulants a. Modafinil and armodafinil (R-isomer of racemic modafinil) i. MOA: Unclear. Stimulates release of dopamine, histamine, norepinephrine, serotonin, and orexin in the central nervous system ii. Higher drug concentration later in the day with armodafinil iii. Also approved for the use of residual daytime sleepiness in obstructive sleep apnea and in shift-work disorder iv. Dose: Modafinil 200-400 mg. Armodafinil 150-250 mg. v. Side effects: Decrease efficacy of hormonal contraceptives (via altering cytochrome P450 activity), nausea, rash vi. Not FDA-approved in children due to concern for drug-related skin rashes vii. Use with caution in premenopausal women given effects on hormonal contraceptives and potential teratogenic effects

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b. Methylphenidate i. MOA: Inhibits reuptake of dopamine and norepinephrine ii. Dose: 10-100 mg iii. Longer acting forms preferable to decrease risk of abuse. Less potential for abuse compared to amphetamine-dextroamphetamine. iv. Immediate release can be used as needed for emergencies or sleep attacks (e.g., if there is a need for driving) c. Amphetamine-dextroamphetamine i. MOA: Promotes release of dopamine and norepinephrine ii. Dose: 10-60 mg iii. Side effects: Irritability, anxiety, high blood pressure iv. Potential for abuse and tolerance d. Solriamfetol i. MOA: Inhibits reuptake of dopamine and norepinephrine ii. Also approved for the use of residual daytime sleepiness in obstructive sleep apnea iii. Dose: 75-150 mg. Increase every 3 days based on response and tolerability. iv. Side effects: High blood pressure (ensure that blood pressure is controlled before initiating), insomnia, headache, nausea, increased heart rate e. Pitolisant i. MOA: Histamine H3 receptor antagonist/inverse agonist ii. Also approved for the use of residual daytime sleepiness in obstructive sleep apnea iii. Decreases rates of cataplexy in addition to improving wakefulness iv. Dose: 8.9-36.6 mg. Increase dose weekly.

CATAPLEXY IN NARCOLEPSY TYPE I 1. Concomitant improvement in sleep paralysis and hypnagogic hallucinations often seen with pharmacological treatment of cataplexy 2. Venlafaxine ER a. MOA: Increases noradrenergic and serotonergic by inhibiting reuptake. Suppresses pathway from REM sleep/cataplexy. b. Dose: 37.5-150 mg c. Response in < 1 week d. Rebound cataplexy occurs when stopping medication i. Extended formulation preferred to prevent rebound e. Side effects: Nausea, dry mouth 3. Sodium oxybate and pitolisant are also effective for cataplexy

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OBSTRUCTIVE SLEEP APNEA (OSA) 1. Primary therapies a. No pharmacological therapy is currently recommended for primary treatment of OSA b. Potential mechanisms for the primary treatment of OSA include activation of the genioglossus muscle, increasing arousal threshold, and decreasing loop gain c. Activation of the genioglossus muscle i. Most important dilator muscle of the upper airway ii. Serotonin, noradrenaline, and acetylcholine are key neurotransmitters involved in regulation of the genioglossus muscle iii. Small studies with fluoxetine, paroxetine, protriptyline, venlafaxine, nicotine, physostigmine, and donepezil have shown no to small effects in improving the apnea-hypopnea index (AHI) iv. Atomoxetine (norepinephrine reuptake inhibitor) and oxybutynin (antimuscarinic) in combination have been shown to significantly decrease AHI (≥ 50%) and increase genioglossus muscle responsiveness in a small study from 2019 v. Dronabinol, a partial agonist for cannabinoid type 1 and type 2 receptors, has shown a dose-dependent reduction in AHI  Mechanism is thought to be due to attenuation of vagal feedback leading to stabilization of respiratory patterns and upper airway dilation d. Increasing the respiratory arousal threshold i. Low arousal threshold contributes to OSA in a subset of patients. These patients will tend to have an arousal during a respiratory event rather than maintaining sleep, which would allow for potential respiratory stabilization/re-establishment of airway patency. ii. Z-drugs and benzodiazepines increase respiratory threshold. Effects on AHI have been variable in studies. Most studies did not establish if patients had a low arousal threshold at baseline. iii. Trazodone increases arousal threshold with some small studies showing an improvement in AHI e. Decreasing loop gain i. High loop gain (ventilatory control instability) contributes to OSA in a subset of patients ii. Carbonic anhydrase inhibitors (acetazolamide and zonisamide) have been shown to reduce loop gain (acetazolamide) and AHI in several small studies  MOA: Lowers partial pressure of carbon dioxide (pCO2) via inducing a metabolic acidosis. Decrease in baseline pCO2 reduces pCO2 variation during sleep.

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iii. Oxygen therapy has been shown to decrease AHI in patients with OSA and high loop gain. Little effect is seen in studies with undifferentiated OSA cohorts.  MOA: Decreases chemosensitivity, i.e., ventilatory response to pCO2 f. In patients with resistant hypertension, spironolactone (diuretic, aldosterone antagonist) has been shown to modestly decrease AHI i. MOA: Decreases upper airway edema g. Estrogen therapy has little to no effect on OSA and is not recommended for treatment of the disorder 2. Weight-loss therapies a. Successful weight loss tends to improve severity of OSA in patients with obesity b. No weight-loss medication is FDA-approved or commonly used for the treatment of OSA c. Phentermine/topiramate and liraglutide have been shown to improve AHI in patients who are obese and diagnosed with moderate-severe OSA in randomized, placebo-controlled studies. Improvement in AHI correlated with degree of weight loss 3. Adjunctive therapies a. Nasal decongestive i. Nasal obstruction is a risk factor for OSA ii. Both allergic and non-allergic rhinitis is common in patients with OSA iii. Nasal symptoms can make it difficult to tolerate nasal continuous positive airway pressure (CPAP) therapy b. Topical intranasal steroids (e.g., fluticasone propionate, mometasone furoate) i. MOA: Anti-inflammatory effect on mucosal tissue via stimulation of glucocorticoid receptors ii. Recommended in patients with OSA and concomitant allergic rhinitis. Can be considered in non-allergic rhinitis. iii. May have some benefit in reducing AHI c. Ipratropium bromide nasal spray i. MOA: Anticholinergic effect that inhibits mucous gland secretion ii. Option for rhinorrhea for predominately nonallergic and mixed rhinitis d. Azelastine nasal spray i. MOA: Histamine H1-receptor antagonist; also has anti-inflammatory effect and mast cell stabilizing properties ii. Recommended for nonallergic and mixed rhinitis. Alternative treatment for allergic rhinitis. iii. Faster onset of action compared to intranasal steroids iv. Notable side effects include bitter taste and nasal burning

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Oxymetazoline i. MOA: Mucosal vasoconstriction via selective α1 agonism and partial α2 agonism ii. May have minor effect on AHI iii. Not recommended for chronic use due to concern for rebound rhinitis after more than 5-10 days f. Montelukast i. MOA: Leukotriene receptor antagonist; reduces adenoidal hypertrophy ii. Improved AHI in pediatric patients in short-term trials (12-16 weeks) iii. Carries FDA black box warning for neuropsychiatric events including suicidality, nightmares, and behavioral problems in children 4. Residual excessive daytime sleepiness a. Up to 12-13% of OSA patients have residual excessive daytime sleepiness (EDS) despite compliance with CPAP b. FDA-approved medications for EDS in patients with OSA include modafinil, armodafinil, and solriamfetol c. Modafinil/armodafinil improves both EDS and attention/alertness in several studies for residual EDS in OSA patients d. Solriamfetol i. Improves EDS with a dose-dependent effect ii. Improvement in sleep latency on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were used as clinical outcomes in studies iii. Starts at a lower dose compared to when used in narcolepsy (37.5 mg versus 75 mg) e. Pitolisant i. Improves EDS based on subjective measures (e.g., ESS) for patients with OSA ± CPAP therapy. No improvement in sleep latency on MWT. 5. Insomnia therapy in OSA a. Insomnia is a common comorbid condition in patients with OSA. Problem with sleep maintenance is a particularly common symptom. Prevalence of insomnia complaints ranges from 24-84%. b. Insomnia may negatively affect CPAP adherence c. No medication is currently preferred for treating insomnia in patients with OSA. Initial approach in managing insomnia would be the same in those without OSA— address underlying/exacerbating factors (e.g., restless legs syndrome, pain, medication effect) and consider cognitive behavior therapy for insomnia d. Based on a review of several small studies, benzodiazepine and Z-drugs do not appear to significantly worsen severity of OSA

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Ramelteon was shown in one study to improved sleep onset in older adults with insomnia complaints who were started on PAP therapy for OSA A 2-week course of eszopiclone during initial CPAP therapy may improve short-term adherence to CPAP therapy in patients newly diagnosed with OSA i. Eszopiclone may also improve quality of polysomnography and CPAP titration if given before the study. Studies that support these findings were not limited to patients with insomnia.

RESTLESS LEGS SYNDROME (RLS) 1. Initial Approach for RLS a. Assess for aggravating factors: i. Medications (Table 3) ii. Smoking iii. Sedentary lifestyle iv. Vigorous exercise v. Stress vi. Obesity vii. Co-morbid sleep disorders, e.g., OSA b. Consider non-pharmacological interventions: i. Heat ii. Moderate exercise iii. Vibratory stimulation c. Assess iron status and replete if ferritin ≤ 75 mcg/L 2. Chronic persistent symptoms a. Symptoms occur at least 2x/week for past year b. Choose first-line agent (dopamine agonist or gabapentinoid) based on comorbidities i. Obesity, depression  choose a dopamine agonist ii. Insomnia, peripheral neuropathy  choose a gabapentinoid c. Time administration of medication BEFORE symptom onset 3. Intermittent symptoms a. < 2x/week for past year with at least 5 lifetime events b. Carbidopa/levodopa can be used as needed for known triggering events or intermittent symptoms given its short onset of action 4. Refractory symptoms a. Combination therapy with dopamine agonist and gabapentinoid ± benzodiazepine b. Opioid therapy

ligand/gabapentinoid

α2δ calcium channel

Non-ergot dopamine agonist

Medication Iron replacement

* Considered first-line therapy

(1) Chronic persistent symptoms (2) Pediatric patients (3) Breast-feeding patients

* Considered first-line therapy

Indications (1) Fasting ferritin ≤ 75 mcg/L or transferrin saturation < 20% (2) Intermittent and chronic persistent symptoms (1) Chronic persistent symptoms

Unknown mechanism for RLS

Stimulates dopamine receptors

MOA Repletes relative iron deficiency in substantia nigra

Pramipexole: Start 0.125 mg. Max 0.75 mg. Ropinirole: Start 0.25 mg. Max 4 mg. Rotigotine: 24-hour transdermal patch. Start 1 mg/24 hours. Max 3 mg/24 hours. • Take 1-3 hours before symptom onset • Aim for lowest effective dose • Increase every 4-7 days as needed for pramipexole and ropinirole; weekly for rotigotine Gabapentin enacarbil: (FDAapproved) Start 600 mg. Studied with max dose of 1200 mg. Take with fatty food at 5-7 PM. Gabapentin: Start 100-300 mg depending on age. Max 900-1200 mg. Pregabalin: Start 50-75 mg depending on age. Max 450 mg. • Longer titration period compared to dopamine agonists • Take 1-3 hours before symptom onset • Aim for lowest effective dose • Increase every 4-7 days as needed

Doses Oral: Ferrous sulfate 325 mg every other day with 200 mg vitamin C. Take 1 hour before a meal. IV: Ferric carboxymaltose 1000 mg over 10-15 minutes (preferred). Iron sucrose 200 mg for 5 infusions. Iron dextran 1000 mg over 1 hour (requires test dose).

Table 2. RLS medications

Somnolence, sleep attacks, dizziness, weight gain and edema (seen more with pregabalin), depression or suicidal thoughts/behaviors

Ropinirole: Skin reaction

Nausea (can give with food but will delay onset for 1 hour), somnolence, impulse control disorder (hypersexuality, excess gambling, shopping, eating), augmentation, rebound

Ferric carboxymaltose: Associated with hypophosphatemia.

Side Effects Oral: Nausea, constipation, black stools IV: Transfusion reaction (rare).

• Preferred over dopamine agonists in those with comorbid insomnia, chronic pain, or peripheral neuropathy • Gabapentin enacarbil uses different solute transporters compared to gabapentin, which leads to doseproportional bioavailability (vs. dose-dependent bioavailability) • Renal adjustment needed

Screen for symptoms of impulse control disorder regularly—patients may not initially perceive symptoms as an adverse effect

Ropinirole is excreted via the liver, and pramipexole via the kidneys

Comments • Oral iron absorption decreases with increasing ferritin; limited absorption in those with ferritin 50-75 mcg/L • Goal ferritin 200-300 mcg/L • Recommend rechecking iron studies in 4-6 weeks

Opioid

Benzodiazepine

Medication Levodopa

(1) Refractory symptoms (not controlled with firstline agents due to poor response or adverse events)

Indication (1) Intermittent symptom (daily therapy not required). Can use for bedtime or for triggering events, e.g., travel, sedentary activities. (2) Pregnancy (1) Intermittent symptoms (2) Pregnancy Unknown mechanism for RLS. Potentially treats insomnia associated with RLS. Unknown mechanism for RLS

MOA Dopamine precursor

Low-potency Codeine: Start 30 mg. Usual effective dose 60-180 mg. Tramadol: Start 50 mg (100 mg ER). Usual effective dose 100-200 mg. High-potency Methadone: Start 2.5-5 mg. Usual effect dose: 5-20 mg. Morphine CR: Start 7.5-15 mg. Usual effect dose 15-45 mg. Oxycodone (IR or ER): Start 5-10 mg. Usual effect dose 10-30 mg Hydrocodone (IR or ER): Start 10-15 mg. Usual effective dose 20-45 mcg.

Methadone: QT prolongation Tramadol: Augmentation

Constipation, nausea, tolerance

Long half-life (30-40 hours) can lead to morning drowsiness and unsteadiness

Low risk for augmentation when used intermittently and at recommended doses

Quick onset of action (15-30 minutes on empty stomach). Duration 6-8 hours.

Clonazepam: 0.5-1 mg at bedtime

Side Effects Nausea, dizziness, sleepiness (usually mild), rebound

Doses Carbidopa-levodopa 25 mg/100 mg: half to full tablet.

High-potency and longer-acting opioid usually required for refractory RLS

Initiation of long-term opioid therapy should include risk assessment for abuse, opioid contract, and usage of state prescription monitoring program

Comments Controlled-release version better suited for those with nocturnal awakenings.

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Kimberly Y. Kreitinger and Atul Malhotra Table 3. RLS aggravating medications Aggravating Medications Dopamine-blocking antiemetics Meclizine Promethazine Hydroxyzine Metoclopramide Sedating antihistamines Diphenhydramine Doxylamine

Alternatives 5-HT3 receptor antagonists Ondansetron Antimuscarinics Scopolamine

Antidepressants Selective serotonin reuptake inhibitors Serotonin-norepinephrine reuptake inhibitors Tricyclic antidepressants Antipsychotics Atypical antipsychotics Lithium

Second generation antihistamines Fexofenadine Cetirizine Loratadine Bupropion

Aripiprazole (partial dopamine agonist) possibly more favorable

RLS AND AUGMENTATION 1. Associated with levodopa and dopamine agonists; tramadol has also been linked to augmentation 2. Onset usually occurs within months to years 3. Risk related to longer duration and higher dose of causative medication 4. Annual rate of augmentation is 7% for pramipexole 5. Characterization: a. Earlier onset of symptoms b. Increased intensity of symptoms c. Spread of symptom to other body parts Decreased duration of medication effect 6. Stopping causative medication leads to improvement, but cessation is often a difficult process due to severity of symptoms 7. Rule out new aggravating factors (new medications, lifestyle changes) and low iron storage 8. Management: a. Move dose earlier before symptom onset b. Split dose. First dose before symptom onset, second dose at bedtime. c. Switch to gabapentinoid using a cross-taper d. Switch to a long-acting rotigotine patch e. Switch to a low-dose, long-acting opioid

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RLS AND PREGNANCY 1. 2. 3. 4.

Symptoms usually resolve after delivery First-line recommendation: Low-dose clonazepam or carbidopa/levodopa Refractory RLS: Low-dose oxycodone Lactation: Gabapentin or low-dose clonazepam

RLS AND CHILDREN 1. 2. 3. 4. 5.

No medications have been FDA-approved in the pediatric population First-line recommendation: Gabapentin Alternatives: Low-dose clonazepam and temazepam Refractory RLS: Dopamine agonist Clonidine used for sleep onset problems associated with RLS

REM BEHAVIOR DISORDER (RBD) 1. General considerations before initiating pharmacological therapy a. Ensure a safe sleep environment b. Discuss the strong association of RBD with synucleinopathies (Parkinson’s disease, multiple system atrophy, and Lewy body dementia) i. Note: Pharmacological treatment of RBD does not affect progression to synucleinopathies 2. Melatonin a. MOA: Unclear. May inhibit activity of anterior horn cell neurons of the spinal cord. b. Decreases degree of REM without atonia on PSG c. Often consider first-line treatment due to better side effect profile compared to clonazepam d. Dose: 3-12 mg 3. Clonazepam a. MOA: Unknown. May inhibit locomotor pattern generators in the brainstem or modify dream content. Has not been shown to decrease REM without atonia or suppress REM sleep. b. Symptoms promptly return after medication cessation c. Dose: 0.5-2 mg i. Women many require a higher dose to control symptoms d. Side effects: Somnolence, motor impairment, cognitive impairment i. Use with caution in patients with gait disorder or dementia

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NON-REM PARASOMNIAS 1. If episodes are rare or expected to be out-grown, treatment is often not necessary 2. No FDA-approved medication is available. Evidence for pharmacological treatment is overall weak. 3. Consider pharmacological treatment for the following: a. Symptoms are persistent and disruptive despite non-pharmacological interventions b. Significant functional impairment c. High risk of injury during episodes 4. General considerations before initiating pharmacological therapy a. Ensure a safe sleep environment b. Advise on sleep hygiene and obtaining adequate sleep times c. Assess and treat for co-morbid sleep disorders (e.g., OSA, RLS, insomnia) d. Assess for situational stress and anxiety and consider referral for cognitive behavior therapy e. Consider planned awakenings or hypnosis 5. Clonazepam a. MOA: Unclear. May be due to sedative effects, decreases in slow wave sleep, or suppression of cortical arousals. b. Most used and studied medication for non-REM parasomnia c. Shown to be effective for sleepwalking and sleep terrors in small observational studies d. Dose: 0.5-2 mg 6. Melatonin can be considered, especially in those with concomitant RBD 7. Antidepressants (SSRIs, TCA, and trazodone) have been reported to be effective in case reports and small case series. MOA is unclear. 8. Topiramate has been shown to decrease sleep-related eating disorder events in a small randomized, placebo-controlled trial a. Dose: 25-300 mg. Usually doses are 100-150 mg. b. Side effects: Somnolence, paresthesia, and cognitive impairment

CIRCADIAN RHYTHM DISORDERS 1. Timed melatonin in conjunction with light therapy is often used in the treatment of circadian rhythm disorders. Studied doses vary considerably. 2. Shift work disorder (SWD) a. General considerations before initiating pharmacological therapy i. Consider timed napping, timed melatonin, and light therapy b. Modafinil and caffeine can be considered to promote alertness during night shifts in SWD i. Monitor for effects on daytime sleep c. Suvorexant 10-20 mg has been shown to increase total daytime sleep in SWD in a small, randomized trial

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ENURESIS 1. General considerations before initiating pharmacological therapy a. Consider and treat exacerbating causes (e.g., constipation, OSA) b. Trial alarm system (first-line treatment) 2. Vasopressin a. MOA: Decrease urine production by increasing water absorption b. Given in 3-month blocks of treatment. Can also be used as needed (e.g., camp, sleepovers). c. Success rate: 30% full responders. 40% partial responders. d. High rate of relapse when medication is stopped. Taper is recommended when stopping the medication. e. Dose: 0.2-0.4 mg f. Side effects: Risk of water intoxication and hyponatremia i. Restrict evening water intake to 250 mL and avoid nocturnal water intake 3. Imipramine a. MOA: Relaxes detrusor muscles b. Used for refractory enuresis c. Success rate: 40% d. Dose: 10-25 mg e. Side effects: QT prolongation, dry mouth, mood changes i. Screen for long QT syndrome with ECG before starting medication

KEY CLINICAL POINTS 1. For insomnia, first consider non-pharmacological therapies (e.g., cognitive behavioral therapy for insomnia) before starting a medication. Assess risk factors for significant motor and neurocognitive impairment before starting a benzodiazepine or Z-drug. Half-life of the drug will determine if a medication is suitable for sleep onset or sleep maintenance. 2. Sodium oxybate is an effective treatment for narcolepsy type I for symptoms of sleep fragmentation, cataplexy, and daytime sleepiness. Usage of sodium oxybate requires close monitoring given potential for abuse and sedating effects. Modafinil, pitolisant, and solriamfetol are effective treatments for daytime sleepiness in narcolepsy. 3. No pharmacological treatment is recommended for the primary treatment of OSA. Modafinil and solriamfetol can be used for residual daytime sleepiness in patients being treated for OSA. 4. For RLS, oral and intravenous iron therapy is recommended in those with ferritin ≤ 75 mcg/L. Dopamine agonists and gabapentinoid are first-line therapies for patients with chronic persistent RLS; medication should be chosen based on patients’ relevant comorbidities if applicable. Dopamine agonists carry a risk of augmentation. When augmentation develops, timing of administration of the dose can be advanced, or medication can be switched to another class.

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Kimberly Y. Kreitinger and Atul Malhotra 5. There are no FDA-approved treatments for parasomnia. Clonazepam and melatonin are commonly for both REM and NREM parasomnias. Treat when there is a significant distress or risk of injury.

QUESTIONS 1. Which of the following medications is most associated with augmentation for RLS? a. Gabapentin b. Trazodone c. Pramipexole d. Methadone 2. Which of the following medications does not treat cataplexy? a. Sodium oxybate b. Pitolisant c. Solriamfetol d. Venlafaxine ER 3. Which of the following medications is used primarily for sleep onset versus sleep maintenance in the context of insomnia treatment? a. Zaleplon b. Doxepin c. Suvorexant d. Temazepam 4. Which of the following is not an indication for modafinil? a. Shift-work disorder b. Residual excessive daytime sleepiness in OSA c. Narcolepsy d. Sleep-related eating disorder 5. What medication is commonly used as a first-line treatment for REM behavioral disorder? a. Carbidopa/levodopa b. Melatonin c. Escitalopram d. Trazodone

REFERENCES Abad VC. An evaluation of sodium oxybate as a treatment option for narcolepsy. Expert Opin Pharmacother. 2019;20(10):1189-1199. doi:10.1080/14656566.2019.1617273.

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 7

SLEEP IN WOMEN Jessica A. Mong, PhD and Katie Kruk Department of Pharmacology, Program in Neuroscience, University of Maryland Baltimore, Baltimore, MD, USA

SUMMARY 1. Quality sleep is imperative for the maintenance of good health 2. Many biological, social, and environmental factors influence sleep 3. Gonadal steroids and gender are implicated as risk factors for sleep disruptions and insomnia 4. Complaints such as insufficient sleep and insomnia are ~40% more prevalent in women than men 5. Sleep dysregulation may have more severe health consequences for women than men 6. However, the mechanisms by which ovarian steroids influence sleep is poorly understood 7. A better understanding of the mechanisms governing sleep in the female brain is needed to more fully know why women are more at risk for sleep disorders throughout their lifespan

OVERVIEW 1. Compared to men and boys, women and girls are almost twice as likely to experience sleep disruptions and insomnia throughout their lifespan 2. Gonadal steroids and gender are risk factors for sleep disruptions and insomnia a. The mechanisms underlying the influence of ovarian steroids on the sleepwake neurocircuitry remains a significant gap in our knowledge 3. The increased risks for sleep disturbances in women emerge at the time of puberty and have been linked to fluctuations in the gonadal steroid milieu

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In women approaching menopause, the loss of ovarian steroids is associated with insomnia, frequent night-time awakenings and poor sleep b. In women of reproductive age the presence of estrogens and progesterone appear to be a contributing factor to sleep disturbances 4. Before we can appreciate the biological basis for these apparent paradoxical effects of estrogens on sleep disturbances across a women’s lifespan, we need a better understanding of exactly how estrogens are influencing the sleep-circuitry

SEX AND GENDER DIFFERENCES IN SLEEP AND CIRCADIAN TIMING 1. Objective measures of sleep (polysomnography (PSG)) find healthy women have higher sleep quality compared to healthy men 2. Women have: a. Less total wake time b. More Non-Rapid Eye Movement (NREM) sleep c. Shorter latency to sleep onset d. Better sleep efficiency e. Greater amounts of slow wave sleep (SWS; Stage N3) f. Greater amounts of slow wave activity (SWA) (measure of SWS sleep intensity) 3. Subjective measures of sleep (i.e., self-reports) find women across all ages report more sleep problems than men 4. Women report: a. Disrupted Sleep b. Insufficient Sleep c. Poor sleep quality d. Difficulty falling asleep e. Frequent night awakenings f. Time spent awake during the night 5. This paradox between objective and subjective measures of sleep in women may rest on the limitations of PSG a. PSG cannot measure sleep under natural settings i. Sleep lab vs. home environment ii. Home setting may contribute to disrupted and poor sleep b. PSG is not sensitive enough to capture subcortical brain activity i. May be different in individuals with insomnia ii. Possibility of sex differences in subcortical brain activity 6. Poorer subjective sleep quality correlates with higher levels of anxiety and depressive symptoms in the absence of any objective sleep disturbances 7. Throughout the lifespan women are at a 40% greater risk of insomnia compared to men 8. Sex differences in circadian timing may also contribute to the increase of self-reported poor sleep in women a. Women have a significantly shorter circadian period compared to men

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b. Sleep is tightly linked to circadian timing i. Women tend to go to bed earlier and wake earlier than men ii. Desynchrony (i.e., mismatch) between circadian timing and sleep timing causes sleep disturbances iii. Women may be at a greater risk for desynchrony leading to:  Difficulties with sleep maintenance  Early morning awakenings  Increased risk of insomnia and poor sleep quality 9. Gonadal (or sex) steroids, namely testosterone in men and estrogens and progesterone in women are implicated in sleep regulation 10. Sleep in women is more sensitive to changes in the ovarian steroidal milieu 11. Fluctuations in ovarian steroids are associated with: i. Changes in sleep and circadian rhythms ii. Increased prevalence of sleep disturbance and insomnia

IMPACT OF RACIAL AND ETHNIC DISPARITIES ON SLEEP IN WOMEN 1. Race, ethnicity, and socioeconomic status contribute to sleep health 2. In the United States: a. Black women tend to have shorter sleep than white women b. Women of Mexican descent or Women of Asian or Arab backgrounds have worse sleep than white women 3. Black and Mexican women in the United States are less likely than others to report sleep difficulty to their health care provider a. Health care providers may not screen for sleep disorders b. Women may lack a recognition of the negative consequences of sleep disorders 4. Anxiety, depression, and trauma symptoms are common in ethnically and racially diverse women and tightly associated with poor sleep quality 5. Significant majority of ethnically and racially diverse women report co-sleeping with children which may contribute to poor sleep quality

SLEEP IN SEXUAL AND GENDER MINORITIES 1. Studies investigating sleep health among lesbian, gay, bisexual, transgender and queer (LGBTQ) populations are needed 2. In the few studies that exist, findings are mixed 3. The available data suggests transgender individuals and bisexual women report the highest rate of sleep disturbances 4. Findings suggest that sleep health among LGBTQ individuals may be an unmet health need a. LGBTQ populations have disproportionate acute and chronic health problems

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Jessica A. Mong and Katie Kruk b. Health disparities stem from high burden of chronic minority stressors, including discrimination, prejudice, victimization and stigma c. Chronic stressors are known to impact sleep health

OVARIAN STEROIDS AND SLEEP 1. From puberty to menopause, women experience fluctuations in the ovarian steroids, estrogens and progesterone a. Three forms of ovarian estrogens are estradiol, estrone and estriol b. Estradiol is the most potent estrogen and most often associated with changes in sleep 2. The role of ovarian steroids (estradiol and progesterone) in healthy sleep is poorly understood a. Historically, women have been excluded form sleep studies until about three decades ago b. Effects of ovarian steroids on healthy sleep in women are still understudied today c. The studies that do exist are often underpowered yielding mixed and confusing results 3. Disrupted and poor sleep typically coincide with periods of ovarian steroid fluctuation such as puberty, the menstrual cycle, pregnancy, and the menopausal transition 4. A consensus from sleep studies across the menstrual cycle in healthy women suggests sleep is most disturbed during the mid-luteal phase when ovarian steroid levels are still elevated but starting to decline a. PSG studies report increased awakenings and arousal during sleep and decreased SWS during the luteal versus the follicular phase b. Sleep spindles in the luteal phase compared with the follicular phase exhibit marked increases in number, duration, and higher electroencephalogram (EEG) spectral frequency (14 – 17 Hz) 5. PSG studies examining the effects of hormonal contraception find sleep is influenced by exogenous steroids a. Women taking oral contraceptives have: i. Increased N2 (NREM) stage sleep ii. Increased rapid-eye movement (REM) sleep iii. Decreased SWS (N3 stage) and SWA b. Together these findings suggest that hormonal contraceptive use results in poorer sleep quality i. But these studies did not address whether estrogens or progestins are contributing to the changes ii. Typically, hormonal contraception contains synthetic estrogen (ethinyl estradiol) and progestins iii. Women taking hormonal contraception have high levels of synthetic hormones but low levels of endogenous estradiol and/or progesterone iv. Levels are similar to the follicular phase of non-users

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6. Subjective sleep studies evaluating the impact of hormonal contraceptive on sleep found that contraceptive use is associated with an overall worse quality of sleep a. Contraceptive users compared to non-users report: i. More sleep-related problems including a decrease in perceived total sleep time ii. Higher prevalence of excessive daytime sleepiness iii. Increased insomnia symptoms b. Progestins-only users compared to combined (estrogen/progestin) contraceptive users report: i. Lower sleep durations ii. Higher prevalence of excessive daytime sleepiness iii. Increase in perceived sleep problems iv. Findings suggest that progestin-only users have worse perceived sleep overall 7. The menopausal transition is marked by erratic fluctuations and eventual decline in ovarian steroids and is tightly associated with increased sleep complaints and symptoms of insomnia a. Strongly suggests that ovarian steroids play a major role in maintaining healthy sleep in women b. Women who undergo surgical menopause (bilateral oophorectomy) have the highest prevalence of sleep difficulties among midlife women c. Estrogen therapy with or without progestin (hormone therapy (HT)) remains the most effective treatment for vasomotor (hot flashes), sleep and genitourinary symptoms associated with menopause i. Due to risks and benefits associated with use of combined HT in postmenopausal women, current guidelines recommend:  Lowest effective dose  Shortest possible duration d. Wide array of HT formulations includes: i. Oral preparations  Conjugated equine estrogens (CEE)  Micronized 17-beta estradiol (improved absorption)  Ethinyl estradiol (an esterified estrogen of high potency; used at much lower dosages for HT than for oral contraception)  Combination estrogen-progestin ii. Topical applications  Transdermal patch of 17-beta estradiol  Various transdermal patch formulations of combined estrogen-progestin e. More studies are needed to understand how different formulations affect sleep f. Overall studies tend to support that HT significantly improves sleep quality i. Transdermal estradiol decreases sleep complaints and night-time arousals in hysterectomized postmenopausal women ii. Oral 17-beta estradiol reduces insomnia symptoms and improves subjective sleep quality, but this may be associated with vasomotor

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Jessica A. Mong and Katie Kruk iii. CEE or esterified estrogens reduces frequent night-time awakenings, sleep latency, time awake and increases SWS and SWA g. Contributions of progestins are unclear and studies clarifying the effects of estrogens and progestins on sleep are needed

SLEEP ACROSS THE LIFE SPAN IN WOMEN 1. Puberty a. Sleep is essential for many aspects of youth development i. Emotional ii. Cognitive iii. Physical b. Across adolescence, bedtimes get later and total sleep time decreases i. Onset of a circadian delay ii. Slower accumulation of homeostatic sleep pressure (i.e., sleep drive) iii. Precipitous decrease in SWS and SWA; may reflect cortical reorganization c. Early maturing girls are at a greater risk of shorter sleep duration d. These physiological measures occur at an earlier age in girls compared to boys i. Result in less sleep throughout adolescence ii. Increased risk for insomnia e. The onset of menses in adolescent girls is tightly associated with an increased risk of insomnia i. Insomnia affects approximately 10-19% of adolescents ii. Girls have a higher prevalence of insomnia than boys iii. Prevalence of insomnia symptoms is highest in girls ages 11 to 12 years and associated with clinically significant PSG sleep disturbances (but not in boys) iv. Prevalence of insomnia symptoms increases across pubertal development and may be related to hormonal changes v. Insomnia symptoms are highly associated with behavioral problems and poor mental health in both girls and boys vi. Girls are more susceptible to emotional and behavioral difficulties associated with insomnia vii. Insomnia can be an early predictor of depression and suicide risk f. Narcolepsy typically emerges during adolescents i. Equally common in girls and boys ii. Significant delay in proper diagnosis in girls/women g. Delayed sleep-wake phase disorders tend to emerge in adolescents i. Approximately 16% of adolescents experience delayed sleep-wake phase disorder ii. Associated with depression, anxiety, and poor school performance iii. Sex differences are not clear

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h. Racial/Ethnic differences in sleep emerge at puberty i. Black girls have earliest pubertal development, followed by Hispanic, white, and Asian girls ii. Overall, black girls reported significantly shorter sleep duration than Hispanic, Asian and White girls 2. Childbearing age a. Women of childbearing age are at risk for sleep deficiency due to multiple biological, behavioral, social, and environmental factors b. Sleep deficiency in women of childbearing age may contribute to short- and longer-term health outcomes c. Gonadotropic hormones (Luteinizing hormone (LH) and Follicle stimulating hormone (FSH)) and sex steroids fluctuate across the menstrual cycle and influence sleep i. At the start of the cycle in the preovulatory follicular phase:  FSH stimulates ovarian follicle growths  maturing follicles produces estrogens  circulating levels of estradiol begin to rise ii. Ovulation occurs at mid-cycle when:  Estradiol level reach peak concentration  LH levels surge  releases oocyte and newly formed corpus luteum iii. The cycle ends with the postovulatory luteal phase:  Corpus luteum releases progesterone  Estradiol levels precipitously decrease  Progesterone is the dominant steroid  If fertilization does not occur, the uterine lining is shed d. In healthy women, sleep complaints commonly occur during the postovulatory luteal phase i. Very limited number of studies mixed results ii. PSG studies comparing luteal to follicular phase find:  Decreases in REM sleep  Increases in stage 2 sleep  Increases in sleep spindle frequency  No changes in sleep propensity and quality iii. Subjective studies report complaints of disturbed sleep during the lateluteal phase and premenstrual days e. In women suffering from premenstrual dysphoric disorder (PMDD) sleep complaints are more severe i. PMDD is mood disorder affecting ~3-8% of women ii. Defined by the timing of symptoms within the context of the menstrual cycle:  Begin during late luteal phase  Remit after menses  Asymptomatic during follicular phase

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Core symptoms include depressed mood, anxiety/tension, anger/irritability, and decreased interest  Severity sufficient to disrupt social, academic, and/or professional functioning iii. Disrupted sleep is characteristic symptom of PMDD iv. Compared to healthy controls, PSG studies in PMDD patients reveal during the luteal phase:  Reduced REM sleep  Decreased SWS sleep (stage 3) and across menstrual cycle  Increased nighttime arousal f. Sleep disturbances are twice as common in women with Polycystic Ovary Syndrome (PCOS) compared to the general population i. PCOS is a common condition in reproductive-aged women ii. Affects ~9-18% of women of childbearing age iii. Women with PCOS have a greater occurrence being overweight and obese iv. Clinical features include:  Menstrual irregularity  Hyperandrogenism/hirsutism  Ovarian cysts  Fertility problems v. Recognized sleep disturbances include:  Difficulty falling asleep  Difficulty maintaining sleep  Obstructive sleep apnea (may be associated with body weight) vi. Women with PCOS are 30 times more likely to have sleep apnea vii. Obesity in women with PCOS has a relatively minor role in sleep disruptions (not including sleep apnea) compared with non-obese women with PCOS viii. Depressive symptoms are tightly linked to sleep disruption in women with PCOS ix. Women with PCOS have heightened stress reactivity that may underlie sleep disturbances g. Studies on the role of sleep disorders in infertility are limited i. Infertility rates in American women of childbearing age are between 715% ii. Existing studies highlight a complex interaction between sleep and sex hormones iii. Insufficient sleep, poor sleep quality, and sleep apnea are associated with elevated prolactin, testosterone, and estradiol levels iv. Women with elevated prolactin, testosterone, and estradiol are predisposed to anovulation and infertility v. Shift workers are more likely to experience irregular menses, dysmenorrhea and a longer time to achieve pregnancy

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vi. Insomnia disproportionately affects women of childbearing age compared to men in same age group  Chronic insomnia in women is associated with higher levels of stress hormones  Cortisol and adrenocorticotropic hormone  Stress hormones implicated in reduced fertility 3. Pregnancy a. 66%-94% of women report changes in sleep across all three trimesters of pregnancy b. Numerous physiological and physical changes occur throughout pregnancy that could impact health i. Increases in estrogens, progesterone, and prolactin ii. Fetal movement iii. Increased weight and body size iv. Bladder distention c. Sleep problems during pregnancy are often overlooked by clinicians who do not recognize their clinical importance i. First and second trimester:  Significant rise in progesterone  Marked by increases in feelings of tiredness  Increases in daytime sleepiness ii. Third trimester  Women tend to have poor quality sleep  Report daytime sleepiness and disrupted nighttime sleep  PSG studies confirm reports of disrupted/disturbed sleep  Increased wakefulness and decreased REM sleep d. Common sleep disorders during pregnancy include: i. Sleep apnea  Higher body mass index (BMI) increases risk  Associated with pregnancy-induced hypertension, preeclampsia, gestational diabetes, caesarean delivery, and small for gestational age infants ii. Restless Leg Syndrome (RLS)  12–26% of women experience RLS by the third trimester of pregnancy compared to 10% in the general population  Associated with decreased folate levels, gestational diabetes and/or increased iron needs  Associated with hypertensive pregnancy disorders iii. Insomnia  20-60% of pregnant women experience insomnia  Negative outcomes associated with insomnia during pregnancy include  Preeclampsia  Preterm labor

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 Increased incidence of caesarean delivery  Gestational diabetes  Perinatal depression Cognitive behavioral therapy for insomnia (CBT-I) is a promising treatment during pregnancy

4. Postpartum a. Postpartum period is marked by significant sleep deprivation (i.e., shorten and disrupted sleep) in new mothers i. Usually attributed to caring for the infant in early period as mother and infant slept tightly coupled ii. Later in the postpartum period mother’s sleep continues to be disturbed despite improvements in infant sleep iii. Postpartum sleep difficulties may occur because the body’s internal clock is disrupted during the perinatal period due to altered sleep-wake cycles b. Disturbed postpartum sleep is associated with: i. Chronic illness such as obesity or diabetes in later life ii. Poor mental health outcomes iii. Increased risk for postpartum depression iv. CBT-I has been used with success in women with postpartum depression c. In general, studies report that the mothers’ sleep is more fragmented at night than fathers’/partners’ i. Reflects the fact that mothers perform most of the nighttime childcare ii. Increased paternal/partner involvement in nighttime care improves both mother and infant sleep, even in breastfeeding families 5. Perimenopausal/menopausal transition a. Menopause is defined as the time of the final menstrual period i. Natural process in normal female aging ii. Results from depletion of ovarian follicles and hence cessation of estradiol and progesterone production iii. Occurs at a median age of 51 years iv. Transition usually starts at about 47 years and is marked by erratic fluctuations in ovarian steroids b. The transition to menopause is associated with a stark increase in sleep problems, particularly frequent nighttime awakenings c. The Study of Women’s Health Across the Nation (SWAN) reports the prevalence of sleep disturbance: i. From 16% to 42% in premenopausal women ii. From 39% to 47% in perimenopausal women iii. From 35% to 60% in postmenopausal women d. Sleep problems are one of the most bothersome symptoms that impact quality of life in many women going through the menopausal transition i. The most common sleep-related complaint is nighttime awakening ii. Women report difficulty falling asleep and staying asleep

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The increase in sleep problems is attributed to several factors: i. Menopausal hormone changes ii. Hot flashes and night sweats (i.e., vasomotor flushes) iii. Depressed mood iv. Psychosocial factors (e.g., life stress) v. Comorbid conditions like sleep apnea f. Not all women experience sleep difficulties and other menopausal symptoms, suggesting that some women may be more vulnerable to the effects of hormonal fluctuations than others g. Insomnia is the main sleep disturbance reported by perimenopausal/ menopausal women i. Primary disorder ii. Secondary to vasomotor flushes, mood disorders, psychosocial factors, and other sleep disorders, such as OSA or RLS iii. Exact relationship between the various menopausal symptoms and disrupted sleep is not well understood h. Vasomotor flushes are tightly linked to with sleep disturbances and disruption of sleep architecture i. In general, most women transitioning through menopause experience vasomotor flushes ii. PSG studies found that with vasomotor flushes:  Awakening are coincident with the majority (69%) of flushes  Increases in nighttime awakenings  Increases in wake duration (after waking)  Increases in amount of Stage 1 sleep i. HT is effective at treating menopausal symptoms including sleep j. CBT-I is emerging as one of most effective the first-line treatments for insomnia in perimenopausal/ menopausal women k. Paroxetine, a selective-serotonin reuptake inhibitor antidepressant is the first non-hormonal treatment approved to treat menopausal vasomotor flushes i. Increases sleep in women with vasomotor flushes ii. Not clear if sleep is improved in women that do not report vasomotor flushes iii. Several studies report increase in sleep disturbances with use 6. Older Age a. Sleep is important for successful aging b. Women across all ages are at a higher risk for developing insomnia compared to men c. Elderly women are at the highest risk for developing insomnia d. Relationship between sleep and aging is bidirectional i. Poor sleep increases the risk of common chronic age-related disorders ii. Age-related disorders contribute to poor sleep

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SLEEP DISORDERS PREVALENT IN WOMEN Insomnia and RLS are more prevalent in women than men. Sleep apnea and REM sleep behavior (RBD) disorder are more prevalent in men than women. In women: a. Sleep apnea and RBD often go undiagnosed b. Women often present with “atypical” symptoms of these disorders c. Clinicians may be less vigilant in screening for these conditions 1. Insomnia a. In simplest terms characterized by the inability to fall asleep and/or stay asleep i. Causes daytime sleepiness and problems concentrating ii. Negative consequences to overall health such as cardiovascular disease, metabolic syndrome and neurological pathologies (i.e., Alzheimer’s Disease) b. Over the course of the lifespan, insomnia is 40-70% more common in women compared to men i. The onset of the first menses is associated with a 2.75-fold increased risk for insomnia ii. At midlife women have about a 40% increased risk of insomnia iii. Over the age of 65 years women have more than a 70% increased risk of insomnia c. In women insomnia is often comorbid with mood disorders and pain syndromes that can interfere with normal sleep d. CBT-I is considered the primary intervention for patients with chronic insomnia i. More effective than pharmacotherapy in the long term ii. Emerging studies suggest sex/gender differences in how CBT-I treatment improves sleep quality iii. Women with insomnia comorbid with other conditions have greater improvement 2. Restless Leg Syndrome (RLS) a. A well-established neurological disorder i. Characterized by unpleasant feeling in the legs (aching, tingling, or crawling in nature) that improves somewhat by moving them ii. Typically occurs at rest iii. Cause significant sleep disruptions and subsequent fatigue iv. RLS patients typically have daytime sleepiness, low energy, irritability, and depressed mood b. Twice as prevalent in women compared to men i. increased incidence with pregnancy is ~12-26% ii. Women with gestational RLS are at fourfold increased risk of RLS later in life 3. Circadian rhythm sleep-wake disorders (CRSWDs) a. Defined by defined by a mismatch/misalignment between the timing of the internal clock and the external environment (i.e., social, school, or work schedule) or by a disrupted internal clock

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b. Mismatches occur due to: i. A biological clock that is timed too early or too late ii. Shift work iii. Jet lag iv. Desynchronized internal clock to the light-dark cycle/environment c. CRSWDs are associated with obesity, diabetes, substance abuse, mood disorders, and cancer d. Shift-Work Sleep-Wake disorder (SWSWD) is commonly due to misalignment between the internal circadian rhythms and the required timing work i. Characterized by clinically relevant excessive sleepiness and/or sleep disturbance associated with work schedules ii. Women shift workers appear to be disproportionately affected  Women show higher levels of sleepiness during the biological night and shorter sleep duration during the biological day  Childcare outside of work hours may exacerbate short sleep duration in shift working women iii. Overall little research has been done to examine sex and gender differences in CRSWDs 4. Obstructive Sleep Apnea a. Characterized by repetitive pauses in breathing during sleep b. Results in: i. Fragmented sleep ii. Hypoxemia iii. Sleepiness iv. Cognitive deficits c. In women approximately 90% of sleep apnea cases are undiagnosed i. Women with sleep apnea may report symptoms of insomnia, mood disturbances, and fatigue rather than sleepiness ii. Women may present with shorter apneas associated with arousals rather than hypoxemia iii. Home sleep apnea tests may contribute to misdiagnosis d. Risk of apnea in women increases during pregnancy and menopause i. Increases risk of poor pregnancy outcomes ii. Associated with myriad of chronic health conditions 5. REM sleep behavior disorder (RBD) a. A REM specific parasomnia associated with a loss of REM-related atonia b. The loss of motor inhibition results in a wide spectrum of behavioral release during sleep i. Simple limb movements ii. Complex movements iii. Typical of patients to act dreams iv. Can result in violent and dangerous behaviors c. Strongly associated with the risk of neurodegeneration, particularly Parkinson’s disease and other α-synucleinopathies i. Non-motor symptom

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Jessica A. Mong and Katie Kruk ii. Onset is ~10-15 years prior to onset of motor symptoms d. Thought to be predominate in men e. RBD is under-recognized in women i. Recent findings suggest ratio of women to men with RBD is closer to 1:1.62 ii. Presentation in men is more violent physical movements while dreaming iii. Men’s dreams tend to be more violent than women’s iv. Women with RBD tend to present with more vocalizations and verbal arguments while dreaming

IMPACT OF SLEEP ON NEUROLOGICAL, PSYCHOLOGICAL AND OVERALL WELL-BEING 1. Mental health a. Overview i. Sleep problems and psychiatric disorders have a bidirectional relationship ii. Depression and mania most often comorbid with sleep disturbances iii. Individuals with anxiety disorders, schizophrenia, and substance use disorders commonly report sleep problems iv. Emerging evidence strongly supports treating comorbid insomnia and sleep disturbances significantly improves treatment outcomes for psychiatric illness b. Depression i. Depressed patients have prolonged sleep latency, increased REM sleep and more subjective sleep problems  Wide recognition that insomnia should be a distinct entity when it coexists with depression and anxiety disorders  Primary insomnia and major depression have distinct PSG profiles ii. Women have a higher risk of insomnia and depression compared to men iii. Women with menopausal insomnia disorder report lower levels of depression symptoms after successful insomnia remission iv. Low levels of estrogens are associated with negative effects on sleep quality and an increase in depressive symptoms 2. Cognition and dementia a. Insomnia and sleep-deprivation is tightly associated with cognitive decline b. Sex differences in cognitive functions as an outcome of insomnia are unclear and understudied c. Longitudinal studies indicate that a long-term consequence of mid-life insomnia is an increased risk of dementia and Alzheimer’s disease

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i. Overall, women are at a greater risk than men of developing dementia and Alzheimer’s disease ii. Not known whether changes in ovarian steroids (i.e., menopausal transition) or biological sex impact the link between insomnia and dementia 3. Cardiovascular heath a. Cardiovascular disease (CVD) includes coronary heart disease, heart failure, stroke, and hypertension b. CVD is affects nearly half of adults in the United States c. Chronic insufficient sleep and sleep disturbances contribute to a higher risk of CVD and adverse outcomes i. Poor sleep is linked to high blood pressure, arrhythmia, stroke, heart attack, and heart failure ii. Mechanisms linking sleep disruption to increased cardiovascular risk are not fully understood d. Women appear to be more vulnerable to the negative cardiovascular consequences associated with poor and chronic insufficient sleep i. CVD is the leading cause of death in women overall (when age is not considered) ii. Women are particularly vulnerable to the negative effects of sleep disturbances during pregnancy and after menopause iii. Pathways linking sleep disturbances and adverse cardiovascular outcomes are not well understood 4. Metabolic health a. Chronic insufficient sleep and poor sleep are closely associated with increases in type 2 diabetes (T2D) and obesity b. Short sleep and poor sleep influence changes in: i. Appetite ii. Reproductive hormones iii. Energy expenditure iv. Body adiposity c. Changes in sleep patterns that are associated with the menopausal transition may metabolic health consequences

CHRONIC DISORDERS AND SLEEP 1. Pain a.

A bidirectional association between insomnia and pain i. Short sleep duration associated with increased pain symptoms ii. Pain disrupts sleep leading to insomnia iii. Sleep disorders amplify pain symptoms iv. Overall, management of insomnia improves pain symptoms/perception b. Women are more likely to have comorbid insomnia and pain conditions including migraines, fibromyalgia (FM), and rheumatoid arthritis

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A survey of women in the United States reports that in ~25% of women, pain and physical discomfort disrupts sleep 2. Autoimmune disease a. Individuals with autoimmune disorders commonly report fatigue, insomnia, and daytime sleepiness i. Auto autoimmune diseases are estimated to afflict over 20 million individuals in the United States ii. Over 100 recognized autoimmune diseases iii. Over 2/3 of the affected population report fatigue as profound and debilitating b. A bidirectional relationship appears to exist between sleep and circadian disturbances with autoimmune disease i. Chronic insomnia and short sleep durations are associated with increased incidence ii. Overactivation of immune system associated with disturbed sleep and fatigue iii. Exact mechanism behind sleep problems and autoimmune disorders is not fully understood c. Chronic pain, particularity muscle and joint pain is tightly linked with autoimmune disease i. Poor management of rheumatoid arthritis is highly associated with a reduction in sleep quality ii. 88% of individuals with chronic pain also report disturbed sleep iii. 50% of individuals with insomnia also indicate enhanced pain which could contribute to fatigue d. The associations of sleep loss with inflammatory markers are stronger in females than males i. Higher levels of circulating Interleukin-6 (IL-6) in women than in men ii. Longer sleep-onset latency associated with higher levels of circulating IL-6 and C-Reactive Protein (CRP) in women but not in men  CRP has higher association with short sleep in men versus women  Women with short sleep (< 5 hours) have higher CRP compared to women with longer sleep (~7 hours) 3. Fibromyalgia (FM) a. FM is characterized by the presence of persistent and widespread pain b. Associated with multiple clinical symptoms such as sleep disturbance, fatigue, cognitive dysfunction, and depression c. FM has a prevalence of 2%-8% world-wide i. Women are disproportionally affected ii. Mid-life women have the highest prevalence of FM iii. Symptoms tend to worsen with menopause iv. The decrease in hormone levels may contribute to developing or worsening FM symptoms d. Individuals with FM demonstrate decreased amounts of NREM sleep e. A clear bidirectional relationship to exist between sleep and FM

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i. ~90% of individuals with FM report poor sleep ii. Poor sleep quality is associated with worsening of FM symptoms iii. NREM sleep deprivation linked to increases in painful musculoskeletal symptoms and intense muscular tenderness d. Emerging evidence suggests improved sleep quality and treating sleep disorders is effective in pain management 4. Cancer a. Chronic insufficient sleep, sleep apnea and circadian disruptions increase cancer risks b. Cancer and cancer treatments contribute to poor and disrupted sleep c. Shift-working women have a significant increased risk for breast and endometrial cancers d. In women with breast cancer: i. ~70% report sleep complaints including insomnia ii. Sleep complaints are a major contributor to cancer-related poor quality of life issues iii. Impairments may be directly related to cancer iv. Treatments such as endocrine therapies (ET) also contribute to sleep disruptions  Insomnia is a primary complaint of women on ET such as aromatase inhibitors and tamoxifen

ET-ASSOCIATED INSOMNIA MOST LIKELY THE RESULT OF ET-INDUCED MENOPAUSAL SYMPTOMS SUCH AS DISRUPTED SLEEP, HOT FLASHES, MOOD CHANGESSLEEP AIDS AND TREATMENTS 1. Historically, women (and female animals) have been underrepresented in sleep studies/clinical trial of sleep and sleep aids 2. Majority of sleep aids are based on male physiology 3. Some treatment for sleep and circadian rhythm sleep-wake disorders requires different courses for men and women a. Zolpidem (Ambien), sedative hypnotic used to treat insomnia, is metabolized differently in women and men i. Women tend to have a slower liver metabolism ii. FDA recommended lower dosage for women in 2013 b. Treatment for sleep apnea, women require lower continuous positive airway pressure than men and may require CPAP masks specifically designed to fit a woman’s face 4. Life events such as pregnancy, breastfeeding, and menopause as well as medications like birth control pills and other hormone therapies should be considered when choosing the right treatment options for sleep and circadian rhythm sleep-wake disorders in women

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KEY CLINICAL POINTS Special Treatment Considerations for Women Life-stage Puberty

Pregnancy

Postpartum

Menopause

Chronic Disease

Treatment Considerations Critical period that sees the risk of insomnia significantly increase in girls. Clinicians treating insomnia in female adolescents should be mindful of behavioral changes such as increased electronic use at nighttime which can increase arousal and delay sleeponset. Also, psychological well-being (depression/affective disorders) is a significant consideration. Risk of insomnia is 2 times higher later in the pregnancy compared to that in early pregnancy. Reductions in sleep quality in pregnant women are expected; however, it is important to be attentive of pregnant women who meet clinical criteria for insomnia and require intervention. CBT-I compared to pharmacotherapy has been shown to be more effective in pregnant women. Sleep deprivation is common during the postpartum period. The lack of sleep may contribute to postpartum depression. New mothers may benefit from sleep education about infant sleep, what to expect after childbirth, and acquiring skills to optimize sleep while caring for infants. Menopause-related sleep problems are common in midlife women. Important for clinicians treating menopausal women to understand that many of the menopausal symptoms such as vasomotor flushes and depression are precipitating factors for insomnia. CBT-I compared to pharmacotherapy has been shown to be highly effective in treating menopause related-insomnia. Typically, bidirectional relationships exist between chronic diseases states and sleep. Mitigating sleep disruptions can often improve disease related symptoms. Pain symptoms are particularly amenable to mitigation by improving sleep.

QUESTIONS 1. Which of the following is not associated with insufficient sleep and/or poor sleep? a. Pain b. Depression/Affective Mood c. Dementia d. REM sleep behavior disorder 2. Which life stage in women is associated with an increased risk of insomnia? a. Pregnancy b. Puberty c. Menopause d. All of the above e. None of the above 3. What sleep disorders are most prevalent in women? a. REM Behavioral Disorder and Restless Leg Syndrome b. Insomnia and Sleep Apnea c. Sleep Apnea and Circadian rhythm sleep-wake disorders d. Restless Leg Syndrome and Insomnia

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4. What is the approximate prevalence of insomnia in midlife women? a. 5% b. 20% c. 40% d. 70% 5. What therapy appears to be most efficacious in treating insomnia in women? a. Sleep-aids (Pharmacotherapy) b. Oral contraceptives c. Cognitive Behavioral Therapy for Insomnia d. Selective Serotonin Uptake Inhibitors

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 8

SLEEP AND AGING Kathleen L. Yaremchuk1,2,3, MD and Andrea M. Plawecki1, MD 1

Department of Otolaryngology, Head & Neck Surgery, Henry Ford Hospital, Detroit, MI, USA 2 Department of Sleep Medicine, Henry Ford Hospital, Detroit, MI, USA 3 Wayne State University School of Medicine, Detroit, MI, USA

Physiologic changes in sleeping patterns are part of the normal aging process. It is important to understand and recognize expected changes while being aware of primary and secondary sleep disorders that can coexist in the aging population. More than half of elderly patients will report a sleep complaint. Some of these issues can be addressed by patient education or behavioral adjustments, and others should prompt further testing or referral to a sleep specialist. Proper diagnosis and management of sleep-related disorders has the potential to improve the quality of life and safety of the aging patient.

NORMAL PHYSIOLOGIC CHANGES OF SLEEP PATTERNS WITH AGE 1. Changes in sleep parameters naturally occur throughout the human lifespan a. Sleep latency tends to increase with age Table 1. AASM/SRS Sleep Duration Recommendations in the United States Age Group Age Newborns 0–3 months Infants 4–12 months Toddlers 1–2 years Preschoolers 3–5 years Children 6–12 years Teenagers 13–18 years Adults 18–60 years Older adults 60+ years AASM, American Academy of Sleep Medicine; SRS, Sleep Research Society.

Recommendation No recommendation 12–16 hours 11–14 hours 10–13 hours 9–12 hours 8–10 hours 7+ hours No recommendation

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Kathleen L. Yaremchuk and Andrea M. Plawecki b. Sleep duration decreases with age, as does the recommended amount of sleep (Table 1) c. Interestingly, when left in a room devoid of environmental cues, including light/dark cycles, social signals, or a clock to display time, adult humans will revert to an average sleep time of 7 hours 15 minutes d. Sleep efficiency (the amount of actual sleep time divided by time spent in bed) decreases with age i. Only sleep parameter that appears to continue to significantly decrease after age 60 2. Sleep quality and architecture changes in the older population a. Age-related changes in circadian rhythms i. Circadian rhythms become less of a driver for the sleep-wake cycle in older age ii. Development of advanced sleep phase disorder iii. More difficulty adjusting to circadian phase shifts (such as in jet lag and shift work) b. Changes in daytime activity of the elderly lead to alterations in sleep and waking times i. Lack of a set wake/sleep schedule secondary to retirement ii. Earlier bedtimes can lead to early morning awakenings iii. Mid-day napping can cause difficulty falling asleep c. Changes in time spent in various sleep stages i. N1 (light sleep) increases ii. N2 (light sleep) increases iii. N3 (deep, slow wave sleep) decreases iv. Rapid eye movement (REM) decreases d. Increased nighttime arousals and sleep fragmentation i. Easier arousal from auditory stimuli ii. Longer duration of wake after sleep onset (WASO) iii. Frequent nocturia iv. Difficulty staying asleep v. Effect tends to plateau around age 60

ASSESSMENT OF SLEEP Changes in sleep quality can be a significant source of aggravation in this population and can be perceived by the patient as problematic. A sleep diary can be a helpful tool to help patients identify factors contributing to their frustrations and insight into behaviors they can modify.

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SAMPLE SLEEP DIARY 1. A sleep diary will help track sleep, allowing a physician to identify habits and trends that are helping an individual promote sleep or that can be eliminated to improve sleep. There are several versions in existence. (Figure 1)

Figure 1. Consensus Sleep Diary-Core, the result of an outgrowth project of the 2005 Insomnia Assessment Conference, developed by a committee of insomnia research experts. Adapted from Carney CE, Buysse DJ, Ancoli-Israel S, et al. The consensus sleep diary: standardizing prospective sleep self-monitoring. Sleep 2012;35:295. Reproduction Permission Granted for Clinical Use Only. Permission to use the diary can be obtained from the first author.

2. In the modern era, electronic versions of sleep diaries and mobile applications have shown a rise in utilization, due to their convenience and ease of use a. Early reports have demonstrated comparable outcomes in the performance of electronic and traditional paper versions 3. Changes in sleep patterns have the potential to become sleep problems when combined with other factors

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Kathleen L. Yaremchuk and Andrea M. Plawecki a. They should not be merely written off as part of the normal aging process b. Sleep problems in older adults are commonly multifactorial and may not be due to aging alone

EPWORTH SLEEPINESS SCALE 1. The Epworth Sleepiness Scale (ESS) is one of the most widely used questionnaires for assessment of hypersomnolence or excessive daytime sleepiness (Figure 2)

Figure 2. Epworth Sleepiness Scale questionnaire/ ESS © MW Johns 1990-1997. Used under License. Contact information and permission to use: Mapi Research Trust, Lyon, France. – Internet: https://eprovide.mapi-trust.org.

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a.

It is a validated tool aimed at determining likelihood of falling asleep under various circumstances b. It is not a tool used to diagnose obstructive sleep apnea

SLEEP HYGIENE TIPS 1. Maintain regular sleep schedule a. Sleep and waking times should be consistent each day, ideally within 20 minutes 2. Minimize daytime napping a. For difficulty with sleep initiation and early morning awakening 3. The bed should only be used as a place for sleep and for intimacy a. Avoid activities like watching television to fall asleep, work, or eating in the bedroom 4. Do not spend more than 30 minutes in bed trying to fall asleep a. Sit in a chair in the quiet room until ready to return to bed b. Avoid television, internet, and other stimulating sources during these times 5. Minimize use of caffeine, alcohol, and nicotine, especially later in the day a. Effects of caffeine last several hours; caffeine consumption should stop after noon b. Alcohol and other substances lead to fragmented sleep 6. Maintain regular exercise habits a. Ideally exercise in morning or early afternoon b. Avoid rigorous exercise before bed, may lead to trouble initiating sleep 7. Don’t be a clock watcher a. Individuals often watch the clock to see how long they have been asleep and when they need to wake up. These are alerting mechanisms that prevent return to sleep. Turn the clock away if necessary, to avoid anxiety associated with watching the clock. 8. Have a quiet comfortable bedroom a. Don’t share the bed with pets b. Keep ambient lighting low

SLEEP DISTURBANCES IN THE OLDER POPULATION As with any other age group reporting subjective sleepiness, it is important to differentiate true sleep-related issues in an older patient from other states that can mimic sleep disorders in this population. 1. Mental and physical states may appear as somnolence in the elderly a. Fatigue b. Chronic pain c. Depression d. Dementia

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Kathleen L. Yaremchuk and Andrea M. Plawecki 2. Secondary sleep disturbances due to other primary disorders increase in older adults a. More medical comorbidities b. Psychiatric illnesses c. Changes in neuroendocrine function and hormone levels d. Polypharmacy and medication side effects

PRIMARY SLEEP-RELATED DISORDERS IN THE OLDER POPULATION 1. Advanced sleep phase disorder a. Sleep pattern that is scheduled several hours earlier than what is usual or desired i. Common circadian rhythm change in the older population ii. Earlier bedtimes, such as 8pm iii. Earlier awakenings, such as 4am b. Difficulty returning to sleep in early morning (can be perceived as poor sleep even after an adequate amount of sleep) c. Early awakening times may lead to mid-day sleepiness and naps d. Generally similar prevalence among men and women, although some limited evidence suggests elderly women may be affected more e. Diagnosis i. No standard amount for how much this pattern deviates from normal sleep-wake times ii. Diagnosis depends rather on distress due to inability to maintain conventional sleep schedule iii. Polysomnography not routinely indicated for diagnosis, unless needed to rule out other disorders f. Predisposing factors in older adults i. Retirement status ii. Fewer daytime obligations, social engagements, or activities iii. Evidence of genetic link, more common if a relative is affected g. Management i. Recognize that this can strain familial and social relationships ii. Encourage ways to reset circadian clock to promote more socially acceptable sleep schedule  Exposure to daylight  Bright light therapy in late afternoon h. Caution with late afternoon or evening driving due to drowsiness 2. Other circadian rhythm disorders may also be encountered in the elderly a. Hypnotic medications carry increased risk of adverse events in this population b. Avoid use of sleep-promoting medications in demented elderly patients with irregular sleep-wake rhythm disorders

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INSOMNIA Insomnia is a persistent disturbance of sleep quantity and/or quality, characterized by difficulty with sleep initiation, maintenance, or early morning awakenings. It results in general sleep dissatisfaction and can lead to clinically significant distress or impairment. 1. Prevalence a. More commonly diagnosed in elderly adults than younger individuals b. Tends to present more in older adults with comorbidities and multiple medications rather than in the healthy elderly c. Seen more often in women than men; may be due to combination of behavioral and hormonal factors 2. Predisposing factors in older adults a. Lifestyle changes i. Sedentary lifestyle with much time spent in bed watching television, reading, or eating ii. Social isolation iii. More frequent trips to bathroom at night iv. More daytime napping—about 25% of adults 75-84 years of age report daytime naps b. Presence of other sleep-related disturbances c. Presence of psychiatric disorders (e.g., depression, anxiety, chronic pain) d. Medications that cause insomnia-like symptoms (see Table 2) Table 2. Common Medications in Older Adults and their Effects on Sleep Drug class Acetylcholinesterase inhibitors (used for cognitive enhancement in patients with Alzheimer’s disease) Beta-blockers

Bronchodilators Corticosteroids Decongestants Diuretics

Examples Donepezil, galanthamine

Atenolol, metoprolol, propranolol

Theophylline Prednisone Pseudoephedrine Furosemide, hydrochlorothiazide Stimulating antidepressants SSRIs (fluoxetine, sertraline), venlafaxine, bupropion Thyroid replacement hormone Levothyroxine REM, rapid eye movement; SSRI, selective serotonin reuptake inhibitor

Sleep-related effects Vivid dreams or nightmares, shortened REM latency, increased REM sleep (inconsistent evidence for galanthamine) Insomnia (may be associated with melatonin suppression), nightmares, nighttime awakenings Wakefulness, difficulty falling asleep Daytime restlessness, insomnia, delirium Daytime restlessness, insomnia Increased nocturia, nighttime cramps Insomnia

High doses can cause sleep difficulties

3. Management a. Reinforce proper sleep hygiene b. Cognitive behavioral therapy for insomnia i. Technique used for treating insomnia ii. Usually consists of 4-6 sessions lasting about 30 to 60 minutes each

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c.

iii. Aim is to identify thoughts and behaviors that affect ability to sleep and to develop strategies to improve sleep habits and overcome negative emotions associated with inability to sleep iv. Studies have demonstrated substantial and longstanding success with this technique, even after completion of therapy Pharmacologic sleep aids (see Table 3) i. Must be wary of polypharmacy and drug interactions in the older population, especially those with dementia or physical debility ii. Caution in the elderly due to increased risk of falls, especially if getting up at night to use bathroom iii. Certain sleep-promoting medications have been associated with other addictive and compulsive behaviors iv. Elderly more likely to have slower metabolism or compromised renal or hepatic function, which can lead to decreased clearance and dangerous levels of these medications v. Any pharmacologic treatment in an elderly patient should be started at the lowest dose and, if a higher dose is needed, increased gradually vi. Need to balance importance of adequate sleep with risks of sleep medications

Table 3. Pharmacologic Sleep Aids and Special Considerations in the Elderly Medication Antihistamines (i.e., diphenhydramine, hydroxyzine)

Benzodiazepines

Melatonin Nonbenzodiazepine hypnotics (i.e., zolpidem, zaleplon)

Trazodone Sedating antidepressants Tricyclic antidepressants

Special considerations in older patients  Not FDA-approved as hypnotic but frequently used OTC  Evidence limited on safety and efficacy in geriatric population  Can cause over sedation, dizziness, impaired cognitive and psychomotor function  Not first-line for elderly patients  More sensitivity to adverse effects, including sedation, cognitive impairment, and risk of falls  If using these, preference is for low dosage, short-term use, and shorter half-life agents  Well tolerated in most  Improves sleep onset and duration  May play a role in prevention of delirium or sundowning  Generally well tolerated in older patients, but they may be more sensitive to motor and cognitive side effects  Evidence limited, suggests improved sleep latency and efficiency  Generally well tolerated in elderly, improves sleep quality  Be cautious of side effects (dizziness, sedation, priapism, orthostatic hypotension, psychomotor impairment)  Can be used in depressed and nondepressed patients  Poor side effect profile, especially anticholinergic and cardiac side effects  Be wary of multiple drug interactions  Can be useful in patients with insomnia and depression

d. Natural sleep aids and herbal supplements i. Use of natural and alternative supplements for sleep disorders has grown in popularity in recent years

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ii. Generally purchased over-the-counter iii. Herbal supplements are generally not regulated by the U.S. Food and Drug Administration, so should be used with caution iv. Limited evidence to support efficacy, but investigation is ongoing v. Common natural remedies used for sleep disturbance:  Melatonin – to promote sleep  Chamomile – to promote relaxation and sleep  Valerian root – anxiolytic, to promote sleep  Lavender – to improve sleep quality  Ginseng – to promote sleep

SLEEP-DISORDERED BREATHING AND OBSTRUCTIVE SLEEP APNEA Sleep-disordered breathing (SDB) refers to a spectrum of disorders defined by cessation or restriction of inspiratory airflow during sleep; includes snoring and obstructive sleep apnea (OSA). 1. OSA prevalence a. Affects at least 2%–4% of the adult population, buy may affect up to 30%– 80% of older adults b. Increasing incidence in recent decades, often associated with obesity epidemic, although obesity is a less strong risk factor in the elderly c. Major risk factors are older age, male gender, postmenopausal status, and obesity 2. OSA in the elderly a. It has been reported that prevalence in older adults increases with age, even among the healthy elderly i. Decreased pharyngeal muscle tone leading to increased collapsibility of upper airway ii. Bone resorption in edentulous patients, associated with mouth breathing iii. Greater prevalence in older men versus women, although difference between genders less pronounced after menopause b. Presentation can differ from that of younger patients i. Snoring less common ii. Atypical symptoms in elderly: nocturia, falls, motor vehicle accidents, cognitive decline and difficulty with memory c. Presence of SDB in the elderly has been associated with cognitive impairment 3. Management a. Polysomnography: necessary for diagnosis and required by most insurance providers for treatment i. Diagnostic polysomnography ii. Portable or home sleep apnea test – more easily available, less expensive, more convenient for patient

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Kathleen L. Yaremchuk and Andrea M. Plawecki b. Avoid prescribing hypnotics for older patients with OSA c. Important to screen for other medical conditions that could be contributing to SDB, especially when newly diagnosed in older age i. Prior stroke ii. Hypothyroidism iii. Congestive heart failure iv. Hypertension v. Diabetes vi. Chronic lung disease d. Treatment options: lifestyle modifications, weight loss for overweight patients, positive airway pressure (PAP) devices, positional therapy (i.e., a sleep shirt), oral appliance, surgery e. Surgical options for OSA in the elderly i. Advanced age in itself is not a contraindication to surgery, but the balance of risk vs. benefit must be carefully considered ii. Higher rate of postoperative complications in the elderly when compared to younger patients, especially wound dehiscence and urinary tract infections iii. Complication rate for sleep surgery in the elderly is still low overall, so surgery is a reasonable option for those healthy enough to undergo anesthesia f. Barriers to OSA treatment in the elderly i. Cognitive impairment or dementia (PAP, positional therapy, oral appliance) ii. Lack of manual dexterity (PAP, positional therapy) iii. Edentulous oral cavity or poor dentition (oral appliance) iv. Can overcome some barriers by involvement of caregiver or sleep partner

SLEEP-RELATED MOVEMENT DISORDERS MORE COMMON IN OLDER ADULTS 1. Restless Leg Syndrome (RLS) a. Characterized by an uncontrollable need to move the legs; occurs when sitting or lying b. Features can be remembered by the acronym URGE: i. Urge to move legs, usually associated with paresthesias or dysesthesias ii. Rest induces or worsens symptoms iii. Getting active brings relief iv. Evening or nighttime worsening of symptoms c. Periodic leg movements in sleep (PLMS) occur in 80-90% of patients with RLS d. Present in about 10% of the population

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Family history is common in patients; may have autosomal dominant transmission f. Incidence increases and symptoms worsen with age g. Etiology i. Commonly believed to be due to dysfunction of dopaminergic cells ii. Associations with other medical conditions  Iron deficiency  Diabetes  Pregnancy  End-stage renal disease  Parkinson’s disease h. Effects on sleep i. Insomnia due to discomfort ii. Increased sleep fragmentation due to urge to ambulate or move iii. Decreased sleep duration i. Management i. Assess ferritin levels; iron supplementation if low ii. Primarily treated with dopamine agonists: pramipexole, ropinirole iii. Other medication options: levodopa with dopa decarboxylase inhibitor, gabapentin, pregabalin, carbamazepine, clonidine iv. Limited evidence on efficacy of non-pharmacologic therapies, such as cognitive behavioral therapy and exercise therapy 2. Periodic Limb Movement Disorder (PLMD) a. Characterized by periodic episodes of repeated limb movements, such as kicks or extremity jerks, during sleep i. Most often involves lower extremities, and occasionally upper extremities ii. May cause arousals, which can lead to sleep disturbance or fatigue b. PLMD is relatively rare as an isolated diagnosis, although PLMS is often associated with other disorders (RLS, REM sleep behavior disorder, narcolepsy) c. More common in the elderly, compared with younger patients d. There is insufficient evidence evaluating use of pharmacologic therapy for PLMD alone i. Has been treated by some with dopaminergic medications ii. Pharmacologic treatment generally not recommended unless patient has significant fatigue or clinical sleep disturbance 3. REM Sleep Behavior Disorder a. Characterized by movement during REM sleep (i.e., acting out dreams, kicking, punching, getting out of bed) b. May cause injury to bed partner due to often violent movements c. Male predominant d. Usually occurs after age 50 e. Diagnosed via sleep study: muscle tone present during REM sleep

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May be associated with underlying neurologic disorders, such as Parkinson’s, or prior stroke

g. Melatonin preferred as the initial drug of choice for treatment h. Caution use of clonazepam in those with dementia or OSA due to its sedative effect.

SLEEP DISTURBANCE ASSOCIATED WITH COMORBID DISORDERS 1. Alzheimer’s Disease a. Associated with multiple sleep-wake cycle disturbances i. increased daytime sleepiness ii. abnormal sleep timing iii. decreased nocturnal sleep duration iv. increased sleep latency v. increased sleep fragmentation b. Specific changes to sleep architecture with progression of disease i. decreased N3 slow-wave sleep ii. decreased REM sleep c. Sundowning i. Phenomenon that can be seen in forms of dementia like Alzheimer’s ii. Characterized by worsening of confusion and agitation that occurs later in the day or evening iii. Etiology not well understood but speculated to be related to the disease’s effect on disruption of circadian rhythm 2. Lewy Body Dementia a. Sleep disturbance is a characteristic feature of Lewy body dementia, a form of dementia that usually develops after the age of 50 b. REM-sleep behavior sleep disorder, in particular, is frequently seen i. Can present years before other dementia symptoms manifest c. Symptoms of insomnia and daytime sleepiness also common 3. Parkinson’s Disease a. Sleep dysfunction in patients has been well-reported i. Present in up to 90% of patients with Parkinson’s Disease ii. May precede other Parkinson’s symptoms by decades b. Pathogenesis i. Dopamine is the primary neurotransmitter implicated in its pathogenesis and has been shown to have an important effect on sleep and circadian rhythm ii. Etiology of sleep impairment is multifactorial, including the neurodegenerative nature of the disease, motor symptoms leading to nighttime disturbances, and medication effects

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4.

5.

6.

7.

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Most common sleep disorders reported in these patients include: i. Insomnia ii. Excessive daytime sleepiness iii. Restless leg syndrome iv. REM-sleep behavior disorder Chronic Obstructive Pulmonary Disease a. Chronic obstructive pulmonary disease (COPD) in the older population i. Risk of developing COPD increases with age ii. Nocturnal hypoxia and hypercarbia more common in these individuals iii. A significant number of patients with moderate or severe COPD also meet criteria for diagnosis of OSA iv. Experience excessive daytime sleepiness, poor quality of sleep, and impaired sleep maintenance v. Avoid hypnotic medications in this population—can lead to hypoventilation and worsen nighttime hypoxia Nocturia a. Nocturia and sleep disruption i. Common symptom in older adults ii. Disturbs sleep due to increased nighttime arousals b. Can be associated with conditions like benign prostatic hypertrophy, diabetes, bladder hypersensitivity, overactive bladder, renal problems, or diuretic use c. Pharmacologic treatment options for nocturia limited due to risk of anticholinergic side effects or electrolyte imbalances in the elderly Chronic Pain a. Chronic pain can lead to sleep impairment i. Increased sleep latency ii. Decreased sleep efficiency due to sleep fragmentation iii. More nighttime arousals b. Sleep disturbance from chronic pain is challenging to treat in the elderly i. Causative conditions include arthritis, peripheral neuropathy, fibromyalgia, and degenerative musculoskeletal disorders ii. Overlap of chronic pain with depression and insomnia symptoms iii. Risk of adverse effects associated with pain medications, greater in older adults iv. Symptom management, if possible, can help to improve sleep quality Delirium a. Disturbance of the sleep-wake cycle is often seen in delirium, either as a predisposing factor or a symptomatic manifestation i. The elderly can be especially prone to delirium secondary to sleep disturbances, especially in critically ill patients b. Factors that contribute to circadian disruption in acute care facilities or hospital settings: i. Lack of natural daylight cycles ii. Frequency of nighttime awakenings associated with patient care and noise

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Recommendations to improve sleep-wake cycles for these patients i. Minimization of nocturnal disturbances ii. Maintaining quiet hours and low lighting during the night iii. Clustering nighttime care interventions

KEY CLINICAL POINTS 1. The initial evaluation of sleep-related complaints in older adults should include a thorough history of sleep patterns and habits, as well as of comorbid medical conditions, psychiatric illness, and current medications. The assessment of sleep disturbance in the elderly should take into account normal physiologic changes in sleep patterns that occur with aging; however, other causes of sleep impairment should also be investigated in this population. Patient education and reinforcement of proper sleep hygiene should be the first steps in counseling patients with complaints determined to be secondary to normal age-related changes. 2. Polysomnography is not routinely indicated for diagnosis of circadian rhythm sleep disorders, unless needed to rule out other primary sleep disorders. Advanced sleep phase disorder (ASPD) is a common circadian rhythm change in the older population. Clinicians should treat adult patients with ASPD with evening light therapy. 3. Hypnotic medications in elderly patients, especially those with dementia, carry an increased risk of adverse events. Clinicians should not start pharmacologic therapy to promote sleep in elderly patients without investigating medications and comorbid diseases. Hypnotic medications in the elderly should generally be started at low dose and increased slowly. Avoid use of sleep-promoting medications to treat demented elderly patients with irregular sleep-wake rhythm disorder. 4. Questions regarding hypersomnolence and obstructive sleep apnea (OSA) should be incorporated into routine health evaluations of older adults. Older age, snoring, and hypersomnolence should trigger suspicion of OSA. If a diagnosis of OSA is suspected, the clinician should proceed with a sleep-oriented history and physical examination, objective testing, and patient education. OSA should not be diagnosed by clinical features alone. Objective testing is needed for diagnosis of OSA and should consist of polysomnography or, alternatively, by home sleep apnea testing in appropriate patients. The presence or absence of OSA, and severity if present, should be determined prior to initiation of treatment. Upon establishment of a diagnosis, the patient and/or caregiver should be included in deciding the appropriate treatment strategy. Patients with OSA, including elderly patients, require long-term, multidisciplinary management. 5. Sleep related movement disorders are more prevalent in older adults. Polysomnography is not routinely indicated for diagnosis of restless leg syndrome (RLS), unless an additional sleep disorder like OSA is suspected. Patients with RLS should be treated with pramipexole or ropinirole. Other options for treatment of RLS may include levodopa with dopa decarboxylase inhibitor, gabapentin, pregabalin, carbamazepine, clonidine, and iron supplementation. There is currently insufficient evidence to evaluate pharmacologic therapies for periodic leg movement disorder alone.

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QUESTIONS 1. Which of the following sleep parameters tends to increase with age? a. Sleep latency b. Sleep duration c. Sleep efficiency d. Recommended amount of sleep 2. Which of the following statements regarding change in time spent in various sleep stages is false? a. N1 (light sleep) increases with age b. N2 (light sleep) increases with age c. N3 (deep, slow wave sleep) decreases with age d. Rapid eye movement (REM) increases with age 3. An 80-year-old woman goes to bed around 8pm and wakes up around 4am. She reports frustration due to her difficulty falling back asleep at that time and finds herself requiring naps in the middle of the day. How would you best characterize her sleep pattern? a. Insomnia b. Normal physiologic pattern for age c. Advanced sleep phase d. Delayed sleep phase 4. Which statement regarding sleep-disordered breathing in the elderly is correct? a. There is no association between SDB and cognitive impairment in elderly patients b. Decreased pharyngeal muscle tone and edentulous status with mouth breathing may contribute to its development in later age c. Hypnotic medications should be used to promote restful sleep in this population d. Advanced age is a contraindication to surgical intervention in this population 5. Which intervention should not be part of the initial assessment of an elderly patient presenting with hypersomnolence? a. Polysomnography b. Review of sleep patterns, such as via a sleep diary c. Epworth sleepiness scale d. Review of current medications

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Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017 Mar 15;13(3):479-504. doi: 10.5664/jcsm.6506. 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(4):499-521. doi: 10.1093/sleep/28.4.499. Markowitz JS, Gutterman EM, Lilienfeld S, Papadopoulos G. Sleep-related outcomes in persons with mild to moderate Alzheimer disease in a placebo-controlled trial of galantamine. Sleep. 2003;26(5):602-606. doi: 10.1093/sleep/26.5.602. McCall WV. Sleep in the Elderly: Burden, Diagnosis, and Treatment. Prim Care Companion J Clin Psychiatry. 2004;6(1):9-20. doi: 10.4088/pcc.v06n0104. Moe KE, Prinz PN, Vitiello MV, Marks AL, Larsen LH. Healthy elderly women and men have different entrained circadian temperature rhythms. J Am Geriatr Soc. 1991;39(4):383-387. doi: 10.1111/j.1532-5415.1991.tb02904.x. Morin CM, Gibson D, Wade J. Self-reported sleep and mood disturbance in chronic pain patients. Clin J Pain. 1998;14(4):311-314. doi:10.1097/00002508-199812000-00007. Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. Sleep. 2004;27(7):1255-1273. doi: 10.1093/sleep/27.7.1255. Paruthi S, Brooks LJ, D'Ambrosio C, Hall WA, Kotagal S, Lloyd RM, Malow BA, Maski K, Nichols C, Quan SF, Rosen CL, Troester MM, Wise MS. Recommended Amount of Sleep for Pediatric Populations: A Consensus Statement of the American Academy of Sleep Medicine. J Clin Sleep Med. 2016 Jun 15;12(6):785-6. doi: 10.5664/jcsm.5866. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev. 2015;19:29-38. doi: 10.1016/j.smrv.2014.03.007. Riemann D, Gann H, Dressing H, Müller WE, Aldenhoff JB. Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep. Psychiatry Res. 1994;51(3):253267. doi: 10.1016/0165-1781(94)90013-2. Schredl M, Weber B, Leins ML, Heuser I. Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons. Exp Gerontol. 2001;36(2):353361. doi: 10.1016/s0531-5565(00)00206-0. Schrempf W, Brandt MD, Storch A, Reichmann H. Sleep disorders in Parkinson's disease. J Parkinsons Dis. 2014;4(2):211-221. doi: 10.3233/JPD-130301. Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W. Influence of beta-blockers on melatonin release. Eur J Clin Pharmacol. 1999 Apr;55(2):111-5. doi: 10.1007/s002280050604 Tonetti L, Mingozzi R, Natale V. Comparison between paper and electronic sleep diary. Biol Rhythm Res. 2016;47(5):743-753. doi: 10.1080/09291016.2016.1191689. Videnovic A, Golombek D. Circadian and sleep disorders in Parkinson's disease. Exp Neurol. 2013;243:45-56. doi: 10.1016/j.expneurol.2012.08.018. Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, Dinges DF, Gangwisch J, Grandner MA, Kushida C, Malhotra RK, Martin JL, Patel SR, Quan SF, Tasali E. Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 9

SLEEP AND MEDICAL CONDITIONS Gerald D. Suh, MD Princeton ENT and Sleep, LLC, Princeton, NJ, USA Penn Medicine Princeton Health, Plainsboro, NJ, USA Affiliate of Penn Medicine Department of Otolaryngology, Philadelphia, PA, USA

INTRODUCTION This chapter highlights some of the emerging body of knowledge regarding the impact of various sleep disorders on a large number of diverse medical conditions and vice versa. The list seems to grow on a daily basis.

SLEEP AND CARDIOLOGY 1. Impact of sleep stages on the heart a. Rapid eye movement (REM) sleep i. Characterized by surges in sympathetic and vagus nerve activity, as well as a surge in heart rate ii. These are well tolerated in normal individuals but may result in cardiac arrhythmias, myocardial ischemia, and myocardial infarction in those with heart disease iii. The major indirect effects include an impaired oxygen supplydemand ratio resulting from increased cardiac metabolic activity and coronary vasoconstriction, particularly in vessels with injured endothelium and in the context of altered preload and afterload  During non-REM (NREM) sleep, systemic blood pressure may fall, potentially reducing flow through stenotic coronary vessels, which may precipitate myocardial ischemia or infarction

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Gerald Suh b. Sleep-disordered breathing (SDB) and the heart i. Heavy snoring by itself (> 50% of the night) has been associated with increased carotid atherosclerosis independent of other risk factors such as nocturnal hypoxemia and obstructive sleep apnea (OSA) severity ii. The impact of OSA on cardiovascular disease is to be discussed in further detail elsewhere iii. With regards to the association between heart failure and SDB, approximately 50% of individuals with left ventricular (LV) systolic dysfunction, both asymptomatic and symptomatic, suffer from moderate to severe OSA iv. The results of several recent series reported an apnea-hypopnea index (AHI) of 15 per hour as the threshold for increased association with heart disease  53% of 1607 patients with heart failure had moderate to severe sleep apnea  34% had central sleep apnea (CSA)  19% had OSA

SLEEP AND ENDOCRINOLOGY 1. The endocrine system as a whole a. The endocrine system can be conceptualized as an array of hypothalamuspituitary-target organ (HPT) axes i. Target organs can be represented by the “effector” endocrine glands  thyroid, adrenal, gonads, adipose tissue b. Given the multiple functions of the hypothalamus, its damage may be associated with a wide variety of sleep symptoms: i. Sleepiness, fatigue, and disturbances in the sleep-wake regulatory system and circadian rhythms c. Many case reports or short series illustrate that pathology of the lateral hypothalamus can lead to hypersomnia or narcolepsy i. Involvement by infiltrative, inflammatory, or neoplastic conditions of the anterior hypothalamus may disrupt the circadian clock of these patients or lead to severe insomnia 2. Excess growth hormone a. The neuroendocrine condition of growth hormone (GH) excess leads to acromegaly in adults and gigantism in children b. SDB is very common in acromegaly i. Studies have shown that up to 70% of patients diagnosed with acromegaly have sleep apnea, even after correction for obesity c. CSA was the predominant type of apnea in 33% of patients i. Recognizing that SDB is under-assessed in patients with acromegaly, current guidelines recommend that every patient diagnosed with this

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condition should be evaluated upfront for daytime symptoms or assessed by polysomnography (PSG) in collaboration with a sleep specialist d. OSA improves in many patients with acromegaly after GH tumor resection surgery. i. Prospective studies show that OSA persists in at least 40% of patients cured of acromegaly, requiring periodic reassessment e. There is also increased prevalence of restless leg syndrome (RLS) in patients with active acromegaly i. A few studies have shown approximately 21-25% of patients with acromegaly had RLS ii. May be related to associated osteoarthropathy 3. Thyroid disorders a. Thyroid hormones influence many central nervous system (CNS) neurochemical pathways and networks involved in the sleep-wake homeostasis i. Disturbances of the HPT axis such as altered thyroid function or abnormal thyroid-stimulating hormone (TSH) levels may affect the arousal-promoting system ii. The effects of thyroid hormones are more likely activating than soporific b. Hypothyroidism is one of the most common endocrine disorders i. Its prevalence tends to increase with age and is more common in women ii. Hypothyroidism and OSA have several common clinical manifestations and major comorbidities  Clinically they can be very easily confused with each other  For example, OSA is characterized by snoring, excessive daytime sleepiness, fatigue, apathy, frequent headaches, and memory impairments and is often associated with obesity or depression; these manifestations are somewhat nonspecific and also frequently seen in hypothyroidism. iii. A number of investigators have found OSA and hypothyroidism to coexist in 1.2% to 11% of the population studied c. Large goiters can also cause upper airway compression, ventilatory impairment, and possibly OSA 4. The adipose system a. The adipose tissue represents one of the largest and most active endocrine organs i. Several major protein hormones are synthesized and secreted by adipocytes  The most prominent are leptin and adiponectin  Produced primarily (not exclusively) in the fat cells b. Ghrelin is a hormone secreted by the stomach i. Stimulates appetite and is increased by sleep loss

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Leptin is a hormone secreted by adipose tissue i. Increases satiety d. Sleep loss is associated with: i. Impaired glucose metabolism ii. Lower leptin levels iii. Higher ghrelin levels iv. This would tend to increase food intake and perhaps decrease energy utilization resulting in an increased risk of obesity e. The relationship between quantity of sleep or total sleep time (TST) and obesity has been extensively examined in the past i. Most of the studies found a significant association between obesity and short sleep in children and a weaker association in adults f. A longitudinal study analyzed the association between sleep and body mass index (BMI) over a 13-year period and reported that the odds ratio for sleep duration predicting obesity was 0.50 i. This means that every extra hour of sleep duration was associated with a 50% reduction in the risk of obesity g. Both TST reduction (with preserved slow wave sleep (SWS)) and SWS suppression (with preserved TST) have been shown to be associated with insulin resistance (without compensatory hyperinsulinemia), resulting in impaired glucose tolerance and increased risk for type 2 diabetes mellitus

SLEEP AND GASTROENTEROLOGY 1. Gastroesophageal Reflux Disease (GERD) and sleep a. Symptoms of nocturnal gastro-esophageal reflux (GER) include prolonged sleep latency, frequent awakenings, substernal burning or chest discomfort, indigestion, and heartburn i. Other symptoms include a sour or bitter taste in the mouth, regurgitation, coughing, and choking b. 45–50% of patients with GERD have nocturnal symptoms i. The normal defense mechanisms to minimize the detrimental effects of GER are not present during sleep  Saliva secretion virtually stops and reflex swallowing to clear refluxed material is not present  This results in a prolonged acid contact time (ACT). Thus, nocturnal GER is potentially more injurious than diurnal GER because acid clearance mechanisms are impaired during sleep. c. Esophageal pH testing is used to diagnose GERD and has a sensitivity and specificity of approximately 90% i. ACT, defined as the time with a pH less than 4, is often computed as absolute time or as a percentage of monitoring time or sleep time ii. Normal ACT is often assumed to be less than 4%

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d. The absence of symptoms does not eliminate the presence of GERD. Esophageal pH monitoring often shows significant GER episodes in asymptomatic patients. 2. OSA and GERD a. Nocturnal GERD is common in patients with OSA (50-75%) and is improved with continuous positive airway pressure (CPAP) treatment i. It is thought to be related to the negative intrathoracic pressure during obstructive apnea and the frequent arousals from sleep b. CPAP, by increasing the pressure gradient between the thorax and the stomach, may also reduce GER independent of the effects of CPAP on OSA c. GER episodes should be suspected on routine PSG if there is an arousal followed by a prolonged period of increased chin electromyogram (manifestation of swallowing) i. Most nocturnal GER episodes occur during prolonged wake or after arousal from stage N2 sleep

SLEEP AND HEMATOLOGY/ONCOLOGY 1. Sleep disorders seen in cancer patients a. Insomnia and fatigue are common in cancer patients before treatment, while undergoing chemotherapy or radiation therapy, and after the completion of therapy b. As many as half of all patients with cancer have problems sleeping i. This is mainly due to insomnia and an abnormal sleep-wake cycle c. There are many reasons a cancer patient may have trouble sleeping, including: i. Physical changes caused by the cancer (i.e., tumor pressing on various structures causing pain or trouble breathing) or from surgery ii. Side effects of drugs or other treatments iii. Being in the hospital iv. Stress about having cancer d. The relationship between sleep disruption and fatigue appears to be bidirectional i. Fatigue is a common consequence of insomnia, but it can also increase the risk for insomnia  This is most likely through behavioral changes (e.g., napping) that disturb the sleep-wake cycle ii. Several cancer-specific factors may trigger the onset of sleep disturbances:  Adjuvant treatments, nocturnal hot flashes, pain, opioids, and antiemetic medications iii. Fatigue may also be caused by a combination of factors:  Physical (e.g., cachexia, inflammation, hematologic and endocrine abnormalities)  Psychological (e.g., depression)

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Gerald Suh  Social factors iv. There is accumulating evidence supporting the efficacy of psychological interventions (cognitive-behavioral therapy in particular), activity-based interventions, and bright-light therapy to treat cancer-related sleep disturbances and fatigue 2. Sleep disorders and risk of cancer a. Although cumulatively, study results have been mixed, there is growing research that has identified links between several common sleep disorders and higher cancer risk b. A 2015 study found people with insomnia, OSA, and parasomnias all had elevated risks for developing several types of cancer, including breast, oral, and prostate c. A 2014 study found lack of sleep increases damage to DNA, injury and dysfunction to cells, including heightened cell death, increased cell proliferation, and increased risk for cell replication errors

SLEEP AND INFECTIOUS DISEASE 1. Effect of infection on sleep a. Sleepiness, like fever, is commonly experienced at the onset of an infection or other cause of systemic inflammation i. Changes in sleep in response to microbes appear to be one facet of the acute phase response ii. Typically, soon after infectious challenge, time spent in NREM sleep increases and REM sleep is suppressed b. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are key players in the development of the acute phase response induced by infectious agents i. During the initial response to infectious challenge these proinflammatory cytokines are upregulated, leading to the acute phase sleep response c. After an acute viral infection (e.g., mononucleosis, pneumonia), patients may develop a (postviral) syndrome of excessive daytime sleepiness (EDS) with features similar to those of chronic fatigue i. In some of these patients, an encephalitic process or elevated levels of inflammatory cytokines may play a role d. Human African trypanosomiasis, which is due to the transmission of trypanosomes by tsetse flies, is a frequent cause of severe hypersomnia throughout Africa i. After an extensive immune reaction during the initial stage, severe sleep and wakefulness impairment follows, and the disorder at this point is referred to as “sleeping sickness” ii. The possibility of human African trypanosomiasis needs to be assessed in travelers and individuals migrating from Africa with EDS

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2. Sleep and the immune system a. Although few studies have been conducted within the context of sleep, some suggest relationships between sleep and functional immune outcomes i. Shift workers are considered chronically sleep deprived ii. A large population study reveals increased incidence of infections in those who experienced the most shift changes iii. Self-reports of sleep duration and sleep efficiency before controlled challenge with a “cold” virus suggest that individuals sleeping less than 7 hours per night, or with sleep efficiency of less than 92%, are more likely to develop colds b. Several studies of human volunteers have examined the effects of sleep loss on subsequent antibody responses to vaccines i. In one study, sleep-restricted subjects 10 days after vaccination produced less than half the antibody titers of control subjects who were allowed 8 hours of sleep opportunity per night ii. In a different study, subjects were given a hepatitis A vaccination and then deprived of sleep for one night. Antibody titers in sleep-deprived subjects 4 weeks after the vaccination were reduced by about 50% relative to those of control (non− sleep-deprived) subjects. c. Innate host response i. Sleep and sleep loss are associated with changes in natural killer (NK) cell activity ii. NK cell activity is reduced in patients with insomnia and decreases after partial night sleep restriction

SLEEP AND NEPHROLOGY 1. Atrial Natriuretic Peptide (ANP) and OSA a. ANP is secreted by the atrial myocytes in response to stretch and other influences b. Causes an increase in the renal excretion of sodium and is a mechanism to respond to fluid overload c. ANP is elevated in untreated sleep apnea (negative intrathoracic pressure swings stretch the atria) resulting in nocturia and nocturnal natriuresis 2. Sleep disorders and chronic kidney disease a. The prevalence of sleep disorders in patients with end-stage renal disease (ESRD) requiring dialysis is well established i. Poor sleep, as defined as sleep-wake complaints, sleep-disordered breathing, and EDS, occurs in 45% to 80% of dialysis patients b. Chronic kidney disease (CKD) may promote sleep disturbances with anemia, resulting in RLS and periodic limb movements during sleep (PLMS), or in fluid gain that is noted in CKD, resulting in SDB i. SDB may result in hypertension, which may then worsen chronic kidney disease

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Prevalence of RLS in CKD patients not yet on dialysis is reported to be 1126%. Among patients with ESRD requiring hemodialysis (HD), RLS is present in 14-58%. d. A study using 48-hour seven-channel ambulatory PSG that included electromyogram signals from bilateral anterior tibialis muscles, found PLMS (defined by periodic limb movement index [PLMI] ≥ 5/ hour of sleep) to be present in 85.4% of HD subjects i. Defining “clinically relevant” as PLMI ≥ 25/ hour, 71% met that criterion e. The exact mechanism of how CKD results in increased RLS remains elusive i. Some proposed theories associate the sleep-related movement disorder to uremia and low intact parathyroid hormone ii. The association with reduced ferritin has been much less robust compared with subjects without CKD f. Another consistent finding is the increasing prevalence of OSA with worsening renal function i. Using a respiratory disturbance index of 15 or greater:  38% of subjects with CKD were shown to have OSA  51% of subjects with ESRD had OSA ii. It has been demonstrated that for each 10 mL/ minute per 1.73 m2 decrease in eGFR, the odds ratio for OSA is 1.42, even after adjustment for age, BMI, and presence of diabetes g. Patients on hemodialysis (HD) with sleep apnea tend to have CSApredominant sleep apnea (defined by CSA index > 5) i. In these CSA-predominant subjects, there is a greater incidence of atrial fibrillation ii. Interestingly, the central apnea index is lower on the night of HD, suggesting that volume overload may contribute to the development of CSA in susceptible patients

SLEEP AND NEUROLOGY 1. Sleep and seizures/ epilepsy a. Nocturnal epilepsy can be difficult to differentiate from parasomnias i. Some patients have seizures only at night, scalp electroencephalogram (EEG) findings may not be visible during seizures, bizarre movements can occur during partial seizures, consciousness can be maintained, and minimal postictal confusion may be present in some cases ii. A seizure is a single occurrence, whereas epilepsy is a neurological condition characterized by two or more unprovoked seizures b. Factors favoring nocturnal frontal lobe epilepsy (NFLE) over a parasomnia include multiple episodes per night, stereotypical manifestations, onset out of

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stage N2 versus N3, and certain behaviors (e.g., cycling, fencing, pelvic thrusting) as well as immediate alertness after the episode c. Nocturnal seizure disorders are much more common in NREM and rare during REM sleep d. A normal EEG does NOT rule out epilepsy e. An abnormal EEG (epileptiform activity) does NOT rule in epilepsy f. As many as 10% to 40% of seizures occur exclusively or mainly during sleep g. Epileptiform activity includes spikes, spike and waves, and polyspike complexes h. In general, true spike and wave complexes have a “field” i. True spike and wave activity should be seen in derivations containing several contiguous electrodes i. One 2003 study of unselected adult epilepsy patients found an OSA prevalence of 10.2% (15.4% in men and 5.4% in women) i. An even higher frequency has been found in patients with refractory epilepsy j. A randomized, pilot-controlled study of CPAP vs. sham in a group of patients with medically refractory epilepsy and coexistent OSA found a trend for improvement in nocturnal seizures frequency 2. Sleep and degenerative disorders a. Alzheimer’s Disease i. With regards to degenerative disorders, Alzheimer’s Disease (AD) is the most common cause of dementia (> 60% of dementias) and can be associated with the irregular sleep-wake rhythm disorder and sun downing, which is defined as nocturnal exacerbation of disruptive behavior or agitation in older patients  This is likely the most common cause of institutionalization in patients with AD ii. In early AD, there is irregular sleep-wake rhythms with large amounts of daytime sleep, nocturnal awakenings and a decrease in stage N3  In late AD, there is a decrease in REM sleep and an increase in the REM latency as well as EDS iii. OSA is common in AD patients and, if successfully treated with CPAP, can improve sleep quality and mood as well as slow the rate of cognitive decline b. Progressive Supranuclear Palsy (PSP) i. PSP is characterized by vertical gaze palsy and prominent sleepmaintenance insomnia (worse than in AD) and nocturia ii. PSP patients have a large reduction in the amount of REM sleep  PSG will often show absence of vertical eye movements during REM sleep iii. REM Behavior Disorder (RBD) occurs in approximately 13% to 30% of PSP patients

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When RBD is present on PSG it typically presents concomitant with other findings (motor and cognitive dysfunction) iv. RBD can occur many years before the onset of Parkinson’s Disease 3. Parkinson’s Disease (PD) a. PD is a chronic neurodegenerative disorder associated with a loss of dopaminergic neurons (substantia nigra and other sites) b. The sleep of patients with PD is impaired by rigidity, tremor (tends to resolve with sleep onset), dyskinesias, OSA, RBD (20-40%), and nocturnal hallucinations c. Patients with PD can manifest EDS even if OSA is not present 4. Parkinsonism a. The term parkinsonism is used to refer to a group of manifestations including tremor, rigidity, bradykinesia, and postural instability. b. Parkinsonism is found in both PD and Parkinson Plus (PD+) disorders (The PD+ disorders include those characterized by parkinsonism and other manifestations. i. The PD+ disorders include PSP, Diffuse Lewy Body Dementia (DLBD), and Multiple System Atrophy (MSA) ii. Of note, the brains of PD patients do have Lewy bodies, but in DLBD, the distribution of Lewy bodies is denser and more diverse iii. DLBD patients have more prominent dementia than noted in patients with PD. The dementia of DLBD also present much earlier in the course of the disease than the dementia associated with PD.  There is overlap between PD and DLBD  The PD+ disorders tend to progress more quickly than PD  The typical anti-PD medications are either less effective or completely ineffective in PD+ disorders  PD+ patients are also very sensitive to dopamine blockers. c. Diffuse Lewy Body Dementia (DLBD) i. DLBD is a type of dementia characterized anatomically by the presence of Lewy bodies, clumps of alpha synuclein and ubiquitine proteins in neurons ii. In this disorder, loss of cholinergic neurons results in cognitive dysfunction and loss of dopamine neurons results in parkinsonism iii. RBD is very common (50–80%) iv. Life-threatening rigidity or malignant neuroleptic syndrome with dopamine blockers d. Multiple System Atrophy (MSA) i. MSA patients have various amounts of striatonigral degeneration (rigidity and bradykinesia), olivopontocerebellar degeneration (cerebellar dysfunction, ataxia, falls), and autonomic dysfunction (erectile dysfunction, orthostatic hypotension, bladder dysfunction) ii. RBD is very common in MSA patients (80-95%)

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iii. Stridor (especially during sleep) is a well-known manifestation of MSA and denotes a poor prognosis. A normal laryngeal examination during wakefulness does not rule out the problem.  CPAP or tracheostomy may be necessary to manage the stridor iv. Patients with MSA often have OSA as well as worsening stridor during sleep  The etiology of stridor is controversial but is likely due to overactivity of the vocal cord adductors and underactivity of vocal cord abductors (posterior cricoarytenoid muscles) v. CSA, nocturnal hypoventilation, and Cheyne-Stokes breathing (CSB) have been reported in MSA, especially in patients with prominent autonomic features 5. Stroke and sleep disorders a. There is a high prevalence of sleep apnea in patients who have had a recent stroke i. OSA is the most common form of sleep apnea but CSA (including CSB) can occur, especially early after a stroke ii. CSB tends to dissipate over time b. SDB occurs in 50-70% of stroke patients (defined by AHI > 10/hr) i. However, the presence of sleep apnea following a cerebrovascular accident (CVA) raises questions about the temporal relationship with stroke  Does brain damage from CVA cause sleep apnea or did sleep apnea precede the stroke?  If so, is the presence of sleep apnea an independent risk factor for the development of a CVA? c. The Sleep Heart Health Study did show an increased risk of having a CVA (prevalence) when OSA was present i. Presence of OSA was associated with a worse prognosis ii. CPAP treatment can improve outcomes d. After stroke, other sleep-wake disorders may impair recovery i. Insomnia can occur but treatment should be cautious until sleep apnea is excluded ii. EDS can occur even if sleep apnea is not present iii. Post-stroke hypersomnia can be found after subcortical (caudateputamen), thalamomesencephalic, medial pontomedullary, and cortical strokes e. In one study, up to 12% of patients developed new-onset RLS after a stroke i. Pontine-tegmental strokes can lead to RBD

SLEEP AND PULMONOLOGY 1. Chronic Obstructive Pulmonary Disease (COPD) and sleep disorders a. Overview

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Gerald Suh i. 5 to 10% of the world population have COPD ii. Prevalence of OSA in COPD patients, Overlap Syndrome (OVS), is 10-15%  One study demonstrated a 66% prevalence of OSA among patients with moderate to severe COPD, possibly related to upper airway edema or myopathy due to cor pulmonale or skeletal muscle myopathy directly related to COPD iii. The co-occurrence of OSA and COPD has been associated with poor outcomes. Mortality associated with OVS is higher than that associated with OSA or COPD alone. iv. It is also worthwhile to differentiate between COPD sub-types: emphysema (typically low BMI, hyperinflated) vs chronic bronchitis (high BMI, right-sided heart failure, peripheral edema). The chronic bronchitis type is more likely to be associated with OSA. v. Patients with COPD may experience nocturnal dyspnea without discrete apneas or hypopneas and is typically worse during REM sleep  The dyspnea is characterized by long periods of irregular and reduced tidal volume vi. A saw tooth pattern on a nocturnal oximetry tracing in a COPD patient suggests the possibility of coexisting OSA vii. If the awake SaO2 is low, even the normal fall in PO2 with sleep will result in greater desaturation (drop in SaO2) due to the initial position on the steep portion of the oxyhemoglobin dissociation curve viii. Patients with OVS often require treatment with a combination of positive airway pressure (PAP) and supplemental oxygen  Bilevel PAP (BiPAP) may be better tolerated than CPAP in some patients with the combination of COPD and OSA b. Diagnosis i. Typically made by a full, in-lab PSG on a patient with COPD who presents with sleep-related complaints ii. Screening for OSA in all patients with COPD (especially with chronic bronchitis) should be considered due to the significant morbidity associated with the overlap syndrome iii. For patients with mild to moderate COPD, home sleep testing has been used, although the detection of hypopneas is more challenging because detection methods for decreased ventilation leading to oxygen desaturation and arousals may be dampened in COPD by hyperinflation and/or the presence of carboxyhemoglobin iv. Cannot just use AHI to determine OSA severity in OVS patients. There is a potential that sustained hypoxemia due to hypoventilation may only be counted as a single hypopnea or repetitive respiratory events with blunted oxygen desaturations my not be counted as hypopneas. Less likely, arousals with irregular breathing due to hyperinflation or nocturnal cough could be scored as a hypopnea.

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v. Occasionally, the possibility of underlying COPD can be raised on a routine PSG (saw-tooth pattern) for evaluation of OSA vi. Patients with OVS have worse blood gases than those with COPD or OSA alone and develop daytime hypercapnia at a relatedly preserved lung function, rather than when the lung function becomes severely compromised in COPD patients and at a lower BMI and AHI than patients with OSA alone. In addition, hypoxemia is more prolonged and profound in patients with OVS. There is also an increased prevalence of pulmonary hypertension. c. Management i. May need to consider treatment with PAP therapy in patients with COPD at a lower AHI than normal due to concerns outlined previously, especially in patients with moderate to severe COPD ii. Due to major oxygen desaturations during REM sleep, likely due to hypoventilation, OVS patients may benefit from bilevel positive airway pressure (BiPAP) therapy iii. Adequate PAP therapy has a significant impact on survival / mortality of OVS patients iv. An in-lab PAP titration study should be considered, both to assess if BiPAP therapy is needed as well as possible nocturnal supplemental oxygen therapy. It is possible that PAP therapy alone may eliminate oxygen desaturations, eliminating the need for nocturnal O2, with its added expense and risk. v. Nocturnal oxygen therapy alone is considered ineffective and can worsen hypercapnia vi. Inhaled, long-acting beta-agonist and anticholinergic therapy, as well as supplemental oxygen to address the COPD component may be necessary d. Nocturnal oxygen supplementation has not been proven to improve sleep quality in patients with COPD alone, but does improve survival in COPD patients with daytime hypoxemia (PaO2 ≤ 55 mm Hg, SaO2 ≤ 88% OR PaO2 55–59 mmHg and evidence of cor pulmonale) e. Poor sleep quality in COPD patients is believed to be due to medication side effects, nocturnal cough, and dyspnea 2. Asthma and sleep a. Nocturnal asthma is usually defined as occurring in patients with a 15% or greater drop in the peak flow (or FEV1) between bedtime and morning awakening b. There is a normal circadian variation in lung function with the best function around 4 PM and the worst at 4 AM i. However, the variation is much greater in patients with asthma ii. Asthmatic patients can experience a 20% to 50% drop in the FEV1 from bedtime until morning c. The presence and frequency of nocturnal asthma (nocturnal awakening) is one of the criteria for determining the severity of asthma i. Persistent mild asthma: 3 to 4 times/month

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Gerald Suh ii. Persistent moderate asthma: more than once weekly but not nightly iii. Persistent severe asthma: usually 7 times/week

SLEEP AND PSYCHIATRY Overview a.

Psychiatric disorders are among the most common health problems i. Over 15% to 20% of Americans are treated for a significant psychiatric illness in any given year b. Almost one third of individuals with significant complaints of insomnia or hypersomnia show evidence of psychiatric disorders c. Psychiatric disorders account for the largest diagnostic category for patients with sleep complaints i. Sleep complaints are part of the diagnostic criteria for many psychiatric disorders and are a source of considerable morbidity 1. Sleep disorders and depression a. Insomnia or hypersomnia nearly every day is one of the nine major criteria for diagnosis of a major depressive episode b. During a major depressive episode, approximately 80% of patients complain of symptoms of insomnia (frequent awakenings, early morning awakening) and 20% complain of hypersomnia c. A PSG during a depressive episode shows a long sleep latency, reduced sleep efficiency, reduced stage N3, a short REM latency, a longer first REM period, and a higher REM density early in the night i. Early morning awakening may also be present d. Insomnia can precede a major depressive episode and is often the last symptom of depression to resolve i. Some but not all studies suggest that the persistence of sleep complaints is a risk factor for relapse of depression e. Individuals with persistent insomnia have been found to be 4 to 10 times more likely to subsequently develop depression than those with short-term insomnia or no insomnia f. Patients with depression and persistent insomnia are 1.8 to 3.5 times more likely to remain depressed, compared with patients with no insomnia 2. Sleep disorders and mania a. During manic episodes (MEs), the patient reports a decreased need for sleep (feeling rested on a few hours of sleep) i. Sleep loss can precipitate a ME b. MEs are associated with marked insomnia, but the patient awakens refreshed after a few hours of sleep c. PSG findings include reduced stage N3, a short REM latency, and an increased REM density

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3. Sleep and panic disorder a. Most patients with nocturnal panic attacks have similar episodes during the day. However, panic attacks can occur mainly at night and must be differentiated from NREM parasomnias such as sleep terrors. b. Majority of patients with panic disorder have at least one nocturnal panic attack i. Many report the symptom of dyspnea c. One third or more of patients with panic disorder have recurrent nocturnal panic attacks i. Usually during NREM sleep at transition to stage N3 d. Two thirds of patients with panic disorder report sleep-onset and sleepmaintenance insomnia with fear of returning to sleep e. In contrast to a NREM parasomnia such as night terrors, the patient is awake f. In contrast to nightmares, there is no dream recall 4. Post-Traumatic Stress Disorder (PTSD) and sleep a. Disturbing nightmares are a significant problem impairing sleep in PTSD b. Recurrent distressing dreams (i.e., nightmares) of the traumatic event are one of the diagnostic features of PTSD. For many patients with PTSD, the associated nightmares represent one of the most frequently occurring and problematic aspects of the disorder. i. Persistent nightmares may also be one of the most enduring symptoms in PTSD c. High percentages of patients (70–90%) describe subjective sleep disturbance. i. PSG studies of patients with PTSD have yielded variable and inconclusive findings in regard to abnormalities in REM sleep, and controlled studies have not found consistent abnormalities with sleep architecture d. Cognitive behavioral therapy is typically first-line treatment i. Prazosin is often used if medicine is needed

SLEEP AND RHEUMATOLOGY 1. Sleep disorders and fibromyalgia a. Fibromyalgia syndrome (FS) is defined by the American College of Rheumatology as the presence of widespread musculoskeletal pain for at least 3 months, which is bilateral above and below the waist, including axial pain and the presence of 11 of 18 tender points i. FS should be considered a syndrome rather than a disease process ii. It affects about 3% of the population aged 30 to 50 years and 70-90% of patients are women b. Sleep in patients with the FS is abnormal and studies have shown decreased TST, increased arousals, and decreased stage N3 and REM sleep i. In a majority of patients, a poor night of sleep is associated with worse daytime symptoms

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Alpha-delta sleep (alpha anomaly or alpha intrusion into stage N3 sleep) is seen but is not specific to fibromyalgia i. Alpha anomaly may be seen in psychiatric disorders such as depression, in many chronic pain syndromes, and in normal individuals (15%)

SLEEP AND ATHLETIC PERFORMANCE 1. Sleep is becoming more and more recognized as one of the most obvious and natural performance enhancers in sports, the same could be said for work and academic performance 2. When evaluating sleep for athletic performance: a. Screening tools i. ESS, STOP-BANG, wearables (i.e., Fitbit), sleep diary b. Medical and surgical history c. Psychiatric history d. Medications e. Social history > tobacco, alcohol, elicit f. Diet, daytime routine g. Physical exam > full upper airway evaluation > nasal valve, deviated septum, turbinate hypertrophy, nasal polyps, enlarged tonsils/ adenoids, palate position, tongue size (modified Mallampati/Friedman tongue position), thyroid h. Fiberoptic exam, acoustic rhinomanometry, pH monitoring i. HSAT, PSG, actigraphy j. CXR, PFTs, EKG k. Bloodwork > CBC (anemia), CMP (kidney/ liver disease), TIBC/ferritin/ serum iron (PLMD), Vitamin B12, TFTs, testosterone/ cortisol, CRP, ESR, RF/ ANA titers l. Urinalysis with microscopic examination m. Assess for circadian rhythm issues (advanced/ delayed sleep phase) n. Travel needs > issues related to jet lag, (especially traveling east, 2 or more time zones)

KEY CLINICAL POINTS FOR THE EVALUATION OF NOCTURNAL AROUSALS 1. Timing, frequency, and associated symptoms a. Chronic vs acute b. Repetitive vs isolated c. Timing during sleep, behavior and thoughts during arousals d. Associated symptoms > leg kicking/ cramping, back pains, nocturia, etc.

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2. Medical history a. Thyroid disease > hyperthyroidism b. CHF > paroxysmal nocturnal dyspnea c. CAD, arrhythmia d. OSA/ CSA e. Asthma/ COPD f. GERD > nocturnal laryngospasms g. Arthritis, fibromyalgia h. BPH i. Peripheral vascular disease j. Psychiatric conditions, i.e., depression, mania, PTSD, panic disorder k. Seizure/ epilepsy, Alzheimers/ Parkinsons 3. Medications: prescribed, OTC 4. Social history > nicotine, alcohol, elicit 5. Physical exam a. Nose and throat exam > nasal obstruction, OSA, goiter b. Laryngoscopy > Müeller’s maneuver, LPR c. Chest > asthma, arrhythmia 6. Sleep testing a. HSAT > snoring vs OSA b. PSG > OSA, CSA, PLMD, seizure, RBD, nocturnal myoclonus, leg cramps, bruxism, fibromyalgia c. Sleep diary, actigraphy/wearables > insomnia, circadian rhythm 7. Bloodwork a. TIBC, serum iron and ferritin levels > PLMD b. Low K, Ca, Mg > leg cramps c. BMP/ hepatic profile > Kidney and liver disease d. TSH, T3. T4 > hyperthyroidism e. RA, SLE titers > chronic pain f. Plasma free metanephrines > pheochromocytoma 8. Additional Testing/ Imaging a. MRI brain > seizure, Alzheimers/Parkinson’s (RBD) b. CXR, PFTS > asthma, COPD c. EKG, angiography > CAD, arrhythmia d. Neck/ back imaging > chronic pain, spinal stenosis 9. Appropriate Referral

KEY CLINICAL POINTS FOR THE EVALUATION OF SLEEP AS RELATED TO ATHLETIC/ACADEMIC PERFORMANCE 1. Individualized/ tailored approach to management based on finding 2. Rules of Sleep hygiene applies to almost everybody 3. Assess for residual sleep and daytime symptoms following treatment

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QUESTIONS 1. A 48-year-old obese male has a room air blood gas showing a PaO2 of 60 mmHg. He undergoes nocturnal oximetry that reveals 200 minutes with an SaO2 less than 88%. There are long periods in which the average SaO2 is around 85%. A saw-tooth pattern is seen in about half of the tracing. The patient reports snoring but no daytime sleepiness. What do you recommend? a. Treatment with supplemental oxygen at 2 L/min. b. Treatment with supplemental oxygen at 2 L/min and repeat the oximetry. c. PSG. d. Addition of an inhaled long-acting beta agonist and repeat the oximetry. 2. Which of the following characterizes the propensity of nocturnal seizures? a. NREM > REM > wake. b. Wake > REM > NREM. c. NREM > wake > REM. d. Wake > NREM > REM. 3. Which of the following is a common PSG finding during a major depressive episode? a. Short sleep latency. b. Short REM latency. c. Increased total sleep time. d. Increased REM sleep in the last part of the night. e. Decreased REM density. 4. In which of the following dementias is RBD relatively uncommon? a. Progressive Supranuclear Palsy b. Alzheimer’s Disease c. Parkinson’s Disease d. Multiple System Atrophy e. Diffuse Lewy Body Dementia 5. Sleep-disordered breathing (SDB) has been described in clinical studies in what percentage of patients with acromegaly? a. 5% to 10% b. 20% c. 40% d. 70% to 80%

REFERENCES Berry, R. Fundamentals of Sleep Medicine. Philadelphia, PA: W.B. Saunders; 2012. Kryger, MH; Roth, T; Dement, WC. Principles and Practice of Sleep Medicine. 6th ed. Cambridge, MA: Elsevier Health Sciences; 2016.

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Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5): 487– 504.

PART II: ADULT SLEEP-RELATED BREATHING DISORDERS

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 10

ADULT OSA OVERVIEW Yi Cai, MD, Andrew N. Goldberg, MD and Jolie L. Chang, MD Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA

DEFINITIONS 1. Sleep disordered breathing (SDB) encompasses a range of breathing disorders during sleep, the most common of which is obstructive sleep apnea (OSA). 2. OSA is characterized by recurrent and repeated collapse of the upper airway during sleep. a. Complete (apneas) and partial (hypopneas) cessation of airflow results from upper airway collapse and can lead to arousals from sleep and oxyhemoglobin desaturations. b. Diagnosis of OSA is based on both clinical symptoms and objective data from the sleep study. c. Treatment guidelines take into account several factors including sleep study data, presence of symptoms and associated comorbidities. 3. Obstructive Sleep Apnea Syndrome (OSAS) diagnosis definitions: a. ≥ 5 obstructive respiratory events/hour (apnea, hypopnea, or respiratory effort-related arousals) with symptoms, OR b. ≥ 15 obstructive respiratory events/hour with or without symptoms. 4. Common adult OSA symptoms include daytime sleepiness, sleep disturbance, loud snoring, restless and unrefreshing sleep. 5. Health risks associated with OSA include hypertension, diabetes, cardiovascular disease, stroke, memory issues, and motor vehicle accidents. 6. Objective sleep testing is used for diagnosis and OSA classification. Types of testing include: a. Attended in-lab polysomnography (PSG): widely accepted as the gold standard test for diagnosis of OSA. b. Home Sleep Apnea Test (HSAT) is an alternative method that may be less costly and more efficient.

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SLEEP STUDY OBJECTIVE MEASURES 1. Apnea a. Event defined by ≥ 10 seconds of complete upper airway collapse with a ≥ 90% reduction in airflow from baseline, as measured using an oronasal thermal sensor or apnea sensor. b. No requirement for a desaturation or an arousal. 2. Hypopnea a. American Academy of Sleep Medicine (AASM) recommended definition, abbreviated as “AHI 3%” (apnea-hypopnea index): i. Hypopnea event defined by ≥10 seconds of partial upper airway collapse with a reduction in airflow from baseline by ≥30% AND either ≥3% oxygen desaturation from baseline OR a cortical arousal on electroencephalogram (EEG). b. Current Center for Medicare and Medicaid (CMS) definition, abbreviated as “AHI 4%”: i. Hypopnea event defined by ≥ 10 seconds of partial upper airway collapse with a reduction in airflow from baseline by ≥ 30% AND ≥ 4% oxygen desaturation. c. Variable reporting on hypopneas based on these definitions can account for inconsistencies in AHI values between sleep studies or sleep centers. 3. Respiratory effort-related arousals (RERAs) a. Event defined by ≥10 seconds of increasing respiratory effort that terminates with an arousal and does not meet the criteria for an apnea or hypopnea. b. Inclusion in PSG reporting is optional. c. AHI 3% classifies more RERAs as hypopneas than does the AHI 4% scoring criteria. d. Requires EEG signal for most accurate grading of arousal in sleep (i.e., in-lab PSG). 4. Apnea-Hypopnea Index (AHI) is defined as the number of apnea and hypopnea events per hour of sleep. a. Used for classification of OSA severity. Higher values reflect more severe disease. b. AHI often includes both central and obstructive events. c. Mild OSA: AHI ≥ 5 to 30 f. OAI = obstructive apnea event index g. CAI = central apnea event index h. Central events are defined by reduced airflow (apnea or hypopnea) without respiratory effort and can be related to heart failure, opiate use, high-altitude, primary or idiopathic central sleep apnea, or treatment-emergent central sleep apnea.

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5. Respiratory disturbance index (RDI): total number of apneas, hypopneas, and RERAs per hour of sleep. a. RDI = AHI + RERAs 6. Respiratory event index (REI): number of apnea and hypopnea events per hour of estimated sleep time on a HSAT. a. Used in HSAT or out-of-center sleep testing where devices are not able to precisely measure sleep versus wake times. i. Total sleep time is estimated on HSAT. b. HSAT can underestimate the AHI. 7. Oxygen desaturation index (ODI): number of oxygen desaturation (≥ 3% or ≥ 4%) events per hour of sleep. a. ODI is determined from the oxygen saturation signal alone and is reported relative to baseline saturation levels. b. Highly correlated with AHI and may be useful in screening for undiagnosed SDB in surgical patients. i. Oximetry alone is not recommended for OSA classification. c. Use of ODI for OSA classification may miss diagnosis in populations less likely to desaturate with obstructive events (i.e., younger, non-obese, female patients). 8. Apneas and hypopneas can occur in all phases of sleep a. More common in N1, N2 and rapid eye movement (REM) sleep than in N3 sleep. b. In REM, upper airway muscle activity and respiratory drive are lower, resulting in longer apneic events and larger desaturations. c. REM AHI measures AHI levels during REM sleep. Elevations in REMspecific AHI can be associated with daytime sleepiness even in patients with normal or mild overall AHI levels.

EPIDEMIOLOGY 1. Prevalence a. OSA prevalence varies across studies due to differing criteria used to define OSA. b. Estimated prevalence of adult OSA: i. OSAS in ages 30-70 years:  5% in women, 14% in men. i. OSA rates reported between 9% to 50%.  Mean 17% in women.  Mean 22% in men. i. Moderate to severe OSA: 6% to 17%. ii. OSA in adults 60+ years: 54%.  Moderate to severe OSA: 20%. c. Effects around 54 million in USA and 936 million globally, ages 30-69. i. For moderate to severe disease, 24 million in USA and 425 million globally.

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RISK FACTORS ASSOCIATED WITH OSA 1. Genetics a. OSA has been shown to aggregate in families (independent of obesity), suggesting inherited genetic factors play a role in OSA. b. Genome wide association studies have been used to identify genes and polymorphisms associated with OSA, though studies identify differing genetic variants. c. PSG metrics (e.g., AHI and ODI) and sleep events (such as heart rate response to arousal) have been shown to be heritable. d. Craniofacial abnormalities and variations in upper airway structures associated with OSA are heritable and explain some family clustering of OSA. 2. Obesity a. Principal risk factor in OSA, with a correlation between body mass index (BMI) and AHI in over 70% of patients with OSA i. Individual weight gain of 10% is associated with 30% increase in AHI and 6-fold increase in risk for moderate to severe OSA. ii. Weight gain impacts AHI greater in men than in women. iii. 56% of men with BMI ≥ 40 have moderate or severe OSA (AHI ≥ 15). iv. Impact of BMI on OSA decreases with age. b. Fat distribution in the upper body is an important factor; central obesity is a risk factor for OSA compared to peripheral obesity. i. Obesity increases upper airway collapsibility and blunts neuromuscular responses to apnea. ii. Fat deposition in the parapharyngeal space, tongue, and retropalatal space contribute to upper airway collapse. iii. Neck circumference and waist-to-hip ratio are associated with OSA severity. c. OSA is separately associated with metabolic alterations that can lead to weight gain and difficulty with weight loss.

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3. Gender a. Prevalence of OSA is higher in men than women with male:female ratio of 2:1 or higher, partly because women are less likely to report classic OSA symptoms and may be underdiagnosed. b. Anatomic factors may account for some differences. i. Men have longer and more collapsible upper airways. c. Hormonal differences are likely to play important roles in the gender difference. d. Prevalence rate of OSA in women increases significantly after menopause. e. Differences in PSG: i. Studies have demonstrated women have lower AHI and fewer desaturations, but a higher proportion of events in REM sleep. 4. Age a. Older adults (60+ years) have a higher prevalence of OSA than younger adults. i. Increased prevalence with age may be related to increased airway collapsibility due to loss of muscle tone of upper airway. ii. Increasing incidence of OSA with age plateaus over age 60 years. b. In men, moderate and severe OSA increase with age. c. In women, mild OSA is more common than moderate and severe OSA in the older population. i. OSA prevalence increases in postmenopausal women not on hormone replacement therapy, driving OSA prevalence in older women closer to that of men. 5. Race and ethnicity a. In the United States, Blacks, Hispanics, and Asians have higher odds of OSA after adjusting for obesity. i. Some differences in prevalence may be related to certain craniofacial features associated with OSA (i.e., shorter midface). ii. Varying prevalence estimates may also be related to racial differences in metabolic disease and obesity. iii. Socioeconomic status and healthcare disparities may also contribute to the association between OSA and ethnic minorities. iv. Minority populations have lower rates of clinical diagnosis despite higher prevalence than the white population.

KEY CLINICAL POINTS 1. OSA diagnosis requires understanding both clinical symptoms and objective sleep study testing with in-lab or home sleep testing. a. Pulse oximetry monitoring alone is insufficient to diagnose OSA. 2. Differing definitions of hypopneas contribute to variable AHI reporting between studies and centers. 3. Multiple factors including gender, age, obesity, race and genetics contribute to risks for obstructive sleep apnea.

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QUESTIONS 1. True or false: Pulse oximetry monitoring alone is sufficient to diagnose OSA.  True  False 2. Which of the following is incorrect? a. The criteria for apnea must include ≥ 90% reduction in airflow for ≥ 10 seconds. b. The criteria for apnea must include either a ≥3% or ≥4% desaturation. c. The criteria for hypopnea must include a decrease of airflow of ≥30% for ≥10 seconds. d. The criteria for hypopnea must include a reduction in airflow from baseline by ≥ 30%. 3. Which of the following factors is the strongest risk factor for adult OSA? a. Genetic predisposition b. Gender c. Obesity d. Age 4. Which of the following minority populations within the United States have higher odds of OSA? a. Blacks b. Asians c. Hispanics d. All of the above e. A & C 5. Individual weight gain of 10% is associated with how much of an increase in AHI? a. 10% b. 20% c. 30% d. 50%

REFERENCES Benjafield A V, Ayas N T, Eastwood P R, Heinzer R, Ip M S M, Morrell M J, Nunez C M, Patel S R, Penzel T, Pépin J L, Peppard P E, Sinha S, Tufik S, Valentine K, Malhotra A.

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Estimation of the global prevalence and burden of obstructive sleep apnoea: a literaturebased analysis. Lancet Respir. Med. 2019 Aug;7(8):687-698. doi: 10.1016/S22132600(19)30198-5. Chen X, Wang R, Zee P, Lutsey P L, Javaheri S, Alcántara C, Jackson C L, Williams M A, Redline S. Racial/Ethnic Differences in Sleep Disturbances: The Multi-Ethnic Study of Atherosclerosis (MESA). Sleep. 2015 Jun 1;38(6):877-88. doi: 10.5665/sleep.4732. Glasser M, Bailey N, McMillan A, Goff E, Morrell M J. Sleep apnoea in older people. Breathe. 2011;7(3):248-256. Guglielmi O, Lanteri P, Garbarino S. Association between socioeconomic status, belonging to an ethnic minority and obstructive sleep apnea: a systematic review of the literature. Sleep Med. 2019 May;57:100-106. doi: 10.1016/j.sleep.2019.01.042. Kapur V K, Auckley D H, Chowdhuri S, Kuhlmann D C, Mehra R, Ramar K, Harrod C G. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J. Clin. Sleep. Med. 2017 Mar 15;13(3):479-504. doi: 10.5664/jcsm.6506. Lee W, Nagubadi S, Kryger M H, Mokhlesi B. Epidemiology of Obstructive Sleep Apnea: a Population-based Perspective. Expert Rev. Respir. Med. 2008 Jun 1;2(3):349-364. doi: 10.1586/17476348.2.3.349. O’Connor C, Thornley K S, Hanly P J. Gender differences in the polysomnographic features of obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 2000 May;161(5):1465-72. doi: 10.1164/ajrccm.161.5.9904121. Punjabi N M. The epidemiology of adult obstructive sleep apnea. Proc. Am. Thorac. Soc. 2008 Feb 15;5(2):136-43. doi: 10.1513/pats.200709-155MG. Romero-Corral A, Caples S M, Lopez-Jimenez F, Somers V K. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest. 2010 Mar;137(3):711-9. doi: 10.1378/chest.09-0360. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014 Nov;146(5):1387-1394. doi: 10.1378/chest.14-0970. Senaratna C V, Perret J L, Lodge C J, Lowe A J, Campbell BE, Matheson M C, Hamilton G S, Dharmage S C. Prevalence of obstructive sleep apnea in the general population: A systematic review. Sleep Med. Rev. 2017 Aug;34:70-81. doi: 10.1016/j.smrv.2016. 07.002. Varvarigou V, Dahabreh I J, Malhotra A, Kales S N. A review of genetic association studies of obstructive sleep apnea: field synopsis and meta-analysis. Sleep. 2011 Nov 1;34(11):14618. doi: 10.5665/sleep.1376. 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 Apr 29;328(17):1230-5. doi: 10.1056/NEJM199304293281704. Young T, Shahar E, Nieto F J, Redline S, Newman A B, Gottlieb D J, Walsleben J A, Finn L, Enright P, Samet J M; Sleep Heart Health Study Research Group. Predictors of sleepdisordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch. Intern. Med. 2002 Apr 22;162(8):893-900. doi: 10.1001/archinte.162.8.893.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 11

PATHOGENESIS AND ENDOTYPES OF OSA Luke D. J. Thomson1,2,, Caroline J. Beatty1,2, , Shane A. Landry1, PhD and Bradley A. Edwards1,2, PhD 1

Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia 2 School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, Australia

PATHOGENESIS AND ENDOTYPES OF OBSTRUCTIVE SLEEP APNEA 1. Obstructive sleep apnea (OSA) is now recognized to be caused by a combination of anatomical and non-anatomical factors or ‘endotypes’ (i.e., the pathogenic mechanism(s) responsible for causing the disease/disorder) 2. While a narrow or compromised pharyngeal anatomy is the key driver in whether an individual will develop OSA, it is now recognized that the majority (~69%) of patients also have additional non-anatomical endotypes that contribute to OSA. These include: a. Poor neuromuscular compensation b. A hypersensitive ventilatory system (i.e., high loop gain) c. A low respiratory arousal threshold

UPPER AIRWAY ANATOMY 1. To develop OSA, every individual must have some degree of impairment in their upper airway anatomy 2. The human upper airway has few rigid or bony support structures and depends mainly on the upper airway muscles to remain patent. During sleep onset, the upper airway muscle activity typically reduces, leaving the airway more prone to collapse. 

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Luke D. J. Thomson, Caroline J. Beatty, Shane A. Landry et al. 3. Notably, individuals with OSA tend to have smaller more narrow airways which predisposes them towards airway collapse during sleep a. Narrow airways may be due to multiple factors such as obesity or other upper airway anatomical abnormalities 4. The collapsible portion of the upper airway extends from the soft palate to the epiglottis. The most common site of collapse during sleep is the retropalatal region, although there is much variation between individuals (see Figure 1).

Figure 1. Anatomy of the upper airway.

Pathogenesis 1. The degree and type of anatomical impairment varies greatly between individuals with OSA. The presence of certain anatomical risk factors that predispose the airway to collapse include: a. Increased adipose tissue deposition, particularly around the neck and torso may contribute to OSA by causing a narrowing of the upper airway and increasing the mechanical load on breathing i. Central obesity is often associated with an increased prevalence of OSA b. Certain craniofacial structures may contribute to the pathogenesis of OSA i. A longer airway, shorter mandible, inferior positioned hyoid bone and retroposition of the maxilla have been shown to impede airway space and/or increase collapsibility of the upper airway c. Low lung volumes, typically seen in obese individuals, can reduce the caudal traction placed on the upper airway thereby increasing the propensity towards collapse d. Airway edema increases tissue size in the upper airway (at the expense of the airway size), particularly during sleep and while in the recumbent posture when fluid from the legs shifts into the upper body e. High mucosal surface tension in the upper airway may contribute to the pathogenesis of OSA

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i. Studies administering surfactants to reduce surface tension have been shown to improve both pharyngeal collapsibility and OSA severity

Individual Trait Variability 1. Studies using Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) have revealed anatomical differences between people with and without OSA which may predispose individuals towards upper airway collapse 2. In comparison to those without OSA, individuals with OSA tend to have: a. Smaller pharyngeal airways b. Larger tongue volumes (as well as a higher proportion of fat deposited in the tongue) c. Thicker lateral pharyngeal walls d. Enlarged soft palates 3. There is much overlap between the characteristics of mild/moderate vs severe OSA, however, there are some key observable differences (see Table 1): 4. The key observable differences between a person without OSA, compared to those with mild OSA and severe OSA is evident in Figure 2 5. While the degree of anatomical compromise is often assessed through a variety of different imaging modalities, a key limitation of these techniques is that they are often static images taken while the individual is awake, and thus may not reflect the dynamic behavior of the airway during sleep 6. As such, investigators have also assessed an individual’s airway collapsibility during sleep as a functional assessment of the degree of anatomical compromise Table 1. Observed Anatomical Differences between Mild/Moderate OSA and Severe OSA Mild/ Moderate OSA Less collapsible upper airway Typical area of collapse: retropalatal region

Severe OSA More collapsible upper airway Typical area of collapse: retroglossal region Greater lateral wall movement Longer pharyngeal airway length Lower hyoid bone position Thicker soft palates Longer hyoid to mandibular plane lengths

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Figure 2. Differences in Upper Airway Anatomy between Non-OSA, Mild OSA and Severe OSA. Sagittal magnetic resonance image from a 31-year-old, non-obese male with no OSA, a 33-year-old, non-obese male with mild OSA (total AHI = 6.6 events/h) and a 54-year- old female with severe OSA (AHI = 92.7 events/h). Note the differences in pharyngeal size in the individual with severe OSA (e.g., appears to be narrower) and other potential contributing factors (e.g., large tongue volume).

Airway Collapsibility 1. While there are a number of techniques utilized to assess airway collapsibility during sleep, the most common is the Pharyngeal Critical Closing Pressure (Pcrit) technique a. Measuring Pcrit typically involves assessing the relationship between pressure in the upper airway and peak inspiratory flow at varying degrees of pressure support b. Pcrit represents the pressure at which the airway closes 2. Studies that have assessed airway collapsibility using this technique suggest: a. Those with OSA typically have higher collapsibility compared to those without sleep apnea b. People with a Pcrit value less than -5cmH2O typically do not have OSA c. Men typically have more collapsible airways in comparison to women i. This may be due to men having a longer pharyngeal airway length and greater soft tissue structures in the upper airway as well as more central fat distribution d. Increasing levels of obesity have been shown to be positively associated with airway collapsibility, as fat deposits reduce the size of the airway i. Increased fat in the abdominal region may reduce lung volume which further contributes to an increased propensity of the upper airway to collapse e. Pcrit (as well as other measures of collapsibility) is weakly associated with the severity of disease which suggests that other factors must also contribute to OSA

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NEUROMUSCULAR COMPENSATION 1. Despite the presence of a compromised airway anatomy, OSA patients are able to maintain airway patency while awake by reflexive activation of the upper airway dilator muscles (UADM) 2. At sleep onset, however, neurochemical drive to upper airway motoneurons is diminished a. This results in hypotonic UADM that in many instances are inadequate to support surrounding collapsing forces 3. Whether an airway is prone to collapse during sleep in therefore often discussed as the product of an imbalance between a. The mechanical load (i.e., collapsing forces) placed on the airway b. The degree of neuromuscular compensation (i.e., a reflexive dynamic increase in UADM activation that counteracts collapsing forces to restore airway patency) that can be achieved 4. If an arousal occurs before this neuromuscular compensation can be achieved then the individual will exhibit unstable cycling between wake/sleep and apnea/hyperpnea (Figure 3) 5. Deficiencies in the both the pharyngeal dilator muscles responsiveness and/or effectiveness (defined below) can disturb the load/compensation balance and instigate OSA 6. How responsive these muscles are to collapsing stimuli and their corresponding effectiveness at reopening the airway is a primary cause of OSA

Pathogenesis 1. Neuromuscular compensation is driven by two factors: a. The neural responsiveness of the muscles to provide appropriate and timely activation in response to elevations in negative pharyngeal pressure and ventilatory disturbances (primarily hypercapnia) b. The mechanical effectiveness to recruit UADM with sufficient strength to oppose collapsing forces and restore eupneic ventilation 2. Both the responsiveness and effectiveness of the UADM are negatively impacted by transition from wake to sleep a. This is primarily due to the loss of wakefulness drive to breathe which has an excitatory effect on muscle stimulation, particularly on the genioglossus (the main upper airway dilator muscle and most extensively studied) 3. This impact is more pronounced in OSA patients compared to healthy controls because of an over reliance on the negative pressure reflex to maintain airway patency, which is substantially diminished at sleep onset 4. Compared to healthy controls, OSA patients experience a greater sleep onset reduction in muscle activity of the genioglossus and approximately more than onethird of OSA patients generate insufficient genioglossus activity in response to increasing negative pharyngeal pressure

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Luke D. J. Thomson, Caroline J. Beatty, Shane A. Landry et al. 5. Some OSA patients can generate appropriate muscular response to airway narrowing but are unable to convert this into effective airway dilation a. Possible reasons for this may be due to exposure of repeated bouts of mechanical trauma associated with obstructed breathing, along with chronic intermittent hypoxia/hypercapnia which may lead to neural injury, sensory impairment and musculature dysfunction of the upper airway b. It is estimated that two-thirds of OSA patients have mild anatomic collapsibility that could be alleviated if effective muscle compensation was able to occur

Figure 3. Raw examples of both good (A) and poor (B) responsiveness of the main upper airway dilator muscles and the subsequent effect on airflow. Panel (A) demonstrates excellent responsiveness and effectiveness of the upper airway dilator muscles. Progressively increasing negative pressure swings (i.e., increasing ventilatory drive; [purple dashed line]) has been matched with an appropriate response of the Genioglossus and the Tensor Palatini [orange dashed lines] which in turn have resulted in effective dilation of the airway as evidenced by the increase in airflow [blue dashed line]. Panel (B) provides a contrary example of poor muscle responsiveness (and therefore poor muscle effectiveness) as shown by no discernable increase in muscle activity [orange dashed line] despite an increasingly narrow airway due to a transient reduction in continuous positive airway pressure (Pmask). Pharyngeal muscle activity, and therefore airflow, is only increased when an EEG arousal occurs. A.u. = arbitrary units, EEG = electroencephalogram, EMG = electromyography, EMG % max = rectified, moving time average (100 ms) of the raw EMG signal as a % of maximal activation measured awake (in response to a swallow or tongue protrusion), GG = genioglossus muscle, Pepi = epiglottic pressure, TP = tensor palatini muscle.

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Measurement of Neuromuscular Compensation (Figure 3) 1. Responsiveness is typically assessed by plotting how the electromyographic (EMG) activity of the UADM changes in response to ventilatory drive (i.e., nadir pharyngeal pressure) on breath-by-breath basis when the airway is partially or completely collapsed due to either spontaneous or experimentally-induced loading on the airway 2. Muscle effectiveness describes the relationship between changes in ventilatory drive and observed airflow/minute ventilation a. The mechanical effectiveness and dilatory mechanics of the upper airway musculature can be assessed via direct observation using either invasive visualization techniques (e.g., drug induced sleep endoscopy) or dynamic magnetic resonance (MR) imaging

Individual Trait Variability 1. While there is little variability between OSA severity groups according to the apneahypopnea index (AHI), OSA patients with a moderately collapsible airway (Pcrit -5 and -2 cmH2O) tend to have a poorer muscle activation response compared to OSA patients with a highly collapsible airway (Pcrit > +2 cmH2O) and healthy controls with a similar level of collapsibility 2. This demonstrates that a compromised airway can be protected by effective neuromuscular compensation 3. In regards to muscle effectiveness: a. Mild-to-moderate OSA patients trend towards having more beneficial genioglossus movement i. The tongue moves uniformly anterior thus dilating the airway b. Severe patients show more counterproductive movement i. The tongue moves posteriorly or bidirectionally creating airway narrowing c. Individuals with very severe OSA show minimal movement, if any at all

HYPERSENSITIVE VENTILATORY CONTROL SYSTEM 1. Approximately 30% of all individuals with OSA are believed to have a hypersensitive ventilatory control system a. This is often referred to as a system with a high loop gain b. Loop gain refers to the sensitivity of any system that is controlled by a feedback loop 2. In the context of OSA pathophysiology, loop gain refers to the negative feedback loop that controls ventilation a. Loop gain can broadly be thought of as the ratio of the ventilatory response to any given ventilatory disturbance

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Pathogenesis 1. In individuals with high loop gain, the ventilatory response is often larger than the initial ventilatory disturbance (i.e., loop gain > 1) and the resulting oscillations in breathing grow until self-sustaining oscillations in ventilation/ventilatory drive occur (Figure 4) 2. During the nadir (or trough) phase of these cyclic fluctuations in ventilatory drive there is a coincident decrease in drive to the upper airway muscles a. When combined with a compromised upper airway anatomy (as is the case in individuals with OSA) this can perpetuate repetitive upper airway collapse 3. In the respiratory feedback loop, if the response to the original breathing disturbance is less than 1 (loop gain < 1) as is depicted in the graph on the left of Figure 4, the resulting oscillations will be diminished over time 4. The lower the loop gain, the faster respiratory oscillations will dampen out 5. If the response to the original disturbance is greater than 1, as is depicted in the graph on the right of Figure 4, the resulting oscillations will increase until periodic breathing (cyclic central sleep apnea) occurs. This is a case of loop gain > 1. 6. Loop gain is determined by two key factors which are referred to as the “controller” and the “plant,” which are expressed in the equation in Figure 5 a. In Figure 5, G refers to the sensitivity of the peripheral and central chemoreceptors (i.e., O2 and CO2 sensors) and are often collectively referred to as the “controller” b. The “plant,” is comprised of the: i. PICO2 represents the inspired levels of CO2 ii. PaCO2 represents the alveolar levels of CO2 iii. T represents the timing delays in the system

Figure 4. Resulting oscillations in ventilation from a Loop Gain 1.

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Figure 5. Loop gain expression.

Figure 6. Feedback loop controlling ventilation. The respiratory control system is best thought of as a single feedback loop where the chemoreceptors in the ‘controller’ detect changes in CO 2 levels, producing a ventilatory drive to alter CO2 from the lungs or the ‘plant.’ Any disturbance to the feedback loop such as arousal from sleep would be expected to increase ventilation which then reduces CO2 levels. This reduction in CO2 is sensed by the chemoreceptors which produce a reduction in ventilatory drive to oppose the original disturbance.

7. In the ventilatory control feedback loop (Figure 6), the central and peripheral chemoreceptors of the “controller” are sensitive to changing O2/CO2 levels a. Higher controller gain indicates a greater change in ventilator drive for any given change in O2/CO2 levels 8. If disturbances in ventilation occur such as an arousal from sleep, the resulting increase in ventilation causes CO2 levels to reduce determined via the characteristics of the ‘plant’ 9. Characteristics such as a low lung volume can increase the extent to which arterial CO2 changes for any given change in ventilation 10. There is a time delay (T), driven predominantly by circulation time, before which changes in ventilation impact blood gases a. Longer delays increase the time before which the “controller” can respond to a ventilatory disturbance b. They are associated with a higher “plant” gain (and overall loop gain)

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Individual Trait Variability 1. Several studies have reported an elevated loop gain in individuals with OSA compared to healthy controls a. Other studies have also reported no differences. Reasons for the discrepancies between findings may be related to: i. Failure to control for key factors known to influence loop gain, such as age and body mass index ii. Different methodologies utilized for measuring loop gain 2. Studies that have assessed the relationship between loop gain and OSA severity have reported variable findings a. Some studies show no relationship whereas other have found a positive association 3. A hypersensitive ventilatory control system seems to have an impact on OSA severity in individuals with OSA depending on the collapsibility of their upper airway

Measurement of Loop Gain 1. There are a number of methods that have been employed to measure loop gain, each with their own advantages and limitations 2. Techniques typically vary by: a. What signals need to be recorded (i.e., ventilation, end-tidal PCO2 and endtidal O2) b. The condition of the recording (unstimulated vs. stimulated, steady state vs. dynamic) c. The modelling approaches used to quantify loop gain (autoregressive vs. transfer function) 3. Examples of unstimulated recordings typically assess the ventilatory pattern that occurs following or during: a. Spontaneous sighs b. Natural fluctuations in spontaneous breathing c. Patterns of breathing during central and obstructive respiratory events during sleep 4. Alternatively, loop gain can be measured using physiological manipulations (i.e., stimulated) such as: a. Induced sighs or breath holds b. Response to inspired gases (O2/CO2) c. Response to continuous positive airway pressure (CPAP) manipulations

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LOW RESPIRATORY AROUSAL THRESHOLD 1. The respiratory arousal threshold (ArTH) reflects the level of ventilatory drive (i.e., neuromuscular-mechanical pressure) present at the end of the apnea/hypopnea that causes a cortical arousal from sleep a. Defined as > 3 seconds of high frequency activity on the electroencephalography (EEG) 2. Individuals who have a low ArTH tend to arouse to smaller increments of inspiratory effort and respiratory disturbances a. More than one third of OSA patients are estimated to have a low ArTH

Pathogenesis 1. Although cortical arousals can serve as a protective mechanism against airway collapse, they are not always essential a. Some respiratory events do not terminate in an arousal 2. Cortical arousals are not always essential for airway reopening in up to 40% of OSA patients 3. This suggests that if appropriate time can be afforded for respiratory drive to accumulate and effectively recruit UADM, then airway patency can be restored and normal breathing can resume without sleep disruption (Figure 3A) 4. Having a low ArTH is a pathophysiological mechanism that promotes sleep apnea due to the following: a. Prevents the acquisition of sufficient chemical (i.e., hypercapnia, hypoxia) and mechanical (i.e., negative intrathoracic pressure) respiratory stimuli that is necessary for neural drive to successfully increase activation of the pharyngeal dilator muscles i. See section II Neuromuscular Compensation b. Promotes hyper-ventilatory overshoot upon awakening and subsequent hypocapnia at resumption of sleep onset leading to overall ventilatory instability i. See section III Hypersensitive Ventilatory Control System c. Increases sleep fragmentation while limiting time spent in deeper more stable sleep

Measurement of Respiratory Arousal Threshold 1. The gold-standard technique for measuring the respiratory arousal threshold typically involves measuring the degree of respiratory effort (i.e., epiglottic/esophageal pressure or diaphragmatic EMG) on the breath immediately prior to an EEG arousal (Figure 7) a. A ‘low’ ArTH has typically been defined as a negative pressure deflection that is less negative than −15cmH2O

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Luke D. J. Thomson, Caroline J. Beatty, Shane A. Landry et al. b. A ‘high’ arousal threshold as more negative than −15cmH2O 2. The ArTH is not routinely measured in clinical sleep laboratories due to the somewhat invasive nature of placing epiglottic or esophageal pressure sensors a. Newer methods have focused on measuring the arousal threshold from clinically collected data b. One such measure has been developed which employs a 3-point screening tool based on the following factors: i. Nadir oxygen saturation > 82.5% ii. AHI < 30 events/hr iii. Percentage of respiratory events that are hypopneas > 58.3% Where 1-point is allocated for each criterion satisfied and a score of ≥ 2 accurately predicted the presence of a low arousal threshold in 84% of patients

Figure 7. Measuring the respiratory arousal threshold. This individual has a respiratory arousal threshold of -17cmH20 as determined by the nadir negative intrapharyngeal pressure swing just prior to an EEG arousal. EEG = electroencephalogram, Pepi = epiglottic pressure, SaO2 = arterial oxygen-hemoglobin saturation.

Individual Trait Variability 1. The ArTH can be highly variable between OSA patients and contributes more to the etiology of airway collapse in mild OSA patients rather than severe a. Greater OSA severity (i.e., higher AHI) is often positively correlated with a higher ArTH (i.e., harder to wake up) b. The proportion of individuals with a low ArTH reported in one study of mild, moderate and severe OSA patients was 88%, 73% and 23%, respectively

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2. The ArTH can be highly variable within individual sleep as well a. For example, a higher ArTH (i.e., less arousable) is associated with sleep stages (NREM 3) and states associated with greater EEG delta power (i.e., sleep deprivation/use of sedation), while sleep stages (NREM 2) and states associated with faster EEG frequency (i.e., chronic pain/medical conditions) are typically associated with lower ArTH

Interaction of the OSA Endotypes 1. Each of these endotypes described above can contribute to OSA, but to different degrees, such that OSA occurs for different reasons in different people 2. The pathophysiology causing OSA is impacted by a variety of factors: a. Age b. Gender c. Obesity d. Ethnicity/race 3. The relative importance of each of the non-anatomical endotypes appears dependent upon the degree of anatomical compromise/upper airway collapsibility a. Non-anatomical endotypes play a larger role if the upper airway is moderately collapsible as opposed to if there is high or minimal anatomical compromise b. Whether an individual will develop OSA depends on the interaction of these endotypes (Figure 8) 4. Clinical utility of measuring the OSA endotypes a. There is growing evidence that understanding the contribution and interaction of OSA endotypes is an important consideration in the management of OSA and the application of both established and novel therapies b. OSA endotyping may: i. Better predict those likely to gain the greatest benefit (a reduction in AHI) from both existing and novel therapies  Example: Mild collapsibility and lower loop gain predict treatment success using Oral Appliances; high loop gain predicts surgical failure ii. Be useful towards improving treatment adherence strategies  Example: Poor CPAP adherence is related to a low respiratory ArTH which may be improved with sedatives c. For the ~56% of patients who have OSA due to predominately nonanatomical causes, and similarly for those who are unable to tolerate conventional CPAP therapy, clinical endotyping may provide the means by which alternative novel and combination therapies may be prescribed with greater success and confidence

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Figure 8. Contributing factors in the pathogenesis of OSA.

QUESTIONS 1. Individuals with obstructive sleep apnea and a high arousal threshold typically are... a. Easily awoken and more likely to have mild OSA b. Less impacted by the number of arousals that occur c. Harder to wake and more likely to have severe OSA d. Predicted to respond well to treatment with sedatives e. Have a shorter duration of breathing disturbances 2. A patient with severe OSA typically shows what kind of movement of the genioglossus during sleep? a. anterior b. posterior c. lateral d. minimal or no movement e. bidirectional 3. A subtype of a condition that has a distinct functional or pathobiological mechanism is best characterised by which of the following terms? a. genotype b. endotype c. phenotype d. prototype e. ectotype

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4. Of the pathogenic mechanisms underlying OSA, which one is always present to some degree in every person with OSA? a. Poor neuromuscular compensation b. A hypersensitive ventilatory system c. Impaired upper airway anatomy d. Increased adipose tissue deposition e. A low respiratory arousal threshold 5. Which gain a. b. c. d. e.

one of the following factors would be expected to raise and individuals loop Hypercapnia at rest Hyposensitive peripheral chemoreceptors Low lung volume Short circulatory delay Increased inspired CO2

REFERENCES Brown EC, Cheng S, McKenzie DK, Butler JE, Gandevia SC, Bilston LE. Respiratory Movement of Upper Airway Tissue in Obstructive Sleep Apnea. Sleep. 2013 Jul 1;36(7), 1069–1076. doi: 10.5665/sleep.2812. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of Sleep Apnea. Physiol Rev. 2010 Jan;90(1), 47–112. doi: 10.1152/physrev.00043.2008. Eckert, DJ. Phenotypic approaches to obstructive sleep apnoea – New pathways for targeted therapy. Sleep Med. Rev. 2018 Feb;37, 45–59. doi: 10.1016/j.smrv.2016.12.003. Eckert DJ, Malhotra A, Jordan AS. Mechanisms of Apnea. Progress in Cardiovascular Diseases. 2009;51(4), 313–323. doi: 10.1016/j.pcad.2008.02.003. Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman, A. Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets. Am J Respir Crit Care Med. 2013 Oct 15;188(8), 996–1004. doi: 10.1164/rccm.201303-0448OC. Eckert DJ, Younes MK. Arousal from sleep: Implications for obstructive sleep apnea pathogenesis and treatment. Journal of Applied Physiology. 2014;116(3), 302–313. doi: 10.1152/japplphysiol.00649.2013. Edwards BA, Andara C, Landry S, Sands SA, Joosten SA, Owens RL, White DP, Hamilton Edwards BA, Eckert DJ, Jordan AS. Obstructive sleep apnoea pathogenesis from mild to severe: Is it all the same?: OSA pathophysiology: mild-to-severe. Respirology. 2017;22(1), 33–42. doi: 10.1111/resp.12913. Edwards BA, Eckert DJ, McSharry DG, Sands SA, Desai A, Kehlmann G, Bakker JP, Genta PR, Owens RL, White DP, Wellman A, Malhotra, A. Clinical Predictors of the Respiratory Arousal Threshold in Patients with Obstructive Sleep Apnea. Am J Respir and Crit Care Med. 2014;190(11), 1293–1300. doi: 10.1164/rccm.201404-0718OC. Edwards BA, White DP. Control of the pharyngeal musculature during wakefulness and sleep: Implications in normal controls and sleep apnea. Head & Neck. 2011;33(S1), S37–S45. doi: 10.1002/hed.21841.

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Fogel RB, Malhotra A, Pillar G, Edwards JK, Beauregard J, Shea SA, White DP. Genioglossal Activation in Patients with Obstructive Sleep Apnea versus Control Subjects: Mechanisms of Muscle Control. Am J Respir Crit Care Med. 2011;164(11), 2025–2030. doi: 10.1164/ajrccm.164.11.2102048. Fogel RB, Trinder J, White DP, Malhotra A, Raneri J, Schory K, Kleverlaan D, Pierce RJ. The effect of sleep onset on upper airway muscle activity in patients with sleep apnoea versus controls: Genioglossal activity in OSA versus normals during sleep onset. J Physiol. 2005;564(2), 549–562. doi: 10.1113/jphysiol.2005.083659. Gleeson K, Zwillich CW, White DP. The Influence of Increasing Ventilatory Effort on Arousal from Sleep. Am Rev Respir Dis. 1990;142(2), 295–300. doi: 10.1164/ ajrccm/142.2.295. Haponik EF, Smith PL, Bohlman ME, Allen RP, Goldman SM, Bleecker ER. Computerized tomography in obstructive sleep apnea. Correlation of airway size with physiology during sleep and wakefulness. Am Rev Respir Dis. 1983;127(2), 221–26. Joosten SA, Leong P, Landry SA, Sands SA, Terrill PI, Mann D, Turton A, Rangaswamy J, Andara C, Burgess G, Mansfield D, Hamilton GS, Edwards BA. Loop Gain Predicts the Response to Upper Airway Surgery in Patients With Obstructive Sleep Apnea. Sleep. 2017;40(7). doi: 10.1093/sleep/zsx094. Jordan AS, Wellman A, Heinzer RC, Lo Y-L, Schory K, Dover L, Gautam S, Malhotra A, White DP. Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans. Thorax. 2007;62(10), 861–867. doi: 10.1136/thx.2006.070300. Jordan, AS, O’Donoghue FJ, Cori JM, Trinder J. Physiology of Arousal in Obstructive Sleep Apnea and Potential Impacts for Sedative Treatment. Am J Respir Crit Care Med. 2017;196(7), 814–821. doi: 10.1164/rccm.201612-2511PP. McGinley BM, Schwartz AR, Schneider H, Kirkness JP, Smith PL, Patil SP. Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea. J Appl Physiol. 2008;105(1), 197–205. doi: 10.1152/japplphysiol.01214.2007. 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(2), 547–556. doi: 10.1152/japplphysiol.00282.2006. Saboisky JP, Butler JE, McKenzie DK, Gorman RB, Trinder JA, White DP, Gandevia SC. Neural drive to human genioglossus in obstructive sleep apnoea: Genioglossus motor unit behaviour. J Appl Physiol. 2007;585(1), 135–146. doi: 10.1113/jphysiol.2007.139584. Schwab, RJ, Gupta KB, Gefter WB, Metzger LJ, Hoffman EA, Pack AI. Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Crit Care Med. 1995;152(5), 1673–1689. doi: 10.1164/ajrccm.152.5.7582313. Schwartz AR, Patil SP, Laffan AM, Polotsky V, Schneider H, Smith PL. Obesity and Obstructive Sleep Apnea: Pathogenic Mechanisms and Therapeutic Approaches. Proceedings of the American Thoracic Society. 2008;5(2), 185–192. doi: 10.1513/pats.200708-137MG. Suratt PM, Dee P, Atkinson RL, Armstrong P, Wilhoit SC. Fluoroscopic and Computed Tomographic Features of the Pharyngeal Airway in Obstructive Sleep Apnea 1– 3. Am Rev Respir Dis. 1983;127(4), 487–492. doi: 10.1164/arrd.1983.127.4.487.

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Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol. 2008;105(5), 1389–1405. doi: 10.1152/japplphysiol. 90408.2008. Younes M, Loewen AHS, Ostrowski M, Laprairie J, Maturino F, Hanly PJ. Genioglossus activity available via non-arousal mechanisms vs. That required for opening the airway in obstructive apnea patients. J Appl Physiol. 2012a;112(2), 249–258. doi: 10.1152/japplphysiol.00312.2011. Younes M, Loewen AHS, Ostrowski M, Laprairie J, Maturino F, Hanly PJ. Genioglossus activity available via non-arousal mechanisms vs. That required for opening the airway in obstructive apnea patients. J Appl Physiol. 2012b;112(2), 249–258. doi: 10.1152/ japplphysiol.00312.2011.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 12

DIAGNOSIS AND ASSESSMENT OF ADULT OSA Jason L. Yu1,2, MD, Erica R. Thaler1, MD and Richard J. Schwab2, MD 1

Division of Sleep Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, PA, USA 2 Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, PA, USA

DIAGNOSIS 1. Obstructive sleep apnea (OSA) is a sleep-related breathing disorder defined by recurrent episodes of upper airway collapse and obstruction of respiration during sleep 2. OSA is defined by the number of apneas (complete) and hypopneas (partial obstructive respiratory events) that occur per hour of sleep a. This is the apnea-hypopnea index (AHI) b. Obstructive Apnea: a > 90% decrease in nasal pressure or respiratory flow for greater than 10 seconds duration with intact chest and abdominal effort c. Obstructive Hypopnea: a > 30% decrease in nasal pressure or respiratory flow for greater than 10 seconds in duration with intact chest and abdominal effort and an associated 4% decrease in oxygen saturation or an electroencephalographic arousal 3. OSA must be distinguished from central sleep apnea (CSA), which is characterized by recurrent pauses in respiratory effort without chest and abdominal effort a. Central Apnea: a > 90% decrease in nasal pressure or respiratory flow for greater than 10 seconds duration without observed chest and abdominal effort 4. Additionally, there are respiratory events that contain both a central and obstructive component described as a mixed apnea a. Mixed Apnea: > 90% decrease in nasal pressure or respiratory flow for greater than 10 seconds duration without observed respiratory effort in the

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5.

6. 7. 8.

initial portion of the event followed by resumption of respiratory effort in the second portion of the event OSA in adults is divided into three categories of severity based on the frequency of apneas and hypopneas: a. Normal: 0-5 events/hour b. Mild: 5-15 events/hour c. Moderate: 15-30 events/hour d. Severe: > 30 events/hour To be diagnosed as OSA, > 50% of respiratory events must be obstructive apneas, obstructive hypopneas, or mixed apneas CSA is diagnosed when > 50% of respiratory events are central apneas Diagnosis of OSA can be made by sleep studies performed in the home or in the sleep laboratory. There are 4 different sleep study types based on different physiologic data: a. Type 1: also known as a polysomnogram (PSG), is an overnight sleep study performed in a sleep laboratory and overseen by a sleep technician with the following physiologic measurements: i. Electroencephalogram (EEG) ii. Electrooculogram (EOG) iii. Electrocardiogram (ECG) iv. Chin electromyogram (EMG) v. Respiratory effort belts (chest/abdomen) vi. Airflow (nasal pressure, thermistor) vii. Snoring viii. Pulse oximetry (O2 saturation) ix. Position (supine, lateral decubitus, prone) x. Periodic limb movements xi. Optional measurements:  CO2 measured via end tidal or transcutaneous b. Type 2: a study with all the physiologic measurements of a Type 1 study but is unattended by a sleep technician c. Type 3: unattended study that includes a minimum of 4 physiologic measurements including ECG/heart rate, oxygen saturation, respiratory effort and airflow i. Home sleep apnea testing (HSAT) is most commonly a type 3 study ii. Most HSAT studies do not have a sleep EEG and cannot measure actual sleep time iii. Because the AHI is defined by events during sleep, HSAT does not report an AHI but instead, a respiratory event index (REI) iv. Newer HSAT technologies can allow for EEG monitoring and sleep staging d. Type 4: an unattended study that includes three or fewer physiologic measurements, one of which is airflow

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9. HSATs should be used in lieu of polysomnography only in persons in whom clinical suspicion is high for moderate to severe disease and in whom there are no comorbid conditions that can confound results including: a. Cardiorespiratory disease b. Congestive heart failure c. Stroke d. Hypoventilation related to pulmonary, neuromuscular disease or morbid obesity e. Regular opiate use f. Oxygen use g. Patients needing a positive airway pressure (PAP) titration, non-invasive ventilation, hypoglossal nerve stimulation titration 10. A positive HSAT study can be used to diagnose OSA but a negative HSAT should not rule out OSA if clinical suspicion is high 11. A Type 1 in-lab polysomnogram is recommended in the setting of a negative HSAT with clinically high suspicion for OSA

HISTORY AND PHYSICAL ASSESSMENT OF OSA 1. The clinical assessment for risk of OSA is important for determining whether a sleep test is required as well as the type of sleep study (PSG vs. HSAT) that should be selected 2. History a. Obtaining a detailed medical and sleep history is important in determining risk of OSA b. Sleep history should be obtained from the patient but also from bedpartners and other members of the household when possible who may have witnessed symptoms during sleep 3. Common symptoms related to OSA a. Loud snoring b. Witnessed pauses in breathing (nocturnal gasping/choking) c. Multiple overnight arousals d. Frequent episodes of nocturia e. Abnormal sleep behavior including acting out of dreams (rapid eye movement (REM) behavior disorder) f. Unrefreshing sleep quality regardless of duration g. Increased fatigue h. Dry mouth on awakening i. Morning headaches j. Excessive daytime sleepiness 4. Obesity is the most important risk factor for obstructive sleep apnea a. OSA is present in 40% of those with a body mass index (BMI) of > 30kg/m2 b. Associated with increased adipose tissue within the tongue and surrounding pharyngeal structures leading to narrowing of the upper airway

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Jason L. Yu, Erica R. Thaler and Richard J. Schwab 5. Sex differences a. Males are at increased risk of developing OSA b. Pre-menopausal females have lower rates of OSA i. Risk of OSA increases in females after menopause 6. Age a. Increasing age is associated with increased risk of developing OSA b. Age-related increase in prevalence is thought to be related to: i. Increased deposition of fat in the parapharyngeal area ii. Changes in neuromuscular tone iii. Lengthening of the soft palate 7. Other sleep disorders that may be contributing to poor sleep a. Insomnia b. Narcolepsy c. Idiopathic hypersomnolence d. Restless leg syndrome/periodic limb movements e. REM behavior disorder 8. Associated medical comorbidities to consider in patients being evaluated for OSA a. Gastroesophageal reflux b. Cardiovascular risks i. Hypertension ii. Coronary artery disease iii. Congestive heart failure – associated with central sleep apnea iv. Arrhythmias (atrial fibrillation) c. Stroke d. Neuromuscular and neurodegenerative disorders e. Mood Disorders i. Depression ii. Bipolar disorder 9. Behavioral risk factors that can influence the severity of OSA a. Alcohol i. Decreases upper airway muscle tone b. Sedative medications – benzodiazepines, narcotics, hypnotics i. All these medications decrease upper airway muscle tone c. Cigarette smoking i. Associated with increased risk of OSA in active smokers but not in former smokers, mechanism is unclear 10. Physical Assessment a. A variety of physical exam findings of the upper airway have been associated with OSA patients either contributing to risk or may be important in subsequent management of therapy. These findings include: i. Increased neck circumference of > 17 inches in men and 16 inches in women ii. Tonsillar hypertrophy iii. High Modified Mallampati (MM)/Friedman Tongue Position (FTP) stage (macroglossia) iv. Tongue ridging

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v. vi. vii. viii. ix. x.

Enlarged and elongated uvula Narrow palatal arch dept and width Retrognathia Lateral pharyngeal wall narrowing Overbite/Overjet Deviated septum – can be managed to improve adherence to continuous positive airway pressure (CPAP) xi. Inferior turbinate hypertrophy – can be managed to improve adherence to CPAP

11. Imaging a. There are craniofacial and soft tissue findings on imaging that are associated with increased OSA risk b. Lateral Cephalometry: analysis performed in the sagittal view of the head typically obtained from plain film radiographs or midline sagittal views on computed tomography. Findings associated with OSA risk on lateral cephalometry compared to non-OSA controls include: i. Increase in the anterior facial height ii. Decrease in the posterior facial height iii. Inferiorly and posteriorly positioned hyoid iv. Short anterior cranial base angle v. Decrease in the cranial base length vi. Short maxillary length vii. Short mandibular length viii. Increase in the mandible rotation ix. Retroposition of the mandible c. Computed Tomography: allows for greater detail on examining the bony dimensions of the upper airway in axial, coronal, and sagittal dimensions i. Decrease in the transverse maxillary width is associated with OSA ii. Increase in pharyngeal airway length is associated with OSA iii. Increase in the volume of the upper airway soft tissue structures (tongue, lateral walls, soft palate) is associated with OSA iv. Decreased cross sectional area of the retropalatal and retrolingual upper airway is associated with OSA v. Decrease in mandibular and maxillary length, width and depth d. Magnetic Resonance Imaging (MRI): higher quality evaluation of the soft tissues including lateral pharyngeal walls, soft palate, and tongue i. Increase in the volume of the upper airway soft tissue structures (tongue, lateral walls, soft palate) is associated with increased OSA risk ii. Increase in the volume of tongue fat percentage on MRI are associated with increased OSA risk iii. Palatine and lingual tonsil hypertrophy is associated with OSA particularly in younger adults iv. Decrease in mandibular and maxillary length, width and depth e. Awake Nasopharyngolaryngoscopy: allows for in office direct visualization of upper airway structures i. Presence of septal deviation and inferior turbinate hypertrophy

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Adenoid hypertrophy Lingual tonsil hypertrophy Retroflexion and folding of the epiglottis Abnormal masses in the upper airway Findings related to other associated medical comorbidities  Sinus disease/nasal polyposis  Laryngopharyngeal reflux

ASSESSMENT TOOLS FOR THE EVALUATION OF OSA 1. Several validated tools have been developed to quantitatively assess OSA risk and its symptomatic consequences 2. STOP-BANG Questionnaire a validated screening tool for predicting OSA risk. a. Risk is defined by the number of positive answers to the following questions: S – Snore loudly T – Tired, fatigued, or sleepy O – Observed pauses in breathing or choking/gasping during sleep P – elevated blood Pressure B – BMI > 35kg/m2 A – Age older than 50 N – Neck size > 16 inches G – Gender = male b. If yes to: i. 0-2 questions – Low OSA risk ii. 3-4 questions – Intermediate risk, iii.  4 questions – High risk c. Intermediate and high-risk individuals should have a sleep study to confirm diagnosis of OSA 3. The Epworth Sleepiness Scale (ESS) is a validated metric of sleepiness a. Based on responses to the following situations scored on a scale: 0 - never, 1 - sometimes, 2 - most of the time, 3 - always i. Sitting and reading ii. Watching TV iii. Sitting inactive in a public place iv. As a passenger in a car for an hour without a break v. Lying down to rest in the afternoon when circumstances permit vi. Sitting and talking to someone vii. Sitting quietly after lunch b. General interpretation of ESS values are as follows: i. 0-5 lower normal daytime sleepiness ii. 6-10 higher normal daytime sleepiness iii. 11-12 mild excessive daytime sleepiness iv. 13-15 moderate excessive daytime sleepiness

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v. 16-24 severe excessive daytime sleepiness 4. The functional outcomes of sleep questionnaire (FOSQ) is a validated metric of the effect of sleepiness on daily activities and quality of life a. The questionnaire consists of 30 questions about performing activities divided into five categories: i. Activity level ii. Vigilance iii. Intimacy and sexual relationships iii. General productivity iv. Social outcome b. Question responses are reported based on difficulty graded on a scale of 1-4 i. 1 - Extreme difficulty with task ii. 2 - Moderate difficulty with task iii. 3 - Minimal difficulty with task iv. 4 - No difficulty with task c. Responses in each category are averaged and then combined as a total reported score ranging from 5-20 d. There is an abbreviated version of the FOSQ that consists of 10 questions (FOSQ-10) representing the same 5 categories, scaled 1-4, also reported as a score ranging from 5-20 e. FOSQ scores do not have a defined cutoff considered to be abnormal, but higher scores indicate better functional status f. FOSQ scores allow for objective measurements of improvements in sleepiness and its effect on daily activities after therapeutic intervention g. An increase of 2.2 points in FOSQ has been shown to be a clinically important response metric in improving symptoms when treating OSA 5. Insomnia Severity Index (ISI) – validated questionnaire for the evaluation of quality of sleep a. Based on responses to 7 questions graded on a scale based on sleep from the prior two weeks: 0 – never, 1 – a little, 2 – somewhat, 3 – much, 4 – very much i. Difficulty falling asleep ii. Difficulty staying asleep iii. Problem waking up too early iv. How dissatisfied are you with your current sleep pattern? v. How noticeable to others do you think your sleep problem is in terms of impairing the quality of your life? vi. How worried/distressed are you about your current sleep problem? vii. To what extent do you consider your sleep problem to interfere with your daily functioning (e.g., daytime fatigue, mood, ability to function at work/daily chores, concentration, memory, mood, etc.) currently? b. General interpretation of ISI values are as follows: i. 0-7 = no clinically significant insomnia ii. 8-14 = subthreshold insomnia iii. 15-21 = clinical insomnia (moderate severity) iv. 22-28 = clinical insomnia (severe)

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Standardized questionnaires (ESS, FOSQ, ISI) can be used to assess severity of sleep symptoms prior to intervention and can be used to gauge improvement after treatment

ASSESSMENT OF THERAPEUTIC OPTIONS FOR OSA 1. Assessment for CPAP therapy a. Continuous positive airway pressure remains the first line therapy for management of OSA b. Adherence to CPAP remains variable with data suggesting that 29% to 83% of users will continue to use CPAP at 4 years when adherent use is defined as ≥ 4hr a night 5 nights a week c. Various measures can improve CPAP comfort i. Humidification and heating of CPAP tubing ii. Changing mask size and type  Full face mask  Nasal mask  Nasal pillow interface iii. Use of Bilevel PAP (BIPAP) device  BIPAP lowers the pressure during expiration making it easier to exhale d. Various interventions can be employed to improve CPAP adherence i. Education ii. Frequent support and encouragement iii. Cognitive behavioral therapies 2. Assessment for Non-CPAP Therapies a. Surgical interventions i. ablative (i.e., uvulopalatopharyngoplasty (UPPP)) ii. non-ablative (hypoglossal nerve stimulation) b. Other PAP alternative therapies are second/third line therapies for those who cannot tolerate or do not wish to use CPAP i. mandibular repositioning devices ii. lateral sleep positioning devices c. There is currently no widely adopted comprehensive schematic for the evaluation and recommendation of specific surgeries or other non-CPAP therapies i. However, the history, physical exam, and ancillary imaging and procedures can be used to help guide CPAP alternative treatments 3. Assessment of sleep study data for Non-CPAP Therapies a. PSG or HSAT reports can provide additional data outside of the overall AHI that may help guide management i. Lateral and supine AHI in patients with positional OSA ii. Distribution of apneas and hypopneas iii. Length of obstructive events

Diagnosis and Assessment of Adult OSA iv. v. vi. vii.

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Frequency and severity of oxygen desaturations Total sleep time spent with oxygen saturations < 88% Rapid eye movement (REM) specific apnea* Additional sleep disorders (periodic limb movements, REM behavior disorder)* *HSAT does not stage sleep and cannot determine sleep stage specific OSA findings such as REM related apnea b. Accurate assessment of OSA disease severity is important when determining CPAP alternative therapy. Consider repeating a sleep study on patients being evaluated for Non-CPAP therapy if: i. Recent weight gain ii. Recent changes to health (stroke, congestive heart failure, chronic obstructive pulmonary disease (COPD), etc.) iii. Most recent study is 2 years or older 4. Assessment based on weight and weight loss interventions a. Weight loss can lead to significant improvement in OSA: i. 10 kg weight loss is associated with OSA resolution in 50% of patients with mild OSA disease ii. Weight loss leads to a reduction in tongue fat volume which is a primary driver of AHI reduction in obese OSA patients b. Bariatric surgery should be considered for severe obesity (BMI > 35 - 40 kg/m2) c. Associated with significant AHI reductions although complete resolution of OSA is uncommon d. BMI > 35kg/m2 is considered a contraindication for upper airway stimulation e. BMI > 40kg/m2 is considered a contraindication for UPPP based on the Friedman Staging f. Elevated BMI is also associated with comorbid medical conditions and additional risk undergoing general anesthesia 5. Palatine tonsillar hypertrophy – Palatine tonsillectomy a. Isolated palatine tonsillectomy in patients with grade IV tonsils can have an > 80% surgical success rate b. Presence of tonsils is also associated with greater chance of AHI reduction in UPPP no matter the size although grade III-IV are associated with greater odds of surgical success 6. Pharyngeal exam - Friedman Staging Criteria: a. Incorporates tonsil grade, FTP, and BMI to determine likelihood of surgical success in uvulopalatopharyngoplasty Friedman Stage I II III IV

FTP 1,2 3,4 3,4 1,2,3,4

Tonsil Size 3,4 3,4 0,1,2 0,1,2,3,4

BMI (kg/m2) 10% of previous weight, then one repeat polysomnogram (PSG) is a Qualified Option. When the patient had a sleep study done in the past, currently has suspicion for worsening or new OSA, and new diagnosis of stroke, congestive heart failure, COPD, or neurodegenerative disease, then one repeat polysomnogram (PSG) is a Qualified Option.

Patient characteristics Home sleep study negative for OSA High clinical suspicion for OSA Answer “yes” to ≥ 3 of the following criteria: S – Snore loudly T – Tired, fatigued, or sleepy O – Observed pauses in breathing or choking/gasping during sleep P – elevated blood Pressure B – BMI > 35kg/m2 A – Age older than 50 N – Neck size >16 inches G – Gender = male Poor CPAP adherence: use < 4 hours / night, or < 5 nights / week) Past polysomnogram Suspicion for worsening or new OSA Weight gain of >10 kg or >10% of previous weight Past polysomnogram Suspicion for worsening or new OSA Recent new diagnosis of: Stroke (CVA), Congestive heart failure (CHF), COPD, or neurodegenerative disease

Qualified Option(s) Type 1 polysomnogram (PSG) Polysomnogram (PSG)

Humidification and heating of CPAP tubing Changing mask size and type Switch to Bilevel PAP (BIPAP) device One repeat polysomnogram (PSG)

One repeat polysomnogram (PSG)

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QUESTIONS 1. A 52-year-old male comes to you for evaluation of poor sleep. He reports multiple nighttime arousals and will go to the bathroom 4 times a night. He wakes up in the morning with significant dry mouth and unrefreshing sleep. He His BMI is 32 kg/m2and he has a neck circumference of 18 inches. You obtain a home sleep apnea test showing an AHI of 4 events/hr. The patient reports having trouble sleeping because of discomfort from the testing equipment and only thinks he slept 4 hours. What is the next step? a. b. c. d.

Evaluate patient for other underlying sleep disorders Obtain a repeat home sleep apnea test Obtain an in-lab polysomnogram No further evaluation, he is suffering from insufficient sleep and needs to increase his sleep duration

2. A 60-year-old male presents to your office because his wife is concerned about his sleep. She has witnessed him having worsened snoring over the past several months as well as episodes where he stops breathing in his sleep. He reports increased fatigue and sleepiness during the day. His BMI is 26kg/m2 and neck circumference is 15 inches. He has lost about 20lbs since he had a heart attack 3 months ago. His current ejection fraction is 25%. What is the next appropriate step in evaluating his sleep? a. In-lab polysomnogram b. Home sleep apnea testing c. Overnight pulse oximetry d. No sleep testing, he is fatigued due to heart failure. 3. A 56-year-old female presents to your clinic for evaluation of poor sleep. She reports multiple nighttime arousals, excessive daytime sleepiness, and her husband tells her she is now snoring louder than ever before. Her last menstrual cycle was 14 months ago. She has gained 10lbs over the past year and her BMI is 29kg/m2. You obtain a polysomnogram which shows an AHI of 15 events/hr and she is prescribed CPAP for management. What is the most significant factor explaining her recent new diagnosis of OSA. a. Recent weight gain b. Increased age c. Post-menopausal status d. Female gender 4. A 42-year-old male with history of severe obstructive sleep apnea comes to your clinic because he is interested in getting surgery for treatment of his OSA. He was recently diagnosed with OSA with an AHI of 32events/hr. Physical exam is significant for FTP IV, tonsil size I, BMI 34kg/m2. He has good dentition except his wisdom teeth were removed as a teenager. He comes to your clinic because he

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Jason L. Yu, Erica R. Thaler and Richard J. Schwab received a CPAP unit and used it for only two nights. He did not like the feeling of the mask because it covered his entire face and he was feeling smothered. What is the next appropriate step in management? a. Drug induced sleep endoscopy to evaluate the upper airway for surgery b. Uvulopalatopharyngoplasty c. Oral mandibular advancement device d. Hypoglossal nerve stimulation surgery e. Recommend retrying CPAP with alternative mask 5. A 35-year-old male presents for follow up in your clinic after starting use of an oral mandibular device for the treatment of moderate OSA. Prior to his diagnosis of OSA he reported significant daytime sleepiness that was affecting his daily activities as well as difficulty remaining asleep at night. Now on treatment, he is unsure if the device is helping him at night though his wife reports he is snoring less loudly than before. What tools could have been used to assess if he had clinical improvement a. Epworth sleepiness scale b. Insomnia severity index c. Functional outcomes of sleep questionnaire d. STOP-BANG e. a,b,c f. a, b, c, d

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 13

ASSOCIATED HEALTH RISKS OF OSA Josephine H. Nguyen, MD Sacramento Ear, Nose, and Throat Surgical and Medical Group, Inc., Stockton, CA, USA

MORTALITY 1. Untreated obstructive sleep apnea (OSA) increases risks of death from: a. Cardiovascular events b. Stroke (apnea-hypopnea index (AHI) > 30) c. Perioperative period d. Overall number from any cause 2. Risk of death peaks during sleep Table 1. Probability of cumulative 8-year survival AHI < 20 0.96

AHI > 20 0.63

Table 2. Mortality rate over 14 years Mild OSA 6.5%

No OSA 7.7%

Moderate to severe OSA 33%

3. Difference is most accurate for people in their 40s and 50s, in whom mortality from other causes is uncommon a. Difference is more pronounced in men younger than 70 b. In the elderly, mortality rate is not affected by OSA i. This may be related to survival bias, as middle-aged hypertensive OSA patients may not survive into old age

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Josephine H. Nguyen ii. Another hypothesis is that older people have reduced acute cardiovascular response to arousal from sleep, compared with younger subjects 4. Mechanisms of sudden death include: a. Malignant arrhythmias c. Extreme hypoxia, especially if morbidly obese d. Blunted arousal response to pharyngeal closure 5. Treatment with continuous positive airway pressure (CPAP) attenuates the risk of fatal cardiovascular events

CARDIOVASCULAR DISORDERS 1. OSA is a significant risk factor for cardiovascular diseases, including: a. Atrial fibrillation (a-fib), incidence is 3-4 folds higher in severe OSA b. Recurrence of a-fib following cardioversion c. Nocturnal arrythmias, 2-18 times increased risk i. Including complex ventricular ectopy, a-fib, supraventricular tachycardia (SVT), conduction delays and tachyarrhythmias ii. Prevalence and complexity increase with increasing OSA severity d. Atherosclerosis and coronary artery disease i. Worsens with increasing OSA severity  Odds ratios: 2.1 for mild, 2.4 for moderate, 3.3 for severe OSA ii. Rapid deoxygenation and reoxygenation (oxidative stress) lead to systemic inflammatory changes (lymphocyte activation, vascular smooth cell activation, decrease in macrophages, increased lipid levels, lipid peroxidation, high-density lipoprotein (HDL) dysfunction), then endothelial dysfunction, which leads to atherosclerosis e. Myocardial infarction (MI), especially nocturnal i. In the general population, the onset of MI is usually between 6-11 am ii. Almost half of OSA patients have their onset of MI during sleep hours, between 10 pm and 6 am f. Acute congestive heart failure (CHF) i. Negative intrathoracic pressure during obstructive events leads to increased left ventricular (LV) afterload, increased myocardial work, and decreased stroke volume ii. Myocardial ischemia further worsens LV dysfunction g. Acute pulmonary edema 2. Proposed mechanism by which OSA induces ventricular arrhythmias: a. Initially, increased vagal tone is observed during apnea due to hypoxic stimulation of the carotid bodies during absent ventilation b. Once respiration resumes, inflation of the lungs decreases vagal tone, while the hypoxic influences on sympathetic tone are unmasked with resulting tachycardia

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c.

These episodes of tachycardia and post-apneic elevated blood pressure increase myocardial oxygen demands in the presence of hypoxemia, predisposing to ischemia and possibly tachyarrhythmias d. Conversely, in healthy subjects, sleep is typically a time of reduced tachyarrhythmias and ischemia 3. Use of CPAP decreases: a. Ventricular premature beats (by 58% after 1 month) b. Nocturnal angina and ST depression

HYPERTENSION 1. Systemic hypertension (HTN): a. At least 45% of patients with OSA have systemic HTN i. Both during wakefulness and during sleep b. Wisconsin Sleep Cohort Study, one of the largest population-based studies (n=1060), reported a close dose-response relationship between OSA and HTN c. Oxygen desaturation index (ODI) has stronger correlation than AHI according to European Sleep Apnea Database (ESADA) d. Hypoxia leads to increased sympathetic activity via chemo- and baroreflex activation, which leads to increase in catecholamines e. Lack of normal decrease in blood pressure during sleep, often described as “non-dipping,” may be the earliest sign of OSA-induced hypertension f. Increased negative intrathoracic pressures (promoting venous return) and arousal from sleep in association with apneic events contribute to the rise in blood pressure seen in OSA 2. Pulmonary hypertension: a. Usually mild with pulmonary artery (PA) pressure < 30 mmHg b. No correlation with OSA severity c. Higher PA pressures with co-morbid disease such as chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS), LV dysfunction 3. Treating OSA with PAP has been shown to reduce systolic blood pressures only modestly a. This may still be clinically significant because reductions in systolic blood pressure (SBP) of only 1-2 mmHg are associated with reduced cardiovascular events

METABOLIC DISORDERS 1. 87% of obese patients with type 2 diabetes mellitus (T2DM) were found to have clinically significant OSA 2. OSA is a risk factor for DM and diabetic complications (Figure 1) a. This may be because both conditions have obesity as a primary risk factor

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Figure 1. Relationship between OSA, obesity, and diabetes.

Table 3. OSA and T2DM Prevalence

No OSA Mild OSA Moderate OSA Severe OSA

Odd ratio of type 2 DM prevalence 1 1.33 1.73 1.87

4. Possible etiology: a. Intermittent hypoxia and sleep fragmentation activate sympathetic nervous system and proinflammatory pathways b. Cortical and autonomic arousals alter sympathetic / parasympathetic balance 5. 6 months of CPAP treatment was associated with lower levels of circulating leptin and triglyceride

STROKE 1. Both OSA and snoring have been associated with stroke risk 2. 14% of OSA subjects develop stroke after 10 years a. Odd ratio of 4.33 for prevalence of stroke in moderate-to-severe OSA (AHI > 20). Vice versa, stroke patients have high prevalence for OSA.

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3. There is a direct relationship between nocturnal oxygen dipping, intima media thickness, and atherosclerotic plaques in the carotid arteries, independent of the presence of systemic hypertension b. This supports a direct relation between OSA, atherosclerosis, and subsequent stroke 4. The relationship between OSA and a-fib may also contribute indirectly to the increased risk of stroke in patients with OSA 5. Serum levels of sCD40L and sP-selectin are elevated, and silent brain infarct is more common in patients with moderate to severe OSA, leading to elevated stroke risk a. CPAP may be useful for decreasing risk in patients with moderate to severe OSA 6. Mild OSA increased stroke risk in persons with underlying coronary artery disease (CAD) b. No other clear data about mild OSA impact on cardiovascular outcomes or all-cause mortality 7. Heavy snoring with minimal OSA increases the risk of carotid artery atherosclerosis c. Mechanism: inspiratory vibration causes injury to arterial wall, which initiates the formation of plaque. Vibration can also embolize existing plaques.

COGNITIVE IMPAIRMENT 1. OSA has negative functional and anatomic effects on: a. Memory b. Concentration / executive attention / reaction time c. Learning ability d. Communication e. Alertness and arousal f. Inhibition to inappropriate behaviors and ideas g. Future planning h. Depression and irritability i. Axonal dysfunction or injury j. Myelin metabolism impairment in frontal periventricular white matter k. Amount of amyloid in cerebrospinal fluid (CSF) in cognitively normal elderly l. Brain size 2. AHI is not a good predictor for excessive daytime sleepiness a. There is only weak correlation between AHI and subjective or objective measures 3. Subjects can show cognitive impairment without feeling sleepy 4. Not all cognitive dysfunctions can be reversed by CPAP. Effective treatment of sleepy OSA does not always abolish daytime sleepiness.

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MALIGNANCIES 1. OSA is independent risk factor for increased cancer incidence and overall cancer mortality a. Those who spent > 1.2% of the night with SO2 below 90% had increased risk of cancer b. Those who spent > 12% of the night with SO2 below 90% had > 2 folds adjusted risk of cancer incidence c. Adjusted hazard ratio (HR) of 1.07 for every additional 10% of SO2 time < 90% 2. Wisconsin Cohort Study: HR of 2.0 for cancer mortality in moderate OSA, HR of 4.8 for severe OSA 3. Australian study: HR of 3.4 for cancer mortality in moderate-to-severe OSA 4. AHI criteria may not be applicable to subjects > 65 years old 5. Possible Mechanism: a. Increased oxidative stress b. Both chronic and intermittent hypoxia can modify gene expression of transcription factors involved in regulation of tumor genesis (e.g., hypoxiainducible factor 1) c. Hypoxia-inducible factor 1 promotes angiogenesis and enhance tumor progression

MOTOR VEHICULAR ACCIDENTS 1. OSA leads to hypersomnolence, which leads to 2-7 times rise in motor vehicle accidents 2. Correlation with increased AHI in some studies, and with Epworth Sleepiness Scale > 15 in other studies 3. With use of CPAP, effective incidence decreases from 1.6 to 1.1 per patient and number of near misses decrease from 4.5 to 1.8 per patient

OTHER ASSOCIATED HEALTH RISKS 1. OSA causes airway inflammation a. Resolution of chronic cough with CPAP for OSA suggests a direct link between OSA and cough b. PAP improves also other conditions such as asthma, gastroesophageal reflux disease (GERD) and upper airway cough syndrome / postnasal drip syndrome 2. OSA increases utilization of medical resources, including number of hospitalizations, emergency department visits, office visits, and higher consumption of medications 3. OSA patients are found to have increased sick leave, decreased work performance, increased medical costs, and increased divorce rate

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KEY CLINICAL POINTS 1. OSA should be aggressively diagnosed and treated to avoid many associated morbidities and increased overall mortality, aside from huge social and economic consequences. 2. Emphasis should be placed on treatment of moderate to severe OSA to lower mortality rate from all causes. 3. Although there is not much evidence that mild OSA or primary snoring affect mortality rate, these should still be treated to decrease risk of morbidity, such as stroke and type 2 diabetes mellitus. 4. Additional therapy to PAP may be required to improve daytime sleepiness and associated cognitive impairment. 5. Although not absolutely required, young patients with obesity, hypertension, or diabetes may benefit from screening for concomitant OSA, as early diagnosis and treatment lead to the most benefit.

QUESTIONS 1. Which of the following patients have increased mortality rate compared to matched control at same age? a. 45-year-old male with severe untreated OSA and no other comorbidity b. 50-year-old female with mild untreated OSA and no other comorbidity c. 80-year-old male with moderate untreated OSA and treated mild HTN d. 55-year-old female with moderate untreated OSA and CAD e. Both A and D 2. Which type morbidity may NOT be reversible with PAP? a. Ventricular premature beats b. Certain type of cognitive impairment c. Elevated serum leptin and triglycerides d. Nocturnal angina and ST depression 3. A large number of OSA patients have onset of myocardial infarction shifted to which time period? a. 6 am to 11 am b. 10 am to 6 pm c. 10 pm to 6 am d. 6 pm to 11 pm 4. Which of the following is associated with increased risk of developing a stroke? a. Severe OSA b. Moderate OSA c. Mild OSA d. Primary snoring e. All of the above

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Josephine H. Nguyen 5. A 60-year-old man spent >12% of the night with SO2 below 90%. What is his adjust hazard ratio of developing cancer? a. 2.2 b. 3.5 c. 1.7 d. 1

REFERENCES He J, Kryger M H, Zorick F J, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest. 1988; 94(1): 9-14. Ip M S, Lam K S, Ho C, Tsang K W, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest. 2000 Sep;118(3):580-6. doi: 10.1378/ chest.118. 3.580. Kent B D, Grote L, Ryan S, Pépin J L, Bonsignore M R, Tkacova R, Saaresranta T, Verbraecken J, Lévy P, Hedner J, McNicholas W T. Diabetes mellitus prevalence and control in sleepdisordered breathing: the European Sleep Apnea Cohort (ESADA) study. Chest. 2014 Oct;146(4):982-990. doi: 10.1378/chest.13-2403. Marshall N S, Wong K K, Liu P Y, Cullen S R, Knuiman M W, Grunstein RR. Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study. Sleep. 2008 Aug;31(8):1079-85. Minoguchi K, Yokoe T, Tazaki T, Minoguchi H, Oda N, Tanaka A, Yamamoto M, Ohta S, O’Donnell C P, Adachi M. Silent brain infarction and platelet activation in obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 2007 Mar 15;175(6):612-7. doi: 10.1164/rccm.200608-1141OC. Rahangdale S, Campana L, Malhotra A. Not so good vibrations. Commentary on Lee et al. Heavy snoring as a cause of carotid artery atherosclerosis. Sleep. 2008;31(9):1207-1213. Sleep. 2008 Sep;31(9):1204-5. Steinberg S, Louis M. Medical Evaluation of Patients with Obstructive Sleep Apnea. In: Salman SO, ed. Modern Management of Obstructive Sleep Apnea. Cham, Switzerland: Springer Nature Switzerland AG; 2019: Chapter 1. Verse T, de Vries N. Current Concepts of Sleep Apnea Surgery. New York, New York: Thieme Publishers; 2019: Chapter 2. Westerman DE. The Concise Sleep Medicine Handbook, 5th ed. Atlanta, Georgia: GSSD Publisher, LLC; 2019: Chapter 10.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 14

SNORING Anders Sideris and Stuart Mackay Department of Otolaryngology Head and Neck Surgery, The Wollongong Hospital, Illawarra Shoalhaven Local Health District, Wollongong, New South Wales, Australia; Illawarra ENT Head and Neck Clinic, Wollongong, New South Wales, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia; University of Wollongong, School of Medicine, Wollongong, New South Wales, Australia

DEFINITION OF SNORING 1. Habitual snoring refers to the phonatory sound that is produced by the vibration of soft tissue in the upper airway as a result of turbulent airflow and increased resistance in the airway during sleep 2. Snoring may be produced by a number of factors: a. Intraluminal i. Soft tissue factors such as predisposing anatomy (e.g., long uvula or soft palate), reduced compliance and redundant mucosal tissue ii. Airway shape and collapse pattern iii. Obstructive pathology such as neoplasia b. Extraluminal i. Neuromuscular tone ii. External obstruction iii. Obesity and resultant external airway compression 3. Habitual snoring occurs in the absence of apnea or desaturations (apnea-hypopnea index (AHI) < 10, or alternative AHI < 15 or AHI < 5) a. Snorers are more likely to develop OSA over their lifetime but up to a third exhibit no significant apnea on polysomnography b. Arousal and daytime somnolence may be associated with primary snoring

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PATHOPHYSIOLOGY OF SNORING 1. Snorers produce higher negative inspiratory pressures and prolonged inspiratory time than non-snorers, the volume and nature of which is often irregular 2. Tongue base dominant snoring has been found to produce the highest mean frequency (or pitch) followed by epiglottic and palatal dominant snoring respectively 3. Simple snorers tend to snore in a low frequency (100-300 Hz) “rhythmic” manner, while those with OSA produce higher mean frequency (~1000 Hz) and “non-rhythmic” snoring

DEMOGRAPHICS OF SNORING 1. 2. 3. 4.

Men snore more frequently than women Increased BMI is associated with snoring Geographic variation exists Estimates of snoring prevalence are plagued by difficulty in obtaining accurate data at a population level

CONSEQUENCES OF SNORING 1. Social a. Snoring is socially problematic b. The majority of complaints to clinicians come from partners, friends and acquaintances of the patient c. Complaints vary from minor annoyance, to having to move rooms for adequate sleep quality d. It carries social stigma, can produce embarrassment and has led to relationship breakdown 2. Medical a. Mortality, cardiovascular, and cerebrovascular risk b. Contention exists within the current literature about the health risks of snoring in the absence of apnea c. Pro Arguments i. Snoring without excessive daytime sleepiness has been associated with incident hypertension and diabetes ii. Simple snorers may be at higher risk of adjacent carotid artery intimamedia thickening and stenosis iii. Postulated mechanisms include surface acoustic waves producing local inflammation, oxidative stress, endothelial damage, and increased binding kinetics/receptor mediated endocytosis of lowdensity lipoproteins

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d. Con Arguments i. Large community cohorts have not linked simple snoring to all-cause mortality, cardiovascular or cerebrovascular event risk ii. Most studies that link primary snoring to cardiovascular risk are likely confounded by clinical referral bias iii. Obese patients who snore may be at higher risk from obesity and associated metabolic abnormalities than from snoring 3. Daytime somnolence a. Some snorers complain of poor daytime cognitive function and wake unrefreshed b. Snoring severity has been positively correlated with excessive daytime sleepiness c. Sleepiness is associated with increased motor vehicle and workplace accident risk, decreased productivity and decreased quality of life 4. Other health risks a. Other studies have identified cross-sectional associations of snoring with depression and mental health conditions

ASSESSMENT OF PATIENTS WITH SNORING 1. History a. Collaborative history is paramount b. Self-reporting of snoring and its severity is reliably unreliable c. Parents, partners, friends or witnesses of the snoring should accompany the patient during consultation d. Key components of history: i. Frequency – “How often do you or your partner snore? Nightly, a few times a week, only with certain behaviors?”, “Do you snore all night, most of the night (> 50%) or some of the night (< 50%)?” ii. Volume – “Can the snoring be heard in the same room, outside the room, down the hall or on another level of the house?” iii. Position – “Do you or your partner snore in all positions or only on their back?”  Supine snoring should be differentiated from prone or lateral snoring as supine snoring may be treated with positional devices iv. Associated behaviors (e.g., alcohol consumption, tiredness, sleep deprivation, night shift, poor sleep architecture) v. Day-to-day function: tiredness, sleepiness, productivity in day-to-day activities and history of motor vehicle accident related to sleepiness 2. The Snoring Severity Scale is a validated questionnaire that is a useful tool for physicians but its accuracy should always be reconciled during consultation, particularly with a witness (Table 1)

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Please pick the answer in each of the three questions below that best describes your partner’s snoring? 1. How often does your partner/spouse snore? (a) Every night. (b) Snores on most nights (i.e., more than 50% of nights). (c) Snores on some nights (i.e., less than 50% of nights). (d) Snores on very rare occasions or never snores. 2. How much does your partner/spouse snore? (a) Snores all the time throughout the night. (b) Snores most of the time throughout the night (i.e., more than 50% of the time). (c) Snores some of the time during the night (i.e., less than 50% of the time). (d) Hardly snores or no snoring. 3. How loud is the snore? (a) Snoring can be heard throughout the floor/flat or louder with the bedroom door closed. (b) Snoring can be heard in the next room with the bedroom door closed. (c) Snoring can only be heard in the bedroom. (d) There is no snoring noise.

Score 3 2 1 0 3 2 1 0 3 2 1 0

Lim PVH, Curry AR. A new method for evaluating and reporting the severity of snoring. J Laryngol Otol 1999;113:336 – 40. doi: 10.1017/s0022215100143919.

a.

Commercially available smartphone applications have the capacity to identify and record snoring episodes b. These applications have been difficult to validate c. There is little evidence that they reliably assess frequency of snoring, identify apnea, arousal or provide an accurate assessment of sleep quality or phases of sleep 3. Examination a. Comprehensive examination includes assessment of the airway from level of the nose to the glottis by external examination and fiberoptic flexible nasal endoscopy (awake or under drug-induced sleep conditions) b. Oral and Dental Exam i. Friedman Tongue position ii. Modified Mallampati Classification: Grade A-D iii. Hard palate: arch height and maxillary width iv. Dental occlusion: class I-III v. Retrognathia vi. Micrognathia vii. Maxillary set-back viii. Hyoid position relative to mandible c. Oropharyngeal exam i. Tonsil size: Grade I-V (complemented by identification of tonsillar generated collapse on dynamic airway assessment) ii. Uvula length iii. Soft palate anteroposterior length: complemented by nasal endoscopy d. Nasal exam i. Anterior rhinoscopy  Caudal septal position

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    

Septal deflection Turbinate hypertrophy and inferior meatal patency Mucosal appearance Cobblestoning and allergic appearance Excess mucus stranding ii. Palpation caudal septum iii. Nasal valve collapse  Cottle and Modified Cottle Maneuver to assess for subjective airflow improvement e. Nasopharynx i. Adult adenoid tissue or other f. Soft palate i. Nasal endoscopic assessment of palatal shape ii. Key landmarks: 1) Hard/soft palate junction 2) Genu and 3) Velum  Phenotypes  Oblique: Hard palate (deep), Genu (deep), Velum (narrow) o Collapse pattern: concentric  Intermediate: Hard palate (deep), Genu (narrow), Velum (narrow) o Collapse pattern: predominant anteroposterior (AP)  Vertical - Hard palate (narrow), Genu (narrow), Velum (narrow) o Collapse pattern: total AP g. Uvula i. Posterior bulk ii. Length h. Retro-lingual segment i. Base of tongue bulk and extent of retro-lingual obstruction  Dynamic maneuver: forward tongue protrusion and mandibular advancement ii. Lingual tonsil size  Grade 1-4 Table 2. Combined Friedman staging system Stage Stage 1

Friedman Palate Position Tonsil Size BMI 1 3, 4 4 hours/night or have comorbid insomnia  Motivational enhancement therapy also increases CPAP adherence  Acclimatization/desensitization  Use techniques to familiarize patients with PAP therapy:

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



Instruct patient to practice breathing through the mask for one hour while watching television, reading or performing sedentary activity  Start using CPAP while lying down awake  Use CPAP for a short nap  Begin using CPAP for a few hours of nocturnal sleep Associated with increased CPAP use at 30 days

BENEFITS 1. Efficacy a. PAP reliably reduces the AHI; a meta-analysis of randomized controlled trials (RCTs) demonstrated a mean decrease of 23 events/hour b. Symptoms i. Nocturnal  Sleep quality  Improved sleep architecture: fewer arousals, decreased lighter (Stage N1) sleep, and increased deeper (Stage N3) sleep  Snoring  Effective, safe and reversible therapy for snoring in patients with OSA  Nocturia  CPAP can reduce nocturia associated with OSA and improve quality of life, possibly by reducing intrathoracic negative pressure and thereby avoiding expansion of cardiac atria and decreasing atrial natriuretic peptide secretion and reducing nocturnal urine volume ii. Diurnal  Excessive daytime sleepiness (EDS)  CPAP effectively reduces EDS in OSA patients, with a larger effect in more severe and sleepier patients  Quality of life  Health-related quality of life in OSA patients improves with CPAP  The biggest improvement is in the vitality scale, which measures energy and fatigue  Cognitive function  CPAP improves working memory, long-term verbal memory and short-term visuospatial memory and results in mild, transient improvement in frontal lobe and executive functioning

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c.

In patients with mild cognitive impairment and OSA, CPAP results in significant improvements in psychomotor and cognitive processing at 1 year  Motor vehicle accidents  CPAP reduces the increased crash risk among drivers with moderate to severe OSA  Drowsy driving is also reduced after adherent PAP use Health Outcomes i. Mortality  While moderate to severe OSA is independently associated with increased all-cause mortality, RCTs of CPAP have not convincingly shown improvement in this outcome  Short term follow-up and adherence problems may account for the lack of mortality benefit in these trials ii. Hypertension  PAP therapy in OSA patients reduces systolic blood pressure by a small, but clinically significant, number (2-3 mmHg) with larger reductions seen in patients with refractory or uncontrolled hypertension  Reductions are most pronounced in those with severe OSA and EDS  CPAP is synergistic with anti-hypertensive medications in reducing blood pressure in resistant hypertension iii. Arrhythmias  Atrial fibrillation (AF)  AF recurrence after cardioversion has been shown to be approximately half (42% vs 82%) in PAP treated versus untreated OSA patients  An even larger effect has been found for AF recurrence after catheter ablation (28% vs 63% in PAP treated vs untreated OSA patients, respectively)  Other arrhythmias  CPAP is associated with a decrease in occurrence of ventricular bradycardia, asystole and nocturnal heart block  CPAP reduces the occurrence of premature ventricular beats by more than half in OSA patients with heart failure iv. Sudden cardiac death  In long-term follow up, patients who discontinued PAP therapy for OSA have higher rates of sudden cardiac death v. Heart failure  Small RCTs have found that CPAP improved left ventricular ejection fraction in patients with comorbid heart failure and OSA

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vi. Cardiovascular prevention  Primary prevention  Spanish Sleep and Breathing Network Study (n=725)  In moderate to severe OSA, CPAP did not result in decreasing the incidence of arterial hypertension or cardiovascular events during a 4-year follow-up period, although sub-analysis showed reductions in both in those who demonstrated adherence to PAP ≥ 4 hours/night  Secondary prevention  RICCADSA study (n = 244): o OSA patients without daytime sleepiness who underwent coronary revascularization o No differences in CPAP-treated patients compared to control with regards to primary cardiovascular endpoints o Subgroup of adherent patients of ≥ 4 hours/night had a lower cardiovascular risk than untreated and nonadherent patients  SAVE study (n = 2717): o Moderate to severe OSA patients with cardiovascular or cerebrovascular disease o CPAP did not significantly reduce recurrent serious cardiovascular events in the intentionto-treat analysis o Significant reduction in daytime sleepiness and improved quality of life  ISAACC study (n = 2551): o Moderate to severe OSA patients with acute coronary syndrome (ACS) o Similar incidence of cardiovascular events in CPAP and controls o No association between cardiovascular events and hours of CPAP adherence  RCTs have been limited by low levels of adherence to PAP, inclusion of patients with mild OSA, and exclusion of symptomatic OSA patients due to ethical reasons vii. Stroke  Primary prevention  Observational studies have demonstrated a 27% riskreduction with CPAP  Secondary prevention and neurologic recovery  Several RCTs have shown improved short-term neurologic outcomes in acute stroke patients newly diagnosed with OSA and treated with PAP

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KEY CLINICAL POINTS 1. CPAP (either fixed or auto-adjusting) is currently the first-line mode of PAP for symptomatic patients with uncomplicated OSA and OHS that occurs in the context of moderate to severe OSA 2. Nasal CPAP is the preferred mask type for most patients although interface choice should ultimately be tailored to the individual’s patient characteristics 3. The threshold to initiate treatment with PAP may be lower in patients with particular comorbidities, such as resistant hypertension, arrhythmias, and/or stroke 4. After starting PAP, the patient should be followed closely for adherence, objective efficacy and subjective symptom improvement with interventions taken as needed to address patient concerns 5. PAP may be combined with other modalities to increase adherence and/or lower pressure requirements

QUESTIONS 1. 62-year-old train conductor with no past medical history presents with excessive daytime sleepiness interfering with work. He undergoes a polysomnography and is found to have severe OSA with an AHI of 32 events/hour, supine AHI of 40 events/hour and a nadir oxygen saturation of 83%. Which of the following is the most appropriate initial treatment for his OSA? a. Mandibular advancement through a custom made oral appliance b. Modafinil c. Positive airway pressure d. Positional therapy e. Uvulopalatopharyngoplasty

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2. Which positive airway pressure modality allows for adjustment of both inspiratory and expiratory pressures? a. Continuous positive airway pressure b. Adaptive servo-ventilation c. Auto-adjusting positive airway pressure d. Bilevel positive airway pressure e. B & D 3. Which of the following is NOT an absolute contraindication to continuous positive airway pressure? a. Recent pneumothorax b. Recent significant head trauma c. Chronic obstructive pulmonary disease d. Recent transphenoidal surgery 4. A 32-year-old female with severe obstructive sleep apnea (AHI = 35 events/hour) and excessive daytime sleepiness returns for follow-up after initiating CPAP therapy. She reports persistent diurnal sleepiness and unrefreshing sleep and frequently wakes up with a dry mouth. Her CPAP data reveals she has been using her CPAP for an average of 3 hours/night. Which of the following is the best feedback for the patient? a. The patient is using her CPAP enough to obtain optimal benefit. b. The patient is below the accepted level of adherence. The rest of the visit should focus on interventions that would help increase her nightly CPAP use. c. The patient has failed CPAP and there is no use in continuing therapy. d. The patient should switch to oral appliance therapy. e. The patient should stop CPAP and be evaluated for surgical treatment. 5. A 45-year-old man with severe OSA stopped his nasal CPAP (set to 16 cm H2O) due to feeling that the pressure was “too much.” He has had trouble falling asleep at this setting and, if he does, he wakes up frequently throughout the night. Which interventions below can be attempted to help the patient adjust to his PAP therapy? a. Auto-adjusting PAP b. Bilevel PAP c. Use of the ramp feature or SenseAwake d. Exhalation modification features e. All of the above

REFERENCES Andrade, RGS; Viana, FM; Nascimento, JA; Drager, LF; Moffa, A; Brunoni, AR; Genta, PR; Lorenzi-Filho, G. Nasal vs Oronasal CPAP for OSA Treatment: A Meta-Analysis. Chest., 2018 Mar, 153(3), 665-674. doi: 10.1016/j.chest.2017.10.044. Ayas, NT; Patel, SR; Malhotra, A; Schulzer, M; Malhotra, M; Jung, D; Fleetham, J; White, DP. Auto-titrating versus standard continuous positive airway pressure for the treatment of

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obstructive sleep apnea: results of a meta-analysis. Sleep., 2004, Mar 15, 27(2), 249-53. doi: 10.1093/sleep/27.2.249. Bakker, JP; Marshall, NS. Flexible pressure delivery modification of continuous positive airway pressure for obstructive sleep apnea does not improve compliance with therapy: systematic review and meta-analysis. Chest., Jun 2011, 139(6), 1322-1330. doi: 10.1378/chest.10-2379. Bachour, A; Avellan-Hietanen, H; Palotie, T; Virkkula, P. Practical Aspects of Interface Application in CPAP Treatment. Can Respir J., 2019, 2019, 7215258. doi:10.1155/2019/7215258. Barbé, F; Durán-Cantolla, J; Sánchez-de-la-Torre, M; Martínez-Alonso, M; Carmona, C; Barceló, A; Chiner, E; Masa, JF; Gonzalez, M; Marín, JM; Garcia-Rio, F; Diaz de Atauri, J; Terán, J; Mayos, M; de la Peña, M; Monasterio, C; del Campo, F; Montserrat, JM. Effect of Continuous Positive Airway Pressure on the Incidence of Hypertension and Cardiovascular Events in Nonsleepy Patients With Obstructive Sleep Apnea. JAMA., 2012, 307(20). doi:10.1001/jama.2012.4366. Bradley, TD; Logan, AG; Kimoff, RJ; Sériès, F; Morrison, D; Ferguson, K; Belenkie, I; Pfeifer, M; Fleetham, J; Hanly, P; Smilovitch, M; Tomlinson, G; Floras, JS. CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med., 2005, Nov 10, 353(19), 2025-33. doi: 10.1056/NEJMoa051001. Camacho, M; Riaz, M; Capasso, R; Ruoff, CM; Guilleminault, C; Kushida, CA; Certal, V. The effect of nasal surgery on continuous positive airway pressure device use and therapeutic treatment pressures: a systematic review and meta-analysis. Sleep., 2015, Feb 1, 38(2), 279-86. doi: 10.5665/sleep.4414. Doherty, LS; Kiely, JL; Swan, V; McNicholas, WT. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest., Jun 2005, 127(6), 2076-84. doi: 10.1378/chest.127.6.2076. Fava, C; Dorigoni, S; Dalle Vedove, F; Danese, E; Montagnana, M; Guidi, GC; Narkiewicz, K; Minuz, P. Effect of CPAP on blood pressure in patients with OSA/hypopnea a systematic review and meta-analysis. Chest., 2014 Apr, 145(4), 762-771. doi: 10.1378/chest.13-1115. Freedman, N. Positive Airway Pressure Treatment of Obstructive Sleep Apnea. Principles and Practice of Sleep Medicine. Sixth ed. Elsevier, 2017, chap 115. Gagnadoux, F; Le Vaillant, M; Paris, A; Pigeanne, T; Leclair-Visonneau, L; Bizieux-Thaminy, A; Alizon, C; Humeau, MP; Nguyen, XL; Rouault, B; Trzepizur, W; Meslier, N. Institut de Recherche en Santé Respiratoire des Pays de la Loire Sleep Cohort Group. Relationship Between OSA Clinical Phenotypes and CPAP Treatment Outcomes. Chest., 2016 Jan, 149(1), 288-90. doi: 10.1016/j.chest.2015.09.032. Gupta, MA; Simpson, FC. Obstructive sleep apnea and psychiatric disorders: a systematic review. J Clin Sleep Med., Jan 15, 2015, 11(2), 165-75. doi: 10.5664/jcsm.4466. Jonas, DE; Amick, HR; Feltner, C; Weber, RP; Arvanitis, M; Stine, A; Lux, L; Harris, RP. Screening for Obstructive Sleep Apnea in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. Jama., Jan 24, 2017, 317(4), 415-433. doi:10.1001/jama.2016.19635. Kanagala, R; Murali, NS; Friedman, PA; Ammash, NM; Gersh, BJ; Ballman, KV; Shamsuzzaman, AS; Somers, VK. Obstructive sleep apnea and the recurrence of atrial

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fibrillation. Circulation., May 27, 2003, 107(20), 2589-94. doi: 10.1161/01.CIR.0000068337.25994.21. Kim, Y; Koo, YS; Lee, HY; Lee, SY. Can Continuous Positive Airway Pressure Reduce the Risk of Stroke in Obstructive Sleep Apnea Patients? A Systematic Review and MetaAnalysis. PLoS One., 2016, 11(1), e0146317. doi: 10.1371/journal.pone.0146317. Kuhn, E; Schwarz, EI; Bratton, DJ; Rossi, VA; Kohler, M. Effects of CPAP and Mandibular Advancement Devices on Health-Related Quality of Life in OSA: A Systematic Review and Meta-analysis. Chest., Apr 2017, 151(4), 786-794. doi:10.1016/j.chest.2017.01.020. Kushida, CA; Chediak, A; Berry, RB; Brown, LK; Gozal, D; Iber, C; Parthasarathy, S; Quan, SF; Rowley, JA. Clinical guidelines for the manual titration of positive airway pressure in patients with obstructive sleep apnea. J Clin Sleep Med., Apr 15, 2008, 4(2), 157-71. 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, Dec 1, 35(12), 1593-602. doi: 10.5665/sleep.2226. Léotard, A; Lesgoirres, M; Daabek, N; Lebret, M; Bailly, S; Verain, A; Series, F; Pépin, JL; Borel, JC. Adherence to CPAP with a nasal mask combined with mandibular advancement device versus an oronasal mask: a randomized crossover trial. Sleep Breath., 2019 Sep, 23(3), 885-888. doi: 10.1007/s11325-018-01772-5. Lisan, Q; Van Sloten, T; Marques Vidal, P; Haba Rubio, J; Heinzer, R; Empana, JP. Association of Positive Airway Pressure Prescription With Mortality in Patients With Obesity and Severe Obstructive Sleep Apnea: The Sleep Heart Health Study. JAMA Otolaryngol Head Neck Surg., Jun 1, 2019, 145(6), 509-515. doi: 10.1001/jamaoto.2019.0281. Martínez-García, MA; Capote, F; Campos-Rodríguez, F; Lloberes, P; Díaz de Atauri, MJ; Somoza, M; Masa, JF; González M; Sacristán, L; Barbé, F; Durán-Cantolla, J; Aizpuru, F; Mañas, E; Barreiro, B; Mosteiro M; Cebrián, JJ; de la Peña, M; García-Río, F; Maimó, A; Zapater, J; Hernández, C; Grau SanMarti, N; Montserrat, JM. Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA., 2013, Dec 11, 310(22), 2407-15. doi: 10.1001/jama.2013.281250. McArdle, N; Devereux, G; Heidarnejad, H; Engleman, HM; Mackay, TW; Douglas, NJ. Longterm use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med., Apr 1999, 159(4 Pt 1), 1108-14. doi: 10.1164/ajrccm.159.4.9807111. McArdle, N; Douglas, NJ. Effect of continuous positive airway pressure on sleep architecture in the sleep apnea-hypopnea syndrome: a randomized controlled trial. Am J Respir Crit Care Med., Oct 15, 2001, 164(8 Pt 1), 1459-63. doi: 10.1164/ajrccm.164.8.2008146. McEvoy, RD; Antic, NA; Heeley, E; Luo, Y; Ou, Q; Zhang, X; Mediano, O; Chen, R; Drager, LF; Liu, Z; Chen, G; Du, B; McArdle, N; Mukherjee, S; Tripathi, M; Billot, L; Li, Q; Lorenzi-Filho, G; Barbe, F; Redline, S; Wang, J; Arima, H; Neal, B; White, DP; Grunstein, RR; Zhong, N; Anderson, CS, SAVE Investigators and Coordinators. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med., 2016, Sep 8, 375(10), 919-31. doi: 10.1056/NEJMoa1606599.

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Mokhlesi, B; Grimaldi, D; Beccuti, G; Abraham, V; Whitmore, H; Delebecque, F; Van Cauter, E. Effect of One Week of 8-Hour Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea on Glycemic Control in Type 2 Diabetes: A Proof-of-Concept Study. Am J Respir Crit Care Med., 2016, Aug 15, 194(4), 516-9. doi: 10.1164/rccm.201602-0396LE. Montesi, SB; Edwards, BA; Malhotra, A; Bakker, JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med., Oct 15, 2012, 8(5), 587-96. doi: 10.5664/jcsm.2170. Patil, SP; Ayappa, IA; Caples, SM; Kimoff, RJ; Patel, SR; Harrod, CG. Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. J Clin Sleep Med., Feb 15, 2019, 15(2), 301-334. doi: 10.5664/jcsm.7638. Pamidi, S; Wroblewski, K; Stepien, M; Sharif-Sidi, K; Kilkus, J; Whitmore, H; Tasali, E. Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial. Am J Respir Crit Care Med., 2015, Jul 1, 192(1), 96-105. doi: 10.1164/rccm.201408-1564OC. 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 Sep 1, 194(5), 613-20. doi: 10.1164/rccm.201601-0088OC. Redline, S; Yenokyan, G; Gottlieb, DJ; Shahar, E; O’Connor, GT; Resnick, HE; Diener-West, M; Sanders, MH; Wolf, PA; Geraghty, EM; Ali, T; Lebowitz, M; Punjabi, NM. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med., 2010, Jul 15, 182(2), 269-77. doi: 10.1164/rccm.200911-1746OC. Reeves-Hoché, MK; Hudgel, DW; Meck, R; Witteman, R; Ross, A; Zwillich, CW. Continuous versus bilevel positive airway pressure for obstructive sleep apnea. Am J Respir Crit Care Med., Feb 1995, 151(2 Pt 1), 443-9. doi: 10.1164/ajrccm.151.2.7842204. Reutrakul, S; Mokhlesi, B. Obstructive Sleep Apnea and Diabetes: A State of the Art Review. Chest., Nov 2017, 152(5), 1070-1086. doi: 10.1016/j.chest.2017.05.009. Sánchez-de-la-Torre, M; Sánchez-de-la-Torre, A; Bertran, S; Abad, J; Duran-Cantolla, J; Cabriada, V; Mediano, O; Masdeu, MJ; Alonso, ML; Masa, JF; Barceló, A; de la Peña, M; Mayos, M; Coloma, R; Montserrat, JM; Chiner, E; Perelló, S; Rubinós, G; Mínguez, O; Pascual, L; Cortijo, A; Martínez, D; Aldomà, A; Dalmases, M; McEvoy, RD; Barbé, F. Spanish Sleep Network. Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial. Lancet Respir Med., 2020 Apr, 8(4), 359-367. doi: 10.1016/S2213-2600(19)30271-1. 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., Dec 2011, 15(6), 343-56. doi: 10.1016/j.smrv.2011.01.003. Schwab, RJ; Badr, SM; Epstein, LJ; Gay, PC; Gozal, D; Kohler, M; Lévy, P; Malhotra, A; Phillips, BA; Rosen, IM; Strohl, KP; Strollo, PJ; Weaver, EM; Weaver, TE. ATS Subcommittee on CPAP Adherence Tracking Systems. An official American Thoracic Society statement: continuous positive airway pressure adherence tracking systems. The

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 17

ORAL APPLIANCE THERAPY FOR OSA Ryan J. Soose1, MD and Nicole D. Chenet2, DDS 1

University of Pittsburgh Department of Otolaryngology, Pittsburgh, PA, USA 2 Sleep Apnea Dental Center, Pittsburgh, PA, USA

INTRODUCTION/OVERVIEW 1. Oral appliances have been used for the management of snoring and obstructive sleep apnea (OSA) for decades 2. They remain an underutilized tool in many patient populations a. This is perhaps due to simply a lack of familiarity of this treatment modality by the pulmonologists, neurologists, otolaryngologists, and even dentists who see patients with sleep-disordered breathing 3. The most commonly used appliances fall under the general category of mandibular repositioning appliances (MRAs) also known as mandibular advancement devices (MADs), and to a far lesser extent tongue retaining devices (TRDs) that hold the tongue in a protrusive position 4. Today, over 120 appliance designs are Food and Drug Administration (FDA)approved for the treatment of sleep-disordered breathing 5. The first practice guidelines for oral appliance therapy were established by the American Academy of Sleep Medicine in 1995 6. In 2006 an extensive review of the literature and practice parameters for the use of oral appliances in sleep-disordered breathing were published through the American Academy of Sleep Medicine (AASM) and the American Academy of Dental Sleep Medicine (AADSM) a. This was later updated in 2015 7. Although oral appliance therapy was traditionally considered for milder disease, prospective studies now demonstrate oral appliance effectiveness in more severe OSA as well

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TYPES OF DEVICES 1. Custom Mandibular Advancement Device (MAD) (Figure 1A) a. The MAD is by far the most common type of oral appliance used today for sleep-disordered breathing b. The MAD comes in two basic forms: a non-titratable type and a titratable type c. The Herbst appliance is a commonly used example of a titratable device i. The Herbst is composed of both a maxillary and a mandibular arch with metal adjustable arms and an internal mechanism on both arms that allows for advancement

Figure 1. Types of oral appliances. The Herbst appliance (A) is one of the commonly used, custom, titratable mandibular advancement devices (MAD) which works by advancing and stabilizing the mandible during sleep. The tongue retaining device (B) uses a suction bulb mechanism to stabilize the tongue anteriorly and may be relevant for a small subset of edentulous patients. Over-the-counter thermoplastic splints (C) may provide a low-cost alternative for select patients who are unable to obtain a custom MAD (e.g., non-apneic snoring).

2. Tongue Retaining Device (TRD) (Figure 1B) a. The TRD holds the tongue forward in a suction bulb mechanism b. Today, TRDs are used far less often than MADs but may be a viable option for certain patient population: i. Edentulous patients ii. Specific macroglossia patient subpopulations

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iii. Patients with temporomandibular joint (TMJ) disorders 3. Thermoplastic Splint (Figure 1C) c. Boil-and-bite appliances consist of one-piece prefabricated thermoplastic splints d. They are significantly less expensive than custom-made devices and often can be ordered online and fitted directly by the patient i. These cost-savings, however, must be cautiously weighed against the documented inferior efficacy, increased side effects, and lack of clinical follow-up and dental monitoring compared to a custom-made MAD implemented by a trained expert e. A randomized, controlled, crossover trial concluded that compared to boiland-bite thermoplastic appliances, a custom-made MAD resulted in i. Improved mandibular advancement ii. Increased efficacy iii. Fewer side effects iv. Less noncompliance

MECHANISM OF ACTION

Figure 2. MAD mechanism of action. In the left panel (no MAD), the baseline natural bite position and corresponding axial computed tomography (CT) imaging is shown. In the right panel (with MAD in place), the mandible is stabilized in a protrusive position. Note the radiographic improvement of both the anterior-posterior and lateral dimensions of the oropharyngeal airway. Imaging courtesy of Michael Van Leeuwen, DMD, Salt Lake City, UT.

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Ryan J. Soose and Nicole D. Chenet 1. The mechanism of action of oral appliances, as with most successful treatments for OSA, involves enlarging the upper airway and reducing upper airway collapsibility 2. MADs protrude and stabilize the mandible during sleep (Figure 2) a. This anterior protrusion of the mandible increases airway dimensions in a multilevel fashion at both the retropalatal and retrolingual portions of the upper airway 3. Successful MAD therapy is associated with enlargement and stabilization of the lateral dimension of the oropharyngeal airway 4. The multilevel effect and the impact on the lateral dimension of the airway are attributable, at least in part, to the coupling between the mandible and pharyngeal musculature via the pterygomandibular raphe 5. Electromyography studies demonstrate that oral appliances also increase activity of the masseter, lateral pterygoid, genioglossus, and geniohyoid muscles a. This suggests that neuromuscular activation may contribute to the upper airway effect

INDICATIONS 1. Oral appliance therapy can play multiple roles in the comprehensive management of sleep apnea patients 2. For many patients, oral appliances may be used as first-line and sole therapy, particularly for patients who a. Are non-obese b. Have mild-to-moderate disease and less collapsible airways c. Have with a component of mandibular deficiency 3. For continuous positive airway pressure (CPAP)-intolerant patients, oral appliance therapy may be used as a CPAP alternative or second-line treatment 4. Yet for other patients, particularly for those with more severe or multifactorial disease, the oral appliance may serve as a key component of a multimodality treatment approach that includes weight loss, positional therapy, lowering of nasal resistance, upper airway surgery, and even in conjunction with CPAP therapy 5. Per the 2015 AASM and AADSM clinical practice guidelines, oral appliance therapy is indicated for patients with following conditions: a. OSA who prefer oral appliance therapy to CPAP or who are intolerant to CPAP (including patients who are not appropriate candidates for CPAP or do not respond to CPAP or other conservative measures) b. Primary snoring who fail (or are not candidates for) conservative measures such as weight loss or positional therapy 6. Note that the latest AASM guidelines do not state a specific apnea-hypopnea index (AHI) range for MAD treatment pathways due to lack of evidence correlating MAD outcomes to AHI response a. Current Medicare guidelines provide insurance coverage of oral appliance therapy for mild-to-moderate OSA (AHI 5 to 29) as first-line treatment or for severe OSA (AHI ≥ 30) as second-line treatment after CPAP failure

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b. Clinical practice guidelines recommend: i. A qualified dentist should use a custom titratable appliance over noncustom devices ii. A qualified dentist should provide long-term clinical monitoring for and mitigation of dental-related side effects or occlusal changes iii. A sleep physician should provide appropriate clinical follow-up and sleep testing to assess treatment efficacy and outcomes iv. A sleep physician and a qualified dentist should instruct the oral appliance therapy patient to return for periodic office visits in a longitudinal care model 7. Clinical considerations for optimizing MAD patient selection: a. Sleep Medicine perspective: i. Mild-to-moderate pharyngeal collapsibility (rather than severe) ii. Lower body mass index (BMI) iii. Fewer non-anatomic pathophysiologic contributions (e.g., loop gain, arousal threshold) b. Otolaryngology perspective: i. Adequate nasal airway ii. Absence of enlarged tonsils or other lymphoid hyperplasia c. Dental perspective: i. Detailed in the next section

DENTAL ASSESSMENT AND DEVICE FITTING 1. Comprehensive Dental Sleep Evaluation a. Required documentation i. Prescription from the referring physician ii. Clinical notes from the referring physician iii. Diagnostic sleep study results b. Dental history i. Medical history ii. Prior dental and orthodontic treatment iii. History of TMJ pain/dysfunction or jaw trauma iv. History of oral surgery (periodontal, maxillofacial, endodontic) c. Dental examination i. Complete dental and periodontal exam ii. Panorex X-ray iii. TMJ exam iv. Occlusion (Angle’s classification) v. Nasal airway assessment vi. Pharyngeal airway exam vii. Extraoral and intraoral photos 2. Dental candidacy for MAD therapy a. Indications

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Ryan J. Soose and Nicole D. Chenet i. Full maxillary and mandibular dentition (ideal) ii. At least 8 teeth on the maxilla and mandible (minimum) iii. Partial dentures, crowns, veneers, bridges, fillings, dental implants (are also candidates) iv. Implant-retained dentures b. Contraindications i. Significant bone loss ii. Mobile teeth iii. Dental caries or fractured teeth iv. Edentulous

DEVICE IMPRESSIONS AND RECORDS 1. Taking dental impressions a. Polyvinyl siloxane material (traditional) b. Three-dimensional scanning i. Reduced gag and patient discomfort ii. Improved accuracy and fit 2. Establishing protrusive range a. Protrusive range is determined with a George Gauge with 2-8mm vertical opening between the maxillary and mandibular incisors b. Optimal protrusive starting position balances both comfort and symptomatic response and is established by testing a variety of vertical and protrusive positions 3. Determining appliance position a. Degree of mandibular advancement i. Start at 50% of maximal protrusive position and gradually advance as tolerated b. Degree of vertical opening i. Start with 2-8mm inter-incisal distance and adjust to optimize nasal breathing, lip seal, tongue position, inability to snore, and other factors 4. Selecting MAD subtype a. Interlocking appliance (Figure 3A) i. Key features: Dorsal fin (“shark fin”) design bilaterally on both the maxillary and mandibular trays. Adjustable key pushes the mandibular dorsal fin anteriorly, further protruding the mandible. ii. Advantages:  Two separate pieces works well for patients missing some anterior or posterior teeth  Increased tongue space  No mechanical parts that could potentially irritate the buccal mucosa

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Figure 3. MAD appliance designs. Dozens of appliance designs are available, each with unique features, mechanisms, advantages, and disadvantages. Examples include interlocking appliances, e.g., Respire Blue (A); anterior hook appliances, e.g., TAP appliance (B); bilateral push appliances, e.g., ProSomnus Precision (C); bilateral pull appliances, e.g., EMA appliance (D); printed or milled appliances, e.g., Panthera (E); and chrome appliances, e.g., Respire Pink Chrome (F). The sleep dental specialist uses intraoral anatomy, dental examination, medical history, patient preferences, and other clinical information to optimize appliance selection.

iii. Disadvantages:  Limited lateral movement  Not ideal for bruxism  Does not assure mouth closure (possible vertical mouth opening overnight) b. Anterior hook appliance (Figure 3B) i. Key features: Design utilizing a hook behind the anterior teeth on the maxillary or mandibular tray that hooks into a chrome bar on the opposing tray. A key is used to advance the hook position which mechanically pulls the mandible forward. ii. Advantages:  Hook design maintains mouth closure  Allows for lateral movement  Easy to adjust iii. Disadvantages:  Most force on the maxillary anterior teeth  Not ideal for patients with periodontal disease, claustrophobia, or mouth-breathing c. Bilateral push appliance (Figure 3C) i. Key features: Bilateral adjustable piston to “push” the mandible forward. ii. Advantages:  Allows for lateral movement

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Ryan J. Soose and Nicole D. Chenet  Suitable for sleep bruxism  Increased tongue space iii. Disadvantages:  Difficult for patients with limited dexterity  Not ideal for small mandibles and steep mandibular plane angles  Does not assure mouth closure (but has option to add clasps for orthodontic rubber bands) d. Bilateral pull appliance (Figure 3D) i. Key features: Bilateral interchangeable arm mechanism to ‘pull’ the mandible forward. As the arm size decreases, the mandible protrudes more anteriorly. ii. Advantages:  Ideal for healthy dental occlusion  Allows lateral movement  Suitable for patients with limited tongue space, small mandible, or strong gag reflex iii. Disadvantages:  Not ideal for patients with missing teeth, crowns or restorations, decreased crown height, or heavy bruxism e. Three-dimensional (3D) printed or milled appliances (Figure 3E) i. Key features: Computer-aided design and manufacturing (CAD/CAM) process utilizing 3D printed nylon and incorporating various design features above. ii. Advantages:  Metal-free  Lightweight and flexible  Ideal for patients with a gag reflex and limited tongue space iii. Disadvantages:  Not ideal for patients with multiple crowns, veneers, or restorations  Increased cost f. Chrome structure appliance (Figure 3F) i. Key features: Stronger chrome base material, rather than traditional dental acrylics, utilizing interlocking and bilateral push designs ii. Advantages:  Ideal for heavy bruxism, occlusal trauma, mandibular exostoses, narrow arches, strong gag reflexes, and the presence of several restorations  Increased tongue space due to thinner and less material intraorally  Durability iii. Disadvantages:  Contraindicated in patients with metal allergies

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5. Device delivery and fitting a. Insert the appliance after construction complete (3-4 weeks after impressions) b. Assure proper fit and comfort c. Educate patient to insert and remove the device independently d. Provide instructions on appliance advancement and self-titration e. Fabricate morning re-aligner to use for 5-10 minutes after awakening and removing the MAD i. Along with physical therapy exercises, the re-aligner restores the normal bite position to reduce the likelihood of occlusal changes 6. Post-delivery follow-up a. Scheduled outpatient follow-up in the first and second months to assess: i. Comfort and adherence ii. Fit and retention iii. Symptomatic response b. Targeted device adjustments as indicated c. Referral back to the physician for follow-up sleep testing and sleep medicine outcomes assessment

EFFECTIVENESS 1. Outcomes assessment a. After treatment initiation, all oral appliance therapy patients should have clinical follow-up with the ordering physician to assess outcome measures b. For patients with mild OSA (no evidence of cardiovascular risk), outcomes assessment focuses on symptomatic response and therapy adherence c. For patients with moderate-to-severe OSA, in addition to the above two outcome categories, repeat sleep testing is recommended to ensure adequate improvement in objective measures of disease severity and associated health risks d. Once confirmation of adequate adherence and effectiveness is achieved, patients may be transitioned to a long-term care pathway for routine clinical monitoring e. For suboptimal adherence or inadequate outcomes, a targeted troubleshooting program should be implemented to further improve results i. Includes appliance adjustment, patient education, positional therapy, weight loss, lowering of nasal resistance, adjunctive surgical therapy, or revisiting alternative treatments 2. Results a. Polysomnography metrics: i. In the 2006 AASM-directed review of the literature on oral appliances, the overall effectiveness for controlling OSA based on polysomnographic criteria (defined as AHI less than 10 events/hour) was 52%

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Ryan J. Soose and Nicole D. Chenet ii. These results must be interpreted with caution, as the collated data represented a very heterogeneous group of patients, types of devices, titration protocols, treatment outcomes, and clinician expertise iii. When only randomized, crossover, placebo-controlled studies were analyzed (five studies), the combined rate of “success” (treatment AHI less than 10 events/hour) and “response” (AHI reduction of 50%) was 64% iv. As of the 2015 updated clinical practice guidelines, 34 randomized controlled trials (RCT) with over 1300 patients were available for metaanalysis that reported a mean AHI reduction of 13.6 events/hour v. Meta-analysis of RCT data also demonstrates that custom MAD’s are associated with improvements in oxygen saturations and arousal index b. Hypertension and other health metrics: i. Multiple studies have evaluated the effect of oral appliance therapy on hypertension and report a statistically significant reduction in blood pressure measurements ii. A 2017 systematic review and meta-analysis reported significant reductions in daytime systolic (-1.8 mmHg) and diastolic (-2.2 mmHg) blood pressure with active MAD therapy compared to placebo or inactive treatment iii. One observational study reported reduction in cardiovascular mortality with MAD but pooled RCT data on MAD and other cardiovascular outcomes (e.g., heart rate variability, biomarkers, endothelial function) remains inconclusive c. Patient-reported metrics: i. MAD therapy may improve any OSA-related nocturnal and daytime symptoms but may also improve sleep-related symptoms associated with jaw musculature such as sleep-related bruxism and morning headaches ii. In multiple studies, MADs significantly improve patient-reported daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) iii. Although MADs may be associated with smaller AHI reduction compared to CPAP, a meta-analysis of 67 studies found that both CPAP and MADs demonstrate effective reduction of patient-reported daytime sleepiness iv. Similarly, MADs are associated with similar improvements in sleeprelated quality of life measures (Functional Outcomes of Sleep Questionnaire or FOSQ) as well as general health quality of life (36item Short Form Health Survey or SF-36)

ADHERENCE 1. As with any device-related treatment for sleep-disordered breathing, successful management is critically dependent on usage

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2. Assessment of adherence in the literature is complicated by heterogeneity in a. Types of devices and titration protocols used b. Patient characteristics and disease severity c. Level of clinical care and provider expertise 3. Further confounding assessment is that the amount of nightly use required for improvement in symptoms and health outcomes is unknown and likely varies between individuals 4. One-year self-reported adherence rates range from 25% to 100%, with a median use of 77% of nights during the first year a. As with CPAP and other medical devices, adherence rates tend to decrease with duration of use past 1 year 5. Hoffstein combined adherence reports from 21 studies evaluating over 3,000 patients and found an overall average adherence of 56% to 68% at an average of 33 months follow-up 6. In crossover studies comparing CPAP and oral appliances, adherence rates were similar between the two devices

ADVERSE EVENTS 1. A portion of non-adherent patients may discontinue oral appliance use as a result of any number of side effects or adverse events 2. Many of side effects are minor and do not significantly affect long-term use or morbidity 3. Permanent complications include a. Bite changes b. Malocclusion c. TMJ dysfunction 4. This supports the notion that oral appliances should be fitted, titrated, and managed by a clinician with training and expertise in both dental care and sleep-related breathing disorders (Table 1) 5. Commonly reported minor side effects include a. Jaw pain b. Tooth pain c. Headache d. Facial pain e. Excessive salivation f. Dry mouth g. Gingival irritation h. Morning-after temporary occlusal changes 6. There are a wide range of reported minor side effects from 6% to 86% a. Many of these side effects are reported to be transient and occur with initiation of treatment b. Most authors report frequent improvement in these side effects with regular use and occasional adjustment of the device

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Ryan J. Soose and Nicole D. Chenet 7. More severe and persistent adverse sequelae include clinically significant TMJ dysfunction, tooth movement, and permanent changes in occlusion, and often necessitate device discontinuation 8. The pathophysiology of and risk factors for these more severe complications are not yet fully understood but are likely multifactorial 9. A landmark study in 2014 assessed the progression of occlusal changes over a decade of MAD treatment a. Results from this study confirmed that long-term MAD treatment leads to occlusal changes in the majority of patients (posterior open bite in 51% and anterior crossbite in 62% of the study population), and the changes were most often progressive with ongoing MAD use Table 1. Potential MAD Adverse Events (AE)

Potential MAD Adverse Events (AE) Minor AE Serious AE Drooling Permanent occlusal change Dry mouth TMJ dysfunction Discomfort Tooth fracture  Tooth or gingival  Jaw or TMJ  Muscle tenderness Gag reflex Anxiety Sensitivity to appliance material Transient morning occlusal change The majority of side effects from MAD use are minor, temporary, and reversible with ongoing accommodation to device use. Targeted troubleshooting including device adjustments, physical therapy exercises, and the use of a morning re-aligner may also mitigate minor AE’s. Some adverse side effects, however, may be more severe and permanent, such as significant change in occlusion or TMJ dysfunction, which may necessitate discontinuation of therapy.

PREDICTING AND IMPROVING MAD RESPONSE In addition to the patient selection and appliance design features discussed above, the optimization of oral appliance outcomes continues to improve and evolve. 1. Clinical factors: a. Clinical assessment of MAD candidacy and likelihood of success remains complex – owing to the very heterogenous nature of OSA pathophysiology b. Although multiple anatomic and non-anatomic factors affect outcomes, three key factors come up consistently in the oral appliance literature: i. Body weight and fat distribution ii. Nasal airway iii. Body position

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In a comparison of MAD responders and non-responders, only BMI (body mass index) and nasal resistance were independently predictive of MAD outcomes d. Similarly, one-third of patients treated with MAD therapy may have residual clinically significant positional (supine-dependent) OSA e. As such, weight loss, treatment of the nasal airway, and/or positional therapy may provide the most effective targets to positively augment oral appliance outcome 2. Endoscopy: a. Drug-induced sleep endoscopy (DISE) represents one tool with promising potential to improve patient outcomes with oral appliance b. Studies have used DISE to determine the likelihood of success with oral appliance therapy i. The authors concluded that sleep endoscopy, with concomitant mandibular advancement to mimic treatment effect, could be a valuable prognostic indicator for successful management of both snoring and OSA c. DISE may also be implemented to troubleshoot incomplete MAD response and to evaluate for adjunctive medical or surgical treatment options 3. Combination therapy: a. Particularly in patients with more severe and multifactorial OSA, combination therapy may be needed b. More broadly, the field of OSA management is shifting toward individual endotyping and a personalized multimodality treatment plan customized to each patient i. As such, the addition of positional therapy, weight management, lowering of nasal resistance, upper airway surgery, and other adjunctive measures may also provide an opportunity to further strengthen MAD outcomes c. MAD therapy can even be combined with CPAP (Figure 4) or hypoglossal nerve stimulation therapy (Figure 5) 4. Objective adherence monitoring: a. Although oral appliance adherence data has relied primarily on patient selfreporting in the past, new technology has been developed, and clinical trials are underway, utilizing objective monitors embedded in the appliance during fabrication in order to quantify use (e.g., DentiTrac device, Braebon Medical Corp, Ontario) b. Objective adherence monitors may be particular relevance to commercial drivers, pilots, and other occupations that require objective documentation of long-term therapy use

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Figure 4. Combination therapy: MAD and CPAP. Combining MAD therapy with other medical or surgical treatments for OSA may further improve outcomes, particularly for patients with more severe and complex disease. A nasal pillows CPAP interface has been fabricated to the custom MAD. Combination MAD-CPAP therapy may lower CPAP pressure requirements.

Figure 5. Combination therapy: MAD and hypoglossal nerve stimulation (HNS) therapy. MAD may be combined with HNS therapy and other otolaryngology interventions including upper airway surgery. This 5-minute polysomnography snapshot shows improved control of breathing in the 3 minutes on the left (green panel) with combination MAD and HNS, compared to the OSA events in the 2 minutes on the right (red panel) immediately after the HNS therapy is turned off.

5. Remote-controlled titration study: a. The MATRx plus system (Zephyr Sleep Technologies, Calgary) uses athome sleep testing and an automated mandibular positioner with feedback control, to record changes in the patient’s OSA parameters at various jaw positions during an overnight study b. The system provides clinicians with information i. To identify patients who will respond to MAD therapy (before fabrication) and ii. To determine the most effective therapeutic position of the mandible

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KEY CLINICAL POINTS 1. Oral appliance therapy is indicated for OSA patients who prefer oral appliance therapy to CPAP or who are intolerant to CPAP (including patients who are not appropriate candidates for CPAP or do not respond to CPAP or other conservative measures). 2. Oral appliance therapy is indicated for primary snoring patients who fail (or are not candidates for) conservative measures such as weight loss or positional therapy. 3. Although medical insurance policies may cover oral appliance therapy for mild-tomoderate OSA (AHI 5 to 29) as first-line treatment, or for severe OSA (AHI ≥ 30) as second-line treatment after CPAP failure, the latest AASM guidelines do not include a specific AHI range for MAD treatment pathways due to lack of evidence correlating MAD outcomes to AHI response. 4. A qualified dentist should use a custom titratable appliance over non-custom devices, and should provide long-term clinical monitoring for and mitigation of dental-related side effects or occlusal changes. 5. A sleep physician should provide appropriate clinical follow-up and sleep testing to assess treatment efficacy and outcomes, and to transition oral appliance patients to a longitudinal care model.

QUESTIONS 1.

According to the latest clinical practice guidelines, oral appliance therapy is indicated in: a. Mild OSA patients only b. Severe OSA patients only c. OSA patients who prefer oral appliance therapy to CPAP or who are intolerant to CPAP d. OSA patients only after they have failed uvulopalatopharyngoplasty

2.

The primary anatomic effect on the upper airway with successful mandibular advancement device therapy is: a. Mouth opening to increase the fraction of oral breathing b. Prevention of bruxism thus diverting muscle activity from the jaw to the tongue c. Altering hyoid bone position to increase the vertical length of the airway d. Increased lateral dimension and stabilization of the oropharyngeal airway via coupling between the mandible and pharyngeal musculature

3.

Long-term occlusal changes may be seen in approximately what percentage of patients treated with oral appliance therapy? a. 0% b. 25% c. 50% d. 100%

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4.

Oral appliance therapy can provide successful sole therapy for which of the following sleep-related breathing disorders? a. Obstructive sleep apnea (OSA) b. Central sleep apnea (CSA) c. Obesity hypoventilation syndrome (OHS) d. All of the above

5.

Which of the following adjunctive treatment strategies commonly augment the effectiveness of oral appliance therapy? a. Weight loss b. Treatment of nasal obstruction c. Positional therapy d. All of the above

REFERENCES Anandam A, Patil M, Akinnusi M, et al. Cardiovascular mortality in obstructive sleep apnea treated with continuous positive airway pressure or oral appliance: an observational study. Respirology. 2013;17:659-66. Barnes M, McEvoy RD, Banks S, Tarquinio N, Murray CG, Vowles N, Pierce RJ. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med. 2004 Sep 15;170(6):656-64. doi: 10.1164/rccm.2003111571OC. Bratton DJ, Gaisl T, Schlatzer C, Kohler M. Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis. Lancet Respir Med. 2015 Nov;3(11):869-78. doi: 10.1016/S2213-2600(15)00416-6. Brown EC, Cheng S, McKenzie DK, Butler JE, Gandevia SC, Bilston LE. Tongue and lateral upper airway movement with mandibular advancement. Sleep. 2013 Mar 1;36(3):397-404. doi: 10.5665/sleep.2458. Chan AS, Lee RW, Srinivasan VK, Darendeliler MA, Grunstein RR, Cistulli PA. Nasopharyngoscopic evaluation of oral appliance therapy for obstructive sleep apnoea. Eur Respir J. 2010 Apr;35(4):836-42. doi: 10.1183/09031936.00077409. Chang ET, Fernandez-Salvador C, Giambo J, Nesbitt B, Liu SY, Capasso R, Kushida CA, Camacho M. Tongue retaining devices for obstructive sleep apnea: A systematic review and meta-analysis. Am J Otolaryngol. 2017 May-Jun;38(3):272-278. doi: 10.1016/j.amjoto.2017.01.006. Clark GT, Sohn JW, Hong CN. Treating obstructive sleep apnea and snoring: assessment of an anterior mandibular positioning device. J Am Dent Assoc. 2000 Jun;131(6):765-71. doi: 10.14219/jada.archive.2000.0275. de Almeida FR, Lowe AA, Tsuiki S, Otsuka R, Wong M, Fastlicht S, Ryan F. Long-term compliance and side effects of oral appliances used for the treatment of snoring and obstructive sleep apnea syndrome. J Clin Sleep Med. 2005 Apr 15;1(2):143-52.

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de Vries GE, Wijkstra PJ, Houwerzijl EJ, Kerstjens HAM, Hoekema A. Cardiovascular effects of oral appliance therapy in obstructive sleep apnea: A systematic review and metaanalysis. Sleep Med Rev. 2018 Aug;40:55-68. doi: 10.1016/j.smrv.2017.10.004. Dieltjens M, Braem MJ, Van de Heyning PH, Wouters K, Vanderveken OM. Prevalence and clinical significance of supine-dependent obstructive sleep apnea in patients using oral appliance therapy. J Clin Sleep Med. 2014 Sep 15;10(9):959-64. doi: 10.5664/jcsm.4024. Ferguson KA, Cartwright R, Rogers R, Schmidt-Nowara W. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep. 2006 Feb;29(2):244-62. doi: 10.1093/sleep/29.2.244. Ferguson KA, Ono T, Lowe AA, al-Majed S, Love LL, Fleetham JA. A short-term controlled trial of an adjustable oral appliance for the treatment of mild to moderate obstructive sleep apnoea. Thorax. 1997 Apr;52(4):362-8. doi: 10.1136/thx.52.4.362. Ferguson KA, Ono T, Lowe AA, Keenan SP, Fleetham JA. A randomized crossover study of an oral appliance vs nasal-continuous positive airway pressure in the treatment of mildmoderate obstructive sleep apnea. Chest. 1996 May;109(5):1269-75. doi: 10.1378/chest.109.5.1269. Gotsopoulos H, Chen C, Qian J, Cistulli PA. Oral appliance therapy improves symptoms in obstructive sleep apnea: a randomized, controlled trial. Am J Respir Crit Care Med. 2002 Sep 1;166(5):743-8. doi: 10.1164/rccm.200203-208OC. Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep. 2004 Aug 1;27(5):934-41. doi: 10.1093/sleep/27.5.934. Hoffstein V. Review of oral appliances for treatment of sleep-disordered breathing. Sleep Breath. 2007 Mar;11(1):1-22. doi: 10.1007/s11325-006-0084-8. Johal A, Battagel JM, Kotecha BT. Sleep nasendoscopy: a diagnostic tool for predicting treatment success with mandibular advancement splints in obstructive sleep apnoea. Eur J Orthod. 2005 Dec;27(6):607-14. doi: 10.1093/ejo/cji063. Johal A, Gill G, Ferman A, McLaughlin K. The effect of mandibular advancement appliances on awake upper airway and masticatory muscle activity in patients with obstructive sleep apnoea. Clin Physiol Funct Imaging. 2007 Jan;27(1):47-53. doi: 10.1111/j.1475097X.2007.00714.x. Johal A, Hector MP, Battagel JM, Kotecha BT. Impact of sleep nasendoscopy on the outcome of mandibular advancement splint therapy in subjects with sleep-related breathing disorders. J Laryngol Otol. 2007 Jul;121(7):668-75. doi: 10.1017/S0022215106003203. Johnston CD, Gleadhill IC, Cinnamond MJ, Gabbey J, Burden DJ. Mandibular advancement appliances and obstructive sleep apnoea: a randomized clinical trial. Eur J Orthod. 2002 Jun;24(3):251-62. doi: 10.1093/ejo/24.3.251. Kent DT, Rogers R, Soose RJ. Drug-Induced Sedation Endoscopy in the Evaluation of OSA Patients with Incomplete Oral Appliance Therapy Response. Otolaryngol Head Neck Surg. 2015 Aug;153(2):302-7. doi: 10.1177/0194599815586978. Kuhn E, Schwarz EI, Bratton DJ, Rossi VA, Kohler M. Effects of CPAP and Mandibular Advancement Devices on Health-Related Quality of Life in OSA: A Systematic Review and Meta-analysis. Chest. 2017 Apr;151(4):786-794. doi: 10.1016/j.chest.2017.01.020. Kurtulmus H, Cotert S, Bilgen C, On AY, Boyacioglu H. The effect of a mandibular advancement splint on electromyographic activity of the submental and masseter muscles in patients with obstructive sleep apnea. Int J Prosthodont. 2009 Nov-Dec;22(6):586-93.

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Kushida CA, Morgenthaler TI, Littner MR, Alessi CA, Bailey D, Coleman J Jr, Friedman L, Hirshkowitz M, Kapen S, Kramer M, Lee-Chiong T, Owens J, Pancer JP; American Academy of Sleep. Practice parameters for the treatment of snoring and Obstructive Sleep Apnea with oral appliances: an update for 2005. Sleep. 2006 Feb;29(2):240-3. doi: 10.1093/sleep/29.2.240. Lam B, Sam K, Lam JC, Lai AY, Lam CL, Ip MS. The efficacy of oral appliances in the treatment of severe obstructive sleep apnea. Sleep Breath. 2011 May;15(2):195-201. doi: 10.1007/s11325-011-0496-y. Lee JJ, Sahu N, Rogers R, Soose RJ. Severe obstructive sleep apnea treated with combination hypoglossal nerve stimulation and oral appliance therapy. J Dent Sleep Med 2015;2(4):185–186. Mehta A, Qian J, Petocz P, Darendeliler MA, Cistulli PA. A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med. 2001 May;163(6):1457-61. doi: 10.1164/ajrccm.163.6.2004213. Naismith SL, Winter VR, Hickie IB, Cistulli PA. Effect of oral appliance therapy on neurobehavioral functioning in obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med. 2005 Oct 15;1(4):374-80. Ng JH, Yow M. Oral Appliances in the Management of Obstructive Sleep Apnea. Sleep Med Clin. 2019 Mar;14(1):109-118. doi: 10.1016/j.jsmc.2018.10.012. Pliska BT, Nam H, Chen H, Lowe AA, Almeida FR. Obstructive sleep apnea and mandibular advancement splints: occlusal effects and progression of changes associated with a decade of treatment. J Clin Sleep Med. 2014 Dec 15;10(12):1285-91. doi: 10.5664/jcsm.4278. 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 Jul 15;11(7):773-827. doi: 10.5664/jcsm.4858. Remmers J, Charkhandeh S, Grosse J, Topor Z, Brant R, Santosham P, Bruehlmann S. Remotely controlled mandibular protrusion during sleep predicts therapeutic success with oral appliances in patients with obstructive sleep apnea. Sleep. 2013 Oct 1;36(10):151725, 1525A. doi: 10.5665/sleep.3048. Ryan CF, Love LL, Peat D, Fleetham JA, Lowe AA. Mandibular advancement oral appliance therapy for obstructive sleep apnoea: effect on awake calibre of the velopharynx. Thorax. 1999 Nov;54(11):972-7. doi: 10.1136/thx.54.11.972. Sutherland K, Vanderveken OM, Tsuda H, Marklund M, Gagnadoux F, Kushida CA, Cistulli PA. Oral appliance treatment for obstructive sleep apnea: an update. J Clin Sleep Med. 2014 Feb 15;10(2):215-27. doi: 10.5664/jcsm.3460. 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 Jul 15;178(2):197-202. doi: 10.1164/rccm.200701-114OC. Walker-Engström ML, Tegelberg A, Wilhelmsson B, Ringqvist I. 4-year follow-up of treatment with dental appliance or uvulopalatopharyngoplasty in patients with obstructive sleep apnea: a randomized study. Chest. 2002 Mar;121(3):739-46. doi: 10.1378/chest.121.3.739. Yoshida K. Effect on blood pressure of oral appliance therapy for sleep apnea syndrome. Int J Prosthodont 2006;19:61–66.

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 18

SURGERY FOR OSA Robert M. Frederick and M. Boyd Gillespie, MD Department of Otolaryngology-Head and Neck Surgery, University of Tennessee Health Science Center, Memphis, TN, USA

SLEEP SURGERY INDICATIONS 1. Symptoms of obstructive sleep apnea (OSA): a. Nightly snoring b. Restless and unrefreshing sleep c. Witnessed gasping or choking while sleeping d. Excessive daytime sleepiness (or fatigue) e. Poor concentration f. Short-term memory loss g. Morning headaches h. Nocturia 2. Untreated OSA carries high risk of morbidity and mortality: a. Systemic and pulmonary hypertension b. Cardiac arrhythmias c. Coronary artery disease (CAD) d. Congestive heart failure (CHF) e. Cerebrovascular disease (CVD) f. Increased risk of motor vehicle accidents (MVA) 3. Signs and symptoms of OSA require additional testing: a. Home sleep apnea testing (HSAT) generally first-line b. Laboratory polysomnogram (PSG) indicated if complex issues (chronic obstructive pulmonary disease (COPD); seizure; cardiac arrythmia) or ongoing suspicion with negative HSAT c. Diagnosis requires apnea-hypopnea index (AHI) > 5 plus signs and symptoms or AHI > 15 with/without signs and symptoms

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Robert M. Frederick and M. Boyd Gillespie d. Measure of OSA severity: mild (AHI 5 - 70% of nights 5. CPAP Non-adherence: a. Patients with ≤ 4 hours a night of use may be candidates for CPAP salvage surgery b. CPAP non-adherence stable at 34% despite improved mask interfaces, behavioral intervention, and patient coaching c. Factors contributing to noncompliance include lack of education, high pressures, nasal obstruction, facial discomfort, social concerns, and claustrophobia 6. Sleep surgery seeks to improve airflow via: a. Removal of redundant/hypertrophied tissues b. Re-enforcement to resist excessive airway collapsibility c. Repositioning of structurally narrow airway

ROLE OF SLEEP SURGERY 1. Adjunct to CPAP to improve CPAP adherence 2. First-line option in select circumstance a. Significant tonsillar hypertrophy (3-4+ tonsils) 3. Second-line option for CPAP intolerance (moderate-severe OSA) or failure of behavioral modifications (weight loss; alcohol avoidance; sleep positioning) 4. Requires individual approach based on anatomy and OSA severity

SLEEP SURGERY EVALUATION 1. Patient factors to assess prior to sleep surgery a. OSA severity (AHI) b. Body habitus/BMI (better outcomes with BMI ≤ 35) c. Craniofacial structure (retrognathia; malocclusion; maxillary retrusion) d. Nasal patency (allergy; polyps; chronic sinusitis; deviated septum; inferior turbinate hypertrophy; nasal valve collapse) e. Tonsil size – Brodsky Scale typically used i. Grade 0- surgically absent tonsils ii. Grade 1- tonsils confined to tonsillar fossa iii. Grade 2- tonsils extending to edge of tonsillar fossa

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iv. Grade 3- tonsils extending toward midline of pharynx v. Grade 4- tonsils touch extend to midline (e.g., kissing tonsils) f. Soft palate/uvula length and thickness g. Modified Mallampati/Friedman Score- tongue size relative to the oral cavity i. I - complete visualization of tonsil fossa and uvula ii. II- complete visualization of soft palate and uvula (tonsils incompletely seen) iii. III- visualization of soft palate only (uvula incompletely viewed) iv. IV- visualization of hard palate only (soft palate incompletely viewed) h. Modified Mallampati/Friedman Scores III/IV indicate possible need for tongue procedures 2. Awake supine endoscopy a. Identifies upper airway inflammation requiring medical therapy (chronic rhinitis; nasal polyps; laryngopharyngeal reflux) b. Visualization of adenoid hypertrophy c. Lingual tonsil grading i. Grade 1- visible tonsil tissue at vallecula ii. Grade 2- raised tonsil tissue on vallecula iii. Grade 3- tonsil tissue fills vallecula/height of epiglottis iv. Grade 4- tonsil tissue extends beyond vallecula/above epiglottis d. Position of epiglottis i. Anterior- full view of anterior commissure ii. Neutral- full of mid and posterior vocal folds iii. Retroflexed- contact with posterior pharynx; arytenoid view only e. Müller maneuver (inspiration against pinched nostrils with scope in place) i. Fujita Classification-describes location of airway collapse  Type I- retropalatal  Type II- retropalatal and retrolingual  Type III- retrolingual ii. Findings not predictive of uvulopalatopharyngoplasty (UPPP) outcomes therefore some debate its utility 3. Drug-Induced Sleep Endoscopy (DISE) a. Accounts for changes in upper airway anatomy during sleep b. Allows better assessment of patients without obvious anatomic obstruction c. Required prior to hypoglossal nerve stimulation (HNS) to rule out concentric (circular collapse) at soft palate d. DISE Technique: i. Performed with flexible endoscopy in monitored setting with sleep surgeon and anesthesia staff ii. Light sedation to mimic sleep (unresponsive to verbal stimuli; snoring; brief apneas) iii. Anesthetics of choice- Propofol or Dexmedetomidine iv. Assessment of levels, severity, and configurations of upper airway collapse

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VOTE (velopharynx, oropharynx, tongue, epiglottis) Scoring System i. Used to score DISE ii. Each level grade as no (0), partial (1), or complete (2) collapse iii. Total scores range from 0 to 8-point scale iv. Configuration of collapse at each level (anteroposterior/AP; concentric; lateral) f. DISE detects severe retrolingual collapse 85% of time vs 36% with awake fiberoptic nasal endoscopy with Müller’s Maneuver, especially in those with Friedman I-III tongue positions (normal size tongues) g. DISE is 58% more likely to identify retrolingual collapse than awake endoscopy

SELECTION OF SLEEP SURGERY PROCEDURE 1. Three main categories of airway collapse causing OSA: a. Too little space (craniofacial anomaly) b. Too much tissue (tissue hypertrophy/obesity) c. Tissue too lax (increased tissue collapsibility; poor neuromuscular tone) 2. Too Little Space: soft tissue compressed into a limited craniofacial structure a. Commonly seen in younger and non-obese patients b. Normal size tongue in small jaw structure (relative macroglossia) c. Associated with jaw abnormalities: i. Retrognathia/Micrognathia ii. High arched maxilla/hard palate iii. Narrow mandibular arch iv. Open or cross bite v. Class II or III malocclusion d. Surgeries for Too Little Space: i. Maxillo-mandibular advancement ii. Horizontal maxillary expansion e. Non-surgical Option for mild-to-moderate OSA (AHI ≤ 30): i. Oral Appliance (OA) 3. Too Much Tissue: adenotonsillar hypertrophy or obesity with increased tongue and pharyngeal fat deposits within normal skeletal structure a. Common in the obese patient (BMI ≥ 30kg/m2) b. Tongue enlargement within a normal jaw structure (acquired macroglossia) c. Dental indentations typically seen on edges of tongue d. DISE examination finding include bulky base of tongue squeezed and folded in oropharynx and/or large lingual tonsils e. Surgeries for Too Much Tissue: i. Tonsillectomy ii. Lingual Tonsillectomy iii. UPPP iv. Partial Glossectomy

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Primary Tonsillectomy Option: i. Lower BMI < 25 ii. Curative potential with Grade III or IV tonsils and mild to moderate OSA  Overall success rate of 85% (AHI < 20 and > 50% reduction rate) and 57% cured (AHI < 5)  Preop AHI < 30 a predictor for success (100% surgical success and 84% with overall AHI ≤ 5) iii. Requires repeat OSA testing after tonsillectomy to determine new baseline AHI iv. If CPAP trial required postoperatively, surgery can result in lower CPAP pressures v. CPAP intolerant patients are often more tolerant post-tonsillectomy vi. Isolated tonsillectomy can be successful as treatment for adults with OSA, especially those with large tonsils and mild to moderate OSA g. Effective UPPP: i. In addition to tissue excision, newer techniques such as expansion pharyngoplasty focus on stiffening and repositioning of the tissues  Removal of hypertrophied tissue (tonsils; distal uvula)  Repositioning of the palatopharyngeus muscle to enlarge the lateral and retropalatal airway h. Partial Glossectomy is option for the following: i. Moderate to severe OSA (AHI ≥ 15) ii. Retroglossal collapse and a Friedman score III or IV iii. Performed with coblation or transoral robotic surgery (TORS) iv. Removes tissue (1 cm deep) in middle third of tongue from circumvallate papilla to vallecula v. Lingual artery at-risk in lateral third of the tongue adjacent to tonsillar fossa vi. Requires removal of any hypertrophied lingual tonsil tissue i. Submucosal Minimally Invasive Lingual Excision (SMILE): i. Less morbid form of partial glossectomy first described in children ii. Indicated for mild-moderate OSA (AHI < 30) iii. Submucosal channeling to reduce middle third of tongue through puncture site at circumvallate papilla. iv. Risk of bleeding from lingual artery if channel too deep (> 1 cm) or too lateral (> 1 cm off midline) j. Tongue Base Radiofrequency Ablation: i. Option for tongue base hypertrophy ii. Indicated for mild-moderate OSA (AHI < 30) iii. May be repeated to titrate for effect iv. May reduce AHI by mean of 10 points after mean of 3 treatments v. Rare complication of tongue base abscess- fever, dysphagia 2-3 days after treatment

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Robert M. Frederick and M. Boyd Gillespie vi. Risk of abscess reduce by post-operative antibiotics and steroid therapy 4. Tissue Too Lax: increased levels of passive airway collapsibility and reduced neuromuscular tone during sleep a. Predominant cause of OSA onset in middle and later age b. Increase prevalence in women after menopause c. Patient with lower BMI/normal weight d. Normal tongue size (Mallampati score (MP) I and II) e. Normal craniofacial structure f. Increased AHI during supine sleep (2:1 supine/non-supine ratio=positional) g. Increased AHI during REM sleep (REM-related muscle paralysis causes tongue prolapse) h. DISE assists in identification of collapse that may be missed by awake endoscopy i. Oral appliance (OA) also an effective option for mild-to-moderate OSA (AHI < 30) j. Surgeries for Tissue too Lax: i. Hyoid Myotomy and Suspension:  Improved lift with hyomandibular suspension (versus thyrohyoidal)  Option if retroflexed epiglottis and/or non-visualization of vallecula on DISE  Supports the base of tongue (hyoglossus; mylohyoid muscles)  Creates tension on lower hypopharyngeal wall (stylohyoid muscle)  Enlarges the retro-epiglottic airway (hyoepiglottic ligament) ii. Hypoglossal Nerve Stimulation (HNS):  Opens retroglossal airspace via stimulation of tongue protrusors (genioglossus; geniohyoid; intrinsic tongue muscles)  Opens retropalatal airspace via palatoglossal tension and reduced tongue contact with soft palate 5. Single Level versus Multi-Level Surgery: a. Majority of OSA patients have collapse of multiple segments of upper airway b. Multi-level approach can improve success of UPPP: i. Cure rate for UPPP is < 50% in unselected patients ii. Success rate increases with surgery on additional airway site iii. Obese patients with a crowded oropharynx/ tonsillar hypertrophy have more success with multilevel operations than UPPP alone c. Examples of multi-level surgery: i. Maxillomandibular advancement (MMA):  LeFort I and bilateral sagittal split ramus osteotomies to advance the maxilla, mandible, hyoid bone enlarges the retrolingual and retropalatal airspace

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MMA is the most successful single multilevel surgery but may lack availability, patient acceptance, and insurance coverage ii. UPPP + a hypopharyngeal procedure:  No defined standard of best hypopharyngeal procedure for a given patient  UPPP with tongue base suspension has reported success rate of 82%  UPPP with hyoid myotomy and suspension improves AHI success rates compared to the other procedures alone  UPPP with radiofrequency ablation (RFA) improves AHI success rates compared to the other procedures alone iii. Hypoglossal nerve stimulation (HNS):  Opens retropalatal and retroglossal airways in properly selected patients.  Preoperative DISE excludes patients with complete concentric palatal collapse since this collapse is independent of tongue position, as opposed to anteroposterior (AP) collapse which is improved with forward tongue displacement d. No demonstrated increased perioperative risk, readmissions, or reoperation rate in multi-level compared to single level surgeries for OSA e. Longer length of hospital stay for UPPP + base of tongue (BOT) procedure 6. Criteria for outpatient (ambulatory) OSA surgery: a. The American Society of Anesthesiologist recommends most OSA surgery in adults and in children < 3 years of age not be performed in an outpatient setting b. Clinical judgement may be used, however, on an individual basis to determine each patient’s viability for outpatient surgery c. Ambulatory surgery safety recommendations require: i. Difficult airway equipment ii. Respiratory care equipment iii. Radiology facilities iv. Clinical laboratory d. A review of 452 adult Medicaid OSA patients receiving airway surgery (nasal and/or pharyngeal surgery), 404 (89%) were ambulatory: i. No deaths or major complications in ambulatory patients ii. Adverse events (postoperative inpatient admission; ER visit; 3 or more physician follow-up visits; or any observation stay between 130 days of surgery) were 22% for outpatient surgery and 19% for inpatient surgery

OUTCOMES OF SLEEP SURGERY 1. OSA is a chronic disorder requiring long-term follow-up: a. Monitor adherence to CPAP or OA

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Determination of residual OSA after sleep surgery with repeat sleep testing Assessment of therapy side-effects Resolution of symptoms (e.g., snoring, daytime sleepiness, poor sleep quality) Risk factor modification (BP control, weight loss, avoidance of sedatives/alcohol, sleep hygiene) f. Assessment of secondary associated medical conditions (hypertension, cardiac arrhythmias, CAD, CHF, TIA/CVA) 2. Primary goals of sleep surgery: a. Reduce the severity of OSA even if cure is not achievable b. Improve AHI; ODI; RDI c. Improve snoring, daytime sleepiness, and sleep quality d. Reduced OSA severity decreases risk of secondary health complications including reduced cardiovascular morbidity and improves overall quality of life e. Specific Outcomes by Surgery Type: i. Uvulopalatopharyngoplasty (UPPP)  UPPP is the most common surgery used to treat OSA  Short-term complications:  Airway access/Failure to intubate  Post-obstructive pulmonary edema  Post-operative bleeding (1-2%; up to 2 weeks post-op)  Dehydration  Prolonged pain (> 2 weeks); and airway/intubationrelated issues  Long-term complications:  Dysphagia- untreated GERD associated with finding  Taste disturbance  Globus sensation- up to 31%  Velopharyngeal insufficiency (VPI)- rare but may be higher than previously reported  UPPP modifications to reduce associated risks include:  Uvulopalatal flap with uvular preservation reduces the risk of VPI (velopharyngeal incompetence) and is associated with less postoperative pain  Anterior advancement palatoplasty provides forward displacement of the soft palate while preserving the distal edge of the soft palate  Expansion sphincter pharyngoplasty spares mucosa but repositions the palatopharyngeal muscle anteriorly with a suspension suture to the superior pharyngeal constrictor fascia or hamulus  Potential Health Benefits of UPPP:  Reduces the incidence of congestive heart failure and atrial fibrillation

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iv.

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Reduces levels of depression but not to level of nonOSA controls Maxillary Expansion/Maxillomandibular Expansion:  Longer mean recovery times compared to alternative OSA surgeries  Potential complications:  Bony nonunion  Malocclusion  Nerve damage (inferior alveolar; greater/lesser palatine; V2, maxillary)  Dental injury  Facial deformity; change in cosmetic appearance  Health Benefits:  Considered successful at reducing the AHI to < 10  Better outcomes in younger (< 40 years), non-obese patients  Maxillary expansion reduces AHI by > 50% on average and significantly reduces sleepiness TORS (Trans Oral Robotic Surgery) Partial Glossectomy  Health Benefits:  When TORS was compared to Plasma ablation for BOT reduction, both were seen to effectively treat OSA and provide comparable results  The clinician should choose which method to use based on patient factors, availability, and costs  TORS has longer op time, less frequent postop bleeding, greater ESS reduction, shorter follow up duration, and similar surgical success rates Hyoid Myotomy and Suspension (HMS):  HMS designed to address hypopharyngeal collapse  Most common complication is neck seroma  Neck seroma can occur despite drain placement  Health Benefits:  Stand-alone HMS decreases ESS and AHI (mean reduction 15) in non-obese patients with moderate-tosevere OSA  30% of patients achieved AHI < 10 Hypoglossal Nerve Stimulation (HNS):  Inclusion criteria:  AHI 15-65 (less than 25% central)  BMI< 35 kg/m2  Failure of prior trial of CPAP therapy  Absence of circular (concentric) collapse at soft palate on DISE

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Tongue paresis (temporary) most significant complication in initial trial (18%) – resolved within days to weeks with no permanent weakness  Device-related malfunction is 6% at 5-years  Health Benefits post-implant:  Significant reduction in daytime sleepiness (ESS) at five years  Significant increase in sleep-related quality of life (FOSQ) at five years  Significant mean reduction in AHI and ODI at five years  Mean AHI reduction ≥ 50% at one-year (ADHERE Registry)  Predictors of response: Female sex and lower BMI  High patient satisfaction with 96% of patients recommending therapy  Higher cure rates (AHI < 5) than UPPP v. Midline Glossectomy:  Commonly performed with either coblation or transoral robotic surgery (TORS)  Appropriate in patients with severe OSA (AHI > 30); BMI (> 35); large tongues (acquired macroglossia)  Complications include bleeding; tongue edema; loss of taste  No complications specifically related to robot  Health Benefits:  Mean surgical success rate of 59.6% and cure rate of 22.5% (meta-analysis)  Associated with significant improvement in AHI, nocturnal oxygen levels, daytime sleepiness, and snoring  TORS and Coblation provide comparable results; method depends on patient factors, availability, and costs  TORS has longer operative time, reduced postop bleeding, greater ESS reduction, and similar surgical success rates vi. Radiofrequency Ablation (RFA):  Submucosal stiffening to counteract increased passive airway collapsibility  Multi-level treatment: nasal turbinates, soft palate, base of tongue  Safe with minimal trauma to surrounding tissues  Globus sensation most common complication  Health Benefits:  31% reduction in ESS at 12 months

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

31% and 45% reduction in 12-month and 24-month RDI, respectively vii. Tracheostomy:  Best treatment after failure of other therapy; obesityhypoventilation; significant cardiopulmonary problems; congestive heart failure  Near uniform success rate for OSA  Bypasses regions of upper airway obstruction  Considerable economic and quality of life consequences  Long-term risk of permanent tracheal damage; stenosis Key Clinical Points (Moderate to Severe OSA Surgery) Patient History

Testing

 Daytime sleepiness (Epworth ≥ 10)  Fatigue  Poor sleep quality  Snoring  Witnessed gasping/choking

 Home sleep test or polysomnogram  Awake fiberoptic examination

1st Line Treatment Options  Weight loss (recommended)  Avoidance of sedatives (recommended)  Trial of positive airway pressure (PAP) (recommended)  Oral appliance therapy (if AHI < 30) (option)  Primary tonsillectomy (3-4+ tonsils) (option)  Nasal surgery (if nonresponsive to medical therapy and likely to preclude use of PAP) (option)

2nd Line Treatment Options (if intolerant to PAP therapy)  Drug-induced sleep endoscopy (option)  Bariatric surgery (option)  Sleep surgery (option)  Too little space (craniofacial anomaly)  Maxillomandibular advancement (MMA)  Maxillary expansion  Genioglossal advancement  Too Much Tissue  Uvulopalatopharyngoplasty (UPPP)  Tonsillectomy/Lingual Tonsillectomy  Partial glossectomy/Tongue base reduction  Tissue Too Lax (Increased passive collapsibility; poor neuromuscular tone)  Hyoid suspension  Upper airway radiofrequency reduction  Hypoglossal nerve stimulation

QUESTIONS 1. A patient presents with moderate OSA (AHI 19). History and physical examination reveal a mildly overweight patient (BMI 27) with a history of chronic pharyngitis and 4+ tonsils. Which of the following is a reasonable treatment strategy? a. Oral appliance therapy b. Uvulopalatopharyngoplasty (UPPP) c. Primary tonsillectomy d. BiPAP

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Robert M. Frederick and M. Boyd Gillespie 2. Which of the following would be an anticipated outcome in an OSA patient undergoing nasal surgery? a. Reduction in the apnea-hypopnea index (AHI) b. Reduction in the respiratory disturbance index (RDI) c. Increase in the lowest oxygen (O2) saturation level d. Increased in the percentage of non-rapid eye movement sleep (NREM) 3. Awake supine endoscopy is a helpful adjunct to the physical examination of the OSA patient for which of the following reasons? a. Identifies site of upper airway collapse b. Improves outcomes from uvulopalatopharyngoplasty (UPPP) c. Identifies patients who are eligible for hypoglossal nerve stimulation (HNS) d. Identifies specific obstructions such as adenoid/lingual tonsil hypertrophy 4. Which of the following is a contraindication to hypoglossal nerve stimulation (HGN)? a. Presence of complete anteroposterior (AP) collapse at the level of the soft palate during drug-induced sleep endoscopy (DISE) b. Presence of epiglottic collapse during DISE c. Apnea-Hypopnea Index (AHI) > 50 d. Body Mass Index (BMI) > 35 kg/m2 5. Which of the following characteristics is associated with OSA secondary to poor neuromuscular tone? a. Increased apnea-hypopnea index (AHI) during rapid eye movement (REM) sleep b. High BMI (> 35 kg/m2) c. Retrognathia d. 3-4+ tonsil hypertrophy

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Soares D, Folbe AJ, Yoo G, Badr MS, Rowley JA, Lin HS. Drug-induced sleep endoscopy vs awake Müller's maneuver in the diagnosis of severe upper airway obstruction. Otolaryngol Head Neck Surg. 2013 Jan;148(1):151-6. doi: 10.1177/0194599812460505. 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 L, Strohl KP; STAR Trial Group. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014 Jan 9;370(2):139-49. doi: 10.1056/NEJMoa1308659. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet. 1981 Apr 18;1(8225):862-5. doi: 10.1016/s0140-6736(81)92140-1. Sutherland K, Vanderveken OM, Tsuda H, et al. Oral appliance treatment for obstructive sleep apnea: an update. J Clin Sleep Med. 2014 Feb 15;10(2):215-227. doi:10.5664/jcsm.3460. Tang JA, Salapatas AM, Bonzelaar LB, Friedman M. Long-Term Incidence of Velopharyngeal Insufficiency and Other Sequelae following Uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg. 2017 Apr;156(4):606-610. doi: 10.1177/0194599816 688646. Thaler E, Schwab R, Maurer J, Soose R, Larsen C, Stevens S, Stevens D, Boon M, Huntley C, Doghramji K, Waters T, Kominsky A, Steffen A, Kezirian E, Hofauer B, Sommer U, Withrow K, Strohl K, Heiser C. Results of the ADHERE upper airway stimulation registry and predictors of therapy efficacy. Laryngoscope. 2020 May;130(5):1333-1338. doi: 10.1002/lary.28286. Tregear S, Reston J, Schoelles K, Phillips B. Continuous positive airway pressure reduces risk of motor vehicle crash among drivers with obstructive sleep apnea: systematic review and meta-analysis. Sleep 2010;33(10):1373–1380. doi: 10.1093/sleep/33.10.1373. Tregear S, Reston J, Schoelles K, Phillips B. Obstructive sleep apnea and risk of motor vehicle crash: systematic review and meta-analysis. J Clin Sleep Med 2009;5(6):573–581. Vasu TS, Grewal R, Doghramji K. Obstructive sleep apnea syndrome and perioperative complications: a systematic review of the literature. J Clin Sleep Med 2012;8(2):199–207. doi: 10.5664/jcsm.1784. Woodson BT, Karakoc O. Expansion sphincter pharyngoplasty for obstructive sleep apnea. In: Yaremchuk Kathleen L, Wardrop PA, eds. Sleep Medicine. San Diego: Plural Publishing Inc, 2011:301–311. Woodson BT, Robinson S, Lim HJ. Transpalatal advancement pharyngoplasty outcomes compared with uvulopalatopharygoplasty. Otolaryngol Head Neck Surg 2005;133(2):211– 217. doi: 10.1016/j.otohns.2005.03.061. 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 Jul;159(1):194-202. doi: 10.1177/0194599818762383.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 19

PERI-OPERATIVE CONSIDERATIONS IN SLEEP SURGERY Brian W. Rotenberg, MD and Sarah Zahabi, MD Department of Otolaryngology – Head and Neck Surgery, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

SLEEP SURGERY FOR PATIENTS WITH OBSTRUCTIVE SLEEP APNEA 1. Obstructive sleep apnea (OSA): a. A disorder in which the upper airway collapses during sleep leading to disrupted sleep and oxygen desaturations b. Patients with OSA snore, experience apneic events and suffer from daytime fatigue c. Risk factors include male sex, obesity, age and smoking d. Linked to traffic accidents, hypertension, myocardial infarction, congestive heart failure, stroke and diabetes mellitus e. The first-line treatment for OSA is continuous positive airway pressure (CPAP) f. Candidates for upper airway surgery (UAS), with the goal of expanding the pharyngeal airway, fail or are non-compliant to CPAP g. Drug-induced sleep endoscopy can be used to assess the sites of upper airway collapse and assist in surgical treatment planning 2. Common options for UAS for OSA include: a. Isolated tonsillectomy b. Uvulopalatopharyngoplasty (UPPP) c. Uvulopalatal flap d. Expansion sphincteroplasty e. Transpalatal advancement pharyngoplasty f. Cautery assisted palate stiffening operation g. Tongue base modification procedures such as ablation or lingual tonsillectomy

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Brian W. Rotenber and Sarah Zahabi h. Recent data strongly suggests that hypoglossal nerve stimulation is also a useful procedure in select patients 3. Surgical intervention can improve OSA severity as determined by metrics including: a. The Epworth Sleepiness Scale (ESS) b. Sleep Apnea Quality of Life Index (SAQLI-E) c. Blood pressure d. Apnea-Hypopnea Index (AHI) 4. Patients with OSA undergoing UAS are considered at higher risk for peri-operative complications a. They require peri-operative care to prevent complications from comorbidities such as: i. Cardiovascular disease ii. Heart failure iii. Arrhythmias iv. Hypertension v. Stroke vi. Metabolic syndrome b. Complications from UAS include: i. An increased number of oxygen desaturation events ii. Difficult intubation iii. Atrial fibrillation iv. Increased mortality 5. In a patient undergoing UAS as a treatment modality for OSA, the following factors must be considered: a. The impact of anesthetic and analgesic medications on upper airway stability and ventilatory drive b. Sedative effects of opioid analgesics c. Cardiopulmonary effects of OSA d. Abnormal upper airway anatomy e. Edema following surgical manipulation

POST-OPERATIVE COMPLICATION IN SLEEP SURGERY 1. The post-operative complications associated with UAS are based on the anatomical area repaired in a multi-level surgery a. Palate surgery can cause respiratory distress, bleeding requiring surgery and readmission, reintubation, and tracheostomy b. Tonsillectomy can cause bleeding which may require surgery c. Tongue base surgery can lead to bleeding, edema and aspiration d. Epiglottis surgery can cause bleeding e. Upper airway stimulation can lead to hematoma formation, infection and temporary tongue weakness

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f.

Tracheostomy, although rarely performed for OSA, can be complicated by dislodgement of the cannula, pulmonary edema, peristomal infection and bleeding g. Other complications from UAS include velopharyngeal insufficiency and nasopharyngeal stenosis

PERI-OPERATIVE CPAP USE 1. Pre-operative setting a. It remains unclear whether there is a benefit to pre-operative positive airway pressure (PAP) use for patients with OSA undergoing UAS i. There is no established recommendation on optimal length of use preoperatively ii. The scarcity of the literature on this topic is likely related to PAP failure as an indication for sleep surgery for OSA b. Expert consensus recommends continued PAP therapy pre-operatively in patients who tolerate it and are compliant, as it may reduce the risk of postoperative airway complications c. PAP can be used to: i. Decrease airway edema ii. Increase lung functional residual capacity iii. Increase lung volume d. CPAP has also been reported to lower the risk of post-operative: i. Complications ii. Cardiac events iii. Intensive care unit (ICU) transfers e. Although evidence in the literature to support this is lacking, experts recommend trial of non-invasive positive pressure ventilation (NIPPV) in patients who do not respond to or do not tolerate CPAP 2. Post-operative setting a. Benefits of post-operative PAP use: i. Reduced respiratory compromise ii. Improved cardiorespiratory outcomes iii. Improved ventilatory function b. Unless contraindicated, CPAP or NIPPV (with or without supplemental oxygen) should be continued post-operatively in patients using these modalities in the pre-operative setting c. Patients having undergone UAS are able to better tolerate CPAP in the postoperative setting d. Short-term CPAP use for 3 months post-operatively may improve OSA severity outcomes in patients having undergone velopharyngeal surgery e. Contraindications to post-operative PAP use: i. Experts recommend against the use of PAP after maxillofacial surgery secondary to risk of facial subcutaneous emphysema and

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Brian W. Rotenber and Sarah Zahabi pneumocephalus, blowing air into the stomach and suffocation due to oral occlusion and lip edema ii. PAP use is also contraindicated after base of skull or endonasal orbital surgery, where air can be trapped in the brain or eye due to high pressures f. Experts recommend full-face mask PAP after nasal surgery if indicated g. The duration of time post-op after which PAP use can be resumed remains insufficiently studied to offer comment

POST-OPERATIVE MONITORING 1. This must be tailored to the individual patient taking into consideration the extent of surgery as well as the severity of underlying OSA and associated comorbidities 2. While there are theoretical risks of airway compromise or respiratory depression after UAS, the overall frequency of major complications after UAS for OSA in the early post-operative period is very low 3. Expert consensus has established weak recommendations based on low quality evidence for the post-operative patient which include the following: a. Avoid supine position b. Elevate the head of the bed c. Use of steroids and cooling tissue to reduce edema d. Use of oral appliance, positional therapy, or a nasal airway stent in patients who do not tolerate PAP e. Consider OSA severity in determining if overnight stay is indicated f. Consider tracheotomy in patients undergoing aggressive tongue base UAS, regardless of OSA severity g. No post-operative monitoring when nasal surgery is sole modality for UAS to treat OSA unless posterior nasal packs have been placed 4. Breathing monitoring: a. Use of pulse oximetry in addition to standard monitoring in the recovery ward is recommended b. Monitoring can also be done using: i. Clinical observation including respiratory rate ii. Capnography (end-tidal carbon dioxide monitoring) iii. Photoplethysmography iv. Respiratory volume monitors v. Thoracic breathing volume monitored by impedance electrodes c. Continuous pulse oximetry has been shown to be effective at monitoring hypoxemic events in the immediate post-operative period 5. Overnight stay versus same day monitoring: a. Recommendations vary depending on type and extent of procedure being performed for OSA b. The following procedures can be performed as day surgery:

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i. Nasal surgery ii. Minimally invasive surgery of the palate and/or base of tongue (small incisions or none to these areas) iii. Routine UPPP with or without tonsillectomy iv. Hypoglossal nerve stimulation c. The following procedures should require an overnight stay: i. Invasive lower pharyngeal surgery ii. Maxillofacial surgery d. Despite these recommendations, there remains to be some disagreement as multiple studies have demonstrated that UPPP surgery, for instance, can be safely done in the outpatient setting with minimal risk to the patient e. Careful evaluation of the following predictive risk factors should be done in order to determine if a patient is a candidate for day surgery without requiring an overnight stay for OSA: i. Comorbidities ii. Severity of OSA iii. Body mass index (BMI) iv. Minimum oxygen saturation f. Other factors to consider for admission: i. OSA severity is also a factor to consider when determining duration of inpatient stay as well as whether the patient is appropriate for routine care or requires a high-intensity unit, ICU or step-down unit stay ii. Elevated AHI iii. Cardiovascular comorbidities iv. Whether the patient will be undergoing major tongue base surgery 6. Prolonged post-operative monitoring: a. This is not recommended in patients undergoing hypoglossal nerve stimulation surgery b. It is recommended for maxillomandibular advancement surgery and invasive lower pharyngeal airway surgery 7. Events that nursing staff should monitor for: a. Bradypnea b. Apnea greater than or equal to 10 seconds c. Oxygen desaturations less than 90% despite being on nasal cannula oxygen d. Pain-sedation mismatch i. These findings increase the risk for post-operative complications and if noted in the immediate post-operative period, may warrant overnight or prolonged hospital stay ii. There is evidence to suggest that anesthetics, analgesics and surgery can disturb post-operative sleep architecture, increase AHI, and lead to breathing disturbances during sleep based on polysomnographic findings iii. These findings were most significant in the first 72 hours of the postoperative period 8. Reduction of edema can be accomplished using: a. Corticosteroids

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Brian W. Rotenber and Sarah Zahabi i. There remains debate on which specific surgeries require steroids ii. Pre-operative corticosteroid administration may also be of benefit in patients in whom this is deemed appropriate b. Elevation of head of bed to 30-60 degrees c. Cooling tissue d. Avoidance of the supine position in order to decrease frequency and severity of apneic or hypopneic events 9. Temporary tracheotomy: a. Considered in patients undergoing aggressive base of tongue surgery independent of OSA severity in order to prevent severe respiratory complications

PERI-OPERATIVE ANESTHETIC CONSIDERATIONS    

OSA diagnosis and severity are taken into account in the peri-operative setting because of the potential implications in maintaining a patent airway while under anesthetic This has consequences in terms of increasing risk of morbidity and mortality OSA is a consideration for post-operative analgesics A patient and their family should be informed of the consequences that this may have in the perioperative setting prior to consenting for surgery

Pre-Operative Considerations a.

Pre-operative evaluation of the patient should include assessment of risk factors associated with complications such as: i. High BMI ii. Male sex iii. Large neck circumference iv. OSA severity b. This information will be obtained through medical history assessment with the patient and/or family member, careful review of medical records and by completing a physical examination c. Note the following patient characteristics: i. Hypertension ii. History of stroke iii. History of myocardial infarction iv. Diabetes mellitus v. Abnormal cephalometic measurements d. Patient history questions should include: i. Snoring ii. Apneic episodes iii. Arousals during sleep iv. Morning headaches

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f.

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v. Daytime somnolence If the anesthesiologist and surgeon agree that the risk of OSA is high based on the above assessments, a joint decision should be made on whether to plan for pre-operative optimization of the patient using: i. CPAP ii. NIPPV iii. Use of mandibular advancement or oral appliances iv. Weight loss Patients’ characteristics used in order to determine if the patient is appropriate for surgery as an outpatient or requires overnight monitoring: i. Sleep apnea status ii. Anatomical and physiological abnormalities iii. Status of coexisting diseases iv. Extent of the surgery v. Implications of general anesthesia vi. Use of post-operative opioids for analgesia vii. Patient age viii. Post-discharge observation conditions unique to the patient ix. Elevated STOP-BANG questionnaire score (greater than 3)

Intra-Operative Considerations a.

Intra-operative recommendations in order to optimize UAS for a patient with OSA include: i. Avoiding sedative pre-medication ii. Minimizing or avoiding use of opioid agents iii. Initially giving opioids in a monitored setting, if required  Preferred use of non-opioid agents i. Planning for difficult intubation/airway management and difficult mask ventilation ii. Monitoring after extubation to decrease risk of airway compromise and pulmonary edema  Patients with OSA have increased likelihood of difficult airways and should be managed accordingly b. Intubation: i. If indicated, ramped up induction and intubation, and/or application of PAP or NIPPV during induction and rapid sequence induction can be considered by the anesthesiologist ii. General anesthesia with a secure airway is the preferred method of sedation c. Sedation: i. Experts recommend against the use of sedative premedication ii. Sedatives, opioids and inhaled anesthetics have respiratory depressant and airway effects that may lead to respiratory compromise in the postoperative period in patients with OSA

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Brian W. Rotenber and Sarah Zahabi iii. Anesthetic agents may impair hypoglossal nerve function and contribute to upper airway obstruction from the tongue iv. Sedatives can impact/cause:  Arousal response  Ventilatory response  Minute ventilation  Respiratory depression d. Extubation i. Awake extubation is recommended for patients undergoing UAS for OSA ii. Extubation should be performed once the patient is conscious and paralytic agents as well as inhalational agents are fully reversed and verified  Semi-upright, lateral or other non-supine positions are preferred in the immediate post-operative period iii. Emergency equipment such as an oropharyngeal airway tube, a nasopharyngeal airway tube and a tracheotomy kit should be prepared and easily accessible by personnel iv. The anesthesiologist may consider placing a nasopharyngeal tube after extubation or nasal PAP

Post-Operative Considerations a.

Post-operative analgesia i. For post-operative analgesia, see details in section entitled PostOperative Pain Management below b. Oxygenation i. Supplemental oxygen should be administered until patients are able to maintain their baseline oxygen saturation while breathing on room air ii. Continuous pulse oximetry monitoring is recommended iii. CPAP or NIPPV can be considered if not contraindicated especially in patients who have airway obstruction or hypoxemia post-operatively iv. It is recommended that patients who were prescribed CPAP or NIPPV pre-operatively bring their own machines to the hospital for use in the post-operative setting c. Patient positioning d. Optimal patient positioning in the post-operative setting is non-supine and semi-upright e. Post-operative monitoring i. For details regarding post-operative monitoring, see section entitled Post-Operative Monitoring above ii. Discharge to an unmonitored setting is appropriate when risk of respiratory depression is low. This can ideally be assessed and determined while observing the patient while asleep.

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Post-Operative Pain Management Intra-Operative Considerations a. Intra-operative dexmedetomidine infusion, ketamine or infiltration with local anesthetic such as lidocaine or bupivacaine may be considered for patients in order to assist with post-operative pain b. Sedative agents such as benzodiazepines and barbiturates should be avoided secondary to the increased risk of respiratory depression and airway obstruction Post-Operative Considerations i. Oral administration of opioid analgesics when indicated is preferred in order to decrease the risk of respiratory suppression associated with intramuscular or intravenous routes of administration ii. Systemic opioids should be minimized iii. Alternatives to opioids include nonsteroidal anti-inflammatory drugs such as Ketorolac, cyclooxygenase-2 inhibitors and intranasal butorphanol iv. Intravenous lidocaine, ice, transcutaneous electrical nerve stimulation and magnesium may be considered v. Total dose of narcotics including short-acting versus long-acting should be considered vi. Multi-modal pain control is preferred using the pharmacologic options listed above vii. Lower doses to start of narcotics are preferred in order to allow for titration of pain control while monitoring the patient’s respiratory status viii. Multi-level surgery is associated with higher levels of pain requiring increasing analgesia when compared single-level surgery ix. Post-operative sedation in the post-anesthesia care unit can provide comfort and decrease need for mechanical ventilation, length of stay in hospital and bleeding x. This can be achieved with dexmedetomidine

KEY CLINICAL POINTS 1. Patients undergoing pharyngeal expansion surgery for sleep apnea who are able to use CPAP should continue to use this in both the pre- and immediate post-op period. 2. For patients planned with an advanced sleep apnea procedure, or for those with perioperative co-morbidities, a pre-operative anesthetic consultation should be considered. 3. Routine post-operative monitoring of patients undergoing sleep surgery is not indicated unless they are deemed at higher risk of post-operative respiratory compromise. 4. Oral opioid medication is preferred over intra-muscular or intra-venous in order minimize respiratory depression.

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Brian W. Rotenber and Sarah Zahabi 5. Sleep surgery that does not involve the base of tongue can in many cases safely be performed as outpatient surgery for appropriately selected patients.

QUESTIONS 1. Use of CPAP in the pre-operative setting is recommended for patients with OSA undergoing UAS because of the following theoretical benefits, except one: a. Decrease in airway edema b. Increase in lung functional residual capacity c. Hypoxia in the post-operative setting d. Increase in lung volume 2. The recommended route of anesthesia for a patient with OSA undergoing UAS is: a. Regional anesthesia b. Local anesthesia c. General anesthesia d. Sedation 3. If indicated, the following is the preferred route of administration of opioids in the peri-operative setting in a patient with OSA undergoing UAS: a. Oral b. Intravenous c. Subcutaneous d. Intramuscular 4. Intra-operative anesthetic considerations in a patient with OSA undergoing UAS include all of the following, except: a. Avoiding sedative pre-medication b. Minimizing use of opioids c. Planning for difficult intubation d. Prior surgeries 5. In which of the following scenarios does the patient require overnight monitoring postoperatively after having undergone UAS for OSA: a. Patient with severe sleep apnea, multiple comorbidities including prior cardiac events and multiple witnessed desaturation events requiring CPAP in the post-operative setting b. Patient undergoing UPPP who is otherwise healthy and has mild OSA c. Patient undergoing nasal surgery to facilitate CPAP use d. Patient who is breathing comfortably on room air without any significant desaturation events in the recovery room

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Brian W. Rotenber and Sarah Zahabi Koutsourelakis I, Safiruddin F, Ravesloot M, Zakynthinos S, de Vries N. Surgery for obstructive sleep apnea: Sleep endoscopy determinants of outcome. Laryngoscope. 2012;122: 2587-2591. doi: 10.1002/lary.23462. Meoli A L, Rosen C L, Kristo D, Kohrman M, Gooneratne N, Aguillard R N, Fayle R, Troell R, Kramer R, Casey K R, Coleman J Jr; Clinical Practice Review Committee; American Academy of Sleep Medicine. Upper airway management of the adult patient with obstructive sleep apnea in the perioperative period--avoiding complications. Sleep. 2003 Dec 15;26(8):1060-5. doi: 10.1093/sleep/26.8.1060. Nagappa M, Mokhlesi B, Wong J, Wong D T, Kaw R, Chung F. The effects of continuous positive airway pressure on postoperative outcomes in obstructive sleep apnea patients undergoing surgery: a systematic review and meta-analysis. Anesth. Analg. 2015;120(5): 1013-1023. doi: 10.1213/ANE.0000000000000634. 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 Preparation of Patients with Sleep-Disordered Breathing. Anesth. Analg. 2016 May;122(5):1321-34. doi: 10.1213/ANE.0000000000001178. Porhomayon J, Nader N D, Leissner K B, El-Solh A A. Respiratory perioperative management of patients with obstructive sleep apnea. J. Intensive Care Med. 2014 May-Jun;29(3):145-53. doi: 10.1177/0885066612446411. 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;120:268–286. Rafferty T D, Ruskis A, Sasaki C, Gee JB. Perioperative considerations in the management of tracheotomy for the obstructive sleep apnoea patient: three illustrative case reports. Br. J. Anaesth. 1980;52(6):619-622. doi: 10.1093/ bja/52.6.619. Ravesloot M J L, de Raaff C A L, van de Beek M J, Benoist L B L, Beyers J, Corso R M, Edenharter G, den Haan C, Heydari Azad J, Ho J T F, Hofauer B, Kezirian E J, van Maanen J P, Maes S, Mulier J P, Randerath W, Vanderveken O M, Verbraecken J, Vonk P E, Weaver E M, de Vries N. Perioperative Care of Patients With Obstructive Sleep Apnea Undergoing Upper Airway Surgery: A Review and Consensus Recommendations. JAMA Otolaryngol. Head Neck Surg. 2019 Jun 27. doi: 10.1001/jamaoto.2019.1448. Rotenberg B W, Theriault J, Gottesman S. Redefining the timing of surgery for obstructive sleep apnea in anatomically favorable patients. Laryngoscope. 2014 Sep;124 Suppl 4:S1-9. doi: 10.1002/lary.24720. Rotenberg, B. Obstructive Sleep Apnea. In: K. J. Lee. Essential Otolaryngology, Eleventh Edition. New York: McGraw-Hill Education, 2015. Seet E, Chua M, Liaw C M. High STOP-BANG questionnaire scores predict intraoperative and early postoperative adverse events. Singapore Med. J. 2015 Apr;56(4):212-6. doi: 10.11622/smedj.2015034. Spence D L, Han T, McGuire J, Couture D. Obstructive Sleep Apnea and the Adult Perioperative Patient. J. Perianesth. Nurs. 2015 Dec;30(6):528-545. doi: 10.1016/ j.jopan. 2014.07.014.

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 20

THE NOSE AND SLEEP APNEA Amrita Ray, MD and Ashutosh Kacker, MD Department of Otolaryngology, Weill Cornell Medical College, New York, NY, USA

INTRODUCTION 1. Understanding the nasal contribution to obstructive sleep apnea (OSA) requires an understanding of both static and dynamic contributors to nasal physiology 2. Evaluation and treatment of nasal obstruction should be part of a multi-level, multimodality approach for OSA treatment a. Treatment should be performed in a graduated manner, and may include medical and surgical options 3. Minute improvements in nasal obstruction can have dramatic improvements in nasal airflow, resistance and nasal collapse a. These are related to Poiseuille’s law and Bernoulli’s equation 4. Although nasal surgery does not directly improve apnea-hypopnea index (AHI), it provides significant benefits including subjective improvement in symptoms, as well as improved adherence to continuous positive airway pressure (CPAP) 5. Nasal surgery can involve any combination of nasal subsites including the internal or external nasal valve, septum, turbinates, and sinuses

CLINICAL HISTORY AND PRESENTATION OF OSA 1. General principles a. The discussion regarding the role of nasal function and sleep disordered breathing (SDB) has existed since noted by Walter Wells in 1898 b. Symptomatic OSA may be prevalent in up to 2% of women and 4% of men over 50 years old c. Concurrent sleep disorders may be present in over 30% of patients

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Amrita Ray and Ashutosh Kacker d. Consider screening at time of initial OSA diagnosis or in patients with persistent disease despite medical or surgical treatment e. Consider the physics of airflow i. Bernoulli’s principle, at constant depth/height  P1+½ρv12=P2+½ρv22  P1: Pressure at point 1 i.e., external nose | P2: Pressure at point 2 i.e., internal nose | ρ: density | v1: velocity of airflow at point 2 | v2: velocity of airflow at point 2  Flow is fastest in the narrowest site of the nasal cavity faster airflow has reduced pressure on the surrounding structures and thus causes a collapsing effect of the nasal airway ii. Poiseuille equation

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R = resistance | n = substance viscosity | l = length | π = pi | r = radius  Airway resistance is inversely proportional to radius, by a power of 4  i.e., doubling radius causes a 16-fold decrease in airflow resistance  Minute, millimeter changes in airway diameter have significant impact on nasal airflow iii. Thus, reduction of any nasal obstruction not only increases amount of airflow in, but also reduces air velocity and degree of collapse 2. Clinical History and Symptoms a. Full evaluation should include detailed sleep history, daytime and nighttime symptoms, comorbidities, and role of nasal obstruction in symptomology and treatment b. Sleep history i. Sleep hygiene ii. Medication use or substance abuse iii. Inefficient or insufficient sleep iv. Circadian disorders: advanced or delayed sleep, jet lag, or shift work sleep disorder c. Consider OSA screening and quality of life (QOL) questionnaires i. OSA Screening: STOP BANG, OSA50, Berlin questionnaire ii. Daytime Sleepiness: Epworth sleepiness scale (ESS), Stanford Sleepiness Scale iii. Sleep quality: Pittsburgh Sleep Quality Index (PSQI) d. Daytime symptoms i. Morning headache due to nocturnal CO2 retention ii. Daytime fatigue or somnolence iii. Unrefreshing sleep despite adequate sleep time iv. Neurocognitive dysfunction or labile mood

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v. Women are more likely to report atypical symptoms of OSA including heart palpitations, insomnia, and ankle edema e. Nighttime symptoms i. Poor quality sleep ii. Witnessed gasping, choking or apneic episodes iii. Frequent nocturnal awakenings and/or nocturia iv. Parasomnias v. Snoring  Most often the presenting symptom, and the most common symptom of OSA  Occurs in at least 40% of men and 20% of women  However, it is not pathological in and of itself  All patients with OSA will snore, although not all snoring patients have OSA  No straightforward association or predictor of OSA  Significant source of social and psychological distress to patient and/or bed partner  Procedures to improve nasal obstruction also demonstrate subjective improvement in snoring  New emerging evidence that carotid artery stenosis and strokes may be secondary to the physical vibrations of snoring f. Comorbid conditions i. Obesity ii. Hypertension iii. Cardiovascular disease iv. Cerebrovascular disease v. Sleep disorders including insomnia, narcolepsy vi. Mood disorders vii. Hypothyroidism g. Nasal/nasopharyngeal obstruction or congestion i. The association of nasal obstruction, snoring, and poor sleep quality is widely accepted  Nasal obstruction may increase airway resistance, leading to mouth breathing and increased upper airway collapsibility, ultimately worsening OSA  Prevalence of nasal obstruction is unknown. However, it is rarely the sole cause of OSA. ii. Identify any disparity between subjective complaints of nasal obstruction and objective findings/OSA severity  Patients may have significant nasal obstruction due to mucosal edema or a septal deviation, but have negligible symptoms  Empty nose syndrome-a controversial diagnosis. Patients perceive paradoxical symptoms of nasal obstruction despite widely open nasal passages. Often attributed to extensive turbinate resection.

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Consider nasal quality of life and symptomology questionnaires  Sinonasal Outcomes Test 22 (SNOT22): validated questionnaire, evaluates sinonasal symptoms and QOL measures  Nasal Obstruction Symptom Evaluation Survey (NOSE): validated, disease specific instrument for objective measurement of nasal obstruction symptoms Patients already on CPAP for OSA often complain of intolerance due to nasal obstruction  Treating the nasal airway allows for decreased CPAP pressure and improved tolerance, but is rarely curative of OSA History is important in understanding the static and/or dynamic nature of nasal obstruction  Laterality  Symptom severity, frequency and duration  History of sinus disease  Exacerbating factors  History of smoking, alcohol or drug use (particularly cocaine)  Prior treatments or surgeries, and outcomes Static components of nasal resistance  See Nasal Exam section below Dynamic components of nasal resistance  Temperature – warm air can open the airway  Exertional status near time of testing – hyperventilation can enlarge the airway  Use of topical decongestant medications  Nasal cycle – a cyclic vascular engorgement of erectile tissue in the inferior and middle turbinate that occurs every 2-4 hours  Engorgement of tissue can affect nasal airway cross section, particularly if there are inherent anatomic obstructions  Can be enhanced in dependent positions  Occurs 24/7 Stage of sleep  Each stage of sleep has varying levels of tonal input and degree of muscular collapse, impacting nasal resistance and airflow.  Evidence suggests that nasal congestion is highest during REM sleep Positioning and Route of breathing  Dependent positions, in general, increase nasal resistance  The lateral recumbent position can compound the effect of the nasal cycle on the ipsilateral nasal passage, significantly increasing nasal resistance

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Nasal vs. oral breathing  Nasal breathing is the preferred route  If impaired due to nasal obstruction or increased work of breathing, patients may transition to oral breathing  Dry mouth is often a primary complaint  Oral breathing may cause increased upper airway resistance and instability in sleep and respiration  Oral breathing narrows the pharyngeal lumen secondary to decreased muscular tone and a posteriorly displacement mandible and tongue

NASAL EVALUATION AND TESTING 1. General principles a. The three major areas of obstruction are: i. Nasal cavity/nasopharynx: septal deviation, turbinate hypertrophy, nasal valve collapse, nasal polyps, adenoid tissue ii. Oral cavity/Oropharyx: elongated palate or uvula, tonsillar hypertrophy, retrognathia- velopharynx is the most common location of collapse iii. Hypopharyx: laryngotracheomalacia or stenosis, omega shaped epiglottis b. For comprehensive evaluation discussion, see chapter on Diagnosis and Assessment of Adult OSA c. Associated exam findings in the OSA patient: i. Overall obesity, large body habitus iv. Palatine and/or lingual tonsil hypertrophy v. Enlarged or elongated uvula, or elongated soft palate vi. Macroglossia or posterior tongue positioning vii. Tongue base collapse viii. Retrognathia (Angle classification II) or micrognathia ix. Submental lipomatosis x. Narrow oropharynx due to medialized lateral pharyngeal walls xi. Increased neck circumference (≥ 17 inches males; ≥ 15.5 inches females) 2. Nasal exam a. Direct visualization can help to understand the contribution of fixed anatomic variants including bony/cartilaginous deformations or soft tissue changes i. Instrumentation in the nose can cause some level of distortion that may not be naturally present ii. Anterior rhinoscopy and nasopharyngoscopy may not be representative of the issues present during true sleep as they are done on an awake, upright patient

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Consider the impact of patient alertness, head and body position, changes in neuromuscular tone, and respiratory drive on dynamic compressibility

b. External nose: i. Note any obvious deformities, narrowing or trauma of nasal vestibule ii. Identify external nasal valve/nasal vestibule collapse  Comprised of:  Columella  Paired Lower Lateral Cartilages (LLC)  Nasal sill  Consider the tone of the alar muscles and stabilization by bone and cartilage  Some degree of collapse of lateral nasal wall or alar rim on strong inspiration is expected  Cottle maneuver and modified cottle maneuver  Cottle- pull laterally at nose to see if breathing improves  Modified Cottle- instrument in nose to see if breathing improves c. Internal nose i. Evaluate with Anterior Rhinoscopy and/or Fiberoptic Nasopharyngoscopy  Evaluate the nasal cavity before and after decongestion  Identity site of obstruction: often there is multilevel obstruction  Consider supine flexible laryngoscopy with Muller’s maneuver: measures degree of retropalatal and retrolingual collapse on attempted inspiration with nose and mouth closure. While it can guide surgical decision making, it is not useful in patients with multilevel obstruction.  Identify inferior turbinate hypertrophy or edema in the setting of vascular engorgement  Note anatomic obstructions including septal deviation, polyps, masses  Evaluate for sinus disease, mucopurulence or rhinorrhea  Evaluate for nasopharyngeal obstruction by adenoid tissue iii. Identify internal nasal valve collapse  Area of nose with the smallest cross-sectional area for airflow and responsible for 1/2 to 2/3 of nasal resistance  Compromised of:  Head of Inferior turbinate  Septum  Lower edge of Upper Lateral Cartilages (ULC)

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d. Drug-Induced Sleep Endoscopy (DISE) i. Helps understand dynamic anatomic changes in upper airway subsites during sleep including location and severity of airway obstruction ii. However, it does not provide a thorough picture of how different stages of sleep or changes in ventilatory drive affect the upper airway iii. Standardized reporting of DISE findings include the VOTE method: commenting on Velum, Oropharynx, Tongue base, Epiglottis iv. Usually done in the operating room with propofol or midazolam, but it has been suggested that dexmedetomidine be used as primary sedative due to less cardiovascular instability and respiratory depression, mimicking natural sleep better v. Consider DISE if clinical findings don’t match polysomnogram (PSG), prior to major surgery, if patient has failed primary surgery, or to evaluate for the hypoglossal nerve stimulator implant 3. Objective measures of nasal function a. Consider objective testing of nasal obstruction, particularly if there is a discrepancy between subjective symptoms and objective exam findings i. Consider that the reproducibility of objective measurements may be affected by any of the dynamic components noted above b. Polysomnogram (PSG) i. Gold standard to assess for OSA, as well as track response to therapy  Full night, 7 channel, in lab diagnostic study yields most accurate information (Type 1 sleep study) ii. Titration study is used to identify pressures needed to overcome upper airway resistance iii. Additionally, PSG does not identify the site(s) of airway obstruction c. Lateral cephalometric analysis i. 2-dimensional representation of airway with measurements of bony and soft tissue landmarks via x-ray imaging  Common findings in OSA patients include shortened anterior cranial base, inferior hyoid displacement, retrognathia, narrowed posterior airway space and longer soft palate ii. Despite broad availability and relatively low cost, this should not be solely used to diagnose OSA d. Maxillofacial computerized tomography (CT) scan or Magnetic Resonance Imaging (MRI) i. Can evaluate for any underlying sinus pathology that may be contributing to nasal obstruction ii. CT provides an excellent global view of sinus and nasal anatomy and dimensions of the nasal airway  Newer research applications incorporate algorithms of fluid dynamics on CT imaging to predict airflow patterns iii. MRI provides soft tissue detail, particularly if there is concern for pathology that extends beyond the nasal cavity or sinuses

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It is not useful in distinguishing between OSA and non-OSA patients  MRI avoids radiation exposure, but can be more expensive, difficult to tolerate, and is not as widely available Rhinomanometry i. Measures transnasal airflow and pressure over the course of respiration  Used to calculate nasal resistance = pressure/flow ii. Tests each side of the nasal airway independently. Can be done to evaluate effects of dilators and/or decongestants. Acoustic Rhinometry i. Uses soundwaves to measure cross-sectional area of the nasal airway ii. Variations in reflected sound are used to identify the site of maximal narrowing iii. Tests each side of the nasal airway independently. Can be done to evaluate effects of decongestants. iv. Patient must hold their breath and avoid swallowing during testing to avoid distorting test results v. Rapid test, requires minimal cooperation, and can be done on children

TREATMENT 1. Treatment principles a. OSA is a multi-level, multifactorial problem with significant morbidity b. Many treatment options exist; a multi-modality approach should consider conservative measures before more aggressive surgical options. c. Appropriate treatment should include weight loss and follow up sleep testing to gauge efficacy d. Considerations for surgical treatment should include i. The failure of more conservative measures ii. CPAP intolerance iii. Severity of symptoms or disease iv. Patient comorbidities v. Site and severity of upper airway collapse vi. Patient wishes e. Surgical intervention often needs to address multiple levels of airway obstruction, and is often a multistage procedure i. Given associated comorbidities, it is important to obtain a comprehensive medical exam and clearance prior to surgery 2. Non-surgical management a. Behavioral modifications i. Global weight loss can significantly reduce AHI ii. Avoid alcohol and sedative medications that reduce respiratory drive iii. Improve sleep hygiene and positioning

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b. Continuous Positive Airway Pressure (CPAP) i. Gold standard ii. See chapter 16 for further details iii. Applied via nasal or oronasal route iv. Recommended therapy, defined by American Academy of Sleep Medicine, is 4 hours/night, 5 nights/week v.  50% CPAP noncompliance  Severity of symptoms is correlated with compliance, not AHI  Noncompliance and effectiveness are often limited by:  Cost or convenience  Claustrophobia o Consider nasal routing for those with claustrophobia or if unable to tolerate facial masks  Nasal irritation: dryness or rhinorrhea o Consider adding heated humidification to minimize irritation  Excessive nasal pressure o Often manifests as symptoms of nasal congestion or obstruction o High titration pressure is often needed to bypass structural nasal obstructions o Reducing upper airway obstruction can reduce pressure requirements and improve CPAP compliance vi. If medical management is insufficient, consider surgical procedures to address structural obstructions such as septal deviation, turbinate hypertrophy- see “Surgical Management section below” c. Oral appliance i. See chapter 17 for further details ii. Helps hold the mandible in protrusion to prevent pharyngeal soft tissue from collapsing into airway iii. Recommended either as adjuvant therapy to improve CPAP tolerance and compliance, or as second line treatment for patients with mild-tomoderate OSA who do not tolerate CPAP iv. Efficacy with oral appliances improve when nasal obstruction is reduced v. Common complaints are mainly related to the temporomandibular joint (tooth and jaw muscle pain, difficulty chewing in the morning) and excessive salivation vi. Although CPAP is technically more effective in reducing AHI, oral appliances show similar improvements in health outcomes, likely due to increased comfort and higher rates of compliance

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Amrita Ray and Ashutosh Kacker d. Addressing internal nasal obstruction i. Intranasal steroids  Medications include fluticasone, mometazone, budesonide, triamcinolone, dexamethasone  When used alone, intranasal steroids are not found to affect AHI, but may improve sleep quality parameters  Additionally, they appear to reduce AHI particularly when used in combination with nasal decongestants, or in patients with co-existent rhinitis  Intranasal steroids are not recommended as a single intervention for treatment of adult OSA ii. Decongestants  Medications include oxymetazoline, phenylephrine, pseudoephedrine  Can result in significant AHI reduction, but not curative as sole treatment  Avoid long term use to prevent rhinitis medicamentosa/ rebound congestion  Rhinitis medicamentosa- rebound congestion due to overuse of intranasal vasoconstrictions, particularly oxymetazoline or phenylephrine  Avoid use of medications for greater than 5 days  Decongestants can also be contraindicated in patients with certain medical conditions including hypertension, diabetes, glaucoma, heart or thyroid problems e. Addressing external nasal obstruction/nasal valve collapse i. Products include external nasal dilator strips (Figure 1), nasal stents/cones, nasal clips, and septal stimulators (Figure 2)

Figure 1. Nasal dilator.

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Externally, nasal dilators strips use adhesive to bridge open the nasal valve, increasing nasal cross-sectional area and decreasing airway resistance  Internally, nasal stents/cones and nasal clips help stent open the internal nasal valve  Septal stimulators apply low continuous pressure to the nerves on nasal septum, reducing secretory production and mucosal swelling ii. These are easily accessible (over the counter), low-cost alternatives for manually addressing nasal valve collapse iii. In non-OSA patients, dilators have been shown to significantly reduce snoring, mouth breathing and sleepiness iv. In OSA patients, there is limited evidence to support recommendation  Consider trial of external dilators and nasal clips prior to surgical intervention  Combination with nasal dilator strips and decongestant (oxymetazoline) was found to reduce mouth breathing and OSA severity 3. Surgical management a. Surgical goal is to address the various sites of obstruction (multilevel surgery) i. Correction of obstructed nasal airway should be included in the treatment plan for sleep disordered breathing  Available data suggests that nasal surgery alone is usually ineffective at reducing AHI  Instead, nasal surgery works best as a part of targeted multilevel therapy  There is improved success in patients who can be converted to nasal breathing postoperatively b. Tracheostomy is definitive treatment, as it bypasses all upper airway sites of obstruction i. Consider for life threatening OSA, developmentally challenged patients, or patients who have failed all other OSA treatments ii. Rarely a desirable option given perceived inconvenience and morbidity c. Morbidly obese patients may benefit from bariatric surgery to induce significant weight loss i. Recent evidence reveals that surgically induced weight loss significantly improves obesity-related OSA and parameters of sleep quality d. Tonsil & Palate surgery e. Tongue base & hypopharyngeal surgery f. Orthognathic surgery g. Nasal and nasopharyngeal surgery i. The nose is NOT a collapsible segment, thus alterations do not reduce AHI

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Amrita Ray and Ashutosh Kacker ii. Isolated nasal surgery is not recommended as a sole intervention for OSA  However, it may be considered an initial step to facilitate CPAP adherence iii. Isolated nasal and sinus surgery to decrease nasal resistance has been shown to:  Reduce extent and sites of multilevel obstruction  Improve tolerance to CPAP and reduce pressure requirements  Improve subjective sleep parameters: sleep quality, daytime sleepiness/ESS, and decrease snoring  May restore physiologic nasal breathing iv. Advantages  Nasal surgeries are relatively simple procedures with easier recovery  May potentially be done as in-office procedures  Include some of the best surgical methods to improve CPAP compliance v. Risks and Disadvantages  Only addresses one site of airway obstruction  Surgery has associated risks of undergoing anesthesia, bleeding, need for revision surgery and/or other complications as listed below vi. Nasal valve surgery  May result in a cosmetic change, depending on the procedure  Open or closed/endonasal approach may be utilized, depending on goals and extent of surgery  External valve collapse  Complaints of narrow, pinched nostril or lateral nasal wall collapse on inspiration  Alar batten graft (Figure 2) o Can be used for internal and external nasal valve collapse o Helps support weak or deficient lower lateral cartilages o Grafts are placed at the junction of the upper and lower lateral cartilages, extending to over the pyriform aperture  Lower lateral crural strut graft (Figure 3) o Straight, strong long piece of cartilage placed under LLC to augment and straighten LLC

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Figure 2. Alar batten graft.

Figure 3. Lower lateral crural strut graft.

Figure 4. Latera.

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Figure 5. Spreader graft.

Figure 6. Butterfly graft.

LATERA® (Figure 4) o In office procedure- dissolvable implant injected over LLC, ULC and nasal bone to reinforce lateral nasal wall o Provides direct cantilever support, but also initiates fibrosis and long-term support as the stent dissolves Internal valve collapse:  Alar batten grafts- see above  Spreader grafts (Figure 5) o Cartilage graft placed between dorsal septum and ULC o Helps also prevent nasal vault collapse  Spreader Flaps o Functions similar to spreader grafts, but rolls the medial attachment of the ULC onto the septum to create space

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Butterfly graft (Figure 6) o Uses auricular cartilage to graft open the apex of the INV by stenting open and widening the angle between the septum and ULC vii. Deviated septum  Septoplasty  Can be done open vs. endoscopic  Goal is to improve nasal area and reduce resistance for improved tolerance of CPAP  Complications:  Bleeding  Septal perforation  Septal hematoma  Adhesions  Infection or prolonged healing  Anosmia/hyposmia  Cerebrospinal fluid leak  Teeth anesthesia due to injury to nasopalatine nerve  Cosmetic deformity including saddle nose or tip ptosis viii. Turbinate Surgery  Inferior turbinate reduction  Several treatment methods exist including radiofrequency ablation, laser cautery, ultrasound reduction, partial or total turbinectomy, electrocautery, cryotherapy, and submucosal resection  Submucosal resection (with lateral displacement) appears to provide greatest long-term improvement in nasal obstruction  (Submucosal) Microdebrider assisted turbinoplasty is mucosal preserving and has widespread familiarity  No consensus as to which surgical technique is most effective in decreasing nasal obstruction  Address abnormal middle turbinate anatomy  Paradoxical middle turbinate  Concha bullosa  Complications  Bleeding  Atrophic rhinitis/Empty nose syndrome ix. Sinonasal disease  Nasal masses- depending on the nature, these may require further workup, biopsy, and/or removal  For chronic rhinosinusitis (CRS) pathology, address disease in nasal cavities and adjacent sinuses with functional endoscopic sinus surgery

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Although endoscopic sinus surgery improves subjective sleep quality and CRS-specific QOL, it does not improve objective sleep measures Complications:  Bleeding  Intraorbital injury  Intracranial injury including cerebrospinal fluid leak  Need for revision surgery

QUESTIONS 1. Improving nasal obstruction may cause a reduction in: a. Patient discomfort b. AHI c. Oxygen saturation d. All of the above 2. The site of greatest nasal resistance for airflow is: a. Internal nasal valve b. External nasal valve c. Lateral nasal valve d. Upper lateral cartilage 3. Curative surgery for OSA includes a. Uvulopalatoplasty b. Septoplasty and turbinate reduction c. Tracheostomy d. Maxillomandibular advancement e. All of the above 4. Isolated nasal and sinus surgery to decrease nasal resistance has been shown to do all except: a. Restore physiologic nasal breathing b. Improve subjective sleep parameters c. Improve tolerate to CPAP d. Reduce CPAP pressure requirements e. Reduce AHI f. Reduce extent and sites of multilevel obstruction 5. The most common site of collapse is: a. Nasal cavity b. Velopharynx c. Retrolingual d. Hypopharyx

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 21

TONSILLECTOMY AND PALATAL SURGERY FOR OSA B. Tucker Woodson1, MD and Erin Harvey2, MD 1

Division of Sleep Medicine and Surgery, Department of Otolaryngology and Human Communication, Medical College Wisconsin, Milwaukee, WI, USA 2 Department of Otolaryngology and Human Communication, Medical College Wisconsin, Milwaukee, WI, USA

ANATOMY AND PHYSIOLOGY OF THE PALATE 1. Anatomy of the Hard Palate a. Anterior 2/3 of palate i. Bony components: Palatine process of mandible anteriorly, horizontal plate of the palatine bones posteriorly ii. Stratified squamous epithelium attached to bone b. Foramina i. Incisive foramen: Lies midline, contains nasopalatine nerve, a branch of the sphenopalatine artery ii. Greater palatine foramina: 1 cm medial to second molar, greater palatine nerve and descending palatine artery (a.) and vein (v.) iii. Foramen is junction of maxillary alveolar, maxillary palatine process, and palatine bones iv. Lesser palatine foramina: Posterior to greater palatine foramen, contains the lesser palatine nerve (n.) and a. c. Sensory Innervation i. Nasopalatine and greater palatine nerves, cranial nerve (CN) V2 d. Vascular Supply i. Arterial: Maxillary artery  descending palatine a.  greater palatine a. ii. Venous: Hard palate veins  pterygoid plexus  internal jugular v

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Lymphatic: i. Upper cervical lymphatics, retropharyngeal 2. Anatomy of the Soft Palate a. Muscles i. Palatoglossus (anterior pillar): Narrows the oropharyngeal opening, involved in swallowing ii. Palatopharyngeus (posterior pillar): Raises the larynx & pharynx, closing oropharyngeal aperture iii. Palatopharyngeus (posterior pillar): With stable larynx increases lateral pharyngeal wall tension and opens nasopharynx iv. Musculus uvulae: Shortens the uvula v. Levator veli palatini: Raises the soft palate to contact posterior pharyngeal wall vi. Tensor veli palatini (CN-V2): It is controversial if any soft palate muscular action pulling laterally due to fixed attachment to hamulus, contracts the eustachian tube b. Sensory Innervation i. Glossopharyngeal n. CNIX and lesser palatine n. (CN-V2) ii. Obstructive sleep apnea (OSA) is associated with decreased pharyngeal sensation iii. OSA is also associated with a higher percentage of pharyngeal paresthesia c. Vascular supply i. Arterial  Maxillary a.  descending palatine a.  lesser palatine a.  Facial a.  ascending palatine a. ii. Venous  Soft palate veins  pharyngeal plexus  internal jugular vein (IJV)  Soft palate veins  external palatine vein  tonsillar fossa  facial vein d. Lymphatic i. Deep cervical lymph nodes e. Soft palate segments i. Aponeurotic: Tensor aponeurosis abuts nasopharyngeal mucosa, no muscular layer, ventral fibroadipose layer ii. Muscular: Middle 50% defined by tensor levator palatini muscle (m.) iii. Velar: Lower 1/3 below tensor levator palatini m. 3. Pharyngeal Tonsil Arterial Supply a. Facial a.  tonsillar branch  tonsil (main) b. Facial a.  ascending palatine c. Lingual  dorsal lingual d. Ascending pharyngeal e. Maxillary  descending palatine  lesser palatine

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PHYSICAL EXAMINATION OF PATIENT AND OROPHARYNX 1. Tonsil size and position a. Brodsky scale 0-4 i. 0: Absent ii. 1+: Within fossa iii. 2+: Outside fossa less 50% iv. 3+: Greater than 50% v. 4+: > 75% Touching tonsils b. Position and size of superior pole within soft palate often defines the “choke point” of the retropalatal segment 2. Soft palate thickness and position a. Consideration of submucous cleft, bifid uvula, aberrant carotid artery 3. Uvular size, wrinkles, thickness, and position a. “Telescoping” is associated with severe OSA 4. Medialized lateral pharyngeal walls 5. Assessment of the Friedman staging Table 1. Friedman staging

Stage I Stage II Stage III

Palate Position

Tonsil Size

BMI

1 2 1,2 3,4 3 4

3,4 3,4 0,1,2 3,4 0,1,2 0,1,2

< 40 < 40 < 40 < 40 All All

All

All

> 40

UPPP Success Rate 80% 40% < 10%

Adapted from Friedman 2002.

a.

0= No tonsil; 1= Small, lateral to pillars; 2= Extend to edge of tonsil pillars; 3= Extend beyond tonsil pillars; 4= Hypertrophic and midline contact b. Friedman tongue position scale: I = Posterior pharyngeal wall visible, tonsils, pillars and entire uvula; II = Uvula visible without tonsils and pillars; III= Soft palate visible and base of uvula; IV= Only hard palate visible c. Modified Friedman tongue position scale: 1= Tonsils, pillars and entire uvula visible; IIa = Uvula visible without tonsils or pillars; IIb = Base of uvula and most of soft palate visible without tonsils and pillars; III = Some of soft palate visible without base of uvula; IV=Only hard palate visible d. Overall Friedman staging includes the chart below, along with associated uvulopalatopharyngoplasty (UPPP) outcomes 6. Müeller maneuver: Inspiratory effort against a closed nostril a. Independently score the upper and lower airway segments based on obstruction i. 1+ 0-25%

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7.

8.

9. 10. 11.

ii. 2+ 25-50% iii. 3+ 50-75% iv. 4+ > 75% b. Studies quantifying results associate with UPPP outcomes but it is controversial if they are predictive of UPPP outcomes c. May provide important insight on the collapsibility of lateral pharyngeal walls Fujita classification for obstruction a. Isolated oropharyngeal (I) b. Oropharynx and hypopharynx (II) c. Isolated hypopharyngeal (III) Lateral cephalography: Only the distance from mandibular plane to hyoid (MPH) is shown in systematic review to be strongly associated with surgical outcomes a. SNA (sella, nasion, subspinale) normal > 83 (+/- 2) degrees b. SNB (sella, nasion, supramentale) normal > 80 (+/- 2) degrees c. MPH (mandibular plane (Go to Gn) to hyoid distance) normal < 21 mm, with longer distance indicating longer soft tissue pharyngeal airway and has been the only cephalometric X-ray measure associated with poorer UPPP outcomes Nasopharyngoscopy Drug Induced Sleep Endoscopy (DISE) Polysomnogram (PSG)

SURGICAL OPTIONS FOR TONSIL AND PALATAL OBSTRUCTION IN OSA 1. Considerations a. Airway obstruction in OSA is a consequence of vulnerable structure and loss of muscle tone during sleep, and outcomes depend on control of compensatory muscle tone b. The structure of the retropalatal airway and velopharynx is most vulnerable to obstruction during sleep due to smallest cross-sectional area and highest tissue compliance with up to 80% having palate obstruction i. This includes multilevel obstruction c. Oral airway resistance is higher in patients with OSA when awake, specifically when supine i. Smallest cross-sectional area, high compliance of palate and lateral walls, 90 degree change in conduit flow from nose to larynx d. There is variable correlation between pharyngeal cross-sectional areas/volumes and severity of OSA with hypotonic showing better correlation than awake e. Tonsil size and lower percentage of time with oxygen saturation < 90% have been shown as possible predictors for palatal surgery responders f. Patients with OSA are known to have higher total pharyngeal paraesthesia scores, compared to control, indicating irritated throats

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g. Recent metanalysis indicated that there was no significant effect of surgical treatments for snoring or OSA on glottic function and nasalance 2. Surgical procedures  Technical differences poorly defined  Some consider all to be UPPP (CPT 45145) a. Isolated tonsillectomy i. 10 - 12% of adult population has Friedman grade 3 or 4 tonsils ii. Potential high success rate in select subgroup  Adults with large/very large tonsils  Mild-moderate OSA (apnea-hypopnea index (AHI) < 30 events/hour)  Uncertain confounding variables b. UPPP (± Tonsillectomy) i. Initially presented as a surgical approach to OSA in 1981 by Fujita ii. Historical effect, Fujita techniques effective in less than 50% of adult patients with OSA  Higher success in Friedman stage 1, low success in Friedman stage 3  Reduces respiratory events and daytime sleepiness in adult patients compared to controls iii. Systematic review with success rates reported range 35-95% iv. Mean AHI change 18.6 events/hour v. Large effect changes in Epworth sleepiness score (ESS) (mean change 5.4) vi. Steps:  Incision through mucosa of soft palate from superior pole of tonsillar fossa toward uvula  Mucosa of soft palate, tonsillar fossa, lateral aspect of uvula undermined and excised  Mucosal edges between anterior to posterior arches reapproximated with interrupted sutures  If uvula elongated, during procedure it was shortened or removed c. Laser Assisted Uvulopalatoplasty (LAUP) i. Reported by Kamami in 1994 ii. Can be performed under local anesthesia, removes uvular mucosa and creates trans-palatal vertical troughs, hemostasis by silver nitrate or topical agents iii. Often staged procedures 3-5 sessions iv. Option for patients with snoring v. Poor levels of evidence of effect on patients with OSA on improving quality of life, reducing apnea, snoring or sleepiness vi. High morbidity with persistent difficulty swallowing, globus sensation and voice changes

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B. Tucker Woodson and Erin Harvey d. Palatal stiffening i. Pillar implants Reported by Ho et al. 2004 as outpatient procedure for snoring  Polyethylene terephthalate implants initiate an inflammatory reaction creating fibrosis and stiffening of the soft palate ii. Long term results by Rotenberg et al. 2012 showing decreased subjective improvement overtime and minimal sustainability at 4 years post-operative iii. Injection of sclerosing agents by Brietzke et al. 2001  Sodium tetradecyl sulfate (STS) is injected into the submucosal layer of the soft palate to induce scarring and reduce flutter snoring using local anesthetic with statistically significant decreases in flutter snoring and palatal loudness  Ethanol: equally effective as STS in canine model, found to have similar results with higher rate of transient palatal fistula e. Cautery Assisted Palatal Stiffening Operation (CAPSO) i. Introduced by Mair et al. 2000, modified by Pang et al. 2007 ii. Can be performed under local anesthesia as isolated procedure primarily mild moderate OSA iii. Isolated CAPSO improves AHI (6.9 events/hour) combined with tonsillectomy (14.2 events/hour) or expansion pharyngoplasty (14.1 events/hour) iv. Epworth Sleepiness Scale (ESS) reduced 11.8 to 5.1 v. Snoring reduced from 7.9 to 2.5 on visual analog scales (0 - 10 scale) f. Relocation pharyngoplasty i. Reported by Li HY et al. in 2009 ii. Meant to improve sagittal collapse of velopharynx by stabilization of lateral pharyngeal wall iii. Steps:  Tonsillectomy  Removal of supratonsillar mucosa and adipose tissue  Splinting the lateral pharyngeal wall by suturing the placating superior pharyngeal constrictor m. to the anterior pillar  Suturing posterior pillar flap cephalad and lateral to the supratonsillar fossa g. Lateral pharyngoplasty i. Reported by Cahali 2003 ii. Multiple iterations iii. Steps:  Tonsillectomy performed. If prior tonsillectomy, the mucosa removed to reveal the palatoglossus and palatopharyngeus muscles  Superior pharyngeal constrictor m. elevated, caudally sectioned and muscle flaps sutured anteriorly to the palatoglossus m.

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h. Expansion sphincter pharyngoplasty i. Reported by Pang and Woodson 2007 ii. Compared to traditional UPPP in Friedman Stage 2-3 and lateral collapse, increased success in randomized controlled trial (RCT) iii. Steps:  Tonsillectomy  Palatopharyngeus m. identified and transected, rotated superolaterally  Incision on anterior pillar to identify palatoglossus m.  Palatopharyngeus attached to arching fibers of the soft palate  Partial uvulectomy performed i. Barbed reposition pharygoplasty i. Reported by Vincini et al. 2015 ii. Uses knotless bidirectional resorbable barbed sutures to stich palatopharyngeus muscles to pterygomandibular raphe j. Palatal Advancement Pharyngoplasty i. Reported by Woodson in 1993 ii. Performed with or without UPPP, intended for patients where a low probability of success with UPPP iii. Increases retropalatal size and decreases retropalatal collapsibility compared with UPPP alone iv. Risk of oronasal fistula v. Systematic review showing overall decrease in AHI random effects modeling demonstrated a mean difference (MD) of -36.3 events/hour 3. Success of palate surgery: a. Increases with multilevel surgery b. Combination palate and or tongue procedures with nasal surgery can improve outcomes in subjective sleepiness and apneic events c. Combination palate surgery with lingual tonsillectomy has demonstrated improvement in AHI, minimal arterial oxygen saturation and overall sleepiness 4. Long term outcomes palate surgery: a. Success on AHI decreases overtime, overall daytime sleepiness has been shown to not decrease significantly b. Correlation of baseline body mass index, lowest arterial oxygen saturation, and proportion of sleep time with oxygen saturation < 90% with long-term surgical response 5. Surgical complications: a. Immediate i. Pain, infection, bleeding, velopharyngeal insufficiency, nasopharyngeal stenosis, globus sensation, taste changes b. Long term i. Swallowing and sensation side effects more common but severity varies

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B. Tucker Woodson and Erin Harvey ii. Dry throat (7.8%), throat lump feeling (11.5%), throat phlegm (10.1%), throat scar feeling (3.7%), and difficulty swallowing (0.5%) were reported by Pang et al. with the lowest number of complaints in patients who underwent expansion pharyngoplasty iii. Newer techniques may have fewer side effects iv. Aggressive resection has been shown to have similar outcomes with higher rates of complications v. Voice changes and velopharyngeal incompetence uncommon after UPPP vi. Tissue preserving reconstructive techniques that avoid aggressive resection do not alter continuous positive airway pressure (CPAP) adherence/effectiveness in most patients

KEY CLINICAL POINTS 1. UPPP or tonsillectomy may be considered for the treatment of OSA in patients who have failed or been intolerant of less invasive therapies and in whom preoperative evaluation documents obstruction at the site of surgical treatment. (Option) 2. Since signs and symptoms of OSA are not sufficient to diagnose OSA and polysomnography or home sleep apnea testing with a technically adequate device should be used for the diagnosis of OSA in uncomplicated adult patients prior to surgical treatment. (Option) 3. Continuous positive airway pressure treatment is an initial therapy for patients diagnosed with moderate of severe OSA. (Standard) 4. Assessment of OSA symptoms at initial evaluation includes the presence of snoring and daytime sleepiness. (Standard) 5. Data on success rates of palatal surgical interventions is often limited to short-term follow-up studies Long term outcomes and complications may be insufficiently studied. These limitations need to be discussed critically with patients prior to surgery. (Standard)

QUESTIONS 1. A male 50-year-old patient with severe OSA, BMI 36 kg/M2 presents with Brodsky 3+ tonsils. The uvula is visible on oral examination without a tongue depressor. SNB angle is 73 degrees and MPH is 20 mm. What is the likelihood of surgical success with UPPP? a. High likelihood, 80% chance of success b. Low likelihood, 20% chance of success c. Medium likelihood, 40-50% change of success d. Indeterminant chance of success

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2. Following palatal surgery: a. Success rates improve and complications are more common following aggressive compared to conservative resection b. Objective but not subjective nasalance is common after UPPP c. CPAP adherence is unaffected d. The risk of abnormal mucus sensation correlated to the degree of uvula preservation 3. Which of the following is true regarding tonsillectomy for OSA? a. Isolated tonsillectomy is only indicated in mild OSA b. Is a safe outpatient procedure c. Should only be indicated with large or very large tonsils d. May require modified technique with combined lingual tonsillectomy 4. A patient presents with severe OSA, 2+ tonsils with decreased retropalatal space on awake flexible laryngoscopy, BMI 36 kg/M2, SNA 77 degrees, SNB 75 degrees, MPH 27 mm, and lingual tonsillar hypertrophy, what is the best course of action given he is not compliant with CPAP? a. Hypoglossal nerve stimulation implantation b. UPPP with lingual tonsillectomy c. Sedated flexible laryngoscopy with UPPP if palate only obstruction d. Continued attempts at compliance of CPAP 5. Regarding work up of OSA, which of the following is true? a. If computed topography (CT) does not provide enough diagnostic information, MRI should be ordered b. Mandibular plane in lateral cephalography may be indicative of possible poor outcome after UPPP c. Lateral cephalography is predictive of snoring severity d. The Müeller maneuver is indicative of nasal airway obstruction

REFERENCES An, Y., Gao, F., Su, X., Zhou, C., Huang, J., Chen, S., Liu, T., Lu, Z. Characteristics of pharyngeal paraesthesia symptoms in patients with obstructive sleep apnoea. Sleep Breath., 2021 Feb. 18. doi: 10.1007/s11325-021-02325-z. Binar, M., Akcam, T., Vardareli, O. S., Genc, H., Karakoc, O. Voice outcomes for patients undergoing surgery for obstructive sleep apnea: A systematic review and meta-analysis. Eur. Arch. Otorhinolaryngol., 2020 Dec.; 277(12):3261 - 3281. doi: 10.1007/ s00405-02006101-9. Binar, M., Karakoc, O. Anterior Palatoplasty for Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Otolaryngol. Head Neck Surg., 2018 Mar.; 158(3):443 - 449. doi: 10.1177/0194599817739857.

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Brietzke, S. E., Mair, E. A. Injection snoreplasty: how to treat snoring without all the pain and expense. Otolaryngol. Head Neck Surg., 2001 May; 124(5):503 - 10. doi: 10.1067/mhn.2001.115400. Brietzke, S. E., Mair, E. A. Injection snoreplasty: Investigation of alternative sclerotherapy agents. Otolaryngol. Head Neck Surg., 2004 Jan.; 130(1):47 - 57. doi: 10.1016/j.otohns.2003.08.004. Cahali, M. B. Lateral pharyngoplasty: A new treatment for obstructive sleep apnea hypopnea syndrome. Laryngoscope, 2003 Nov.; 113(11):1961 - 8. doi: 10.1097/ 00005537200311000-00020. Camacho, M., Li, D., Kawai, M., Zaghi, S., Teixeira, J., Senchak, A. J., Brietzke, S. E., Frasier, S., Certal, V. Tonsillectomy for adult obstructive sleep apnea: A systematic review and meta-analysis. Laryngoscope, 2016 Sep.; 126(9):2176 - 86. doi: 10.1002/ lary.25931. Camacho, M., Nesbitt, N. B., Lambert, E., Song, S. A., Chang, E. T., Liu, S. Y., Kushida, C. A., Zaghi, S. Laser-Assisted Uvulopalatoplasty for Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis. Sleep, 2017 Mar. 1; 40(3). doi: 10.1093/sleep/zsx004. Franklin, K. A., Anttila, H., Axelsson, S., Gislason, T., Maasilta, P., Myhre, K. I., Rehnqvist, N. Effects and side-effects of surgery for snoring and obstructive sleep apnea--a systematic review. Sleep, 2009 Jan.; 32(1):27 - 36. Friedman, M., Ibrahim, H., Bass, L. Clinical staging for sleep-disordered breathing. Otolaryngol. Head Neck Surg., 2002 Jul.; 127(1):13 - 21. doi: 10.1067/ mhn.2002.126477. He, M., Yin, G., Zhan, S., Xu, J., Cao, X., Li, J., Ye, J. Long-term Efficacy of Uvulopalatopharyngoplasty among Adult Patients with Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Otolaryngol. Head Neck Surg., 2019 Sep.; 161(3):401 - 411. doi: 10.1177/0194599819840356. Ho, W. K., Wei, W. I., Chung, K. F. Managing disturbing snoring with palatal implants: A pilot study. Arch. Otolaryngol. Head Neck Surg., 2004 Jun.; 130(6):753 - 8. doi: 10.1001/archotol.130.6.753. Kamami, Y. V. Outpatient treatment of snoring with CO2 laser: laser-assisted UPPP. J. Otolaryngol., 1994 Dec.; 23(6):391 - 4. Li, H. Y., Lee, L. A. Relocation pharyngoplasty for obstructive sleep apnea. Laryngoscope, 2009 Dec.; 119(12):2472 - 7. doi: 10.1002/lary.20634. Llewellyn, C. M., Noller, M. W., Camacho, M. Cautery-assisted palatal stiffening operation for obstructive sleep apnea: A systematic review and meta-analysis. World J. Otorhinolaryngol. Head Neck Surg., 2018 Sep. 25; 5(1):49 - 56. doi: 10.1016/ j.wjorl.2018.05.007. MacKay, S., Carney, A. S., Catcheside, P. G., Chai-Coetzer, C. L., Chia, M., Cistulli, P. A., Hodge, J. C., Jones, A., Kaambwa, B., Lewis, R., Ooi, E. H., Pinczel, A. J., McArdle, N., Rees, G., Singh, B., Stow, N., Weaver, E. M., Woodman, R. J., Woods, C. M., Yeo, A., McEvoy, R. D. 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 Randomized Clinical Trial. JAMA, 2020 Sep. 22; 324(12):1168 - 1179. doi: 10.1001/ jama.2020.14265. Martínez-Ruíz de Apodaca, P., Carrasco-Llatas, M., Matarredona-Quiles, S., Valenzuela-Gras, M., Dalmau-Galofre, J. Long-term stability of results following surgery for obstructive sleep apnea (OSA). Eur. Arch. Otorhinolaryngol., 2021 Apr. 2. doi: 10.1007/s00405-02106781-x.

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Mulholland, G. B., Jeffery, C. C., Ziai, H., Hans, V., Seikaly, H., Pang, K. P., Rotenberg, B. W. Multilevel Palate and Tongue Base Surgical Treatment of Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Laryngoscope, 2019 Jul.; 129(7):1712 - 1721. doi: 10.1002/lary.27597. Pang, K. P., Montevecchi, F., Vicini, C., Carrasco-Llatas, M., Baptista, P. M., Olszewska, E., Braverman, I., Kishore, S., Chandra, S., Yang, H. C., Chan, Y. H., Pang, S. B., Pang, K. A., Pang, E. B., Rotenberg, B. Does nasal surgery improve multilevel surgical outcome in obstructive sleep apnea: A multicenter study on 735 patients. Laryngoscope Investig. Otolaryngol., 2020 Oct. 8; 5(6):1233 - 1239. doi: 10.1002/ lio2.452. Pang, K. P., Vicini, C., Montevecchi, F., Piccin, O., Chandra, S., Yang, H. C., Agrawal, V., Chung, J. C. K., Chan, Y. H., Pang, S. B., Pang, K. A., Pang, E. B., Rotenberg, B. Longterm Complications of Palate Surgery: A Multicenter Study of 217 Patients. Laryngoscope, 2020 Sep.; 130(9):2281 - 2284. doi: 10.1002/lary.28432. Pang, K. P., Woodson, B. T. Expansion sphincter pharyngoplasty: A new technique for the treatment of obstructive sleep apnea. Otolaryngol. Head Neck Surg., 2007 Jul.; 137(1):110 - 4. doi: 10.1016/j.otohns.2007.03.014. Rotenberg, B. W., Luu, K. Four-year outcomes of palatal implants for primary snoring treatment: A prospective longitudinal study. Laryngoscope, 2012 Mar.; 122(3):696 - 9. doi: 10.1002/lary.22510. Samutsakorn, P., Hirunwiwatkul, P., Chaitusaney, B., Charakorn, N. Lingual tonsillectomy with palatal surgery for the treatment of obstructive sleep apnea in adults: A systematic review and meta-analysis. Eur. Arch. Otorhinolaryngol., 2018 Apr.; 275(4):1005 - 1013. doi: 10.1007/s00405-018-4887-6. Shepard, J. W. Jr., Thawley, S. E. Evaluation of the upper airway by computerized tomography in patients undergoing uvulopalatopharyngoplasty for obstructive sleep apnea. Am. Rev. Respir. Dis., 1989 Sep.; 140(3):711 - 6. doi: 10.1164/ajrccm/140.3.711. Sher, A. E., Thorpy, M. J., Shprintzen, R. J., Spielman, A. J., Burack, B., McGregor, P. A. Predictive value of Müller maneuver in selection of patients for uvulopalatopharyngoplasty. Laryngoscope, 1985 Dec.; 95(12):1483 - 7. doi: 10.1288/ 00005537-198512000-00009. Stauffer, J. L., Zwillich, C. W., Cadieux, R. J., Bixler, E. O., Kales, A., Varano, L. A., White, D. P. Pharyngeal size and resistance in obstructive sleep apnea. Am. Rev. Respir. Dis., 1987 Sep.; 136(3):623 - 7. doi: 10.1164/ajrccm/136.3.623. Stuck, B., Ravesloot, M. J. L., Eschenhagen, T., de Vet, H. C. W., Ulrich Sommer, J. Uvulopalatopharyngoplasty with or without tonsillectomy in the treatment of adult obstructive sleep apnea - A systematic review. Sleep Med., 2018; 50:152 - 165. doi:10.1016/j.sleep.2018.05.004. Sundman, J., Browaldh, N., Fehrm, J., Friberg, D. Eight-Year Follow-up of Modified Uvulopalatopharyngoplasty in Patients with Obstructive Sleep Apnea. Laryngoscope, 2021 Jan.; 131(1):E307 - E313. doi: 10.1002/lary.28960. Vicini, C., Hendawy, E., Campanini, A., Eesa, M., Bahgat, A., AlGhamdi, S., Meccariello, G., DeVito, A., Montevecchi, F., Mantovani, M. Barbed reposition pharyngoplasty (BRP) for OSAHS: A feasibility, safety, efficacy and teachability pilot study. “We are on the giant's shoulders”. Eur. Arch. Otorhinolaryngol., 2015 Oct.; 272(10):3065 - 70. doi: 10.1007/s00405-015-3628-3.

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Volner, K., Dunn, B., Chang, E. T., Song, S. A., Liu, S. Y., Brietzke, S. E., O'Connor, P., Camacho, M. Transpalatal advancement pharyngoplasty for obstructive sleep apnea: A systematic review and meta-analysis. Eur. Arch. Otorhinolaryngol., 2017 Mar.; 274(3):1197 - 1203. doi: 10.1007/s00405-016-4121-3. Woodson, B. T., Conley, S. F. Prediction of uvulopalatopharyngoplasty response using cephalometric radiographs. Am. J. Otolaryngol., 1997 May-Jun.; 18(3):179 - 84. doi: 10.1016/s0196-0709(97)90079-x. Yin, G., He, M., Cao, X., Xu, J., Zhang, Y., Kang, D., Ye, J. Five-Year Objective and Subjective Outcomes of Velopharyngeal Surgery for Patients with Obstructive Sleep Apnea. Otolaryngol. Head Neck Surg., 2020 Jan.; 162(1):148 - 154. doi: 10.1177/ 0194599819884889.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 22

SURGERY TO ADDRESS THE TONGUE BASE AND HYPOPHARYNX Mark A. D’Agostino1,2,3,4, MD and Michael Hajek3, MD 1

Southern New England Ear, Nose, Throat and Facial Plastic Surgery Group, New Haven, CT, USA 2 Frank H. Netter School of Medicine, Quinnipiac University, North Haven, CT, USA 3 Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA 4 Otolaryngology Section, Middlesex Hospital, Middletown, CT, USA

INTRODUCTION 1. There is an expansive range of anatomic and physiologic causes of obstructive sleep apnea (OSA) 2. Until relatively recently, the hypopharynx and tongue base were underappreciated as major sites of upper airway collapse in OSA patients 3. Accurate identification of the collapsing segments during drug induced sleep endoscopy (DISE) is critical in determining the appropriate therapy 4. Given that up to 85% of patients with OSA have evidence of multilevel collapse, it is unsurprising that isolated palatal surgeries do not demonstrate adequate outcomes in patients where there is significant obstruction from the tongue base, lateral pharyngeal walls, and/or epiglottis 5. Obese patients with severe OSA (apnea-hypopnea index (AHI) > 30 event/hour) tend to have more collapse from the lateral pharyngeal walls and/or the tongue base 6. Outcomes following OSA surgery have improved immensely as surgical techniques have become more tailored to the specific areas of obstruction a. Unless otherwise specified, surgical success is defined as a 50% or greater reduction in AHI, with final AHI of < 20 events/hour (Sher criteria) 7. Commonly used procedures to address collapse at the tongue base and hypopharynx include: a. Hyoid suspension b. Tongue suspension

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Mark D’Agostino and Michael Hajek c. Genioglossus advancement d. Radiofrequency ablation of the tongue base e. Posterior midline glossectomy f. Partial glossectomy/Lingual tonsillectomy - transoral robotic surgery (TORS) g. Epiglottoplasty/Supraglottoplasty h. Tracheostomy 8. One of the keys in understanding and deciding between the different surgical techniques to address this area lies in understanding that retrolingual collapse can occur due to one or more of the following factors: a. Macroglossia b. Hypotonia c. Retrognathia d. Lingual tonsil hypertrophy

HYOID SUSPENSION 1. Hyoid suspension is a low morbidity surgical technique used to expand and stabilize the retrolingual airway 2. In some patients, the hyoid bone is posteriorly and/or inferiorly positioned, which can pull the tongue backwards, causing obstruction at the hypopharyngeal airway and prolapse of the epiglottis posteriorly 3. Stabilizing the hyoid bone anteriorly via suspension opens the retrolingual and retroepiglottic airway in the anterior-posterior (AP) dimension and reduces resistance to airflow 4. Main advantages are that it is adjustable and reversible 5. Main indications include: a. Mild to severe OSA b. Patients with anterior-posterior collapse at the hypopharynx with epiglottic retroflexion c. Patients with position dependent collapse in these areas i. This can indicate laxity around the hyoid’s tendon-musculature complex 6. Contraindications a. Patients with a thyroglossal duct cyst, and patients who have had previous Sistrunk procedure 7. The epiglottis poses a unique problem with continuous positive airway pressure (CPAP) therapy, as positive pressure can close the epiglottis over the airway 8. The hyoid bone is a U-shaped, unique bone that articulates directly with no other bones, and is instead suspended by several muscles and ligaments, maintaining the patency of the hypopharyngeal airway a. It is a favorable method for reducing resistance of the airway, as it is mobile and serves as an anchor to much of the soft tissue in the hypopharynx and supraglottis b. Hyoid attachments include:

Surgery to Address the Tongue Base and Hypopharynx i. Suprahyoid muscles  Stylohyoid  Digastric  Mylohyoid  Geniohyoid ii. Infrahyoid muscles  Omohyoid  Sternohyoid  Thyrohyoid iii. Important external tongue musculature  Genioglossus  Hyoglossus iv. Middle constrictor of pharynx v. Epiglottis via hyoepiglottic ligament vi. Thyroid cartilage via thyrohyoid ligament 9. The two main approaches involve suspending the hyoid bone either: a. Anteriorly to the mandible (Figure 1) b. Anteroinferiorly to the lamina of the thyroid cartilage (Figure 2) 10. Initially described by Riley using fascia lata, and later using wires and sutures a. Commercially available kits are also available

Figure 1. Hyoid suspension to mandible. Siesta Medical, Los Gatos, CA, USA.

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Figure 2: Hyoid suspension to thyroid cartilage. Benoist, L. B. L., van Maanen, J. P., & de Vries, N. (2015). Hyoid suspension: hyothyroid and hyomandibular options. Operative Techniques in Otolaryngology-Head and Neck Surgery, 26(4), 178182. doi:https://doi.org/10.1016/j.otot.2015.10.001.

11. Surgical Technique a. Hyoidthyroidpexia, (adapted from Benoist, et al.) i. 5 cm horizontal incision at level of thyrohoid membrane ii. Infrahyoid strap muscles divided from hyoid bone iii. Hyoid is mobilized anteroinferiorly and sutured to thyroid cartilage with 2 nonabsorbable sutures on each side of the hyoid iv. Suture pierces through thyroid lamina and is passed around the hyoid bone v. Incision is closed b. Hyo-mandibular suspension, (commercially available Siesta Medical Airlift™ Procedure) i. 2 cm incision midway between hyoid bone and mandible ii. Expose hyoid bone and using the Revolution™ suture passer the suspension sutures are passed around the hyoid bone iii. Undersurface of anterior mandible exposed and two Encore™ system suture anchors are used to anchor the suspension sutures to the mandible iv. The suspension sutures are pulled tight through the suspension anchors, advancing the tongue base and epiglottis, and stabilizing the lateral oropharyngeal walls v. Incision is closed

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12. Efficacy a. Hyoid suspension can be performed either as singular treatment for isolated hypopharyngeal collapse or as part of multilevel surgery, commonly with genioglossus advancement and/or radiofrequency ablation of the tongue base b. Surgical success rates range from 17 - 78% c. Hyoid surgery alone can significantly improve subjective and objective measures, with recent meta-analysis showing 38% reduction in AHI in appropriate patients d. Its efficacy largely depends on appropriate patient selection. As with most surgery to address the tongue base and hypopharynx, higher pre-operative AHI and body mass index (BMI) trend towards lower success rates. 13. Hyoid suspension is generally well tolerated without high risk for major complications a. Significant changes to voice or swallow function are generally not seen. Minor complications include: i. Fistula ii. Bleeding iii. Infection with or without wound abscess

TONGUE SUSPENSION 1. Tongue suspension aims to prevent posterior displacement of the tongue during sleep by suspending the tongue base to a screw in the genial tubercle of the mandible with suture 2. This is a minimally invasive technique with efficacy similar to genioglossus advancement 3. Tongue suspension is commonly performed in conjunction with uvulopalatopharyngoplasty (UPPP) 4. This can also safely be performed in concert with tongue base resection for severe collapse at the tongue base to create additional retrolingual space 5. The Encore system (Siesta Medical, Los Gatos, California) is currently the only approved system for tongue suspension in the United States 6. Advantages of tongue suspension: a. Easy to perform b. Minimally invasive c. Reversible 7. Indications include: a. Mild-moderate OSA b. Patients unable to tolerate CPAP c. Evidence of collapse at tongue base (Fujita III, or Fujita II with concurrent palatal surgery) d. AP collapse pattern with Müeller’s maneuver or on DISE e. Patients BMI > 30-32 tend to have poorer outcomes with tongue suspension

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Mark D’Agostino and Michael Hajek 8. Contraindications a. Severe periodontal disease b. History of radiation to mandible c. History of root canal at mandibular incisors 9. Surgical technique (Encore system): a. Submental incision b. Suture passer creates a loop of suture extending to tongue base and back out from incision c. Loop of suture is used to pull suspension line along course of previous temporary suture i. Suture loop is within tongue base, therefore no mucosal violation of tongue d. Blunt dissection to expose mandible e. Anchor screw is placed just inferior to genial tubercle f. Both ends of suspension line are passed through anchor screw and tightened (the supension line can be retightened if residual obstruction) g. Incision is closed 10. Efficacy: a. As a standalone procedure, success rate found to be 11 - 75% (average 37%) b. When paired with UPPP, success rate averages 20 - 81% (average 62%) c. Morbid obesity is associated with poorer outcomes with tongue suspension i. This is likely because obesity is associated with macroglossia, which is more effectively treated with tongue reduction procedures d. Efficacy of tongue suspension is dependent on the tension of suture i. More tension in suspension will help treat apnea but may lead to issues with tongue mobility and comfort e. There is conflicting evidence regarding the durability of success with this technique due to suture migration in the tongue base i. Most agree that long term success is fairly durable, and that foreign body reaction creates fibrosis within tongue base that helps prevent collapse 11. Complications (overall complication rate of 12-18%): a. Hematoma b. Floor of mouth edema i. Less likely now with submental approach c. Suture breakage/migration d. Sialadenitis i. Likely secondary to obstruction at Wharton’s duct e. Osteomyelitis i. Rare f. Injury to hypoglossal nerve i. If suture is passed too laterally g. Velopharyngeal insufficiency

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GENIOGLOSSUS ADVANCEMENT WITH OR WITHOUT HYOID MYOTOMY AND SUSPENSION 1. Genioglossus advancement is a surgical technique that pulls the genioglossus muscle anteriorly via a mandibular osteotomy and helps open the retrolingual airway by pulling the tongue base anteriorly and increasing the tone of the tongue, making it less prone to collapse during sleep 2. The genioglossus muscle is the largest muscle of the tongue a. It arises from the genial tubercle at the posterior edge of the midline mandible, and fans out to insert at the tip of the tongue, the dorsum of the tongue, and the hyoid bone 3. Contraction of the genioglossus muscle: a. Protrudes the tongue b. Widens and stabilizes the retrolingual airway 4. Main indications include: a. Patients with significant obstruction at the tongue base b. Obstruction is that is largely muscular, as opposed to lymphatic (lingual tonsil) 5. First described by Riley et al. in 1984, genioglossus advancement has evolved over the past decades, with the rectangular window technique being most commonly used 6. Understanding the patient’s specific anatomy of the genial tubercle is critical in genioglossus advancement 7. The osteotomy must be large enough to advance as much muscle as possible, while sparing the tooth roots and providing enough stability of the mandible to avoid fracture a. The genioglossal insertion to the mandible is quite variable, with the width ranging from 3-15 mm b. Intraoral palpation and preoperative computerized tomography (CT) scans can be helpful in accurately localizing the genioglossal attachment 8. Surgical technique (rectangular window, adapted from Li et al.) (Figure 3): a. Mucosal incision made 10-15 mm below mucogingival junction b. Symphysis is exposed via subperiosteal flap c. Mental nerves are identified d. Superior horizontal osteotomy is performed 5 mm below tooth root apices e. Inferior horizontal osteotomy is preformed 10 mm above inferior border of mandible f. Vertical osteotomies, completing the rectangle. Screws are placed through outer cortex to control bone flap before completing osteotomies. g. Bone flap is advanced anteriorly, along with its attachment to genioglossus, and rotated 90 degrees h. Buccal cortex is removed with cutting burr drill to take down height difference between bone flap and mandible i. Bone flap is secured inferiorly with 2 mm lag screw j. If desired, hyoid can be suspended to mandible via two sutures around hyoid and through newly created osteotomy (separate incision overlying hyoid bone)

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Mark D’Agostino and Michael Hajek i. This can be helpful if patient has collapse at the epiglottic level k. Mentalis is reapproximated, mucosal incision is closed 9. Efficacy a. Genioglossus advancement with hyoid suspension showed a 23-77% surgical success rate i. Recent metanalysis found that genioglossus advancement performed in conjunction with UPPP showed a surgical success rate of 61% b. Genioglossus advancement alone shows similar success rates c. Success rates tend to be higher in patients with lower BMI and lower preoperative AHI 10. Complications include: a. Dental injury b. Mental nerve injury c. Fracture of the mandible d. Hematoma

Figure 3. Before (A) and after (B) genioglossus advancement with hyoid suspension. Terris, D. J. (2000). Multilevel pharyngeal surgery for obstructive sleep apnea: Indications and techniques. Operative Techniques in Otolaryngology-Head and Neck Surgery, 11(1), 12-20. doi:https://doi.org/10.1016/S1043-1810(00)80005-6.

RADIOFREQUENCY ABLATION OF THE TONGUE BASE 1. Radiofrequency ablation (RFA) of the tongue base is a minimally invasive approach to reduce tongue volume with the use of alternating current, which heats targeted areas of tongue tissue in a controlled manner and stimulates fibrosis

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2. The resultant contraction and firming of the tongue helps reduce tongue volume and prevent laxity and collapse during sleep, without significantly effecting normal tongue function 3. RFA of the tongue base can be performed as a primary treatment or as a part of multilevel surgery a. This was first described in humans by Powell et al. in 1999, with 5.5 treatments reducing tongue volume by 17% 4. Advantages of RFA: a. Minimally invasive b. Less post-operative pain when compared to other tongue reduction techniques c. Short recovery time d. Can be done under local or general anesthesia 5. Disadvantages: a. Usually requires multiple sessions b. Durability of results decreases in some patients over the course of years 6. Main indications include: a. Failure to tolerate CPAP b. Evidence of obstruction at the tongue base c. Mild to moderate OSA d. Snoring e. Likely more effective in patients without morbid obesity 7. Surgical technique (Adapted from Riley, with 2003 ventral tongue adjunct): a. Local anesthetic injected to circumvallate papilla and ventral tongue, median/paramedian position b. 1-2 treatments with radiofrequency electrode (Somnoplasty system, GyrusENT, Memphis, Tennessee) at circumvallate papilla i. 465 kHz (kilohertz) ii. 85° C (degrees Celsius) goal temperature c. 1-2 treatments with same electrode at ventral tongue (genioglossus insertion), same settings d. 3-6 treatments, at least 3-4 weeks apart 8. Efficacy a. Measured surgical success rate of 38 – 63% i. Recent metanalysis RFA of the tongue base alone can cause a significant increase in lowest oxygen saturation and 40% reduction in RDI b. Most patients treated with RFA of the tongue base tended to have lower BMI and pre-operative AHI when compared to other surgical techniques described c. Success in this procedure is dependent on BMI d. Quality of life and OSA improvement seem to endure with time 9. Complications: a. Ulceration of the tongue base b. Infections (rarely, tongue abscess) c. Bleeding d. Dysgeusia

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Tongue weakness Globus sensation

POSTERIOR MIDLINE GLOSSECTOMY 1. Midline glossectomy is an effective procedure aimed at reducing tongue volume in the midline 2. There can be several underlying causes of obstruction at the tongue base a. Excessive weight gain can result in fat deposition in the tongue b. Patients with macroglossia are prone to obstruction in the area 3. As opposed to suspension procedures, midline glossectomy physically resects excessive tissue at the base of tongue a. It is important to note that midline glossectomy likely does not address obstruction at the oropharyngeal lateral walls or epiglottis, though does help open the oropharyngeal airway b. Of note, submucosal lingualplasty (SML) will be included in this section, as it involves the removal of midline tongue tissue 4. Main indications include: a. Adult or pediatric patients with macroglossia as a primary cause of obstruction i. Tongue reduction procedures have gained popularity in children with Downs and Beckwith-Wiedemann syndrome b. Patients with mild to severe sleep apnea (usually reserved for moderate to severe) c. Fujita type II or III obstruction 5. Contraindications for midline glossectomy include: a. Poor pulmonary reserve b. Severe and refractory gastroesophageal reflux 6. It was initially described by Fujita in 1991, where the CO2 laser was used to remove a significant portion of the midline tongue base a. Due to high patient morbidity, newer approaches that have been developed to reduce pain and swelling b. In 2007, Woodson described an open approach to midline glossectomy using endoscopic visualization with plasma coblation c. Maturo and Mair described the submucosal minimally invasive lingual excision (SMILE) technique, where plama coblation is performed through a small incision in the tongue, and progress is monitored by intermittently inserting and endoscope through the incision d. Radiofrequency ablation and endoscopic microdebrider techniques have also been described for midline glossectomy 7. Anatomic considerations a. Excellent understanding of anatomy of the lingual arteries and hypoglossal nerves laterally is crucial in tongue reduction procedures, which will be discussed in more detail in lingual tonsillectomy/TORS section

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b. Note that the lingual artery lies medial to the hypoglossal nerve, and resection should remain within 1 cm of midline 8. Surgical technique a. Nasotracheal intubation b. Dental rolls or gag to open mouth c. Ultrasound identification of neurovascular bundles laterally d. Silk suture to midline anterior tongue for anterior retraction e. Starting at foramen cecum, elliptical incision 2 centimeters (cm) wide (1 cm on either side of midline), extending from border of anterior and middle third of tongue, to posterior third of tongue (including foramen cecum) i. This can be done either open or submucosally ii. Staying within 1 cm of midline will help prevent damage to neurovascular bundle f. Retraction sutures around incision g. Wedge midline glossectomy taken down to genioglossus h. Plane developed 5-10 mm superficial to bilateral neurovascular bundles with hemostat i. Extension of wound bed posteriorly, with excision of excessive tissue j. Extension of wound bed laterally and superiorly, with excision of excessive tissue. Care should be taken to leave a 1 cm cuff of mucosa and underlying tongue musculature to reduce effects on tongue function. i. Partially close incision or leave open to granulate k. Submucosal minimally invasive lingual excision i. Traction suture placed in anterior tongue ii. Doppler ultrasonography of lingual arteries, marked on tongue iii. Small midline incision created 2 cm from tip of tongue, blunt dissection iv. Plasma coblation through incision, staying medial to marked lingual arteries v. Intermittent endoscopic visualization vi. Incision is left open 9. Efficacy a. Midline glossectomy is an effective treatment for mild to severe OSA i. This is especially true when performed in conjunction with procedures addressing other levels of collapse b. Midline glossectomy techniques, as part of multilevel surgery, have a surgical success rate of 25% - 83% i. Recent metanalysis shows a 59.6% surgical success rate and 22.5% surgical cure rate c. Midline glossectomy can reduce AHI by 40% as a standalone procedure in pooled analyses d. Submucosal lingualplasty (with concurrent palatal surgery) in select patients shows a 65 - 74% surgical success rate e. Success after partial midline glossectomy tends to be AHI and BMI dependent

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Mark D’Agostino and Michael Hajek 10. Complications a. Bleeding i. Can be large volume if lingual artery is injured b. Hematoma i. Can be life threatening and securing the airway is of utmost importance c. Abscess i. Risk in submucosal technique d. Wound dehiscence e. Hypoglossal nerve injury f. Swelling g. Odynophagia and pain i. Short term, tend to be significantly less with mucosal sparing techniques, such as SML h. Change in tongue function (longer term, limiting lateral extent of dissection and sparing mucosa is likely to help reduce rates) i. Speech  Up to 1/2 of patients ii. Swallow  Up to 1/3 of patients iii. Taste  Up to 1/3 of patients

PARTIAL GLOSSECTOMY/LINGUAL TONSILLECTOMY TRANSORAL ROBOTIC SURGERY (TORS) 1. Lingual tonsillectomy involves removal of the lymphoid tissue at the base of tongue (part of Waldeyer’s ring) and surrounding tongue base 2. This can be effective in patients where the base of tongue and/or hypertrophic lingual tonsils form a major source of collapse 3. Initially described by Chabolle in 1999 using a transcervical approach to remove both lingual tonsillar tissue and tongue muscle, it is now performed transorally, commonly with transoral robotic surgery (TORS) a. TORS was pioneered by O’Malley and Weinstein for oropharyngeal cancers with the DaVinci robotic system (Intuitive Surgical, Sunnyvale, California) b. TORS base of tongue resection was described by Vinici in 2010 and is now approved for benign base of tongue resection for OSA based on Hoff, D’Agostino, and Thaler’s safety and feasibility study in 2015 4. Advantages of TORS: a. Great exposure of the base of tongue and pharynx b. Lower risk of injury to neurovascular bundle c. Faster operative times d. No neck scar 5. Ideal candidate has a. Low lying obstruction

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7.

8.

9.

10.

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b. Excessive lymphoid tissue (as opposed to all muscle) at tongue base c. Localized obstruction Indications include patients with: a. Moderate to severe OSA b. Failure of positive pressure therapy c. Evidence of retrolingual collapse from prominent base of tongue and/or lingual tonsillar tissue (via in office fiberoptic laryngoscopy with Müeller maneuver, or with DISE) Contraindications include patients with: a. Trismus with interincisive distance of < 2.5 cm or small oral cavity b. Significant cervical disease and inability to extend the neck c. Dysphagia that is not secondary to lingual tonsillar hypertrophy d. American Society of Anesthesiologists (ASA) status > 3 e. Significant psychiatric illness Relevant anatomy: It is critical to understand the anatomy of the neurovascular bundle in the tongue base to avoid inadvertent injury a. Lingual artery i. Branch of the external carotid ii. Runs anteriorly along greater cornu of hyoid bone iii. Runs on lateral surface of genioglossus muscle iv. Gives off dorsal lingual branch to supply the tongue base  Runs superomedially b. Hypoglossal nerve i. Is deeper and more lateral than lingual artery ii. Runs laterally to hyoglossus muscle Surgical technique utilizing the DaVinci system a. Nasotracheal (preferred) or orotracheal intubation b. Silk retraction suture placed at midline tongue tip to retract tongue anteriorly c. Tongue base is exposed with either Feyh-Kastenbauer (FK) retractor (Gyrus Medical Inc, Cardiff, United Kingdom) or a Crowe-Davis mouth gag (Karl Storz SE, Tuttlingen, Germany) d. Using spatula tip monopolar cautery and Maryland dissector, dissection of lingual tonsillar tissue beginning from circumvallate papillae down to base of epiglottis and valleculae bilaterally i. Tension created via assistant’s suction and surgeon’s dissector to allow resection in plane between lymphoid tissue and tongue musculature e. Up to 10 mm of muscle can be safely resected in similar fashion bilaterally, with an additional 5 mm of muscle in midline i. Exercise caution in this step to avoid injury to lingual artery, lingual nerve, and hypoglossal nerve f. Hemostasis with monopolar cautery Efficacy: a. Surgical success rates described from 30 – 75% b. Surgical success rates tend to depend on volume of tissue removed in appropriate candidates c. Responders tend to have:

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Mark D’Agostino and Michael Hajek i. AHI < 60 ii. BMI < 30 iii. Absence of lateral oropharyngeal wall collapse on DISE 11. Complications: a. Dysphagia i. Aspiration is rare (~6%) ii. Dysphagia usually resolves within 2-3 weeks b. Taste disturbance i. Usually resolves within months ii. Unclear pathophysiology, but may involve the removal of taste buds at the tongue base c. Bleeding i. 3-4% of cases ii. Generally occurs 2-3 weeks post operatively iii. If transoral management fails to control bleeding, transcervical ligation of lingual artery is indicated and effective d. Oropharyngeal stenosis i. Can occur with extensive lateral dissection ii. Should consider staging of procedures if UPPP is to be performed

EPIGLOTTOPLASTY/SUPRAGLOTTOPLASTY 1. Epiglottic and supraglottic collapse, well known to contribute to dynamic airway collapse in children, is also increasingly being shown to play a role in adult sleep apnea 2. DISE studies have shown that epiglottic obstruction, whether due to retroflexion or mass effect from the tongue base, can occur in up to 25% of adult OSA patients 3. Interestingly, as opposed to pediatric patients with laryngomalacia, negative intrathoracic pressure with attempted respiration is thought to be the etiology of primary epiglottic collapse in adults 4. Moreover, positive airway pressure (PAP) therapy, the gold standard treatment for OSA, can precipitate epiglottic retroflexion and may be a crucial factor in some patients’ inability to tolerate CPAP 5. Epiglottoplasty and supraglottoplasty describe a variety of techniques used to surgically prevent collapse at the epiglottis, arytenoids, and aryepiglottic folds a. This can involve resection of the suprahyoid epiglottis, glossoepiglottopexy, or excision of redundant arytenoid/aryepiglottic fold mucosa 6. Main indications include: a. Epiglottic collapse on DISE b. Supraglottic structure prolapse on DISE c. While traditionally performed in children with laryngomalacia, epiglottoplasty/supraglottoplasty can be used in adults d. For TORS procedures, standard contraindications apply, as discussed previously

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7. Supraglottoplasty should follow principles of laryngeal surgery a. Opposed edges of cut tissue overlying the airway should be avoided to prevent scarring and airway stenosis b. 4 mm of healthy epiglottic cartilage and mucosa should be preserved to assist with passing of food bolus through piriform sinuses c. Sparing laryngeal mucosa is important to preserve physiologic laryngeal reflexes d. Airway fire precautions must be taken, especially when utilizing laser. Effective communication with the anesthesiologist is crucial. i. Laser safe endotracheal tubes ii. Most patties overlying endotracheal tube cuff iii. Minimize fraction of inspire oxygen (FiO2) (< 30% preferred) 8. Surgical technique a. TORS epiglottoplasty (often performed with concurrent lingual tonsillectomy, as described by Vicini et al., 2012) i. Exposure of tongue base and supraglottis with tongue tip retraction suture and mouth gag as previously described ii. Grasp tip of epiglottis with dissector to stabilize iii. Vertical midline split of epiglottis with monopolar cautery, to 5 mm above level of vallecular plane iv. Horizontal cut to remove half of suprahyoid epiglottis v. Completion horizontal cut to remove other half of suprahyoid epiglottis vi. Preservation of lateral fold mucosa may help with swallow function b. Glossoepiglottopexy (modified from Monierre’s experience with pediatric patients, as described by Roustan et al., 2018) i. Exposure of tongue base and epiglottis with Benjamin-Lindholm or Sataloff (Medtronic ENT, Jacksonville, Florida, United States) laryngoscope ii. CO2 laser (3 watt (W), slightly defocused) used to vaporize oval shaped mucosa of midline tongue base and lingual surface of epiglottis  Care should be taken to remove all mucosa of tissue that is to be opposed to one another to prevent retention cyst formation  This will cause cicatricial retraction during wound healing, pulling epiglottis to tongue base iii. Epiglottis is then sutured to tongue base, either endoscopically or secured to skin overlying hyoid bone iv. Suture is removed 4 weeks post-operatively 9. Efficacy a. Though limited in adult patient numbers, transoral glossoepiglottopexy with concurrent pharyngoplasty demonstrated statistically significant improvements in AHI, Epworth Sleepiness Scale (ESS), respiratory disturbance index (RDI), and mean oxygen saturation 6 months postoperatively 10. Complications a. Bleeding (rare) b. Infection

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Dysphagia

TRACHEOSTOMY 1. Tracheostomy is the most effective treatment for OSA with near 100% efficacy, as the collapsing upper airway segments are bypassed i. It is rarely performed for OSA nowadays due to morbidity and quality-of-life changes 2. Indications include: i. Failure of positive airway therapy, +/- surgery ii. Patients who are not candidates for pharyngeal expansion surgery iii. OSA contributing to significant cardiovascular comorbidities iv. OSA contributing to inability to function at work or socially v. Life threatening OSA 3. Surgical technique i. Standard tracheostomy with or without Bjork flap can be performed ii. Permanent tracheostomy for OSA, adapted from Maisel et al.: i. Horizontal H skin incision with trapezoidal skin flap extensions, with superior flap at level of 1st and 2nd tracheal rings, and inferior flap at level of 3rd and 4th rings  Vertical portion of incision in midline, between cricoid and sternal notch ii. Subplatysmal flaps raised, subplatysmal fat debulked iii. Divide strap muscles and thyroid isthmus, clear fascia from trachea iv. Vertical H-shaped tracheotomy (horizontal incision between 2nd and 3rd tracheal rings [or 3rd and 4th]) v. Superior and inferior tracheal flaps (containing 1 or 2 rings each) sutured to skin flaps with absorbable sutures  Epidermis approximated with tracheal mucosa vi. Lateral skin flaps sutured to trachea as above vii. Reinforced with nonabsorbable sutures 4. Efficacy: i. Tracheostomy is nearly 100% effective in curing obstructive sleep apnea ii. Care should be taken in recognizing concurrent obesity hypoventilation syndrome if gas exchange is not normalized after tracheostomy 5. Complications: i. Post-obstructive pulmonary edema i. Up to 2/3 of patients can develop new or worsening pulmonary edema after tracheotomy ii. Bleeding i. Generally peristomal and easily controlled ii. Tracheoinnominate fistulas are rare but highly fatal and represent an airway emergency

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Mucous plugging Tracheitis Airway stenosis Tracheocutaneous fistula Accidental decannulation

QUESTIONS 1. Procedures commonly used to address collapse at the tongue base include: 1. Hyoid suspension 2. Expansion sphincteroplasty 3. Genioglossus advancement 4. DISE a. b. c. d. e.

1, 2 and 3 1&3 2&4 4 only All of the above

2. When performing tongue reduction procedures for OSA it is critical to understand the anatomy of the tongue. Which of the following statements is true? 1. The lingual artery is medial to the hypoglossal nerve 2. The hyoglossus muscle is the main protrussor muscle of the tongue 3. Staying within 1 cm of the midline will help protect the neurovascular bundle 4. The hypoglossal nerve is medial to the lingual artery a. b. c. d. e.

1, 2 and 3 1&3 2&4 4 only All of the above

3. Disadvantages of Radiofrequency ablation of the tongue base include which of the following: 1. Requires general anesthesia 2. Longer recovery 3. Considered fairly invasive 4. Requires multiple sessions a. b. c. d. e.

1, 2, 3 1&3 2&4 4 only All of the above

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4. Which of the following statements regarding hyoid suspension are true? 1. When performing a hyoid suspension the genioglossus and hyoglossus muscles are cut 2. The hyoid bone may be suspended inferiorly to the thyroid cartilage 3. When performing a hyoid suspension the suprahyoid muscles are cut 4. The hyoid bone may be suspended anterior superiorly to the mandible a. b. c. d. e.

1, 2, 3 1&3 2&4 4 only All of the above

5. Epiglottic collapse contributing to airway obstruction can be addressed by which of the following procedures: 1. Hyoid suspension 2. Tongue suspension 3. Supraglottoplasty 4. Genioglossal advancement a. b. c. d. e.

1, 2, 3 1&3 2&4 4 only All of the above

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Lewis MR, Ducic Y. Genioglossus muscle advancement with the genioglossus bone advancement technique for base of tongue obstruction. J Otolaryngol. 2003 Jun;32(3):16873. doi: 10.2310/7070.2003.40315. Li HY, Wang PC, Hsu CY, Chen NH, Lee LA, Fang TJ. Same-stage palatopharyngeal and hypopharyngeal surgery for severe obstructive sleep apnea. Acta Otolaryngol. 2004 Sep;124(7):820-6. doi: 10.1080/00016480410018034. Li KK, Riley RW, Powell NB, Troell RJ. Obstructive sleep apnea surgery: genioglossus advancement revisited. J Oral Maxillofac Surg. 2001 Oct;59(10):1181-4; discussion 1185. doi: 10.1053/joms.2001.27111. Lin HS, Rowley JA, Folbe AJ, Yoo GH, Badr MS, Chen W. Transoral robotic surgery for treatment of obstructive sleep apnea: factors predicting surgical response. Laryngoscope. 2015 Apr;125(4):1013-20. doi: 10.1002/lary.24970. Maisel RH, Yang RZ. Permanent but reversible tracheostomy for severe symptomatic obstructive sleep apnea. Oper Tech Otolaryngol-Head Neck Surg. 2015;26(4), 203-207. doi: 10.1016/j.otot.2015.08.005. Maturo SC, Mair EA. Submucosal minimally invasive lingual excision: an effective, novel surgery for pediatric tongue base reduction. Ann Otol Rhinol Laryngol. 2006 Aug;115(8):624-30. doi: 10.1177/000348940611500809. Mickelson SA, Rosenthal L. Midline glossectomy and epiglottidectomy for obstructive sleep apnea syndrome. Laryngoscope. 1997 May;107(5):614-9. doi: 10.1097/00005537199705000-00011. Miller FR, Watson D, Malis D. Role of the tongue base suspension suture with The Repose System bone screw in the multilevel surgical management of obstructive sleep apnea. Otolaryngol Head Neck Surg. 2002 Apr;126(4):392-8. doi: 10.1067/mhn.2002.123548. Mintz SM, Ettinger AC, Geist JR, Geist RY. Anatomic relationship of the genial tubercles to the dentition as determined by cross-sectional tomography. J Oral Maxillofac Surg. 1995 Nov;53(11):1324-6. doi: 10.1016/0278-2391(95)90594-4. Monnier P. 2010. Pediatric airway surgery: management of laryngotracheal stenosis in infants and children: Springer Science & Business Media. Moore KE, Phillips C. A practical method for describing patterns of tongue-base narrowing (modification of Fujita) in awake adult patients with obstructive sleep apnea. J Oral Maxillofac Surg. 2002 Mar;60(3):252-60; discussion 260-1. doi: 10.1053/joms.2002. 30567. Murphey AW, Kandl JA, Nguyen SA, Weber AC, Gillespie MB. The Effect of Glossectomy for Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 2015 Sep;153(3):334-42. doi: 10.1177/0194599815594347. Neruntarat C. Hyoid myotomy with suspension under local anesthesia for obstructive sleep apnea syndrome. Eur Arch Otorhinolaryngol. 2003 May;260(5):286-90. doi: 10.1007/ s00405-002-0560-0. O'Malley BW Jr, Weinstein GS, Snyder W, Hockstein NG. Transoral robotic surgery (TORS) for base of tongue neoplasms. Laryngoscope. 2006 Aug;116(8):1465-72. doi: 10.1097/01.mlg.0000227184.90514.1a. Omur M, Ozturan D, Elez F, Unver C, Derman S. Tongue base suspension combined with UPPP in severe OSA patients. Otolaryngol Head Neck Surg. 2005 Aug;133(2):218-23. doi: 10.1016/j.otohns.2005.02.009.

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Ong AA, Buttram J, Nguyen SA, Platter D, Abidin MR, Gillespie MB. Hyoid myotomy and suspension without simultaneous palate or tongue base surgery for obstructive sleep apnea. World J Otorhinolaryngol Head Neck Surg. 2017 Jun 13;3(2):110-114. doi: 10.1016/j.wjorl.2017.05.008. Pavelec V, Hamans E, Stuck BA. A study of the new generation of the advance system tongue implants: three- and six-month effects of tongue to mandible tethering for obstructive sleep apnea. Laryngoscope. 2011 Nov;121(11):2487-93. doi: 10.1002/lary.22173. Riley R, Guilleminault C, Powell N, Derman S. Mandibular osteotomy and hyoid bone advancement for obstructive sleep apnea: a case report. Sleep. 1984;7(1):79-82. doi: 10.1093/sleep/7.1.79. Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea and the hyoid: a revised surgical procedure. Otolaryngol Head Neck Surg. 1994 Dec;111(6):717-21. doi: 10.1177/019459989411100604. Riley RW, Powell NB, Li KK, Weaver EM, Guilleminault C. An adjunctive method of radiofrequency volumetric tissue reduction of the tongue for OSAS. Otolaryngol Head Neck Surg. 2003 Jul;129(1):37-42. doi: 10.1016/s0194-5998(03)00482-0. Rosenbluth KH, Kwiat DA, Harrison MR, Kezirian EJ. Hyoid bone advancement for improving airway patency: cadaver study of a magnet-based system. Otolaryngol Head Neck Surg. 2012 Mar;146(3):491-6. doi: 10.1177/0194599811429522. Roustan V, Barbieri M, Incandela F, Missale F, Camera H, Braido F, Mora R, Peretti G. Transoral glossoepiglottopexy in the treatment of adult obstructive sleep apnoea: a surgical approach. Acta Otorhinolaryngol Ital. 2018 Feb;38(1):38-44. doi: 10.14639/0392-100X1857. Sezen OS, Aydin E, Eraslan G, Haytoglu S, Coskuner T, Unver S. Modified tongue base suspension for multilevel or single level obstructions in sleep apnea: clinical and radiologic results. Auris Nasus Larynx. 2011 Aug;38(4):487-94. doi: 10.1016/j.anl.2010. 11.013. Sher AE, Schechtman KB, Piccirillo JF. The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep. 1996 Feb;19(2):156-77. doi: 10.1093/sleep/19.2.156. Silverstein K, Costello BJ, Giannakpoulos H, Hendler B. Genioglossus muscle attachments: an anatomic analysis and the implications for genioglossus advancement. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Dec;90(6):686-8. doi: 10.1067/moe.2000. 111187. Song SA, Wei JM, Buttram J, Tolisano AM, Chang ET, Liu SY, Certal V, Camacho M. Hyoid surgery alone for obstructive sleep apnea: A systematic review and meta-analysis. Laryngoscope. 2016 Jul;126(7):1702-8. doi: 10.1002/lary.25847. Steward DL. Effectiveness of multilevel (tongue and palate) radiofrequency tissue ablation for patients with obstructive sleep apnea syndrome. Laryngoscope. 2004 Dec;114(12):207384. doi: 10.1097/01.mlg.0000149438.35855.af. Terris, DJ (2000). Multilevel pharyngeal surgery for obstructive sleep apnea: Indications and techniques. Oper Tech Otolaryngol-Head Neck Surg. 2000;11(1), 12-20. doi: 10.1016/S1043-1810(00)80005-6. Thaler ER, Rassekh CH, Lee JM, Weinstein GS, O'Malley BW Jr. Outcomes for multilevel surgery for sleep apnea: Obstructive sleep apnea, transoral robotic surgery, and

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uvulopalatopharyngoplasty. Laryngoscope. 2016 Jan;126(1):266-9. doi: 10.1002/lary. 25353. Turhan M, Bostanci A. Robotic Tongue-Base Resection Combined With Tongue-Base Suspension for Obstructive Sleep Apnea. Laryngoscope. 2020 Sep;130(9):2285-2291. doi: 10.1002/lary.28443. Vicini C, Dallan I, Canzi P, Frassineti S, La Pietra MG, Montevecchi F. Transoral robotic tongue base resection in obstructive sleep apnoea-hypopnoea syndrome: a preliminary report. ORL J Otorhinolaryngol Relat Spec. 2010;72(1):22-7. doi: 10.1159/000284352. Vicini C, Montevecchi F, Tenti G, Canzi P, Dallan I, Huntley TC. Transoral robotic surgery: Tongue base reduction and supraglottoplasty for obstructive sleep apnea. Oper Tech Otolaryngol-Head Neck Surg. 2012;23(1), 45-47. doi: 10.1016/j.otot.2011.07.003. Weinstein GS, O'malley BW Jr, Hockstein NG. Transoral robotic surgery: supraglottic laryngectomy in a canine model. Laryngoscope. 2005 Jul;115(7):1315-9. doi: 10.1097/01.MLG.0000170848.76045.47. Woodson BT. A tongue suspension suture for obstructive sleep apnea and snorers. Otolaryngol Head Neck Surg. 2001 Mar;124(3):297-303. doi: 10.1067/mhn.2001. 113661. Woodson BT. Innovative technique for lingual tonsillectomy and midline posterior glossectomy for obstructive sleep apnea. Oper Tech Otolaryngol-Head Neck Surg. 2007;18(1), 20-28. doi: 10.1016/j.otot.2007.03.004. Woodson BT, Derowe A, Hawke M, Wenig B, Ross EB Jr, Katsantonis GP, Mickelson SA, Bonham RE, Benbadis S. Pharyngeal suspension suture with repose bone screw for obstructive sleep apnea. Otolaryngol Head Neck Surg. 2000 Mar;122(3):395-401. doi: 10.1016/S0194-5998(00)70055-6. Woodson BT, Steward DL, Weaver EM, Javaheri S. A randomized trial of temperaturecontrolled radiofrequency, continuous positive airway pressure, and placebo for obstructive sleep apnea syndrome. Otolaryngol Head Neck Surg. 2003 Jun;128(6):848-61. doi: 10.1016/s0194-5998(03)00461-3.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 23

SKELETAL SURGERY FOR OSA Robson Capasso1, MD, Tahir Mirza2 and Badr Ibrahim3, MD 1

Sleep Surgery Division, Department of Otolaryngology- Head and Neck Surgery, Global Biodesign, SoM, Stanford University School of Medicine, Stanford, CA, USA 2 Oral & Maxillofacial Surgery Department, Bedfordshire Hospitals NHS Foundation Trust, Luton, Bedfordshire, UK 3 Department of Surgery, Division of Otolaryngology Head and Neck Surgery, University of Montreal, Canada

INTRODUCTION 1. Skeletal surgery exerts its effect both by structural augmentation of the dimension of the airway and by increased muscle tension. The end result is a decreased tendency of soft tissue to collapse in a larger airway 2. Skeletal surgery procedures can be used as effective standalone surgical interventions for treating obstructive sleep apnea (OSA) in well selected subjects, or as adjuvants to improve outcomes in multi-level surgery

ANATOMY 1. The airway can be divided in 5 segments a. Nasal airway b. Pharyngeal airway i. Nasopharyngeal ii. Oropharyngeal iii. Hypopharyngeal c. Laryngeal airway d. The overwhelming majority of apnea-inducing obstructive sites in adult OSA are confined to the pharyngeal airway

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The pharyngeal airway is comprised mostly of the superior and middle pharyngeal constrictor muscles i. Their skeletal attachments can be summarized as:  Superiorly to the skull base (the body of the sphenoid and the basilar part of the occipital bone) via the pharyngobasilar fascia  Supero-laterally to the styloid process via the stylopharyngeus’ suspensory action on the pharyngeal musculature and the styloid ligament  Antero-laterally via the attachment of the superior constrictor to the pterygomandibular raphe and the pterygoid hamulus  Inferiorly via the attachments of the middle constrictor to the lesser and greater horns of the hyoid bone 3. The maxilla and palatine bones a. The maxilla and palatine bones together comprise the hard palate b. The hard palate is the roof of the oral cavity and the floor of the nasal cavity c. The maxillary bones are paired and composed of 5 segments: i. Body ii. Frontal process iii. Zygomatic process iv. Palatine process  The palatine process makes up most of the hard palate and articulates with the palatine bone in order to create the hard palate  The incisive foramen is found anteriorly on the palatine process v. Alveolar process  The palatine process and the alveolar process make up the structure of the oral cavity and nasal airway  The alveolar process is the tooth bearing segment of the maxilla extending inferiorly d. The palatine bone is an L shaped bone located posteriorly to the maxillary bone and is comprised of 3 segments: i. Perpendicular plate  Part of the pterygopalatine fossa and lateral wall of the nasal cavity ii. Horizontal plate  The horizontal plate is the posterior portion of the hard palate and the posterior nasal spine and sits at the midline junction of the two horizontal plates of the paired palatine bones iii. Pyramidal process e. The hard palate and maxillae are richly vascularized by the ascending palatine artery from the facial artery, the palatine branch of the ascending pharyngeal artery, as well as multiple branches of the third segment of the internal maxillary artery (IMAX):

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i. ii. iii.

Posterior superior alveolar artery Infraorbital artery Descending palatine artery  Later branching into greater and lesser palatine arteries iv. Sphenopalatine artery f. Cranial nerve (CN) V2 exits the skull at the infraorbital foramen located on the maxilla g. The sensory innervation to the midface, maxillary dental arch and gums is provided by CN V2 and its various branches prior to exiting the skull at the infraorbital foramen 4. The Mandible a. The mandible is an unpaired horseshoe shaped bone b. Each hemi mandible can be separated in 6 segments: i. Parasymphysis ii. Body iii. Angle iv. Ramus v. Condyle vi. Coronoid process c. The junction of the two parasymphyseal segments is called the symphysis d. Genial tubercles on the lingual aspect of the symphysis allow attachment of the genioglossus and geniohyoid muscles, providing anterior tongue support e. CN V3 enters the mandible at the mandibular foramen as the inferior alveolar nerve providing sensation to the teeth and gums. It exits the mandible at the mental foramen as the mental nerve to provide sensation to the chin and lower lip. f. The mandible has a dual blood supply i. Endosteal irrigation mainly by the inferior alveolar artery entering the mandible and travelling along the inferior alveolar nerve ii. Periosteal irrigation

MAXILLO-MANDIBULAR ADVANCEMENT (MMA) 1. General Principle a. By anteriorly repositioning the facial skeleton, MMA aims to effect skeletal expansion, resulting in dilatation and stabilization of the pharyngeal airway b. MMA is an effective, single surgical procedure with multilevel modification of the airway by design i. It offers an opening at the level of the tongue and palate musculature given these structures attach to the maxilla and mandible 2. Indications and contraindications a. Indications i. Moderate to severe OSA intolerant to continuous positive airway pressure (CPAP)

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OSA with an existing dentofacial deformity OSA with lateral pharyngeal wall collapse and concentric collapse at the velum  Lateral pharyngeal wall collapse—especially in the low oropharynx/hypopharynx region is a more compelling argument for proposing skeletal surgery  Concentric collapse at the velum alone can be corrected by soft tissue surgery iv. Recurring OSA following soft tissue surgery at the velum and/or tongue base including genioglossus advancement b. Contraindications i. There are no procedure-specific absolute contraindications to MMA ii. All contraindications are relative contraindications and are to be weighed on a case-by-case basis depending on each patient’s particular clinical picture, anatomy and preferences  Unfavorable esthetic profile  Maxillary and mandibular prognathism with a reduced nasolabial angle and buried incisors  Patients with class I skeletal relationship with or without bimaxillary retrusion do not represent de facto unfavorable esthetic profiles. On the contrary, bimaxillary retrusion often offers extra lee way for advancing the maxilla and the mandible.  Pre-existing temporomandibular joint disease  Poor oral hygiene/periodontal state precluding safe orthodontia  Morbid obesity  No formal body mass index (BMI) cut off is currently accepted in literature  It is to be expected that higher BMI may result in poorer outcomes as BMI is an independent risk factor of OSA severity  Advanced age  Medical co-morbidities precluding elective surgery  Particularly cardiovascular disease, pulmonary disease, and haematologic disorders  Psychological instability (including body dysmorphic syndrome)  Alcohol or drug abuse  Unrealistic expectations of outcome 3. Clinical evaluation a. A thorough clinical evaluation of the facial skeleton in sagittal, coronal and axial planes, as well as an evaluation of the occlusion is the necessary first step in planning MMA i. Skeletal analysis:

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Evaluation of skeletal profile with relative contributions of the maxilla and mandible and chin This step can be complemented by an evaluation of the bony bases and their relationship to the skull base using a lateral cephalogram and known angles that define these skeletal profiles (Figure 1)  SNA: Sella (S) - Nasion (N) - Point of the deepest concavity anterior to the maxillary alveolus (A)  SNB: Sella (S) - Nasion (N) - Point of the deepest concavity anterior on the mandibular symphysis (B)  ANB: Point of the deepest concavity anterior to the maxillary alveolus - Nasion (N) - Point of the deepest concavity anterior on the mandibular symphysis (B)

Figure 1. SNA SNB and ANB on lateral cephalogram.

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Comparing the position of the mandibular and maxillary arches to the patient’s anatomic midline and bi-pupillary line to identify any concomitant occlusal cant and/or midline deviation to be corrected ii. Dental analysis:  Occlusion class (Class I vs Class II vs Class III): incisor, canine and molar maxillo-mandibular relationships (Figure 2)  Presence or absence of deep bite deformity  Dental crowding  Incisal show at rest and on maximal smile to evaluate the need to correct a gummy smile and the potential for impaction and counterclockwise rotation without burying the incisors iii. Maxillary transverse dimension and presence of posterior crossbite. Even in the absence of posterior crossbite, a narrow maxilla should prompt the surgeon to discuss maxillary expansion as part of the global surgical treatment plan with the patient and the orthodontist. b. Need for pre-operative and/or post-operative bite correction vs. functional stable bite that should remain unchanged postoperatively c. The clinical evaluation must also incorporate features from the classical facial analysis (nasolabial angle, labio-mental angle, lip position, cervico-mental

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Figure 2. Molar, canine and incisor maxillary -mandibular relationship classification.

d. The synthesis of the soft tissue and skeleto-dental evaluation helps the surgeon determine the amount of advancement and rotation that a particular patient needs i. It also sets the limits that can be tolerated without inducing adverse esthetic and functional results 4. Orthodontic considerations a. All cases of MMA must be planned in coordination with an orthodontist competent in the management of surgical orthodontic cases i. This includes cases where no changes to the pre-existing bite are planned b. Patients with class I occlusion with no planned changes to the occlusion may not require significant pre and postoperative orthodontia c. Patients with Class II and Class III bite require variable amounts of orthodontia pre- and post-operatively for dental decompensation and final occlusal adjustments i. In conjunction with the orthodontist, and according to the planned dental movements, the team may decide on a “surgery first” or “surgery early” approach

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ii.

These approaches allow for rapid execution of the corrective movements of the bony bases by using an “acceptable” stable bite for the immediate postoperative period iii. This bite will then be corrected to the final bite after the surgery by capitalizing on the rapid bone remodeling that occurs in the months following MMA iv. This allows the orthodontist to make significant changes in the bite in a reduced time frame 5. Surgical planning a. MMA can be performed following a Maxilla first approach or a Mandible first approach i. The merits and limitations of each approach are beyond the scope of the present chapter b. Based on the synthesis of the clinical and dental evaluation, the degree of advancement and rotation of the maxillomandibular complex are chosen c. To optimize the advancement of the mandible, a counterclockwise (CCW) rotation of the maxilla can be performed i. In this manner, mandibular autorotation about the TMJ axis allows the mandibular incisors to travel higher along the arc of circle described by the mandible’s rotation ii. This results in a net gain in the antero-posterior advancement of the mandibular incisors (Figure 3), with reduced advancement of the maxilla along with its associated soft tissue esthetic effects

Figure 3. The effect of counter clockwise (CCW) rotation on the advancement of the mandibular incisor and pogonion.

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CCW is limited by the inclination of the upper incisors  Overly labially tipped incisors limit this movement The degree of incisal showing at rest  CCW decreases incisal showing The smile arc  CCW rotation causes increased gumminess of the posterior portion of the smile arc

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Robson Capasso, Tahir Mirza and Badr Ibrahim  The final projected position of the chin d. Care must be taken to consider yaw, pitch and roll movements of both the maxilla and mandible, as well as pre-existing deformities in any of these dimensions in order to include corrections to these deformities in the final movements e. The surgery is then simulated with precise replication of the movements of the bony bases in the three dimensions i. The simulation can be computer based (virtual surgical planning) or performed manually on mounted dental casts (model surgery) ii. Occlusal guides are created at every step of the simulation (intermediate splint and final splint) in order to guide the positioning of the maxilla and mandible relative to the skull bases and to each other in a manner that corresponds to the movements that were set out to be performed iii. The occlusal guides can be handmade during model surgery or 3dimensional (3D) printed following virtual surgical planning and are brought to the operating room to guide the surgeon during MMA

Figure 4. Pre-operative, postoperative positions of the maxilla and mandible with intermediate and final splints.

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6. Surgical steps (Figure 4) a. Depending on which sequence is chosen: i. The 1st jaw is osteotomized, repositioned and then fixated utilizing the intermediate splint ii. The 2nd jaw can then be repositioned utilizing the final splint with the 1st jaw as a new reference point b. Regardless of the method chosen, MMA requires: i. A sub labial midface degloving approach with a Lefort I osteotomy with pterygomaxillary disjunction and down fracture of the maxilla ii. Incisions along the external oblique line of the mandible and subperiosteal dissection of the mandibular angle, body and proximal ramus on the buccal cortex side  At the level of the proximal ramus, a subperiosteal dissection on the lingual cortex side is also necessary to gain access to the mandibular foramen in order to guide the osteotomy lines to perform the bilateral sagittal split osteotomies (BSSO) iii. Intermaxillary fixation with metal wires is used to stabilize the bony bases on the intermediate occlusal splint that helps guide the positioning of the first bone base that is moved  The intermediate splint carries the information required to ensure precise 3D repositioning of the 1st jaw, as per the surgical simulation  Stabilizing the jaws in the relationship defined by the intermediate splint prior to fixation of the mobilized bone base ensures that that bone base will be fixated in the right spatial orientation in relation to the other jaw and the skull base  Once the first mobilized jaw is rigidly fixated, the intermaxillary fixation is removed and the intermediate splint is set aside iv. The procedure then follows with the mobilization of the second jaw  Once the second jaw is fully mobile, the final occlusal splint is used to position the jaws one relative to the other  This relationship is stabilized by an intermaxillary fixation until the second jaw is rigidly fixated  Only then can the intermaxillary fixation be removed once again  At that point, both jaws will have assumed the new position planned pre-operatively v. Use of rigid fixation for the Lefort I and BSSO  MMA usually entails larger movements than classic orthognathic surgery  Relapse from extensive muscle pull can be expected in case of inadequate fixation

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Key steps to optimize outcomes of MMA include: i. Adequate mobilization of the maxilla for it to reach passively its planned advancement site  This step may require subperiosteal dissection of the pterygoid musculature at the pterygo-maxillary disjunction site to improve anterior positioning of the maxilla ii. Passive repositioning of the maxilla on the skull base  This requires removing all bony interferences at the posterior nasal septum, pterygoid plates, and medial maxillary sinus walls iii. Prior to repositioning and rigid fixation of the maxilla, care must be taken to insure:  The nasal septum is not buckling against the maxilla. Septoplasty should therefore be performed as needed.  Conservative inferior turbinate reduction should also be performed to optimize the nasal airway  Pyriform plasty should be performed to enlarge the nasal aperture and optimize nasal breathing iv. Passive apposition of the proximal segment of the BSSO along the distal segment  Any bony interference preventing passive apposition should be removed prior to fixation v. Appropriate repositioning of the proximal segment of the BSSO (carrying the condylar head) into the glenoid fossa at the superiorposterior most position in the glenoid fossa at the time of rigid fixation vi. Meticulous wash and closure of all incisions vii. Intermaxillary fixation with elastic bands to guide the bite and provide passive support to the mandible in the early postoperative period 7. Outcomes a. The outcomes of MMA have been described by three large scale metaanalyses pooling 518, 627, and 462 patients in 45, 22, and 20 studies respectively b. These studies demonstrate surgical success rates (defined as a postoperative apnea-hypopnea index (AHI) lower than 20 events/hour and a 50% reduction from preoperative AHI value) ranging from 80.6% to 86% and cure rates of 35.5% to 43.2% based on a postoperative AHI below 5 i. The cure rate increased up to 66.7% and 55.7% in patients with preoperative AHI below 30 events/hour ii. The mean AHI reduction ranged from 44.8 to 54.4 events/hour and the mean respiratory disturbance index (RDI) reduction ranged from 44.4 to 57.1 events/hour iii. The mean lowest O2 saturation increase ranged from 10.2% to 16.9%.

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.

c.

MMA was associated with a substantial decrease in excessive daytime sleepiness with a mean Epworth sleepiness scale reduction ranging from 8.0 to 10.3 points i. Multiple individual cohorts demonstrated improvement in daytime symptomatology with reduction of morning headaches, memory loss, and impaired concentration ii. Quality of life benefits post MMA were demonstrated using the Functional outcomes of sleep questionnaire (FOSQ) d. While 67% of patients reported by Hotly et al. had previous or concurrent Phase I surgery (i.e., uvulopalatopharyngoplasty), it was demonstrated in a multivariate logistic regression model that concurrent Phase I surgery was not a predictor of success of MMA e. The predictors of surgical success were: i. Lower pre-op BMI ii. Lower age iii. Lower pre-operative AHI iv. Greater degree of maxillary advancement  Greater chance of success with maxillary advancement > 10 mm f. A strong linear correlation exists between pre-operative AHI and the magnitude in the reduction of the AHI post operatively with higher preoperative AHI benefitting from a larger reduction in absolute terms and percentage of change g. The largest meta-analyses reported mean and median mandibular advancements of 10.2 and 10.6 mm respectively i. It is therefore commonly accepted that a 10 mm mandibular advancement should be achieved h. It could not be demonstrated that the degree of advancement of the mandible was a predictor of surgical success i. A 10 mm target should be used as guiding value rather than a fixed objective to meet Individualized treatment planning may require smaller mandibular advancement that would still provide the overall benefits of airway size increase and stabilization provided by MMA while mitigating complication risks and poor esthetic and functional outcomes associated with larger advancements for a particular patient 8. Longevity of treatment with MMA a. The long-term benefits of MMA on OSA, specifically AHI, sleepiness and lowest O2 saturation have been shown to be maintained on the long-term (4-8 years) and very long-term (more than 8 years) in a recent meta-analysis of 6 studies pooling 122 patients i. In the very long term, despite a mean decrease of 29.9 points of the AHI from pre-operative value, the mean residual AHI had reached 23.1 (moderate OSA) ii. The paucity of published long term and very long-term data, as well as the absence of patient level data to determine the influence of

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change in BMI limit the conclusions that can be drawn from this first and sole meta-analysis on this topic Moreover, the normal and expected increase in prevalence of OSA with aging may contribute to dampen the results of MMA over the very long term. This does not, however, decrease the value of the procedure

9. Complications a. Major complications are rare, approximately 1%, and no death are reported from MMA b. Patients should be counseled about the following risks/consequences of MMA as part of the informed consent: i. Perceived unfavorable facial esthetics ii. Mandibular fracture and/or hardware failure needing repeat open reduction and internal fixation with postoperative intermaxillary fixation iii. Discomfort related to the hardware with the need for hardware removal once bone healing is confirmed clinically and radiographically iv. Temporomandibular joint (TMJ) internal derangement, ranging from asymptomatic click to condylar resorption, with a possible degree of ensuing malocclusion  Most patients do experience some degree of TMJ remodeling associated with transient discomfort  Conservative management and occasional use of botulinum toxin injections is by in large the mainstay of treatment for the majority of post MMA TMJ derangements v. Undesired occlusal changes needing prolonged orthodontia vi. Facial paresthesia: inevitably present in the early postoperative period in CN V2 and CN V3 distributions  CN V2 tends to resolve within the first weeks postoperatively while the CN V3 paresthesia resolves partially on a longer time frame  A degree of permanent CN V3 hypoesthesia should be expected at all times  The clinical significance and burden of the residual hypoesthesia to an individual patient varies greatly and is difficult to quantify or predict vii. Nasal obstruction

GENIAL TUBERCLE ADVANCEMENT (GTA) 1. General Principle a. This procedure aims to advance a segment of the mandible carrying the genial tubercles, along with attached musculature

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b. The impact of this procedure is predominantly on the retrolingual airway space c. Multiple different osteotomy shapes and modifications exist in order to capture the bony fragment of the mandible containing the genial tubercle, and hence the attachments of the genioglossus muscle, to be pulled anteriorly and fixated d. Generally considered as an adjunctive procedure rather than a standalone treatment 2. Indications and contraindications a. Indications: i. Moderate to severe OSA with retroglossal obstruction (Fujita Type II and III) unrelated to hypertrophied lingual tonsils Moderate to severe OSA with significant anterior-posterior (A-P) collapse of the tongue base on drug induced sleep endoscopy (DISE) b. Contraindications: i. Exclusive retropalatal and/or hypopharyngeal obstruction without tongue base involvement Poor general health status Insufficient mandibular bone height 3. Key Surgical Steps a. Planning i. Obtain pre-operative imaging (panorex and/or computerized tomography (CT) scan) to plan the position of the osteotomy lines. This process can also be performed pre-operatively via virtual surgical planning.  Mark the height of the genial tubercle from the inferior mandibular border and from the root of the incisors and canine roots  Mark the position of the mental foramina in relation to the genial tubercle and canine roots  All osteotomy lines must remain 5-10 mm inferior to the mental foramina and dental roots and leave a minimum of 10 mm of inferior mandibular height (in the case of a box osteotomy)  If virtual surgical planning (VSP) is used, a 3D printed occlusal-based cutting guide can be used to transfer the information of the osteotomy design from the VSP to the patient intra-operatively b. Approach: i. Under general anesthesia  Local anesthetic with epinephrine infiltration of the chin and lower labial soft tissue ii. Inverted V-shaped mucosal incision 5-10 mm away from the mucogingival junction going from canine to canine

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c.

Incision through the mentalis muscle leaving an adequate soft tissue cuff proximally for closure iv. Subperiosteal dissection to the inferior border of the mandible and extending laterally to allow adequate exposure of bilateral mental nerves Osteotomy i. The two most widely used osteotomy designs for GTA are (Figure 5):

Figure 5. Sliding genioplasty, mortised genioplasty and box genial tubercle advancement.

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

Sliding genioplasty and mortised genioplasty:  A curvilinear osteotomy is performed from one mandibular inferior border to the other  In the case of mortised genioplasty, a superior extension in the incisor region is performed  The bony fragment created by this osteotomy contains the inferior portion of the mandibular symphysis and the genial tubercle  This fragment is freely mobile from the rest of the mandible and is advanced by the desired amount taking into consideration the esthetic impact of an overall chin augmentation on the patient’s profile and lip competence  Miniplate fixation Box osteotomy - genioglossus advancement (GGA):  A rectangular osteotomy, wider than tall, centered on the genial tubercle is executed  The box osteotomy is then advanced until the lingual cortex of the box fragment is slightly beyond the buccal cortex of the remaining mandible  The box is then rotated 90 degrees and allowed to rest on the mandible  The osteotomized fragment is fixated to the mandible by lag screws

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The buccal cortex and the medullary bone are then shaved off to avoid an unsightly augmentation of the chin

d. Closure i. Abundant irrigation 2-layer closure:  Reapproximation and suspension of mentalis muscle to avoid “witch’s chin” deformity  Mucosal closure 4. Outcomes a. Only one small meta-analysis evaluates the OSA outcomes of genioplasty and genial tubercle advancement b. Isolated genial tubercle advancement and genioplasty yield low to moderate improvements in AHI (11.08 and 7.78 points decrease respectively), lowest O2 saturation (mean increase of 2 points), and excessive daytime sleepiness c. These results are greatly improved if genial tubercle advancement or genioplasty is associated with hyoid suspension d. The addition of genial tubercle advancement/genioplasty to MMA did not demonstrate improved OSA related outcomes compared to MMA alone e. Concerns regarding the reported efficacy of genioplasty are related to variations in technique leading to inadequate capture of the genial tubercles in the sliding segment and/or detachment of the genioglossus muscle from their bony attachment to the mandible during the procedure, as well as resorption of the bony segment (mainly in box osteotomy) with loss of tension on the genioglossus muscle over time 5. Complications a. Facial swelling and mental nerve transient hypoesthesia are to be expected b. Uncommon: floor of mouth hematoma with potential airway compromise, surgical site infection, mandibular fracture, tooth root injury

MAXILLARY EXPANSION 1. General principle a. The hard palate is the roof of the oral cavity and the floor of the nasal cavity b. A narrow maxilla leads to a restriction of the nasal airway at the level of the internal and external nasal valves c. Expanding the maxilla is thought to improve the nasal airway, widen the pharyngeal airway and result in an increased stability of the airway during sleep with a concomitant reduction of polygraphic indices d. In adults, expanding the maxilla may require surgically splitting the fused mid-palatal suture and mechanical distraction of the segments in a controlled manner in order to induce osteogenesis

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Maxillary expansion induces a change in occlusion with a necessary orthodontic realignment for restoring functional occlusion following the completion of the expansion f. For the time being, maxillary expansion should be viewed an adjunctive procedure to improve outcomes in OSA surgery and/or CPAP tolerance despite promising results on select patients with OSA as a standalone procedure in emerging studies 2. Indications and contraindications a. All potential candidates for maxillary expansion have to be evaluated by an orthodontist to confirm the indications and feasibility of maxillary expansion b. Indications i. OSA or upper airway resistance syndrome (UARS) patient with transverse maxillary discrepancy and posterior cross bite OSA or UARS patient without posterior crossbite but persistent nasal obstruction, narrow nasal floor, and high arched palate Moderate or severe OSA patients prior to other sleep surgeries with skeletal maxillary hypoplasia and narrow high arched palate c. Contraindication i. Advanced age Orthodontically non-correctible/unstable after expansion 3. Key surgical Steps a. Different surgical techniques exist for performing surgically assisted maxillary expansions b. The most commonly reported on are: i. Surgically Assisted Rapid Maxillary Expansion (SARPE) Distraction Osteogenesis Maxillary Expansion (DOME) c. Both SARPE and DOME require a Lefort I osteotomy and a mid-palatal osteotomy to weaken the areas of maxilla resistance to lateral force and split the maxilla in two halves between the central incisors i. Care must be taken during the latter osteotomy to prevent damage to the incisor roots The Lefort I and mid palatal osteotomy is performed via a sub labial mid face degloving approach or endoscopically d. SARPE classically requires also a pterygomaxillary disjunction e. DOME obviates the need for such a disjunction as it aims to create larger anterior than posterior palatal and nasal enlargement f. Once the bony cuts are performed, a maxillary expander device is activated in order to start the expansion process i. Various protocols exist with regard to the speed of expansion and type of expander used The expansion process is closely monitored by the collaborating orthodontist g. A key difference in technique is the use of micro-implanted expander with mini screws through both palatal cortices at the height of the palatal vault in DOME. Indeed, applying force directly in the paramedian region of the mid palatal sutures via the micro-implanted distractor (implanted by the

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orthodontist prior to the day of surgery or on the day of surgery by the surgeon) allows for more targeted expansion of the palatal portion proper of the maxillary bone and the nasal floor. i. SARPE uses a classical expander exerting its force on a dental anchoring point The resulting force can cause a greater degree of alveolar bone expansion and dental tilting as opposed to pure palatal roof growth h. A variable period (6 – 12 months) of retention is planned by the orthodontist during which the expander is left in place to avoid relapse as the bone forms and solidifies. i. A concomitant course of orthodontia is planned to correct the incisor diastema that has been created and correct the occlusion following expansion and/or prepare the occlusion for upcoming MMA j. Some authors advocate non-surgical expansions using bone anchored devices in carefully selected patients with yet unfused mid palatal sutures i. This technique is called micro-implant- Assisted Rapid Palatal Expansion (MARPE) It is usually performed by the orthodontist Its use for OSA treatment has yet to be proven 4. Outcomes a. Maxillary expansion was classically performed to correct dentofacial deformity i. Its role in the treatment of adult nasal obstruction and obstructive sleep apnea specifically is emerging in the literature b. The most widely studied technique and largest published series of adult maxillary expansion for OSA and nasal obstruction use DOME c. Outcomes of DOME on objective polygraphic measurements showed an AHI reduction of 53.8%, RDI reduction of 49.9%, and oxygen desaturation index (ODI) reduction of 60.9% d. DOME also improved subjective assessment of nasal obstruction and daytime sleepiness with a mean reduction of NOSE score by 70% and Epworth sleepiness scale reduction of 36.2% i. This subjective improvement is correlated to an objective increase in cross sectional area of the internal nasal valve e. SARPE also demonstrated promising results for OSA with a similar AHI reduction of 56.6% i. Beneficial effects on upper and lower pharyngeal airway volumes was objectively demonstrated using pre- and post-operative CT scan f. Only one systematic review and meta-analysis on the role of maxillary expansion in adults (surgical and non-surgical) exists i. The results show statistically significant pooled mean decrease in nasal resistance (mean reduction of 0.27 Pa/cm3/s) and improvement in subjective assessment of nasal obstruction (mean reduction of 40 points on NOSE score) following maxillary expansion Significant heterogeneity between studies due to the use of different surgical techniques, different outcomes measured, and different

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Robson Capasso, Tahir Mirza and Badr Ibrahim methods to measure outcomes limit the conclusion on any further benefit of maxillary expansion at this time 5. Complications a. Complications vary greatly according to the technique i. Maxillary expansion is considered a safe procedure with rare major complications Possible complications include: bleeding, malunion, non-union, relapse, oronasal fistula, tooth root damage, and/or loss of incisor vitality requiring root canal treatment b. Transient CN V2 paresthesia can be expected in techniques requiring a Lefort I osteotomy with midfacial degloving

KEY CLINICAL POINTS 1. MMA is a proven safe and effective long-term treatment for select patients with moderate to severe OSA patients intolerant of/failing CPAP. 2. MMA should be proposed to patients seeking a surgical treatment for OSA with an underlying dentofacial deformity, in patient with selected patterns of pharyngeal closure on DISE, and/or after failure of soft tissue and nasal surgery. 3. Selected maxillary expansion surgeries improve both OSA outcomes and nasal obstruction outcomes. Maxillary expansion should be considered as an adjunctive procedure in the surgical care of selected OSA patients. 4. Any bite altering procedure should be planned during a collaborative consultation with the patient and their orthodontist to determine feasibility and confirm the surgical plan. 5. Genial tubercle advancement is an adjunctive procedure that can be coupled to soft tissue surgery or MMA. It does not represent a standalone treatment for OSA.

QUESTIONS 1. Which is NOT an indication of MMA? a. Moderate and Severe obstructive sleep apnea (OSA) intolerant to CPAP b. Loud snoring with dentofacial deformity c. OSA with lateral pharyngeal wall collapse and concentric collapse at the velum d. Recurring OSA following soft tissue surgery at the velum and/or tongue base including genioglossus advancement 2. Which is NOT a demonstrated predictor of surgical success of MMA? a. lower pre-op BMI b. lower age c. lower pre-operative AHI d. Greater degree of mandibular advancement e. Greater degree of maxillary advancement

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3. Which is/are proven outcomes of genial tubercle advancement? a. Low to moderate AHI improvement b. Improved lowest O2 saturation c. Improved excessive daytime sleepiness d. All of the above

4. Which is true of genial tubercle advancement? a. It yields better results when combined to hyoid suspension b. It has shown to positively impact OSA related outcomes of MMA c. Has uniform outcomes across techniques and osteotomy designs d. Is rarely associated to mental nerve hypoesthesia 5. Which of the following maxillary expansion technique/s have proven to have beneficial OSA specific outcomes? a. MARPE i. SARPE ii. DOME

REFERENCES Abdelwahab M, Yoon A, Okland T, Poomkonsarn S, Gouveia C, Liu SY. Impact of Distraction Osteogenesis Maxillary Expansion on the Internal Nasal Valve in Obstructive Sleep Apnea. Otolaryngol Head Neck Surg. 2019 Aug;161(2):362–7. doi: 10.1177/ 0194599819842808. Boyd SB, Chigurupati R, Cillo JE Jr, Eskes G, Goodday R, Meisami T, Viozzi CF, Waite P, Wilson J. Maxillomandibular Advancement Improves Multiple Health-Related and Functional Outcomes in Patients With Obstructive Sleep Apnea: A Multicenter Study. J Oral Maxillofac Surg. 2019 Feb;77(2):352-370. doi: 10.1016/j.joms.2018.06.173. Boyd SB, Walters AS, Song Y, Wang L. Comparative Effectiveness of Maxillomandibular Advancement and Uvulopalatopharyngoplasty for the Treatment of Moderate to Severe Obstructive Sleep Apnea. J Oral Maxillofac Surg. 2013 Apr 1;71(4):743–51. doi: 10.1016/j.joms.2012.10.003. Brunetto DP, Sant Anna EF, Machado AW, Moon W. Non-surgical treatment of transverse deficiency in adults using Microimplant-assisted Rapid Palatal Expansion (MARPE). Dent Press J Orthod. 2017;22:110–25. doi: 10.1590/2177-6709.22.1.110-125.sar. Calvo-Henriquez C, Megias-Barrera J, Chiesa-Estomba C, Lechien JR, Maldonado Alvarado B, Ibrahim B, Suarez-Quintanilla D, Kahn S, Capasso R. The Impact of Maxillary Expansion on Adults' Nasal Breathing: A Systematic Review and Meta-Analysis. Am J Rhinol Allergy. 2021 Feb 14:1945892421995350. doi: 10.1177/1945892421995350. Camacho M, Noller MW, Del Do M, Wei JM, Gouveia CJ, Zaghi S, Boyd SB, Guilleminault C. Long-term Results for Maxillomandibular Advancement to Treat Obstructive Sleep

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Apnea: A Meta-analysis. Otolaryngol Head Neck Surg. 2019 Apr;160(4):580-593. doi: 10.1177/0194599818815158. Holty JE, Guilleminault C. Surgical options for the treatment of obstructive sleep apnea. Med Clin North Am. 2010/05/11 ed. 2010 May;94(3):479–515. doi: 10.1016/j.mcna.2010. 02.001. Holty J-EC, Guilleminault C. Maxillomandibular advancement for the treatment of obstructive sleep apnea: A systematic review and meta-analysis. Sleep Med Rev. 2010 Oct 1;14(5):287–97. doi: 10.1016/j.smrv.2009.11.003. Li K, Quo S, Guilleminault C. Endoscopically-assisted surgical expansion (EASE) for the treatment of obstructive sleep apnea. Sleep Med. 2019 Aug 1;60:53–9. doi: 10.1016/j. sleep.2018.09.008. Liu SY, Huon LK, Zaghi S, Riley R, Torre C. An Accurate Method of Designing and Performing Individual-Specific Genioglossus Advancement. Otolaryngol Head Neck Surg. 2017 Jan;156(1):194-197. doi: 10.1177/0194599816670366. Liu SY, Wayne Riley R, Pogrel A, Guilleminault C. Sleep Surgery in the Era of Precision Medicine. Atlas Oral Maxillofac Surg Clin North Am. 2019 Mar;27(1):1-5. doi: 10.1016/j.cxom.2018.11.012. Liu SY-C, Guilleminault C, Huon L-K, Yoon A. Distraction Osteogenesis Maxillary Expansion (DOME) for Adult Obstructive Sleep Apnea Patients with High Arched Palate. Otolaryngol Neck Surg. 2017 Aug 1;157(2):345–8. doi: 10.1177/019459981 7707168. Lye KW, Waite PD, Meara D, Wang D. Quality of Life Evaluation of Maxillomandibular Advancement Surgery for Treatment of Obstructive Sleep Apnea. J Oral Maxillofac Surg. 2008 May 1;66(5):968–72. doi: 10.1016/j.joms.2007.11.031. Perez D, Ellis E. Implications of Sequencing in Simultaneous Maxillary and Mandibular Orthognathic Surgery. Atlas Oral Maxillofac Surg Clin North Am. 2016 Mar;24(1):45–53. doi: 10.1016/j.cxom.2015.10.004. Posnick JC. 16 - Complications Associated with Orthognathic Surgery. In: Posnick JC, editor. Orthognathic Surgery [Internet]. St. Louis: W.B. Saunders; 2014. p. 475–542. Available from: http://www.sciencedirect.com/science/article/pii/B9781455726981000162 Powell NB, Riley RW. Chapter 108 - Surgical Management for Obstructive Sleep-Disordered Breathing. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine (Fifth Edition) [Internet]. Philadelphia: W.B. Saunders; 2011. p. 1250–65. Available from: http://www.sciencedirect.com/science/article/pii/B9781416066453 001080 Song SA, Chang ET, Certal V, Del Do M, Zaghi S, Liu SY, Capasso R, Camacho M. Genial tubercle advancement and genioplasty for obstructive sleep apnea: A systematic review and meta-analysis. Laryngoscope. 2017 Apr;127(4):984-992. doi: 10.1002/lary.26218. Vinha PP, Thuler ER, de Mello-Filho FV. Effects of surgically assisted rapid maxillary expansion on the modification of the pharynx and hard palate and on obstructive sleep apnea, and their correlations. J Cranio-Maxillofac Surg. 2020 Apr 1;48(4):339–48. doi: 10.1016/j.jcms.2020.02.007. Williams R, Patel V, Chen YF, Tangbumrungtham N, Thamboo A, Most SP, Nayak JV, Liu SYC. The Upper Airway Nasal Complex: Structural Contribution to Persistent Nasal Obstruction. Otolaryngol Head Neck Surg. 2019 Jul;161(1):171-177. doi: 10.1177/ 0194599819838262.

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Yoon A, Guilleminault C, Zaghi S, Liu SY-C. Distraction Osteogenesis Maxillary Expansion (DOME) for adult obstructive sleep apnea patients with narrow maxilla and nasal floor. Sleep Med. 2020 Jan 1;65:172–6. doi: 10.1016/j.sleep.2019.06.002. Zaghi S, Holty JE, Certal V, Abdullatif J, Guilleminault C, Powell NB, Riley RW, Camacho M. Maxillomandibular Advancement for Treatment of Obstructive Sleep Apnea: A Metaanalysis. JAMA Otolaryngol Head Neck Surg. 2016 Jan;142(1):58-66. doi: 10.1001/ jamaoto.2015.2678.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 24

HYPOGLOSSAL NERVE STIMULATION FOR TREATMENT OF OSA Maurits Boon1, MD and Maria V. Suurna2, MD 1

Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA 2 Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medicine, New York, NY, USA

INTRODUCTION 1. Hypoglossal nerve stimulation (HNS) therapy is a novel obstructive sleep apnea (OSA) treatment for select positive airway pressure (PAP) intolerant patients 2. Inspire Medical is the only company with an FDA approved device a. As of 2020, 2 other companies have devices that are used worldwide and are in trials in the United States b. These include LivaNova and Nyxoah 3. Implanted neurostimulation device stimulates branches on the hypoglossal nerve leading to stiffening and forward motion of the tongue to keep the upper airway open during sleep 4. Selective implantation of the medial branch of the hypoglossal nerve is critical to success 5. Single intervention that produces multilevel airway opening 6. Growing body of literature supporting good outcomes with limited complications

HYPOGLOSSAL NERVE 1. Cranial nerve 12 (CN XII) a. Innervates muscles of the tongue b. Tongue function is important for speech, swallowing and breathing

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Maurits Boon and Maria Suurna 2. Arises from the medulla oblongata 3. Exits cranium via the hypoglossal canal 4. Courses deep to the submandibular gland, mylohyoid muscle as well as posterior belly and tendon of digastric muscle 5. Runs superficial to the hyoglossus muscle 6. Pure motor nerve innervates extrinsic and intrinsic tongue muscles and consistently organizes into medial and lateral divisions (Figure 1)

Figure 1. Intraoperative hypoglossal (HG) (XII) nerve anatomy. Lateral division styloglossus/hyoglossus (l-XII SG/HG), medial division genioglossus horizontal (m-XII GGh) and genioglossus oblique (m-XII GGo), cervical nerve 1 (C1), Ranine vein.

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Extrinsic muscles i. Medial division  Genioglossus horizontal (GGh) extends from the mandible to the tongue base and pulls the tongue base forward  Genioglossus oblique (GGo) extends from the mandible to the tongue body and pulls the tongue base down ii. Lateral division  Hyoglossus (HG) extends from the hyoid bone to the tongue side retracts and depresses the tongue  Styloglossus (SG) extends from the styloid process to the tongue side and retracts and elevates the tongue b. Intrinsic muscles i. Medial division  Inferior longitudinal medial (m-IL) extends from the tongue base to the inferior tongue tip

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

Transverse muscle (T) extends from the median septum to lateral margin of the tongue and narrows the tongue  Vertical muscle (V) extends from dorsal mucosa to ventral mucosa of the tongue and flattens the tongue ii. Lateral division  Superior longitudinal (SL) extends from the tongue base to the superior tongue tip  Inferior longitudinal lateral (l-IL) extends from the tongue base to the inferior tongue tip 7. Extracranially, joined by spinal nerve rootlets C1/C2 which later depart and contribute to ansa cervicalis as well as innervate geniohyoid (GH) and thyrohyoid muscles 8. Ranine vein accompanies the nerve a. More dominant vessel is usually located inferior to the nerve b. Smaller branch is superior to the nerve c. Frequently crossing branches overlie the nerve d. Vein can be preserved in most cases during HNS implant surgery 9. Anatomic organization of the nerve is exploited in positioning of cuff on medial branches of the nerve to ideally produce stiffening and unrestricted protrusion of the tongue with stimulation

HYPOGLOSSAL NERVE STIMULATION THERAPY (INSPIRE MEDICAL) (FIGURE 2) 1. Implantable device a. Implantable pulse generator (IPG) implanted below the clavicle b. Neurostimulation cuff placed on the medial branch of the hypoglossal nerve in the submandibular area c. Respiratory sensor placed in the intercostal space 2. Mechanism of action: a. Knowledge of anatomy of the nerve is key to understanding this therapy b. Selective stimulation of medial nerve branch produces stiffening and protrusion of tongue c. Stiffened and protruding tongue will produce base of tongue anterior movement, epiglottic movement, hypopharyngeal expansion, and retropalatal opening i. Epiglottic engagement can be secondary to incorporation of C1 nerve branch innervating GH muscle ii. Mechanism of palatal engagement is thought to be secondary to coupling resulting from palatoglossus muscle anchored to tongue musculature d. In appropriate responders, hypoglossal nerve stimulation produces multi-level airway opening by improving retropalatal, retroglossal and possibly retroepiglottic posterior airway space

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Figure 2. Diagram of hypoglossal nerve stimulation therapy.

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Phasic stimulation of nerve i. Tonic stimulation of any motor nerve produces muscle fatigue f. Respiratory sensor monitors breathing pattern and signals to the IPG to deliver neurostimulation at the initiation of each breath g. Long term effects of stimulation do not alter airway physiology, thus discontinuation of the therapy is possible 3. Indications and selection criteria: a. Documented trial of continuous positive airway pressure (CPAP)/bilevel positive airway pressure (BiPAP) with intolerance b. Age 18 or greater i. Trials are being performed on use in children with Down syndrome c. Body mass index (BMI) of 35 kg/m2 or less. d. Apnea hypopnea index (AHI) 15-65 events per hour e. Less than 25% of mixed or central apneas in overall AHI. f. No complete concentric collapse (CCC) of the palate on drug induced sleep endoscopy (DISE) i. The palate determines candidacy – CCC is thought to represent a phenotype that will not produce palatal coupling to open the retropalatal airway

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g. Additional contraindications: i. History of neuromuscular disorders ii. Active psychiatric disease iii. Untreated sleep disorders such as insomnia iv. Pregnancy v. Severe cardiopulmonary disease vi. Need for routine MRI of chest, abdomen or pelvis  Current HNS model is magnetic resonance imaging (MRI) conditional 4. Predictors of success: a. No universal consensus as to ideal candidate for HGNS. However, some predictors that have been identified: i. BMI  Some conflicting data  However, as BMI increases there is general consensus that outcomes are worse especially in extremes of BMI ii. Age  Multicenter registry evaluating outcomes with upper airway stimulation (ADHERE)  Increasing age associated with better outcomes iii. Gender  ADHERE registry data: Females have better outcomes iv. Expert consensus is that significant lateral oropharyngeal wall collapse suggests poor response (unpublished data) 5. Surgical Technique: a. General anesthesia with oral or nasotracheal intubation b. Nerve integrity monitoring (NIM) Prass Paired 18 mm needle electrodes placed into the tongue muscles: i. SG/HG muscle: submucosal placement on the ventral lateral side of the tongue approximately 5 cm from the tip superficial tongue to monitor activation of the lateral branches of the nerve to be excluded from stimulation cuff ii. GG muscle: placement in the floor of mouth slightly off midline to monitor medial branches of the nerve to be included in the stimulation cuff c. Right sided approach is standard i. Left side can be considered in select circumstances (Table 1) d. 3-5 cm incision is placed in the neck crease of the submandibular area from the midpoint of the submandibular gland and extending towards midline e. Anterior border of the submandibular gland is identified and the gland is retracted posteriorly f. Posterior belly and tendon of digastric muscle is retracted inferiorly g. Mylohyoid muscle is visualized and retracted anteriorly

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Maurits Boon and Maria Suurna Table 1. Indications for left sided implant

Occupation or activities that require right arm or shoulder that could be impaired by an IPG in chest Law enforcement Professional athlete Right-handed hunter Existence of an implantable medical device on the right Pacemaker AICD Prior surgery in the right neck or chest which may distort surgical planes Neck dissection Submandibular gland excision Mastectomy Unilateral breast reconstruction with implant Prior radiation to the right neck History of hypoglossal nerve palsy on the right

Figure 3. A. EMG response on the Genioglossus (GG) channel to stimulation of the medial division. B. Synchronous activity of Styoglossus/Hyoglossus (SG/HG) channel mimicking the wave in GG channel indicating presence of fibers to intrinsic muscles. C. Monophasic response in the GG channel and erratic, polyphasic response in the SG/HG channel indicating presence of retained late retractor fibers.

h. This allows identification of the hypoglossal nerve and its associated ranine vein i. Selective placement of stimulation cuff on medial branch of hypoglossal nerve i. Bipolar stimulation probe (Medtronic, Minneapolis, MN) used to confirm anatomic identification of the medial branch by recording of characteristic electromyography (EMG) signal on NIM monitor and by visual observation of muscles being stimulated (Figure 3A) ii. Division of lateral and medial branches or breakpoint is usually evident by presence of vasa vasorum that runs parallel on the superior aspect of the medial division (Figure 1) iii. Dissection is performed to separate lateral and medial divisions iv. Identification and inclusion of C1/C2 is recommended

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Bipolar stimulation at the superior edge of the medial division is performed to identify and isolate late takeoff retractor nerve fibers  Observation of a synchronous, monophasic EMG wave on the SH/HG channel mimicking the EMG wave on the GG channel indicates presence of T/V nerve fibers (Figure 3B)  Observation of an erratic, polyphasic EMG wave on the SH/GH channel in a different phase from GG channel indicates presence of a retractor branch (Figure 3C)  Further dissection of the retained retractor branch should be performed prior to placement of the stimulation cuff vi. Ranine vein can be preserved in most cases j. Implantable pulse generator pocket created in upper right chest superficial to pectoralis major k. Respiratory sensor placed using the same incision as the IPG. i. Historically, a 3rd incision was made anterior to mid axillary line in the 4th or 5th intercocostal space for placement of respiratory sensor lead. ii. After completing pocket for IPG, pectoralis major muscle is bluntly dissected over the 2nd intercostal space and fibers separated to allow exposure of deep musculature. iii. External intercostal muscle is identified and dissected to allow the exposure of underlying internal intercostal muscle.  External intercostal muscle is frequently dehiscent as you approach the sternum and may only be associated with a fascial layer.  Pectoralis minor has variable position and may appear to have similar orientation and appearance as the external intercostal. iv. Sensor placed in a medial to lateral direction inbetween the external and internal intercostal muscles. v. Sensor should be placed away from the neurovascular bundle running on inferior aspect of the rib (superior aspect of intercostal space). vi. Anchor is fixed to the external intercostal muscle and the secondary anchor can be placed deep to the pectoralis muscle or brought out through pectoralis to sit superficial to the muscle. vii. Stimulation lead tunneled to the IPG pocket in subplatysmal plane l. Leads connected to IPG m. IPG secured to chest wall n. System interrogated for appropriate function i. Respiratory wave evaluated ii. Stimulation carried out to identify unrestricted tongue protrusion straight forward or to contralateral side of the implant iii. Identification of mixed activation when tongue pulls to the ipsilateral side of the implant requires re-exploration of the nerve and replacement of the cuff to exclude any late hyoglossus nerve branches

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Maurits Boon and Maria Suurna o. Chest X-ray and lateral neck X-ray obtained in recovery room i. Rule out pneumothorax ii. Identify baseline position of stimulation cuff and respiratory sensing lead 6. Follow up and Programming: a. Patients seen at 1 week postoperatively for evaluation of appropriate healing and adverse events b. Therapy remains inactive for 4 weeks to allow adequate healing prior to initiating therapy c. Stimulation initiated at sub-therapeutic levels to allow patients to acclimate to the therapy d. Follow up sleep study obtained to confirm adequate reduction in disease burden as measured by AHI/respiratory events index (REI) e. Patients struggling with therapy may require advanced programming or adjunctive therapy i. Discomfort with/intolerance of therapy ii. Persistent symptoms of OSA iii. Inadequate reduction in AHI/REI iv. Combination of any of the above f. Neurostimulation cuff contains 3 electrodes which can be selectively programed as a cathode (-) or an anode (+) which allow the field of stimulation to be changed i. Bipolar settings [+-+, -+-] ii. Unipolar settings [-o-; o-o; ---], IPG is programmed as anode (+) g. Additional programming to adjust pulse width and pulse rate can be performed to further improve therapy tolerance and airway opening i. Default settings: +-+; pulse width 90 µs, rate 33 Hz h. Patient compliance and usage is monitored by downloading the data from the remote used to activate the therapy 7. Outcomes: a. First published date came from stimulation therapy for apnea reduction (STAR trial) i. Median reduction in AHI of 68% from 29.3 to 9.0 at 12 months ii. Improvements in quality-of-life measures including Epworth sleepiness scale (ESS) and functional outcomes of sleep questionnaire (FOSQ) iii. Serious adverse events < 2% iv. Randomized therapy withdrawal with recurrence of symptoms and evidence of at least moderate OSA b. Multiple subsequent reports of efficacy and low complications i. ADHERE registry  Largest cohort of patients reported to date  Mean AHI decrease from 35.6 to 10.2  Average device usage 6.5 hours/night

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8. Complications/Adverse events: a. Overall morbidity is low i. In the ADHERE registry most common complication was therapy related discomfort which occurred in 12% and decreased to 8% at 1 year of therapy use b. Complications associated with the therapy: i. Therapy related discomfort  Most common complication  Includes tongue discomfort/abrasions from stimulation, arousal from stimulation, occipital or neck pain from stimulation  Can usually be resolved with altering stimulation parameters  Tongue abrasions/discomfort may benefit from dental appliance  Rarely necessitates explantation ii. Hypoglossal nerve injury  Transient paresis or paralysis occurs in < 1%  No permanent injury is reported to date  Therapy activation should be delayed until nerve function returns to normal iii. Marginal mandibular nerve injury  Lower lip weakness can be due to platysma being cut during surgery and resolves within weeks after surgery  Permanent injury is rare iv. Pneumothorax  Asymptomatic can be managed conservatively with observation and serial chest X-ray  Large or symptomatic may require chest tube and may require delay in placing the respiratory sensor v. Infection  Superficial cellulitis – managed by oral or IV antibiotic and close follow up  Deep infection – complete device explant and antibiotic therapy vi. Hematoma  Increased risk with anticoagulant use  Manage any anticoagulant medication  Pressure dressing  Avoid incision or aspiration due to infection risk  Most hematomas or seromas resolve with conservative management  Expanding hematoma – managed by operative exploration under sterile conditions vii. Mixed activation

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viii.

ix.

x.

xi.

xii.

Stimulation with unfavorable tongue motion Caused by inclusion of retractor fibers within the stimulation cuff Usually identified at activation Associated with lower responder rate May require repositioning of stimulation lead Precise intraoperative stimulation cuff placement on the medial nerve division helps avoid postoperative mixed activation

Pain  IPG site discomfort may require repositioning of IPG  Neuropathic pain in the respiratory sensor lead area – replace lead in new intercostal space or in posterior orientation in same intercostal space Lead visibility  Can be noted on the stimulation lead with tenting of skin with neck extension  Most often managed by range of motion exercises  Incidence reduced by subplatysmal tunneling Device malfunction  Can result from manufacturer related issues as well as damage to lead or the system during implantation  Long term dysfunction or breakage can result from stress forces on leads with movement  Iatrogenic injury has been reported with cardioversion  In majority of cases revision surgery with replacement of the malfunctioning component is required Hypertrophic scar  Most common at the IPG site  Can be managed conservatively  Caution with injection of corticosteroids to minimize infection due to hardware in close proximity Implant exposure / migration  IPG rotation:  More common in women due to breast tissue that may allow more movement of IPG  Incidence reduced by securing IPG using medial and lateral anchor holes  Most commonly associated with unpleasant sensation or discomfort  Long term can result in lead damage or displacement  Twiddler’s syndrome:  First described with pacemakers

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Intentional manipulation of IPG, rotating device with subsequent lead damage/displacement

9. Special Populations a. Down Syndrome: i. Limited data in adults with suggestion of success in select patients ii. Pediatric trials underway with positive results b. Outside of FDA indications: i. Limited data on use in BMI > 35, AHI > 65, and CCC ii. Need for further investigation to identify ideal candidates and whether use in these populations is beneficial 10. Multidisciplinary Approach: a. General acceptance that multidisciplinary approach optimizes patient care i. Sleep Medicine ii. Otolaryngology iii. Sleep dentistry iv. Bariatrics v. Oral surgery vi. Cardiology vii. Psychiatry b. Complexity of patient population i. Co-existent sleep disorders that require independent treatment  Insomnia  Restless legs  Periodic limb movement disorder  Idiopathic hypersomnolence ii. Co-morbid medical disorders that require attention (perioperatively and postoperatively)  Cardiac disorders  Metabolic syndrome  Psychiatric disorders iii. Impact of non-anatomic factors on pathophysiology of OSA  Neuromuscular tone  Loop gain  Low arousal threshold c. Consideration of adjunctive therapy to optimize outcomes i. Anatomy altering surgery ii. Oral appliance therapy iii. Positional therapy iv. Chin strap

DEVICES UNDER INVESTIGATION 1. Aura6000 System (LivaNova)

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Maurits Boon and Maria Suurna a.

Consists of rechargeable battery neurostimulator implant and 6 electrode stimulation cuff lead b. Neurostimulator is implanted below the clavicle c. Stimulation cuff is placed through a submandibular incision on the main trunk of the hypoglossal nerve d. It delivers continuous stimulation e. Stimulation is not synchronized with respirations 2. Genio Implantable Stimulation System (Nyxoah) a. Consists of two sets of paired stimulating electrodes and a receiving antenna b. Implanted under the chin on top of both genioglossus muscles bilaterally c. Uses external adhesive device activation unit d. Stimulation is not synchronized with respirations

KEY CLINICAL POINTS 1. HNS therapy should be considered as an alternative treatment options in patients with moderated to severe OSA who are PAP intolerant 2. HNS therapy is indicated for PAP intolerant adult patients who meet the following criteria a. AHI 15-65 b. BMI < 35 kg/m2 c. Absence of CCC on DISE d. < 25% of central and mixed apneas 3. Therapy programming and adjustments should be performed based on individual therapy response assure optimal therapy compliance and outcomes 4. Combination treatment should be considered in patients with incomplete resolution of OSA with HNS therapy use 5. Multidisciplinary approach should be implemented to provide best treatment options and outcomes for patients with OSA

QUESTIONS 1. A 75-year-old female is referred for evaluation of upper airway stimulation. She was initially diagnosed with moderate OSA with an AHI of 25 and attempted an oral appliance as first line therapy but could not tolerate due to temporomandibular joint discomfort. Her body mass index at presentation was 33.5. A drug induced sleep endoscopy was performed revealing a vote score of 4 with complete anterior posterior collapse of the palate, and complete tongue base collapse. Which of the following is true? a. Hypoglossal nerve stimulation is contraindicated as her age is outside of current indications. b. She meets appropriate consideration for hypoglossal nerve stimulation and should be offered this therapy.

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c.

Hypoglossal nerve stimulation is contraindicated as she has not attempted CPAP therapy. d. Hypoglossal nerve stimulation is contraindicated due to her elevated BMI. 2. During a procedure to implant a hypoglossal nerve stimulator, the nerve is exposed and stimulated with a bipolar stimulation probe. The following image is obtained:

Which of the following is true? a. This image depicts stimulation of the medial branch of the hypoglossal nerve with inclusion of the TV branch and it would be appropriate to place the stimulation cuff without further dissection. b. This image depicts stimulation that includes a late retrusor branch of the hypoglossal nerve. Further dissection of the nerve is warranted to identify any late branches and exclude them from the cuff. c. This image depicts stimulation of C1/C2 which should be excluded from the cuff. d. This image depicts stimulation of specific fibers that innervate the gengioglossus muscle without evidence of stimulation of any other tongue muscles. 3. Which of the following is not true regarding anatomy of the hypoglossal nerve: a. The hypoglossal nerve exits the hypoglossal canal, runs deep to the digastric muscle and superficial to the hyoglossus muscle.

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Maurits Boon and Maria Suurna b. The hypoglossal nerve is consistently accompanied by the ranine vein which may have branches both above and below the nerve. c. The hypoglossal nerve is divided into a medial and lateral branch. The lateral branch innervates muscles primarily responsible for stiffening and protruding the tongue. d. The hypoglossal nerve is a pure motor nerve. It is consistently accompanied by C1 and C2 spinal nerves which exit the main branch to form a portion of ansa-cervicalis. 4. Which of the following is true regarding complications of hypoglossal nerve stimulation therapy and the surgery for implantation? a. Hypoglossal paresis following surgery is common but typically resolves within 1 year following surgery. b. Since pneumothorax is most commonly identified during the surgery, postoperative chest X-ray is not indicated for uncomplicated hypoglossal nerve stimulation placement. c. When patient presents with hematoma at the site of the chest incision, needle aspiration should be performed to prevent infection. d. Most complaints of therapy discomfort can be addressed with setting adjustments. 5. A patient returns 2 weeks after hypoglossal nerve stimulator implantation and is noted to have significant swelling overlying the IPG site that is mildly erythematous and fluctuant. The patient notes discomfort over the site. The patient is afebrile, there is no drainage from the wound and the other operative sites appear to be consistent with normal postoperative healing without erythema or abnormal swelling. He does not appreciate significant change in the size of the collection since first noticed 48 hours prior. He recalls doing moderate activity with his arm on the affected side prior to onset. Recommendations for management would include which of the following: a. Conservative care with minimizing movement of the arm on the affected side, close follow up and a pressure dressing. b. Needle aspiration of the affected area to ensure that the collection is not purulent, decompress the area and to obtain culture. c. This likely represents deep infection and would warrant complete explantation, culture of affected wounds and antibiotic therapy. d. This is consistent with an expanding hematoma and would warrant urgent exploration under sterile conditions.

REFERENCES Boon M, Huntley C, Steffen A, Maurer J T, Sommer J U, Schwab R, Thaler E, Soose R, Chou C, Strollo P, Kezirian E J, Chia S, Withrow K, Weidenbecher M, Strohl K, Doghramji K, Hofauer B, Heiser C; ADHERE Registry Investigators. Upper Airway Stimulation for

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Obstructive Sleep Apnea: Results from the ADHERE Registry. Otolaryngol. Head Neck Surg. 2018 Aug;159(2):379-385. doi: 10.1177/0194599818764896. Diercks G R, Wentland C, Keamy D, Kinane T B, Skotko B, de Guzman V, Grealish E, Dobrowski J, Soose R, Hartnick C J. Hypoglossal Nerve Stimulation in Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol. Head Neck Surg. 2018 Jan 1;144(1):37-42. doi: 10.1001/jamaoto.2017.1871. Heiser C, Steffen A, Boon M, Hofauer B, Doghramji K, Maurer J T, Sommer J U, Soose R, Strollo P J Jr, Schwab R, Thaler E, Withrow K, Kominsky A, Larsen C, Kezirian E J, Hsia J, Chia S, Harwick J, Strohl K, Mehra R; ADHERE registry investigators. Post-approval upper airway stimulation predictors of treatment effectiveness in the ADHERE registry. Eur. Respir. J. 2019 Jan 3;53(1):1801405. doi: 10.1183/13993003.01405-2018. Heiser C, Thaler E, Boon M, Soose R J, Woodson B T. Updates of operative techniques for upper airway stimulation. Laryngoscope. 2016 Sep;126 Suppl 7:S12-6. doi: 10.1002/lary. 26158. Huntley C, Steffen A, Doghramji K, Hofauer B, Heiser C, Boon M. Upper Airway Stimulation in Patients With Obstructive Sleep Apnea and an Elevated Body Mass Index: A Multiinstitutional Review. Laryngoscope. 2018 Oct;128(10):2425-2428. doi: 10.1002/lary. 27426. Lee J J, Sahu N, Rogers R, Soose R J. Severe obstructive sleep apnea treated with combination hypoglossal nerve stimulation and oral appliance therapy. J. Dental Sleep Med. 2015;2(4): 185-186. Li C, Boon M, Ishman S L, Suurna M V. Hypoglossal nerve stimulation in three adults with down syndrome and severe obstructive sleep apnea. Laryngoscope. 2019 Nov;129(11): E402-E406. doi: 10.1002/lary.27723. Mu, L. and I. Sanders, Human Tongue Neuroanatomy: Nerve Supply and Motor Endplates. Clinical anatomy (New York, N.Y.). 2010;23(7): p. 777-791. Ramaswamy A T, Li C, Suurna M V. A case of hypoglossal nerve stimulator-resistant obstructive sleep apnea cured with the addition of a chin strap. Laryngoscope. 2018 Jul; 128(7):1727-1729. doi: 10.1002/lary.27010. Steffen A, Abrams N, Suurna M V, Wollenberg B, Hasselbacher K. Upper-Airway Stimulation Before, After, or Without Uvulopalatopharyngoplasty: A Two-Year Perspective. Laryngoscope. 2019 Feb;129(2):514-518. doi: 10.1002/lary.27357. Steffen A, Hartmann J T, König I R, Ravesloot M J L, Hofauer B, Heiser C. Evaluation of body position in upper airway stimulation for obstructive sleep apnea-is continuous voltage sufficient enough? Sleep Breath. 2018 Dec;22(4):1207-1212. doi: 10.1007/s11325-0181716-5. Strollo P J Jr, Soose R J, Maurer J T, de Vries N, Cornelius J, Froymovich O, Hanson R D, Padhya T A, Steward D L, Gillespie M B, Woodson B T, Van de Heyning P H, Goetting M G, Vanderveken O M, Feldman N, Knaack L, Strohl K P; STAR Trial Group. Upperairway stimulation for obstructive sleep apnea. N. Engl. J. Med. 2014 Jan 9;370(2):139-49. doi: 10.1056/NEJMoa1308659. Thaler E, Schwab R, Maurer J, Soose R, Larsen C, Stevens S, Stevens D, Boon M, Huntley C, Doghramji K, Waters T, Kominsky A, Steffen A, Kezirian E, Hofauer B, Sommer U, Withrow K, Strohl K, Heiser C. Results of the ADHERE upper airway stimulation registry and predictors of therapy efficacy. Laryngoscope. 2020 May;130(5):1333-1338. doi: 10. 1002/lary.28286.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 25

BARIATRIC SURGERY FOR OSA Roberta Leu1,2,4, MD, Nikhila Raol1,2,3, MD and Kelli-Lee Harford1,2,4, PhD Children’s Healthcare of Atlanta, Atlanta, GA, USA Emory University School of Medicine, Atlanta, GA, USA 3 Department of Otolaryngology-Head and Neck Surgery, Division of Pediatric Otolaryngology, Atlanta, GA, USA 4Department of Pediatrics, Division of Pulmonary, Allergy/Immunology, Cystic Fibrosis and Sleep, Atlanta, GA, USA 1

2

BARIATRIC SURGERY 1. Gastrointestinal surgery to result in restriction of food volume and/or malabsorption for treatment of morbid obesity 2. Incidence of bariatric surgery a. As of 2018, incidence in the US was ~252,000 (majority being sleeve gastrectomy, ~15% were bariatric surgery revisions) b. As of 2014, incidence worldwide was ~580,000 (majority being sleeve gastrectomy). 3. Indications for bariatric surgery, see Table 1 a. Consider bariatric surgery if weight loss to prevent obesity related complication cannot be achieved with lifestyle and medical management b. Benefits of undergoing bariatric surgery should outweigh associated risks of surgery. c. Lower BMI criteria is used for Asians i. 18.5-22.9 kg/m2 normal ii. 23-24.9 kg/m2 overweight iii. ≥25 kg/m2 obese. d. Above criteria now used for adolescent bariatric patients as well.

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Roberta Leu, Nikhila Raol and Kelli Lee Harford Table 1. Indications for bariatric surgery

Body Mass Index (BMI) ≥40 kg/m2 ≥35 kg/m2

30-34.9 kg/m2

Co-existing medical condition No required co-existing medical condition ≥1 severe obesity related medical condition that can be improved with weight loss Examples: Cardiopulmonary Poorly controlled hypertension (HTN) Obesity related cardiomyopathy Obstructive sleep apnea (OSA) Obesity hypoventilation syndrome (OHS) Severe venous stasis Endocrine High risk for or has Type 2 diabetes mellitus Metabolic syndrome Gastrointestinal Gastroesophageal reflux Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis Musculoskeletal Osteoarthritis of hip or knee Immobility due to obesity Neurology Idiopathic intracranial hypertension Urology Urinary stress incontinence Impaired quality of life Type 2 diabetes mellitus and hyperglycemia that is uncontrolled with medical/lifestyle management

4. Relative contraindications for bariatric surgery a. Active cancer b. Cirrhosis with portal hypertension c. Crohn’s disease d. Drug or alcohol addiction e. End-stage lung disease f. Severe heart failure g. Unstable coronary artery disease h. Severe intellectual disability i. Current pregnancy or plan for pregnancy within 1-2 years. 5. Types of bariatric surgery. a. Choose the type of bariatric surgery according to goals of therapy for that individual patient and the associated risks of that bariatric procedure b. No longer widely used due to side effects, higher risk of reoperation and nonsustained long-term efficacy i. Biliopancreatic diversion with duodenal switch ii. Jejunoileal bypass iii. Laparoscopic adjustable gastric banding iv. Vertical banded gastroplasty.

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Most commonly used due to tolerability, safety, more sustained efficacy in weight loss and glycemic control. i. Roux-en-Y gastric bypass ii. Sleeve gastrectomy.

OBSTRUCTIVE SLEEP APNEA (OSA) 1. See chapters 12 and 34 respectively for diagnostic criteria of OSA in adult and pediatrics 2. Risk of developing OSA increases by 1.14 for each 1 kg/m2 increase in BMI 3. Prevalence of Obstructive Sleep Apnea (OSA) in the bariatric surgery population. a. Adult - 35-94% (most studies report prevalence >60%) b. Adolescents - 27-57%.

OBESITY HYPOVENTILATION SYNDROME (OHS) 1. Diagnostic criteria: a. BMI ≥ 30 kg/m2 for adults or BMI > 95th% in age and sex group for children b. Awake, resting PaCO2 ≥ 45 mmHg at sea level c. Other causes of hypoventilation have been excluded. 2. American Thoracic Society 2019 guideline a. Obtaining arterial blood gas for awake PaCO2 measurement can delay OHS diagnosis b. If low to moderate probability of OHS (e.g., BMI 30-40 kg/m2), then check serum bicarbonate. i. Serum bicarbonate < 27 mmol/L indicates OHS unlikely ii. Serum bicarbonate ≥ 27 mmol/L indicates OHS possible, proceed with checking PaCO2. c. If high probability of OHS (e.g., severe obesity, symptoms of OSA/OHS, hypoxemia awake and/or asleep), then proceed with checking PaCO2. 3. Associated symptoms: a. Neurocognitive i. Morning headaches ii. Hypersomnia iii. Fatigue iv. Mood disturbance v. Memory/concentration difficulties. b. Cardiopulmonary i. Acute on chronic respiratory failure ii. Arrhythmia iii. Pulmonary hypertension iv. Heart failure.

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Roberta Leu, Nikhila Raol and Kelli Lee Harford c. Increased mortality. 4. Prevalence of Obesity Hypoventilation Syndrome (OHS) in obese patients presenting to sleep centers for sleep disordered breathing evaluation a. 8-20% (prevalence in general population unknown). 5. 20% of obese patients with OSA also have OHS 6. 90% of OHS patients have OSA (defined as apnea hypopnea index ≥5 events/hour).

PERIOPERATIVE CONSIDERATIONS FOR OSA PATIENTS UNDERGOING BARIATRIC SURGERY 1. ↑ perioperative complications in bariatric surgery patients with obstructive sleep apnea 2. ↑ morbidity and mortality post-bariatric surgery in patients with co-existing OSA and OHS.

PREOPERATIVE RECOMMENDATIONS 1. Screen all bariatric surgery patients for OSA and OHS 2. See Table 2 for examples of validated sleep questionnaires a. Of these validated questionnaires, the Epworth Sleepiness Score has been deemed to have the lowest sensitivity and specificity, as well as ability to discriminate between categories of severity of OSA, in the obese population that is awaiting bariatric surgery b. STOP-Bang and Berlin questionnaire can be used to screen for OSA risk. 3. Current recommendation is for all patients undergoing bariatric surgery to have preoperative polysomnography if OSA screen is positive, though this may not always be possible due to resource limitations a. If polysomnography is not available, then Type 3 home sleep test can be used in a patient with a high-pre-test probability for OSA. 4. Treatment of OSA. a. Timing - As soon after OSA diagnosis as possible. i. This is especially true if starting continuous positive airway pressure (CPAP) as increased time on CPAP will help with acclimatization. b. CPAP for apnea-hypopnea index (AHI) ≥ 15 events/hour i. Use of nasal or full-face mask depends on patient comfort. c. Positional OSA can be treated with positional therapy if CPAP is not tolerated d. Mandibular advancement device (MAD) acceptable if it effectively treats the OSA e. Patients should bring their CPAP and/or MAD to surgery so that it can be used postoperatively.

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Table 2. Preoperative OSA Screening Tools Screening tool

Components

STOP-BANG

 Snoring  Tired  Observed apneas  (Blood) Pressure  BMI ≥ 35 kg/m2  Age ≥ 55 years  Neck circumference ≥ 40cm  (Male) Gender. Chance of dozing off in various situations (score of 0-3)  Reading  Watching television  Sitting in a public place  Lying down to rest in the afternoon  Sitting and talking to someone  Sitting quietly after lunch  Sitting in a car as a passenger for an hour  Sitting in car while stopped for a few minutes in traffic.  Neck circumference ≥ 42 cm  BMI  ≥  42 kg/m2 (Obesity)  Observed apnea  Snoring  Age  ≥  37 years  (Male) Sex.  Neck circumference  60 kg/m2 d. Open (instead of laparoscopic) surgery. 2. Patients with OSA may have poorly controlled postoperative pain

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3. No significant difference in cardiopulmonary or non-cardiopulmonary complications within 30 days of surgery 4. No significant increase in rates of anastomotic and staple line leakage with CPAP usage. a. Increase in risk of leakage associated only with revision surgery.

OSA OUTCOMES AFTER BARIATRIC SURGERY 1. Bariatric surgery associated with: a. Significant weight loss and improvement in BMI, but remained in the obese range b. Reduction in OSA severity c. Improvement in daytime sleepiness measured by Epworth Sleepiness Score. 2. BMI and AHI improvement a. % reduction in BMI and AHI from bariatric surgery weight loss is 2x greater than from non-surgical weight loss b. However, majority of bariatric surgery and non-surgical weight loss patients continue to have residual OSA at 1 year follow up. 3. Meta-analyses have not identified a relationship between change in weight loss and change in AHI, but weight loss of ~10% can improve AHI 4. Resolution of OSA can be seen in patients who had mild OSA prior to bariatric surgery.

OHS OUTCOMES AFTER BARIATRIC SURGERY 1. Very limited data evaluating OHS in bariatric surgery patients 2. OHS treated with Continuous Positive Airway Pressure or Noninvasive Ventilation without weight loss results in continued metabolic and cardiovascular morbidity and mortality 3. Non-surgical weight loss typically results in 2-12 kg weight loss. This is unlikely to significantly improve OHS. 4. American Thoracic Society suggests sustained weight loss of 25-30% of actual body weight can improve hypoventilation. a. This degree of weight loss is more likely from bariatric surgery.

RE-EVALUATING OSA AND OHS AFTER BARIATRIC SURGERY 1. Patients should not discontinue OSA or OHS therapy without re-evaluation and documentation that therapy is no longer warranted 2. Clinically judge (based on weight loss and OSA/OHS symptoms) when to repeat polysomnogram to evaluate for residual disease 3. Screening questionnaires are not reliable to detect residual OSA/OHS after bariatric surgery.

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KEY CLINICAL POINTS 1. 2. 3. 4.

Screen all bariatric surgery patients for OSA. All bariatric surgery patients with OSA should be screened for OHS. Use a ramped position for induction, intubation, and ventilation. At the end of the bariatric surgery procedure, extubation should not be done until the patient is almost fully awake, neuromuscular blockade is fully reversed, and muscle function is restored. 5. OSA/OHS therapy during sleep should be re-initiated in the immediate post-operative period. Patients should not discontinue OSA/OHS therapy until they are re-evaluated and documented to not necessitate these therapies anymore.

QUESTIONS 1. Most studies have shown prevalence rates of obstructive sleep apnea in the adult bariatric surgery population to be greater than: a. 30% b. 45% c. 60% d. 76% e. 90%. 2. Which of the following statements does NOT accurately reflect OSA outcomes after bariatric surgery? a. Non-surgical weight loss shows better outcomes in AHI improvement in comparison to bariatric surgery. b. Some patients will continue to have residual OSA after bariatric surgery. c. Bariatric surgery has been found to be more effective at improving OSA than non-surgical weight loss. d. Patients will typically report improvements in daytime sleepiness following bariatric surgery. e. After weight loss from bariatric surgery, OSA may resolve for some patients with mild disease. 3. Which of the following statements is accurate regarding OSA screening for bariatric patients? a. An Epworth sleepiness score >10 indicates high risk for OSA in patients awaiting bariatric surgery. b. Bariatric surgery patients should only be screened for OHS if they exhibit symptoms of OHS such as hypersomnolence, fatigue, or signs of heart failure. c. If a bariatric patient’s STOP-BANG score is 4, then polysomnography is recommended to evaluate for OSA. d. OSA screening questionnaires can reliably detect residual OSA/OHS after bariatric surgery.

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4. A 32-year-old woman with a BMI of 35 kg/m2 is being worked up for bariatric surgery. Due to a history of snoring, observed apneas, and hypertension, she was referred for a polysomnogram which showed the following:  Apnea hypopnea index (AHI) 15 events/hour  REM AHI 20 events/hour  Supine AHI 16 events/hour  Mean SpO2 in sleep 95%  ETCO2 not reported. In clinic, her SpO2 is 98% awake and blood work shows a serum bicarbonate level of 26 mmol/L. Your next step in management is: a. Obtain an awake arterial blood gas to check PaCO2. b. Initiate CPAP therapy. c. Start O2 per nasal cannula in sleep. d. Advise that she sleep on her side. 5. Intraoperative and postoperative recommendations for bariatric patients with OSA include: a. Lying flat for induction, intubation, and ventilation. b. Requiring the patient be almost fully awake, has full reversal of neuromuscular blockade, and restored muscle function before extubation after surgery. c. Delaying use of CPAP post-operatively to decrease risk of anastomotic and staple line leakage. d. Admission to ICU for observation after surgery.

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Carneiro G., Flório R. T., Zanella M. T., Pradella-Hallinan M., Ribeiro-Filho F. F., Tufik S., Togeiro S. M. Is mandatory screening for obstructive sleep apnea with polysomnography in all severely obese patients indicated? Sleep Breath. 2012 Mar;16(1):163-8. doi: https:// 10.1007/s11325-010-0468-7. 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(2):130-134. doi: https://10.1016/j.jclinane.2006.08.006. Chung F., Yegneswaran B., Liao P., et al., STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology. 2008;108(5):812-821. doi: https://10.1097/ ALN.0b013e31816d83e4. Daltro C., Gregorio P. B., Alves E., Abreu M., Bomfim D., Chicourel M. H., Araújo L., Cotrim H. P. Prevalence and severity of sleep apnea in a group of morbidly obese patients. Obes Surg. 2007 Jun;17(6):809-14. doi: https://10.1007/s11695-007-9147-6. Erratum in: Obes Surg. 2007 Jul;17(7):996. De Baerdemaeker L., Margarson M. Best anaesthetic drug strategy for morbidly obese patients. Curr Opin Anaesthesiol. 2016;29(1):119-128. doi: https://10.1097/ACO. 0000000000000286. de Raaff C. A. L., de Vries N., van Wagensveld B. A. Obstructive sleep apnea and bariatric surgical guidelines: summary and update. Curr Opin Anaesthesiol. 2018;31(1):104-109. doi: https://10.1097/ACO.0000000000000542. de Raaff C. A. L., Gorter-Stam M. A. W., de Vries N., Sinha A. C., Jaap Bonjer H., Chung F., Coblijn U. K., Dahan A., van den Helder R. S., Hilgevoord A. A. J., Hillman D. R., Margarson M. P., Mattar S. G., Mulier J. P., Ravesloot M. J. L., Reiber B. M. M., van Rijswijk A. S., Singh P. M., Steenhuis R., Tenhagen M., Vanderveken O. M., Verbraecken J., White D. P., van der Wielen N., van Wagensveld B. A. Perioperative management of obstructive sleep apnea in bariatric surgery: a consensus guideline. Surg Obes Relat Dis. 2017 Jul;13(7):1095-1109. doi: https://10.1016/j.soard.2017.03.022. de Raaff C. A. L., Kalff M. C., Coblijn U. K., de Vries C. E. E., de Vries N., Bonjer H. J., van Wagensveld B. A. Influence of continuous positive airway pressure on postoperative leakage in bariatric surgery. Surg Obes Relat Dis. 2018 Feb;14(2):186-190. doi: https:// 10.1016/j.soard.2017.10.017. Duarte R. L., Magalhães-da-Silveira F. J. Factors predictive of obstructive sleep apnea in patients undergoing pre-operative evaluation for bariatric surgery and referred to a sleep laboratory for polysomnography. J Bras Pneumol. 2015;41(5):440-448. doi: https://10. 1590/S1806-37132015000000027. Duarte R. L. M., Magalhães-da-Silveira F. J., Gozal D. Validation of the GOAL Questionnaire as an Obstructive Sleep Apnea Screening Instrument in Bariatric Surgery Candidates: a Brazilian Single-Center Study. Obes Surg. 2020;30(12):4802-4809. doi: https://10.1007/s11695-020-04888-4. Duarte R. L. M., Rabahi M. F., Magalhães-da-Silveira F. J., de Oliveira E. S. T. S., Mello F. C. Q., Gozal D. Simplifying the Screening of Obstructive Sleep Apnea With a 2-Item Model, No-Apnea: A Cross-Sectional Study. J Clin Sleep Med. 2018;14(7):1097-1107. doi: https://10.5664/jcsm.7202. Falcone V., Stopp T., Feichtinger M., Kiss H., Eppel W., Husslein P. W., Prager G., Göbl C. S. Pregnancy after bariatric surgery: a narrative literature review and discussion of impact

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on pregnancy management and outcome. BMC Pregnancy Childbirth. 2018 Dec 27;18(1):507. doi: https://10.1186/s12884-018-2124-3. Glazer S. A., Erickson A. L., Crosby R. D., Kieda J., Zawisza A., Deitel M. The Evaluation of Screening Questionnaires for Obstructive Sleep Apnea to Identify High-Risk Obese Patients Undergoing Bariatric Surgery. Obes Surg. 2018;28(11):3544-3552. doi: https:// 10.1007/s11695-018-3391-9. Johns M. W. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540-545. doi: https://10.1093/sleep/14.6.540. Kreitinger K. Y., Lui M. M. S., Owens R. L., Schmickl C. N., Grunvald E., Horgan S., Raphelson J. R., Malhotra A. Screening for Obstructive Sleep Apnea in a Diverse Bariatric Surgery Population. Obesity (Silver Spring). 2020 Nov;28(11):2028-2034. doi: https://10.1002/oby.23021. Luo J. M., Zhang D. M., Xiao Y., Huang R., Zhu H. J., Yu J. C., Zhao Y. [Perioperative Evaluation of Obstructive Sleep Apnea in Bariatric Surgery Population]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018 Oct 30;40(5):617-624. Chinese. doi: https://10. 3881/j.issn.1000-503X.10518. Mechanick J. I., Apovian C., Brethauer S., Garvey W. T., Joffe A. M., Kim J., Kushner R. F., Lindquist R., Pessah-Pollack R., Seger J., Urman R. D., Adams S., Cleek J. B., Correa R., Figaro M. K., Flanders K., Grams J., Hurley D. L., Kothari S., Seger M. V., Still C. D. Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures - 2019 Update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists - Executive Summary. Endocr Pract. 2019 Dec;25(12):1346-1359. doi: https://10.4158/GL-2019-0406. Mokhlesi B., Masa J. F., Brozek J. L., Gurubhagavatula I., Murphy P. B., Piper A. J., Tulaimat A., Afshar M., Balachandran J. S., Dweik R. A., Grunstein R. R., Hart N., Kaw R., LorenziFilho G., Pamidi S., Patel B. K., Patil S. P., Pépin J. L., Soghier I., Tamae Kakazu M., Teodorescu M. Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2019 Aug 1;200(3):e6-e24. doi: https://10.1164/rccm.201905-1071ST. Erratum in: Am J Respir Crit Care Med. 2019 Nov 15;200(10):1326. Netzer N. C., Stoohs R. A., Netzer C. M., Clark K., Strohl K. P. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999;131(7):485491. doi: https://10.7326/0003-4819-131-7-199910050-00002. NIH conference. Gastrointestinal surgery for severe obesity. Consensus Development Conference Panel. Ann Intern Med. 1991;115(12):956-961. Reijers S. N. H., Nijland L. M. G., Bosschieter P. F. N., de Raaff C. A. L., Ravesloot M. J. L., van Veen R. N., de Castro S. M. M., de Vries N. The effect of postoperative CPAP use on anastomotic and staple line leakage after bariatric surgery. Sleep Breath. 2020 Sep 28. doi: https://10.1007/s11325-020-02199-7. Rubino F., Nathan D. M., Eckel R. H., Schauer P. R., Alberti K. G., Zimmet P. Z., Del Prato S., Ji L., Sadikot S. M., Herman W. H., Amiel S. A., Kaplan L. M., Taroncher-Oldenburg G., Cummings D. E. Delegates of the 2nd Diabetes Surgery Summit. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes

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Organizations. Diabetes Care. 2016 Jun;39(6):861-77. doi: https://10.2337/dc 16-0236. SAGES Guidelines Committee. SAGES guideline for clinical application of laparoscopic bariatric surgery. Surg Endosc. 2008;22(10):2281-2300. doi: https://10.1007/s00464-0089913-0. Shah U., Wong J., Wong D. T., Chung F. Preoxygenation and intraoperative ventilation strategies in obese patients: a comprehensive review. Curr Opin Anaesthesiol. 2016;29(1):109-118. doi: https://10.1097/ACO.0000000000000267. Tishler P. V., Larkin E. K., Schluchter M. D., Redline S. Incidence of Sleep-Disordered Breathing in an Urban Adult Population: The Relative Importance of Risk Factors in the Development of Sleep-Disordered Breathing. JAMA. 2003;289(17):2230-2237. doi: https://10.1001/jama.289.17.2230. Vaughns J. D., Martin C., Nelson J., Nadler E., Quezado Z. M. Dexmedetomidine as an adjuvant for perioperative pain management in adolescents undergoing bariatric surgery: An observational cohort study. J Pediatr Surg. 2017;52(11):1787-1790. doi: https://10. 1016/j.jpedsurg.2017.04.007. Wong A. M., Barnes H. N., Joosten S. A., Landry S. A., Dabscheck E., Mansfield D. R., Dharmage S. C., Senaratna C. V., Edwards B. A., Hamilton G. S. The effect of surgical weight loss on obstructive sleep apnoea: A systematic review and meta-analysis. Sleep Med Rev. 2018 Dec;42:85-99. doi: https://10.1016/j.smrv.2018.06.001. Zaremba S., Shin C. H., Hutter M. M., Malviya S. A., Grabitz S. D., MacDonald T., Diaz-Gil D., Ramachandran S. K., Hess D., Malhotra A., Eikermann M. Continuous Positive Airway Pressure Mitigates Opioid-induced Worsening of Sleep-disordered Breathing Early after Bariatric Surgery. Anesthesiology. 2016 Jul;125(1):92-104. doi: https://10. 1097/ALN.0000000000001160. Zeller M. H., Inge T. H., Modi A. C., Jenkins T. M., Michalsky M. P., Helmrath M., Courcoulas A., Harmon C. M., Rofey D., Baughcum A., Austin H., Price K., Xanthakos S. A., Brandt M. L., Horlick M., Buncher R. Teen Longitudinal Assessment of Bariatric Surgery (TeenLABS) Consortium. Severe obesity and comorbid condition impact on the weight-related quality of life of the adolescent patient. J Pediatr. 2015 Mar;166(3):651-9.e4. doi: https://10.1016/j.jpeds.2014.11.022.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 26

COMBINATION THERAPY FOR OSA Nithin S. Peddireddy, MD, Jeffrey J. Stanley, MD and Paul T. Hoff, MD Department of Otolaryngology, Head & Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA

COMBINATION THERAPIES FOR OBSTRUCTIVE SLEEP APNEA 1. The gold-standard for treatment of Obstructive Sleep Apnea (OSA) is continuous positive-airway pressure (CPAP) a. Compliance can be quite poor 2. There are a variety of factors that affect compliance including type of mask, anatomical differences, as well as varying levels of pressure 3. Given the lack of compliance, other treatment modalities have been developed a. These include both surgical and medical options 4. This chapter will describe some of the more recent advances in medical and surgical management of OSA including new devices 5. It will discuss various combinations of therapies, their outcomes, and demonstrate a decision pathway for treatment 6. A physician’s responsibility is to determine the best course of treatment for these treatment refractory patients, and an understanding of the options available allow us to be uniquely qualified to help patients make a shared decision regarding the treatment they wish to pursue

HISTORY AND PHYSICAL EXAM 1. Given the multiple different options for combination therapies, a thorough history and physical exam must be performed in order to customize the treatment plan for each patient

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Nithin S. Peddireddy, Jeffrey J. Stanley and Paul T. Hoff 2. History a. A thorough sleep history should be obtained b. Objective measures can include: i. Epworth Sleepiness Scale (ESS) ii. Stanford Sleepiness Scale (SSS) iii. Analog Scale of Well Being iv. Functional Outcomes of Sleepiness Questionnaire (FOSQ) v. Berlin Sleep Questionnaire c. The patient’s overall swallowing function and level of dysphagia should be elucidated prior to any surgical intervention using the Dysphagia Handicap Index (DHI) or the MD Anderson Dysphagia Index (MDADI) d. The patient’s overall medical history including anticoagulation status, comorbidities and American Society of Anesthesiologists (ASA) class should be documented e. Complete assessment of mental well-being and previous psychiatric diagnoses is critical f. Objective data such as the most recent polysomnogram (PSG), adherence to positive airway pressure (PAP) therapy and body mass index (BMI) should be reviewed 3. Physical exam: A comprehensive head and neck examination and a sleep surgery directed physical exam should be performed a. Nasal cavity i. Evaluate turbinate Size  Administer oxymetazoline spray and ask patients if they feel their breathing is improved; can guide utility of radiofrequency ablation (RFA) of turbinates ii. Evaluate nasal septum for deviation iii. Evaluate the nasal valve  Cottle maneuver iv. Evaluate for other causes of obstruction  Nasal polyps  Adenoid hypertrophy b. Oral cavity i. Dentition: Provides guidance on efficacy of mandibular advancement surgeries and access for transoral procedures  Angle classification  Class 1: orthognathic  Class 2: retrognathic  Class 3: prognathic  Interincisor distance  Less than 2 cm means difficult transoral surgical exposure  Quality of dentition  Supportive of mandibular advancement device

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ii. Tongue  Friedman Tongue Position (FTP)  FTP 1: Able to see the entire uvula and tonsils  FTP 2a: Able to see entire uvula and part of the tonsils  FTP 2b: Able to see entire soft palate to the base of the uvula without being able to see the entire uvula or the tonsils  FTP 3: Able to see some of the soft palate  FTP 4: Able to see the hard palate only  Friedman Lingual Tonsil Hypertrophy System  Grade 0: Absence of Lingual Tonsil Tissue  Grade 1: Lymphoid tissue scattered across the tongue base  Grade 2: Lymphoid tissue across the entire tongue base with mild vertical thickness  Grade 3: Lymphoid tissue across the entire tongue base with moderate thickness and fills the vallecula.  Grade 4: Lymphoid tissue across the entire tongue base with significant (>1 centimeter (cm)) thickness and extends beyond confines of the vallecula  Moore Tongue Base Classification  Class A = isolated high muscular tongue  Class B = diffuse obstruction both high and low  Class C = isolated low-lying obstruction in vallecula iii. Palatine Tonsil Hypertrophy (Brodskey)  Grade 0: Absence of Tissue  Grade 1: Within the tonsillar pillars  Grade 2: Extending to the tonsillar pillars  Grade 3: Extending past the tonsillar pillars  Grade 4: Extending to the midline iv. Uvula length and width v. Soft Palate Configuration  Length of soft palate  Medialization of palatopharyngeus muscle vi. Hard palate configuration  High arched palate (“Gothic arch”)  Broad arched palate (“Roman arch”) vii. Woodson phenotype - trans-nasal endoscopic evaluation of palate  Type A - Oblique  Type B - Intermediate  Type C - Vertical viii. Lateral cephalogram  Hyoid-mandibular plane

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

>2.5 cm corresponds to a vertical tongue base - Moore A. Skeletal class  A point - Nasion - B point (ANB) angle measure relative position of maxilla to mandible: o Normal values: 1. Sella - Nasion - A point (SNA) 82 +/-2 degrees 2. Sella - Nasion - B point (SNB) 80 +/-2 degrees  ANB = SNA-SNB  Positive ANB correspond to class 1 (orthognathic) or 2 (retrognathic) skeletal class  Negative ANB corresponds to class 3 skeletal class (prognathic)

NON-SURGICAL TREATMENT OPTIONS: (CONSERVATIVE APPROACH) 1. Devices: a. Positive Airway Pressure i. The treatment of choice for OSA is positive airway pressure (PAP) ii. CPAP has been shown to improve apnea-hypopnea index (AHI), improve daytime sleepiness, and improve sleep architecture iii. This can be delivered as bilevel (BiPAP) vs. continuous positive pressure (CPAP) and also can be delivered either via a full-face mask, nasal mask or nasal pillows iv. Patients with significant central sleep or complex apnea can be treated with Adaptive Servo Ventilation (ASV)  ASV is similar to CPAP, but there are significant differences  The device continuously adjusts to the patients breathing pattern  When an apneic event is detected, the device intervenes and provides pressure support to restore 90% of a normal breath b. Oral Appliances i. Non-invasive devices that are used in the oral cavity of patients with the goal of providing stabilization and protrusion of the mandible or maintenance of the tongue anteriorly ii. Though their use for snoring is beyond the scope of this chapter, the American Academy of Sleep Medicine (AASM) has recommended the use of oral appliances in those patients with mild to moderate OSA who are unable to tolerate CPAP or who request other therapy

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2. Medications a. There are no current Food and Drug Administration (FDA) approved drugs to treat OSA b. There are some medications that are approved to treat the sequelae of OSA such as excessive daytime sleepiness, however, these do not treat the underlying disease 3. Weight Loss a. There have been numerous studies that have demonstrated that successful weight loss through dietary modifications can improve OSA b. When considering weight loss as a primary treatment, the AASM recommends that adjunct treatments such as CPAP and/or oral appliances are used in conjunction since residual less severe OSA is often present despite significant weight loss 4. Positional Therapy a. Positional OSA (POSA) is defined as an AHI that is lower in the non-supine than the supine position i. Clinically significant POSA can be defined as an AHI twice as high in the supine position vs. other sleep positions b. Patients with mild to moderate OSA are more likely to demonstrate POSA and as many as 35% demonstrate a normalized AHI < 5 in non-supine sleep c. For those subsets of patients who have positional OSA, positional therapy (PT) may be considered in addition to other adjuncts such as CPAP/Oral Appliances i. Home-made positional therapy devices which enforce lateral sleep as well as commercial wedge pillow which eleveate the head of bed are inexpensive, but compliance is low ii. Vibro-tactile devices have been shown to be very effective for the treatment of positional OSA, but further studies are needed to evaluate the long-term compliance 5. Myofunctional Therapy a. Oral myofunctional therapy is a therapy that is designed to improve the muscle tone of the upper airways in patients with OSA b. This has been shown to both improve AHI as well as improved quality of life and daytime sleepiness Table 1. Non-surgical treatment options Type of Therapy Positive Airway Pressure Oral Appliance Medications Weight loss via dietary modifications Positional Therapy Myofunctional therapy

When to Consider Gold Standard Therapy In patients with mild to moderate OSA for whom CPAP isn’t tolerated No FDA approved medications to treat OSA Overweight patients; should be combined with CPAP or oral appliance therapy Adjunct with CPAP/oral appliances in patients with mild to moderate OSA with a positional component Snoring and mild to moderate OSA

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Figure 1. VOTE Classification. This scoring system measures both the location of collapse as well as direction and degree of collapse. The degree of collapse is measured by the following numbers: 0 is no obstruction, 1 is partial obstruction, 2 is complete obstruction, X is not able to observe. For example, a patient may score: V 1AP, O 1L, T 1AP, E 1AP Total VOTE score: 4.

SURGICAL TREATMENT OPTIONS 1. Surgical options are determined based on the site of obstruction as well as the severity of sleep apnea a. The decision on type of surgery, single-level versus multi-level surgery, and the inclusion of neuro-stimulation is quite complex 2. Detailed in-office physical examination can help to guide appropriate surgical decision making a. In-office maneuvers (flexible laryngoscopy) can provide some information on the sites of obstruction 3. Drug-induced sleep endoscopy (DISE) is a useful tool to help determine the anatomical level of obstruction in an individual patient under sedation in a sleep-like state a. It may better assess dynamic collapse (vs. awake endoscopy) and should be especially considered in revision surgery or in patients for whom the site of obstruction is not readily apparent b. It is also required for pre-operative evaluation of neuro-stimulation candidates c. Croft and Pringle developed sleep nasoendoscopy (now referred to as drug induced sleep endoscopy - DISE) in 1999 d. Kezirian et al. Introduced the VOTE scoring system in 2011 for adults i. The VOTE system allows for the objective classification of both the direction and degree of collapse of the airway (Figure 1) e. In children, the Chan Parikh scoring system is routinely used 4. Surgical Success a. Once the site of obstruction is determined and the surgical procedure(s) are chosen, success is defined according to a set of criteria b. Classically, the Sher criteria was used, where surgical success was defined as a post-operative decrease in AHI greater than or equal 50% compared to preoperative AHI and AHI < 20 events/hour (the previously used cut off for mild OSA, now defined as an AHI 50%

Mod to severe OSA BMI > 35

79% Surgical Success Rate UPPP achieved an AHI of 5 or less in 24% and an AHI of 10 or less in 33% of patients

Velum

Oropharynx

Lateral collapse

77% reduction in AHI

Oropharynx

Vertical phenotype

65% reduction AHI

Hypoglossal Nerve Stimulation (HGNS)

Multilevel collapse

BMI < 32 AHI 15-65 Central apnea index (CAI) < 25%

72% reduction in AHI at 1 year and a 63% responder rate at 5 years

Hyoid suspension and pharyngoplasty

Hypopharynx and Oropharynx

Bariatric Surgery

N/A

Tracheostomy

N/A

***

67% reduction in AHI BMI > 40 BMI > 35 with one obesity related comorbidity

75% of patients had improvement in their sleep apnea AHI reduced by 38.2 events/hour 100% effective

It is important to note that these results are all from experienced surgeons and that data reporting across studies is not consistent. Treatment options should be tailored to each specific patient and their phenotype.

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Nithin S. Peddireddy, Jeffrey J. Stanley and Paul T. Hoff 5. Consideration of staging a. Given the multiple areas of potential obstruction as well as based on severity of OSA, patients may have more than one site of obstruction b. Multi-level surgery/combination therapy is sometimes needed for treatment of their underlying OSA i. Drug induced sleep endoscopy plays an important role in confirming multilevel obstruction c. When considering multi-level surgery, it is important to consider staging surgery, particularly if there is a risk of pharyngeal scarring that could contribute to dysphagia and a persistent postoperative globus sensation

ALGORITHMS 1. Two algorithms that may be helpful to guide surgical decision making 2. It is important to note that these are only guides, not absolutes, and that each patient’s treatment should be individualized a. If a patient has known dysphagia or is on blood thinners, they may not be candidates for pharyngeal/tongue base surgery b. Other medical history such as co-morbid insomnia or anxiety may preclude patients from being ideal candidates for specific surgeries such as HGNS

*

Surgical failures should undergo DISE to identify site(s) of failure if patient is considering revision.

Figure 2. Algorithm for the treatment of mild OSA.

3. Mild OSA (Figure 2) a. Surgical treatment should start with treatment of nasal obstruction if present b. Tonsils should be evaluated

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i. ii.

If enlarged, tonsillectomy alone can be performed If they are absent or small, site specific surgical treatment should be performed c. DISE may be a helpful adjunct to help providers decide on what surgery to perform as well as an adjunct to guide surgical decision making in previous surgical failures 4. Moderate OSA (Figure 3) a. Treatment may require multi-stage operations and/or multi-modality treatment b. Nasal obstruction, if present, should always be corrected c. Options include hypoglossal nerve stimulation as well as other site-specific surgical options d. DISE should be considered for any patients who are surgical failures

*

Surgical failures should undergo DISE to identify site(s) of failure if patient is considering revision.

Figure 3. Algorithm for the treatment of moderate to severe OSA.

MEDICAL AND SURGICAL THERAPY COMBINATION OPTIONS Combination therapy for OSA can include numerous medical and surgical therapies when considering treatment options for moderate to severe sleep apnea 1. Mandibular Advancement Device (MAD) with CPAP a. MAD/CPAP combination therapy was found to have on average 9.2 cm H2O lower pressures than CPAP alone

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Nithin S. Peddireddy, Jeffrey J. Stanley and Paul T. Hoff 2. CPAP and nasal surgery a. Nasal surgery lowers nasal resistance and is associated with a reduction in CPAP requirement of 2-3 cm H2O and as a result improved CPAP compliance 3. HGNS followed by adjunctive treatments a. For those patients for whom HGNS provides an incomplete response, additional therapies such as weight loss, positional therapy, nasal surgery, and other upper airway surgeries should be considered b. At this time, there is no best practice guideline for these patients and adjunct treatment should be individualized 4. Upper airway surgery followed by CPAP a. In select patients, especially those with pressure intolerance, upper airway surgery can lower CPAP pressure requirements and improve CPAP tolerance

FUTURE DIRECTIONS 1. New technologies and treatments for OSA continue to evolve 2. Understanding of physiologic mechanisms of OSA such as loop gain, arousal thresholds, and critical pressure (Pcrit) can help with best treatment selection 3. As precision medicine continues to advance, predicting individual success of CPAP versus surgical management for patients with OSA should become easier

KEY CLINICAL POINTS 1. It is necessary to be familiar with the bevy of different options that are available for treatment of OSA and to work closely in a multidisciplinary fashion to decide on the best plan for patients 2. For treatment of mild OSA, unimodality therapy is often enough 3. For treatment of moderate to severe OSA, combination therapy is often required

QUESTIONS 1. The criteria for HGNS include all of the following except? a. BMI < 32 b. AHI 15-65 c. DISE shows no concentric collapse in velum (V2c) using VOTE classification d. Age < 50 2. What medications are approved for treatment of OSA? a. Ritalin b. Modafinil c. Acetazolamide d. There are no approved medications for the treatment of OSA

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3. When should DISE be utilized? a. In cases of revision b. In patients who are candidates for HGNS c. When the site of obstruction is not apparent d. All of the above 4. What are the 4 anatomical areas that are examined for the VOTE classification? a. Velum, oropharynx, tongue base, and epiglottis b. Palate, oropharynx, uvula, epiglottis c. tongue base, oropharynx, oral cavity, hypopharynx d. pyriform sinus, epiglottis, velum, hypopharynx

5. How is surgical success defined? a. Decrease in AHI greater than or equal 50% compared to preoperative AHI and AHI < 20 events/hour b. Post-operative ESS < 10 and an AHI < 15 events/hour c. a and b d. none of the above

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Ong AA, Buttram J, Nguyen SA, Platter D, Abidin MR, Gillespie MB. Hyoid myotomy and suspension without simultaneous palate or tongue base surgery for obstructive sleep apnea. World J. Otorhinolaryngol. Head Neck Surg. 2017;3(2):110-114. doi: 10.1016/j. wjorl.2017.05.008. Pavwoski P, Shelgikar AV. Treatment options for obstructive sleep apnea. Neurol. Clin. Pract. 2017 Feb;7(1):77-85. doi: 10.1212/CPJ.0000000000000320. Poirrier J, George C, Rotenberg B. The effect of nasal surgery on nasal continuous positive airway pressure compliance. Laryngoscope. 2014;129:81-87. doi: 10.1002/lary.24131. Pringle MB, Croft CB. A grading system for patients with obstructive sleep apnoea-based on sleep nasendoscopy. Clin. Otolaryngol. Allied Sci. 1993 Dec;18(6):480-4. doi: 10.1111/j. 1365-2273.1993.tb00618.x. 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 Jul 15;11(7):773-827. doi: 10.5664/jcsm.4858. Rangabashyam M, Huang W, Hao Y, Han HJ, Loh S, Toh S. State of the art transoral robotic surgery for obstructive sleep apnea-hypopnea syndrome. Robot Surg. 2016;3:13-28 doi: 10.2147/RSRR.S95607. Sarkhosh K, Switzer NJ, El-Hadi M, Birch DW, Shi X, Karmali S. The impact of bariatric surgery on obstructive sleep apnea: a systematic review. Obes. Surg. 2013 Mar;23(3):41423. doi: 10.1007/s11695-012-0862-2. Scherr SC, Dort LC, Almeida FR, Bennett KM, Blumenstock NT, Demko BG, Essick GK, Katz SG, McLornan PM, Phillips KS, Prehn RS, Rogers RR, Schell TG, Sheats RD, & Sreshta FP. (2014). Definition of an Effective Oral Appliance for the Treatment of Obstructive Sleep Apnea and Snoring: A Report of the American Academy of Dental Sleep Medicine. Journal of Dental Sleep Medicine. Sher AE, Schechtman KB, Piccirillo JF. The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep. 1996 Feb;19(2):156-77. doi: 10.1093/sleep/19.2.156. Smith PL, Gold AR, Meyers DA, Haponik EF, Bleecker ER. Weight loss in mildly to moderately obese patients with obstructive sleep apnea. Ann. Intern. Med. 1985 Dec;103(6 (Pt 1)):850-5. doi: 10.7326/0003-4819-103-6-850. Standards of Practice Committee of the American Academy of Sleep Medicine, Morgenthaler TI, Kapen S, Lee-Chiong T, Alessi C, Boehlecke B, Brown T, Coleman J, Friedman L, Kapur V, Owens J, Pancer J, Swick T. Practice Parameters for the Medical Therapy of Obstructive Sleep Apnea. Sleep. 2006;29(8):1031-1035. Thaler E, Schwab R, Maurer J, Soose R, Larsen C, Stevens S, Stevens D, Boon M, Huntley C, Doghramji K, Waters T, Kominsky A, Steffen A, Kezirian E, Hofauer B, Sommer U, Withrow K, Strohl K, Heiser C. Results of the ADHERE upper airway stimulation registry and predictors of therapy efficacy. Laryngoscope. 2020 May;130(5):1333-1338. doi: 10.1002/lary.28286. Volner K, Dunn B, Chang ET, Song SA, Liu SY, Brietzke SE, O’Connor P, Camacho M. Transpalatal advancement pharyngoplasty for obstructive sleep apnea: a systematic review and meta-analysis. Eur. Arch. Otorhinolaryngol. 2017 Mar;274(3):1197-1203. doi: 10.1007/s00405-016-4121-3.

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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 Jul;159(1):194-202. doi: 10.1177/0194599818762383.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 27

CENTRAL SLEEP APNEA Shahrokh Javaheri1,2 3, MD and Robin Germany4, MD 1

Bethesda Montgomery Sleep Laboratory, Bethesda North Hospital, Cincinnati, Ohio, USA 2 University of Cincinnati College of Medicine, Cincinnati, Ohio,USA 3 Division of Cardiology, The Ohio State University, Columbus, Ohio, USA 4 University of Oklahoma Health Sciences Center, Cardiovascular Division, Oklahoma City, Oklahoma, USA

INTRODUCTION 1. Central apnea a. Due to temporary failure in the pontomedullary pacemaker which generates breathing rhythm b. Results in the loss of ventilatory effort c. Lasts at least 10 seconds (2 breaths or more) in adults d. No medullary inspiratory neural output through the nerves innervating inspiratory thoracic pump muscles (the diaphragm and the intercostal muscles) 2. Central sleep apnea (CSA) on polysomnography a. Characterized by absence of naso-oral airflow and thoracoabdominal excursions (Figure 1) b. Central apnea index of ≥ 5 per hour of sleep as abnormal 3. Contrast with obstructive apnea a. Cranial nerves continue to stimulate the lower inspiratory muscles b. Drive to dilator muscles of the upper airway is reduced, resulting in pharyngeal collapse (Figure 2)

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Figure 1. Polysomnographic example of CSA. Tracings are: electro-oculogram (EOG, 1st and 2nd), chin electromyogram (EMG, 3rd), electroencephalogram (EEG, 4th and 5th), ECG (7th), airflow measured by thermocouple (8th) and CO2 (9th), combined (10th) rib cage (RC) and abdominal (ABD), RC (11th) and ABD (12th) excursions, time in seconds (13th) and esophageal pressure (14th). Airflow is absent in the effort channels observed on rib cage, abdominal and esophageal pressure tracings. Note the smooth and gradual changes in the thoracoabdominal excursions and esophageal pressure in the crescendo and decrescendo arms of the cycle. The arousal occurs at the peak of hyperventilation. Modified from Javaheri et al, JACC, 2017.

Figure 2. Obstructive apnea. Tracings are: electro-oculogram (EOG, 1st and 2nd), chin electromyogram (EMG, 3rd), electroencephalogram (EEG, 4th and 5th), ECG (7th), airflow measured by thermocouple (8th) and CO2 (9th), combined (10th) rib cage (RC) and abdominal (ABD), RC (11th) and ABD (12th) excursions, time in seconds (13th) and esophageal pressure (14th). Note persistent thoracoabdominal excursions and absence of naso-oral airflow. Modified from Javaheri et al. JACC, 2017.

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Mechanisms of CSA 1. Sleep a. Causes the removal of wakefulness and behavioral drive to breathe b. Unmasks two physiological mechanisms promoting periodic breathing and central sleep apnea i. A PCO2 level below which rhythmic breathing ceases resulting in central apnea ii. The apneic threshold PCO2, is only 2 to 4 mmHg below the awake level of arterial PCO2 iii. A small rise in ventilation, e.g., due to a 3 second arousal or change in position, could lower the prevailing PCO2 below apneic threshold PCO2 causing central apnea when sleep resumes iv. Commonly observed during the first few minutes after sleep and is referred to as sleep-onset central apnea v. As a result of central apnea, PCO2 rises and after it exceeds the apneic threshold PCO2, breathing resumes a. The rise in PCO2 elicits a hyperventilatory response, and hyperventilation decreases PCO2, and the cycle repeats itself (Figure 3) b. The occurrence of central apneas with repeated cyclic periods of over- and under-ventilation during sleep is mediated by an elevated loop gain (> 1) of the respiratory control system (Figure 4) c. Loop gain is an engineering term, and in the respiratory system, the gain defines the ratio of the magnitude of the ventilatory response for a given change in ventilation i. The respiratory system is a negative feedback loop and regulates ventilation in response to a ventilatory disturbance ii. If loop gain is ≥ 1, the magnitude of the increase in ventilation is greater than or equal to the magnitude of the preceding apnea or hypopnea iii. In CSA, if for any reason, a short pause in breathing occurs  The system is so sensitive that it overcorrects increasing ventilation excessively  Breathing becomes unstable fluctuating between under- and overventilation  The best examples are disorders associated with left ventricular dysfunction and chronic heart failure, particularly with reduced left ventricular function  For further details see references

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Causes of Central Sleep Apnea (Table 1) Table 1. Some common causes of central sleep apnea 1. 2. 3. 4.

5.

Central sleep apnea in congestive heart failure (Hunter-Cheyne-Stokes breathing) Central sleep apnea related to opioids High altitude periodic breathing Treatment-emergent central sleep apnea (TECSA; Complex CSA) a. CPAP b. Nasal expiratory positive airway device c. Oral appliance d. Hypoglossal nerve stimulation e. Tracheostomy f. Tonsillectomy g. Maxillomandibular surgery Idiopathic central sleep apnea

1. Congestive Heart Failure (Hunter-Cheyne-Stokes breathing (HCSB)) a. Heart failure (HF) is a major public health problem and is associated with excess hospitalization and mortality i. Estimated 6.2 million Americans ≥ 20 years of age have HF ii. Prevalence will increase 46% from 2012 to 2030, resulting in > 8 million people ≥ 18 years of age with HF iii. In 2017 alone, 809,000 patients were discharged from the hospital and 80,480 individuals died from HF iv. 2 phenotypes of HF  Predominantly diastolic, referred to as heart failure with preserved ejection fraction (HFpEF) when the ejection fraction (EF) is greater than 50%  Combined systolic and diastolic dysfunction, referred to as heart failure with reduced ejection fraction (HFrEF) when EF is less than 45% v. Symptoms  Result from both diminished cardiac output and/or the concomitant diastolic dysfunction  Include shortness of breath, orthopnea, nocturnal dyspnea, nocturia, fatigue, and exercise intolerance  Overlap with those of sleep apnea, making it difficult to suspect sleep apnea when comorbid with heart failure vi. One of the factors which may contribute to hospital readmission and mortality of HF is CSA, which is highly prevalent in left ventricular dysfunction, both in symptomatic and asymptomatic subjects b. Polysomnogram of HF patients with CSA i. Distinct pattern of periodic breathing characterized by repeated long cycles of crescendo-decrescendo cycles with a central apnea or hypopnea amidst of the 2 arms (Figure 3)

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ii. Prolonged cycle is due to a long arterial circulation time, a pathophysiological feature of heart failure iii. This pattern of periodic breathing as Hunter-Cheyne-Stokes breathing (HCSB)  John Hunter, a surgeon, described it 37 years before John Cheyne’s description c. Prevalence of CSA in HF i. The most systematic study using polysomnography after one night of adaptation  100 ambulatory male patients with stable, treated heart failure  114 consecutive eligible subjects who were followed in a cardiology and a primary care clinic were asked to participate (88% recruitment)  No regards to any symptom of sleep apnea  Used an apnea-hypopnea index of 15 per hour or greater as the threshold to define presence of at least moderate to severe sleep apnea  49 subjects (49% of all patients) had moderate to severe sleep apnea-hypopnea  Average index of 44 per hour  Predominant CSA in 37% of the total population d. Considerable variation in the prevalence of the two forms of sleep apnea (central vs. obstructive) i. Issues include the criteria used to define and accurately classify a hypopnea (obstructive versus central)  Current distinction requires presence of snoring, flow limitations and paradoxical thoracoabdominal excursion to classify the hypopnea as obstructive  Many obstructive hypopneas may be present without paradoxical excursions 2. Opioid-induced CSA a. Opioid medications i. Considered a significant component in the multidisciplinary management of chronic pain ii. Use has dramatically risen iii. Morbidity and mortality  Involved in nearly 17,000 overdose deaths  Typically found deceased in bed, but the actual cause of death remains unknown  Blood tests show presence of opioid and other drugs such as benzodiazepines and antidepressants  Potential causes could be respiratory depression with terminal apnea or torsade de pointe, as some opioids, such as methadone, prolong QT interval

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Modified from Javaheri et al. JACC, 2017. Figure 3. A 5 min polysomnographic example of Hunter-Cheyne-Stokes breathing. Tracings as in Figures 1 and 2. This pt is 80 years old; M/H: HTN, Heart surgery in 1993; AHI = 69/hr; Lowest oxygen = 87%; D O T= 11/21/04.

Figure 4. Depicts the critical role of normal (A) and elevated loop gain (B). With normal LG, when reduction in breathing occurs (a), the system does not over-react. However, if the response to the initial disturbance is inappropriate, then breathing becomes unstable. Modified from: Javaheri S, Dempsey JA. Central sleep apnea. Comprehensive Physiology 2013; 3:141-163.

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Respiratory depressants with profound effects during sleep encompassing a spectrum of ventilatory derangements  Hypoventilation  Hypoxemia  Central apneas  Obstructive apneas  Ataxic or irregular breathing (Figure 4) b. Polysomnographic patterns i. Distinctly different and easy to distinguish from HCSB (Compare Figure 3, Figure 4) ii. Underlying mechanisms are understood c. Physiology i. Two distinct respiratory rhythm generators located in the ventrolateral medullary portion of the neonatal rat brainstem  Both are normally coupled and generate normal respiratory rhythm  The retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG)  The pre-Botzinger complex (pre-BotC)  Site of inspiratory rhythmogenesis in mammals  Both intravenous and selective application of opioid agonist to the neurons of pre-Botzinger complex depresses breathing  Selective application of naloxone to the neurons of preBotzinger complex, a mu receptor antagonist reversed depressed breathing  Opioid’s induction of CSA is strongly supported  Opioid use was associated with CSA as well as persistent complex CSA  Reversed with discontinuation of opioids  Best approach to treat opioid-induced CSA is withdrawal, generally a difficult task (See the section on treatment of CSA) 3. CSA at high altitude a. With the increasing popularity of mountain sports worldwide, each year several million people travel to high altitudes b. 2500 m has been used as the threshold for high-altitude illnesses c. Multiple conditions are associated with high altitude i. Acute and chronic mountain sickness ii. High-altitude pulmonary edema iii. Central sleep apnea d. Polysomnographic findings i. Sleep stages are generally shifted from deeper toward lighter sleep  Increased arousals: both spontaneous and also as a result of sleep disordered breathing (SDB)

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More N1 and less N3 and REM sleep Demonstrated by conventional and spectral analysis of the sleep electroencephalogram (EEG)  Reflected in subjective complains of poor quality of sleep ii. Resembles HCSB in heart failure except short breathing cycle at about 20 to 25 seconds iii. This is in contrast to periodic breathing in heart failure which has long cycle (40 seconds or longer) with orchestrated crescendo decrescendo arms because of increased circulation time iv. Repeated cluster-type pattern of a few augmented breaths followed by apnea v. High altitude CSA is similar to that of opioid-induced CSA a. Physiology i. Underlying mechanism of high-altitude CSA is hypoxemia  Occurs at high altitude as the barometric pressure decreases  Fractional concentration of O2 is similar to that at sea level  Hypoxemia  Narrows the difference between spontaneous PCO2 and the apneic threshold PCO2  Increases hypocapnic chemosensitivity below the apneic threshold  While asleep, when apneic threshold is unmasked, and central apnea occurs as PCO2 falls below apneic threshold  With apnea, PCO2 rises and breathing resumes  As breathing increases, the consequent reduction in PCO2 perpetuates the cycle  It is noteworthy that when subjects with OSA sojourn to high altitude, the phenotype of sleep apnea converts to primarily CSA  Inhalation of supplemental oxygen and small amount of CO2 has been shown to decrease periodic breathing 4. TECSA: Treatment-emergent CSA in obstructive sleep apnea a. Central apneas may be observed in polysomnograms of patients with obstructive sleep apnea (OSA) i. Typically are few in number and no clinical significance ii. Can increase significantly during the first night of titration with continuous positive airway pressure (CPAP) b. Previously referred to as complex sleep apnea i. Recent studies have shown emergent CSA with other modalities of used to treat OSA, and the nomenclature has now changed to treatment-emergent CSA ii. The prevalence of TECSA is higher with CPAP treatment of OSA than other modalities

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Prevalence i. Varies from 7% to 20% on the first night of titration ii. In the largest number of prospective patients studied to date (n = 1286)  The monthly incidence of CSA during initial CPAP titration varied from 3% to 10% during a 1-year period  An average of 6.5%  The lower incidence rate of CSA may have to do with the large number of patients enrolled and the use of separate nights for diagnostic polysomnography and CPAP titration  Prevalence decreases after 6 weeks of CPAP use iii. Largest number of patients with OSA receiving CPAP reviewed (n = 1776)  28 patients (1.57%) had CSA at the time of CPAP therapy  Eliminated those with elevated B-type natriuretic peptide (BNP) iv. Prevalence appears to be higher in split-night studies, those with severe OSA, with preexisting cardiac disease and use of opioids v. Subclinical left ventricular dysfunction may account for higher prevalence of CSA in some studies a. TECSA in non-mask therapy of OSA i. Post-tracheostomy  No systematic studies are available to determine the frequency and clinical significance of central apneas after tracheostomy  Repeat polysomnography showed that some patients developed CSA ii. Also seen following tonsillectomy, nasal expiratory positive airway device (Provent), surgical relief of nasal obstruction OSA, maxillomandibular surgery for OSA, mandibular advancement device, tongue stabilizing device, oral appliance and hypoglossal nerve stimulation iii. The most common association has been with CPAP b. Natural history of TECSA i. Continued use of CPAP is associated with resolution of CSA ii. After the use of CPAP (average time/night=5.6 h) for few weeks  Prevalence of CPAP-persistent CSA decreased from 6.5% to estimated 1.5% of 1286 patients with OSA  Long-term treatment of OSA with CPAP, CSA will generally be eliminated iii. Guilleminault and colleagues noted that patients with OSA who underwent tracheostomy initially developed CSA which improved over an extended period of time iv. The underlying mechanism is increased loop gain which improves after long-term use of the device

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Treatment of CSA    

Multiple options for the treatment of central sleep apnea (Table 2) Depends on the etiology of the CSA No single treatment option has been completely effective in suppressing CSA disorder as opposed to OSA Positive airway pressure devices and phrenic nerve stimulation have been studied in long term clinical trials and are the most widely used therapies for the treatment of CSA of various etiologies Table 2. Treatment of central sleep apnea

1. 2. 3. 4.

Medications (theophylline and acetazolamide) Oxygen Positive airway pressure devices (CPAP, BiPAP, ASV) Phrenic nerve stimulation

1. Medications and oxygen therapy a. Several medications have been tested b. Acetazolamide i. Used in treatment of CSA in heart failure, high altitude, and idiopathic CSA c. Theophylline has been used in heart failure d. Nocturnal oxygen therapy i. Most systematically studied in HFrEF ii. Quite effective in treatment of high-altitude-induced CSA

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e. Pharmacological therapy of CSA has been reviewed extensively elsewhere 2. Positive airway pressure (PAP) therapy a. Continuous positive airway pressure devices i. Treatment of choice in OSA ii. Studied as a treatment of CSA associated with HFrEF, opioids and for idiopathic CSA iii. Data in HFrEF  CSA is suppressed in almost 50% of the subjects treated with CPAP both acutely and chronically  If CSA is not suppressed, continued use of CPAP is associated with excess mortality due to excess intrathoracic pressure imposing hemodynamic consequences iv. CPAP is virtually completely ineffective in opioid-induced CSA v. CPAP effectiveness is limited in ICSA a. Bilevel devices i. Should be avoided for treatment of CSA of any cause ii. Excess ventilation imposed by bilevel devices lowers the PaCO2 below the apneic threshold PCO2 aggravating CSA b. Adaptive servoventilation (ASV) i. Advanced form of PAP therapy  Modifies inspiratory and expiratory pressures based on the needs of the patient  Provides automatic end-expiratory pressure which increases in response to upper airway narrowing (hypopnea) or closure (apnea)  Delivers variable inspiratory pressure support (inspiratory pressure minus expiratory pressure) which is an anticyclic to intrinsic breathing pattern of the patient  Has an automatic backup rate to abort impending apneas ii. HFrEF  ASV devices are now contraindicated for treatment of CSA in HFrEF due to an increase in cardiovascular mortality  In a multicenter, randomized controlled trial (RCT), the SERVE-HF trial, compared to the usual care, use of ASV was associated with excess CV mortality  These results were similar to the CPAP randomized trial  It was suggested that excess mortality might have been in part due to excess intrathoracic pressure as suggested for CPAP trial iii. Opioid-induced CSA  ASV appears to be effective  Pressure settings must be appropriately iv. TECSA  ASV appears to be effective

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In one RCT, CPAP vs. ASV, the differences in AHI were somewhat limited and there were no differences in adherence to either PAP devices, or in any quality of life (QoL) examined v. High-altitude CSA  No systematic studies 3. Neurostimulation a. Transvenous phrenic nerve stimulation (TPNS) i. Latest therapy for central sleep apnea ii. Received FDA approval in 2017

Figure 5. A 10 min polysomnographic example of opioids-associated sleep apnea. Breathing is ataxic, distinctly different from HCSB in Fig 3. From: Javaheri S, Malik A, Smith J, Chung E. Adaptive Servoventilation: A Novel Treatment for Sleep Apnea Associated with the Use of Opioids. Modified from Javaheri et al., J Clin Sleep Med 2008;4:305-310.

iii. Device and function  Implantable pulse generator with a stimulation lead and a sensing lead (Figure 6)  Unique algorithm that stimulates the phrenic nerve to move the diaphragm and stabilize breathing (Figure 7)  Designed to activate automatically at night when the patient is sleeping to ensure compliance  Algorithm is very different than other phrenic nerve stimulators designed for respiratory insufficiency patients

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Phrenic Nerve Stimulation Implanted

Figure 6. Transvenous phrenic nerve stimulation implanted depicting the stimulation lead in the left pericardiophrenic vein and the sensing lead in a side branch of the azygos vein. Courtesy of Respicardia, Inc.

Transvenous Phrenic Nerve Stimulation wuth Therapy Activated

Figure 7. Changes in breathing pattern with phrenic nerve stimulation. The left side demonstrates central sleep apnea and the right site demonstrates stabilization of the breathing pattern with phrenic nerve stimulation. From: Costanzo MR, Augostini R, Goldberg LR, et al. Design of the remedē® System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea. J Card Fail 2015;21:892-902.

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Shahrokh Javaheri and Robin Germany iv. Clinical studies  Safety and efficacy of TPNS was evaluated in a multi-centered randomized clinical trial  Therapy was shown to be effective both in acute and chronic treatment in a broad patient population  Improvements were noted in sleep quality, daytime sleepiness, and quality of life  Post-hoc analyses showed similar effectiveness in patients with and without heart failure and in the idiopathic patient population

KEY CLINICAL POINTS 1. 2. 3. 4.

Central apneas occur in many pathophysiological conditions Central apneas may not be clinically significant In some disorders central apneas result in pathophysiological consequences Diagnosis and treatment of central sleep apnea may improve: a. Quality of life b. Morbidity c. May improve mortality, but additional data is needed 5. Much less is known about the clinical signification of central sleep apnea compared to obstructive sleep apnea 6. Continued research on CSA is needed

QUESTIONS 1. Among the following medications, which is/are associated with CSA? (Choose all applicable) a. Diphenhydramine b. Zolpidem (Ambien) c. Diazepine (Valium) d. Methadone e. Valerian 2. In regards to heart failure (HF), which is correct? a. Only patients with heart failure and reduced ejection fraction are at risk of having sleep apnea. b. Patients with heart failure and preserved ejection fraction are at risk primarily for central sleep apnea (CSA). c. HF is the most common cause of CSA in the general population. d. HF patients with sleep apnea commonly complain of excessive daytime sleepiness.

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3. Regarding mortality when sleep apnea is comorbid with heart failure, which of the following best describes the association? a. There is no convincing evidence that either OSA or CSA is associated with excess mortality. b. Observational studies suggest that CSA is associated with increased hospitalization and premature mortality. c. Observational studies suggest that CSA and not OSA is associated with premature mortality. d. None of the above. 4. For treatment of CSA comorbid with heart failure: a. Nocturnal oxygen is approved to treat CSA b. Acetazolamine is approved to treat CSA c. Theophylline is approved to treat CSA d. Adaptive servoventilation is approved to treat CSA e. Unilateral transvenous phrenic nerve stimulation is approved to treat CSA 5. Regarding sleep and CSA which statement is incorrect? a. The apneic threshold is unmasked during sleep, which explains why CSA occurs during sleep. b. CSA occurs mostly in REM sleep. c. During sleep, metabolic rate, functional residual capacity (in supine position) and cardiac output decrease. d. During sleep, ventilation decreased and PCO2 increases e. In the treatment of OSA, sometimes CSA is observed.

CONFLICT OF INTEREST Javaheri S Consultant to Respicardia, Inc. Germany R Salary from Respicardia.

REFERENCES Javaheri S, Cao M. Opioid Induced Central Sleep Apnea. In Proceedings of the X World Congress on Sleep Apnea, Section: Respiratory Disorders and Snoring. Ed. Mario Fabiani. Edizioni Minerva Medica, Turin. 2012; pp 133-137. Javaheri S, Dempsey JA. Central sleep apnea. Compr. Physiol. 2013;3:141-163. doi: 10.1002/cphy.c110057. Javaheri S, Harris N, Howard J, Chung E. Adaptive servo-ventilation for treatment of opioidsassociated central sleep apnea. J. Clin. Sleep. Med. 2014;10:637-643. doi: 10.5664/jcsm.3788. Javaheri S, Malik A, Smith J and Chung J. Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids. J. Clin. Med. 2008;4(4):305-310.

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Randerath W, Verbraecken J, Andreas S, Arzt M, Bloch K E, Brack T, Buyse B, De Backer W, Eckert D J, Grote L, Hagmeyer L, Hedner J, Jennum P, La Rovere M T, Miltz C, McNicholas J, Naughton M, Pepin JL, Pevernagie D, Sanner B, Testelmans D, Tonia T, Vrijsen B, Wijkstra P, Levy P. Definition, discrimination, diagnosis and treatment of central W T, Montserrat breathing disturbances during sleep. Eur. Respir. J. 2017 Jan 18;49(1):1600959. doi: 10.1183/13993003.00959-2016. Rezayat T and Chang M. A Case of Hypoglossal Nerve Stimulation Induced Cheyne-Stoke Central Sleep Apnea. Sleep 2020;43:A468. 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 nasal continuous positive airway pressure. Am. J. Respir. Crit. Care Med. 2010 Jan 15;181(2):189-93. doi: 10.1164/rccm.200810-1658OC. San T, Polat S, Cingi C, Eskiizmir G, Oghan F, and Cakir B. Effects of high altitude on sleep and respiratory system and their adaptations. Scientific World J. 2013 Apr 17;241569. doi: 10.1155/2013/241569. Schwartz A R, Sgambati F P, James K J, Goblish T P, Germany R E, Jackson S E, Samtani N, Berger R D. Novel phrenic nerve stimulator treats Cheyne-Stokes respiration: polysomnographic insights. J. Clin. Sleep Med. 2020 May 15;16(5):817-820. doi: 10.5664/jcsm.8328. Smith J C, Ellenberger H H, Ballanyi K, Richter D W, Feldman J L. Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science. 1991 Nov 1;254(5032):726-9. doi: 10.1126/science.1683005. Sutton J R, Houston C S, Mansell A L, McFadden M D, Hackett P M, Rigg J R, Powles A C. Effect of acetazolamide on hypoxemia during sleep at high altitude. N. Engl. J. Med. 1979 Dec 13;301(24):1329–31. doi: 10.1056/NEJM197912133012406. Virani S S, Alonso A, Benjamin E J, Bittencourt M S, Callaway C W, Carson A P, Chamberlain A M, Chang A R, Cheng S, Delling F N, Djousse L, Elkind MSV, Ferguson J F, Fornage M, Khan S S, Kissela B M, Knutson K L, Kwan T W, Lackland D T, Lewis T T, Lichtman J H, Longenecker C T, Loop M S, Lutsey P L, Martin S S, Matsushita K, Moran AE, Mussolino M E, Perak A M, Rosamond W D, Roth G A, Sampson U K A, Satou G M, Schroeder E B, Shah S H, Shay C M, Spartano N L, Stokes A, Tirschwell D L, VanWagner L B, Tsao C W; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 Mar 3;141(9):e139-e596. doi: 10.1161/CIR.0000000000000757. Westhoff M, Arzt M, Litterst P. Prevalence and treatment of central sleep apnoea emerging after initiation of continuous positive airway pressure in patients with obstructive sleep apnoea without evidence of heart failure. Sleep Breath. 2012 Mar;16(1):71-8. doi: 10.1007/ s11325-011-0486-0. White D P, Zwillich C S, Pickett C K, Douglas N J, Findley L J, Weil J V. Central sleep apnea improvement with acetazolamide therapy. Arch Intern. Med. 1982 Oct;142 (10):1816– 1819. 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 Dec;152(6 Pt 1):1950-5. doi: 10.1164/ajrccm.152.6.8520761.

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PART III: OTHER SLEEP DISORDERS

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 28

INSOMNIA Ashwin Anath1, MD, Karl Doghramji1, MD and Colin Huntley1,2, MD 1

Jefferson Sleep Disorders Center, Thomas Jefferson University, Philadelphia, PA, USA 2 Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, USA

DEFINITIONS 1. Insomnia is defined as a subjective complaint of: a. Persistent difficulty with sleep initiation, duration, consolidation, or quality b. That occurs despite adequate opportunity and circumstances for sleep c. And results in some form of daytime impairment  Note: Variations in diagnostic criteria exist between the International Classification of Sleep Disorders-3 (ICSD-3), Diagnostic and Statistical Manual (DSM-5), and International Classification of Diseases-10 (ICD10) definitions, but the core features are the same. In this chapter we will adhere to the ICSD3 nosology to avoid confusion.

DEMOGRAPHICS 1. Sleep difficulty is the second most common complaint in medical practice after pain 2. 1/3 of all adults will experience insomnia during any year 3. Risk Factors a. Female gender i. Especially during pregnancy, peri/post-menopause b. Old age c. Solitude i. Divorced, single, widowed

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Ashwin Anath, Karl Doghramji and Colin Huntley d. Shift workers e. Unemployed or low socioeconomic status f. Comorbid medical and psychiatric disorders i. May be unrelated, or related to insomnia in a bidirectional manner g. Substance abuse h. Genetic vulnerability 4. Classification a. ICSD-3 i. Classifies insomnia into 2 major types  Short-term insomnia disorder  Less than 3 months in duration  Chronic insomnia disorder  Symptoms 3 or more nights per week for 3 months or more  Note: The following subtypes of chronic insomnia disorder were considered primary diagnoses in ICSD-2. Although they are no longer used as primary diagnoses, they may still have relevance for clinical care.  Psychophysiological o Heightened arousal and learned sleeppreventing associations cause insomnia o Elevated levels of cognitive and somatic arousal o Exaggerated concern with lack of sleep and its consequences o Often able to sleep in novel sleep settings or when not trying to sleep  Idiopathic o Longstanding and unremitting insomnia with insidious onset, usually beginning in childhood without discernible cause o Thought to arise from genetic or congenital aberrations  Paradoxical o Also referred to as sleep state misperception o Marked underestimation of amount of sleep based on objective polysomnography (PSG) or actigraphy data  Inadequate sleep hygiene o Daily activities hamper ability to attain quality sleep o Examples include: 1. Variable bedtime 2. Use of electronics in bed

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3. Stimulating activities near bedtime 4. Stimulating substances near bedtime  Caffeine, alcohol, nicotine 5. Napping near bedtime, bedrest 6. Frequent travel and shift work 7. Exposure to bright light before or during sleep hours 5. Pathophysiology a. Insomnia disorder is based in a state of hyperarousal i. Associations with increase in:  Basal metabolic rate  Heart rate  Body temperature  Cortisol and adrenocorticotropic hormone (ACTH) secretion at night ii. Genetic vulnerability may play a role  Monozygotic twins have a higher incidence than dizygotic twins 6. Evaluation a. History i. Nighttime symptoms  Nocturnal pattern  Initiation, maintenance, termination  Duration  Frequency  Precipitants  Perpetuating factors  Clock watching, sleep hygiene habits ii. Daytime symptoms  Fatigue, irritability  Mood changes  Memory impairment  Falling asleep at inappropriate times iii. Sleep history  Bedtime  Sleep latency  Time to fall asleep after lights out  Number and duration of awakenings  Final morning awakening time  Time out of bed in the morning  Daytime napping habits  Bedtime habits  Light/noise exposure, etc.

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Ashwin Anath, Karl Doghramji and Colin Huntley b. Testing i. There is no standard objective test for insomnia, diagnosis is clinical and based on patient complaint ii. Insomnia Severity Index (ISI)  Quantifies severity of insomnia, useful at baseline and after treatment iii. Sleep Logs  Useful for following patterns over time  Must use nightly as insomniacs tend to selectively report worst nights of sleep iv. Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS)  Useful for quantifying daytime consequences v. General laboratory testing to rule out comorbid conditions  Thyroid stimulating hormone (TSH)  Complete blood count (CBC)  Comprehensive metabolic panel (CMP) vi. Polysomnography is not routinely recommended, unless:  Consideration of comorbid sleep disorder  Obstructive sleep apnea (OSA), periodic limb movement disorder (PLMD), parasomnias  Objective quantification of sleep time in sleep-state misperception  Poor or inappropriate response to treatment 7. Differential diagnosis a. Chronic insomnia disorder b. Comorbid insomnia – treat comorbidity or treat insomnia directly in addition to comorbid disorders. These commonly include, but are not limited to i. Medical conditions  Gastroesophageal reflux disorder (GERD)  Anemia  Benign prostatic hyperplasia (BPH)  Chronic obstructive pulmonary disease (COPD)  Pain ii. Psychiatric Conditions  Generalized anxiety disorder  Depression  Post-traumatic stress disorder (PTSD) iii. Sleep disorders  OSA  Restless leg syndrome (RLS)/PLMD  Circadian rhythm disorders  Advanced sleep phase syndrome (ASPS)/delayed sleep phase syndrome (DSPS)  Shift work sleep disorder

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iv. Substance use and abuse v. Medications  Antidepressants  Fluoxetine, venlafaxine, bupropion, tricyclic antidepressants (TCAs)  Bronchodilators  Decongestants  Corticosteroids  Stimulants  Certain anticonvulsants  Lamotrigine 8. Management a. Nonpharmacologic i. Compared with medications, nonpharmacologic methods have at least equal efficacy and longer duration of benefit ii. Cognitive behavioral therapy for insomnia (CBT-I)  Sleep restriction  Limit time in bed to improve sleep efficiency  Stimulus control  Improve bedroom as stimulus for sleep  Get out of bed if unable to initiate sleep after 20 minutes  Do something relaxing (e.g., read) and return to bed for another trial of sleep  Sleep hygiene education  Promotes good sleep habits and eliminate interfering habits  Cognitive therapy  Goal is to dispel notions that may worsen sleep and perpetuate insomnia  Relaxation training  Reduces anxiety and promotes relaxation through: o Biofeedback o Progressive muscle relaxation o Yoga, meditation, breathing exercises  Paradoxical intention  Relieves anxiety about initiating sleep by trying to stay awake  Online tools  Myshuti.com, sleepio.com  CBT-I coach app, Night Owl app b. Pharmacologic i. Benzodiazepines (BZD)  Bind to gamma aminobutyric acid A (GABA-A) receptors with variable affinities for subunits

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Ashwin Anath, Karl Doghramji and Colin Huntley  GABA is the main inhibitory neurotransmitter Non-BZD Benzodiazepine receptor agonists (NBRA)  Black box warning: In patients taking these drugs, rare but serious injuries and even deaths have occurred during complex sleep behaviors, such as sleepwalking, sleep driving, and other activities while not fully awake  Eszopiclone, zaleplon, and zolpidem are contraindicated in patients with a history of previous episodes of medicationinduced complex sleep behavior

ii.

iii. Other Agents 





Ramelteon (Rozerem)  Melatonin receptor agonist at MT1 and MT2 receptors o Located in the suprachiasmatic nucleus  Does not depress respiratory drive in mild to moderate OSA/COPD Doxepin (Silenor)  H1 (histamine) receptor antagonist  Avoid in patients on monoamine oxidase inhibitor (MAOI) therapy and in glaucoma Suvorexant (Belsomra) and lemborexant (Dayvigo)  Dual orexin receptor antagonist  Contraindicated in narcolepsy  Suvorexant safety demonstrated for mild to moderate OSA, lemborexant for mild OSA

Table 1. Pharmacotherapy of Adult Insomnia Generic (Trade) Name Estazolam (ProSom) Flurazepam (Dalmane) Quazepam (Doral) Triazolam (Halcion) Temazepam (Restoril) Zolpidem (Ambien) Zolpidem ER (AmbienCR) Zolpidem sublingual (Edluar)

Dose Range (mg) 1-2 15-30 7.5-15 0.125 – 0.25 7.5-30 5-10 6.25-12.5 5-`0

Zolpidem sublingual (Intermezzo)

1.75(female) 3.5(male)

Zolpidem spray (Zolpimist) Eszopiclone (Lunesta) Zaleplon (Sonata) Ramelteon (Rozerem) Doxepin (Silenor) Suvorexant (Belsomra) Lemborexant (Dayvigo)

5 per spray 1-3 5-20 8 3-6 5-20 5-10

Indication (type of insomnia) Sleep initiation, sleep maintenance Sleep initiation, sleep maintenance Sleep initiation, sleep maintenance Sleep initiation Sleep initiation Sleep initiation Sleep initiation, sleep maintenance Sleep initiation Sleep maintenance (taken during nighttime awakening) Sleep initiation Sleep initiation, sleep maintenance Sleep initiation Sleep initiation Sleep maintenance (taken at bedtime) Sleep onset, sleep maintenance Sleep onset, sleep maintenance

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QUESTIONS 1. Which of the following is not required for the diagnosis of insomnia? a. Daytime impairment b. Difficulty initiating or maintaining sleep c. Decreased total sleep time on polysomnography d. Adequate opportunity for sleep 2. Which of the following diagnoses precludes a diagnosis of insomnia? a. Delayed sleep phase b. Obstructive sleep apnea c. Generalized anxiety disorder d. Sleep deprivation 3. Which of the following patients has a contraindication to treatment with a nonbenzodiazepine BZD-receptor agonist for insomnia? a. A patient who works overnight shifts exclusively b. A patient who has untreated obstructive sleep apnea c. A patient who is 68 years old d. A patient with a history of obesity and asthma 4. Ramelteon is an agonist at which of the following receptors? a. BZD b. Melatonin c. Orexin/Hypocretin d. Histamine 5. Which of the following parameters on polysomnography is most important for the evaluation of sleep-state misperception? a. Sleep efficiency b. Total sleep time c. Sleep latency d. Non-REM parasomnias

REFERENCES Doghramji K. The evaluation and management of insomnia. Clin. Chest Med. 2010;31(2):327339. doi:10.1016/j.ccm.2010.03.001. Johnston G A. GABA(A) receptor channel pharmacology. Curr. Pharm Des. 2005;11(15): 1867-1885. doi:10.2174/1381612054021024. Lam A S, Collop N A, Bliwise D L, Dedhia R C. Validated Measures of Insomnia, Function, Sleepiness, and Nasal Obstruction in a CPAP Alternatives Clinic Population. J. Clin. Sleep Med. 2017;13(8):949-957. doi:10.5664/jcsm.6692. Nofzinger E A. What can neuroimaging findings tell us about sleep disorders? Sleep Med. 2004 Jun;5 Suppl 1:S16-22. doi: 10.1016/s1389-9457(04)90003-2.

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Sateia M J, Buysse D J, Krystal A D, Neubauer D N, Heald J L. 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):307-349. doi: 10.5664/jcsm.6470. Sateia M J. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146(5):1387-1394. doi:10.1378/chest.14-0970. Seow L S E, Verma S K, Mok Y M, et al. Evaluating DSM-5 Insomnia Disorder and the Treatment of Sleep Problems in a Psychiatric Population. J. Clin. Sleep Med. 2018;14 (2):237-244. doi:10.5664/jcsm.6942. Watson N F, Goldberg J, Arguelles L, Buchwald D. Genetic and environmental influences on insomnia, daytime sleepiness, and obesity in twins. Sleep. 2006;29(5):645-649. doi:10.1093/sleep/29.5.645.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 29

CENTRAL DISORDERS OF HYPERSOMNOLENCE Anne Marie Morse1, DO, Michael Strunc2, MD and Asim Roy3, MD Division of Pediatric Neurology, Janet Weis Children’s Hospital, Geisinger, Danville, PA, USA 2 Child Neurology and Sleep Medicine, CHKD, Assistant Professor Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA 3 Ohio Sleep Medicine Institute, Northeast Ohio Medical University, Rootstown, OH, USA 1

NARCOLEPSY 1. International classification of sleep disorders 3rd edition (ICSD-3) defines two types a. Type I (NT1) i. Pentad of features  Excessive Daytime Sleepiness (EDS)  Sleep fragmentation  Sleep related hallucinations  Sleep paralysis  Cataplexy  Transient episodes of aberrant tone  Provoked by emotion  Most specific symptoms of NT1 ii. Hypocretin (orexin) deficiency iii. Low levels within cerebrospinal fluid (CSF) iv. Suffer from significant medical co-morbidities  Obesity  Precocious puberty  Cardiovascular (non-dipper blood pressure profile)  Anxiety/mood disturbances/psychosis

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Anne Marie Morse, Michael Strunc and Asim Roy Table 1. Central disorders of hypersomnolence as defined by the ICSD-3

ICSD-3 Classification Narcolepsy type 1 Narcolepsy type 2 Idiopathic hypersomnia

Previous Classification Narcolepsy with cataplexy Narcolepsy without cataplexy Idiopathic hypersomnia with long sleep time Idiopathic hypersomnia without long sleep time

Klein-Levin syndrome Hypersomnia due to a medical disorder Hypersomnia due to a medication or substance Hypersomnia associated with a psychiatric disorder

b. Type II (NT2) i. Tetrad of features  EDS  Sleep fragmentation  Sleep related hallucinations  Sleep paralysis ii. Normal levels of CSF hypocretin 2. Prevalence a. 1 in 2000 individuals have narcolepsy i. 50% undiagnosed b. Diagnosis often delayed 8-10 years i. Presence of cataplexy at onset generally helps achieve a more expedited diagnosis 3. Onset of symptoms a. Bimodal i. Peak around age 15 ii. 2nd smaller peak around age 35 4. Approach to Narcolepsy Symptom Recognition a. Lack of awareness and lack of ability to recognize pentad symptoms causes delay in diagnosis b. AWAKEN survey i. 10% of primary care providers could identify all 5 narcolepsy symptoms ii. 22% of sleep specialists could identify all 5 narcolepsy symptoms c. Pediatric Considerations i. Sleep duration by age (Figure 1) ii. Return of daytime napping iii. Sleep attacks in sedentary situations iv. Compensation against sleepiness  Hyperactivity  Mood instability  Aggressive behavior  Irritability

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Challenges to identify cataplexy in pediatrics  Diverse symptoms  Not always provoked by emotion  Spontaneous/emotionally provoked “cataplectic facies”  Dyskinesis  Active motor phenomena/complex movement disorder (Table 2)  Symptoms can be overlooked, misdiagnosed, or considered typical for childhood

Figure 1. Developmentally appropriate sleep hours by age.

Table 2. Description of Cataplexy types and features Type Mixed

Description “Cataplectic Facies”

Example Facial hypotonia with ptosis, mouth opening and tongue protrusion

Negative

Transient loss of antigravity muscle tone, frequently evoked by emotion (generalized or partial)

knee buckling, loss of tone in hands, head drop, Generalized collapse to the ground with preserved awareness,

Near continuous hypotonia without emotional stimulus

General floppiness, abnormal/semiataxic gait

Hyperkinetic features that may be enhanced by emotional stimuli

facial grimacing, eyebrow raising, Perioral/tongue movements

Complex Movement disorder

Tic like stereotyped motor movements

Active

5. Adult Considerations a. Difficult to diagnosis due to comorbid conditions b. Misdiagnosis c. Medications taken for other indications may help/reduce narcolepsy symptoms d. Underreporting of symptoms because individual has become accustomed to their symptoms

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Rationalize symptoms based on other diagnoses they have received or underestimate the severity due to compensatory actions f. EDS most typically presents with irrepressible need to nap when sedentary g. Mental slowing/clouding h. Motor vehicle accidents related to falling asleep i. Cataplexy is typically described as emotionally provoked transient episodes of loss of tone, but can occur independent of emotion i. Many patients report being clumsy ii. Many patients fail to endorse these symptoms iii. Critical to re-evaluate for symptoms of cataplexy at every visit 6. Other considerations a. Evidence of rapid eye movement (REM) dissociative behaviors b. Sleep paralysis c. Sleep related hallucinations d. Automatic behavior i. Daytime lapses of awareness or dream like state of being engaged in activity that are poorly recalled by the patient e. Sleep onset vivid dreaming i. Vivid dreaming in less than 15 minutes is a clinical indicator of sleep onset REM sleep ii. REM behavior disorder  May be misdiagnosed as nightmare disorder or other nonREM parasomnias f. Sleep fragmentations, nocturnal awakenings, and poor sleep efficiency i. Maybe considered behavioral, hormonal or related to other etiology 7. Management a. Behavior i. Scheduled naps (short)  15-20 min 1-3x/day ii. Sleep hygiene iii. Adequate sleep duration iv. Cognitive therapy v. Physical activity/daily exercise vi. Counseling vii. Peer support viii. Patient and family b. Pharmacologic (see Table 2) i. Modafanil/Armodafanil  Wake promoting via dopamine (hypothesized)  200-400 mg/150-250 mg ii. Pitolisant  H3 receptor antagonist/inverse agonist  Histamine plays a role with:  Increased wakefulness  Attention and memory benefit

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iii.

iv.

v.

vi.

vii.

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 Decreased cataplexy  9 mg-36 mg/day  Non-controlled  FDA approved in 2019 Sodium oxybate/gamma hydroxybutyrate  Gamma aminobutyric acid-B (GABA-B) receptor agonist (hypothesized)  Associated with  Increased slow wave sleep (SWS)  Decreased awakenings/arousals  Reduction of REM sleep period  Improved sleep efficiency  Improves cataplexy  Improves EDS  Different therapeutic doses based on individual  Liquid form taken twice per night (need to set an alarm to take the 2nd dose)  Total recommended dose between 6 g/night to 9 g/night divided  Sodium based medication  Low Na, preparation, add in now or not?  Side effects: nausea, dizziness/confusion, weight loss, enuresis, anxiety and depressive symptoms Methylphenidate  Increase in dopamine/norepinephrine  2nd line agent  Primary effect on EDS  Dose 10 mg-60 mg per day divided 1-4x/day Amphetamines  Increase monamines  High abuse potential  Cardiovascular adverse effects Solriamfetol  Selective dopamine and norepinephrine reuptake inhibitor  Dose 75 mg-150 mg  FDA approved in 2019 Other options for cataplexy  Venlafaxine  Other antidepressants  Fluoxetine  Citalopram  Tricyclic antidepressants o clomipramine, protriptyline

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IDIOPATHIC HYPERSOMNIA (IH) 1. Overview a. Central disorder of hypersomnolence of unknown etiology b. Poorly understood c. Lack of consistent criteria limits ability to quantify prevalence d. Estimated to occur 10-60% as often as narcolepsy e. Sleep periods and naps prolonged in duration i. High efficiency f. Sleep inertia often associated with symptoms g. Diagnosis often made after exclusion of other causes of EDS h. Shares many features with narcolepsy i. Age of onset ii. Chronicity iii. Mean sleep latency i. Unique clinical features: i. Lack of REM dissociated features ii. Severe morning sleep inertia iii. Continuous drowsiness iv. Unrefreshing naps j. Approach to IH symptom recognition i. EDS is most striking feature ii. Hypersomnolence occurs despite:  Normal overnight sleep architecture  Excellent efficiency  Normal to long sleep duration iii. Severe sleep inertia iv. Non-restorative napping v. Difficultly getting out of bed vi. Daily symptoms vii. Hypnogogic hallucinations and sleep paralysis may occur but rarely viii. May have more evening chronotype/delayed sleep phase type circadian pattern

APPROACH TO DIAGNOSIS FOR HYPERSOMNIA DISORDERS 1. Consider use of validated measures to help identify patients with features of narcolepsy a. Especially if there is reduced confidence in ability to recognize or identify features b. The Epworth Sleepiness Scale (ESS) and the child/adolescent version (ESSCHAD) are validated measures in adults/children to identify sleepiness i. Score > 10 are considered sleepy ii. Score > 16 are considered high risk of hypersomnia disorder

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Cataplexy questionnaire to guide easy identification of those at high/low risk for cataplexy d. Swiss Narcolepsy Scale is validated 5-item patient reported scale used to identify patients at high likelihood for narcolepsy type 1 i. Available for free at www.swissnarcolepsyscale.com 2. Important to compliment the use of these validated scales with subjective input from the patient regarding impact of symptoms on quality of life and disability a. This information generally proves to be more valuable in targeting goals that are meaningful to the patient for improvement and adherence to treatment 3. Sleep testing for hypersomnia a. Gold standard i. Overnight polysomnography (PSG) and the following day multiple sleep latency (MSLT) ii. The in-lab PSG should be performed prior to the MSLT  Minimum sleep required is 6 hours prior to MSLT for optimal sensitivity and specificity  PSG may provide additional clued for diagnosis of narcolepsy  Sleep onset REM on overnight PSG iii. MSLT  4 to 5 nap opportunities every 2 hours  Evaluating time to fall asleep or sleep latency (SL)  Evaluating for sleep onset REM periods (SOREMPs)  SOREMPs = the presence of REM sleep within 15 minutes of sleep onset o Normal latency to REM sleep 90-120 minutes iv. Narcolepsy Type 1 and 2 generally diagnosed based on SL of < 8 min and presence of 2 or more SOREMPs on sleep testing v. There are factors that may influence the yield of the MSLT (Table 3) vi. Children have normal sleep latencies that vary by tanner staging and can contribute to diagnostic difficulty vii. Sleep diaries and/or actigraphy are recommended for at least 2 weeks prior  Evaluate for insufficient sleep or delayed sleep phase syndrome which can result in false positive testing for narcolepsy b. Genetic testing (Human Leukocyte Antigen Testing – HLA) i. There are specific HLA haplotypes that have been identified both protective or as a risk factor ii. HLA-DQB1*0602 found in 85-95% of patients with narcolepsy  Risk to develop narcolepsy  7-fold higher with heterozygous twins  25-fold higher with homozygous twins iii. Families with a narcolepsy  Estimated risk for family member is 10-40 times higher than general population

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HLA DQB1*00602 has been found equally represented in hypersomnia patients and controls – therefore HLA typing is not recommended in diagnosis of IH v. Genomics has not been shown to influence course or disease burden vi. 50% of patients with narcolepsy type 2 maybe HLA DQB1*0602 positive vii. This haplotype has been identified in 12-38% of the general population without narcolepsy viii. The lack of specificity has led to HLA testing not routinely being advocated for to identify diagnosis of narcolepsy ix. However, the presence or absence of a specific haplotype may provide excellent diagnostic clues, especially in cases with multiple co-morbidities or medications contributing to an ambiguous presentation Cerebrospinal fluid (CSF) testing i. CSF evaluation may identify low orexin/hypocretin  Less than 110 pg/ml in 87-96% of patients with narcolepsy type 1  Narcolepsy type 2, IH and Kleine-Levin Syndrome (KLS) have normal cell counts, protein, glucose and CSF orexin/hypocretin levels  The lack of cataplexy and normal CSF orexin/hypocretin in narcolepsy type 2 can contribute to difficulty in recognition and distinguishing from IH

Table 3. Prevalence of sleep deficits by country (as reported by the National Sleep Foundation (2013)

Less than 6 hours 6 to 7 hours

US 18% 27%

UK 16% 19%

Germany 9% 21%

Japan 16% 40%

KLEINE-LEVIN SYNDROME (KLS) 1. Overview a. Rare disorder b. Primarily affects males (70%) c. Characteristics i. Recurrent episodes of hypersomnia to various degrees ii. Cognitive or behavioral disturbances iii. Compulsive eating behavior iv. Hypersexuality d. Limited prevalence data but estimated 1-2 per million e. Diagnostic Criteria 1-5

Canada 6% 20%

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i.

Patient experiences at least two recurrent episodes of excessive sleepiness and sleep duration, each persisting for two to five weeks ii. Episodes recur usually more than once a year and at least once every 18 months iii. The patient has normal alertness, cognitive function, behavior and mood between episodes iv. The patient must demonstrate at least one of the following during the episode  Cognitive dysfunction  Altered perception  Eating disorder (anorexia or hyperphagia)  Disinhibited behavior (such as hypersexuality) v. The hypersomnolence and related symptoms are not better explained by another sleep disorder, other medical, neurologic, or psychiatric disorders (especially bipolar) or use of drugs or medications f. Clinical examination, electrophysiological studies, and CNS imaging are expected to be normal in KLS patients g. Therapeutic intervention most likely to be of benefit is lithium, although proof of efficacy is lacking h. Functional neuroimaging maybe helpful but is not diagnostic

INSUFFICIENT SLEEP SYNDROME 1. Overview a. Insufficient sleep is a global problem that is becoming increasingly more common b. The global prevalence of population getting less than 7 hours of sleep based on various surveys is displayed in Table 3 c. Causes i. Combination of factors ii. Shift workers or individuals who work more than 40 hours per week iii. Females slightly higher prevalence iv. There is individual variance on the effects of insufficient sleep  Genetic  Interpersonally driven  Race or ethnicity  Behavioral causes d. Consequences i. Daytime sleepiness ii. Emotional disturbances iii. Effects on function and structure of the brain iv. Effects on body weight v. Glucose metabolism vi. Cardiovascular system

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Inflammation, immune system suppression and increased risk of infection

KEY CLINICAL POINTS 1. Excessive daytime sleepiness can have various presentations. It is important to characterize EDS with validated tools like the Epworth sleepiness scale and patient description of severity and disability associated with sleepiness. 2. Cataplexy are transient episodes of abnormal tone that can be generalized or focal, leading to brief episodes of anything from hand weakness, nodding of head to complete collapse to the ground. 3. Kleine-Levin Syndrome (KLS) is the only described central disorder of hypersomnolence that alternates between complete normalcy and severe EDS. 4. An in-lab polysomnography with a next day multiple sleep latency test is the standard of care for evaluation of any central disorder of hypersomnolence. 5. Idiopathic hypersomnia is generally characterized by severe excessive daytime sleepiness, long sleep periods and a strong sleep inertia, but frequently lack and REM dissociative features that are more commonly present in narcolepsy.

QUESTIONS 1. In a patient with marked hypersomnia clinically, which of the following is the most useful tool to use with a clinical visit to further assess their symptoms? a. ESS b. Connors Scale c. PSG d. Sleep Diary 2. True or False. Idiopathic hypersomnia is more common than narcolepsy? 3. Which of the following is NOT a criterion for Idiopathic Hypersomnia? a. Daytime lapses into sleep or an irrepressible need to sleep on a daily basis, for at least 1 months. b. Insufficient sleep syndrome is confirmed absent, preferably via at least a week of wrist actigraphy. c. MSLT (Multiple Sleep Latency Test) shows one of the following: • Fewer than 2 sleep onset REM periods (SOREMPs, which are REM sleep periods within 15 minutes of sleep onset); Or • No SOREMPs, if the REM latency on the preceding overnight sleep study was less than or equal to 15 minutes. d. The presence of one or both of the following with PSG/MSLT testing: • Average sleep latency of less than or equal to 8 minutes on MSLT; • Total 24hour sleep time is greater than or equal to 660 minutes

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4. An 18-year-old young man presents with 6 months of severe excessive daytime sleepiness (ESS = 17) for initial evaluation. When asked about another other new symptoms or problems, he jokes and says that he is on his 3 new cell phone due to repeated dropping of the phone that he can’t explain. He has a PSG and MSLT performed. The PSG does not show any sleep apnea. The MSLT demonstrates an average sleep latency of 5 minutes and on naps 2 and 4 he went into REM sleep in 5 minutes and 6 minutes. The diagnosis for this patient is: a. Idiopathic Hypersomnia b. Kleine-Levin Syndrome c. Narcolepsy type 1 d. Narcolepsy type 2 e. Insufficient sleep syndrome 5. True or False. Kleine-Levin is a chronic progressive central disorder of hypersomnolence that is more frequent in middle age women.

DISCLOSURE Dr. Morse serves on the speaker bureau, has served on advisory boards and has provided consulting for Jazz Pharmaceuticals. Dr. Morse has served as an investigator for Avadel pharmaceuticals and Jazz Pharmaceuticals. Dr. Morse has grant funding from NIH. Dr. Strunc serves as a consultant and has received research support from Jazz Pharmaceuticals. Dr. Strunc has received research support from Suven Life Sciences and is currently on the speaker bureau for Neurelis. Dr. Roy serves on the speaker bureau, has served on advisory boards and provided consulting for Jazzpharmaceuticals, Harmony Biosciences, and Eisai. Dr. Roy has served as an investigator for Jazz pharmaceutical, Harmony Biosciences, Avadel, pharmaceuticals, Takeda, Inspire.

REFERENCES Aldrich M S. The clinical spectrum of narcolepsy and idiopathic hypersomnia. Neurology. 1996;46(2):393-401. doi:10.1212/wnl.46.2.393. American Academy of Sleep Medicine. International classification of sleep disorders (3rd ed.). 2014. Darien: American Academy of Sleep Medicine. Anderson K N, Pilsworth S, Sharples L D, Smith I E, Shneerson J M. Idiopathic hypersomnia: a study of 77 cases. Sleep. 2007 Oct;30(10):1274-81. doi: 10.1093/sleep/ 30.10.1274. Andlauer O, Moore H, Jouhier L, Drake C, Peppard P E, Han F, Hong S C, Poli F, Plazzi G, O’Hara R, Haffen E, Roth T, Young T, Mignot E. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol. 2013 Jul;70(7):891-902. doi: 10.1001/jamaneurol.2013.1589. Erratum in: JAMA Neurol. 2013 Oct;70(10):1332.

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Anic-Labat S, Guilleminault C, Kraemer H C, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep. 1999 Feb 1;22(1):77-87. Arnulf I, Leu-Semenescu S, Dodet P. Precision medicine for idiopathic hypersomnia. Sleep Med. Clin. 2019;14(3):333-350. doi: S1556-407X(19)30048-7. Carskadon M A. The second decade. Sleeping and Waking Disorders: Indications and Techniques. 1982. 99-125. Chattu V K, Sakhamuri S M, Kumar R, Spence D W, BaHammam A S, Pandi-Perumal S R. Insufficient Sleep Syndrome: Is it time to classify it as a major noncommunicable disease? Sleep Sci. 2018 Mar-Apr;11(2):56-64. doi: 10.5935/1984-0063.20180013. Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, Besset A, Billiard M. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001 Dec 11;57(11):2029-33. doi: 10.1212/wnl.57.11.2029. Dye T J, Gurbani N, Simakajornboon N. Epidemiology and Pathophysiology of Childhood Narcolepsy. Paediatr. Respir. Rev. 2018 Jan; 25:14-18. doi: 10.1016/j.prrv.2016.12.005. Hirshkowitz M, Whiton K, Albert S M, Alessi C, Bruni O, DonCarlos L, Hazen N, Herman J, Katz E S, Kheirandish-Gozal L, Neubauer D N, O’Donnell A E, Ohayon M, Peever J, Rawding R, Sachdeva R C, Setters B, Vitiello M V, Ware J C, Adams Hillard P J. National Sleep Foundation’s sleep time duration recommendations: methodology and results summary. Sleep Health. 2015 Mar;1(1):40-43. doi: 10.1016/j.sleh.2014.12.010. Johns M W. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. doi: 10.1093/sleep/14.6.540. Johns M. The assessment of sleepiness in children and adolescents. Sleep Biol. Rhythms. 13(Suppl 1):97. Littner M R, Kushida C, Wise M, Davila D G, Morgenthaler T, Lee-Chiong T, Hirshkowitz M, Daniel LL, Bailey D, Berry RB, Kapen S, Kramer M; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep. 2005 Jan;28(1):113-21. doi: 10.1093/sleep/28.1.113. Luca G, Haba-Rubio J, Dauvilliers Y, Lammers G J, Overeem S, Donjacour C E, Mayer G, Javidi S, Iranzo A, Santamaria J, Peraita-Adrados R, Hor H, Kutalik Z, Plazzi G, Poli F, Pizza F, Arnulf I, Lecendreux M, Bassetti C, Mathis J, Heinzer R, Jennum P, Knudsen S, Geisler P, Wierzbicka A, Feketeova E, Pfister C, Khatami R, Baumann C, Tafti M; European Narcolepsy Network. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J. Sleep Res. 2013 Oct;22(5):482-95. doi: 10.1111/jsr.12044. Mignot E, Lammers G J, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol. 2002 Oct;59(10):1553-62. doi: 10.1001/archneur.59.10.1553. Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell M, Grumet F, Fernandez-Vina M, Honda M, Risch N. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 2001 Mar;68(3):686-99. doi: 10.1086/318799. Morandin M, Bruck D. Understanding automatic behavior in narcolepsy: New insights using a phenomenological approach. The Open Sleep Journal. 2013;6(1):1-7. doi: 10.2174/187 4620901306010001.

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Morse A M, Licholai G, Yang M, Bron M, Profant J, Villa KF. (2019). Prevalence of diagnosed pediatric narcolepsy in the United States. Sleep. 2019;42 Suppl 1:A306. doi: 10.1093/sleep/zsz067.759. Moscovitch A, Partinen M, Guilleminault C. The positive diagnosis of narcolepsy and narcolepsy's borderland. Neurology. 1993 Jan;43(1):55-60. doi: 10.1212/ wnl.43.1 _part_1.55. Nevsímalová S, Mignot E, Sonka K, Arrigoni J L. Familial aspects of narcolepsy-cataplexy in the Czech Republic. Sleep. 1997 Nov;20(11):1021-6. doi: 10.1093/sleep/20.11.1021. Okun M L, Lin L, Pelin Z, Hong S, Mignot E. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep. 2002 Feb 1;25(1):27-35. doi: 10.1093/sleep/25.1.27. Ollila H M, Ravel J M, Han F, Faraco J, Lin L, Zheng X, Plazzi G, Dauvilliers Y, Pizza F, Hong S C, Jennum P, Knudsen S, Kornum B R, Dong X S, Yan H, Hong H, Coquillard C, Mahlios J, Jolanki O, Einen M, Arnulf I, Högl B, Frauscher B, Crowe C, Partinen M, Huang Y S, Bourgin P, Vaarala O, Désautels A, Montplaisir J, Mack S J, Mindrinos M, FernandezVina M, Mignot E. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am. J. Hum. Genet. 2015 Jan 8;96(1):136-46. doi: 10.1016/j.ajhg. 2014.12.010. Erratum in: Am J Hum Genet. 2015 May 7;96(5):852. Lavault, Sophie [removed]; Arnulf, Isabelle [added]. Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens. 1998 Jan;51(1):96100. doi: 10.1111/j.1399-0039.1998.tb02952.x. Pisko J, Pastorek L, Buskova J, Sonka K, Nevsimalova S. Nightmares in narcolepsy: underinvestigated symptom? Sleep Med. 2014 Aug;15(8):967-72. doi: 10.1016/ j.sleep.2014.03.006. Postiglione, E., Antelmi, E., Pizza, F., Lecendreux, M., Dauvilliers, Y., & Plazzi, G. (2018). The clinical spectrum of childhood narcolepsy. Sleep Medicine Reviews, 38, 70-85. Postiglione E, Antelmi E, Pizza F, Lecendreux M, Dauvilliers Y, Plazzi G. The clinical spectrum of childhood narcolepsy. Sleep Med. Rev. 2018 Apr;38:70-85. doi: 10.1016/j.smrv.2017.04.003. Rosenberg R, Kim A Y. The AWAKEN survey: knowledge of narcolepsy among physicians and the general population. Postgrad. Med. 2014 Jan;126(1):78-86. doi: 10.3810/ pgm.2014.01.2727. Roth B, Nevsimalova S, Rechtschaffen A. Hypersomnia with “sleep drunkenness.” Arch. Gen. Psychiatry. 1972 May;26(5):456-62. doi: 10.1001/archpsyc.1972.01750230066013. Scheer D, Schwartz S W, Parr M, Zgibor J, Sanchez-Anguiano A, Rajaram L. Prevalence and incidence of narcolepsy in a US health care claims database, 2008-2010. Sleep. 2019 Jul 8;42(7):zsz091. doi: 10.1093/sleep/zsz091 Sturzenegger C, Baumann C R, Lammers G J, Kallweit U, van der Zande W L M, Bassetti C L. Swiss narcolepsy scale: A simple screening tool for hypocretin-deficient narcolepsy with cataplexy. Clinical and Translational Neuroscience. 2019 July 1;2(2), doi: 10.1177/2514183X18794175. Young T B. Epidemiology of daytime sleepiness: definitions, symptomatology, and prevalence. J. Clin. Psychiatry. 2004;65 Suppl 16:12-6.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 30

CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS Bala S. C. Koritala1, PhD, Marc D. Ruben2,3, PhD and David F. Smith1,4,5,6, MD, PhD 1

Division of Pediatric Otolaryngology, Head and Neck Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 2 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 3 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA 4 Division of Pulmonary Medicine and the Sleep Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 5 The Center for Circadian Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 6 Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA

OVERVIEW 1. As healthy humans live one-third of their life in “sleep,” it is evident that sleep is important for human survival 2. Though sleep biology is complex, we have clear evidence that sleep is regulated by the circadian system and synchronized to the environmental time cues (zeitgebers) based on earth’s 24-hour rotation 3. It is known that circadian regulation is important for human health and fitness 4. However, modern living conditions may contribute to circadian misalignment of sleepwake cycles. Conditions include: a. Night-time light exposure b. Abnormal feeding c. Shift work d. Jetlag e. Heritable factors

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5. 6.

7. 8.

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f. Medical conditions These factors increase the risk for circadian rhythm sleep-wake disorders (CRSWDs) Our aim for this chapter is to educate health care professionals about the existing knowledge of CRSWDs and associated health conditions, available diagnostics, and therapeutic strategies The circadian clock: Molecular timekeeper that governs ~24-hour rhythms in biology and physiology Circadian rhythm: A ~24-hour oscillation in any biological function, including: a. Sleep-wake b. Melatonin levels c. Body temperature d. Blood pressure e. Gene expression f. Hormone and metabolite levels g. Among many others Key characteristics of the circadian rhythm a. ~24-hour period b. Endogenous: originates within the organism c. Capable of synchronizing with environmental time signals, such as light/dark, temperature, feeding time, etc. d. Persists under a constant environmental condition without any ‘given’ time information i. In constant dark, for example e. Evolutionarily conserved from bacteria to humans

CIRCADIAN RHYTHMS IN HUMANS 1. The ‘central’ circadian oscillator resides in the suprachiasmatic nucleus (SCN) a. A tissue located in the hypothalamus of the brain b. Is mainly entrained through light-dark cycles c. Regulates the most prominent circadian outputs of humans such as: i. Sleep-wake cycles ii. Melatonin rhythms iii. Body temperature fluctuations 2. Peripheral oscillators are located throughout the body and entrained by a range of cues including core body temperature rhythms and time of feeding 3. Circadian phenotypes are the result of coordination between central and peripheral oscillators 4. Genetics of circadian rhythms a. At the cellular level, circadian rhythms are generated by a transcriptionaltranslational feedback mechanism involving a small core set of ‘clock genes’ that function as the molecular clock b. The transcriptional-translational mechanism of the mammalian molecular clock is an autoregulatory loop of positive (BMAL1, CLOCK, NPAS2,

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RORs) and negative (PERs, CRYs, REV-ERBs, DECs) feedback elements and takes approximately 24 hours to complete one loop and generate one circadian rhythm c. The molecular clock drives transcription of a large number of ‘clock-output genes,’ which underlie biochemical, metabolic, and physiological rhythms d. In humans, ~50% genes are expressed with circadian rhythmicity i. Rhythms are also observed with other molecules including proteins, lipids, and metabolites e. Cellular clock outputs can be influenced by: i. Redox state ii. Genetic polymorphisms iii. Epigenetic mechanisms iv. Other interacting pathways including behavioral, endocrine, and nutritional conditions 5. Circadian rhythm analysis a. There are many ways to measure circadian rhythms in the clinic, and each with advantages and disadvantages i. Importantly, all of these methods aim to estimate the same parameters.

Figure 1. One period of a circadian rhythm. Key definitions for circadian rhythms include Period, Amplitude, Phase, and Midline Estimating Statistic of Rhythm (MESOR).

b. Key definitions for circadian rhythms include Period, Amplitude, Phase, and Midline Estimating Statistic of Rhythm (MESOR) (Figure 1) i. Period: The time to complete one oscillation (circadian period: ~24hour)  Period of the endogenous clock (Tau;τ)  Period of external environment (T)

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Amplitude: The magnitude of an oscillation. It is calculated as the difference between the mean (MESOR) and the peak or trough of an oscillation. iii. Phase/Acrophase: The estimated peak time of an oscillation iv. MESOR: Mean of an oscillation 6. Determinants of circadian phase in humans a. The circadian system is maintained through a process called entrainment i. Entrainment: Synchronization of the internal clock with rhythmic environmental time cues b. Light-dark cycles and feeding time are key synchronizers for the mammalian circadian system i. These synchronizers keep our clocks close to 24 hours c. The misalignment of the circadian system caused by modern or self-selected living conditions, including night light exposure, abnormal feeding schedule, and shift work, increases the risk of disrupted clocks d. This can lead to an array of health conditions including sleep-wake disorders, dementia, cancer, cardiovascular disorders, gastrointestinal disorders, and metabolic syndrome

Circadian Rhythm and Sleep 1. Sleep is a vital physiological process 2. The 24-hour structure of sleep-wake behavior in humans is governed by circadian and sleep homeostatic mechanisms 3. In the homeostatic component, sleep pressure builds during wakefulness and is reduced with quality sleep 4. The circadian component opposes the homeostatic drive and promotes wakefulness during the day 5. Circadian rhythm sleep-wake disorders a. Circadian rhythm sleep wake disorders (CRSWDs) are caused by disruption of the endogenous circadian clock or by misalignment of the internal clock with cues from the external environment b. Multiple factors can contribute to CRSWDs including: i. Irregular bedtimes ii. Lack of daylight exposure iii. Irregular work schedules iv. Poor sleep hygiene v. Drugs (prescribed and recreational) vi. Age vii. Health conditions, including blindness c. CRSWDs are mainly classified based on the sleep patterns observed within the 24-hour sleep-wake window i. For example: advanced or delayed sleep-wake rhythm disorders, non24-sleep-wake rhythms disorder, and irregular sleep-wake rhythms disorder (Figure 2)

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Figure 2. A normal sleep period is compared to circadian rhythm sleep wake disorders. Advanced sleep-wake phase disorder is demonstrated by an advanced sleep onset time earlier than the desired sleep onset time. Delayed sleep-wake phase disorder is demonstrated by a delayed sleep onset time later than the desired sleep onset time. Irregular sleep-wake rhythm disorder occurs in individuals who are unable to consolidate a single, normal sleep phase and experience multiple shorter sleep bouts ( 50 years old c. Much more common in males (9:1 male: female predilection) d. If occurring in children and adolescents, typically associated with a comorbid condition such as: i. Narcolepsy (RBD can be the earliest sign of childhood narcolepsy and may be seen before the onset of sleepiness) ii. Psychotropic medications (particularly SSRIs/SNRIs) iii. Brainstem pathology (paraneoplastic neurological disorders)

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3. Clinical features a. Patients may report “acting out dreams” b. Episodes can be violent, including punching, kicking, leaping out of bed, aggressive vocalizations c. Concern for injuries to patient and bed partner d. Eyes typically closed during episodes (vs. NREM parasomnias) e. Individuals usually are quickly oriented and coherent on awakening f. Status dissociatus is a subtype of RBD in which there is lack of any form of sleep state with blurring of REM, NREM, and wake characteristics i. Typically an underlying neurological or medical condition is present, or the patient is experiencing alcohol withdraw 4. Predisposing and precipitating factors a. Strongly associated with alpha-synucleinopathies such as Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), or multiple system atrophy (MSA). i. There is 50-80% of idiopathic RBD phenoconversion to RBD with alpha-synucleinopathy within a decade. b. Medications can unmask or contribute to etiology; in particular antidepressants (particularly SSRIs, SNRIs, and tricyclic antidepressants, as can withdrawal of REM suppressing medications c. Some evidence of association with: i. PTSD ii. Narcolepsy iii. Periodic limb movements (including during NREM) iv. Neurological disorders such as DLB. 5. Diagnosis a. Suspected RBD is one of the few parasomnias where PSG is recommended to confirm diagnosis as opposed to the use of PSG solely to rule out other underlying sleep pathology b. Video during PSG should be included along with consideration for extended EMG leads to increase the chance of capturing dream enactment behavior with a lack of atonia on EMG 6. Management a. Prognostic counseling: Most experts recommend counseling on high degree of phenoconversion to alpha-synucleinopathy b. Consideration for other prognostic indicators of alpha-synucleinopathies (tremor, gait changes, anosmia, orthostatic hypotension, constipation, depression) or neurology referral c. Non-pharmacological i. Goal of therapy is to reduce risk of injury to patient and bed partner ii. Modification of sleep environment for safety concerns iii. Bed alarm has been helpful in small case series d. Pharmacological i. Pharmacotherapy is typically required for reduction of symptoms concerning for injury potential, although no large-scale clinical trials have been undertaken on treatments

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iv.

Clonazepam has traditionally been used for many years to reduce symptoms (although caution if fall risk or sleep disordered breathing) Melatonin is generally considered a safer alternative to clonazepam and often used in practice as first line therapy. There has been some suggestion that, unlike clonazepam, melatonin may improve ability to preserve muscle atonia during REM sleep (though more evaluation is needed). Consideration for sodium oxybate, rivastigmine, pramipexole, imipramine, and CBD all have been suggested, but further studies are needed

RECURRENT ISOLATED SLEEP PARALYSIS 1. Diagnostic criteria a. Recurrent episodes of being unable to voluntarily move upon awakening from sleep b. Episodes can last seconds to several minutes and are disturbing to the patient c. Not attributed to other underlying sleep, medical, or pharmacological/ substance cause 2. Epidemiology a. Reported that approximately 8% have experienced at least one episode over their lifetime b. Typically begins in teens and sleep deprived college students 3. Clinical features a. State dissociation with components of REM and wake overlapping, resulting in conscious experience, but with remaining neuromuscular atonia associated with REM sleep b. May be accompanied by hallucinations or visual, auditory, tactical sensations suggestive of partial REM/dream phenomenon c. Anxiety or fear often present d. Respiratory muscles remain intact e. Care must be taken to exclude narcolepsy and other central disorders of hypersomnolence, in which sleep paralysis can often occur 4. Differential diagnosis include a. Narcolepsy i. Can have sleep paralysis as a symptom, but will have additional PSG and multiple sleep latency test (MSLT) findings specific to the disorder b. Atonic seizures (differentiated on ictal activity seen on EEG) i. Nocturnal panic attacks (will not have atonia) c. Sleep deprivation (symptoms corrected with increased sleep) i. Abrupt withdrawal of analeptic therapy ii. Periodic paralysis (severe episodes of muscle weakness concomitant to variations in blood potassium level)

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5. Predisposing and precipitating factors a. Sleep deprivation, irregular sleep schedules b. Stress c. Psychiatric disorders (depression, bipolar disorder) d. May be more common in supine sleep position 6. Management a. Non-pharmacological i. Reassurance is often all that is needed as condition in isolation is benign ii. Ensure proper sleep hygiene and reduction of potentially exacerbating conditions iii. Consider ruling out other sleep/neurologic conditions if symptoms are atypical, severe, or are concomitant with clinical features suggestive of other pathology b. Pharmacological i. Pharmacotherapy only considered in extreme situations ii. REM suppressing agents such as SSRIs/SNRIs iii. TCAs (clomipramine, imipramine) iv. Sodium oxybate

NIGHTMARE DISORDER 1. Diagnostic criteria a. Recurrent dreams involving remembered threats to survival or fear-inducing content b. Rapid orientation upon awakening c. Causes significant impairment or distress manifested as one of the following: i. Sleep resistance ii. Mood disturbance iii. Behavioral problems iv. Daytime sleepiness or fatigue v. Cognitive impairment vi. Caregiver burden vii. Impaired social or occupational functioning 2. Epidemiology a. Common in children, usually starting between ages 3-6 years, often improvement with age but can persist to be lifelong b. Nightmare disorder occurs in 1.8-6% of patients c. Close to 100% of people have a nightmare in their lifetime d. More common in females 3. Clinical features a. Recurrent episodes of dysphoric disturbing dreams b. Content typically remembered on awakening

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Joshua Roland and Alon Avidan 4. Predisposing and precipitating factors a. Associated with anxiety, PSTD, psychiatric illness, psychosocial stressors b. Low socioeconomic status c. Medications which can alter dreams, potentially impacting likelihood of nightmares, may include: i. Beta blockers ii. Hypnotics iii. Montelukast iv. Antidepressants v. Alpha 2-agonists vi. Stimulants vii. Dopamine agonists viii. Antimicrobials ix. Buspirone x. Amiodarone xi. Withdrawal of REM-suppressing medications 5. Management a. Non-pharmacological i. Reassurance ii. Adequate sleep hygiene iii. Removal of offending agent if possible (e.g., medication) iv. Cognitive therapy v. Image rehearsal therapy:  Patients are asked to re-write the dream/scene  Asked to practice imagining the new dream (re-scripting) it with a different non-threatening ending during the daytime). vi. Low quality evidence suggesting lucid dreaming therapy, exposure therapy, relaxation techniques, and hypnosis may be helpful b. Pharmacological i. If pharmacotherapy is needed, Prazosin has been historyically utilized, although behavioral therapy is considered first-line treatment ii. Clonidine has shown potential benefit, along with cannabinoids, trazodone, topiramate and gabapentin (most of these studies were done are in patients with PTSD-related nightmares) iii. Low dose benzodiazepine, SSRI, and TCA use has been described, but with little supporting evidence

OTHER PARASOMNIAS 1. Parasomnias that are not linked prominently to a NREM or REM state 2. Generally fall into a mixed bag of unusual/abnormal behaviors or experiential phenomenon unrelated to specific sleep state

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EXPLODING HEAD SYNDROME 1. Diagnostic criteria a. Auditory hallucination involving an experience of sudden loud bang/sound or explosion in the head b. Occurs during sleep/wake transition c. Events associated with fear/distress d. Not associated with complaints of significant pain e. Not associated with CNS pathology 2. Epidemiology a. Median age of onset has been cited as 58 years old b. Can occur in any age 3. Clinical features a. Patient complains of waking up at night with sense of painless loud sound which can be described as an explosion, bang, or crash b. Experience usually only lasts a few seconds c. Can occur only rarely or several times a night d. Sense of stabbing in the head (painless), flash of light, and myoclonic jerks can sometimes occur concomitantly e. Insomnia may develop due to anxiety over symptoms f. Differentials include: i. Cluster headaches (can occur at night with additional features such as ocular pain) ii. Sleep related migraines (painful headache) iii. Nocturnal panic attacks iv. Partial seizures (differentiated by its ictal EEG pattern) v. Nightmares (with symptoms related to dream content) 4. Etiology generally unknown. Theories include issues with automatic gain control of sound, potentially due to structures or pathways involved with auditory sensation. a. Predisposing and precipitating factors i. Emotional stress ii. May be more likely in patients with recurrent sleep paralysis b. Management i. Non-pharmacological  Reassurance is often all that is needed (patients often are concerned that phenomenon is a sign of more concerning pathology)  Stress reduction and sleep hygiene ii. Pharmacological  Clomipramine, calcium channel antagonists (flunarizine, nifedipine), and topriamate have all been described as helpful in case reports if events are distressing enough to impact sleep quality, and stress reduction/assurance are not sufficient

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SLEEP-RELATED HALLUCINATIONS 1. Diagnostic criteria a. Recurrent episodes of hallucinations occurring during sleep/wake transition b. Events predominantly visual c. Not explained by another sleep, medical, pharmacological/substance disorder 2. Epidemiology a. In a report from Europe, those having at least one occurrence of sleep-related hallucinations range from 7-37% b. More common in younger patients c. May occur somewhat more frequently in females than males 3. Clinical features a. Encroachment of dream-like phenomenon (usually associated with REM sleep) into wake b. Hypnagogic events described as occurring prior to falling asleep, hypnopompic on awakening c. May be associated with sleep paralysis d. Care must be taken to exclude narcolepsy and central disorders of hypersomnolence 4. Risk factors include: a. Younger age b. Cigarette and substance use c. Anxiety/mood disorders d. Insomnia and sleep deprivation 5. May decrease with age 6. Differentials include: a. Nightmares i. Remembered dreams as opposed to hallucinations b. Exploding head syndrome c. Epileptic seizures i. Will have corresponding ictal EEG findings d. Narcolepsy i. Will have PSG and MSLT features suggestive of pathologic hypersomnolence. e. Peduncular hallucinosis i. Vivid hallucinations during wake sometimes linked to neurological lesions/infections/tumors f. Can sometimes be seen with medications such as beta blockers, hypnotics, antidepressants 7. Predisposing and precipitating factors a. Sleep deprivation b. Substance/alcohol use c. Anxiety/mood disorders

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8. Management a. Non-pharmacological i. Sleep hygiene optimization ii. Avoid sleep deprivation and other potential contributors iii. Reassurance as it is a benign condition iv. Careful assessment for other comorbid sleep (narcolepsy, idiopathic hypersomnia, insomnia) and psychiatric conditions (anxiety/ depression) b. Pharmacological i. There have been a few case reports of improvement with melatonin ii. Most reports fail to show benefit with pharmacological therapy

SLEEP ENURESIS 1. Diagnostic criteria a. Repeated episodes of sleep-related involuntary voiding b. Events occur at least twice a week for at least 3 months duration c. Age > 5 years old d. Two specific phenotypes of sleep enuresis (SE) are defined: i. Primary sleep enuresis: enuresis in a patient who has never been consistently dry at night for at least a 6-month period ii. Secondary sleep enuresis: enuresis in a patient who has previously been dry for a period for at least 6 months 2. Epidemiology a. Occurs in 10-16% of 5-year-olds b. Often improves with age c. More common in males vs. females d. Large hereditary link, especially in primary enuresis 3. Clinical features a. Difficulty to arouse due to urge to void b. If present during the day may be pointing towards physiological cause c. Patients will often be described as deep sleepers 4. Precipitating and precipitating factors a. May occur more often in children with attention-deficit hyperactivity disorder (ADHD) or chronic constipation b. Secondary sleep enuresis can be more common after recent psychosocial stress c. Can occur as medication side effects or with other conditions such as: i. Diabetes ii. Urinary tract infection iii. OSA and other sleep disorders iv. Enlarged prostate

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Joshua Roland and Alon Avidan v. PD with dysautonomia vi. Congestive heart failure vii. Diuretic use viii. Nocturnal epilepsies (urinary incontinence) 5. Management a. Non-pharmacological i. Ruling out of organic causes is paramount ii. Urine analysis, ultrasonography of the pelvis should be considered iii. Treatment of sleep disordered breathing if present iv. Fluid management, motivational therapy, and scheduled voiding v. Avoid caffeine and other diuretics vi. Alarms and bladder training have shown to be the most effective longterm therapy in systematic review b. Pharmacological i. Desmopressin has been described to be used with caution in both adult and pediatric patients with concern for worsen hyponatremia and reduction of seizure threshold ii. TCAs (imipramine) may be beneficial but are used sparingly due to cardiotoxicity and black box warning for suicidality in children/adolescents

KEY CLINICAL POINTS 1. Parasomnias represent a unique diagnostic and treatment challenge with the ability to impact quality of life and sleep, along with patient health and safety 2. They are differentiated by commonly associated sleep stages and clinical characteristics, but often exist on a spectrum with blurring and overlap of features among conditions 3. Polysomnography should be undertaken in atypical cases, when the diagnosis is in question to rule out other contributing sleep disorders or if there is concern for REM behavior disorder 4. Focus on patient safety should be a primary concern with behavioral interventions highly utilized, and pharmacotherapy support used if needed for refractory or complex/severe cases (with the exception of REM behavior disorder where medication if often required)

Typically brief

No

NREM

May see behaviors/arousal from SWS Often resolves with age

Duration

Recall of event

Sleep State

PSG Findings

May see behaviors/arousal from SWS Often resolves with age

NREM

Limited or no

May recall dream content REM

Dream enactment, loss of atonia during REM sleep Seconds to a minute

Eating during sleep

Typically minutes to occasionally hours

Older adult

RBD

Young adult

SRED

REM

Yes

Variable, usually brief

Frequent frightening dreams

Childhood

Nightmare Disorder

On awakening from REM

Frequent episodes of awaking while atonic Seconds to a minute, may seem longer to patient Yes

Recurrent Isolated Sleep Paralysis Teenager

Varies

Yes

Very brief

Exploding Head Syndrome Varies, usually adult Sensation of loud sound in head

On awakening from REM

Yes

Seconds to a minute

Episodes of audio/visual sensation

Variable

Sleep Related Hallucination

Lack of atonia May see May see No particular May see during REM awakening out awakening out associated awakening out sleep of REM sleep of REM sleep findings of REM sleep Prognosis Typically Usually Usually Limited data, Typically worsens with improves with improves with can be selfimproves with age age age limiting age Abbreviations: REM= rapid eye movement, RBD = REM behavior disorder, SRED=sleep-related eating disorder, SWS=slow wave sleep.

Childhood, adolescence Confusional behaviors, eyes often open

Typical Age of Onset Signs

Disorders of Arousal

Table 3. Summary of parasomnia characteristics

Variable, but more commonly during NREM Epileptic findings on EEG Varies

seizure activity during sleep Usually less than a few minutes Variable

Sleep Related Epilepsy Variable

Varies

Occurring during wake

Anytime

N/A

Variable, typically at least a few minutes

Adolescent to adult Dissociative disorders

Psychiatric Phenomenon

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QUESTIONS 1. A 67-year-old man is referred by his PCP for history of frequent nightmares. The patient’s wife reports he will dream of people chasing him and at times wake himself up shouting. He has on occasion jumped out of bed during these dreams. Polysomnography is undertaken and notes increased EMG tone during REM periods. Which of the following signs might be a pertinent clinical finding for the underlying diagnosis? a. Insomnia b. Asthma c. Anosmia d. GERD e. Sleep paralysis 2. A 28-year-old female with a past medical history of anxiety, depression, insomnia, and 5 cigarettes a day tobacco use presents with complaints of weight gain. Her roommate reports she wakes up frequently during the night and eats in her sleep. Afterwards she has no recall of doing so. Which of the following is potentially worsening her symptoms? a. Cigarette use b. Escitalopram c. Zolpidem d. Underlying diabetes e. Nightmares 3. A 69-year-old male with a past medical history of hypertension and diabetes presents with complaints of knocking things off his nightstand during dreams related to fighting intruders. He denies any snoring or breathing issues during sleep. His medications include Lisinopril and metformin. What is the next best step in management? a. Home sleep apnea testing b. Recommend melatonin c. Prescribe clonazepam d. 2-week sleep diary e. Polysomnography with expanded EMG montage 4. A 7-year-old female is brought in by her parents after an episode where she left her room during the night while appearing “glassy eyed” and minimally responsive for a few minutes. She currently has symptoms consistent with an acute upper respiratory infection, but otherwise is healthy. What is the next step in management? a. Home sleep apnea testing b. Reassurance c. Trial of carbamazepine d. Polysomnography e. Insight oriented cognitive behavioral therapy

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5. A 22-year-old male presents with frequent episodes of being unable to move during the night, along with daytime sleepiness. He goes to bed around 10:30 pm and wakes up at 6:45 am or a regular basis. He is observed to fall down whenever he plays tennis. His past medical history is significant for appendectomy when 15 years old and mononucleosis infection 3 months prior to his sleep symptoms. He previously was sleeping without issues. Which of the following is the most appropriate next diagnostic consideration? a. Reassurance, no further diagnostic tools are necessary a. Home sleep apnea testing b. PSG and MSLT c. Measurement of serum ferritin levels. d. Magnetic resonance imaging and angiography of the brain

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In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 32

SLEEP-RELATED MOVEMENT DISORDERS Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas, MD Department of Neurology, Johns Hopkins University School of Medicine; Baltimore, MD, USA

RESTLESS LEG SYNDROME 1. Characteristics and Diagnostic Criteria a. Restless legs syndrome (RLS) is also known as Willis-Ekbom Disease (WED) b. A sensorimotor neurological disorder characterized by a strong urge to move the limbs (legs and/or arms) and can produce uncomfortable sensations i. Symptoms can be described as throbbing, pulling, itching, crawling, or creeping c. Essential characteristics: Patients must experience the URGE symptom criteria of: i. Urge to move the limbs is unpleasant or uncomfortable ii. Rest (inactivity) worsens or precipitates symptoms iii. Getting up and moving or walking improves symptoms iv. Evening (or bedtime) worsens or precipitates symptoms (circadian pattern) 2. RLS is a clinical diagnosis and patients must meet all of Criteria A-C, according to the International Classification of Sleep Disorders (ICSD-3) a. An urge to move the legs, usually accompanied by or thought to be caused by uncomfortable and unpleasant sensations in the legs. Symptoms must have all three of the following: i. Begin or worsen during periods of rest or inactivity such as lying down or sitting ii. Be partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas iii. Occur exclusively or predominantly in the evening or night rather than during the day b. The above features are not solely accounted for as symptoms of another medical or a behavioral condition i. e.g., leg cramps, positional discomfort, myalgia, venous stasis, leg edema, arthritis, habitual foot tapping c. The symptoms of RLS cause concern, distress, sleep disturbance, or impairment in mental, physical, social, occupational, educational, behavioral, or other important areas of functioning 3. Nonessential characteristics a. Family history of RLS b. Symptom improvement to dopaminergic therapy c. Chronic sleep disturbance is reported in 60-90% of RLS patients, with patients gaining only an average of 5 hours of sleep a day d. Periodic limb movements of sleep (PLMS) i. See diagnostic criteria for PLMS in PLMS Section ii. About 80% of patients with RLS have PLMS, but only some patients with PLMS have RLS 4. Differential Diagnosis a. Exclude RLS mimics Table 1. RLS mimics

RLS Mimics Leg cramps

Positional leg discomfort

Neuroleptic-induced Akathisia

Leg pain

Habitual foot tapping Peripheral neuropathy Varicose Veins Peripheral Vascular Disease

Description Painful, palpable knots or disorganized muscle spasms/contractions, usually of the calf or foot. Unlike RLS, cramps occur suddenly and are shorter in duration, with no urge to move. Discomfort can be easily resolved by changing positions after prolonged sitting or lying in the same position. Other key features of RLS are missing. An inner sense of restlessness and an intense desire to move that does not have sensory or circadian characteristics, nor relief from movement that RLS symptoms typically do. Affects whole body, not just limbs. Pain can be due to arthritis, vascular problems, sports/orthopedic injuries, neuropathy, or radiculopathy. Unlike in RLS, leg pain symptoms are not relieved by simple movement and there is no urge to move. Nervous foot motion. Unlike in RLS, symptom is not circadian and there is a limited awareness of the urge to move. Numbness, burning, pain. Unlike in RLS, symptoms do not include an urge to move and are not quickly relieved with movement. Cramps, swelling, achiness, or throbbing in the legs. Unlike in RLS, symptoms show some relief from inactivity. Pain in the legs. Unlike in RLS, symptoms are not circadian, are relieved by rest, and there is no urge to move.

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Table 2. Medications that may exacerbate RLS Drug Class Prokinetic agents

Drug Name (Trade Name)  Metoclopramide (Reglan)  Cinnarizine (Stugeron, Stunarone, Cinarin) All typical antipsychotic with dopamine receptor blocking properties  Sulpiride (Dogmatil)  Flunarizine (Sibelium)  Thiethylperazine (Torecan – discontinued)  Promethazine (Phenadoz, Promethegan, Phenergan)  Alimemazine/trimeprazine (Nedeltran, Panectyl, Repeltin, Therafene, Theralen, Vallergan)  Diphenhydramine (Nytol, Benedryl, Banophen)  Chlorpheniramine (Chlor-Trimeton, Clor-Tabs, Aller-Chlor)  Hydroxyzine (Atarax)  Mirtazapine (SNRI; Remeron, Remeron SolTab)  Fluoxetine (SSRI; Prozac)  Venlafaxine (SNRI; Effexor)  Duloxetine (SNRI; Cymbalta)

Typical antipsychotics Vestibular sedatives

Antihistamines

Antidepressants

b. Exclude medications that could cause or exacerbate RLS symptoms 5. Diagnostic Studies a. Polysomnographic studies indicate increased latency to persistent sleep and higher arousal index, and PLMS occur ≥ 5/hour in 70-80% of adults on a single night b. Suggested Immobilization Test (SIT) with a finding of more than 40 periodic limb movements of wakefulness (PLMW)/hour supports an RLS diagnosis, but SIT is more typically used as a research tool than clinically c. Activity monitors attached to the ankle can track periodic limb movements (PLMs) 6. Common Comorbidities Table 3. Common comorbidities with RLS                

Mood and anxiety disorders ADHD in pediatric and adult patients Narcolepsy Migraines Chronic obstructive pulmonary disease (COPD) Parkinson disease Multiple Sclerosis Peripheral neuropathy Obstructive sleep apnea Diabetes mellitus Fibromyalgia Rheumatoid arthritis Nocturnal eating Obesity Thyroid disease Heart disease

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas 7. Potential challenges to diagnosis a. Symptoms can be absent during the day i. Symptoms can also be present during the day but usually worsens in the evening or during bedtime b. Variable description of symptoms i. “difficult to describe, jittery, soda bubbling in veins, insects/ants crawling, electric current, water moving, fidgets, itching bones” c. Normal neurological tests, such as nerve conduction studies or electromyography d. Patients do not relate their sleep disturbance with their leg disturbance e. RLS in children is frequently misdiagnosed as “growing pains” or as restless sleep disorder, a new type of pediatric sleep disorder

PATHOPHYSIOLOGY 1. Primary vs secondary RLS a. Similar symptoms for both but different causes b. Primary RLS (early onset) is idiopathic i. Younger than 45 years ii. Progresses slowly iii. Present in family history c. Secondary RLS (late onset at any age) arises from a preexisting condition: i. Iron deficiency (decreased serum ferritin) ii. Pregnancy iii. End-stage renal disease iv. Diabetes v. Rheumatoid arthritis vi. Peripheral neuropathy vii. High parathyroid hormone viii. Spinal cord disease ix. Multiple sclerosis x. Parkinson’s Disease 2. Genetic factors a. Strongly heritable condition i. Autosomal dominant inheritance ii. More than 50% of RLS patients also have an affected first-degree relative b. Several polymorphisms linked to RLS i. MEIS1, BTBD9, MAP2K5, and LBOXCOR1 3. Brain iron deficiency a. Most RLS patients have normal peripheral iron levels but reduced central iron levels in their cerebrospinal fluid (CSF) and regional brain areas i. Substantia nigra, putamen and caudate, thalamus

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b. Iron deficiency in the central nervous system may be due to a reduction of transferrin receptors that transport iron across the blood-brain barrier 4. Abnormal neurotransmitter circuitry a. Increased dopamine production causing sensory symptoms and PLMs b. Increased glutamatergic activity causing hyperarousal and sleep loss, and possibly PLMs c. Iron deficiency and downregulation of adenosine A1 receptors may disrupt dopaminergic and glutamatergic neurotransmitter circuits 5. Peripheral causes a. Hyperalgesic neuropathic pain b. Abnormal circulation and thermoregulation of the legs at night could possibly explain burning sensations c. Peripheral hypoxia

EPIDEMIOLOGY 1. Prevalence a. In White populations, RLS of any severity is common among 5-15% of adults i. Clinically significant RLS is common to 2-5% b. Lower rate among Black (< 0.1%) and Asian (< 1%) populations, but Korean adults specifically have a higher prevalence rate (4.5-12.1%) c. Symptoms may begin at any age, but rate increases with age d. Affects women more than men, especially women after the age of 35 years e. Rates among boys and girls are comparable during adolescence (Also see Chapter 34 for more conversation regarding sleep related movement disorders in children) 2. Special Populations a. Pregnant women i. 21% prevalence rate among pregnant women ii. At risk for developing RLS or worsening of existing symptoms iii. Higher risk after multiple pregnancies

TREATMENT Different treatment therapies should be considered when symptoms have moderately to severely impacted daily life, with symptoms occurring at least twice a week on average for the past year. 1. Pharmacologic therapy a. First-line treatment i. Iron replacement therapy IF iron is low  Recommended for patients with serum ferritin levels ≤ 75 mcg/L and transferrin saturation < 45%

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas 

Goal: ferritin level > 75 mcg/L and transferrin saturation between 20-50%  Oral intake o Ferrous sulfate (325 mg twice a day), with Vitamin C (100 to 200 mg with each dose of ferrous sulfate)  IV administration o For patients with iron malabsorption state from oral intake, or a more rapid treatment is needed due to severe symptoms 1) Single 1000 mg dose of low molecular weight iron dextran a. A test dose of 25 mg should be given first, then the rest of the 975 mg given through IV infusion over 1 hour with 250 mL normal saline 2) For patients with moderate to severe RLS: 2 doses of 1000 mg of ferric carboxymaltose, given 5-7 days apart by slow IV push over 7.5 minutes  Monitor with iron blood panel every 3 to 4 months, then every 3 to 6 months until the serum ferritin level is > 75 mcg/L and transferrin saturation is greater than 20% ii. Investigate cause of iron loss iii. Alpha2delta (𝛼2𝛿 ) Ca2+ channel ligand medications  Drugs: Gabapentin, gabapentin enacarbil, pregabalin  Best for patients with comorbid pain, peripheral neuropathy, anxiety, insomnia, or a history of impulse control disorder or addiction from dopamine agonist treatment  𝛼2𝛿 ligand treatment should be initiated before trying dopamine agonist treatment due to a lower risk of augmentation symptoms, but 𝛼2𝛿 ligand treatment can increase risk for suicidal thoughts and behavior  See “Section D. Risk of Augmentation”  Older patients are more prone to side effects of 𝛼2𝛿 ligand medications iv. Dopamine agonist  Drug: Pramipexole, ropinirole, rotigotine transdermal patch  Best for patients with very severe RLS, depression, obesity, or metabolic syndrome  Likely to cause long-term side effects from augmentation  See “Section D. Risk of Augmentation”  Long-term dopamine agonist therapy can increase risk of impulse control disorders (ICD) or behaviors (ICB)

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



Includes pathologic gambling, compulsive eating and shopping, and compulsive inappropriate hypersexuality Dopamine withdrawal symptoms from sudden discontinuation of treatment may include anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving

Table 4. Pharmacologic therapies for RLS Drug (Trade Name) 𝜶𝟐𝜹 Ligand Drug Gabapentin (Neurontin) Pregabalin (Lyrica) Gabapentin enacarbil (Horizant) Dopamine Agonist Drug Pramipexole (Mirapex)

Potential Side Effects Somnolence, gait unsteadiness, weight gain Dizziness, somnolence, fatigue, headache, peripheral edema, weight gain Somnolence, dizziness, weight gain

Nausea, lightheadedness, fatigue, impulse control disorders, augmentation Less frequent side effects:      

Ropinirole (Requip) Rotigotine (transdermal patch) (Neupro)

Nasal stuffiness Constipation Insomnia Leg edema Mental status changes (confusion, psychosis) Excessive daytime sleepiness or sudden sleep attacks at higher doses, especially in Parkinson patients Similar to side effects of pramipexole Application site skin reaction Other side effects are similar to those of oral dopamine agonists

v. Risk of augmentation  Augmentation symptoms were first reported by Allen and Earley (1996) from RLS patients being treated with carbidopa/levodopa  Symptoms occur due to increased or prolonged use of dopamine agonist treatment and can be exacerbated by low iron stores  Augmentation Symptoms: RLS symptoms worsen, have earlier onset, spread to the trunk or arms, or increase in intensity  Drug has decreased efficacy  Can be difficult to identify because augmentation symptoms slowly progress in symptom severity  Augmentation symptoms should be considered if a patient requests increase dosage after at least 6 months of stable treatment vi. Preventative Methods  Not using dopaminergic drugs; using the lowest dose possible for the shortest amount of time needed

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas 

Augmentation can decrease effectiveness of 𝛼2𝛿 ligand medications, but these effects do not occur in the reverse direction  Thus, start initial treatment with 𝛼2𝛿 ligand medications before trying dopaminergic drugs  Long-acting dopamine agonist can lower risk of augmentation  Few treatment methods are available once augmentation symptoms occur b. Second-line treatment i. Benzodiazepine  Clonazepam  For mild cases of RLS or younger patients  Side effects: risk of falls and cognitive impairment among older adults, reduced deep sleep ii. Opioids  Codeine, tramadol, methadone, oxycodone  For refractory RLS that is unresponsive to dopamine agonist or 𝛼2𝛿 ligand medications  Side effects: Substance dependence and tolerance, sedation, depression and anxiety  Despite prescribing a low dosage of opioids, social stigma in the current climate of the opioid crisis makes utilizing this class of medications more challenging Table 5. Symptoms of augmentation  Increase RLS symptom severity, intensity, or frequency  Symptoms occur earlier in the day  Symptoms spread to other body parts/limbs  Decreased duration of treatment benefit; decreased overall therapeutic efficacy  Worsening sleep quality

Table 6. Questionnaire to evaluate the presence of augmentation symptoms A “yes” to any of these may indicate augmentation symptoms:  Do RLS symptoms appear earlier than when the drug was first started?  Are higher doses of the drug now needed or do you need to take the medicine earlier to control the RLS symptoms compared with the original effective dose?  Has the intensity of symptoms worsened since starting the medication?  Have symptoms spread to other parts of the body (e.g., arms) since starting the medication?

2. Nonpharmacologic Therapy a. Mentally stimulating activities during periods of rest or inactivity b. Moderate regular exercise or yoga c. Reduced caffeine intake

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d. Acupuncture e. Cold-water massages or leg baths f. Prescribed vibratory stimulation device g. Compression therapy h. Weighted blanket i. Leg massage 3. Treatment for Special Populations a. Pregnancy i. Can cause secondary RLS or exacerbate symptoms ii. Avoid dopamine agonist and 𝛼2𝛿 ligand medications iii. Iron treatment most recommended (if low) b. End-stage renal disease i. Careful monitoring of medication dosage due to excretion of dopamine agonist and 𝛼2𝛿 ligand by the kidneys ii. Transdermal rotigotine may be most useful iii. Careful monitoring of iron stores c. Children i. Nonpharmacologic treatment is most recommended ii. Iron supplementation to treat other underlying conditions can alleviate RLS symptoms

PERIODIC LIMB MOVEMENTS OF SLEEP (PLMS) 1. Definition a. Periodic episodes of repetitive limb movements (LMs) which occur during sleep 2. Features a. While PLMS itself is not a disorder, PLMS are seen in patients with several sleep disorders including RLS and PLMD b. On PSG, movements last 0.5 to 10 seconds in duration and are typically separated by intervals of 20 to 40 seconds c. Criteria (American Academy of Sleep Medicine): i. A PLMS series includes a minimum of 4 consecutive limb movement (LM) events ii. Time between onset of consecutive LMs is at minimum 5 seconds, and at maximum 90 seconds iii. LMs on different legs which occur < 5 seconds apart are counted as a single movement 3. Epidemiology/Demographics a. PLMS increase in frequency with age and are present in over 80% of patients with RLS and up to 75% of patients with narcolepsy b. Most patients with RLS have PLMS, but only some patients with PLMS have RLS

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PERIODIC LIMB MOVEMENT DISORDER (PLMD) 1. Characterization of PLMD a. Characterized by clinically significant sleep disturbance caused by increased PLMs which cannot be attributed to another sleep disorder b. Diagnostic criteria

Table 7. Sleep Disorders Associated with Periodic Limb Movements of Sleep (PLMS)

Restless Legs Syndrome (RLS)

Periodic Limb Movement Disorder (PLMD)

Presence of Periodic Limb Movements of Sleep (PLMS) Present in over 80% of patients

Present in all patients

i.

Features observed in Polysomnography Latency to persistent sleep and higher arousal index; PLMS with index > 5/hr in a single night PLMS with index > 5/hr in children; > 15/hr in adults

Epidemiology

Notes

Somewhat common, with higher prevalence in pregnant women

Diagnosis of exclusion; RLS excludes PLMD

Extremely rare in adults

Diagnosis of exclusion; RLS excludes PLMD

Clinical history of sleep disturbance or impairment in functioning and documentation through polysomnography of PLMS with index > 5/h in children and > 15/h in adults 2. Epidemiology/Demographics a. Similarly to the demographics of PLMs and RLS, PLMD increases in frequency with age 3. Diagnostic Criteria a. To meet the diagnostic criteria, patients must meet the following: i. A clinical history of sleep disturbance or impairment in functioning ii. No diagnosis of another sleep movement disease (such as RLS) iii. Documentation through polysomnography of PLMs with index > 5/h in children and > 15/h in adults b. Polysomnography should be ordered to evaluate for PLMD when sleep movements negatively impact sleep quality and lead to daytime impairment in functioning or injury 4. PLMD vs RLS a. PLMD is a diagnosis of exclusion so a patient cannot have both PLMD and RLS b. PLMD is extremely rare in adults; some argue whether it truly exists however it is often on the differential for children with possible RLS as it may be hard for them to accurately describe the clinical symptoms needed to make the diagnosis

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5. Treatment a. Limited data exists on treating PLMD; current treatments are not surgical b. Nonpharmacologic therapies are similar to those for RLS i. Behavioral strategies  Avoidance of aggravating factors, moderate regular exercise, and reduced caffeine intake  Exercise such as walking and bicycling, as well as soaking the legs, leg massage, and pneumatic compression may help with symptomatic relief i. Oral iron replacement may be considered for patients with a serum ferritin concentration ≤ 75 mcg/L c. Pharmacologic treatment, if any i. Treatment with a dopamine agonist or alpha2delta (𝛼2𝛿 ) Ca2+ channel ligand medication may be considered  The dosing and long-term complications of which are similar to those in treatment of RLS  While there is limited data on treatments for PLMD, studies have shown improvements in PLMS in patients with RLS taking pramipexole, ropinirole, rotigotine, gabapentin, gabapentin enacarbil, and pregabalin 4. Patient should be re-evaluated for other causes of insomnia or excessive daytime sleepiness if symptoms do not respond to the chosen treatment

SLEEP RELATED LEG CRAMPS 1. Characterization/Definition a. Also called nocturnal leg cramps b. Characterized by involuntary muscle contractions affecting the lower extremities that produce pain and sleep disruption c. Cramps most commonly affect the calf, foot, or thigh, and may last from seconds to minutes and be followed by persistent soreness for several hours. d. Cramps may occur with varying frequency, from less than yearly to multiple per night 2. Epidemiology/Demographics a. Sleep related leg cramps are common b. Increased frequency with age; reported to be present in 40% of adults over the age of 50 c. Typically benign, self-limited, and infrequent in children d. Reported in 7% of children and adolescents with peak occurrence at 16-18 years of age e. No gender preference

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas 3. Diagnostic criteria a. A focused history should be taken to confirm the patient meets the diagnostic criteria, and a physical examination should be conducted to identify possible underlying causes or alternative diagnosis b. To meet diagnostic criteria, patients must have experienced all three of the following: i. A strong muscle contraction indicated by pain in the leg or foot associated with sudden, involuntary muscle hardness or tightness ii. The contractions occur during the time in bed during which the patient may be either awake or asleep Table 8. Treatment of sleep related leg cramps

Nonpharmacologic  Initial preventative therapy includes daily exercises  When experiencing cramps, the patient may stretch the affected muscle for rapid relief, e.g., by active dorsiflexion of the foot

Pharmacologic  Vitamin B and vitamin E supplementation  Diphenhydramine  Calcium channel blocker (diltiazem or verapamil)  Gabapentin

Notes  Nonpharmacologic initial preventative therapies should be recommended prior to use of pharmacologic therapies  Quinine is not recommended due to safety concerns

iii. The pain is relieved by forceful stretching of the affected muscles which releases the contraction c. Sleep related leg cramps is a diagnosis of exclusion d. History and physical examination should exclude other diagnoses including RLS, PLMS, myoclonic jerks, peripheral vascular disease, and other neurologic disorders e. Medications associated with the disorder: oral contraceptives, intravenous iron sucrose, teriparatide, raloxifene, diuretics, long-acting beta-agonists, statins 4. Treatment a. Recurrent cramps may be limited by nonpharmacologic, noninvasive initial preventative therapies such as daily stretching exercises i. When experiencing acute leg cramps, the patient may stretch the affected muscle, for instance by active dorsiflexion of the foot, to provide rapid relief b. For patients who do not respond to the initial preventative therapies, a trial of the following may be used to reduce the frequency or severity of attacks: i. Vitamin B and vitamin E supplementation ii. Diphenhydramine iii. Calcium channel blocker such as diltiazem or verapamil iv. Gabapentin c. Quinine is not recommended due to safety concerns d. Patients for whom pharmacotherapy is ineffective should be referred to a sleep specialist to determine if another underlying sleep disorder may be responsible for their symptoms

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SLEEP RELATED BRUXISM 1. Definition/Characterization a. Defined as repetitive jaw-muscle activity involving clenching or grinding of the teeth that occurs during sleep 2. Epidemiology a. Present in 15-40% of children and 8-10% of adults 3. Risk Factors a. Comorbid sleep disorders, especially obstructive sleep apnea and parasomnias, and psychiatric and neurologic disorders such as anxiety b. Associated with some medications and substances such as: i. Amphetamines ii. Antipsychotics iii. Selective serotonin reuptake inhibitors iv. Serotonin-noradrenaline reuptake inhibitors v. Drugs of misuse with catecholaminergic effects 4. Clinical features a. Symptoms i. Rhythmic, 1Hz contractions of masticator muscles during sleep, in which both jaw closing and opening muscles are coactive ii. Parents or bed partners may hear clicking or grating sound iii. Frequency of bruxism fluctuates night to night, and symptoms may increase with levels of stress iv. Bruxism may cause dental problems, jaw muscle pain, and temporal headaches v. There is high variability in intensity and duration of events; in severe cases, hundreds of events may occur nightly b. Polysomnography i. Polysomnography is not required for diagnosis but may be useful to differentiate it from other orofacial movements or to identify a possible comorbid sleep disorder ii. May appear as rhythmic masticatory muscle activity (RMMA) which occurs at around 1Hz, often concomitant with a micro-arousal from sleep, and lasts 3-15 seconds, or may appear as prolonged isotonic contraction of masticatory muscles lasting several minutes iii. Most events occur in states N1 and N2 of NREM. Occurrence during REM sleep is associated with medication induced bruxism and neurodevelopmental disorders 5. Diagnosis a. Clinical diagnosis of sleep-related bruxism is often established by a history of tooth grinding in sleep b. Patients should be asked about risk and exacerbating factors c. The formal criteria for sleep-related bruxism include (ICSD-3): i. The presence of regular or frequent tooth-grinding sounds occurring during sleep; and

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas ii. The presence of one or more of the following clinical signs:  Abnormal tooth wear consistent with above reports of tooth grinding during sleep  Transient morning jaw muscle pain or fatigue and/or temporal headache, and/or jaw locking upon awakening consistent with above reports of tooth grinding during sleep 6. Treatment/Management a. Many patients do not require any specific treatment for sleep-related bruxism b. Individuals should receive routine dental care to monitor for tooth wear c. Bruxism associated with medications i. Bruxism may improve or resolve itself without medication over time ii. If bruxism persists, dose reductions may alleviate symptoms iii. Co-prescriptions of buspirone or tandospirone may reduce or eliminate symptoms d. Sleep hygiene and behavioral modifications i. Sleep hygiene education and counseling is suggested, though appliance therapy may manage sleep related bruxism more effectively e. Dental devices i. An oral device, most commonly an occlusal splint, which covers the upper and lower teeth may protect the teeth from damage and reduce grinding noises f. Other therapies i. Some evidence indicates botulinum toxin type A injections to the masseter and temporalis muscle may provide symptom relief g. Pharmacotherapy i. No drugs have shown a consistently large effect in managing bruxism, and all have potential side effects

OTHER SLEEP-RELATED DISORDERS 1. Sleep-related rhythmic movement disorder (RMD) a. Definition i. A group of repetitive, stereotypic, and rhythmic movements that usually involve large muscles which typically begin prior to sleep onset and may continue into sleep ii. Movements may manifest in body rocking, head banging, head rolling and other repetitive motions, and can be stopped upon waking b. Epidemiology i. Most commonly seen in children and infants and rarely extends to adulthood

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Diagnostic criteria i. To fit the diagnostic criteria, the movements must meet one or more of the following:  Interfere with sleep  Impair daytime alertness  Place the patient at risk of bodily injury  Cannot be better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder d. Standard treatment i. There is no satisfactory standard treatment ii. RMD in infants and children commonly remits spontaneously by the age of five years old iii. Appropriate safety precautions should be discussed with patients’ caretakers  Extra padding to the sides of a bed or crib may be added to prevent injury to the patient in cases of forceful head banging 2. Propriospinal myoclonus at sleep onset (PSM) a. Definition i. A rare disorder characterized by sudden myoclonic jerks which occur in the transition from wakefulness to sleep, which arise mainly in the axial muscles and spread according to propriospinal propagation b. Diagnostic criteria i. To meet diagnostic criteria, patients must have experienced all five of the following (ICSD-3):  Sudden jerks, mostly of the abdomen, trunk, and neck  The jerks appear in relaxed wakefulness and drowsiness as the patient attempts to sleep  The jerks disappear upon mental activation and with onset of a stable sleep state  The jerks cause difficulty in sleep initiation  The disorder cannot be better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder ii. Characterized on polysomnography by brief myoclonic EMG bursts which recur nonperiodically c. Standard treatment i. The number of studies on PSM treatment is limited ii. Use of clonazepam may reduce the number of myoclonic events, though this treatment is often not effective iii. Patients and caregivers may be counseled on the disorder and that treatment is usually not effective

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Katemanee Burapachaisri, Sofia Romano and Rachel Marie E. Salas Table 9. Brief overview of 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

Characterization of movements/distress Strong urge to move the limbs producing uncomfortable sensations Periodic Limb Movements of Sleep (PLMS) Involuntary muscle contractions of the lower-extremities that produce pain and sleep disruption Repetitive jaw-muscle activity involving clenching or grinding of the teeth Repetitive, stereotypic, and rhythmic movements involving large muscles Sudden myoclonic jerks in the transition from wakefulness to sleep

Location of Distress Discomfort in legs and/or arms Characteristic limb movements Muscles in calf, foot or thigh

Activity of the jaw muscles Diffused; movements manifest in body rocking, head banging, head rolling and other repetitive motions. Myoclonic jerks arise mainly in the axial muscles and spread according to propriospinal propagation; mainly occur in the abdomen, trunk, and neck.

Table 10. Sleep related movement disorders on polysomnography Restless Legs Syndrome Periodic Limb Movement Disorder Sleep Related Bruxism

Propriospinal myoclonus at sleep onset

Latency to persistent sleep and higher arousal index; PLMS with index > 5/hr in a single night PLMS with index > 5/h in children; > 15/h in adults Rhythmic masticatory muscle activity (RMMA) occurring around 1Hz, often concomitant with micro-arousal from sleep, lasting 3-15 seconds. May appear as prolonged isotonic contraction of masticatory muscles lasting several minutes. Most events occur in N1 and N2 of NREM. Occurrence during REM sleep is associated with medication induced bruxism and neurodevelopmental disorders. Brief myoclonic EMG bursts which recur nonperiodically

KEY CLINICAL POINTS Restless Leg Syndrome For mild symptoms:  Consider nonpharmacologic therapy: compression therapy, vibratory stimulatory device, cold-water massages or leg baths, reducing caffeine intake, moderate exercise For moderate to severe symptoms:  Conduct an iron panel  If transferrin saturation is < 45% give iron replacement therapy:  Oral intake of ferrous sulfate with Vitamin C  If oral treatment fails due to iron malabsorption or a more rapid response needed, use IV ferric carboxymaltose  If transferrin saturation is > 45% or IV iron treatment fails:  First, initiate 𝛼2𝛿 ligand drug treatment  Strong evidence: gabapentin enacarbil  Moderate evidence: pregabalin  If unresponsive to 𝛼2𝛿 ligand medications, try or add dopamine agonist  Strong evidence: pramipexole, rotigotine  Moderate evidence: ropinirole  To prevent augmentation, use the lowest dose possible or use a long-acting dopamine agonist  If unresponsive to either treatment alone or in combination, consider opioids  Prolonged-release oxycodone/naloxone

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Periodic Limb Movement Disorder (PLMD) Nonpharmacologic therapies  Similar to treatments for RLS  Behavioral Strategies:  Avoidance of aggravating factors, moderate regular exercise, and reduced caffeine intake  Exercise such as walking and bicycling, as well as soaking the legs, leg massage, and pneumatic compression may help with symptomatic relief  Oral iron replacement may be considered for patients with a serum ferritin concentration ≤ 75 mcg/L Pharmacologic treatment, if any  Treatment with a dopamine agonist or alpha-2-delta calcium channel ligand may be considered  There is limited data on treatments for PLMD; studies have shown improvements in PLMS in patients with RLS with pramipexole, ropinirole, rotigotine, gabapentin, gabapentin enacarbil, and pregabalin Bruxism *Many patients do not require any specific treatment for sleep-related bruxism For bruxism associated with medications  Condition may improve or resolve itself without medication over time  If bruxism persists, dose reductions may alleviate symptoms  Co-prescriptions of buspirone or tandospirone may reduce or eliminate symptoms Sleep hygiene and behavioral modifications  Sleep hygiene education and counseling is suggested, though appliance therapy may manage sleep related bruxism more effectively Dental devices  An oral device, most commonly an occlusal splint, which covers the upper and lower teeth may protect the teeth from damage and reduce grinding noises Other therapies  Some evidence indicates botulinum toxin type A injections to the masseter and temporalis muscle may provide symptom relief Pharmacotherapy  No drugs have shown a consistently large effect in managing bruxism, and all have potential side effects Sleep Related Leg Cramps Nonpharmacologic, noninvasive initial preventative therapies  Daily stretching exercises  Stretching the affected muscle during active cramps Pharmacologic therapies  A trial of the following may be used to reduce the frequency or severity of attacks:  Vitamin B and vitamin E supplementation  Diphenhydramine  Calcium channel blocker such as diltiazem or verapamil  Gabapentin  Note that Quinine is not recommended due to safety concerns Sleep-related Rhythmic Movement Disorder (RMD)  There is no satisfactory standard treatment, and RMD in infants and children commonly remits spontaneously by when they are five years of age  Appropriate safety precautions should be discussed with patients’ caretakers  Extra padding to the sides of a bed or crib may be added to prevent injury to the patient in cases of forceful head banging Propriospinal myoclonus at sleep onset (PSM)  Use of clonazepam may reduce the number of myoclonic events, though this treatment is often not effective  Patients and caregivers may be counseled on the disorder and that treatment is usually not effective

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QUESTIONS 1. What RLS treatments/techniques have been proven efficacious? a. Engaging in distracting activities including card games, arguments, etc. b. Treating sleep apnea c. Opiates d. Both B and C e. All of the above 2. How is PLMD observed on polysomnography? a. PLMS with index > 5/h in children and in adults b. PLMS with index > 5/h in children; > 15/h in adults c. Rhythmic masticatory muscle activity occurring around 1Hz d. Brief myoclonic EMG bursts which recur nonperiodically 3. Which of the following are diagnostic criteria for sleep related leg cramps? I. Experience periodic limb movements of sleep (PLMS) II. Experience strong muscle contraction indicated by pain in the leg or foot associated with sudden, involuntary muscle hardness or tightness III. The contractions occur during the time in bed IV. The pain is relieved by stretching of the affected muscles a. I and II b. II and III c. II, III, and IV d. All of the above 4. Which of the following are risk factors for bruxism? I. Obstructive sleep apnea II. Anxiety III. Use of amphetamines and antipsychotics IV. Use of drugs of abuse with catecholaminergic effects a. I and II b. I, II, and III c. I, III, and IV d. All of the above 5. What is propriospinal myoclonus at sleep onset (PSM)? a. A common disorder characterized by myoclonic jerks in the transition from wakefulness to sleep, which arise mainly in the axial muscles and spread according to propriospinal propagation b. A rare disorder characterized by sudden myoclonic jerks which occur in the transition from wakefulness to sleep, which arise mainly in the axial muscles and spread according to propriospinal propagation

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c.

A common disorder characterized by sudden myoclonic jerks, which occur during deep sleep, which arise mainly in the appendicular muscles and spread according to propriospinal propagation d. A rare disorder characterized by sudden myoclonic jerks, which occur during deep sleep, which arise mainly in the appendicular muscles and spread according to propriospinal propagation

REFERENCES Allen, RP; Earley, CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep., 1996, 19(3), 205-213. doi: 10.1093/sleep/19.3.205. Allen, RP; Picchietti, DL; Auerbach, M; Cho, YW; Connor, JR; Earley, CJ; Garcia-Borreguero, Diego; Kotagal, Suresh; Manconi, Mauro; Ondo, William; Ulfberg, Jan; Winkelman, JW; International Restless Legs Syndrome Study Group (IRLSSG). 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. doi: 10.1016/j.sleep.2017.11.1126. Anderson, KN; Di Maria, C; Allen, J. Novel assessment of microvascular changes in idiopathic restless legs syndrome (Willis-Ekbom disease). J Sleep Res., 2013 Jun, 22(3), 315-21. doi: 10.1111/jsr.12025. Byun, JI; Lee, D; Rhee, HY; Shin, WC. Treatment of Propriospinal Myoclonus at Sleep Onset. J Clin Neurol., 2017 Jul, 13(3), 293-295. doi: 10.3988/jcn.2017.13.3.293. Caviness, JN. Classification and Evaluation of Myoclonus. UpToDate. Published online 2013. Caviness, JN. Treatment of myoclonus. Neurotherapeutics., 2014 Jan, 11(1), 188-200. doi: 10.1007/s13311-013-0216-3. Cogen, JD; Loughmanee, DA. Sleep-Related Movement Disorders. In: Principles and Practice of Pediatric Sleep Medicine: Second Edition. Elsevier Inc., 2012, 333-336. doi: 10.1016/B978-1-4557-0318-0.00042-5. Connor, JR; Patton, SM; Oexle, K; Allen, RP. Iron and restless legs syndrome: treatment; genetics and pathophysiology. Sleep Med., 2017 Mar, 31, 61-70. doi: 10.1016/j.sleep.2016.07.028. DelRosso, LM; Ferri, R; Allen, RP; Bruni, O; Garcia-Borreguero, D; Kotagal, S; Owens, JA; Peirano, P; Simakajornboon, N; Picchietti, DL. International Restless Legs Syndrome Study Group (IRLSSG). Consensus diagnostic criteria for a newly defined pediatric sleep disorder: restless sleep disorder (RSD). Sleep Med., 2020 Nov, 75, 335-340. doi: 10.1016/j.sleep.2020.08.011. Eliasson, AH; Lettieri, CJ. Sequential compression devices for treatment of restless legs syndrome. Medicine (Baltimore)., 2007 Nov, 86(6), 317-323. doi: 10.1097/MD.0b013e31815b1319 Gamaldo, CE; Salas, RE. Polysomnography in the evaluation of abnormal movements during sleep. UpToDate. Published online 2020. Garcia-Borreguero, D; Silber, MH; Winkelman, JW; Högl, B; Bainbridge, J; Buchfuhrer, M; Hadjigeorgiou, G; Inoue, Y; Manconi, M; Oertel, W; Ondo, W; Winkelmann, J; Allen, RP. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease,

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prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med., 2016 May, 21, 1-11. doi: 10.1016/j.sleep.2016.01.017. Garcia-Borreguero, D; Stillman, P; Benes, H; Buschmann, H; Chaudhuri, KR; Gonzalez, Rodríguez, VM; Högl, B; Kohnen, R; Monti, GC; Stiasny-Kolster, K; Trenkwalder, C; Williams, AM; Zucconi, M. Algorithms for the diagnosis and treatment of restless legs syndrome in primary care. BMC Neurol., 2011, Feb 27, 11, 28. doi: 10.1186/1471-237711-28. Garcia-Malo, C; Peralta, SR; Garcia-Borreguero, D. Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders. Continuum (Minneap Minn)., 2020 Aug, 26(4), 963-987. doi: 10.1212/CON.0000000000000886. Gerstner, G. Sleep-related bruxism (tooth grinding). UpToDate. Published online, 2020. Kim, TJ; Yoon, JE; Park, JA; Lee, SK; Chu, MK; Yang, KI; Kim, WJ; Park, SH; Thomas, RJ; Shin, C; Yun, CH. Prevalence and Characteristics of Restless Legs Syndrome in Korean Adults: A Study in Two Independent Samples of the General Population. Neuroepidemiology., 2019, 52(3-4), 193-204. doi: 10.1159/000496839. Kotagal, S. Sleep-related movement disorders in childhood. UpToDate. Published online 2020. Lal, SJ; Weber, KK. Bruxism Management., 2018. Lobbezoo, F; Ahlberg, J; Glaros, AG; Kato, T; Koyano, K; Lavigne, GJ; de Leeuw, R; Manfredini, D; Svensson, P; Winocur, E. Bruxism defined and graded: an international consensus. J Oral Rehabil., 2013 Jan, 40(1), 2-4. doi: 10.1111/joor.12011. Ondo, WG. Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults. In: UpToDate., 2018. Oskarsson, E; Wåhlin-Larsson, B; Ulfberg, J. Reduced daytime intramuscular blood flow in patients with restless legs syndrome/Willis-Ekbom disease. Psychiatry Clin Neurosci., 2014 Aug, 68(8), 640-3. doi: 10.1111/pcn.12170. Rye, DB. The Molecular Genetics of Restless Legs Syndrome. Sleep Med Clin., 2015 Sep, 10(3), 227-33, xii. doi: 10.1016/j.jsmc.2015.05.015. Salas, RE; Allen, RP; Earley, CJ; Gamaldo, CE. A case of compulsive behaviors observed in a restless legs syndrome patient treated with a dopamine agonist. Sleep., 2009 May, 32(5), 587-8. doi: 10.1093/sleep/32.5.587. Salminen, AV; Rimpilä, V; Polo, O. Peripheral hypoxia in restless legs syndrome (WillisEkbom disease). Neurology., 2014 May, 27, 82(21), 1856-61. doi: 10.1212/WNL.0000000000000454. Sateia, MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest., 2014 Nov, 146(5), 1387-1394. doi: 10.1378/chest.14-0970. Silber, MH; Becker, PM; Earley, C; Garcia-Borreguero, D; Ondo, WG. Medical Advisory Board of the Willis-Ekbom Disease Foundation. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc., 2013 Sep, 88(9), 977-86. doi: 10.1016/j.mayocp.2013.06.016. Silber, MH. Treatment of restless legs syndrome and periodic limb movement disorder in adults - UpToDate. UpToDate. Published online 2018. Stefani, A; Högl, B. Diagnostic Criteria, Differential Diagnosis, and Treatment of Minor Motor Activity and Less Well-Known Movement Disorders of Sleep. Curr Treat Options Neurol., 2019, Jan 19, 21(1), 1. doi: 10.1007/s11940-019-0543-8. Winkelman, JW. Nocturnal Leg Cramps. UpToDate. Published online 2020.

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Winkelman, JW; Armstrong, MJ; Allen, RP; Chaudhuri, KR; Ondo, W; Trenkwalder, C; Zee, PC; Gronseth, GS; Gloss, D; Zesiewicz, T. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology., 2016, Dec 13, 87(24), 2585-2593. doi: 10.1212/WNL.0000000000003388. Winkelmann, J; Schormair, B; Xiong, L; Dion, PA; Rye, DB; Rouleau, GA. Genetics of restless legs syndrome. Sleep Med., 2017 Mar, 31, 18-22. doi: 10.1016/j.sleep.2016.10.012.

PART IV: PEDIATRIC SLEEP AND SLEEP DISORDERS

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 33

SLEEP IN CHILDREN Sally Ibrahim1, MD and Carol Rosen2, MD ¹Rainbow Babies and Children’s Hospital of University Hospitals and Case Western Reserve University, Cleveland, OH, USA ²Case Western Reserve University School of Medicine in Cleveland, OH, USA

NORMAL SLEEP IN THE PEDIATRIC POPULATION 1. Sleep Duration a. The need for sleep varies by age, but there is significant individual variation within age groups. b. In brief, the minimum duration of sleep in a 24-hour period associated with optimal health is: i. 12 hours for infant 4 to 12 months ii. 11 hours for toddlers (age 1-2 years) iii. 10 hours for preschool age (3-5 years) iv. 9 hours for school age (6-12 years) v. 8 hours in teens (ages 13 to 18 years). c. Figure 1 illustrates age-related sleep duration ranges associated with optimal health. 2. Napping a. Daytime napping is normal for infants, toddlers, and preschool children i. Naps typically wane between 2-5 years, then disappear ii. Note: napping practices may vary culturally in older children and adults around the world where a siesta is considered normal.

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Figure 1. Healthy sleep duration for children. Data adapted from Paruthi et al., JCSM 2016: an American Academy of Sleep Medicine (AASM) Consensus statement. For children who nap, data represents total 24-hour sleep duration.

b. Daily napping can reappear in school age children when there is insufficient nighttime sleep or irregular sleep schedules i. Daytime naps, especially late in the day, make it harder to fall asleep at bedtime by decreasing sleep drive. c. If a child is getting sufficient hours of sleep for age, then the reappearance of daytime napping should raise concern for a hypersomnia disorder like narcolepsy. 3. Preterm and Infant Sleep a. Developmental changes in sleep stages, from preterm to term gestational age, are summarized in Figure 2 b. REM is the first recognizable sleep state to develop, usually by 28 weeks gestational age followed by precursors to NREM sleep including tracè discontinue and tracè alternant. i. Tracè discontinue is usually seen until 36 weeks postmenstrual age. ii. Tracè alternant can be seen up to 46 weeks postmenstrual age. iii. Postmenstrual age: time lapsed between the first day of the last menstrual period and birth (gestational age) plus the time elapsed after birth (chronological age).

Figure 2. The development of normal sleep changes from preterm to term birth.

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Figure 3. The development of sleep post-term to 3 months.

c.

Development of sleep architecture from term birth to 6 months is shown in Figure 3. i. In the newborn, sleep onset begins in REM sleep which makes up 50% of total sleep time. ii. K complexes, spindles and slow waves begin to appear by 2 months of age and are present by 3 to 6 months of age. d. In infants less than 3 months of age, wake-sleep patterns are characterized by sleep periods lasting 3-4 hours, with periods of wakefulness lasting 1 to 2 hours for feeding around the clock. i. In term infants, a circadian rhythm begins to appear about 2 weeks after birth and sustained sleep cycles begin to lengthen by 6 weeks of age. ii. Sleep periods shift and consolidate with longer sleep periods at night and well-defined daytime naps, usually by 4 months of age.

PEDIATRIC POLYSOMNOGRAPHY 1. Indications for pediatric polysomnography (PSG) a. PSG is useful for the evaluation of both respiratory and non-respiratory conditions in children as outlined in Table 1. Table 1. Respiratory and non-respiratory indications for polysomnography in Children Respiratory Obstructive sleep apnea Sleep related hypoventilation and syndromes (e.g., congenital central hypoventilation) Prior to tracheostomy decannulation Continuous positive airway pressure titration evaluation

Non-respiratory Periodic limb movement disorder Suspected narcolepsy (coupled with daytime multiple sleep latency test) Atypical or injurious parasomnias or other nocturnal spells Suspicion of restless legs syndrome who require supportive data for diagnosis

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Sally Ibrahim and Carol Rosen b. PSG can be performed in children of all ages. i. Guidelines for accommodating children in the sleep laboratory are available to promote quality and pediatric-friendly services. 2. Sleep architecture a. Scoring of sleep is detailed in the American Academy of Sleep Medicine (AASM) Scoring manual. b. Sleep stages in full-term infants up to 2 months are Wake, NREM, REM and Stage T (transitional sleep). i. Scoring approach for former preterm infants should consider postmenstrual age. c. Sleep stages for children and infants older than 2 months are similar to adults. i. Wake, NREM1, NREM2 and NREM3 and REM sleep are easily identifiable by 6 months of age. d. Newborn infants enter sleep through REM sleep. After about age 3 months, most sleep onsets begin in NREM. e. Under 3 months of age, the NREM-REM cycle length is about 60 minutes and increases to 60-90 minutes by age 4-5 years i. By school age, the cycle length is 60-120 minutes resembling adults. f. During infancy, there is a marked reduction in total REM sleep from 50% at birth to 30% by the end of the first year. g. After age 5 years, proportions of NREM and REM sleep remain constant throughout the lifespan h. Normative data for sleep measures for children >2 months are summarized in Table 2. i. Compared with adults, children have fewer arousals and greater sleep efficiency. Table 2. Polysomnographic sleep stages in childhood

Parameter Sleep Efficiency (%) Sleep Latency (minutes) REM Latency (minutes) Arousal index (number/hr) Stage N1 (% TST) Stage N2 (% TST) Stage N3 (%TST) Stage R (% TST) TST: total sleep time

Usual Value >85%, variable 10 minutes bpm: beats per minute; desat: O2 desaturation; NP: Nasal pressure; TST: Total Sleep Time.

4. Normal PSG respiratory variables in children a. Normative respiratory and limb movement indices for pediatric polysomnography differ from adults and are illustrated in Table 4. b. Respiratory rates are higher in infants and children compared with adults c. Multiple respiratory events may be seen in normal healthy term infants i. Normal infants rarely have obstructive apnea and indices less than 1 are normal. ii. The overall AHI varies considerably in infants up to 3 months, ranging from 4.9-21, made up of mostly hypopneas, central and mixed apnea related to immaturity.

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Parameter Respiratory: Apnea-hypopnea index* Central apnea index * SpO2 mean (%) SpO2 nadir (%) Time with SpO2 < 90% (%TST) Time with peak PCO2 ≥ 50 mmHg (%TST) Respiratory Rate (median)

Normal Value

Comments

3 nights a week with a normal polysomnography (PSG) (obstructive apnea-hypopnea index (oAHI) < 1 event/hour) b. Prevalence of habitual snoring: 10-12% 2. Definitions of obstructive sleep apnea (OSA) as defined by the American Academy of Sleep Medicine (AASM) a. Diagnostic criteria i. One or more clinical symptoms AND polysomnographic criteria ii. Clinical symptoms  Habitual snoring  Labored/obstructive breathing  Daytime consequences  Sleepiness  (dozing off, yawning); uncommon in young children but may occur in older obese patients with more severe disease  Hyperactivity  Behavioral problems 

Katwa and Owens are co-principal investigators.

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Megan L. Durr, Umakanth A. Katwa, Judith A. Owens et al.  Learning difficulty iii. Polysomnography criteria: one of the following must be met  1 or more obstructive apnea, mixed apnea, or hypopnea events(s) per hour  Apnea: ≥ 90% decrease in airflow signal  Hypopnea: ≥ 30% decrease in airflow signal, associated with either o Cortical arousal OR o Oxygen desaturation of ≥ 3%  Event duration in pediatric patients must last 2 breathing cycles  OR Obstructive hypoventilation pattern  Hypercapnea (PaCO2 > 50mmHg) for ≥ 25% of sleep time  In association with 1 or more o Snoring o Flattening of nasal pressure waveform o Paradoxical thoracoabdominal movement iv. Polysomnography grading  Not evidence based - but based upon clinical consensus and practice  Mild: oAHI ≥ 1 and < 5 events/hour  Moderate: oAHI ≥5 and 5 events/hour b. However, the significance of CSA is assessed based on various factors such as i. Age of patient ii. Duration of the event iii. Presence of periodic breathing (see Figure 1) iv. Associated severity of desaturations v. Hypercarbia vi. Rapid eye movement (REM) sleep related vii. Occures at sleep wake-transition viii. Occurs post arousal

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Figure 1. This is a 1-week-old 37-week term infant noted to have paused during sleep. The PSG showing excessive periodic breathing.

4. Common causes a. Overall, central apneas are less common in children b. Central apneas are commonly seen in the following conditions: i. Normal physiological pattern in REM sleep ii. Medications (including narcotics) iii. Chiari malformation/meningomyelocele iv. Congenital central hypoventilation syndrome (CCHS) v. Brainstem tumor vi. Post central nervous system (CNS) infection (encephalitis) vii. Hypoxic ischemic encephalopathy viii. Achondroplasia ix. Down Syndrome x. Joubert syndrome xi. Achondroplasia xii. Obesity hypoventilation syndrome 5. Clinical presentation a. The common clinical presentation of CSA in children includes: i. Witnessed apneas during sleep ii. Frequent sigh breaths/gasps iii. Restless sleep iv. Snoring v. Color change (infants) vi. Apparent life-threatening event (ALTE) 6. Diagnosis a. Common diagnostic tests for the evaluation of CSA include i. Overnight PSG (Figure 2)

Sleep Related Breathing Disorders and Other Conditions on Children ii. iii. iv.

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Brainstem magnetic resonance imaging (assessing for CNS causes/Chiari) Blood gases analysis PHOX 2B mutation analysis (to assess for CCHS)

Figure 2. This is a PSG showing central sleep apnea in a 6-year-old boy who presented with gasping breathing, snoring and restless sleep who was subsequently diagnosed with Chiari malformation.

7. Treatment a. Treatment depends on various factors such as age, underlying pulmonary condition, severity of CSA based on AHI, gas exchange abnormalities and or sleep disturbances b. Common treatments include i. Observation/reassurance ii. Supplemental oxygen during sleep iii. Bi-level positive pressure ventilation iv. Acetazolamide v. Treatment of underlying sleep disturbances or OSA 8. Primary central sleep apnea of prematurity a. Apnea of prematurity (AOP) reflects immaturity of brainstem and peripheral chemoreceptors and occurs in essentially all infants born at 20 seconds or ii. Cessation of < 20 seconds if associated with  Bradycardia: HR < 100/minute  Desaturations: SaO2 < 88%

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Presentation: Respiratory pause, cyanosis, desaturation, bradycardia, appears limp or unresponsive d. Consequences: Adverse neurodevelopmental outcomes, developmental delays e. Treatment: i. Evaluate for sepsis ii. Propped up position iii. Caffeine iv. Supplemental oxygen v. Continued positive airway pressure (CPAP) vi. Treatment of comorbid reflux 9. Primary central sleep apnea of infancy a. Commonly seen as frequent central apneas or excessive periodic breathing for age and usually seen in preterm and term born infants i. This is most likely due to delayed maturation of respiratory center and can be associated with OSA as well b. Periodic breathing is defined as (Figure 1) i. > 3 central apneas lasting > 3 seconds separated by 20 seconds of normal breathing c. Central sleep apnea in infants < 1 years (AASM criteria) i. Duration ≥ 20 seconds or ii. Duration > 2 breaths duration and at least 1 of the below:  EEG arousal  ≥ 3% desaturation  HR to < 50 BPM > 5 sec, or < 60 BPM > 15 sec d. Prevalence i. The prevalence of periodic breathing (PB):  Term 1 month: 80%  Upper limit of normal  At birth PB - up to 5% of total sleep time (TST)  At 4 weeks - age up to 10% of TST  Usually resolves by 1-3 months of age e. Clinical presentation i. Witnessed apnea/shallow breathing ii. Cyanosis iii. ALTE iv. Unresponsiveness v. Lethargy f. Diagnosis: Overnight PSG g. Consequences: Recurrent desaturations, reduced cerebral blood flow, and neurodevelopment problems h. Treatment: i. Supplemental oxygen ii. Caffeine

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10. Congenital central alveolar hypoventilation syndrome (CCHS) a. Rare genetic disorder characterized by alveolar hypoventilation which can be seen both during awake and sleep i. Usually presents in infancy but can present during late adulthood. b. Genetics i. PHOX2B mutation ii. This results in polyalanine repeats and the severity of the disease depends on the extent of these repeats c. Common clinical presentation i. Frequent prolonged apnea, desaturation ii. Cyanosis iii. ALTE iv. Failure of extubation following respiratory failure v. Constipation vi. Gastrointestinal dysmotility vii. Temperature instability d. Comorbid presentation i. Neural crest tumors ii. Hirschsprung disease iii. Bradyarrhythmia and heart blocks iv. Autonomic dysregulation e. Diagnosis i. PSG ii. Blood gases iii. PHOX2B genetic testing iv. Holter monitoring f. Treatment: Treatment is based on the severity and the severity of hypoventilation including the presence of daytime hypoventilation/desaturations (seen in 15%) i. Tracheostomy and ventilation ii. Bi-level ventilation iii. Diaphragmatic pacing iv. Supplemental oxygen v. Cardiac pacing

OTHER SLEEP CONDITIONS IN CHILDREN Parasomnias 1. Definition a. Parasomnias in general are defined as episodic undesirable physical events or experiences that occur during entry into sleep, within sleep, or on awakening from sleep b. Parasomnias may be further characterized as occurring primarily during:

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REM sleep  Nightmares ii. Non-REM (NREM) sleep  NREM-related parasomnias - commonly referred to as disorders of arousal or partial arousal parasomnias c. Partial arousal parasomnias include: i. Confusional arousals ii. Sleepwalking (somnambulism) iii. Sleep terrors (pavor nocturnus) d. They are common in childhood. They share features of: i. Autonomic or skeletal muscle disturbances, autonomic behaviors, and disorientation. ii. Occurrence during slow wave sleep (SWS)  Deep, delta, N3 iii. Timing  Typically the first third of the night iv. Resistance to comforting by caregivers  Attempts at awakening the individual may result in prolongation of the event v. Amnesia for the event on the part of the individual experiencing it vi. A genetic/familial predisposition vii. Typical pattern of decreased frequency of events with age with common cessation of events in adolescence (as SWSdeclines) viii. Because these events have a common underlying pathophysiology, multiple forms of partial arousal parasomnias may occur in the same child e. Common causes i. Genetic predisposition ii. Sleep restriction (related to compensatory increase in SWS) iii. Irregular sleep schedule or sleeping in a strange environment (e.g., on vacation) iv. Environmental influences (sudden noises, light) v. Primary sleep disorders such as OSA that are associated with increased arousals and disturbed sleep vi. Although parasomnia events can be exacerbated by stress, especially if associated with disturbed sleep, these events are not usually associated with psychopathology or traumatic events in childhood  This is unlike in adults where events are much more common in adults with partial arousal parasomnias 2. Clinical Presentation a. Confusional arousals involve disorientation and unresponsiveness to the environment, as well as amnesia for the event i. May be triggered by forced awakening, particularly early in the night or upon attempting to awaken in the morning

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They often start with the child sitting up in bed, moaning or muttering and may involve thrashing around and agitation iii. They typically last for several minutes but may be more prolonged in duration iv. Confusional arousals can be present from a very young age (infants) b. Sleepwalking episodes are characterized by the child appearing confused or dazed, the eyes are usually open, and he or she may mumble or give inappropriate answers to questions i. Occasionally, a sleepwalking child may appear agitated ii. A sleepwalker is typically clumsy and may perform bizarre or strange actions such as urinating in a closet iii. Sleepwalking can occur infrequently or on a nightly basis iv. Injuries may occur during sleepwalking, ranging from bruises to more serious injuries as a result of falling down stairs, heading outside, or engaging in other risky behaviors v. Both sleepwalking and sleep terrors often start in early childhood (48 years old) c. Sleep terrors are characterized by a sudden arousal from sleep, accompanied by autonomic (dilated pupils, increased heart and respiratory rate) and behavioral manifestations (screaming, crying, incoherent mumbling or verbal expression) of intense fear i. Children typically are not able to respond and don’t remember these events if not woken up ii. Sleep terrors are much worse to observe than to experience, and much less traumatic to the child than a nightmare or bad dream d. Partial arousal parasomnias can be confused with nocturnal seizures. i. Nocturnal seizure characteristics include:  Timing and age of onset of the latter are usually more variable  Characteristics during the episodes may include incontinence, tongue-biting, drooling, and stereotypic or repetitive behaviors  Daytime sleepiness may occur, which is absent in partial arousal parasomnias 3. Diagnosis a. Diagnosis is usually made by clinical history b. Overnight PSG i. Is not a routine part of the evaluation for disorders of arousal ii. Because these are episodic events, they may not be captured on a single night study iii. However, if there is a concern about an underlying sleep disorder such as OSA, an overnight sleep study is appropriate iv. PSG may also be warranted to differentiate between a disorder of arousal and a seizure disorder c. Videotaping of the event by a caregiver can be quite helpful in differentiating between a partial arousal parasomnia and other episodic nocturnal event

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Megan L. Durr, Umakanth A. Katwa, Judith A. Owens et al. 4. Treatment a. Management typically involves reassurance and education of caregivers, avoidance of exacerbating factors, and treatment of underlying primary sleep disorders if applicable b. Safety precautions such as alarm on the child’s bedroom door and locks on outside doors are paramount with sleepwalking c. Addressing environmental triggers for arousal (e.g., white noise machine in the bedroom to reduce ambient noise) d. Ensuring adequate sleep duration, as sleep restriction results in a compensatory increase in SWS e. Scheduled awakenings in which the child is fully awakened by a caregiver about 30-45 minutes before the event typically occurs over a period of several weeks may be helpful to preempt parasomnias that are frequent (nightly) events that occur at predictable times f. Pharmacologic intervention is rarely needed except may be indicated in cases of frequent or severe episodes, high risk of injury, violent behavior, or serious disruption to the family i. The primary pharmacologic agents used are potent SWS suppressants, primarily benzodiazepines and tricyclic antidepressants

Narcolepsy 1. Definitions a. Excessive daytime sleepiness (EDS) is defined as the inability to stay awake and alert during the day, resulting in periods of irrepressible need for sleep or involuntary lapses into drowsiness or sleep i. There are many causes of EDS including  Chronic insufficient sleep compared to sleep needs (often a result of voluntary sleep curtailment)  Primary sleep disorders such as OSA resulting in sleep disruption b. Hypersomnia is a clinical term that is used to describe a group of disorders characterized by recurrent episodes of EDS, reduced baseline alertness, and/or prolonged nighttime sleep periods that interfere with normal daily functioning c. Central hypersomnias include narcolepsy (type 1 and 2), idiopathic hypersomnia, and Kleine-Levin syndrome d. Narcolepsy is a chronic lifelong CNS disorder typically presenting in adolescence and early adulthood that is characterized by profound daytime sleepiness and resultant significant functional impairment i. Narcolepsy may be further delineated as:  Narcolepsy with cataplexy (type 1)  Narcolepsy without cataplexy (type 2)  Secondary narcolepsy due to medical/neurological conditions

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In contrast to other causes of EDS, narcolepsy is relatively rare with an estimated prevalence reported to be between 3 and 16 per 10,000 i. Prevalence also varies across racial/ethnic groups 2. Etiology a. Both animal and human studies now strongly implicate a specific deficit in the hypothalamic neurotransmitter hypocretin (HRCT)/orexin as a primary causal factor in narcolepsy with cataplexy b. The orexin/HRCT system is known to be involved not only with maintenance of alertness and the stabilization of sleep–wake states, but also with hunger and satiety, energy metabolism, emotional processes, and locomotion c. It has been postulated that autoimmune mechanisms, possibly triggered by viral infections or specific vaccine adjuvants, in combination with a genetic predisposition and environmental factors, may be involved in narcolepsy 3. Clinical Presentation a. The most prominent clinical manifestation of narcolepsy is profound EDS, characterized by both an increased baseline level of daytime sleep propensity, and by the repeated occurrence of sudden and unpredictable sleep episodes or “sleep attacks” i. In children, this may be observed as prolonged nighttime sleep or resumption of daytime naps b. These manifestations of EDS particularly occur during low stimulation conditions but may also be experienced also during activities such as eating and talking c. Other symptoms commonly associated with narcolepsy type 1 may be conceptualized as representing the “intrusion” of REM sleep features (such as muscle atonia and dream mentation) into the waking state and include: i. Cataplexy ii. Hypnagogic (at sleep onset) and hypnopompic (as awakening) hallucinations iii. Sleep paralysis iv. Frequent arousals/fragmented sleep d. Cataplexy i. Considered to be the most distinctive clinical feature of narcolepsy and is virtually pathognomonic for the disease  it is extremely rare outside of the context of narcolepsy ii. Defined as a sudden complete or partial loss of motor control with preserved consciousness lasting for minutes that often is triggered by emotion (laughter, surprise) iii. Patients may describe this as drooping of the head, loss of control of the extremities, or knees buckling, or a sudden collapse to the ground during severe episodes iv. Children may have a unique more prolonged manifestation of cataplexy termed “cataplectic facies” with ptosis and protruding tongue

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Vivid hallucinations involving visual, auditory, tactile and other sensory phenomena may occur at sleep onset (hypnagogic) and upon awakening (hypnopompic) f. Sleep paralysis is a temporary paralysis of voluntary muscles, typically occurring upon awakening and may be accompanied by hallucinations g. Frequent arousals and fragmented sleep somewhat paradoxically often occur in patients with narcolepsy h. Obesity with sudden and often dramatic weight gain and precocious puberty are uniquely associated narcolepsy features in the pediatric population i. Patients with narcolepsy often experience a profound impact on daytime functioning, including cognitive functions, attention, mood, and overall quality of life j. The early manifestations of narcolepsy are often ignored, misinterpreted, or misdiagnosed as other medical, neurological, and psychiatric conditions i. Thus the appropriate diagnosis is commonly delayed for a number of years 4. Diagnosis a. Sleep diaries may be helpful for documenting EDS and napping despite adequate duration of nocturnal sleep b. Subjective measures of EDS such as the Pediatric Daytime Sleepiness Scale and the Modified Epworth Sleepiness Scale assist in delineating the severity of EDS c. Overnight PSG along with a multiple sleep latency test (MSLT) are strongly recommended components of the evaluation of a patient with profound unexplained daytime sleepiness or suspected narcolepsy i. The purpose of the overnight PSG is to evaluate for primary sleep disorders, such as OSA, that may cause EDS  The PSG may also demonstrate abnormalities in REM sleep such as a short REM onset latency that aid in diagnosis  If OSA is present, it must be treated prior to carrying out the MSLT ii. The MSLT is comprised of a series of five scheduled naps of 20 minutes’ duration separated by 2-hour intervals during which the patient should be kept awake  It measures actual sleep during the naps, time to fall asleep (with a calculated mean value over the 5 naps) and the presence of REM sleep during the naps  Caveats to interpretation include documentation of sufficient sleep prior to testing (often by sleep log for 2 weeks prior to testing) and withdrawal of REM-suppressing drugs such as selective serotonin reuptake inhibitors (SSRIs) and sedating medications or stimulants b. Human leukocyte antigen (HLA) testing (DQB1*0602) is not mandatory for the diagnosis of narcolepsy, but may be helpful in some cases

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c.

Although most patients with narcolepsy and cataplexy are HLA positive (75%–90%), it should be kept in mind that some 25% of normal individuals are also positive for these antigens 5. Treatment a. Pharmacologic treatment i. For EDS:  Stimulants such as methylphenidate and dextroamphetamine products  Other wakefulness-promoting drugs such as modafinil and  Newer agents with novel mechanisms such as the histamine receptor antagonist pitolisant  None of these medications are currently indicated for the treatment of narcolepsy in the pediatric population ii. For cataplexy:  Sodium oxybate (the only drug approved for narcolepsy in children/adolescents)  Anti-depressants such as SSRIs and tricyclic antidepressants iii. Cognitive and behavioral management can be extremely helpful in allowing patients to manage their symptoms and include planned naps, adequate nighttime sleep opportunity and a regular sleep schedule, and enhancing coping mechanisms

RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER 1. Definition a. Restless legs syndrome (RLS) is a neurologic, primarily sensory disorder, characterized by an almost irresistible urge to move the legs that is often accompanied by uncomfortable sensations (See also Chapter 32) b. Periodic limb movement disorder (PLMD) is characterized by: i. Periodic limb movement (PLMs) which are a sequence (4 or more) periodic, repetitive, brief (0.5–10 seconds), and highly stereotyped limb jerks typically occurring at 20- to 40-second intervals and separated by >5- and 5 in children). c. As a marker of decreased iron stores, serum ferritin levels in both children and adults with RLS are commonly low i. A ferritin level below 50 ng/mL increases the risk of RLS and is typically the threshold used in children to determine treatment with iron supplementation

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Ferritin is an acute phase reactant and thus may be temporarily elevated with infection, resulting in a false negative for hypoferritinemia

5. Treatment a. Management of RLS/PLMD typically involve the following AIMS: i. Avoidance of exacerbating factors/substances such as caffeine and sedating antihistamines ii. Iron supplementation  Elemental iron based on ferritin level at 3-6mg/kg taken with vitamin C to increase absorption for 3 months before rechecking the ferritin level  Intravenous iron may be considered in rare instances of severe symptoms and intolerance of oral supplements iii. Muscle relaxation, massage, application of cold or heat iv. Sleep practices, including ensuring sufficient sleep on a consistent schedule b. Dopaminergic agents such as pramapexole or ropinerole have not been tested in children and there are no FDA approved medications for children with RLS/PLMD i. Off-label use of medications such as gabapentin and clonidine have been reported in clinical practice, but little empirical evidence exists

DELAYED SLEEP-WAKE PHASE DISORDER 1. Definition a. Circadian rhythm disorders in general either represent a “mismatch” between the individual’s intrinsic sleep–wake schedule and environmental demands i. Delayed and advanced sleep-phase disorders, shift work disorder, jet lag disorder b. Or an internal failure of synchronization of the circadian clock i. Non-24-hour sleep–wake disorder c. By far the most commonly clinically encountered circadian rhythm disorder in the pediatric (especially adolescent) population is delayed sleep–wake phase disorder (DSWPD) i. Involves a habitual, persistent and significant delay in sleep–wake schedule (later sleep onset and wake time) that conflicts with the individual’s normal school, work, and/or lifestyle demands d. It is the timing rather than the quality of sleep per se that is problematic, as individuals with DSWPD typically do not have sleep complaints if they are allowed to sleep on their preferred (later) schedule 2. Etiology a. All adolescents experience a shift in the natural sleep onset and offset times in conjunction with the onset of puberty

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Megan L. Durr, Umakanth A. Katwa, Judith A. Owens et al. b. Adolescents are also more sensitive to the sleep delaying effects of evening light compared to younger children c. The sleep drive also slows in adolescence, making it easier for them to stay up later d. For reasons that remain unclear, in some adolescents this natural tendency towards “eveningness” is exaggerated and significantly interferes with daily functioning e. The release of melatonin, the biomarker of the circadian system, in the evening is significantly delayed in these individuals 3. Clinical Presentation a. The most common clinical presentation is sleep initiation insomnia when the individual attempts to fall asleep at a socially acceptable desired bedtime and is unable to do so b. This is often accompanied by a complaint of extreme difficulty getting up in the morning, even for desired activities, and daytime sleepiness, especially in the morning hours c. Patients may report that their “optimal” alertness occurs in the evening hours 4. Diagnosis a. The diagnosis of DSWPD is made based on the clinical history and ruling out other causes of insomnia and EDS b. Sleep diaries are extremely helpful in the diagnosis, as they typically demonstrate a habitual very late sleep onset time with forced morning awakening on school days with a reversion to the “preferred” schedule on non-school days c. Actigraphy is an evaluation tool that measures body movements with a wristwatch-like device in order to approximate sleep-wake patterns over several weeks d. Questionnaires that assess relative periods of alertness and sleepiness during the 24-hour day (“chronotype”) can also be helpful e. PSG is seldom indicated in the diagnostic evaluation f. Measurement of melatonin levels in saliva are commercially available but not currently widely used 5. Treatment a. Treatment is based on a combination of: i. Gradually adjusting the sleep schedule over time to a target bedtime/wake time goal ii. Timed light exposure  Avoiding light, especially melatonin suppressing blue light from electronic devices in the evening  Increasing light exposure (potentially with a bright light device) in the morning iii. Administration of exogenous melatonin in the evening to promote sleep and advance the circadian phase iv. For most patients with DSWPD, consultation with a sleep medicine provider regarding a treatment program is highly recommended

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KEY CLINICAL POINTS 1. Clinical Practice Guideline: Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome – American Academy of Pediatrics, 2012 2. Clinical Practice Guideline: Polysomnography for Sleep-Disordered Breathing Prior to Tonsillectomy in Children – American Academy of Otolaryngology Head and Neck Surgery 3. International Pediatric Otolaryngology group (IPOG) consensus on the diagnosis and management of pediatric obstructive sleep apnea

QUESTIONS 1. A 4-year-old boy presents with snoring and restless sleep. A polysomnogram is ordered with a sample of the study shown. What is the diagnosis? a. Central Sleep Apnea b. Primary Snoring c. Obstructive Sleep Apnea d. Restless Leg Syndrome

2. A 3-year-old boy presents with witnessed apneas, mouth breathing and gasping during sleep. He had a sleep study which revealed snoring, flow limited breaths with obstructive AHI 6.5/hour and central sleep apnea index of 14/hour, these central apneas are seen mostly following arousals and associated with mild hypercarbia (4652 cm water), and recurrent mild-moderate desaturation with nadir desaturation of 86%. On examination he has adenoids 70% blockage and tonsils 2+. Based on this history, the next appropriate step in management is a. Brainstem MRI and neurological consultation b. Supplemental oxygen therapy during sleep

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Adenotonsillectomy and repeat sleep study to assess resolution of sleep apnea d. Medical management and repeat sleep study in 1 year 3. A 1-week-old term infant presents with stridor. There are no feeding difficulties and gaining weight normally. A nasal endoscopy reveals mild laryngomalacia. A sleep study reveals, intermittent soft stridor, increased periodic breathing of 15% total sleep time with recurrent mild-moderate desaturations with nadir of 77% during REM sleep. What is the most appropriate treatment for this infant? a. Caffeine therapy b. Supraglottoplasty c. Oxygen therapy d. Reassurance and repeat sleep study in 3 months 4. The most common cause of central sleep apnea in children is a. Physiological pattern usually in REM sleep b. Chiari malformation c. Congenital central hypoventilation syndrome d. Medications 5. A 4-year-old boy presents with nocturnal episodes characterized by sudden bursts of screaming and agitation, occurring about 90 minutes after bedtime with no memory of the event the next morning. What should caregivers be instructed to do? a. Attempt to awaken him during the episode b. Put him to bed 90 minutes later c. Video record an episode and forward to you for review d. Have him evaluated by a psychiatrist

REFERENCES Amara A, Maddox M. Pediatric Obstructive Sleep Apnea and Primary Snoring. In: Principles and Practice of Sleep Medicine. 6th ed. Elsevier; 2016. American Academy of Sleep Medicine. The International Classification of Sleep Disorders; 2014. Benedek P, Balakrishnan K, Cunningham MJ, Friedman NR, Goudy SL, Ishman SL, Katona G, Kirkham EM, Lam DJ, Leboulanger N, Lee GS, Le Treut C, Mitchell RB, Muntz HR, Musso MF, Parikh SR, Rahbar R, Roy S, Russell J, Sidell DR, Sie KCY, Smith RJ, Soma MA, Wyatt ME, Zalzal G, Zur KB, Boudewyns A. International Pediatric Otolaryngology group (IPOG) consensus on the diagnosis and management of pediatric obstructive sleep apnea (OSA). Int J Pediatr Otorhinolaryngol. 2020 Nov;138:110276. doi: 10.1016/j.ijporl.2020.110276. Chandrakantan A, Adler A. Pediatric obstructive sleep apnea: neurocognitive consequences. Curr Anesthesiol Rep. 2019;9(2):110-115. doi: 10.1007/s40140-019-00331-2.

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Cielo C, Marcus CL. Central hypoventilation syndromes. Sleep Med Clin.2014;9(1):105-18. doi: 10.1016/j.jsmc.2013.10.005. da Silva Gusmão Cardoso T, Pompéia S, Miranda MC. Cognitive and behavioral effects of obstructive sleep apnea syndrome in children: a systematic literature review. Sleep Medicine. 2018;46:46-55. doi: 10.1016/j.sleep.2017.12.020. Ehsan Z, Ishman SL. Pediatric obstructive sleep apnea. Otolaryngol Clin North Am. 2016;49(6):1449-1464. doi: 10.1016/j.otc.2016.07.001. Gradisar M, Crowley SJ. Delayed sleep phase disorder in youth. Curr Opin Psychiatry. 2013 Nov;26(6):580-5. doi: 10.1097/YCO.0b013e328365a1d4. Katz ES. Disorders of Central Respiratory Control During sleep in children. Therapy in Sleep Medicine. Editor: Barkoukis TJ, Matheson JK, Ferber R, Karl Doghramji K. Oct 2011 Elsevier Health Sciences; 2016. Chapter 34. Marcus CL, Brooks LJ, Draper KA, Gozal D, Halbower AC, Jones J, Schechter MS, Sheldon SH, Spruyt K, Ward SD, Lehmann C, Shiffman RN; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012 Sep;130(3):576-84. doi: 10.1542/peds.2012-1671. Maski K, Owens J. Insomnia, parasomnias, and narcolepsy in children: clinical features, diagnosis, and management. Lancet Neurol 2016; 15: 1170–81. doi: 10.1016/S14744422(16)30204-6. Patrinos ME, Martin RJ. Apnea in the term infant. Semin Fetal Neonatal Med. 2017 Aug;22(4):240-244. doi: 10.1016/j.siny.2017.04.003. Roland PS, Rosenfeld RM, Brooks LJ, Friedman NR, Jones J, Kim TW, Kuhar S, Mitchell RB, Seidman MD, Sheldon SH, Jones S, Robertson P; American Academy of Otolaryngology—Head and Neck Surgery Foundation. Clinical practice guideline: Polysomnography for sleep-disordered breathing prior to tonsillectomy in children. Otolaryngol Head Neck Surg. 2011 Jul;145(1 Suppl):S1-15. doi: 10.1177/0194599 811409837. Stubbs PH, Walters AS. Tools for the Assessment of Pediatric Restless Legs Syndrome. Front Psychiatry. 2020 May 5;11:356. doi: 10.3389/fpsyt.2020.00356. Taylor HG, Bowen SR, Beebe DW, Hodges E, Amin R, Arens R, Chervin RD, Garetz SL, Katz ES, Moore RH, Morales KH, Muzumdar H, Paruthi S, Rosen CL, Sadhwani A, Thomas NH, Ware J, Marcus CL, Ellenberg SS, Redline S, Giordani B. Cognitive effects of adenotonsillectomy for obstructive sleep apnea. Pediatrics. 2016;138(2). doi: 10.1542/peds.2015-4458. Trosman I, Trosman SJ. Cognitive and behavioral consequences of sleep disordered breathing in children. Medical Sciences. 2017;5(4):30. doi: 10.3390/medsci5040030. Wong W, Rivera E, Katwa UA. Central Hypoventilation Syndromes. Essential Pediatric Pulmonology 3rd Edn. Editor: Lodha RL, Kabra SK. Jaypee Brothers, Medical Publishers Pvt. Ltd. June 1, 2018. Chapter 38. Zhao J, Han S, Zhang J, Wang G, Wang H, Xu Z, Tai J, Peng X, Guo Y, Liu H, Tian J, Jin X, Zheng L, Zhang J, Ni X. Association between mild or moderate obstructive sleep apneahypopnea syndrome and cognitive dysfunction in children. Sleep Medicine. 2018;50:132136. doi: 10.1016/j.sleep.2018.04.009.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 35

TREATMENT OF PEDIATRIC OSA Cristina Baldassari1,2, MD, Erin Kirkham3, MD and Derek Lam4, MD 1

Department of Otolaryngology, Eastern Virginia Medical School, Norfolk, VA, USA 2 Department of Pediatric Sleep Medicine, Children’s Hospital of the King’s Daughters, Norfolk, VA, USA 3 University of Michigan Department of Otolaryngology Head and Neck Surgery, Ann Arbor, MI, USA 4 Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA

INTRODUCTION 1. Adenotonsillectomy (T&A) is the first-line treatment for obstructive sleep apnea (OSA) in children 2. Management of pediatric OSA is evolving as new literature emerges on the efficacy of additional non-surgical treatment options including observation, medical therapy, orthodontic management, and positive airway pressure

WATCHFUL WAITING 1. Observation or watchful waiting has emerged as a management strategy for children with non-severe OSA (apnea hypopnea index (AHI) < 10) 2. Natural history of non-severe pediatric OSA is such that: a. 1/3 of children have progression of disease b. 1/3 experience disease resolution c. 1/3 stay the same as they get older d. Risk factors for progression of disease include higher baseline AHI, obesity, and enlarged tonsils

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Cristina Baldassari, Erin Kirkham and Derek Lam 3. The Childhood Adenotonsillectomy Trial (CHAT) was a landmark, multi-institutional, randomized study comparing the efficacy of watchful waiting to adenotonsillectomy for the management of non-severe pediatric OSA in healthy, children a. Neurocognitive outcomes were similar between the watchful waiting and surgery groups i. Surgery did not confer benefit in terms of neurocognition when compared to watchful waiting in children with non-severe OSA at 7months of follow-up b. Approximately 46% of children in the observation group had resolution of OSA on their 7-month follow-up polysomnography (PSG) c. PSG outcomes did not correlate with quality of life and symptom burden in children with non-severe OSA i. The majority of children in the watchful waiting group remained symptomatic with snoring and poor sleep despite improvements in their AHI ii. Only 15% of children in the observation group experienced symptom resolution d. Risk factors for worse outcomes were higher baseline AHI, black race, and obesity 4. The Karolinska AdenoTonsillEctomy (KATE) Study is a recently published trial that examined outcomes in children 2 to 5 years of age with mild-moderate OSA randomized to watchful waiting or adenotonsillectomy a. Both groups of children experienced improvement in AHI b. Children that underwent adenotonsillectomy had significantly better qualityof-life outcomes than children who were managed with watchful waiting 5. Validated assessments of symptom burden and the impact of OSA on quality of life (QOL) such as the OSA-18 QOL instrument are useful in guiding management for non-severe pediatric OSA a. Children who are symptomatic with poor quality of life related to their OSA would benefit from medical or surgical therapy b. Children with a low symptom burden that lack risk factors for OSA progression can potentially be managed with watchful waiting

MEDICAL MANAGEMENT 1. While T&A results in improvements in PSG parameters and daytime sequelae in children with OSA, the significant morbidity associated with this procedure has spurred research to identify effective medical therapies for this disease a. Anti-inflammatory medications improve obstruction in children with nonsevere primary OSA and those with non-severe persistent OSA following prior T&A 2. Intranasal steroids a. Pathophysiology by which intra-nasal steroids result in reduced obstruction is unknown but is likely related to improved nasal patency

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b. Based on the Starling resister model, improving patency of the nasal passages, which can account for up to 50% of upper airway resistance, decreases collapsing forces in the distal airway c. Several studies have demonstrated improvement in AHI in children with nonsevere primary OSA treated with nasal steroids i. Children with co-morbid allergic rhinitis are more likely to respond to intra-nasal steroids ii. Intra-nasal steroids are well tolerated with the most common side effect being epistaxis d. A recent review highlighted the need for further research to clarify the role of intra-nasal steroids in the treatment of pediatric OSA including studies with larger sample sizes and more heterogeneous patient populations 3. Montelukast a. Leukotriene receptor antagonist initially developed for treatment of asthma and allergic rhinitis b. Montelukast results in improvement in both PSG parameters such as AHI and quality-of-life scores in children with non-severe primary OSA and those with non-severe persistent OSA following T&A i. The mechanism by which montelukast improves OSA in children is unknown  Montelukast is a leukotriene receptor antagonist, so it may act by modulating the increased expression of leukotriene receptors that has been found in adenoid and tonsil tissue of children with OSA ii. Montelukast therapy has also been shown to reduce the size of the adenoid on lateral neck x-ray c. Risk factors for failure of medical therapy include age older than 7 years and obesity d. While montelukast is typically well tolerated, the United States Food and Drug Administration recently added a black box warning label for montelukast due to concern for serious mental health side effects i. Behavioral side-effects including aggression and irritability have been reported in children utilizing montelukast for OSA therapy ii. Avoid use in children with a history of mental health disorders or behavioral problems 4. Primary limitation of medical therapy for pediatric OSA is unknown optimal duration of therapy a. Majority of studies recommend at least 3 to 4 months of medical therapy b. Additional limitation is exclusion of children with significant co-morbidities i. Role of medical therapy in children with OSA and significant comorbidities unclear with one recent study suggesting little benefit in children with Down Syndrome managed with Montelukast

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ORAL APPLIANCE 1. Description a. An oral appliance is a removable device worn during sleep to pull the mandible and tongue anteriorly, which increases the retroglossal airspace and decreases airway obstruction b. The appliance should be titratable and fit by an expert certified in dental sleep medicine c. Effectiveness should be measured by a polysomnography performed with the device in place 2. Indications a. Most frequently used in children > 12 years, after eruption of permanent teeth b. Can be used to treat any severity of persistent, post-adenotonsillectomy OSA c. Continuous positive airway pressure (CPAP) intolerance with significant tongue base obstruction 3. Complications a. Dental soreness, drooling, jaw discomfort b. Unknown impacts on growth of the mandible and teeth 4. Effectiveness a. There is limited high-quality evidence of effectiveness in children b. Small series have shown reduction in AHI and improvement in symptoms c. A Cochrane review of randomized studies included a single trial and concluded that there was insufficient evidence to support their use in children d. A second systematic review and meta-analysis showed stable favorable results for oral appliances but the pooled reduction in AHI was very small

RAPID MAXILLARY EXPANSION 1. Description a. Rapid maxillary expansion (RME) is an orthodontic treatment that widens the palate and nasal airway b. The device is affixed to the maxillary molars and bridges the hard palate with an expansion screw at the midline (Figure 1) c. Some devices can be affixed to the hard palate bone, but this is less common than devices applied directly to the teeth d. The screw is turned daily for 3 - 6 weeks i. Each turn widens the palate at the mid-palatal suture ii. After the initial expansion period, the device is left in place for 4 - 6 months

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Figure 1. Rapid Maxillary Expansion at day one and post-expansion.

2. Indications a. Typical age range for RME is 6 - 16 years i. after eruption of the maxillary molars but prior to fusion of the midpalatal suture ii. The treatment can still be used in teens and young adults but is most effective in older patients when combined with a surgical procedure to split the mid-palatal suture b. Children with OSA who have a narrow palate with a crossbite i. Maxillary molars positioned mesial – or medial – to the mandibular molars c. RME can be used in combination with adenotonsillectomy (either before or after) i. Studies generally demonstrate better outcomes in children with no or small tonsils 3. Effectiveness a. Most effective for children with mild OSA b. RME improves AHI and lowest oxygen saturation in children, especially in the short term (< 3-year follow-up)

POSITIVE AIRWAY PRESSURE (PAP) THERAPY 1. Description a. PAP therapy delivers positive airway pressure that stents open the airway via a face or nasal mask b. Two types of PAP therapy are commonly prescribed: continuous (CPAP) and bi-level (BiPAP) c. Types of mask interfaces: nasal, nasal pillow, or full-face d. Nasal masks are the most commonly used in infants and young children while nasal pillows which are inserted into the nares are primarily used in adolescents

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Cristina Baldassari, Erin Kirkham and Derek Lam 2. Indications a. Children who are not candidates for adenotonsillectomy due to high surgical risk or small, non-obstructive tonsils and adenoids b. Children with persistent OSA after adenotonsillectomy 3. Effectiveness a. When used adequately, PAP therapy in children has been associated with improvements OSA symptoms, daytime sleepiness, quality of life, cardiovascular and metabolic risk, and academic performance b. Adherence to PAP therapy in children is challenging i. A recent systematic review found adherence ranging from 24-87%, with an average of 57% and an average nightly use of < 5 hours per night ii. Adherence was most commonly defined as ≥ 4 hours use per night for 70% of nights iii. Adherence decreases with increasing age and greater autonomy iv. There are no studies assessing long-term adherence or impact on OSA sequelae with long-term PAP use in children 4. Complications a. Oronasal or full-face masks have the risk of hypercapnia related to the anatomic dead space of the mask, and there is the potential for aspiration with emesis i. Full face masks should be avoided in young children due to aspiration risk b. Prolonged PAP use at high pressures can impair maxillary and mandibular growth

ADENOTONSILLECTOMY 1. Description a. Many surgical techniques have been described for the removal of the palatine tonsils and adenoids i. Cold dissection ii. Monopolar or bipolar cautery iii. Bipolar radiofrequency (coblation) iv. Microdebrider b. Recent studies have also described partial tonsillectomy (also referred to as intracapsular tonsillectomy or tonsillotomy) where a rind of tonsil tissue and its capsule is left intact in the tonsillar fossa, as an alternative to complete tonsillectomy i. In several randomized trials and systematic reviews, this approach has demonstrated decreased postoperative pain, faster return to normal diet, and less risk of postoperative hemorrhage compared to total tonsillectomy

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ii. Since some lymphoid tissue is left intact, tonsillar regrowth has been observed, leading to completion tonsillectomy in 4 - 6% iii. The risk of tonsillar regrowth is age-related, with far higher risk of regrowth in children < 4 years of age 2. Indications a. Tonsillectomy with or without adenoidectomy is indicated as the first line treatment in children with obstructive sleep disordered breathing (oSDB) and tonsillar hypertrophy (tonsil size Brodsky 2+, 3+, or 4+) or for PSG-proven OSA b. It remains controversial whether children with oSDB and small tonsils (Brodsky 1+) benefit from tonsillectomy i. Tonsil size assessed by routine physical exam has not been consistently associated with severity of OSA or response to tonsillectomy 3. Effectiveness a. Multiple observational and randomized trials have demonstrated the effectiveness of adenotonsillectomy in improving symptoms of: i. oSDB ii. Polysomnography measures iii. Quality of life iv. Neurobehavioral outcomes v. Academic performance b. The CHAT randomized trial of T&A vs. watchful waiting in children ages 59 years demonstrated 79% resolution of OSA with T&A compared to 46% in the watchful waiting group after 7 months c. Two recent randomized trials (KATE and POSTA trials) demonstrated similar outcomes in pre-school age children with mild-moderate OSA i. Both trials demonstrated significant benefit of T&A over watchful waiting with respect to quality of life and subjective assessments of behavior and executive function, and only modest impact of T&A on polysomnography outcomes ii. The POSTA study demonstrated no difference in treatment groups with respect to intelligence quotient d. Persistent OSA after T&A has an estimated prevalence ranging from 21 - 75% depending on the diagnostic definition of OSA i. Risk factors for persistence include African American race, age greater than 7 years, severe baseline OSA, and comorbidities such as obesity, Down syndrome, craniofacial anomalies, and neuromuscular disorders e. Quality of life measures and subjective caregiver assessments of neurobehavioral outcomes clearly demonstrate benefit of T&A in the treatment of sleep disordered breathing (SDB) and OSA f. Objective neurocognitive outcome measures including executive function and intelligence quotient have not demonstrated superiority of T&A over watchful waiting

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Cristina Baldassari, Erin Kirkham and Derek Lam 4. Complications a. Postoperative complications have been estimated in one systematic review to occur in approximately 19% of patients with the most common complications being: i. Respiratory compromise (9.4%) ii. Secondary hemorrhage (2.6%) iii. Primary hemorrhage (2.4%) b. Children with OSA were 4.9 times more likely to have respiratory complications than those without OSA, while bleeding complications were more likely to occur in children without OSA i. Children < 2 years of age are also at elevated risk of respiratory complication ii. While T&A can be safely performed in the outpatient setting for otherwise healthy children with non-severe disease, children that meet the following criteria should be observed overnight after surgery:  < 3 years of age  severe baseline OSA  AHI ≥ 10 events/hr, or oxygen saturation nadir < 80%, or both c. Postoperative pain, nausea, vomiting, inadequate oral intake, fever, and dehydration are also frequently reported

KEY CLINICAL POINTS Guidelines for Management of Nonsevere Pediatric OSA Shared decision making with caregivers can be utilized to determine the best management strategy for non-severe OSA in children. Validated QOL instruments should be used to assess symptom burden. Observation is favored for children who do not have significant day and nighttime sequelae. Medical management with anti-inflammatory medications can be considered for non-obese children under 7 years of age especially if there is a history of allergic rhinitis. Consider surgical intervention for children with a high symptom burden and/or those with risk factors for OSA progression including obese children and those with large tonsils. American Academy of Pediatrics Guidelines (2012) recommend CPAP as first-line treatment for persistent, post-adenotonsillectomy OSA but includes RME as a potential option if patients cannot tolerate CPAP. There are no specific practice guidelines for oral appliances in children. Adult guidelines suggest that oral appliances be prescribed in cases of CPAP noncompliance rather than no therapy. The appliance should be titratable and fit by a practitioner certified in dental sleep medicine. Patients should be monitored for dental side effects. Effectiveness should be measured by a titration polysomnography performed with the device in place.

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QUESTIONS 1. Which of the following is true about rapid maxillary expansion? a. It is not effective if used in a child who has already undergone adenotonsillectomy b. There is no evidence for its effectiveness in treating sleep apnea in children c. It should only be used in a child with small tonsils d. It is indicated in children with narrow palates and posterior cross-bite 2. Which is the best option for a child who snores, has Brodsky 2+ tonsils, but does not have additional daytime or nighttime symptoms? a. Observation b. Adenotonsillectomy c. Rapid maxillary expansion d. Medications 3. Which of the following is true about the natural history of non-severe pediatric OSA? a. The majority (> 80%) of children grow out of their OSA b. OSA worsens over time in obese children, but not in normal-weight children c. Roughly equal proportions of children experience resolution as experience progression of their OSA d. By definition, children with small tonsils do not experience worsening of OSA over time 4. Which of the following is true about intracapsular (partial) tonsillectomy? a. It involves removal of the entire tonsil with its capsule b. Risk of tonsillar regrowth is highest in children < 4 years old c. It carries an increased risk of bleeding compared to complete tonsillectomy d. It results in less pain but a longer recovery compared to complete tonsillectomy 5. Which of the following is false regarding CPAP treatment in children with OSA a. It is first-line treatment for OSA in children b. Adherence to CPAP is lower in teenagers than in toddlers c. There is the potential for aspiration with emesis d. Prolonged PAP use at high pressures can impair maxillary and mandibular growth

REFERENCES Bhattacharjee, R., Kheirandish-Gozal, L., Spruyt, K., Mitchell, R. B., Promchiarak, J., Simakajornboon, N., Kaditis, A. G., Splaingard, D., Splaingard, M., Brooks, L. J., Marcus, C. L., Sin, S., Arens, R., Verhulst, S. L., Gozal, D. Adenotonsillectomy outcomes in

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treatment of obstructive sleep apnea in children: A multicenter retrospective study. Am. J. Respir. Crit. Care Med., 2010 Sep. 1; 182(5):676 - 83. doi: 10.1164/rccm.200912-1930OC. Blackshaw, H., Springford, L. R., Zhang, L. Y., Wang, B., Venekamp, R. P., Schilder, A. G. Tonsillectomy versus tonsillotomy for obstructive sleep-disordered breathing in children. Cochrane Database Syst. Rev., 2020; 4:CD011365. doi: 10.1002/ 14651858.CD011365.pub2. Blinder, H., Momoli, F., Bokhaut, J., Bacal, V., Goldberg, R., Radhakrishnan, D., Katz, S. L. Predictors of adherence to positive airway pressure therapy in children: A systematic review and meta-analysis. Sleep Med., 2020 May; 69:19 - 33. doi: 10.1016/j.sleep.2019.12.015. Bluher, A. E., Brawley, C. C., Cunningham, T. D., Baldassari, C. M. Impact of montelukast and fluticasone on quality of life in mild pediatric sleep apnea. Int. J. Pediatr. Otorhinolaryngol., 2019; 125:66 - 70. doi: 10.1016/j.ijporl.2019.06.027. Borgstrom, A., Nerfeldt, P., Friberg, D. Postoperative pain and bleeding after adenotonsillectomy versus adenotonsillotomy in pediatric obstructive sleep apnea: An RCT. Eur. Arch. Otorhinolaryngol., 2019; 276(11):3231 - 3238. doi: 10.1007/s00405-01905571-w. Camacho, M., Chang, E. T., Song, S. A., Abdullatif, J., Zaghi, S., Pirelli, P., Certal, V., Guilleminault, C. Rapid maxillary expansion for pediatric obstructive sleep apnea: A systematic review and meta-analysis. Laryngoscope, 2017 Jul.; 127(7):1712 - 1719. doi: 10.1002/lary.26352. Carvalho, F. R., Lentini-Oliveira, D. A., Prado, L. B., Prado, G. F., Carvalho, L. B. Oral appliances and functional orthopaedic appliances for obstructive sleep apnoea in children. Cochrane Database Syst. Rev., 2016; 10:CD005520. doi: 10.1002/ 14651858.CD005520.pub3. Chan, C. C., Au, C. T., Lam, H. S., Lee, D. L., Wing, Y. K., Li, A. M. Intranasal corticosteroids for mild childhood obstructive sleep apnea--a randomized, placebo-controlled study. Sleep Med., 2015; 16(3):358 - 363. doi: 10.1016/j.sleep.2014.10.015. Chinnadurai, S., Jordan, A. K., Sathe, N. A., Fonnesbeck, C., McPheeters, M. L., Francis, D. O. Tonsillectomy for Obstructive Sleep-Disordered Breathing: A Meta-analysis. Pediatrics, 2017; 139(2): e20163491. doi: 10.1542/peds.2016-3491. De Luca Canto, G., Pachêco-Pereira, C., Aydinoz, S., Bhattacharjee, R., Tan, H. L., Kheirandish-Gozal, L., Flores-Mir, C., Gozal, D. Adenotonsillectomy Complications: A Meta-analysis. Pediatrics, 2015 Oct.; 136(4):702 - 18. doi: 10.1542/peds.2015-1283. Fehrm, J., Nerfeldt, P., Browaldh, N., Friberg, D. Effectiveness of Adenotonsillectomy vs. Watchful Waiting in Young Children with Mild to Moderate Obstructive Sleep Apnea: A Randomized Clinical Trial. JAMA Otolaryngol. Head Neck Surg., 2020; 146(7):647 - 654. doi: 10.1001/jamaoto.2020.0869. Friedman, M., Wilson, M., Lin, H. C., Chang, H. W. Updated systematic review of tonsillectomy and adenoidectomy for treatment of pediatric obstructive sleep apnea/hypopnea syndrome. Otolaryngol. Head Neck Surg., 2009; 140(6):800 - 808. doi: 10.1016/j.otohns.2009.01.043. Goldbart, A. D., Greenberg-Dotan, S., Tal, A. Montelukast for children with obstructive sleep apnea: A double-blind, placebo-controlled study. Pediatrics, 2012; 130(3):e575 - 580. doi: 10.1542/peds.2012-0310.

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Guilleminault, C., Huang, Y. S., Glamann, C., Li, K., Chan, A. Adenotonsillectomy and obstructive sleep apnea in children: a prospective survey. Otolaryngol. Head Neck Surg., 2007; 136(2):169 - 175. doi: 10.1016/j.otohns.2006.09.021. Howard, N. S., Brietzke, S. E. Pediatric tonsil size: Objective vs. subjective measurements correlated to overnight polysomnogram. Otolaryngol. Head Neck Surg., 2009; 140(5):675 - 681. doi: 10.1016/j.otohns.2009.01.008. Katz, S. L., MacLean, J. E., Hoey, L., Horwood, L., Barrowman, N., Foster, B., Hadjiyannakis, S., Legault, L., Bendiak, G. N., Kirk, V. G., Constantin, E. Insulin Resistance and Hypertension in Obese Youth with Sleep-Disordered Breathing Treated with Positive Airway Pressure: A Prospective Multicenter Study. J. Clin. Sleep Med., 2017 Sep. 15; 13(9):1039 - 1047. doi: 10.5664/jcsm.6718. Kheirandish-Gozal, L., Bhattacharjee, R., Bandla, H. P. R., Gozal, D. Antiinflammatory therapy outcomes for mild OSA in children. Chest, 2014; 146(1):88 - 95. doi: 10.1378/ chest.13-2288. Kim, J. S., Kwon, S. H., Lee, E. J., Yoon, Y. J. Can Intracapsular Tonsillectomy Be an Alternative to Classical Tonsillectomy? A Meta-analysis. Otolaryngol. Head Neck Surg., 2017; 157(2):178 - 189. doi: 10.1177/0194599817700374. Kuhle, S., Hoffmann, D. U., Mitra, S., Urschitz, M. S. Anti-inflammatory medications for obstructive sleep apnoea in children. Cochrane Database Syst. Rev., 2020; 1:CD007074. doi: 10.1002/14651858.CD007074.pub3. Lee, H. S., Yoon, H. Y., Jin, H. J., Hwang, S. H. The safety and efficacy of powered intracapsular tonsillectomy in children: A meta-analysis. Laryngoscope, 2018; 128(3):732 - 744. doi: 10.1002/lary.26886. Marcus, C. L., Brooks, L. J., Draper, K. A., Gozal, D., Halbower, A. C., Jones, J., Schechter, M. S., Sheldon, S. H., Spruyt, K., Ward, S. D., Lehmann, C., Shiffman, R. N.; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics, 2012 Sep.; 130(3):576 - 84. doi: 10.1542/ peds.2012-1671. Marcus, C. L., Moore, R. H., Rosen, C. L., Giordani, B., Garetz, S. L., Taylor, H. G., Mitchell, R. B., Amin, R., Katz, E. S., Arens, R., Paruthi, S., Muzumdar, H., Gozal, D., Thomas, N. H., Ware, J., Beebe, D., Snyder, K., Elden, L., Sprecher, R. C., Willging, P., Jones, D., Bent, J. P., Hoban, T., Chervin, R. D., Ellenberg, S. S., Redline, S.; Childhood Adenotonsillectomy Trial (CHAT). A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl. J. Med., 2013 Jun. 20; 368(25):2366 - 76. doi: 10.1056/NEJMoa1215881. Marcus, C. L., Moore, R. H., Rosen, C. L., Giordani, B., Garetz, S. L., Taylor, H. G., Mitchell, R. B., Amin, R., Katz, E. S., Arens, R., Paruthi, S., Muzumdar, H., Gozal, D., Thomas, N. H., Ware, J., Beebe, D., Snyder, K., Elden, L., Sprecher, R. C., Willging, P., Jones, D., Bent, J. P., Hoban, T., Chervin, R. D., Ellenberg, S. S., Redline, S.; Childhood Adenotonsillectomy Trial (CHAT). A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl. J. Med., 2013 Jun. 20; 368(25):2366 - 76. doi: 10.1056/NEJMoa1215881. Marcus, C. L., Radcliffe, J., Konstantinopoulou, S., Beck, S. E., Cornaglia, M. A., Traylor, J., DiFeo, N., Karamessinis, L. R., Gallagher, P. R., Meltzer, L. J. Effects of positive airway pressure therapy on neurobehavioral outcomes in children with obstructive sleep apnea. Am. J. Respir. Crit. Care Med., 2012 May 1; 185(9):998 - 1003. doi: 10.1164/rccm.201112-2167OC.

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Mitchell, R. B. Adenotonsillectomy for obstructive sleep apnea in children: Outcome evaluated by pre- and postoperative polysomnography. Laryngoscope, 2007; 117(10):1844 - 1854. doi: 10.1097/MLG.0b013e318123ee56. Mitchell, R. B., Archer, S. M., Ishman, S. L. et al. Clinical Practice Guideline: Tonsillectomy in Children (Update). Otolaryngol. Head Neck Surg., 2019; 160(1_suppl.):S1 - S42. doi: 10.1177/0194599818801757. Mitchell, R. B., Kelly, J. Quality of life after adenotonsillectomy for SDB in children. Otolaryngol. Head Neck Surg., 2005; 133(4):569 - 572. doi: 10.1016/ j.otohns.2005.05.040. Odhagen, E., Sunnergren, O., Hemlin, C., Hessen Soderman, A. C., Ericsson, E., Stalfors, J. Risk of reoperation after tonsillotomy versus tonsillectomy: A population-based cohort study. Eur. Arch. Otorhinolaryngol., 2016; 273(10):3263 - 3268. doi: 10.1007/s00405015-3871-7. Parmar, A., Baker, A., Narang, I. Positive airway pressure in pediatric obstructive sleep apnea. Paediatr. Respir. Rev., 2019; 31:43 - 51. doi: 10.1016/j.prrv.2019.04.006. Pierce, B., Brietzke, S. Association of Preoperative, Subjective Pediatric Tonsil Size with Tonsillectomy Outcomes: A Systematic Review. JAMA Otolaryngol. Head Neck Surg., 2019 Jul. 25. doi: 10.1001/jamaoto.2019.1842. Ramar, K., Dort, L. C., Katz, S. G., Lettieri, C. J., Harrod, C. G., Thomas, S. M., Chervin, R. D. 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 Jul. 15; 11(7):773 - 827. doi: 10.5664/jcsm.4858. Roberts, S. D., Kapadia, H., Greenlee, G., Chen, M. L. Midfacial and Dental Changes Associated with Nasal Positive Airway Pressure in Children with Obstructive Sleep Apnea and Craniofacial Conditions. Journal of Clinical Sleep Medicine: JCSM: official publication of the American Academy of Sleep Medicine. 2016; 12(4):469 - 475. doi: 10.5664/jcsm.5668. Sathe, N., Chinnadurai, S., McPheeters, M., Francis, D. O. Comparative Effectiveness of Partial versus Total Tonsillectomy in Children. Otolaryngol. Head Neck Surg., 2017; 156(3):456 - 463. doi: 10.1177/0194599816683916. Statham, M. M., Elluru, R. G., Buncher, R., Kalra, M. Adenotonsillectomy for obstructive sleep apnea syndrome in young children: Prevalence of pulmonary complications. Arch. Otolaryngol. Head Neck Surg., 2006; 132(5):476 - 480. doi: 10.1001/archotol.132.5.476. Villa, M. P., Miano, S., Rizzoli, A. Mandibular advancement devices are an alternative and valid treatment for pediatric obstructive sleep apnea syndrome. Sleep Breath., 2012; 16(4):971 - 976. doi: 10.1007/s11325-011-0595-9. Volsky, P. G., Woughter, M. A., Beydoun, H. A., Derkay, C. S., Baldassari, C. M. Adenotonsillectomy vs observation for management of mild obstructive sleep apnea in children. Otolaryngol. Head Neck Surg., 2014; 150(1):126 - 132. doi: 10.1177/0194599813509780. Watach, A. J., Xanthopoulos, M. S., Afolabi-Brown, O., Saconi, B., Fox, K. A., Qiu, M., Sawyer, A. M. Positive airway pressure adherence in pediatric obstructive sleep apnea: A systematic scoping review. Sleep Med. Rev., 2020 Jun.; 51:101273. doi: 10.1016/j.smrv.2020.101273.

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Waters, K. A., Chawla, J., Harris, M. A., Heussler, H., Black, R. J., Cheng, A. T., Lushington, K. Cognition after Early Tonsillectomy for Mild OSA. Pediatrics, 2020 Feb.; 145(2):e20191450. doi: 10.1542/peds.2019-1450. Yanyan, M., Min, Y., Xuemei, G. Mandibular advancement appliances for the treatment of obstructive sleep apnea in children: A systematic review and meta-analysis. Sleep Med., 2019; 60:145 - 151. doi: 10.1016/j.sleep.2018.12.022. Yu, W., Sarber, K. M., Howard, J. J. M., Huang, G., Hossain, M. M., Heubi, C. H., Lu, X., Simakajornboon, N. Children with Down syndrome and mild OSA: Treatment with medication versus observation. J. Clin. Sleep Med., 2020 Jun. 15; 16(6):899 - 906. doi: 10.5664/jcsm.8358. Zhang, L. Y., Zhong, L., David, M., Cervin, A. Tonsillectomy or tonsillotomy? A systematic review for paediatric sleep-disordered breathing. Int. J. Pediatr. Otorhinolaryngol., 2017; 103:41 - 50. doi: 10.1016/j.ijporl.2017.10.008.

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 36

PEDIATRIC OSA TREATMENT BEYOND TONSILLECTOMY Carol Li, MD3,6, Yann-Fuu Kou4,5, MD and Stacey L. Ishman1,2,3, MD 1

Utilization Management, Healthvine Health Network, Cincinnati, OH, USA 2 Subspecialty Engagement, Tristate Child Health Services, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 3 Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA 4 Department of Otolaryngology-Head & Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA 5 Children’s Health Dallas, Dallas, TX, USA 6 Division of Pediatric Otolaryngology, Head & Neck Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

PATHOPHYSIOLOGY AND RISK FACTORS 1. Persistent obstructive sleep apnea (OSA) is defined as sleep apnea after tonsillectomy and adenoidectomy (T&A) 2. Polysomnography (PSG)-based OSA resolution rates range from 15 to 75% depending on the presence of comorbidities a. Children with the following clinical characteristics and conditions are at higher risk for persistent OSA i. Black race in the United States ii. Age < 2 years iii. Teenagers iv. Obesity v. Down syndrome vi. Craniofacial syndromes

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Carol Li, Yann-Fuu Kou and Stacey Ishman vii. viii. ix. x.

Neuromuscular disorders Severe baseline OSA (apnea-hypopnea index (AHI)>24 events/hour) Sickle Cell Disease Mucopolysaccharidoses

EVALUATION 1. History and physical exam should focus on sleep-related symptoms including: a. Snoring frequency b. Gasping or pauses in breathing c. Daytime sleepiness d. Daytime hyperactivity e. Secondary nocturnal enuresis 2. Quality of life assessments should also be carried out including an assessment of sleepiness (often with the modified Epworth Sleepiness Scale) and sleep specific quality of life (OSA-18 or the Pediatric Sleep Questionnaire (PSQ) are commonly used) a. Bergeron et al. also found that persistent OSA severity is significantly associated with reduced family impact scores (Family Impact Questionnaire) 3. Patients at high risk for persistent OSA or with persistent or recurrent symptoms should undergo PSG after T&A 4. Further evaluation should focus on identification of specific sites of obstruction to guide further treatment 5. Drug-induced sleep endoscopy (DISE) a. Flexible fiberoptic examination of the upper airway that allows for visualization of sites of obstruction and characterization of severity of obstruction at different sites b. Indications i. Children with OSA and small tonsils ii. Children with persistent OSA following T&A iii. Children at high risk of persistent OSA (as listed above) at the time of T&A c. Anesthesia i. Need to balance adequate sedation with maintaining spontaneous ventilation ii. Try to simulate natural sleep-state iii. Multiple anesthetic regimens exist, it is important to communicate and collaborate with anesthesia to create institutional protocol iv. Common agents used:  Dexmedetomidine  Ketamine  Propofol d. Sites of obstruction typically described: i. Nasal: inferior turbinates, septum

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ii.

Nasopharynx: adenoids, velum (assess closure pattern), palate (assess orientation) iii. Oropharynx: palatine tonsils, lateral wall collapse, tongue base, lingual tonsils iv. Larynx: epiglottis, arytenoids, vocal cords e. For adults, the VOTE system is a validated, widely used DISE scoring system to identify and quantify level of obstruction i. Velum ii. Oropharynx/lateral walls iii. Tongue base iv. Epiglottis f. For children, multiple scoring systems exist and are under investigation i. Compared to adult classification schemes, these typically incorporate obstruction at the level of the nasopharynx and supraglottis (Table 1) g. Multi-level obstruction is common h. Small studies have shown improvement in the obstructive apnea-hypopnea index (oAHI) and OSA severity after DISE-directed surgery i. He et al. found significant improvements in mean oAHI and oxygen saturation nadir. Children with lower oAHI were more likely to have success. 6. Cine Magnetic Resonance Imaging (MRI) a. High-resolution dynamic MRI is useful to identify sites of upper airway obstruction b. Like DISE, it is performed during a drug-induced sleep-like state i. It can be coordinated with DISE under the same anesthetic encounter Table 1. Pediatric DISE classification systems

Nasal airway Nasopharynx Adenoids Velum Oropharynx Tongue Base Epiglottis Supraglottis Lingual Tonsils Larynx Hypopharynx Airway intervention required for support

VOTE

SERS + +

+ + + +

+ + + + + +

Chan + + + + + +

Boudewyns

Fishman + +

+ + + +

+ +

+ +

+

+

Bachar + +

+

+ + +

A “+” signifies that the anatomic site or maneuver is evaluated by the scoring system.

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Provides complementary information when used together with DISE i. Allows for improved differentiation between tongue base and lingual tonsil tissue as it can an qualify the depth and volume of lingual tonsil tissue ii. Better for evaluating primary and secondary sites of obstruction when assessing multi-level obstruction which is particularly common in children with Down syndrome and neurologic issues

NON-SURGICAL TREATMENT 1. A multi-disciplinary approach to treatment is ideal. This may include the following providers: a. Sleep medicine (often pulmonary or neurology or otolaryngology) b. Pulmonary medicine c. Otolaryngology d. Plastics/Craniofacial e. Nutrition/Endocrine f. Dental medicine/Oral surgery g. Genetics/Developmental Pediatrics 2. Shared decision making is important as there are often multiple options for each child which may include: a. Observation b. Lifestyle modifications c. Pharmacologic agents (refer to chapter 35 for the utility of anti-inflammatory medications in the primary treatment of OSA) i. Anti-inflammatory medications are also non-surgical options in the treatment of persistent OSA after T&A ii. There are no studies evaluating the sole use of intranasal steroids in persistent OSA after T&A  Studies that use intranasal steroids as an alternative, nonsurgical treatment for mild pediatric OSA show a beneficial effect  In a randomized, double-blind, crossover trial of intranasal budesonide or placebo for 6 weeks followed by an additional 6-week treatment in the alternative treatment, children in the treatment group exhibited a decrease in AHI from 3.7 to 1.3 iii. A 2006 study showed that combined therapy with montelukast and intranasal budesonide in patients with mild OSA following T&A resulted in improvements in AHI (3.9 to 0.3), and the oxygen saturation (SpO2) nadir (87.3% to 92.5%) compared to a control group of patients who received no therapy iv. A 2016 randomized double-blind controlled trial in children between 2-10 years old with OSA on PSG who had not undergone previous T&A and were treated with either oral montelukast or placebo for 16

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vi.

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weeks showed a decrease in the AHI from 9.2 to 4.2 in the treatment group but no improvement in the control group A 2017 study of 58 children with persistent, mild OSA in which 29 patients received montelukast for a 12-week period demonstrated a significant improvement in AHI, nadir SpO2, and PSQ scores in the treatment group These studies and the guidelines from the American Academy of Pediatrics on the management of childhood OSA syndrome support the use of anti-inflammatory medications in persistent OSA following T&A, particularly in patients with an AHI between 1 and 5 A 2008 systematic review of both montelukast and intranasal steroids concluded that combination treatment and montelukast alone are both beneficial for mild pediatric OSA

SURGICAL TREATMENT 1. Nasal Surgery a. Nasal surgery is not typically performed with curative intent i. Adult studies show it can improve patient tolerance of and compliance with positive airway pressure therapy and may result in lower therapeutic levels of positive airway pressure b. Topical nasal corticosteroids should be tried prior to considering nasal surgery (unless contraindicated) c. Inferior turbinate reduction i. Addressing turbinate hypertrophy can improve OSA quality of life (QoL) ii. Cheng et al. retrospectively compared patients undergoing T&A alone versus T&A with turbinate reduction; the turbinate reduction group had significantly better QoL and PSG findings iii. Multiple methods:  Turbinectomy  Radiofrequency ablation (Coblator®)  Electrocautery  Microdebrider  Submucous resection of bone d. Septoplasty i. Generally performed to improve positive pressure compliance and nasal breathing ii. Controversial to remove bony septum in children due to concerns for affecting midface growth  Some argue that left untreated, septal deviation can lead to facial asymmetry

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Nose and septum continue to grow until teenage years, thus many advocate for waiting until after nasal development is complete to avoid affecting midface growth  Nasal development is generally complete around 14 years in girls, and 15-17 years in boys  Studies regarding optimal timing in younger children are lacking  Surgery addressing the cartilaginous septum alone may be performed in younger children 2. Revision adenoidectomy a. Meta-analysis showed an overall 2% revision rate i. 26% revision rate in children with known OSA b. No significant difference with different surgical techniques c. Small studies of DISE findings in patients with persistent OSA report adenoid regrowth rates between 35 and 45% 3. Palate surgery a. The palate is a common site of obstruction and frequently contributes to audible snoring b. Traditionally, uvulopalatopharyngoplasty (UPPP) was the primary procedure for addressing palatal collapse i. UPPP can be performed in conjunction with T&A or when T&A has been performed previously ii. UPPP goal is to shorten the palate to decrease the amount of anteriorposterior collapse and typically includes:  Removal of palatine tonsils  Removal of the some or all of the uvula and a small wedge of palatal mucosa, leaving excess nasal mucosa intact  The tonsillar pillars may be sutured closed iii. Recently, UPPP has fallen out of favor for adults and children, given its complications and low cure rate (40% in unselected patients) iv. Friedman’s staging system has been effective in improving resolution rates to 59% v. DISE has identified that many patients also have lateral pharyngeal wall collapse vi. This has contributed to the increased popularity of expansion sphincter palatoplasty (ESP) c. ESP also referred to expansion pharyngoplasty involves palatal rearrangement and suspension of the palatopharyngeus muscle from the soft palate or lateral wall structures including the lateral raphe and retromolar trigone i. The goal of ESP is to decrease lateral wall collapse ii. Most published literature regarding this is in adults iii. Ulualp compared 25 children with severe OSA who underwent ESP with T&A with 25 AHI-matched children who had T&A alone

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The mean post-operative AHI was lower in the ESP vs T&A group (2.4 vs 6.2, p < .001) iv. Technique used in the paper:  After T&A, the underlying palatopharyngeus muscle was transected horizontally as inferiorly as possible in a full thickness manner  A mucosal incision was made antero-laterally on the palate near the level of the hamulus  A tunnel was created and the suture was placed through the inferior edge of the muscle flap with the needle passing through the incision  The previously isolated palatopharyngeal muscle was then pulled into the tunnel and sutured to the retromolar trigone or around the hamulus laterally  The anterior and posterior tonsillar pillars were sutured together. d. Modifications to the ESP procedure are evolving and include: i. Muscle is often not divided at all or it can be divided between the upper and mid third rather than inferiorly ii. Deep fibers are left attached to the pharyngeal constrictor muscles rather than making a full-thickness cut iii. A tunnel is made bluntly antero-laterally into the soft palate aimed towards the Hamulus,retromolar trigone or ptergomandibular raphe without a mucosal incision iv. Anchoring of the palatopharyngeus to the lateral tissues (such as the retromolar trigone or ptergomandibular raphe) instead of to the hamulus v. No closure of the pillars e. Barbed Anterior Pharyngoplasty i. Minimally invasive technique utilizing barbed knotless bidirectional reabsorbable sutures ii. Central soft palate mucosal flap is dissected and removed to reveal muscular surface iii. Suture is placed in the soft palate adjacent to pterygoid hamulus and exiting the area of the mucosal removal and several passes are made to tighten palatal musculature  The submucosal plane is closed in a similar fashion to approximate wound edges. The soft palate is further stabilized with another barbed suture passed between the posterior nasal spine, edge of soft palate, hamulus region, the posterior pillar, mandibular raphe, and back to the posterior pillar. iv. No need to tie off the suture v. No pediatric trials published but small studies in adults show a reduction in snoring (Snoring Visual Analogic Scale reduced from 9.2 to 2.9) as well as a decrease in AHI (8.9 to 3.8)

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Risks of palate surgery (lower with barbed suture technique) i. Pain, dehydration ii. Velopharyngeal insufficiency iii. Nasopharyngeal stenosis 4. Tongue base surgery a. The tongue base is the most commonly identified site of obstruction in persistent OSA following T&A i. 35-85% of cases b. Macroglossia i. Enlargement of the tongue – often relative macroglossia in patients with Down syndrome (i.e., normal sized tongue with a small oropharynx)  Other anatomic anomalies include absence of the median sulcus and fatty infiltration of the tongue ii. One study showed 74% of patients with Down syndrome with persistent OSA had macroglossia, 60% exhibited fatty infiltration of the tongue on cine MRI, 55% had absent median sulcus c. Glossoptosis i. Posterior displacement of the tongue into the pharynx ii. Yellon grading system  Grade 0 – normal airway  Grade 1 – prolapse of epiglottis against posterior pharyngeal wall, normal position of base of tongue  Grade 2 – prolapse of epiglottis and base of tongue with only tip of epiglottis visible and obliteration of vallecula  Grade 3 – complete prolapse of tongue against posterior pharyngeal wall with no portion of epiglottis visible d. Lingual tonsil hypertrophy i. Hypertrophy of the lingual tonsils may cause retroglossal obstruction ii. Most commonly seen in children with Down syndrome or obesity iii. Size can be overestimated on DISE compared to MRI (e.g., in setting of prominent base of tongue with thin layer of overlying lingual tonsil)) iv. Friedman lingual tonsil scale  0 = complete absence of lymphoid tissue  1 = lymphoid tissue scattered over tongue base  2 = lymphoid tissue covering entirety of tongue base with limited vertical thickness  3 = significantly raised lymphoid tissue covering entire tongue base, approx. 5-10 mm in thickness  4 = lymphoid tissue rising above tip of epiglottis, ≥ 1 cm thickness e. Lingual tonsillectomy i. Most common second-line surgery for pediatric OSA

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Transoral procedure during which the tongue is retracted anteriorly and lingual tonsil is removed to clear the vallecular space iii. Different instruments available for tissue removal  Radiofrequency ablation  Suction cautery  Microdebrider iv. May be accessed with a laryngoscope, or with a bite block and a sinus scope for visualization v. Overall success rate (AHI < 5) is 52% vi. Similar adverse postoperative event rates (return to the emergency room, bleed rates, phone calls after surgery) as T&A f. Posterior midline glossectomy i. Effective for glossoptosis, in particular in patients with relative macroglossia ii. Often performed in combination with lingual tonsillectomy iii. Transoral procedure during which posterior tongue tissue is removed primarily via an open approach, often using radiofrequency ablation  Submucosal lingual excision (SMILE) reported in cadaver studies, risk of injury to the lingual artery without direct access to stop bleeding iv. To avoid lingual artery injury, care should be taken to remain within 1.5 cm of the midline posterior to the foramen cecum and within 1 cm of the midline anterior to the foramen cecum v. Ultrasound can be used to map the course of the lingual artery vi. Outcomes in the pediatric population are limited vii. A 2013 adult study of 50 patients showed an overall success rate (AHI < 20 and decrease of greater than 50%) of 56% viii. Ulualp in 2019 reported that in 10 children who underwent both lingual tonsillectomy and tongue base reduction, there was both subjective improvement in OSA symptoms and median postoperative obstructive AHI decreased from 26.3 to 5.3 g. Tongue base suspension i. Heavy suture is passed through the tongue base and secured to a titanium screw in the genial tubercle of the mandible ii. A 2010 study reported an overall success rate of 61% in 31 patients with tongue base suspension and concurrent radiofrequency ablation; 58% success rate in patients with Down syndrome iii. A 2013 series of 7 children with cerebral palsy and moderate to severe OSA benefited from combined T&A, UPPP, and tongue base suspension with a decrease in mean AHI from 27.2 to 10.7 events/hour

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Figure 1. Epiglottis and Base-of-Tongue Prolapse Grading Scale. A: Grade 0, normal airway. B: Grade 1, epiglottic prolapse against the posterior pharyngeal wall with normal position of the tongue base. C: Grade 2, prolapse of the epiglottis and tongue base with obliteration of the vallecula and only the tip of the epiglottis is visible. D: Grade 3, complete prolapse of the tongue base against the posterior pharyngeal wall.

Figure 2 (Continued).

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Figure 2. Lingual Tonsil Grading System. A: Grade 0, lingual tissue absent. B: Grade 1, scattered lymphoid tissue over the tongue base. C: Grade 2, lymphoid tissue covering the tongue base with limited vertical thickness. D: Grade 3, lymphoid tissue covering the tongue base with approximately 5 – 10 mm of thickness. E: Grade 3, lymphoid tissue covering the tongue base with approximately 10 or more mm of thickness, rising above the tip of the epiglottis.

h. Tongue-lip adhesion i. Commonly utilized for glossoptosis due to micrognathia ii. Flaps are raised along the tongue and lower lip, then sutures are placed to approximate ventral lingual musculature to the submucosal tissue of the lower lip iii. Sometimes a frenulectomy is also performed for tongue protraction iv. Small case series in children with micrognathia demonstrate resolution rates ranging from 38% to 50% v. A 2017 meta-analysis included seven studies with 90 patients and showed improvement in AHI severity from 30.8 ± 22.3 to 15.4 ± 18.9 events per hour vi. A 2018 study of children with Robin sequence and severe OSA showed an improvement in polysomnography parameters, including AHI, oxygen saturation, hypercapnia, and bradycardia, for 29 out of 37 patients. i. Hyoid suspension i. Considered in patients with worsening glossoptosis seen when moving from the upright to supine position during flexible fiberoptic endoscopy in clinic

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Sutures are placed from the anterior hyoid bone to the thyroid cartilage or lower anterior mandible to elevate and retract the hyoid bone anteriorly iii. No published literature in children j. Genioglossus advancement i. The genioglossus muscle and genial tubercle of the mandible are advanced anteriorly through a rectangular window osteotomy ii. Should only be considered in the older pediatric population with welldeveloped mandibles and permanent teeth iii. No published literature in children 5. Laryngeal surgery a. Epiglottopexy i. Epiglottic prolapse can be seen in the setting of glossoptosis or laryngomalacia versus independent movement of the epiglottis ii. The lingual surface of the epiglottis, vallecula, and adjacent base of tongue is de-mucosalized using coblation, cautery, or CO2 laser iii. Suture may be used to anchor the epiglottis to the tongue base iv. Alternatively, secondary healing can result in fibrosis that retracts the epiglottis toward the tongue base v. A 2020 study demonstrated a surgical success rate of 53.6% (AHI < 5) in children undergoing epiglottopexy with and without division of the aryepiglottic folds. AHI decreased from a preoperative value of 5.5 to 2.6 overall with a lower mean postoperative AHI (1.5) in the subgroup undergoing epiglottopexy alone b. Supraglottoplasty i. In some patients with persistent OSA after T&A, supraglottic tissue can collapse and cause obstruction to airflow at all times or in some patients, only during sleep (late onset laryngomalacia or sleepdependent laryngomalacia) ii. Symptoms may include stridor at night or a history of laryngomalacia as an infant iii. Sleep dependent laryngomalacia can present later, 2 to 18 years of age, compared to congenital laryngomalacia iv. Supraglottoplasty involves trimming excess tissue to improve the airway and can include multiple techniques using cold steel or CO2 laser  Unilateral aryepiglottic fold division  Bilateral aryepiglottic fold division  Bilateral aryepiglottic fold division with unilateral removal of redundant arytenoid tissue  Bilateral aryepiglottic fold division with bilateral removal of redundant arytenoid tissue  Trimming the epiglottis may also be considered in select patients where the epiglottis itself is collapsing  May be included with epiglottopexy

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A 2016 meta-analysis included 64 patients with sleep dependent laryngomalacia and 74 patients with congenital laryngomalacia  Both groups exhibited improved AHI and O2 saturation with supraglottoplasty but the majority did not achieve complete cure vi. A 2020 study evaluated the natural history of OSA in 44 patients with laryngomalacia and OSA, some of whom underwent no surgery, T&A, or supraglottoplasty  On follow-up PSG, the largest OSA improvement was in patients who underwent supraglottoplasty, but all patients improved over time vii. A 2019 study evaluated PSG outcomes in 41 patients with laryngomalacia - mean AHI decreased from 26.6 to 7.3 events/hour  Mild to moderate OSA was still present in most children after surgery, suggesting a multifactorial etiology for OSA in this population 6. Orthognathic Surgery a. Rapid maxillary expansion i. Midline palatal suture is open until about 12 years of age before fuding ii. Orthodontic procedure that uses an appliance with an expansion screw to widen and flatten a high-arched palate iii. Maxilla is displaced inferiorly and anteriorly, which widens the nasal vault, increases oral cavity space, and encourages normal tongue position iv. 2016 systematic review and meta-analysis of 17 studies with 314 pediatric patients with transverse maxillary deficiency and OSA demonstrated:  Improvement in AHI and O2 saturation nadir after rapid maxillary expansion in short term follow-up (< 3 years)  Sub-analysis in 46 patients with previous T&A showed a decrease in AHI from 4.0 ± 4.0/hour to 0.6 ± 0.4/hour (85% reduction) v. Long-term (12-year) follow-up in 23 patients with maxillary narrowing and absence of adenotonsillar hypertrophy showed stable, normal PSG findings b. Mandibular advancement i. Mandibular distraction osteogenesis (MDO)  Used in neonates and infants with upper airway obstruction secondary to micrognathia  Commonly performed in patients with Pierre Robin sequence (PRS)  Primary MDO was found to be successful in preventing tracheostomy in 95% of cases

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Syndromic patients have a higher failure rate compared to isolated PRS  Causes of failure include comorbid lower airway obstruction, cental apnea, neurological abnormalities, or cardiovascular disorders ii. A 2018 systematic review included 37 studies and 376 patients and showed a surgical success of 73.4% as defined by AHI and 100% as defined by respiratory disturbance index (RDI)  AHI surgical cure was seen in 25.5% of patients and RDI surgical cure was seen in 37.5% of patients iii. No literature is available on the use of mandibular advancement in patients with persistent OSA iv. Although the benefit of maxillomandibular advancement for OSA has been well-demonstrated in the adult population, optimal timing for the procedure and outcomes are unknown in children  Ideally hold off until growth is completed or understand that multiple MDO procedures may be neccessary 7. Hypoglossal Nerve Stimulation a. An efficacy and safety trial of Hypoglossal Nerve Stimulation (HGNS) in 6 adolescents with Down syndrome showed that the therapy is tolerated well and effective with a significant decrease in the AHI of 56-85% b. A 2019 study of 20 children with DS and persistent severe OSA who underwent HGNS implantation showed an 85% reduction in AHI (Median AHI decreased from 24.1 to 3.0) and a median nightly use of 9.2 hours i. There was also an improvement in quality of life as measured by the OSA-18 questionnaire. 8. Tracheostomy a. Definitive treatment for persistent OSA b. Adult literature supports good outcomes but pediatric data is limited c. A 2017 study described outcomes in 29 children with severe OSA who underwent tracheostomy primarily for the treatment of OSA i. A majority of this study group had a craniofacial abnormality or serious neuromuscular comorbidity ii. Most remained tracheostomy-dependent past 2 years iii. Obesity was not a contributing factor in pediatric OSA patients requiring tracheostomy in this study, which is different than in adult studies

KEY CLINICAL POINTS 1. Persistent OSA following T&A occurs with higher prevalence in pediatric patients with obesity, Down syndrome, craniofacial syndromes, neuromuscular disorders, mucopolysaccharidoses, sickle cell disease, severe baseline OSA, age less than 2 years, and age over 12 years.

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2. In addition to a thorough history and physical examination, clinicians should consider the use of drug-induced sleep endoscopy and/or cine MRI to identify specific sites of obstruction and potential targets for surgery. 3. The management of persistent OSA should include a multi-disciplinary approach with shared decision making. 4. Non-surgical treatments for persistent OSA include observation, lifestyle modifications, and pharmacologic agents, such as leukotriene inhibitors alone or in combination with intranasal steroids. 5. Multiple surgical procedures exist to address different levels of obstruction in persistent OSA. Outcomes in the pediatric population are still under investigation and planned surgeries may be staged in order to prevent excessive scarring and stenosis of the airway.

QUESTIONS 1. For which of the following patients would drug-induced sleep endoscopy be recommended? a. 4 year old with an AHI of 6 events/hour and 3+ tonsils b. 12 year old with recurrent tonsillitis, mild daytime somnolence, and 2+ tonsils c. 10 year old with snoring, witnessed apneas, daytime somnolence, and 3+ tonsils. d. 13 year old girl with history of T&A and persistent obstructive sleep apnea 2. Which of the following is the most common site of obstruction identified on sleep endoscopy for children with persistent obstructive sleep apnea? a. Palate b. Tongue base c. Lateral oropharyngeal wall d. Larynx 3. Which of the following is helpful for avoiding the lingual artery during a posterior midline glossectomy? a. Stay within 1.5 cm of the midline posterior to foramen cecum b. Preoperative cross-sectional imaging c. Stay within 2 cm of the midline anterior to the foramen cecum d. Submucosal technique 4. What is the correct Friedman lingual tonsil classification for a patient who exhibits raised lymphoid tissue covering the entire tongue base, approximately 5 mm in thickness? a. Grade 1 b. Grade 2 c. Grade 3 d. Grade 4

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Carol Li, Yann-Fuu Kou and Stacey Ishman 5. What disorder is associated with a higher prevalence of macroglossia on evaluation for persistent OSA? a. Pierre Robin Sequence b. Down syndrome c. Obesity d. Achondroplasia

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apnea with inferior turbinate hypertrophy. Laryngoscope. 2012;122(12):2850-2854. doi: 10.1002/lary.23590. Cingi C, Muluk NB, Ulusoy S, Lopatin A, Şahin E, Passali D, Bellussi L, Atilla H, Hanci D, Altıntoprak N, Rusetski Y, Sarafoleanu C, Mladina R, Kalogjera L, Manea C. Septoplasty in children. Am J Rhinol Allergy. 2016;30(2):e42-e47. doi: 10.2500/ajra.2016.30.4289. Diercks GR, Wentland C, Keamy D, Kinane TB, Skotko B, de Guzman V, Grealish E, Dobrowski J, Soose R, Hartnick CJ. Hypoglossal nerve stimulation in adolescents with down syndrome and obstructive sleep apnea. JAMA Otolaryngol - Head Neck Surg. 2018;144(1):37-42. doi:10.1001/jamaoto.2017.1871 Donnelly LF, Shott SR, Larose CR, Chini BA, Amin RS. Causes of Persistent Obstructive Sleep Apnea Despite Previous Tonsillectomy and Adenoidectomy in Children with Down Syndrome as Depicted on Static and Dynamic Cine MRI. Vol 183.; 2004. Accessed November 5, 2020. www.ajronline.org. Dorrity J, Wirtz N, Froymovich O, Hamlar D. Genioglossal Advancement, Hyoid Suspension, Tongue Base Radiofrequency, and Endoscopic Partial Midline Glossectomy for Obstructive Sleep Apnea. Otolaryngol Clin North Am. 2016;49(6):1399-1414. doi: 10.1016/j.otc.2016.07.008. Esteller E, Villatoro JC, Agüero A, Matiñó E, Lopez R, Aristimuño A, Nuñez V, Díaz-Herrera MA. Outcome of drug-induced sleep endoscopy-directed surgery for persistent obstructive sleep apnea after adenotonsillar surgery. Int J Pediatr Otorhinolaryngol. 2019;120:118122. doi: 10.1016/j.ijporl.2019.02.004. Fishman G, Zemel M, DeRowe A, Sadot E, Sivan Y, Koltai PJ. Fiber-optic sleep endoscopy in children with persistent obstructive sleep apnea: Inter-observer correlation and comparison with awake endoscopy. Int J Pediatr Otorhinolaryngol. Published online 2013. doi: 10.1016/j.ijporl.2013.02.002. Fricke BL, Donnelly LF, Shott SR, Kalra M, Poe SA, Chini BA, Amin RS. Comparison of lingual tonsil size as depicted on MR imaging between children with obstructive sleep apnea despite previous tonsillectomy and adenoidectomy and normal controls. Pediatr Radiol. 2006;36(6):518-523. doi: 10.1007/s00247-006-0149-7. Friedman M, Ibrahim H, Joseph NJ. Staging of obstructive sleep apnea/hypopnea syndrome: a guide to appropriate treatment. Laryngoscope. 2004;114(3):454-459. doi: 10.1097/00005537-200403000-00013. Friedman M, Yalamanchali S, Gorelick G, Joseph NJ, Hwang MS. A standardized lingual tonsil grading system: Interexaminer agreement. In: Otolaryngology - Head and Neck Surgery (United States). Vol 152. SAGE Publications Inc.; 2015:667-672. doi: 10.1177/0194599815568970. Guimaraes CV, Kalra M, Donnelly LF, Shott SR, Fitz K, Singla S, Amin RS. The frequency of lingual tonsil enlargement in obese children. Am J Roentgenol. 2008;190(4):973-975. doi: 10.2214/AJR.07.3020. He S, Peddireddy NS, Smith DF, Duggins AL, Heubi C, Shott SR, Ishman SL. Outcomes of Drug-Induced Sleep Endoscopy-Directed Surgery for Pediatric Obstructive Sleep Apnea. Otolaryngol Head Neck Surg. 2018;158(3):559-565. doi: 10.1177/0194599817740332. Ishman SL, Chang KW, Kennedy AA. Techniques for evaluation and management of tonguebase obstruction in pediatric obstructive sleep apnea. Curr Opin Otolaryngol Head Neck Surg. 2018;26(6):409-416. doi: 10.1097/MOO.0000000000000489.

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Justicz N, Choi S. When Should Pediatric Septoplasty Be Performed for Nasal Airway Obstruction?. Laryngoscope. 2019;129(7):1489-1490. doi: 10.1002/lary.27602. Kang KT, Koltai PJ, Lee CH, Lin MT, Hsu WC. Lingual tonsillectomy for treatment of pediatric obstructive sleep apnea: A meta-analysis. JAMA Otolaryngol - Head Neck Surg. 2017;143(6):561-568. doi: 10.1001/jamaoto.2016.4274. Kezirian EJ, Hohenhorst W, De Vries N. Drug-induced sleep endoscopy: The VOTE classification. Eur Arch Oto-Rhino-Laryngology. 2011 Aug;268(8):1233-1236. doi: 10.1007/s00405-011-1633-8. Kheirandish L, Goldbart AD, Gozal D. Intranasal steroids and oral leukotriene modifier therapy in residual sleep-disordered breathing after tonsillectomy and adenoidectomy in children. Pediatrics. 2006;117(1):e61-e66. doi: 10.1542/peds.2005-0795. Kheirandish-Gozal L, Bandla HPR, Gozal D. Montelukast for Children with Obstructive Sleep Apnea: Results of a Double-Blind, Randomized, Placebo-Controlled Trial. Ann Am Thorac Soc. 2016;13(10):1736-1741. doi: 10.1513/AnnalsATS.201606-432OC. Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment for children with mild obstructive sleep apnea syndrome. Pediatrics. 2008;122(1). doi: 10.1542/peds.2007-3398. Lam DJ, Weaver EM, Macarthur CJ, Milczuk HA, O'Neill E, Smith TL, Nguyen T, Shea SA. Assessment of pediatric obstructive sleep apnea using a drug-induced sleep endoscopy rating scale. Laryngoscope. Published online 2016. doi:10.1002/lary.25842 Lee CH, Hsu WC, Ko JY, Yeh TH, Lin MT, Kang KT. Revision adenoidectomy in children: a meta-analysis. Rhinology. 2019;57(6):411-419. doi: 10.4193/Rhin19.101. Li KK, Riley RW, Powell NB, Troell RJ. Obstructive sleep apnea surgery: Genioglossus advancement revisited. J Oral Maxillofac Surg. 2001;59(10):1181-1184. doi: 10.1053/joms.2001.27111. Manickam PV, Shott SR, Boss EF, Cohen AP, Meinzen-Derr JK, Amin RS, Ishman SL. Systematic review of site of obstruction identification and non-CPAP treatment options for children with persistent pediatric obstructive sleep apnea. Laryngoscope. 2016;126(2):491500. doi:10.1002/lary.25459. Marcus CL, Brooks LJ, Draper KA, Gozal D, Halbower AC, Jones J, Schechter MS, Sheldon SH, Spruyt K, Ward SD, Lehmann C, Shiffman RN; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012 Sep;130(3):576-84. doi: 10.1542/peds.2012-1671. Noller MW, Guilleminault C, Gouveia CJ, Mack D, Neighbors CL, Zaghi S, Camacho M. Mandibular advancement for pediatric obstructive sleep apnea: A systematic review and meta-analysis. J Craniomaxillofac Surg. 2018 Aug;46(8):1296-1302. doi: 10.1016/j.jcms.2018.04.027. Oomen KPQ, Modi VK. Epiglottopexy with and without lingual tonsillectomy. Laryngoscope. 2014;124(4):1019-1022. doi: 10.1002/lary.24279. Paramaesvaran S, Ahmadzada S, Eslick GD. Incidence and potential risk factors for adenoid regrowth and revision adenoidectomy: A meta-analysis. Int J Pediatr Otorhinolaryngol. 2020;137:110220. doi: 10.1016/j.ijporl.2020.110220. Propst EJ, Amin R, Talwar N, Zaman M, Zweerink A, Blaser S, Zaarour C, Luginbuehl I, Karsli C, Aziza A, Forrest C, Drake J, Narang I. Midline posterior glossectomy and lingual tonsillectomy in obese and nonobese children with down syndrome: Biomarkers for success. Laryngoscope. 2017;127(3):757-763. doi:10.1002/lary.26104.

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Resnick CM, Dentino K, Katz E, Mulliken JB, Padwa BL. Effectiveness of tongue-lip adhesion for obstructive sleep apnea in infants with robin sequence measured by polysomnography. Cleft Palate-Craniofacial J. 2016;53(5):584-588. doi: 10.1597/15-058. Rivero A, Durr M. Lingual Tonsillectomy for Pediatric Persistent Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Otolaryngol - Head Neck Surg (United States). 2017;157(6):940-947. doi: 10.1177/0194599817725708. Rizzi CJ, Amin JD, Isaiah A, Valdez TA, Jeyakumar A, Smart SE, Pereira KD. Tracheostomy for Severe Pediatric Obstructive Sleep Apnea: Indications and Outcomes. Otolaryngol Head Neck Surg (United States). 2017;157(2):309-313. doi: 10.1177/0194599817702369. Salamanca F, Costantini F, Mantovani M, Bianchi A, Amaina T, Colombo E, Zibordi F. Barbed anterior pharyngoplasty: an evolution of anterior palatoplasty. Acta Otorhinolaryngol Ital. 2014 Dec;34(6):434-8. Sedaghat AR, Anderson ICW, McGinley BM, Rossberg MI, Redett RJ, Ishman SL. Characterization of obstructive sleep apnea before and after tongue-lip adhesion in children with micrognathia. Cleft Palate-Craniofacial J. 2012;49(1):21-26. doi: 10.1597/10-240/. Shott SR, Donnelly LF. Cine magnetic resonance imaging: Evaluation of persistent airway obstruction after tonsil and adenoidectomy in children with down syndrome. Laryngoscope. 2004;114(10):1724-1729. doi: 10.1097/00005537-200410000-00009. Suh GD. Evaluation of open midline glossectomy in the multilevel surgical management of obstructive sleep apnea syndrome. Otolaryngol - Head Neck Surg (United States). 2013;148(1):166-171. doi: 10.1177/0194599812464331. Ulualp S. Outcomes of tongue base reduction and lingual tonsillectomy for residual pediatric obstructive sleep apnea after adenotonsillectomy. Int Arch Otorhinolaryngol. 2019;23(4):415-421. doi: 10.1055/s-0039-1685156. Ulualp SO. Modified expansion sphincter pharyngoplasty for treatment of children with obstructive sleep apnea. JAMA Otolaryngol Head Neck Surg. 2014;140(9):817-822. doi: 10.1001/jamaoto.2014.1329. Wilcox LJ, Bergeron M, Reghunathan S, Ishman SL. An updated review of pediatric druginduced sleep endoscopy. Laryngoscope Investig Otolaryngol. 2017;2(6):423-431. doi: 10.1002/lio2.118. Wootten CT, Chinnadurai S, Goudy SL. Beyond adenotonsillectomy: Outcomes of sleep endoscopy-directed treatments in pediatric obstructive sleep apnea. Int J Pediatr Otorhinolaryngol. 2014;78(7):1158-1162. doi: 10.1016/j.ijporl.2014.04.041. Wootten CT, Shott SR. Evolving therapies to treat retroglossal and base-of-tongue obstruction in pediatric obstructive sleep apnea. Arch Otolaryngol - Head Neck Surg. 2010;136(10):983-987. doi: 10.1001/archoto.2010.178. Zalzal HG, Carr M, Nanda N, Coutras S. Drug Induced Sleep Endoscopy Identification of Adenoid Regrowth in Pediatric Obstructive Sleep Apnea. Int J Otolaryngol. 2018;2018:7920907. Published 2018 Apr 26. doi: 10.1155/2018/7920907.

PART V

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 37

HOW TO SET UP A SLEEP LABORATORY Hannah N. Kuhar1, MD, Siobhan Kuhar2, MD, PhD and Gavin Setzen2, MD 1

Department of Otolaryngology-Head and Neck Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA 2 Albany ENT and Allergy Services, Albany, New York, USA

INTRODUCTION 1. Sleep physicians and surgeons are uniquely positioned to evaluate anatomic causes of obstruction, to facilitate additional testing, and to counsel patients regarding options for management of obstructive sleep apnea (OSA) 2. In this chapter we discuss the delivery of services to evaluate and treat OSA, including establishing a sleep apnea testing and treatment center within a sleep practice

SLEEP APNEA TESTING MODELS 1. Sleep medicine practices may provide in-lab attended Polysomnography (PSG) testing, portable monitoring with Home Sleep Apnea Testing (HSAT) or a combination of these options a. There are critical requirements for successful models of evaluation and care delivery 2. First, it is necessary to understand key classifications of testing options and settings

SLEEP FACILITY VS. INDEPENDENT SLEEP PRACTICE 1. The American Academy of Sleep Medicine (AASM) provides accreditation for two different types of sleep disorders testing and treatment centers, a “Sleep Facility” or an “Independent Sleep Practice”

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Hannah N. Kuhar, Siobhan Kuhar and Gavin Setzen 2. “Independent Sleep Practices” focus on the diagnosis and treatment of sleep apnea with HSAT and Auto-adjusting Positive Airway Pressure (APAP) a. These practices refer patients to a “Sleep Facility” for PSG when needed 3. “Sleep Facilities” are comprehensive centers addressing diagnosis and management of the full spectrum of sleep disorders with both HSAT and in-lab attended PSG

ATTENDED POLYSOMNOGRAPHY VS. HOME SLEEP APNEA TESTING 1. PSG is the “gold standard” of testing for OSA a. Typically performed in a Sleep Facility (aka in-lab) with direct monitoring by a sleep technician b. Data is then reviewed and scored by a board-certified sleep physician c. PSG involves the simultaneous recording of multiple physiologic signals during sleep d. In-lab attended PSG are classified as Type 1 testing devices (Table 1) i. Diagnostic indications include:  Central Sleep Apnea  Periodic Limb Movement Disorder  REM Sleep Behavior Disorder  Nocturnal Seizure Disorder  Parasomnias, Narcolepsy  Idiopathic Hypersomnia e. In-lab attended PSG is most often used in the diagnosis and treatment of patients who are not appropriate for HSAT i. AASM recommends attended, in-facility testing for patients with significant cardiopulmonary disease, respiratory muscle weakness due to a neuromuscular condition, awake hypoventilation or high risk of sleep related hypoventilation, chronic opioid medication use, history of stroke or severe insomnia as well as for children ii. PSG is often used when HSAT has failed to diagnose sleep apnea in patients with a high probability for the disorder f. In-lab PSG can also be used for attended titration of Continuous Positive Airway Pressure (CPAP) or Bilevel PAP (BPAP) in those patients deemed inappropriate for Automatic Positive Airways Pressure (APAP) therapy due to their co-morbid conditions or having failed attempts at APAP therapy 2. HSAT is the preferred initial testing modality by most insurers when patients have a high pretest probability for OSA a. The primary differentiating feature from PSG is that HSAT measures the number of respiratory events based on the time the device is on, not the time asleep i. HSAT may therefore underestimate sleep apnea severity b. HSAT utilizes devices solely for diagnosis of sleep apnea in patients with high risk for moderate to severe OSA

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c.

HSATs typically measure respiratory effort, oximetry, air flow, snoring and body position and are classified as Type 2, 3 or 4 devices (Table 1) d. One device (WatchPAT®️) approved by the FDA and sanctioned by the AASM uses pulse transit time, Peripheral Arterial Tone (PAT), in lieu of airflow as a surrogate measure for OSA e. HSAT devices are not designed to measure Respiratory Effort Related Arousals or hypopneas scored based on sleep arousal, thus they are not able to diagnose these forms of sleep disordered breathing despite the fact that they can lead to significant sleep disruption i. For these patients with a normal HSAT but symptoms, an in-lab PSG is recommended f. When positive for OSA, HSAT ultimately has lower direct costs and is not limited by testing capacity (number of beds) in a Sleep Facility Table 1. Types of Sleep Apnea Testing Devices Sleep Test

Description

Personnel

Type 1

Standard PSG performed in a sleep lab

Attended

Type 2 Type 3

Type 4

Comprehensive portable PSG Portable testing limited to sleep apnea Continuous recording of 1 or 2 signals or any test not fitting into the other categories

Minimum Signals Required ≥ 7 signals including: electroencephalogram (EEG), electrooculogram (EOG), chin electromyogram (EMG), electrocardiogram (ECG), airflow, respiratory effort and oxygen saturation

Unattended

Same as type 1

Attended or unattended

≥ 4 signals including: ECG or heart rate, oxygen saturation, and at least 2 channels of respiratory movement or respiratory movement and airflow

Unattended

≥1

START UP AND ACCREDITATION 1. The AASM Accreditation committee has specific requirements for a Sleep Facility or Independent Sleep Practice 2. The mandatory standards for accreditation of Sleep Disorders Centers as established by the AASM are listed in Table 2 a. A full list of AASM standards for accreditation of a sleep facility is available on the AASM Accreditation website. The cost of a new accreditation in 2020 is $4500. Most insurers require AASM accreditation for reimbursement of services. 3. Creating a time frame for constructing, equipping and staffing a state-of-the-art sleep testing and treatment center is necessary

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Hannah N. Kuhar, Siobhan Kuhar and Gavin Setzen 4. The Sleep Facility should meet the needs of the intended project in terms of location, size and furnishings with testing equipment that ensures accurate and precise diagnostic and therapeutic procedures Table 2. Mandatory Standards for Accreditation of Sleep Disorders Centers Accreditation Standards

General Standards

Facility License Medical Code of Ethics HIPAA Rules and Regulations Americans with Disabilities Act (ADA) Rules and Regulations Facility Policies and Procedures Manual Facility Quality Assurance Program Facility Safety Standards

Personnel

Facility Director (Board Certified Sleep Specialist) Board Certified Sleep Technologist Continuing Education Program

Patient Policies

Medical Records requirements Direct Referral Policy Patients’ Bill of Rights

ESTABLISHING MISSION STATEMENT AND GOALS 1. The center must develop a mission statement that reflects the vision and expectations for the center. The mission statement should focus on the type and quality of medical care in terms of diagnostic and therapeutic procedures, while acknowledging the impact of sleep disorders on patient quality of life. a. For example: “A desire to strive to provide patients with the best possible medical care to diagnose and treat possible sleep apnea (or sleep disorders for Sleep Facility) and ultimately improve the quality of patients’ lives.” b. A primary goal would typically be improving patients’ sleep quality and knowledge of their disorder while raising awareness in the community for diagnosis and treatment of sleep disorders 2. Creating Service Objectives a. Identify the diagnostic tools needed to perform and complete PSG and/or HSAT b. Identify the therapeutic tools to provide positive airway pressure therapy c. Identify materials to be used as aids for treatment and health education d. Create a clinic space and/or time for patient consultations and follow-up regarding diagnosis and therapy follow-up e. Create service aims, including a minimum of studies conducted at any given time and services available 24 hours/day, 7 days/week

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PERSONNEL 1. Necessary personnel: a. Board-Certified Sleep Specialist (MD or PhD) b. Mid-level provider (Nurse practitioner or Physician assistant) c. Registered Sleep Technologist (RST, RPSGT or RRT-SDS certified) 2. Both PSG and HSAT models require a board-certified Sleep Medicine physician or doctorate equivalent to interpret studies, provide expertise in sleep disorders diagnosis and treatment, and to obtain AASM accreditation a. A Board-Certified Sleep Specialist is required for administration and scoring of sleep studies and is most often a physician already within or hired by the practice. Their roles are to: i. Identify patients for testing ii. Diagnose sleep disorders iii. Recommend treatment strategies iv. Provide guidance/education to other medical providers b. The decision of whether to obtain board-certification in sleep medicine or hire/partner with a board-certified sleep medicine specialist will largely depend on individual preferences and availability i. Sleep medicine is a field that draws from several medical specialties including Otolaryngology, Pulmonology, Anesthesia, Neurology, Psychiatry, Family Practice and Psychology with training including as least a one-year fellowship program resulting in board eligibility ii. Board-certification is obtained through the American Board of Medical Specialities (ABMS) 3. A Sleep Facility or Independent Sleep Practice requires identification of a manager a. The practice manager should have experience in sleep disorder testing and treatment b. Prior experience in management and maintenance of equipment is ideal i. Most sleep facility managers are Registered Sleep Technologists 4. A Registered Sleep Technologist is necessary for implementation of testing protocols, interpretation of data and maintenance of equipment a. Responsibilities include reviewing orders, conducting the appropriate sleep study, scoring of raw data, quality control, supply ordering, and patient education b. Additional responsibilities may include management of the sleep practice in terms of supporting recruitment, scheduling, staff educational requirements and maintenance of accreditation requirements 5. All other employees in direct contact with patients should be registered polysomnographers and/or graduates of accredited programs related to the field of sleep medicine

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SPACE REQUIREMENTS FOR A SLEEP FACILITY 1. The location should ideally be in a quiet/low traffic area, in a medical community, in a clinical setting that is accessible with visible signage 2. Sleep testing facilities typically plan for a minimum of 2-bedrooms since one sleep technologist can test a maximum of 2 adult patients a. Pediatric testing requires a 1:1 patient to technician ratio 3. The number of bedrooms is typically in multiples of 2, however, a back-up bedroom can eliminate the need to discontinue a study due to equipment failure 4. A supply space for six months of testing equipment is recommended 5. Each patient requires a testing bedroom (10x10 minimum) and a common use or en suite bathroom with shower a. Refer to AASM guidelines and complying with ADA requirements 6. Alternatively, an office/exam room space for consultation and patient exam rooms may be repurposed at night as a testing bedroom utilizing a wall-bed arrangement 7. Control/Scoring room must be easily accessible to the bedrooms 8. A waiting area with refrigerator/sink for patient use, staff lounge, and bathroom facility

EDUCATION, MARKETING AND CUSTOMER SERVICE 1. Committing to medical provider education, patient and public education is critical to the success of the center 2. Educational topics should include sleep disorder education, sleep study interpretation and sleep therapy options 3. Strategies to enhance customer service include timely and convenient contact information, scheduling, orientation/education, medical provider communication, patient communication, and regular patient surveys

SUPPLIES 1. Educational materials, including videos, workbooks, screen and projector, brochures and flyers for distribution to other medical providers, hospitals, clinics 2. Diagnostic sleep systems a. Computers, jack box, servers 3. EEG, EMG and EOG equipment for recording sleep stages, muscle activity and eye movements 4. Airflow thermistors and pressure transducers 5. Respiratory effort belts to measure chest and abdominal motion 6. Snoring microphones 7. Video monitoring, recording system and testing room intercom system 8. CPAP, BPAP, oxygen, and a variety of mask interfaces

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9. Sleep study equipment generally will come with a one full year of warranty coverage included with the system purchased, and the system company should provide training on the system to cover recording, scoring, sleep study and troubleshooting techniques a. Alternatively, lease options are available for PSG testing equipment

SET-UP COSTS 1. Patient room cost a. Furniture, bathroom, camera, speaker 2. Diagnostic sleep system (computers, jack boxes, servers and remote access) a. The average cost of purchasing a diagnostic sleep system is $24,000$50,000/bedroom 3. Home Sleep Apnea Testing Units are typically leased 4. CPAP, BPAP titration equipment and supplemental oxygen if needed 5. Additional equipment: Electrodes for EEG, EMG and EOG, Airflow thermistors, Snore microphones, Respiratory effort belts

ONGOING COSTS 1. 2. 3. 4.

Facility space costs Facility Manager, Sleep technicians, secretarial staff Maintenance contracts for equipment Durable medical equipment (DME) used in testing (masks, tubing, filters)

REIMBURSEMENT FOR ATTENDED PSG IN A SLEEP FACILITY 1. Patients with complaints related to sleep disorders are evaluated for their need for sleep testing based on a comprehensive history and physical exam (i.e., CPT 99203) including evaluation of the upper airway with fiberoptic endoscopy (i.e., CPT 31528) a. After testing, a follow-up appointment is made to review testing results and discuss treatment options (i.e., CPT 99213) b. Ongoing follow-up will be dependent on the sleep diagnosis and treatment plan 2. Reimbursement for HSAT is discussed below and is the same for a Sleep Facility or an Independent Sleep Practice a. CPT codes and 2020 payment values for in-lab attended PSG, CPAP titration and MSLT are provided in Table 3

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Hannah N. Kuhar, Siobhan Kuhar and Gavin Setzen Table 3. Relevant Current Procedural Terminology (CPT) Codes

CPT Code

Description

95805

Multiple Sleep Latency Test Global Technical Component Professional Component

95806

Sleep Study Unattended & Respiratory Effort Global Technical Component Professional Component

95807

Sleep Study Attended Global Technical Component Professional Component

95811

Polysomnography 6/> years CPAP 4/> param Global Technical Component Professional Component

99203

Evaluation and management (E/M) on initial evaluation

31575

Flexible Laryngoscopy

99213

Follow Up After Testing

COSTS OF HOME SLEEP APNEA TESTING IN THE INDEPENDENT SLEEP PRACTICE MODEL 1. Salary for a Board-Certified Sleep Specialist who is required to oversee testing administration and scoring of home sleep studies 2. Salary for a Registered Sleep Technician who is needed to set patients up for testing and are responsible for initial scoring of the data from the HSAT as well as equipment maintenance 3. Costs associated with Accreditation of the Independent Sleep Practice 4. Costs of testing equipment, staffing, scoring costs. For example: a. Average total cost of Tech time/Medical provider time/lease of unit/disposables is approximately $65.00 in 2021 5. Scoring may also be outsourced to a subcontractor who must meet AASM accreditation standards. a. The average cost/study for a scoring subcontractor is $25/study in 2021

REIMBURSEMENT FOR HSAT IN AN INDEPENDENT SLEEP PRACTICE 1. As with a Sleep Facility, patients are evaluated for their need for sleep testing based on a comprehensive history and physical exam (i.e., CPT 99203) including evaluation of the upper airway with fiberoptic endoscopy (i.e., CPT 31528)

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a.

After testing, a follow-up appointment is made to review testing results and discuss treatment options (i.e., CPT 99213) 2. The reimbursement for a HSAT based on the 2020 Medicare reimbursement schedule is $119.10 for CPT 95806 a. However, the equipment needed for the administration and scoring of HSAT is significantly less costly than that of attended PSG and is typically leased and insured against damage 3. Additionally, HSAT is not limited by the physical space required for in lab testing and the number of units leased typically will depend on the demand of the practice

PEDIATRIC SLEEP DISORDER TESTING 1. AAO-HNS recommends PSG prior to adenotonsillectomy in children with medical conditions at high risk for severe OSA (obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses) when need for surgery is uncertain and to guide decisions regarding post-operative overnight monitoring (< 3 years, severe OSA, and/or hypoventilation) 2. Currently, the AASM does not recommend HSAT for the diagnosis of OSA in children a. Although technically feasible, there is insufficient evidence to support use 3. Attended in-lab PSG is the gold standard for diagnosis as it is particularly important in children to be able to assess sleep disruption in addition to respiratory parameters 4. Pediatric PSG typically also includes measures of CO2 (end-tidal or transcutaneous) to evaluate for hypoventilation 5. Attended in-lab PSG for pediatric patients requires 1:1 sleep technician to patient ratio and a place for a parent or legal guardian to stay with the patient during the study

KEY CLINICAL POINTS 1. Evaluation and treatment of OSA is within the scope of expertise of most Otolaryngology practices 2. Designing a strategy for screening, testing and treating patients with OSA can widen the services and expertise of a practice, providing opportunities for improved patient care and creating new streams of revenue within the practice 3. Both models require a minimum infrastructure of a Board-certified sleep specialist and licensed sleep technician for testing, interpretation and treatment 4. The decision as to whether to establish a Sleep Facility that would encompass the full spectrum of testing and treating sleep disorders, versus creating an Independent Sleep Practice focused on a model of HSAT and APAP therapy, is a practice decision that will at least in part depend on the individual needs of the practice and the community served

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5. The administration of testing and PAP treatment does not provide a significant reimbursement and has relatively high overhead. This is offset, however, by the creation of a broader scope of practice, increased referrals for sleep disorders, the increased surgical volume of sleep related problems and the creation of an attractive enrichment to an Otolaryngology practice regarding an important public health problem.

QUESTIONS 1. The following are mandatory for AASM Accreditation of a Sleep Facility and an Independent Sleep Practice: a. Board-certified sleep specialist b. Licensed sleep technician c. Testing bedrooms d. all the above e. a and b only 2. The AAO-HNS academy recommends testing children for sleep apnea under these conditions: a. In-lab attended Polysomnography with CO2 monitoring b. High risk for severe OSA c. When need for adenotonsillectomy is uncertain d. To guide decisions regarding postoperative monitoring e. all the above 3. All of the following are required for Polysomnography (type 1 testing) except for which item? a. Peripheral arterial tonometry (PAT) b. Electroencephalogram (EEG) c. Electrooculogram (EOG) d. Electrocardiogram (ECG) e. Airflow f. Respiratory effort 4. According to AASM recommendations, home sleep testing is appropriate for patients with which of the following conditions? a. Significant cardiopulmonary disease b. High pretest probability of moderate to severe OSA c. Chronic opioid medication d. History of stroke e. Severe insomnia

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5. Requirements for pediatric in-laboratory polysomnography differ from adult requirements in which of the following aspects? a. Sleep technician staffing levels b. In-room bathroom facilities c. Mattress size d. Inclusion of esophageal manometry e. Study duration

REFERENCES AASM. Facility Standards for Accreditation. 2020. AASM. Independent Sleep Practice Standards for Accreditation. 2020. Abrahamyan L, Sahakyan Y, Chung S, Pechlivanoglou P, Bielecki J, Carcone S M, Rac V E, Fitzpatrick M, Krahn M. Diagnostic accuracy of level IV portable sleep monitors versus polysomnography for obstructive sleep apnea: a systematic review and meta-analysis. Sleep Breath 2018;22(3):593-611 doi: 10.1007/s11325-017-1615-1. Berry R B, Budhiraja R, Gottlieb D J, Gozal D, Iber C, Kapur V K, Marcus C L, Mehra R, Parthasarathy S, Quan S F, Redline S, Strohl K P, Davidson Ward S L, Tangredi M M; American Academy of Sleep Medicine. 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 Oct 15;8(5):597-619. doi: 10.5664/jcsm.2172. Colaco B, Herold D, Johnson M, Roellinger D, Naessens JM, Morgenthaler T I. Analyses of the Complexity of Patients Undergoing Attended Polysomnography in the Era of Home Sleep Apnea Tests. J. Clin. Sleep Med. 2018;14(4):631-39 doi: 10.5664/jcsm.7060. Collop N A, Anderson W M, Boehlecke B, Claman D, Goldberg R, Gottlieb D J, Hudgel D, Sateia M, Schwab R; Portable Monitoring Task Force of the American Academy of Sleep Medicine. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J. Clin. Sleep Med. 2007 Dec 15;3(7):737-47. Kapur V K, Auckley D H, Chowdhuri S, Kuhlmann D C, Mehra R, Ramar K, Harrod C G. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J. Clin. Sleep Med. 2017;13(3):479-504 doi: 10.5664/jcsm.6506. Kim R D, Kapur V K, Redline-Bruch J, Rueschman M, Auckley D H, Benca R M, FoldvarySchafer N R, Iber C, Zee P C, Rosen C L, Redline S, Ramsey S D. An Economic Evaluation of Home Versus Laboratory-Based Diagnosis of Obstructive Sleep Apnea. Sleep 2015;38(7):1027-37 doi: 10.5665/sleep.4804. Roland P S, Rosenfeld R M, Brooks L J, Friedman N R, Jones J, Kim T W, Kuhar S, Mitchell R B, Seidman M D, Sheldon S H, Jones S, Robertson P; American Academy of Otolaryngology—Head and Neck Surgery Foundation. Clinical practice guideline: Polysomnography for sleep-disordered breathing prior to tonsillectomy in children. Otolaryngol. Head Neck Surg. 2011 Jul;145(1 Suppl):S1-15. doi: 10.1177/01945998 11409837

In: Essential Sleep Medicine and Surgery Editors: Maria V. Suurna and Stacey L. Ishman

ISBN: 978-1-68507-220-9 © 2022 Nova Science Publishers, Inc.

Chapter 38

THE FUTURE OF SLEEP MEDICINE AND SURGERY AND A GLOSSARY OF ACRONYMS Shi Nee Tan1,5 and K. J. Lee2,3,4, MD 1

KPJ University College School of Medicine, Nilai, Negeri Sembilan, Malaysia 2 Yale University School of Medicine, New Haven, CT, USA 3 Quinnipiac University Netter School of Medicine, New Haven, CT, USA 4 Hofstra University Zucker School of Medicine, Hempstead, NY, USA 5 KPJ Rawang Specialist Hospital, Rawang, Selangor, Malaysia

Science, medicine and surgery progress and evolve constantly, as the knowledge base keeps expanding. In some subspecialties, the evolution starts at a more mature basis. Others evolve from a less clear-cut knowledge base. In September 2019 at the American Academy of Otolaryngology-Head and Neck Surgery Foundation Annual Meeting, Otosclerosis Study Group, the second author presented a video made in 1958 at the Columbia University Presbyterian Hospital Medical Center. The video shows otology giants Drs. Basek, Bellucci, Derlacki, Fowler, Jr., Goodhill, House, Rosen, Schuknecht, Shambaugh and Shea, Jr. proudly demonstrating how stapes mobilization should be done. Each otologist had a different technique and used his special mobilization surgical instrument. At that time, it was the dogma that the stapes cannot be removed, and removal would cause total hearing loss and vertiginous symptoms. Stapes mobilization courses were taught throughout the country, mainly in New York City by Dr. Samuel Rosen of Mount Sinai Medical Center [1]. Otologists travelled great distances to learn the techniques of stapes mobilization. Prior to stapes mobilization for otosclerosis was the fenestration era [2-4]. Drs. Lempert and Shambaugh pioneered fenestration and taught courses. Otologists travelled worldwide to learn the technique of fenestration. During all those times, patients were not really satisfied with the results of both fenestration and stapes mobilization. Fenestration not only did not give the desired outcome of improving hearing but had a prolonged postoperative recovery with many untoward side effects. Stapes mobilization had minimal complications but did not improve hearing in the long term. While Dr. John Shea, Jr., one of the “giants” shown in the 1958 video was experimenting with stapes mobilization, he had the vision and the audacity to go against the dogma. He simply

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removed the stapes and fabricated a prosthesis to replace the fixated otosclerotic stapes. The prosthesis was a small vein harvested from the hand and a tiny piece of polyethylene tube. It was an instant success, and hearing was restored and without any equilibrium problem. Subsequently, refinement of stapedectomy and invention of different prostheses were made [5-8]. Today stapedectomy is a straightforward procedure that can be performed in trained hands under an hour with minimal morbidity and an over 95% success rate of restoring hearing. The Editors, Dr. Suurna and Dr. Ishman, as well as the chapter contributors have produced a very comprehensive state of the art book in a succinct manner as well as incorporating practice guidelines organized by Dr. Josephine Nguyen. With the great work being achieved by many specialists treating sleep disorders and conducting research in this field, the “stapedectomy stage” for treating sleep disorders will be here in the not-too-distant future. Otosclerosis involves one anatomical part, fixation of the stapes. In sleep disorders, the culprit can be located in different anatomical sites. This gives rise to future innovations and opportunities at multiple levels. As demonstrated in this book, great strides have been and are being accomplished. There will be further different breakthroughs from the ranks of our experts to solve the problems of sleep disorders in a streamlined manner with less morbidity and higher success rate. The otosclerosis metaphor may resonate more with those familiar with the historical evolution of fenestration to stapes mobilization to stapedectomy. Otosclerosis was a major cause of hearing loss prior to stapedectomy. It is estimated that 1% of the population in the United States has clinical otosclerosis. Sleep disorders are prevalent in the United States and worldwide. There is a product called Alaxo stents. The original investigative work was done in Germany [9]. It is anticipated that Alaxo will perform peer-reviewed multicenter studies in the United States to evaluate its efficacy in treating sleep apnea and nasal obstruction. It is also anticipated that the first author will help to coordinate the multicenter studies. Another possible treatment is to develop a physical therapy exercise regimen to “strengthen or tone up” the musculature/soft tissues in the hypopharynx-base of tongue-hyoid region. Medicine in general has many acronyms. Sleep medicine and surgery is inundated with more than its share of acronyms. The attached Glossary of Acronyms in Sleep Medicine and Surgery may facilitate communications among ourselves. The interpretation of sleep studies/polysomnogram (PSG) is still not as streamlined and straightforward as the interpretation of other diagnostic tests in medicine. With the great minds in this field, this too will improve.

GLOSSARY A AADSM: American Academy of Dental Sleep Medicine = A non-profit organization in the United States formed in 1991 to practice dental sleep medicine. It is the leading national organization representing the dentists who treat sleep-related breathing disorders. AASM: American Academy of Sleep Medicine = Non-profit Organization in the United States formed in 1975 for the medical subspecialty of sleep medicine.

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ABIM: The American Board of Internal Medicine is a physician-led, non-profit, independent evaluation organization. The Sleep Medicine Certification Program is jointly developed by the American Board of Internal Medicine (ABIM), the American Board of Family Medicine (ABFM), the American Board of Pediatrics (ABP), the American Board of Psychiatry and Neurology (ABPN), the American Board of Otolaryngology (ABOto) and the American Board of Anesthesiology (ABA). The examination is administered to candidates from all Boards simultaneously in the same testing centers. ABIM is responsible for administering the examination. ABSM: The American Board of Sleep Medicine offered a subspecialty certification examination for sleep medicine through 2006. While the ABSM no longer offers a sleep medicine exam, we continue to maintain and verify records for the ABSM Diplomates who hold this lifetime credential. AHI: Apnea-Hypopnea Index = The total number of complete cessations of airflow (apnea) and partial cessation of airflow (hypopnea) events that occur during sleep divided by the number of hours of sleep. It is a metric used to measure the severity of sleep apnea. The severity of sleep apnea according to AHI Severity Normal Mild Moderate Severe

AHI in children 10

AHI in adult 30

AI: Apnea index = The total number of apnea events divided by the total sleep duration in hours. The severity of sleep apnea according to AI Severity Normal Mild Moderate Severe

AI in children 10

AI in adult 30

ALMA: Alternating Leg Muscle Activation = It is a sleep-related movement first described by Chervin et al. that described a brief activation of electromyography of anterior tibialis burst in one leg followed by in the other leg during sleep or arousals from sleep. APAP: Automatic or Auto-titrating Positive Airway Pressure = It is a therapy used to treat sleep apnea by positive airway pressure in which air pressure levels are automatically adjusted according to the patient's breath-to-breath requirements. ASPD: Advanced sleep phase disorder = This is a type of circadian rhythm sleep disorder characterized by a recurrent pattern of early evening sleepiness and early morning awakening. This condition is commonly seen in the older population.

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ASV: Adaptive Servo-ventilation = One of the newer forms of non-invasive positive airway pressure (PAP) therapy used to treat central or complex sleep apnea. AT: Adenotonsillectomy= It is a surgical procedure that removes both the tonsils and adenoids. AWAKE: Awake, Wakeful, Keep Energetic = A support group in the United States that educates people with sleep apnea and other sleep disorders to improve adherence and success with the therapy.

B BPAP: Bilevel Positive Airway Pressure = Bilevel pressure device used to treat sleep apnea. The word “B” refers to two pressures that offer two modes of pressurized air: one for the inspiratory positive airway pressure (IPAP), and another for the expiratory positive airway pressure (EPAP). BMI: Body Mass Index = A number derived from a formula that measures the weight in kilogram(kg) divided by height in meters squared. BMI = Weight (kg) / Height (m2) BMI classification according to WHO guidelines BMI Underweight Normal Overweight Obese Obese Class 1 Obese Class 2 Obese Class 3 (Morbid Obesity)

WHO 102cm for males, >88cm for females Snoring Has your snoring ever bothered other people Apneas Has anyone noticed that you stop breathing during sleep 50 Are you aged 50 years or above? Grading is done based on 0-4: low risk, 5-7: moderate risk, 8-10: high risk

If yes, score 3 3 2 2

P PAP: Positive Airway Pressure = A form of therapy used for treating sleep apnea, that delivers preset ranges of therapeutic air pressure for the user. For example, CPAP, APAP, BiPAP, and ASV therapies. PDR: Posterior Dominant Rhythm = This is a sleep waveform seen in the pediatric sleep stage of wakefulness. It is a dominant reactive electroencephalogram (EEG) rhythm over the occipital regions that is slower during relaxed wakefulness with eye closed and attenuates with eye-opening and attention. PLMI: Periodic Limb Movement Index = A measure of the total number of limb movements during sleep divided by sleep duration in hours.

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Normal Mild Moderate Severe

0 to 4 ≥5 and 25 and 50

PLMS/PLMD: Periodic Leg Movements of Sleep or Periodic Leg Movement Disorder = Characterized by leg movements or jerks that typically occur every 20 to 40 seconds during sleep. Periodic leg movement disorder causes sleep to be disrupted, excessive daytime sleepiness. PLMD is similar to RLS, but this condition only happens during sleep, whereas RLS takes place awake time during the day or at bedtime. POSA: Positional OSA = It is defined as an AHI that is lower in the non-supine than the supine position according to the American Academy of Sleep Medicine (AASM) definition. In practice, positional OSA is defined as an AHI at least twice as high in the supine position as in other positions. POSTS: Positive occipital sharp transients of sleep = Sharply contoured positive waves over the occipital region in PSG, seen in stages N1 and N2. This is a normal variant and should not be confused with spikes. PSG: Polysomnography/Polysomnogram = Also known as Sleep Study. A form of mechanical recording of a person's sleep using many criteria, such as the amount of oxygen in the bloodstream, pulse, brain waves, and eye movement, among others. PSM: Propriospinal Myoclonus at Sleep Onset (PSM) = A rare disorder characterized by sudden myoclonic jerks which occur in the transition from wakefulness to sleep, which arise mainly in the axial muscles and spread according to propriospinal propagation. PSQI: Pittsburgh Sleep Quality Index = A self-administered questionnaire that assesses the sleep quality over a month interval. PT: Positional Therapy = A behavioral therapy by using a device to treat positional sleep apnea that helps keep a person to maintain sleeping side during sleep and for example, using something on the person's back to prevent them from rolling over like a tennis ball, special pillows or alarms.

R RAUP: Radiofrequency assisted uvulopalatoplasty = A non-invasive, time and costeffective, sleep surgery procedure that uses an electrical conduction system to ablate the tissue in the throat using the heat generated from medium frequency alternating current.

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RBD: Rapid eye movement (REM) Behavior Disorder =A sleep disorder (parasomnia) in which the brain fails to paralyze the body's muscles during REM sleep, leading to unpleasant dreams with sudden, violent arm and leg movements during REM sleep, sometimes called as Acting Out Dream Behaviors RDI: Respiratory distress Index/Respiratory disturbance index = A measure of the severity of sleep apnea based on the total number of complete obstructions(apnea), partial obstructions(hypopnea) and respiratory-effort related arousal (RERA) divided by duration of sleep (per hour). The severity of sleep apnea according to RDI RDI in Children (≤ 12years) 10

RDI in Adult (≥ 12 years) 30

Severity Normal Mild Moderate Severe

REI: Respiratory Event Index = A measure of apneas and hypopneas events divided by the total monitoring time in hours. It is typically used for home sleep apnea testing as it is based on monitoring time in contrast to actual sleep time. The severity of sleep apnea according to REI REI 30

Severity Normal Mild Moderate Severe

REM: Rapid eye movement stage of sleep = The stage of sleep in which brain activity and metabolism are active and vivid hallucinatory imaginary or dream occurs with depressed muscle tone. It usually comprises 20% to 25% of total sleep time. RERA: Respiratory Effort-Related Arousal = A type of breathing disorder characterized by increased in the respiratory effort for more than 10 seconds leading to an arousal from sleep that does not fulfil the criteria for hypopnea or apnea. RFA: Radiofrequency Ablation = A minimally invasive procedure that uses heat to remove the soft tissue of the upper airway structure without causing pain. This procedure is effective in the treatment for snoring and mild to moderate OSA. RFP: Radiofrequency Palate Surgery = A local anaesthesia procedure in which a needlelike instrument is inserted into the soft palate and energy is transmitted to the tissue to cause controlled damage.

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RLS: Restless Leg Syndrome = A movement disorder occurs during wakefulness in which unpleasant sensation in the legs described as twitching, a spasm that impede sleep onset. It is synonym with WED: Willis -Ekbom disease. RMD: Rhythmic Movement Disorder = It is a Sleep-related movement disorder where there is a group of repetitive, stereotypic, and rhythmic movements that usually involve large muscles which typically begin prior to sleep onset and may continue into sleep. RME: Rapid Maxillary Expander = A surgical technique performed by the orthodontist by placing a palatal expander or mini implant to widen the upper jaw. Also known as RPE: Rapid Palatal Expander or MARPE: Miniscrew assisted rapid palatal expander. RPE: Rapid Palatal Expander = Same as RME. RRT: Registered Respiratory Therapist = A high level in credentialling through the National Board for Respiratory Care for the therapist that has earned CRT. RPSGT: Registered Polysomnographic Technologist is one who has been credentialed through the BRPT and able to perform polysomnography and related procedures; score and process data and initiate as well as monitor associated therapeutic interventions. RST: Registered Sleep Technologist is one who has been credentialed through ABSM.

S SARPE: Surgically Assisted Rapid Palatal Expansion = A two-stage surgery including bilateral osteotomy of the lateral nasal wall to the pterygomaxillary suture line usually 5 mm above the apices of the teeth, with pterygomaxillary separation, midpalatal separation, and nasal septum release. It is performed in adult patients where maxillary suture lines already fused and cannot be expanded with other techniques. SARME: Surgically Assisted Rapid Maxillary Expansion = Same as SARPE SAQLI-E: Sleep Apnea Quality of Life Index = A new OSA specific questionnaire composed of four core domains: daily functioning, social interactions, emotional functioning, and symptoms which is a tool to assess the quality of life of OSA patients. SD: Sleep Deprivation = A state of lack of sleep due to inadequate quantity or quality of sleep. For example, adults, getting less than the standard needed amount of sleep ranges 7 to 9 hours of sleep per night. SDB: Sleep Disordered Breathing = An alternate name for obstructive sleep apnea in adult. It defined by upper airway narrowing or closure during sleep with continued respiratory efforts.

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SDS: Sleep Disordered Specialist = A person credentialed by the National Board for Respiratory Care that measures the knowledge and skills of respiratory therapists who perform sleep disorders testing and therapeutic intervention. SE: Sleep Efficiency = The percentage of time spent asleep. It is calculated by the ratio total sleep time (in minutes) compared to the total recording time (in minutes). Normal sleep efficiency is 80% or greater. SEM: Slow Eye Movement = an indicator of sleep onset, it is of low frequency (mainly 0.2–0.6 Hz), rolling, horizontal, bidirectional and conjugate movements of the eyes. SIT: Suggested Immobilization Test = A research tool developed to assess the subjective and objective leg movements during a 1-hour period of immobility prior to bedtime. A finding of more than 40/hour supports restless leg syndrome diagnosis. SL: Sleep Latency = amount of time takes for a person who is fully awake to sleep. It is measured by the difference between the sleep onset epoch with the lights out epoch in minutes. SMARPE: Surgically assisted and micro implants-assisted Rapid Palatal Expander. It is performed in adult patients where maxillary sutures are fused already and cannot be expanded with other techniques. SMILE: Submucosal Minimally Invasive Lingual Excision = A minimally invasive surgical technique performed to reduce the enlarged tongue base in the treatment of tongue base obstruction in both pediatric and adult patients. SNOT-22: 22-item Sinonasal Outcome Test= It is a validated questionnaire that evaluates sinonasal symptoms and QOL measures in 22 symptoms which are related to the nasal symptoms, sleep quality, otologic symptoms or emotional symptoms on a scale of 0 =no problem, 1= very mild problem, 2= mild to a slight problem, 3= moderate problem, 4 = severe problem, 5= very severe problem. SO: Sleep Onset =defined as the moment a person fall asleep in the first epoch of greater than 15 sec of cumulative sleep in a 30-sec epoch. SOREMP: Sleep Onset REM Period = A REM period that occurs within 15 minutes of sleep onset. This condition is unusual, as most people transition from wakefulness to stage 1 non-REM sleep. SOREMPs supports the potential for a diagnosis of narcolepsy. SPO2: Blood Oxygen Saturation = A measure of the amount of oxygen in the blood in percentage. SPO2 expressed as a chemical equation where S stands for saturation, the P stands for a pulse, and the O2 stands for oxygen. Normal SPO2 level is between 95%-100%. SRBD: Sleep-related breathing disorder = A term for a constellation of sleep-related breathing disorders and abnormalities of respiration during sleep. They include obstructive sleep apnea disorders, central sleep apnea syndromes, sleep-related hypoventilation disorders,

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sleep-related hypoxemia disorder, isolated symptoms and normal variants based on the international classification of sleep disorders third edition (ICSD-3). SSS: Stanford Sleepiness Scale (SSS) = A measure of subjective sleepiness based on the rating scale of 0 to 7. It frequently used for both research and clinical purposes. Degree of Sleepiness Feeling active, vital and wide awake Functioning at high level, but not at peak; able to concentrate Awake but relaxed; responsive but not fully alert Somewhat foggy, let down Foggy; losing interest in remaining awake, slowed down Sleepy, woozy, fighting sleep; prefer to lie down No longer fighting sleep, sleep onset soon; having dream-like thoughts Asleep

Scale rating 1 2 3 4 5 6 7 X

SRED: Sleep-related eating disorder = A combination of parasomnia and eating disorder. It consists of repeated episodes of compulsive binge eating and drinking after waking up in the night. STAR: Stimulation Therapy for Apnea Reduction = A treatment supported by the Inspire Medical System, Inc, on performing stimulation of the hypoglossal nerve as part of the Inspire Upper Airway Stimulation therapy to treat moderate to severe obstructive sleep apnea. STOP-BANG: The STOP-BANG questionnaire is a validated screening tool to predict the presence of OSA in preoperative settings. The expansion of the acronym STOP-BANG is described below. STOP-BANG Sleep Apnea Questionnaire STOP Do you Snore loudly (louder than talking or loud enough to be heard through closed doors)? Do you often feel Tired, fatigued, or sleepy during daytime? Has anyone Observed you stop breathing during your sleep? Do you have, or are you being treated for high blood Pressure? BANG BMI of more than 35kg/m2 Age over 50 years old Neck circumference >16 inches (40cm) Gender: Male

YES YES YES YES

NO NO NO NO

YES YES YES YES

NO NO NO NO

The total score determined the risk for OSA; high-risk of OSA: Yes 5-8, intermediate risk of OSA: Yes 3-4, low risk of OSA: Yes 0-2.

SWD: Shift work disorder = A type of circadian rhythm sleep disorder usually affecting people whose work hours overlap with the typical sleep period. SWS: Slow Wave Sleep = This is another name for stage 3 non-REM sleep, delta sleep, or deep sleep. It is the most in-depth phase of sleep. Dreaming and sleepwalking can occur during SWS.

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T TECSA: Treatment-emergent CSA = It is a type of sleep-related breathing disorder that is defined as the persistence or emergence of central apneas and hypopneas during the initiation of PAP therapy without backup rate for OSA despite resolution of the obstructive events. TIB: Total in bed = Also known as Total Recording Time (TRT). It is the total time from sleep onset to final awakening (time between lights out and lights on), calculated in minutes. TORS: Transoral Robotic Surgery = A minimally invasive, robotic surgery technique that performs surgery in the mouth and throat, mainly removing the benign and malignant tumors. TPNS: Transvenous phrenic nerve stimulation: A FDA approved therapy in 2017 used to treat moderate to severe central sleep apnea in patients where neurostimulation of the phrenic nerve that lead to contraction of the diaphragm similar to normal breathing. TRT: Total Recording Time = same as TIB. Please refer to TIB. TRD: Tongue retaining devices = The devices used to hold the tongue forward and in position during sleep to prevent upper airway obstruction. TST: Total Sleep Time = The total amount of sleep comprising of Stage N1, N2, N3 and REM calculated in minutes. TSD: Tongue stabilizing devices= Same as Tongue retaining devices (TRD).

U UARS: Upper airway resistance syndrome = A type of sleep-related breathing disorder where repetitive arousals from sleep due to an increase in resistance to airflow in the upper airway resulting in sleep disruption and excessive daytime sleepiness. UPPP: Uvulopalatopharyngoplasty =a surgical procedure of the upper airway used to remove the excess soft tissue in the back of the throat and palatal tissue to widen the pharyngeal airway. URGE: It is an abbreviation used to describe the characteristics of Restless Leg Syndrome that is defined as: U: Urge to move legs, usually associated with paresthesias or dysesthesias R: Rest induces or worsens symptoms G: Getting active brings relief E: Evening or nighttime worsening of symptoms

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V VOTE: VOTE classification system =The classification system used to score the degree of airway narrowing using drug-induced sleep endoscopy. The term “VOTE” stands for V: Velum, O: Oropharynx, T: Tongue, E: Epiglottis. VOTE classification system encompasses these involved structures and grade the degree and configuration of the obstruction related to them.

Structure

Degree of obstruction

Configuration Anteroposterior Lateral

V: Velum O: Oropharynx T: Tongue E: Epiglottis

0: no obstruction 1: partial obstruction (vibration) 2: complete obstruction (collapse) X: not visualized

Concentric

VPI: Velopharyngeal incompetency or insufficiency = A dysfunction of the sphincteric closure action of the soft palate that leads to air escape into the nose during speech(rhinolalia/hypernasality) and regurgitation of fluid into the nose during swallowing.

W WASO: Wake After Sleep Onset = The total amount of time in minutes spent awake after sleep has been initiated. WASO is a marker of sleep fragmentation. The normal WASO would be zero. WED: Willis-Ekbom disease = synonym with RLS. This WED is first described by Willis in 1672 and in 1945, Ekbom refined the term. Refer RLS above.

REFERENCES Fritsch MH, Naumann IC. Phylogeny of the stapes prosthesis. Otol. Neurotol. 2008 Apr;29(3):407-15. doi: 10.1097/MAO.0b013e3181690775. Gjuric M, Rukavina L. Evolution of stapedectomy prostheses over time. In: Otosclerosis and stapes surgery. Vol 65. Karger Publishers; 2007:174-178. Knox GW, Reitan H. Otologic prosthesis. In: Google Patents; 2003. Niyazov D, Borges A, Ishiyama A, Zaragoza E, Lufkin R. Fenestration surgery for otosclerosis: CT findings of an old surgical procedure. AJNR Am. J. Neuroradiol. 2000 Oct;21(9):16702. Pietruski J. Samuel Rosen (1897-1981) odkrywca mobilizacji strzemiaczka [Samuel Rosen (1897-1981): the originator of stapes mobilization]. Otolaryngol. Pol. 1999;53(6):739-42. Polish. Schuknecht HF. A New Stapedectomy Prosthesis. Arch. Otolaryngol. 1964 Oct;80:474. doi: 10.1001/archotol.1964.00750040486019.

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Shambaugh GE Jr. The fenestration operation for otosclerosis. J. Am. Med. Assoc. 1946 Apr 13;130:999-1006. doi: 10.1001/jama.1946.02870150017004. Walsh TE. Fenestration in stapedectomy era. Arch. Otolaryngol. 1965 Oct;82(4):346-54. doi: 10.1001/archotol.1965.00760010348003. Zhang H, Kotecha B. Effect of intranasal stents (AlaxoLito, AlaxoLito Plus and AlaxoLito Xtreme) on the nasal airway: A case report. World Journal of Otorhinolaryngology. 2019;8(1):4-11.

ANSWERS TO MULTIPLE CHOICE QUESTIONS Chapter 1:

Chapter 4:

1. c

1. c

2. d

2. d

3. a

3. d

4. c

4. d

5. c

5. e

Chapter 2:

Chapter 5:

1. a

1. c

2. c

2. c

3. b

3. e

4. d

4. b

5. c

5. b

Chapter 3:

Chapter 6:

1. d

1. c

2. c

2. c

3. e

3. a

4. d

4. d

5. a

5. b

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Answers to Multiple Choice Questions

Chapter 7:

Chapter 11:

1. d

1. c

2. d

2. d

3. d

3. b

4. c

4. c

5. c

5. a

Chapter 8:

Chapter 12:

1. a

1. c

2. d

2. a

3. c

3. c

4. b

4. e

5. a

5. e

Chapter 9:

Chapter 13:

1. c

1. e

2. c

2. b

3. b

3. c

4. b

4. e

5. d

5. a

Chapter 10:

Chapter 14:

1. False

1. b

2. b

2. e

3. c

3. b

4. d

4. a

5. c

5. c

Answers to Multiple Choice Questions

Chapter 15:

Chapter 19:

1. c

1. c

2. a

2. c

3. d

3. a

4. b

4. d

5. b & c

5. a

Chapter 16:

Chapter 20:

1. c

1. a

2. e

2. a

3. c

3. e

4. b

4. f

5. e

5. b

Chapter 17:

Chapter 21:

1. c

1. a

2. d

2. c

3. c

3. d

4. a

4. d

5. d

5. b

Chapter 18:

Chapter 22:

1. c

1. b

2. b

2. b

3. d

3. d

4. d

4. c

5. a

5. b

661

662

Answers to Multiple Choice Questions

Chapter 23:

Chapter 27:

1. b

1. d (only)

2. d

2. c

3. d

3. b

4. a

4. e

5. b & c

5. b

Chapter 24:

Chapter 28:

1. c

1. c

2. a

2. b

3. c

3. b

4. d

4. b

5. a

5. a

Chapter 25:

Chapter 29:

1. c

1. a

2. a

2. False

3. c

3. a

4. b

4. c

5. b

5. False

Chapter 26:

Chapter 30:

1. d

1. c

2. d

2. b

3. d

3. a

4. a

4. b

5. c

5. b

Answers to Multiple Choice Questions

Chapter 31:

Chapter 35:

1. c

1. d

2. c

2. a

3. e

3. c

4. b

4. b

5. c

5. a

Chapter 32:

Chapter 36:

1. e

1. d

2. b

2. b

3. c

3. a

4. d

4. c

5. b

5. b

Chapter 33:

Chapter 37:

1. c

1. d

2. b

2. e

3. d

3. a

4. c

4. b

5. b

5. a

Chapter 34: 1. c 2. c 3. c 4. a 5. c

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ABOUT THE EDITORS AND CONTRIBUTORS EDITORS Maria V. Suurna, MD, FACS† Department of Otolaryngology – Head and Neck Surgery Weill Cornell Medicine New York, New York, USA (†and Contributor to Chapter 24)

Stacey L. Ishman, MD, MPH≠ Healthvine Health Network Tristate Child Health Services Department of Otolaryngology – Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati, Ohio, USA (≠and Contributor to Chapter 36)

ASSISTANT EDITOR Josephine H. Nguyen, MD‡ Sacramento Ear, Nose, and Throat Surgical and Medical Group, Inc. Stockton, California, USA (‡and Contributor to Chapter 13)

CONTRIBUTORS Ashwin Anath, MD Jefferson Sleep Disorders Center Thomas Jefferson University Philadelphia, Pennsylvania, USA

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About the Editors and Contributors

Alon Avidan, MD, MPH, FAASM, FAAN Department of Neurology Sleep Disorders Center David Geffen School of Medicine at University of California Los Angeles Los Angeles, California, USA Cristina Baldassari, MD, FACS, FAAP Department of Otolaryngology East Virginia Medical School Department of Pediatric Sleep Medicine Children’s Hospital of the King’s Daughters Norfolk, Virginia, USA Caroline J. Beatty, B. Psych Department of Physiology Biomedicine Discovery Institute School of Psychological Sciences and Turner Institute for Brain and Mental Health Monash University Melbourne, Victoria, Australia Maurits Boon, MD Department of Otolaryngology – Head and Neck Surgery Thomas Jefferson University Hospital Philadelphia, Pennsylvania, USA Katemanee Burapachaisri Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland, USA Yi Cai, MD Department of Otolaryngology – Head and Neck Surgery University of California San Francisco San Francisco, California, USA Robson Capasso, MD, FAASM Sleep Surgery Division Department of Otolaryngology – Head and Neck Surgery Global Biodesign SoM Stanford University School of Medicine Stanford, California, USA

About the Editors and Contributors Jolie L. Chang, MD Division of Sleep Surgery Department of Otolaryngology – Head and Neck Surgery University of California San Francisco San Francisco, California, USA Nicole D. Chenet, DDS Sleep Apnea Dental Center Pittsburgh, Pennsylvania, USA Nancy Collop, MD Emory Sleep Center Emory University Atlanta, Georgia, USA Julia Crawford, BSc (Med), MBBS (Hons), FRACS St. Vincent’s Hospital Sydney The University of New South Wales Sydney New South Wales, Australia Mark D’Agostino, MD, FACS Southern New England Ear, Nose, and Throat Plastic Surgery Group Section of Otolaryngology Yale School of Medicine New Haven, Connecticut, USA Frank H. Netter School of Medicine Quinnipiac University North Haven, Connecticut, USA Otolaryngology Section Middlesex Hospital Middletown, Connecticut, USA Swapan Dholakia, MD Atlanta VA Medical Center Decatur, Georgia, USA Emory University School of Medicine Atlanta, Georgia, USA Karl Doghramji, MD Jefferson Sleep Disorders Center Thomas Jefferson University Philadelphia, Pennsylvania, USA

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About the Editors and Contributors

Megan L. Durr, MD Kaiser Permanente Department of Otolaryngology – Head and Neck Surgery Oakland, California, USA Bradley A. Edwards, PhD Department of Physiology Biomedicine Discovery Institute School of Psychological Sciences and Turner Institute for Brain and Mental Health Monash University Melbourne, Victoria, Australia Robert M. Frederick Department of Otolaryngology – Head & Neck Surgery University of Tennessee Health Center Memphis, Tennessee, USA Robin Germany, MD University of Oklahoma Health Sciences Center Cardiovascular Division Oklahoma City, Oklahoma, USA M. Boyd Gillespie, MD, MSc Department of Otolaryngology – Head & Neck Surgery University of Tennessee Health Center Memphis, Tennessee, USA Andrew N. Goldberg, MD, MS Division of Rhinology and Sinus Surgery Department of Otolaryngology – Head and Neck Surgery University of California San Francisco San Francisco, California, USA Jay Guevarra, MD Division of Pulmonary, Critical Care, and Sleep Medicine Mouth Sinai Integrative Sleep Center Icahn School of Medicine at Mount Sinai New York, New York, USA Michael Hajek, MD Section of Otolaryngology Yale School of Medicine New Haven, Connecticut, USA

About the Editors and Contributors Kelli Lee Harford, PhD Children’s Healthcare of Atlanta Emory University Atlanta, Georgia, USA Erin Harvey, MD Department of Otolaryngology and Human Communication Medical College Wisconsin Milwaukee, Wisconsin, USA Robert Hiensch, MD Division of Pulmonary, Critical Care, and Sleep Medicine Mouth Sinai Integrative Sleep Center Icahn School of Medicine at Mount Sinai New York, New York, USA Paul T. Hoff, MD, MS Department of Otolaryngology, Head & Neck Surgery University of Michigan Medical School Ann Arbor, Michigan, USA Colin Huntley, MD, FACS Department of Otolaryngology – Head & Neck Surgery Thomas Jefferson University Philadelphia, Pennsylvania, USA Badr Ibrahim, MD Division of Otolaryngology Head and Neck Surgery Department of Surgery University of Montreal Montreal, Quebec, Canada Sally Ibrahim, MD Rainbow Babies and Children’s Hospital University Hospitals and Case Western Reserve University Cleveland, Ohio, USA Ofer Jacobowitz, MD, PhD, FAASM, FAAOA Sleep, ENT, and Allergy Associates Port Jefferson Station, New York, USA

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About the Editors and Contributors

Shahrokh Javaheri, MD Bethesda Montgomery Sleep Laboratory Bethesda North Hospital University of Cincinnati College of Medicine Cincinnati, Ohio, USA Division of Cardiology The Ohio State University Columbus, Ohio, USA Ashutosh Kacker, MD Department of Otolaryngology – Head and Neck Surgery Weill Cornell Medicine New York, New York, USA Umakanth A. Katwa, MD Sleep Center Boston Children’s Hospital Boston, Massachusetts, USA Meena Khan, MD Division of Pulmonary, Critical Care, and Sleep Medicine Department of Internal Medicine and Neurology The Ohio State University Wexner Medical Center Columbus, Ohio, USA Erin Kirkham, MD, MPH Department of Otolaryngology Head and Neck Surgery University of Michigan Ann Arbor, Michigan, USA Bala S.C. Koritala, PhD Division of Pediatric Otolaryngology – Head and Neck Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio, USA Yann-Fuu Kou, MD Department of Otolaryngology – Head & Neck Surgery University of Texas Southwestern Medical Center Children’s Health Dallas Dallas, Texas, USA Kimberly Kreitinger, MD Division of Sleep Medicine Department of Psychiatry and Behavioral Sciences Stanford University Stanford, California, USA

About the Editors and Contributors Katie Kruk Department of Pharmacology Program in Neuroscience University of Maryland Baltimore Baltimore, Maryland, USA Hannah N. Kuhar, MD Department of Otolaryngology – Head and Neck Surgery Ohio State University Wexner Medical Center Columbus, Ohio, USA Siobhan Kuhar, MD, PhD, DABSM Albany ENT and Allergy Services Albany, New York, USA Derek Lam, MD, MPH, FACS Otolaryngology – Head and Neck Surgery Oregon Health and Science University Portland, Oregon, USA Shane A. Landry, PhD Department of Physiology Biomedicine Discovery Institute Monash University Melbourne, Victoria, Australia K. J. Lee, MD, FACS Yale University School of Medicine Quinnipiac University Netter School of Medicine New Haven, Connecticut, USA Hofstra University Zucker School of Medicine Hempstead, New York, USA Roberta Leu, MD Children’s Healthcare of Atlanta Emory University School of Medicine Atlanta, Georgia, USA Carol Li, MD Department of Otolaryngology – Head and Neck Surgery University of Cincinnati College of Medicine Division of Pediatric Otolaryngology – Head & Neck Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio, USA

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About the Editors and Contributors

Stuart Mackay, MBBS, BMedSc (Hons), FRACS (OHNS) Department of Otolaryngology Head and Neck Surgery The Wollongong Hospital Illawarra Shoalhaven Local Health District Illawarra ENT Head and Neck Clinic Illawarra Health and Medical Research Institute School of Medicine University of Wollongong Wollongong, New South Wales, Australia Atul Malhotra, MD Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine University of California San Diego La Jolla, California, USA Tahir Mirza, MBBS, BDS, FRCS (OMFS) Bedfordshire Hospitals NHS Foundation Trust Luton, Bedfordshire, UK Jennifer Molano, MD, FAAN Department of Neurology and Rehabilitative Medicine The University of Cincinnati College of Medicine Cincinnati, Ohio, USA Jessica A. Mong, PhD Department of Pharmacology Program in Neuroscience University of Maryland Baltimore Baltimore, Maryland, USA Anne Marie Morse, MD Division of Pediatric Neurology Janet Weis Children’s Hospital Geisinger Danville, Pennsylvania, USA Judith A. Owens, MD, MPH Sleep Center Boston Children’s Hospital Boston, Massachusetts, USA Nithin S. Peddireddy, MD Department of Otolaryngology, Head & Neck Surgery University of Michigan Medical School Ann Arbor, Michigan, USA

About the Editors and Contributors Andrea M. Plawecki, MD Department of Otolaryngology, Head & Neck Surgery Henry Ford Hospital Detroit, Michigan, USA Nikhila Raol, MD, MPH Division of Pediatric Otolaryngology Children’s Healthcare of Atlanta Department of Otolaryngology – Head and Neck Surgery Emory University School of Medicine Atlanta, Georgia, USA David Rapoport, MD Division of Pulmonary, Critical Care, and Sleep Medicine Mouth Sinai Integrative Sleep Center Icahn School of Medicine at Mount Sinai New York, New York, USA Madeline Ravesloot, MD, PhD, MSc OLVG Amsterdam, The Netherlands Amrita Ray, MD, MPH Department of Otolaryngology – Head and Neck Surgery Weill Cornell Medicine New York, New York, USA Joshua Roland, MD, FAASM Department of Pulmonology, Critical Care, and Sleep Medicine David Geffen School of Medicine at University of California Los Angeles Los Angeles, California, USA Sofia Romano Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland, USA Carol Rosen, MD Case Western Reserve University School of Medicine Cleveland, Ohio, USA Madelyn Rosenthal, MD The Lung Consultants Fort Worth, Texas, USA

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About the Editors and Contributors

Brian W. Rotenberg, MD, MPH, FRSCS Department of Otolaryngology – Head and Neck Surgery Schulich School of Medicine and Dentistry Western University London, Ontario, Canada Asim Roy, MD Ohio Sleep Medicine Institute Northeast Ohio Medical University Rootstown, Ohio, USA Marc D. Ruben, PhD Division of Human Genetics Cincinnati Children’s Hospital Medical Center Department of Pediatrics University of Cincinnati College of Medicine Cincinnati, Ohio, USA Rachel Marie E. Salas, MD, MEd, FAAN, FANA Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland, USA Richard J. Schwab, MD Division of Sleep Medicine Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA Gavin Setzen, MD, FACS, FAAOA, FARS Albany ENT and Allergy Services Albany, New York, USA Lee Shangold, MD, FACS, FAASM Zucker School of Medicine at Hofstra/Northwell Hempstead, New York, USA Anders Sideris, MBBS, BMedSci (Hons), MSci Department of Otolaryngology Head and Neck Surgery The Wollongong Hospital Illawarra Shoalhaven Local Health District Illawarra ENT Head and Neck Clinic Illawarra Health and Medical Research Institute School of Medicine University of Wollongong Wollongong, New South Wales, Australia

About the Editors and Contributors David F. Smith, MD, PhD, FACS, FAAP Division of Pediatric Otolaryngology – Head and Neck Surgery Division of Pulmonary Medicine and the Sleep Center The Center for Circadian Medicine Cincinnati Children’s Hospital Medical Center Department of Otolaryngology – Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati, Ohio, USA Ryan J. Soose, MD Department of Otolaryngology University of Pittsburgh Pittsburgh, Pennsylvania, USA Jeffery J. Stanley, MD Department of Otolaryngology, Head & Neck Surgery University of Michigan Medical School Ann Arbor, Michigan, USA Tracey L. Stierer, MD, FAASM Department of Anesthesiology and Critical Care Medicine Department of Neurology Department of Otolaryngology, Head and Neck Surgery Johns Hopkins Medical Institution Baltimore, Maryland, USA Jennifer Stone, MD Rainbow Babies and Children’s Hospital University Hospitals and Case Western Reserve University Cleveland, Ohio, USA Michael Strunc, MD Child Neurology and Sleep Medicine Children’s Hospital of The King’s Daughters Eastern Virginia Medical School Norfolk, Virginia, USA Gerald Suh, MD Princeton ENT and Sleep, LLC Princeton, New Jersey, USA Penn Medicine Princeton Health Affiliate of Penn Medicine Department of Otolaryngology Plainsboro, New Jersey, USA

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676

About the Editors and Contributors

Shi Nee Tan, MBBS KPJ University College of Medicine Nilai, Negeri Sembilan, Malaysia Erica R. Thaler, MD Division of Sleep Surgery Department of Otorhinolaryngology – Head and Neck Surgery Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA Luke D.J. Thomson, B.Psych, GDipSISci Department of Physiology Biomedicine Discovery Institute School of Psychological Sciences and Turner Institute for Brain and Mental Health Monash University Melbourne, Victoria, Australia B. Tucker Woodson, MD Division of Sleep Medicine and Surgery Department of Otolaryngology and Human Communication Medical College Wisconsin Milwaukee, Wisconsin, USA Christopher C. Xiao, MD Kaiser Permanente Department of Otolaryngology – Head and Neck Surgery Oakland, California, USA Kathleen L. Yaremchuk, MD, MSA Department of Otolaryngology, Head & Neck Surgery Department of Sleep Medicine Henry Ford Hospital Wayne State University School of Medicine Detroit, Michigan, USA Jason L. Yu, MD Division of Sleep Surgery Department of Otorhinolaryngology – Head and Neck Surgery Division of Sleep Medicine Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA

About the Editors and Contributors Sarah Zahabi, MD Department of Otolaryngology – Head and Neck Surgery Schulich School of Medicine and Dentistry Western University London, Ontario, Canada

677

INDEX A accidents, 4, 30, 35, 36, 37, 70, 135, 167, 216, 254, 283, 299, 468 acetazolamide, 90, 104, 446, 453 acoustic rhinometry, 331, 332 acromegaly, 29, 146, 147, 162 actigraphy, 36, 37, 38, 39, 65, 77, 160, 161, 458, 471, 474, 488, 489, 558 adaptive servoventilation (ASV), 248, 249, 426, 446, 447, 448, 452, 638, 648, 649 ADHERE, 292, 298, 399, 403, 409, 410, 435 ADHERE registry, 399, 403, 409 adjunctive treatment, 242, 278, 432 adolescence, 12, 35, 36, 44, 112, 507, 519, 524, 531, 558, 564, 574, 576, 582 advanced sleep phase disorder, 73, 128, 333 advanced sleep-wake phase disorder, 484, 494 aging, 116, 117, 127, 130, 140, 172, 384 alcohol, 46, 71, 72, 77, 78, 85, 86, 88, 131, 160, 161, 221, 225, 240, 244, 284, 290, 316, 320, 412, 459, 486, 507, 508, 511, 516 algorithms, 247, 248, 319, 430 American Thoracic Society, 190, 260, 413, 417, 421 amphetamine-dextroamphetamine, 89 amplitude, 5, 6, 7, 8, 9, 11, 502, 506, 644 apnea-hypopnea index, 90, 146, 168, 181, 193, 211, 219, 240, 247, 266, 283, 294, 313, 341, 349, 382, 414, 426, 441, 567, 602, 603, 639 apparent life-threatening event (ALTE), 570, 572, 573 armodafinil, 88, 92, 101 arrhythmias, 145, 212, 254, 256, 283, 290, 641 atrial fibrillation, 29, 57, 152, 196, 247, 259, 290 attention deficit and hyperactivity disorder (ADHD), 38, 49, 50, 491, 517, 529, 556, 558, 560, 580

augmentation, 94, 95, 96, 99, 100, 102, 143, 373, 386, 387, 532, 533, 534, 542, 546 Australian Modified Uvulopalatopharyngoplasty (Australian modUPPP), 229 autistic spectrum disorder (ASD), 558, 560, 561, 562 auto-adjusting positive airway pressure (APAP), 247, 248, 251, 624, 631, 637, 641, 648, 649 autoimmune disease, 122 Azelastine, 91

B barbed reposition pharygoplasty, 343 bariatric surgery, 240, 323, 330, 411, 412, 413, 414, 415, 417, 418, 419, 420, 421, 422, 435 bedtime routines, 559 behavioral insomnia, 557, 562 benzodiazepines, 12, 86, 90, 196, 240, 307, 441, 507, 576 Berlin Questionnaire, 58, 415, 421 bilateral sagittal split osteotomies (BSSO), 381, 382 bilevel positive airway pressure (BPAP), 157, 248, 251, 260, 398, 624, 628, 629, 638, 642, 647 bisexual, 109 body mass index (BMI), 58, 59, 61, 115, 148, 152, 156, 157, 170, 184, 195, 198, 201, 204, 205, 209, 220, 223, 240, 267, 275, 284, 286, 287, 288, 291, 292, 293, 294, 297, 303, 304, 339, 343, 344, 345, 353, 356, 357, 359, 362, 376, 383, 384, 390, 398, 399, 405, 406, 407, 409, 411, 412, 413, 415, 416, 417, 419, 424, 429, 432, 638, 649, 654 body position, 240, 241, 318, 335, 409, 625 botulinum toxin type A injections, 540, 543 Brodsky Scale, 284 Bruxism, 51, 539, 540, 542, 543, 546, 646 Buspirone, 514

680

Index

Butterfly graft, 326, 327

C cancer, 73, 119, 123, 149, 150, 216, 218, 412, 482, 488, 497 cardiovascular, 27, 39, 50, 71, 73, 118, 121, 146, 167, 212, 213, 215, 220, 221, 233, 236, 255, 258, 260, 261, 271, 272, 290, 296, 319, 364, 376, 417, 447, 482, 487, 496, 592, 614, 642 cardiovascular disease, 71, 118, 146, 167, 212, 236, 261, 376, 496 cataplexy, 35, 43, 63, 65, 73, 75, 77, 88, 89, 99, 100, 103, 466, 467, 468, 469, 471, 472, 476, 477, 524, 576, 577, 579 cautery assisted palatal stiffening operation (CAPSO), 342 central sleep apnea (CSA), 31, 32, 72, 74, 77, 146, 152, 155, 161, 168, 182, 193, 194, 196, 247, 248, 249, 258, 278, 437, 438, 439, 440, 441, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 569, 570, 571, 572, 583, 584, 624, 639, 645, 653, 655 central sleep apnea (CSA), pediatrics, 571, 572 cerebrospinal fluid, 20, 73, 215, 247, 328, 465, 476, 530 Cheyne-Stokes Breathing, 31, 32, 639, 644 children, 11, 24, 25, 32, 33, 34, 38, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 54, 67, 68, 82, 88, 92, 109, 146, 148, 230, 287, 289, 320, 331, 332, 335, 358, 362, 367, 369, 398, 413, 428, 470, 476, 485, 495, 501, 503, 507, 510, 513, 517, 518, 522, 523, 530, 531, 536, 537, 539, 540, 541, 542, 543, 544, 545, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 567, 569, 570, 577, 579, 580, 581, 582, 584, 585, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 603, 604, 605, 606, 608, 609, 611, 612, 613, 614, 615, 616, 617, 618, 619, 624, 631, 632, 633, 637, 639, 644, 647 chronic insomnia, 28, 82, 85, 118, 125, 163, 458, 557, 559 chronic kidney disease, 151 chronic obstructive pulmonary disease (COPD), 139, 155, 156, 157, 161, 201, 204, 213, 248, 283, 460, 462, 529, 639 circadian, 12, 16, 18, 19, 24, 25, 26, 36, 39, 42, 64, 65, 68, 69, 72, 73, 75, 76, 77, 78, 79, 81, 98, 108, 109, 112, 119, 122, 123, 128, 132, 138, 139, 140, 143, 146, 157, 160, 161, 242, 470, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 527, 528, 553, 557, 558, 580, 581, 582, 637, 654 circadian clock, 18, 39, 132, 146, 480, 482, 484, 486, 487, 488, 492, 494, 495, 496, 581

circadian rhythm, 18, 25, 26, 36, 42, 64, 65, 68, 69, 72, 73, 75, 77, 78, 98, 109, 119, 123, 128, 132, 138, 140, 146, 160, 161, 242, 480, 481, 483, 485, 487, 491, 492, 493, 494, 495, 496, 497, 553, 581, 637, 654 circadian rhythm sleep-wake disorders, 42, 123, 480 circadian rhythms, 65, 68, 69, 77, 78, 109, 119, 128, 146, 480, 481, 485, 487, 491, 493, 494, 495, 496, 497 Clonazepam, 77, 95, 97, 98, 100, 104, 512, 534 CO2 laser (carbon dioxide laser), 346, 358, 363, 612 cognitive, 29, 36, 40, 41, 71, 73, 77, 80, 82, 85, 86, 92, 97, 98, 99, 120, 122, 126, 133, 134, 135, 137, 141, 150, 153, 154, 208, 215, 217, 221, 254, 458, 473, 486, 500, 505, 507, 520, 522, 523, 534, 568, 578, 585, 647 cognitive behavioral therapy, 99, 137, 507, 520 combination therapy, 232, 241, 275, 430, 431, 432 complete concentric collapse, 399 confusional arousals, 72, 75, 509, 524 congenital central alveolar hypoventilation syndrome (CCHS), 33, 570, 571, 573, 645 congestive heart failure, 29, 57, 88, 201, 204, 212, 248, 290, 293, 299, 440, 639 continuous positive airway pressure (CPAP), 60, 91, 92, 93, 101, 103, 104, 123, 149, 153, 155, 156, 180, 184, 187, 197, 200, 201, 202, 203, 204, 205, 206, 208, 209, 212, 213, 214, 215, 216, 225, 226, 227, 231, 232, 233, 235, 237, 241, 242, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 266, 272, 273, 275, 276, 277, 278, 279, 284, 287, 289, 291, 294, 295, 296, 297, 298, 299, 301, 305, 306, 307, 308, 309, 310, 311, 313, 316, 320, 321, 324, 327, 328, 329, 330, 333, 344, 345, 350, 353, 357, 362, 371, 375, 388, 390, 398, 407, 414, 416, 417, 419, 420, 421, 422, 423, 426, 427, 431, 432, 434, 435, 440, 444, 445, 446, 447, 448, 452, 453, 463, 572, 590, 591, 594, 595, 618, 624, 628, 629, 630, 639, 641, 642, 648, 649 contraindications for bariatric surgery, 412 Cottle maneuver, 318, 424 cough, 156, 157, 216, 640 CPAP Adherence, 249, 260

D daily stretching exercises, 538 DaVinci robotic system, 360 daytime somnolence, 57, 86, 87, 219, 231, 233, 615 delayed sleep-wake phase disorder (DSWPD), 38, 101, 112, 142, 483, 484, 489, 490, 491, 492, 493, 581, 582, 646 delayed sleep-wake phase disorder, pediatric, 112

Index depression, 10, 22, 35, 36, 37, 38, 39, 47, 57, 58, 71, 73, 93, 94, 109, 112, 116, 120, 122, 124, 126, 133, 134, 139, 147, 149, 158, 160, 161, 213, 217, 221, 236, 249, 256, 291, 295, 302, 306, 307, 319, 416, 441, 452, 511, 513, 517, 520, 532, 533, 534, 558, 560 developmental, 32, 36, 39, 485, 559, 561, 572 devices, 41, 59, 61, 75, 136, 169, 200, 202, 221, 226, 232, 233, 241, 244, 248, 263, 264, 265, 267, 272, 273, 277, 278, 389, 395, 423, 426, 427, 446, 447, 448, 540, 543, 545, 582, 590, 598, 624, 625, 649, 655 diabetes, 4, 29, 47, 51, 72, 115, 116, 119, 121, 139, 148, 152, 167, 213, 214, 217, 220, 299, 322, 412, 496, 497, 520, 569 dim light melatonin onset, 18 Diphenhydramine, 96, 450, 529, 538, 543 distraction osteogenesis maxillary expansion (DOME), 203, 388, 389, 391, 392, 393, 641 dopamine agonist, 93, 94, 96, 105, 137, 508, 509, 532, 533, 534, 535, 537, 542, 543, 546 dopaminergic therapy, 49, 528 doral raphe nucleus (DRN), 15 Down’s syndrome, 358 Doxepin, 87, 100, 462 drug induced sleep endoscopy (DISE), 181, 203, 224, 232, 275, 285, 286, 288, 289, 291, 294, 319, 340, 349, 353, 361, 362, 365, 385, 390, 399, 406, 428, 429, 430, 431, 432, 433, 602, 603, 604, 606, 608, 619, 640 drugs, 37, 52, 62, 86, 90, 92, 149, 240, 242, 243, 307, 335, 427, 441, 462, 473, 494, 524, 533, 534, 540, 543, 544, 578, 579

E elderly, 32, 86, 104, 106, 127, 128, 131, 132, 133, 134, 135, 136, 137, 139, 140, 141, 142, 143, 211, 215, 485, 491, 492, 498 electroencephalogram, 59, 60, 110, 152, 168, 180, 186, 438, 444, 503, 625, 649 electromyogram, 59, 149, 152, 194, 438, 510, 625 empty nose syndrome, 330 entrainment, 39, 482, 485, 491, 494, 496 epidemiology, 173 epiglottoplasty, 203, 362, 363 epiglottoplasty/supraglottoplasty, 362 epilepsy, 47, 52, 53, 54, 152, 153, 161, 501, 510, 558, 638 Epworth Sleepiness Scale, 58, 92, 130, 142, 198, 207, 216, 227, 249, 272, 300, 342, 363, 424, 460, 470, 578, 602, 642 Eszopiclone, 86, 87, 93, 103, 104, 462

681 examination, 57, 140, 155, 160, 222, 232, 267, 269, 286, 293, 294, 304, 344, 424, 428, 473, 538, 583, 602, 615, 637 excessive daytime sleepiness, 4, 28, 62, 75, 76, 77, 88, 92, 100, 103, 111, 130, 139, 147, 150, 198, 199, 205, 215, 220, 221, 235, 242, 256, 257, 330, 383, 387, 391, 427, 450, 474, 475, 485, 486, 537, 650, 655 expansion sphincter pharyngoplasty, 619 external nasal valve, 313, 318, 324, 329, 387

F ferric carboxymaltose, 102, 532, 542 ferrous sulfate, 532, 542 fibromyalgia, 9, 121, 125, 139, 159, 160, 161 Flurazepam, 86, 462 fluticasone propionate, 91 Friedman score, 287 Friedman staging, 223, 339 Fujita classification, 340

G gabapentin, 94, 102, 103, 137, 140, 514, 532, 537, 542, 543, 581 gabapentin enacarbil, 103, 532, 537, 542, 543 gastroesophageal reflux disease (GERD), 30, 32, 73, 148, 149, 161, 216, 250, 290, 460, 520, 643 gay, 109 genetics, 49, 171, 523, 545 genial tubercle advancement (GTA), 384, 386, 387, 391 genioglossus, 90, 179, 180, 181, 188, 190, 266, 288, 353, 355, 356, 357, 359, 361, 366, 367, 368, 369, 370, 375, 376, 385, 386, 387, 390, 396, 406, 612 genioglossus advancement (GGA), 353, 355, 356, 367, 368, 369, 370, 376, 386, 390, 392 genioplasty, 386, 387, 392 glossectomy, 202, 203, 232, 287, 293, 350, 358, 359, 366, 367, 368, 369, 371, 609, 615, 618, 619 glossoepiglottopexy, 362, 363, 370 GOAL (Gender, Obesity, Age, Loud snoring), 415, 420

H habitual snoring, 29, 227, 234, 241, 567 healthy sleep, 110, 111, 559 high altitude periodic breathing, 31

682

Index

high modified Mallampati (MM)/Friedman tongue position (FTP), 196 homeostatic sleep drive, 68, 72, 78, 491, 501 hormonal contraception, 110 Hydrocodone, 95 hyoglossus, 288, 361, 365, 366, 396, 402, 408 hyoid suspension, 232, 237, 356, 366, 367, 387, 391 hypersomnolence, 34, 130, 140, 141, 196, 216, 405, 418, 466, 470, 473, 474, 475, 501, 502, 512, 516, 642, 647 hypertension, 4, 29, 33, 34, 57, 62, 71, 91, 102, 115, 121, 151, 157, 167, 213, 215, 217, 220, 247, 254, 255, 256, 259, 272, 283, 290, 299, 322, 412, 413, 419, 494, 520, 639 hypoglossal nerve, 195, 200, 232, 275, 276, 280, 285, 294, 300, 303, 306, 309, 319, 354, 358, 359, 361, 365, 395, 397, 398, 400, 406, 407, 408, 409, 431, 445, 616, 644, 654 hypoglossal nerve stimulation, 195, 200, 232, 275, 276, 280, 285, 294, 300, 303, 398, 407, 408, 409, 431, 445, 616 hypopharynx, 340, 349, 350, 353, 376, 433, 636 hypopnea(s), 29, 30, 31, 32, 61, 64, 156, 167, 168, 169, 171, 172, 185, 186, 193, 194, 200, 219, 236, 246, 248, 258, 259, 260, 295, 330, 333, 335, 346, 349, 367, 368, 399, 414, 419, 433, 439, 440, 441, 447, 555, 556, 568, 587, 596, 617, 625, 637, 639, 644, 651, 655 hypothyroidism, 29, 37, 147 hypoventilation, 30, 32, 33, 34, 56, 139, 155, 156, 157, 213, 247, 248, 278, 293, 364, 412, 413, 417, 553, 554, 555, 561, 568, 570, 573, 584, 585, 624, 631, 649, 653 hypoxic ventilatory response (HVR), 21, 22

I idiopathic central sleep apnea (ICSA), 168, 446, 447, 452, 453 idiopathic hypersomnia, 62, 64, 88, 475, 476, 517, 576 immune system, 122, 151, 474 indications, 143, 241, 331, 350, 355, 357, 358, 362, 388, 405, 407, 467, 553, 562, 563, 624 infants, 11, 12, 53, 54, 115, 124, 369, 540, 541, 543, 551, 553, 554, 555, 556, 557, 563, 564, 570, 571, 572, 575, 591, 613, 619 inferior turbinate reduction, 202, 332, 382, 616 insomnia, 28, 29, 31, 32, 38, 46, 54, 56, 57, 64, 74, 75, 77, 82, 85, 87, 89, 92, 93, 94, 95, 98, 99, 100, 103, 106, 107, 108, 109, 111, 112, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 129, 133, 134, 138, 139, 142, 146, 149, 150, 151, 153,

158, 159, 161, 163, 199, 206, 234, 243, 247, 249, 252, 315, 399, 430, 446, 457, 458, 460, 461, 462, 463, 464, 483, 485, 491, 498, 501, 502, 508, 517, 520, 521, 523, 526, 532, 537, 557, 558, 559, 560, 561, 562, 564, 582, 624, 632, 639, 642 insufficient sleep syndrome, 64, 72, 75, 77 intermediate, 82, 380, 381, 654 internal nasal valve, 202, 318, 323, 389 International Classification of Sleep Disorders (ICSD), 27, 457, 458, 465, 466, 483, 485, 490, 495, 501, 503, 506, 507, 524, 527, 539, 541, 557, 562, 584, 639, 645, 646, 649, 654 iron deficiency, 49, 94, 530 iron dextran, 105, 532 iron replacement therapy, 542 iron sucrose, 538 irregular sleep-wake rhythm disorder, 132, 140, 153 isolated tonsillectomy, 230

J Jejunoileal bypass, 412

K Klein-Levin syndrome, 466

L laryngomalacia, 362, 367, 584, 612, 613, 616 laser assisted uvulopalatoplasty (LAUP), 230, 341, 647 LATERA®, 326 lateral cephalography, 345 lateral pharyngoplasty, 429 laterodorsal tegmental (LTD), 15, 17 Lefort I osteotomy, 381, 388, 390 Lemborexant, 87, 462 lesbian, 109 lesbian, gay, bisexual, transgender, 109 Levator veli palatini, 338 levodopa, 93, 95, 96, 97, 100, 137, 140, 533, 545 lifestyle modification, 136, 233, 615 limb movements (LMs), 43, 50, 51, 65, 72, 76, 77, 80, 81, 101, 119, 126, 137, 142, 151, 152, 194, 196, 201, 207, 237, 405, 460, 494, 497, 508, 511, 528, 529, 535, 542, 544, 545, 546, 553, 555, 556, 559, 560, 561, 579, 580, 649 limit setting, 557 lingual tonsillectomy, 203, 231, 236, 299, 343, 345, 358, 363, 371, 429, 609, 618, 619

Index

M macroglossia, 196, 264, 286, 292, 354, 358, 608, 609, 616 maintenance of wakefulness test, 65, 142, 476 mammalian molecular clock, 480 mandibular advancement, 202, 206, 223, 225, 236, 241, 252, 259, 263, 264, 265, 268, 275, 277, 278, 279, 280, 286, 305, 383, 390, 424, 445, 452, 614, 648 mandibular advancement device, 202, 206, 241, 252, 259, 263, 264, 277, 278, 424, 445, 452, 648 mandibular advancement splint (MAS), 225, 226, 227, 231, 232, 233, 236, 279, 280 maxillary expansion(s), 203, 286, 377, 388, 389, 390, 391, 392, 590, 595, 596, 613, 616 maxillo-mandibular advancement (MMA), 288, 289, 293, 375, 376, 378, 379, 380, 381, 382, 383, 384, 387, 389, 390, 391, 647, 649 medical, 25, 27, 31, 32, 33, 34, 37, 39, 49, 52, 55, 72, 73, 76, 77, 79, 104, 132, 136, 137, 140, 145, 187, 195, 196, 198, 201, 203, 216, 239, 256, 269, 273, 275, 276, 277, 285, 290, 293, 304, 309, 313, 314, 320, 321, 322, 400, 405, 411, 412, 423, 424, 430, 431, 457, 458, 465, 466, 473, 488, 502, 508, 510, 511, 512, 516, 520, 521, 528, 541, 558, 576, 578, 587, 588, 589, 626, 627, 628, 629, 631, 636, 640, 641, 644 medical management, 321, 411 medical therapy, 104, 285, 293, 587, 589 medication(s), 9, 10, 17, 25, 27, 31, 32, 33, 34, 35, 37, 43, 48, 52, 55, 62, 69, 72, 73, 76, 77, 79, 86, 87, 88, 89, 91, 92, 93, 94, 96, 97, 98, 99, 100, 106, 123, 132, 133, 134, 137, 138, 139, 140, 141, 149, 154, 157, 196, 202, 216, 225, 240, 242, 254, 300, 305, 307,308, 316, 320, 322, 403, 427, 432, 441, 446, 450, 461, 462, 466, 469, 472, 473, 491, 498, 501, 502, 504, 505, 507, 508, 510, 511, 514, 516, 517, 518, 520, 529, 532, 534, 535, 537, 539, 540, 541, 542, 543, 556, 560, 578, 579, 581, 588, 594, 597, 599, 604, 605, 624, 632, 640 melatonin, 18, 24, 38, 39, 69, 73, 77, 79, 87, 98, 100, 103, 133, 143, 485, 489, 490, 491, 492, 493, 494, 496, 497, 505, 507, 512, 517, 520, 523, 560, 561, 562, 582, 641 Methadone, 95, 100, 450 Methylphenidate, 89, 469 midline estimating statistic of rhythm (MESOR), 481, 482 minute ventilation, 181, 248 Modafinil, 88, 92, 98, 99, 101, 102, 256, 432, 477 modified Mallampati, 160, 330

683 modified uvulopalatopharyngoplasty (modUPPP), 228, 229 mometasone furoate, 91 montelukast, 523, 589, 596, 604, 605 mood, 28, 29, 36, 38, 46, 49, 71, 99, 113, 114, 117, 118, 119, 143, 153, 199, 247, 314, 465, 473, 487, 494, 516, 557, 558, 560, 578, 639 morbid obesity, 195, 357, 411 Morphine CR, 95 mortality, 33, 34, 71, 157, 211, 215, 216, 217, 218, 221, 233, 236, 237, 254, 272, 278, 283, 295, 300, 304, 414, 417, 440, 441, 447, 450, 451 Müeller (Müller) maneuver, 285, 334, 339, 345, 347, 361 multilevel airway surgery, 229 multi-level surgery, 288, 300, 373, 428, 430 multiple sleep latency, 65, 142, 249, 471, 474, 476, 512, 553, 563, 578 multiple sleep latency test, 65, 142, 249, 474, 476, 512, 553, 563, 578 muscles of the tongue, 396 myoclonic jerks, 54, 515, 538, 541, 542, 544, 545, 650 myofunctional therapy, 234, 241, 244, 427, 434

N napping, 78, 98, 128, 131, 133, 149, 234, 236, 459, 466, 470, 551, 552, 578 narcolepsy, 10, 12, 43, 44, 46, 48, 62, 63, 64, 73, 76, 77, 82, 88, 92, 99, 100, 102, 103, 105, 137, 146, 209, 315, 462, 466, 467, 470, 471, 472, 474, 475, 476, 477, 508, 510, 512, 516, 517, 535, 552, 553, 556, 576, 577, 578, 579, 585, 648, 653 nasal expiratory positive airway pressure (EPAP), 225, 235, 237, 248, 638, 642 nasal obstruction, 161, 202, 226, 227, 234, 237, 252, 278, 284, 297, 313, 314, 315, 316, 317, 319, 321, 322, 327, 328, 329, 331, 332, 334, 388, 389, 390, 430, 445, 636 Nasal Obstruction Symptom Evaluation Survey (NOSE), 316 nasal surgery, 208, 258, 294, 297, 302, 308, 313, 323, 324, 329, 331, 332, 335, 343, 347, 390, 432, 435, 605 nasal treatment, 332 nasopharyngeal obstruction, 315, 318 neurostimulation, 395, 398, 655 neurotransmitters, 69, 90, 487 newborn, 553 nocturia, 128, 133, 135, 139, 151, 153, 160, 195, 253, 315, 440, 522 nocturnal leg cramps, 537

684

Index

nocturnal seizure(s), 44, 153, 162, 575 non-24-hour sleep-wake rhythm, 483 non-surgical treatment, 233, 587 NO-OSAS, 415 normative, 13, 143, 561

O obesity, 33, 34, 35, 36, 58, 61, 71, 72, 75, 82, 91, 101, 116, 119, 121, 135, 146, 147, 148, 170, 171, 173, 176, 178, 195, 201, 207, 213, 214, 217, 221, 225, 235, 240, 244, 247, 286, 293, 299, 317, 323, 330, 354, 357, 364, 368, 376, 411, 412, 413, 421, 422, 429, 463, 464, 532, 587, 588, 589, 593, 608, 614, 631 obesity hypoventilation, 34, 213, 247, 364 obesity hypoventilation syndrome (OHS), 33, 213, 247, 248, 256, 278, 364, 412, 413, 414, 417, 418, 421, 645, 649 oblique, 381, 396 occlusal splint, 381, 540, 543 opioid-induced CSA, 443, 444, 447 oropharyngeal exercises, 235, 241 orthognathic surgery, 381 OSA outcomes after bariatric surgery, 418 Oxycodone, 95 oxygen desaturation index, 284, 389, 416 Oxymetazoline, 92

P palatal treatment, 227 palatoglossus, 342, 343, 398 palatopharyngeus, 287, 342, 343, 425, 606, 607, 642 PAP Treatment, 245 parasomnia, 40, 47, 48, 56, 86, 98, 100, 119, 152, 159, 502, 503, 506, 509, 510, 519, 522, 525, 574, 575, 651, 654 partial glossectomy, 203, 287 patient education, 127, 140, 239, 271, 627 pediatric polysomnography (PSG), 29, 31, 32, 34, 42, 43, 44, 50, 51, 55, 59, 61, 62, 63, 97, 108, 110, 112, 113, 114, 115, 117, 120, 147, 149, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 167, 168, 170, 171, 194, 195, 200, 204, 283, 319, 340, 424, 458, 471, 474, 475, 502, 503, 506,508, 510, 511, 512, 516, 519, 521, 535, 553, 554, 555, 556, 559, 561, 562, 563, 567, 570, 571, 572, 573, 575, 578, 580, 582, 588, 589, 593, 601, 602, 604, 605, 613, 623, 624, 625, 626, 627, 629, 631, 636, 641, 644, 648, 650 pedunculopontine (PPN), 15, 16, 17

period, 4, 35, 38, 39, 41, 42, 47, 62, 63, 67, 68, 94, 108, 116, 124, 148, 149, 158, 170, 211, 217, 226, 232, 233, 247, 251, 255, 302, 303, 305, 306, 307, 310, 382, 384, 389, 416, 418, 445, 469, 480, 481, 483, 484, 485, 486, 492, 494, 495, 496, 508, 517, 551, 552, 576, 590, 605, 653, 654 periodic breathing, 31, 32, 182, 439, 440, 441, 444, 446, 555, 561, 569, 570, 572, 584 periodic limb movement, 43, 51, 76, 77, 80, 81, 101, 142, 151, 152, 196, 201, 460, 529, 544, 546, 556, 559, 560, 561 periodic limb movement disorder (PLMD), 42, 50, 80, 101, 137, 142, 160, 161, 460, 501, 535, 536, 537, 542, 543, 544, 546, 561, 579, 580, 581, 624, 646, 650 periodic limb movement index, 152 periodic limb movements of sleep (PLMS), 49, 50, 51, 55, 76, 77, 81, 136, 137, 151, 152, 528, 529, 535, 536, 537, 538, 542, 543, 544, 650 pharmacologic therapy, 137, 140 phase, 12, 38, 39, 73, 110, 112, 113, 114, 128, 132, 140, 141, 150, 160, 182, 333, 401, 460, 463, 470, 471, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 494, 495, 496, 497, 498, 558, 581, 582, 585, 637, 639, 654 phenotypes, 440, 480, 495, 517 PHOX2B mutation, 573 pitolisant, 89, 99, 102, 579 Poiseuille equation, 314 polymorphisms linked to RLS, 530 polysomnography, 4, 5, 6, 7, 8, 11, 13, 36, 64, 76, 93, 103, 108, 135, 140, 143, 147, 167, 195, 219, 224, 232, 233, 246, 248, 251, 256, 276, 331, 344, 414, 418, 420, 437, 441, 445, 458, 463, 471, 474, 488, 489, 503, 506, 536, 541, 542, 544, 553, 555, 559, 562, 563, 567, 588, 590, 593, 594, 598, 611, 619, 633, 639, 644, 652 positional therapy, 101, 136, 232, 233, 237, 241, 266, 271, 275, 277, 302, 414, 427, 432, 433 positional therapy if CPAP, 414 postoperative recommendations, 419 postpartum, 116, 124 pramipexole, 94, 96, 137, 140, 512, 525, 533, 537, 542, 543 pregabalin, 94, 102, 137, 140, 532, 537, 542, 543 pregnancy, 49, 102, 110, 114, 115, 116, 118, 119, 121, 123, 124, 412, 421, 457 premenstrual dysphoric disorder, 113, 126 preschool, 551 prevalence, 30, 47, 49, 109, 111, 112, 116, 122, 125, 132, 135, 147, 151, 152, 153, 155, 156, 157, 169, 170, 171, 172, 173, 176, 196, 214, 218, 220, 237, 260, 288, 330, 384, 413, 414, 418, 441, 444, 445,

Index 452, 470, 472, 473, 477, 484, 494, 504, 507, 525, 531, 536, 572, 577, 580, 593, 614, 616 progestin, 111 propiospinal myoclonus at sleep onset (PSM), 54, 541, 543, 544, 650 puberty, 41, 107, 110, 113, 465, 578, 581, 641

Q queer, 109

R radiofrequency ablation, 231, 234, 289, 327, 353, 366, 424, 609 radiofrequency assisted uvulopalatoplasty (RAUP), 230, 650 radiofrequency palate surgery (RFP), 228, 651 Ramelteon, 87, 93, 102, 462, 463 Ranine vein, 396, 397, 401 rapid eye movement (REM), 3, 4, 7, 8, 9, 10, 11, 12, 13, 17, 21, 23, 24, 25, 26, 31, 34, 40, 42, 43, 44, 46, 47, 48, 50, 56, 62, 65, 69, 70, 72, 74, 75, 76, 77, 80, 81, 89, 97, 98, 100, 103, 104, 105, 108, 110, 113, 114, 115, 118, 119, 120, 124, 125, 128, 133, 137, 138, 139, 141,143, 145, 150, 153, 156, 157, 158, 159, 162, 169, 171, 187, 195, 196, 201, 246, 288, 294, 316, 332, 419, 444, 451, 463, 468, 469, 470, 471, 474, 475, 499, 500, 501, 502, 503, 506, 509, 510, 511, 512, 513, 514, 516, 518, 519, 520, 521, 522, 523, 524, 525, 539, 542, 552, 553, 554, 569, 570, 574, 577, 578, 584, 624, 646, 648, 651, 653, 654, 655 reimbursement, 284, 625, 631, 632 REM behavior disorder, 81, 196, 201, 468, 501, 518, 519 REM sleep behavior, 9, 12, 72, 74, 75, 76, 77, 104, 118, 119, 124, 125, 137, 499, 502, 509, 521, 522, 523, 524, 525 REM sleep behavior disorder, 9, 12, 72, 74, 75, 76, 77, 104, 119, 124, 125, 137, 499, 502, 509, 521, 522, 523, 524, 525 respiratory, 19, 20, 22, 26, 28, 29, 30, 31, 33, 59, 60, 64, 75, 90, 152, 156, 167, 168, 169, 175, 182, 183, 184, 185, 186, 187, 189, 191, 193, 194, 230, 242, 243, 245, 246, 248, 252, 294, 300, 301, 302, 304, 305, 306, 307, 318, 319, 320, 329, 331, 341, 363, 382, 401, 402, 403, 404, 413, 416, 434, 439, 441, 443, 448, 452, 453, 462, 502, 506, 520, 553, 554, 555, 561, 562, 563, 564, 569, 572, 573, 575, 594, 614, 624, 625, 631, 633, 639, 648, 651, 652, 653

685 respiratory disturbance index, 64, 152, 230, 294, 363, 382, 614 respiratory effort related arousal, 29 restless legs syndrome (RLS), 42, 48, 49, 50, 55, 56, 72, 74, 75, 76, 80, 81, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 115, 117, 118, 124, 136, 137, 140, 142, 147, 151, 152, 155, 460, 501, 508, 523, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538,542, 543, 544, 545, 546, 547, 553, 556, 579, 580, 581, 583, 585, 646, 650, 652, 653, 655, 656 restless sleep disorder, 530, 545, 563 rhinomanometry, 160 rhythmic masticatory muscle activity (RMMA), 52, 539, 542 risk, 28, 29, 35, 39, 50, 53, 58, 59, 71, 72, 86, 87, 89, 91, 95, 98, 99, 100, 104, 107, 108, 109, 112, 113, 115, 116, 117, 118, 119, 120, 121, 123, 124, 132, 134, 135, 136, 139, 140, 146, 148, 149, 150, 155, 157, 158, 170, 172, 176, 195, 196, 197, 198, 201, 207, 208, 212, 213, 214, 215, 216, 217, 218, 220, 221, 230, 232, 233, 234, 239, 240, 242, 243, 246, 249, 254, 255, 256, 261, 271, 274, 283, 287, 289, 290, 293, 295, 298, 300, 301, 303, 304, 305, 306, 307, 330, 332, 335, 345, 353, 360, 376, 403, 412, 414, 415, 416, 417, 418, 419, 420, 421, 430, 450, 470, 471, 474, 476, 477, 480, 482, 485, 486, 487, 488, 496, 504, 505, 511, 512, 521, 522, 525, 531, 532, 534, 539, 541, 544, 556, 576, 580, 588, 592, 593, 594, 595, 601, 602, 609, 618, 624, 631, 632, 642, 649, 654 ropinirole, 94, 137, 140, 532, 537, 542, 543 rotigotine, 94, 96, 532, 535, 537, 542, 543 rotigotine transdermal patch, 532 Roux-en-Y gastric bypass, 413

S schedule, 38, 39, 44, 74, 76, 78, 85, 118, 128, 131, 132, 482, 483, 486, 490, 491, 492, 496, 558, 559, 560, 561, 574, 579, 581, 582, 631, 641 scoring, 4, 29, 51, 61, 65, 81, 168, 428, 554, 555, 561, 562, 563, 569, 603, 616, 627, 629, 630, 631, 633 secondary RLS, 530, 535 septoplasty, 227, 234, 252, 330 septoplasty and turbinoplasty, 227 sex and gender differences, 119 shift work disorder, 73, 485, 581 Sinonasal Outcomes Test 22, 316 sleep aids, 123, 134

686 sleep architecture, 10, 12, 22, 40, 70, 86, 117, 138, 159, 221, 225, 253, 259, 303, 309, 426, 470, 489, 553 sleep associations, 557, 559 sleep diary, 128, 129, 141, 142, 143, 160, 488, 520, 558 sleep disordered breathing, 57, 61, 64, 238, 313, 323, 366, 414, 443, 512, 518, 568, 585, 593, 625 sleep duration, 36, 37, 38, 67, 68, 70, 71, 74, 76, 77, 79, 81, 111, 112, 113, 119, 121, 122, 137, 138, 148, 151, 205, 234, 468, 470, 473, 504, 551, 552, 561, 576, 637, 649 sleep facility, 625, 627 sleep hygiene, 39, 78, 79, 81, 85, 98, 126, 133, 140, 242, 244, 290, 320, 458, 459, 482, 504, 505, 507, 508, 513, 514, 515, 561, 639 sleep medicine, 271, 563, 582, 590, 594, 627, 636, 637, 639, 649 sleep onset REM periods, 471, 474 sleep paralysis, 35, 75, 89, 470, 509, 512, 515, 516, 522, 525 sleep psychology, 225 sleep quality, 22, 67, 68, 73, 74, 76, 77, 78, 79, 82, 87, 108, 109, 110, 111, 114, 118, 120, 122, 123, 124, 128, 134, 135, 139, 153, 157, 195, 220, 222, 224, 241, 290, 293, 315, 322, 323, 324, 328, 329, 450, 491, 515, 534, 536, 559, 626, 650, 653 sleep related bruxism, 52, 540, 543 sleep related leg cramps, 538, 544 sleep stages, 4, 10, 61, 128, 141, 145, 187, 246, 489, 518, 552, 554, 628, 642 sleep surgery, 136, 284, 290, 301, 307, 424, 650 sleep terrors, 7, 44, 98, 159, 499, 503, 505, 522, 523, 525, 575 sleep-related rhythmic movement disorder (RMD), 540, 541, 543, 646, 652 sleepwalking, 7, 42, 44, 48, 72, 75, 88, 98, 462, 522, 523, 524, 525, 575, 576, 654 sleeve gastrectomy, 411 smoking, 29, 78, 196, 225, 240, 299, 316 snore, 220, 221, 222, 268, 299, 315 snoring, 29, 30, 31, 32, 57, 58, 75, 103, 135, 140, 142, 146, 147, 161, 162, 167, 195, 205, 206, 207, 214, 215, 217, 218, 219, 220, 221, 222, 224, 225, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 241, 244, 248, 249, 253, 263, 264, 266, 275, 277, 278, 279, 280, 283, 285, 290, 292, 295, 297, 315, 323, 324, 329, 330, 332, 334, 341, 342, 344, 345, 346, 347, 390, 419, 426, 441, 502, 506, 520, 567, 571, 583, 588, 606, 607, 615, 625, 648, 649, 651

Index social, 35, 36, 37, 39, 41, 45, 49, 50, 72, 107, 113, 114, 118, 128, 132, 217, 220, 284, 315, 483, 485, 486, 487, 513, 528, 534, 560, 652 sodium oxybate, 48, 88, 99, 100, 512 Solriamfetol, 89, 92, 100, 105, 469 spreader grafts, 326 stage N1, 5, 40, 50, 644 stage N2, 50, 149, 153 stage N3, 50, 153, 158, 159, 160, 500 stage R, 12 STOP Bang Questionnaire (STOP-BANG), 58, 160, 198, 204, 206, 305, 310, 415, 418, 654 stroke, 4, 29, 31, 43, 45, 62, 121, 136, 138, 155, 167, 201, 204, 212, 214, 215, 217, 233, 236, 247, 255, 256, 260, 295, 299, 304, 487, 624, 632, 639 styloglossus, 396 sublaterodorsal nucleus (SLD), 17 submucosal lingualplasty (SML), 358, 360 submucosal minimally invasive lingual excision (SMILE), 287, 358, 367, 609, 653 superchiasmatic nucleus (SCN), 18, 480, 484, 496 supplemental oxygen, 62, 156, 157, 162, 243, 301, 444, 629 suprachiasmatic nucleus, 69, 73, 462, 480 supraglottoplasty, 362, 367, 371, 613 surgical treatment, 225, 227, 231, 232, 233, 257, 275, 276, 299, 309, 314, 320, 341, 344, 377, 390, 391, 427, 431, 587, 615 surgically assisted rapid maxillary expansion (SARPE), 203, 388, 389, 391, 392, 641, 652 surgically assisted rapid palatal expander (SARPE), 203, 388, 389, 391, 641, 652 Suvorexant, 87, 98, 100, 103, 462

T tandospirone, 540, 543 Temazepam, 86, 100, 462 therapies, 85, 90, 91, 99, 123, 137, 140, 187, 200, 203, 232, 239, 333, 344, 418, 423, 431, 432, 446, 492, 521, 531, 533, 537, 538, 540, 543, 560, 561, 588, 619, 641, 649 tobacco, 160, 520 toddlers, 53, 68, 551, 557, 595 tongue surgery, 230, 304 tongue suspension, 353, 354, 371 tonsillectomy, 201, 202, 203, 230, 231, 236, 237, 287, 293, 297, 299, 303, 341, 342, 343, 344, 345, 347, 350, 358, 360, 363, 371, 429, 431, 445, 585, 592, 593, 595, 596, 597, 598, 601, 608, 609, 616, 617, 618, 619, 633, 642 tooth grinding, 51, 539, 540, 546 Topiramate, 98, 106, 521, 525, 526

Index tracheostomy, 155, 300, 364, 369, 445, 553, 613, 614 Tramadol, 95 transgender, 109 transoral robotic surgery (TORS), 287, 291, 292, 296, 350, 358, 360, 362, 363, 369, 370, 429, 435, 655 tranvenous phrenic nerve stimulation (TPNS), 448, 450, 655 Trazodone, 87, 90, 100, 102, 103, 106, 134 treatment of snoring, 226, 233, 278, 280, 346 Triazolam, 85, 462 type 2 diabetes, 121, 148, 213, 217, 496, 497, 569

U uvulopalatopharyngoplasty, 200, 201, 228, 229, 231, 233, 235, 237, 277, 280, 285, 294, 296, 309, 311, 334, 339, 347, 348, 353, 366, 367, 368, 371, 383, 606

V vasomotor flushes, 117, 124

687 velopharynx, 280, 286, 317, 340, 342, 429 Venlafaxine ER, 89, 100 ventrolateral preoptic nucleus (VLPO), 16, 73 vertical, 153, 268, 269, 277, 341, 425, 426, 608, 611 vitamin E, 538, 543 VOTE classification, 203, 224, 331, 432, 433, 434, 618, 656

W weight loss, 91, 136, 170, 201, 240, 266, 271, 275, 277, 284, 290, 296, 320, 323, 411, 412, 413, 417, 418, 422, 427, 432, 434, 469 Willis-Ekbom Disease (WED), 48, 527, 546, 652, 656

Z Zaleplon, 86, 100, 462 Z-drugs, 86, 90, 92 zeitgebers, 18, 479, 484, 492 Zolpidem, 48, 86, 87, 104, 123, 450, 462, 505, 520