Sleep Disorders: An Algorithmic Approach to Differential Diagnosis 3030653013, 9783030653019

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Sleep Disorders An Algorithmic Approach to Differential Diagnosis Ashima S. Sahni Ajay Sampat Hrayr Attarian Editors

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Sleep Disorders

Ashima S. Sahni  •  Ajay Sampat Hrayr Attarian Editors

Sleep Disorders An Algorithmic Approach to Differential Diagnosis

Editors Ashima S. Sahni Division of Pulmonary Critical Care, Sleep and Allergy Department of Medicine University of Illinois at Chicago Chicago, IL USA

Ajay Sampat Department of Neurology University of California, Davis Sacramento, CA USA

Hrayr Attarian Department of Neurology Northwestern University Feinberg School of Medicine Chicago, IL USA

ISBN 978-3-030-65301-9    ISBN 978-3-030-65302-6 (eBook) https://doi.org/10.1007/978-3-030-65302-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

“To my Ma, papa and sister who instilled the virtue of hard work; To my spiritual and academic mentors for being my guiding light; To my beloved husband, for his unwavering faith in me; To my dear daughter Arya, Dream big, work hard and the world be yours”. Love Ashima Synghal Sahni “To my foremost teachers, my patients and as always to my wife Diana Monaghan with unending love” Hrayr P. Attarian “To my parents, wife, and family for always believing in me, to my countless mentors and teachers for always supporting me, and to my daughter Riya – for showing me the true meaning of unconditional love and the real sleep deprivation of new parenthood.” Ajay Sampat

Preface

“Any mediocre doctor can make a diagnosis; the superior clinician comes up with a thorough differential diagnosis,” our professor pronounced emphatically. It is one of the few truisms that has remained with me from the time I was a medical student almost three decades ago. Despite being an old-school adage, differential diagnosis is still the most important tool in an accurate diagnosis and effective treatment. Sleep medicine is one of those fields where differential diagnosis is often ignored as, for a few decades now, almost everyone got a polysomnogram. The trend is slowly shifting primarily due to financial constraints. The current volume, Sleep Disorders: An Algorithmic Approach to Differential Diagnosis, provides the clinician with tools to do just that and help them explore all diagnostic possibilities both common and rare. Edited by two young and dynamic sleep experts, Drs. Ashima S. Sahni and Ajay Sampat, the book is geared towards both those in sleep medicine and in primary care. Dr. Sahni comes from a pulmonary critical care background and Dr. Sampat is a neurologist; thus, they bring to the project extremely important and unique points of view. Richly illustrated by case examples and images as well as detailed discussions, this essential publication comprehensively covers all aspects of sleep medicine. The contributing authors range from junior, mid-career, and senior faculty at major universities around the USA and each one brings a unique touch to the easy-to-read and detailed chapters. The book is divided into parts that are titled after patient complaints such as “snoring,” “sleepiness,” “nightmares,” etc. Given the current pandemic and the increasing emphasis on telehealth, the editors have included a cutting-edge chapter on the use of telemedicine in sleep disorder management. Lastly, the book addresses sleep complaints in both adult and pediatric populations. Sleep Disorders: An Algorithmic Approach to Differential Diagnosis in Sleep Medicine has all the elements to become a classic textbook. It is an essential addition to the literature both because of its unique style as well as the depth of its content. In short, it is a must read for anyone interested in clinical sleep medicine. Chicago, IL, USA

Hrayr Attarian

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Contents

Part I Adult Sleep Medicine 1 Sleepiness����������������������������������������������������������������������������������������������������   3 Alok Sachdeva 2 Insomnia�����������������������������������������������������������������������������������������������������  37 Sabra M. Abbott 3 Nocturnal Awakenings ������������������������������������������������������������������������������  51 Kenneth Lee 4 Restless Sleeper������������������������������������������������������������������������������������������  73 Eunice Torres Rivera and Roneil G. Malkani 5 Breathing Pauses����������������������������������������������������������������������������������������  95 Lindsay McCullough and Alejandra C. Lastra 6 Sleep Paralysis�������������������������������������������������������������������������������������������� 123 Ajay Sampat 7 Nightmares�������������������������������������������������������������������������������������������������� 145 Ann Augustine 8 Inpatient Sleep Consultation�������������������������������������������������������������������� 173 Ikuyo Imayama, Chithra Poongkunran, Matthew Chow, Ashima S. Sahni, Lisa F. Wolfe, and Bharati Prasad 9 Sleep Telemedicine ������������������������������������������������������������������������������������ 201 Sai S. Sunkara, Malvika Kaul, and Amar B. Bhatt Part II Peds Section 10 Snoring and Restlessness During Sleep in Children: Unique Presentations, Diagnosis, and Management�������������������������������������������� 225 Innessa Donskoy, Tanvi H. Mukundan, and Stephen H. Sheldon

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11 Restless Sleeper������������������������������������������������������������������������������������������ 243 Nimra Alvi, Sameer Alvi, and Innessa Donskoy 12 Obstructive Sleep Apnea and Weight Abnormalities in Children �������� 253 Irina Trosman and Samuel J. Trosman Index�������������������������������������������������������������������������������������������������������������������� 275

Contributors

Sabra M. Abbott, MD, PhD  Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Nimra Alvi, MD  Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL, USA Sameer Alvi, MD  Department of Otolaryngology, Northwestern Medicine Delnor Hospital, Geneva, IL, USA Hrayr Attarian, MD  Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Ann  Augustine, MD  Department of Neurology, Duke University School of Medicine, Durham, NC, USA Amar B. Bhatt, MD  Sections of Epilepsy and General Neurology, Department of Neurological Sciences, RUSH University Medical Center, Chicago, IL, USA Matthew Chow, MD  Department of Neurology, UC Davis School of Medicine, Sacramento, CA, USA Innessa  Donskoy, MD  Department of Pediatrics, Advocate Children’s Hospital, Park Ridge, IL, USA Ikuyo  Imayama, MD  Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA Malvika  Kaul, MD  Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois & Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA Alejandra  C.  Lastra, MD  Division of Pulmonary, Critical Care, and Sleep Medicine, Rush University Medical Center, Sleep Disorders Service & Research Center, Chicago, IL, USA Kenneth  Lee, MD  Department of Neurology, University of Chicago Medical Center, Chicago, IL, USA

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Roneil  G.  Malkani, MD  Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Lindsay  McCullough, MD  Division of Pulmonary, Critical Care, and Sleep Medicine, Rush University Medical Center, Sleep Disorders Service & Research Center, Chicago, IL, USA Tanvi H. Mukundan, MD  Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University/Portland VA Medical Center, Portland, OR, USA Chithra  Poongkunran, MD  Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Texas Health Science Center at Houston, Texas, USA Bharati  Prasad, MD  Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL, USA Eunice  Torres  Rivera, MD  Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Alok Sachdeva, MD  Michael S. Aldrich Sleep Disorders Center, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, USA Ashima S. Sahni, MD  Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA Ajay  Sampat, MD  Department of Neurology, UC Davis School of Medicine, Sacramento, CA, USA Stephen H. Sheldon, DO  Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Sai  S.  Sunkara, MD  Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois in Chicago & Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA Irina Trosman, MD  Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Samuel  J.  Trosman, MD  Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Lisa  F.  Wolfe, MD  Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Part I Adult Sleep Medicine

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Sleepiness Alok Sachdeva

Case 1: Obstructive Sleep Apnea (Also refer to Chap. 5, Case 1 for another presentation)

History A 55-year-old non-obese woman presents to a sleep medicine clinic complaining of sleepiness and fatigue. Shortly after the onset of menopause at the age of 51 years, she noticed decreased daytime energy, which started gradually and progressed slowly. She mentioned this to her primary care physician, who ruled out possible medical causes of fatigue, including hypothyroidism and anemia. Unfortunately, her fatigue persisted, and she eventually developed daytime sleepiness, at times necessitating a mid-day nap. She first noticed daytime sleepiness when recovering from influenza at the age of 53 years, and she initially attributed this symptom to her acute viral illness. When her daytime sleepiness had outlasted other viral symptoms by more than 1 month, she assumed the sleepiness was due to hormonal changes or to a depressed mood, which had been present since her youngest daughter left home for college 1 year earlier.

Differential Diagnosis • Insufficient sleep • Circadian rhythm sleep-wake disorder A. Sachdeva (*) Michael S. Aldrich Sleep Disorders Center, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 A. S. Sahni et al. (eds.), Sleep Disorders, https://doi.org/10.1007/978-3-030-65302-6_1

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• • • • •

A. Sachdeva

Sleep-disordered breathing Post-viral hypersomnia Mood disorder Sleepiness due to a medication/substance Sleep-related movement disorder

History Continued The patient’s husband often complains that she snores loudly and is a restless sleeper. In addition, she has awakened from sleep a few times with shortness of breath and gasped for air. When she wakes up in the morning, her mouth is often dry and she sometimes has a sore throat. She wakes up approximately 2–4 times per night for unknown reasons or to urinate, and she can usually fall back asleep quickly. She denies morning headaches. She denies symptoms consistent with parasomnia or narcolepsy. She also denies symptoms of restless legs syndrome, though she has had intermittent burning pain in her toes on both feet for a few months. Her depressed mood has improved since sertraline was started about 3 months ago. She also sees a therapist every 6 months. However, she still at times has difficulty falling asleep and may wake up earlier than she would like. A few times per month, she takes diphenhydramine, which helps her fall asleep, but does not improve sleep quality.

Sleep Schedule/Sleep Hygiene The patient sleeps in a queen-size bed with her husband. They read in bed, but do not use electronics in bed and do not watch television at bedtime. She usually sleeps on her side or her back, and her husband has noticed that she snores more loudly on her back. Time in bed: 10:30 PM Lights out: 11:00 PM Sleep onset latency: 15 minutes; 1–2 times per week, up to 90 minutes Sleep aids: Diphenhydramine 25–50 mg a few times per week Number of awakenings: 3–4 per night Cause of awakenings: Unknown, or to urinate Wake after sleep onset time: 5–10 minutes per awakening Wake time: 7:30  AM; a few times per week, she wakes at 630 AM Rise time: Same as wake time Naps: Approximately 2 per week, usually from 1 to 2 PM. Naps are not refreshing. Total sleep time: Approximately 7–8 hours per 24-hour period

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Scales/Questionnaires STOP-BANG Scale: Epworth Sleepiness Scale: Fatigue Severity Scale: Patient Health Questionnaire-9:

4 points (high risk of obstructive sleep apnea) 13 points (excessive daytime sleepiness) 37 points (clinically relevant fatigue) 8 points (mild depression)

Past Medical History • • • •

Non-insulin-dependent type 2 diabetes mellitus Hypertension Depressive disorder NOS Seasonal allergies

Past Surgical History • Tonsillectomy in childhood • Cholecystectomy at age 43 years

Allergies • Pollen • Dust • Fluoroquinolone antibiotics

Medications • Metformin • Sertraline • Lisinopril •  Fluticasone nasal • Diphenhydramine

1 G PO BID 50 MG PO QAM 10 MG PO QAM 1–2 sprays in each nostril QAM PRN for nasal congestion 25–50 MG PO QHS PRN difficulty sleeping

Family History • • • •

Type 2 diabetes mellitus, father Coronary artery disease, mother Obstructive sleep apnea, mother and brother Ischemic stroke, maternal grandfather

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Social History She is married and has 2 children. Her youngest child is 19 years old and recently left home for college. The patient is a homemaker, and lives at home with her husband. She does not smoke cigarettes or drink alcohol. She does not use recreational drugs.

Review of Systems All systems were reviewed, and all concerns are noted above in the patient’s history.

Vital Signs Blood pressure: 123/76 mmHg Heart rate: 72 beats per minute Respiratory rate: 14 breaths per minute Height: 5 feet 3 inches Weight: 159 pounds BMI: 28 kg/m2

Physical Examination General: Eyes: ENT:

Normal body habitus. No apparent distress. No conjunctival erythema, no scleral icterus. Ears unremarkable, hearing intact, nasal airflow unrestricted, nasal septum deviated to right, inferior nasal turbinates unremarkable, tongue large with scalloping, hard and soft palate unremarkable, uvula long, tonsils not visible, Friedman Class 3 airway. Neck: 12.5-inches neck circumference, no cervical lymphadenopathy. Respiratory: Clear to auscultation bilaterally, no wheezing/rhonchi/crackles. Cardiovascular: Regular rate and rhythm, no murmur, rubs or gallops. No carotid bruit. Musculoskeletal: Normal gait and station. Extremities: No cyanosis, clubbing, or edema. Skin: No rash, lesions ulcers, induration, or nodules in visible regions. Neurologic: Cranial nerves II–XII are intact. Mental status: Alert and fully oriented, judgment and insight are good, her mood is “Down.”

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Differential Diagnosis • Obstructive sleep apnea • Depressive disorder NOS • Sleepiness due to use of diphenhydramine

Diagnostic Testing Diagnostic Polysomnogram (PSG) Total sleep time: 315 minutes Latency to sleep: 53.5 minutes REM latency: 67 minutes Wake after sleep onset: 44.5 minutes Sleep efficiency: 76.1% Apnea-hypopnea index (AHI): 18.5 events per hour of sleep REM AHI: 33.3 events per hour of sleep AHI with 4% O2 desaturation: 2.5 events per hour Obstructive apnea index: 0.0 events per hour Central apnea index: 0.0 events per hour Hypopnea index: 18.5 events per hour Mean sleep % SpO2: 97% Min sleep % SpO2: 87% Periodic limb movement index: 5.5 limb movements per hour

Assessment Symptoms of fatigue, sleepiness, loud snoring, snort arousals, and frequent nocturnal awakenings in this post-menopausal woman with a crowded oropharynx are consistent with her polysomnographic diagnosis of moderate obstructive sleep apnea (OSA) (Figs.  1.1 and 1.2). While mild depression and intermittent use of diphenhydramine as a sleep aid could contribute to sleep fragmentation and reduced daytime energy, these factors are unlikely to be the primary cause of the patient’s symptoms. Diagnosis  Obstructive sleep apnea

Treatment The patient’s sleepiness and fatigue resolved after 1 month of consistent use of auto-­ titrating continuous positive airway pressure (CPAP) for an average of 6 hours per night. Her mood also improved with this treatment, and she was able to discontinue use of diphenhydramine at bedtime.

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Discussion Obstructive sleep apnea is caused by recurrent obstruction of the upper airway during sleep with resulting transient absence of airflow (apnea) or reduction of airflow (hypopnea) despite continued respiratory effort. Apneas and/or hypopneas cause transient hypoxemia, arousals from sleep, or both. A diagnosis of OSA requires five or more obstructive respiratory events per hour in a patient with symptoms of OSA (habitual snoring, witnessed apneas, etc.) or certain comorbidities (hypertension, coronary artery disease, etc.). Alternatively, OSA can be diagnosed if there are 15 or more obstructive respiratory events in the absence of symptoms or associated medical conditions [1]. The number of apneas and hypopneas per hour of sleep (with EEG) or recording time (without EEG) is called the apnea-hypopnea index (AHI) and is a measure of OSA severity (an AHI of 5–15 is “mild,” 15–30 is “moderate,” and greater than 30 is “severe”). The patient in the above case has an AHI of 18.5 (“moderate” OSA). OSA is a relatively common condition with an estimated global prevalence of approximately 3–7% [2]. In the United States, the prevalence of OSA is approximately 15% in men and 5% in women [3]. Risk factors for OSA include increasing age, male gender, obesity, menopause, craniofacial anomalies (e.g., retrognathia), and a family history of OSA. Many studies have confirmed that menopause independently increases the risk of OSA after adjusting for confounding factors; one study showed that post-menopausal women have approximately threefold increased odds of “moderate” OSA (an AHI greater than or equal to 15 events per hour) compared to perimenopausal women [4, 5]. In addition to her increased risk for OSA as a post-menopausal woman, the patient in the above case reports loud snoring, gasp arousals, and excessive daytime sleepiness (EDS), all of which are clinical features commonly encountered in patients with OSA. The Epworth Sleepiness Scale (ESS), a validated measure of one’s average sleep propensity, is often used to quantify sleepiness in patients with and without OSA [6]. ESS scores greater than 10 are indicative of EDS. ESS scores have been shown to increase with the severity of OSA as measured by the respiratory disturbance index (RDI; the average number of obstructive apneas, hypopneas, and respiratory-event-related arousals per hour) [7]. However, one study did not find a statistically significant association between one’s ESS score and AHI, and a “normal” ESS does not rule out OSA [8]. Because EDS in patients with OSA can increase the risk of accidents/injuries and decrease quality of life, many studies have attempted to identify predictors of EDS in patients with OSA [9]. OSA severity as measured by the AHI or RDI does seem to correlate to increased sleepiness, but appears to be less important than sleep fragmentation (total arousals, arousal index, etc.) in provoking excessive sleepiness [10–12]. In addition, intermittent nocturnal hypoxemia without sleep fragmentation does not worsen daytime sleepiness in OSA patients treated with continuous positive airway pressure (CPAP) [13]. Other factors that may be predictive of EDS in

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OSA patients include severe snoring, increased sleep efficiency, and increased total sleep time [14, 15]. Although subjective sleepiness is often reported by patients with OSA, its absence does not rule out OSA; in certain populations of OSA patients, sleepiness may be reported less frequently than fatigue, tiredness, or low energy [16]. Treatment of OSA with CPAP has been shown to result in a greater reduction of subjective (ESS) and objective (multiple sleep latency test; MSLT) measures of sleepiness relative to placebo [17]. Severe OSA (AHI  ≥  30), EDS, a high body movement index (number of body movements per hour of sleep), and high variability of EEG sleep depth have been shown to be predictive of a greater reduction in sleepiness following CPAP therapy [17, 18]. One study showed that increased alertness (as measured by a modified maintenance of wakefulness test) following CPAP therapy correlated strongly with a reduction in measures of sleep fragmentation [19]. Indeed, subjective (Stanford Sleepiness Scale) and objective (MSLT) sleepiness may improve after only one night of CPAP use, and one subsequent night without CPAP can return sleepiness to its pre-treatment level [20]. A linear dose-response relationship (p  10) in patients with OSA corresponds to higher rates of long-term (3+ years) CPAP use, possibly due to a greater perceived benefit from treatment [22]. While the sleepiness of the patient in the above case resolved after treatment with CPAP, some OSA patients struggle with persistent EDS despite CPAP use. In such cases, it is important to ensure complete treatment efficacy and excellent treatment adherence. If the patient struggles with EDS despite optimal CPAP efficacy and adherence, inadequate sleep hygiene and insufficient sleep should be corrected. When clinically indicated, other sleep disorders (e.g., narcolepsy) and medical conditions known to cause sleepiness should be investigated and treated if present (Fig. 1.7) [23]. For OSA patients with EDS despite effective and regular CPAP use in whom no other treatable causes of EDS are present, the wake-promoting medication modafinil may be prescribed and is approved by the Food and Drug Administration (FDA) of the United States of America (USA) for use in this patient population. The efficacy and tolerability of modafinil (for up to 12 weeks) in OSA patients with refractory EDS despite effective CPAP therapy has been shown in a number of randomized, double-blind, placebo-controlled trials [24, 25].

Key Learning Points • Patients with OSA often complain of EDS. • It is important to ask patients about decreased energy or fatigue; the absence of EDS does not rule out OSA.

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• Sleep fragmentation is one of the most important causes of sleepiness in patients with OSA. • Intermittent nocturnal hypoxemia is not a major contributor to EDS in patients with OSA. • Other factors that may predict EDS in OSA patients include severe snoring, increased sleep efficiency, and increased total sleep time. • Treatment of OSA with CPAP can reduce sleepiness, an effect that is due in part to reduced sleep fragmentation. • A longer duration of nightly CPAP use results in a greater reduction in daytime sleepiness. • Greater pre-treatment sleepiness in patients with OSA corresponds to higher rates of long-term CPAP use. • If a patient has EDS despite excellent CPAP efficacy and adherence, sleep hygiene and sleep duration should be optimized. When clinically indicated, other sleep disorders (e.g., narcolepsy) and medical conditions known to cause sleepiness should be investigated and treated if present. • The efficacy and tolerability of modafinil for OSA patients with refractory EDS despite effective CPAP treatment has been shown in a number of randomized, double-blind, placebo-controlled trials.

Fig. 1.1 A 90-second epoch shows an obstructive hypopnea during rapid eye movement (REM) sleep

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Fig. 1.2  A hypnogram shows REM-predominant obstructive sleep apnea, exclusively in the form of obstructive hypopneas

Case 2: Narcolepsy Type 1 History A 23-year-old obese man presents to a sleep medicine clinic complaining of daytime sleepiness. Approximately 4 years ago, when he was a sophomore in college, the patient noticed daytime sleepiness that made it difficult for him to stay awake during lectures and complete assigned coursework. A brief afternoon nap would at times reduce his sleepiness, but the benefit was never sustained. The patient’s academic performance began to decline, so he sought help at the university’s Student Health Services (SHS) office. An SHS physician elicited a history of evening marijuana and alcohol use during weekend social outings with friends, often followed by brief low-quality nocturnal sleep. In addition to recommending cessation of alcohol and marijuana use, the physician ordered a polysomnogram (PSG), which showed mild intermittent snoring without obstructive sleep apnea. A complete blood count and comprehensive metabolic panel also were normal.

Differential Diagnosis • • • • • • •

Insufficient sleep Circadian rhythm sleep-wake disorder Sleep-disordered breathing Central disorder of hypersomnolence (e.g., narcolepsy) Mood disorder (e.g., atypical depression) Sleepiness due to a medication/substance Sleep-related movement disorder

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History Continued Despite discontinuing use of alcohol and marijuana, and ensuring that he slept for at least 7 hours per night, the patient remains sleepy during the day. A few times, he has fallen asleep quickly at work despite his best efforts to remain awake. During the past 4 months, he has also had three episodes of muscle weakness triggered by mirth and laughter. Twice the weakness only affected his face, and once his legs also became weak, causing him to slump to the ground. He remained conscious during these episodes, all of which gradually resolved within 1 minute. Also, approximately once per month during the past year, he has awakened from sleep and been unable to move his body for 10–20 seconds prior to regaining normal motor function. He had experienced this in college as well, but it never occurred more than a few times per year. He denies hypnagogic or hypnopompic hallucinations. His girlfriend told him that he snores loudly at times, but she has never witnessed apneas. He denies symptoms consistent with parasomnia, and denies symptoms of restless legs syndrome. Due in part to occupational and social distress resulting from the above symptoms, the patient endorses a depressed mood.

Sleep Schedule/Sleep Hygiene The patient sleeps alone or with his girlfriend in a full-size bed. He uses his smart phone in bed and watches television in bed. He usually falls asleep on his back, and his girlfriend tells him that he tosses and turns at night, frequently changing his body position. Time in bed: 10:00 PM Lights out: 10:15 PM Sleep onset latency: 5 minutes or less Sleep aids: None Number of awakenings: 0–1 Cause of awakenings: Unknown Wake after sleep onset time: 10–15 minutes Wake time: 6:00 AM Rise time: 6:15 AM Naps: Daily, usually from 12:00 to 12:30  PM.  Naps are refreshing. Total sleep time: Approximately 8 hours per 24-hour period

Scales/Questionnaires STOP-BANG Scale: 2 points (low risk of obstructive sleep apnea) Epworth Sleepiness Scale: 19 points (excessive daytime sleepiness) Patient Health Questionnaire-9: 11 points (moderate depression)

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Past Medical History • Asthma • Obesity • Depressive disorder NOS

Past Surgical History • Adenotonsillectomy at age 4 years • Appendectomy at age 9 years

Allergies • Nuts • Shellfish • Penicillin

Medications •  Albuterol inhaler •  Men’s multivitamin •  Epinephrine (EpiPen)

2 puffs PO BID PRN wheezing One tablet PO QAM 0.3 MG SQ 1–2 times PRN anaphylaxis

Family History • • • •

Celiac disease, mother Depression, father Hypertension, paternal grandfather Rheumatoid arthritis, sister and maternal grandmother

Social History He is unmarried and in a stable relationship with his girlfriend. After completing a bachelor’s degree in accounting and passing his Certified Public Accountant (CPA) examination, he started working at a local accounting firm. He lives alone in an apartment. The patient does not smoke cigarettes and rarely drinks small amounts of alcohol with friends. He does not use recreational drugs.

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Review of Systems All systems were reviewed, and all concerns are noted above in the patient’s history.

Vital Signs Blood pressure: 112/70 mmHg Heart rate: 64 beats per minute Respiratory rate: 12 breaths per minute Height: 6 feet 2 inches Weight: 268 pounds BMI: 34 kg/m2

Physical Examination General: Eyes: ENT:

Obese body habitus. No apparent distress. No conjunctival erythema, no scleral icterus. Ears unremarkable, hearing intact, nasal airflow unrestricted, nasal septum midline, inferior nasal turbinates unremarkable, tongue large without scalloping, hard and soft palate unremarkable, uvula normal, tonsils not visible, Friedman Class 2–3 airway. Neck: 15.5-inches neck circumference, no cervical lymphadenopathy. Respiratory: Clear to auscultation bilaterally, no wheezing/rhonchi/crackles. Cardiovascular: Regular rate and rhythm, no murmur, rubs or gallops. No carotid bruit. Musculoskeletal: Normal gait and station. Extremities: No cyanosis, clubbing, or edema. Skin: No rash, lesions ulcers, induration, or nodules in visible regions. Neurologic: Cranial nerves II–XII are intact. Mental status: Alert and fully oriented, judgment and insight are good, and he describes his mood as “Not very good.”

Differential Diagnosis • Narcolepsy type 1 • Depressive disorder NOS • Sleep-disordered breathing

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Diagnostic Testing Actigraphy and Sleep Diary (2 Weeks) • Regular bedtimes (10:00 PM) and get-up times (6:00–6:30 AM) without circadian rhythm abnormality, and with an average estimated total sleep time of 8 hours per 24-hour period. • Average sleep onset latency of 5 minutes and sleep efficiency of 86%. • Actigraphy supported the content of the sleep diary without significant discrepancies. Diagnostic Polysomnogram (PSG) with End-Tidal CO2 Monitoring Total sleep time: 481 minutes Latency to sleep: 12 minutes Rapid-eye-movement (REM) latency: 100 minutes Wake after sleep onset: 21 minutes Sleep efficiency: 93.4% Apnea-hypopnea index (AHI): 2.2 events per hour of sleep REM AHI: 0.4 events per hour of sleep AHI with 4% O2 desaturation: 2.5 events per hour Obstructive apnea index: 0.1 events per hour Central apnea index: 0.5 events per hour Hypopnea index: 1.6 events per hour Mean sleep % SpO2: 96% Min sleep % SpO2: 85% End-tidal CO2: No evidence of sleep-related hypoventilation Periodic limb movement index: 0.0 limb movements per hour Urine toxicology screen (the morning preceding the multiple sleep latency test): Negative Multiple Sleep Latency Test (MSLT)

Assessment Symptoms of excessive daytime sleepiness, sleep attacks, cataplexy, and recurrent sleep paralysis in this obese young man are strongly suggestive of narcolepsy type 1. This diagnosis was confirmed by studies that showed adequate total sleep time, a normal circadian rhythm, the absence of sleep-disordered breathing (Fig. 1.3), and three sleep-onset REM periods (SOREMPs) on MSLT with a mean sleep latency of 3 minutes (Table 1.1 and Fig. 1.4). Diagnosis  Narcolepsy type 1

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Table 1.1  A chart of five naps shows a mean sleep onset latency of 3 minutes and three sleep-­ onset REM periods (SOREMPs), occurring in the last three naps Results Time test began Time to bed (min) Latencies to (min)  First sleep epoch  Three consecutive sleep epochs  Stage 2 REM sleep Number of REM periods = 3

NAP1 NAP2 NAP3 NAP4 NAP5 Mean 07:56:42 10:04:12 11:58:12 13:56:42 16:02:12 18.5 24.0 17.5 18.5 15.0 4.0 4.0 20 None

7.5 9.5 20.5 None

1.5 1.5 3.5 6.5

2.0 4.0 5.0 5.5

0.0 2.5 2.5 3.5

3 4.3 10.3

Treatment Modafinil was prescribed and significantly reduced the patient’s daytime sleepiness at a dose of 200 MG in the morning. Extended-release venlafaxine also was prescribed for cataplexy and has resulted in resolution of cataplexy at a dose of 75 MG per day; this medication also reduced the severity of the patient’s depressed mood. He established care with a psychotherapist, who he sees every 6 months, and he joined an exercise group that meets three times per week at a local gymnasium. The patient occasionally takes a brief mid-day nap at work and his productivity has increased since he started the treatments above. He continues to sleep at least 7 hours each night and he never drinks alcohol.

Discussion Narcolepsy results from impairment of the orexin (also known as hypocretin) signaling pathway in the brain. Orexin is a wake-promoting neuropeptide made by neurons in the lateral hypothalamus. Patients with narcolepsy type 1 (narcolepsy with cataplexy) have up to 90% less orexin-producing hypothalamic neurons [26]. As a result, these patients have absent or severely deficient (≤110 pg/mL) orexin in their cerebrospinal fluid (CSF) [27]. Due to practical limitations, however, CSF analysis is not routinely performed in the evaluation of patients with suspected narcolepsy. The cause of narcolepsy type 2 (narcolepsy without cataplexy) is unknown, and the majority of these patients have normal CSF orexin levels; it is possible that these patients have abnormal orexin receptors, leading to functional impairment of orexin signaling despite normal orexin levels. Structural damage to orexin-producing neurons and/or pathways can cause secondary narcolepsy, which may be due to neurosarcoidosis, ischemic or hemorrhagic stroke, or neoplasm, for example. The patient in the above case has narcolepsy type 1. In order to diagnose narcolepsy type 1, a patient must have the following: • Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months • One or both of the following:

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–– Cataplexy and a mean sleep latency of ≤8 minutes and two or more SOREMPs on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT. –– CSF hypocretin-1 concentration, measured by immunoreactivity, is either ≤110 pg/mL or less than one-third of mean values obtained in normal subjects with the same standardized assay [28]. Therefore, the above patient meets diagnostic criteria for narcolepsy type 1 based upon a daily irrepressible need to sleep for more than 3 months, cataplexy, a mean sleep latency of 3  minutes, and three SOREMPs on an MSLT.  In addition, there is not an alternative explanation for the patient’s sleepiness (e.g., sleep-disordered breathing), and the SOREMPs are not better explained by sleep deprivation or circadian disruption. Narcolepsy type 1 is uncommon, with an estimated prevalence of up to 1 in 2000 people based primarily on populations of men and women in the United States of America (USA) and Europe [29]. As seen in the above case, symptom onset usually occurs in one’s late teens or early twenties, though initial symptoms at younger and older ages have also been reported. The DQB1*0602 haplotype is found in up to 95% of narcolepsy patients with cataplexy, prompting some scientists to propose that narcolepsy may be triggered by an autoimmune process [30]. It is important to note, however, that the DQB1*0602 haplotype also may be found in 12–30% of the general population, and its presence is therefore not confirmatory of narcolepsy, only supportive of this diagnosis in the right clinical context [31]. Further support for the autoimmune hypothesis derives from studies showing narcolepsy type 1 onset in European patients after administration of the AS03-adjuvanted 2009 H1N1 influenza vaccine, and an April peak of narcolepsy onset in Chinese patients possibly due to winter infection [32, 33]. While the majority of cases of narcolepsy type 1 are sporadic, familial narcolepsy has been reported and the precise genetic mechanisms are unknown. Narcolepsy is fundamentally a disorder of sleep-wake regulation with sleepiness during wakefulness, REM sleep intrusion into wakefulness, prominent sleep fragmentation, and rapid sleep onset. The primary, universal clinical feature of narcolepsy is excessive daytime sleepiness (EDS), which may occur in isolation. Patients with narcolepsy usually have an Epworth Sleepiness Scale score greater than 15, which is significantly higher than that of patients with EDS due to other sleep disorders such as obstructive sleep apnea (OSA) [34]. The sleepiness of narcolepsy is functionally disabling, and may be of maximal severity at onset or worsen gradually over a few years. A relatively high proportion of narcolepsy patients will have sleepiness-­related motor vehicle accidents, and clinicians should counsel patients about safe driving practices [35]. Patients with narcolepsy type 1 or type 2 can also suffer from episodes of sudden-onset, irrepressible daytime sleep sometimes called “sleep attacks.” Naps are classically refreshing for patients with narcolepsy, whereas a patient with OSA may feel sleepier after a nap than they did before it.

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In addition to EDS, patients with narcolepsy may report symptoms consistent with cataplexy, hallucinations during periods of sleep-wake transition (usually hypnagogic), or sleep paralysis (usually upon awakening). However, a minority of narcolepsy patients report all of the above symptoms at the time of initial presentation [36]. Cataplexy is the symptom most specific to narcolepsy, but it does not occur in patients with narcolepsy type 2, and its absence does not rule out narcolepsy of either type. Cataplexy and sleep paralysis are manifestations of REM sleep dysregulation during which the muscle atonia of REM sleep intrudes into periods of wakefulness [37]. Both hypnagogic hallucinations and sleep paralysis can occur in patients without narcolepsy, but usually occur less frequently than in patients with narcolepsy. Patients with narcolepsy have been found to have a higher average body mass index (BMI) than the general population, and clinicians must consider the possibility of comorbid OSA in narcolepsy patients with refractory EDS (Fig. 1.7) [38]. In addition to OSA, it is important to screen for other sleep disorders in patients with narcolepsy; restless legs syndrome (RLS) and REM-sleep behavior disorder (RBD), for example, are more common in patients with narcolepsy than in the general population [39]. Depression and anxiety also are more prevalent in patients with narcolepsy, and it is important to identify and treat these psychiatric comorbidities [40]. Both non-pharmacologic and pharmacologic treatments may be used for patients with narcolepsy. It is important for narcolepsy patients to maintain healthy sleep hygiene and abstain from the use of alcohol and recreational drugs. Brief, scheduled daytime naps may reduce daytime sleepiness and are most beneficial if a patient has consistent sleep and wake times during the dominant (usually nocturnal) sleep period [41]. A number of wake-promoting and stimulant medications are approved for the treatment of EDS in patients with narcolepsy; these include modafinil, armodafinil, methylphenidate, amphetamines, and most recently solriamfetol (a norepinephrine-dopamine reuptake inhibitor) [42–44]. Sodium oxybate, a gamma-­aminobutyric acid (GABA) derivative, may improve both cataplexy and EDS in patients with narcolepsy [45]. Antidepressant mediations such as venlafaxine, fluoxetine, and clomipramine also are effective treatments for cataplexy; after sustained treatment, rapid withdrawal of these medications can cause a prolonged state of rebound cataplexy (“status cataplecticus”) [31]. Initial randomized studies have shown that pitolisant, a histamine H3-receptor inverse agonist, outperforms placebo for the treatment of EDS and cataplexy in narcolepsy patients, and clinical trials of this medication are ongoing [46].

Key Learning Points • Narcolepsy occurs due to impaired orexin (hypocretin) signaling in the central nervous system (CNS). • Patients with narcolepsy type 1 (narcolepsy with cataplexy) have up to 90% less orexin-producing neurons in the lateral hypothalamus and absent or severely deficient (≤110 pg/mL) orexin in the cerebrospinal fluid (CSF).

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• The age of narcolepsy onset is usually in one’s late teens or early twenties, though late-onset narcolepsy in the fourth or fifth decade of life also has been reported. • The DQB1*0602 haplotype is found in 95% of narcolepsy patients with cataplexy; however, the DQB1*0602 haplotype also may be found in 12–30% of the general population, and its presence must be interpreted in light of other diagnostic tests and patient’s clinical symptoms. • The primary, universal clinical feature of narcolepsy is EDS and the corresponding Epworth Sleepiness Scale score is usually ≥15 points. • Cataplexy, hallucinations during periods of sleep-wake transition (usually hypnagogic), and sleep paralysis (usually upon awakening) also may occur in narcolepsy patients, though only one-third of narcolepsy patients report EDS and all of the above symptoms during their initial presentation. • Cataplexy is the most specific narcolepsy symptom, but does not occur in patients with narcolepsy type 2. • Obesity, other sleep disorders (e.g., obstructive sleep apnea), and certain psychiatric disorders (e.g., anxiety and depression) are more common in narcolepsy patients than in the general population. • Clinicians should counsel narcolepsy patients about the risk of motor vehicle accidents, and review safe driving practices. • Pharmacologic treatments for EDS in narcolepsy patients include modafinil, armodafinil, methylphenidate, amphetamines, solriamfetol, and sodium oxybate. Pitolisant shows promise for the treatment of EDS and cataplexy; clinical trials are ongoing.

Fig. 1.3  A hypnogram shows the absence of sleep-disordered breathing, normal sleep architecture, and a short sleep onset latency

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Fig. 1.4  A hypnogram from the multiple sleep latency test (MSLT) shows sleep during all five naps and SOREMPs during the final three naps

Case 3: Idiopathic Hypersomnia History A 25-year-old non-obese woman presents to a sleep medicine clinic complaining of daytime sleepiness. Approximately 1 year ago, as she was completing a master’s program in Library and Information Studies, daytime sleepiness began to limit the patient’s ability to complete research efficiently and decreased her productivity as an assistant manager of the university’s digital archives. While there was no direct trigger for this symptom, 4 months prior to noticing sleepiness, the patient had been informed that her closest childhood friend had died in an automobile accident, a tragedy that provoked within the patient feelings of sadness, guilt, and regret. She sought help from a university psychiatrist, who diagnosed the patient with atypical depression and prescribed sertraline as well as a course of cognitive behavioral therapy (CBT). The patient was also encouraged to commit to a regular schedule of exercise. Basic laboratory studies, including a complete blood count (CBC), comprehensive metabolic panel, thyroid stimulating hormone (TSH), 25-hydroxy-­ vitamin D level, and vitamin B12 level were normal.

Differential Diagnosis • • • •

Mood disorder (e.g., atypical depression) Insufficient sleep Circadian rhythm sleep-wake disorder Sleep-disordered breathing

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• Central disorder of hypersomnolence (e.g., narcolepsy) • Sleepiness due to a medication/substance • Sleep-related movement disorder

History Continued Despite improvement of her mood, the patient reports that daytime sleepiness has worsened. She must drink 1–2 caffeinated beverages every morning and every few hours during the work day to stay alert and accomplish her tasks. Even with caffeine, she struggles to get through a day without taking a nap, though naps do not usually reinvigorate her. She also has had difficulty awakening from naps, and planned 20-minute lunchtime naps have unintentionally lasted up to 3 hours. As a result, the patient now sets three alarms when she naps in her office, and will sometimes ask a fellow librarian to wake her up if she is still asleep after 1 hour. The patient’s husband has told her that she is similarly difficult to awaken if she naps at home on the weekend, and he must help her wake up in the morning to get to work on time or she may oversleep multiple alarms. Approximately five times in the past year, she saw vivid, frightening images as she fell asleep; for example, she once saw a tiger jump through her bedroom window towards her, then disappear. She denies sleep paralysis, cataplexy, and sleep attacks. The patient frequently talks in her sleep and has a history of sleepwalking in childhood, but denies sleepwalking currently. Her husband has never seen her act out her dreams. She snores lightly at times, but her husband has never witnessed apneas. Rarely, she may wake up in the morning with a mild headache that usually resolves spontaneously after 1 hour. When she was 6 years old, the patient was diagnosed with mild obstructive sleep apnea, which resolved following adenotonsillectomy. The patient denies symptoms of restless legs syndrome.

Sleep Schedule/Sleep Hygiene The patient sleeps with her husband in a king-size bed. She often manages the library’s digital archives on her desktop computer in the evening, then continues working on her laptop in bed. She does not always remember to dim the light of her laptop screen. Time in bed: 8:00–9:00 PM Lights out: 8:00–9:00 PM Sleep onset latency: 5 minutes Sleep aids: None Number of awakenings: Zero Cause of awakenings: N/A Wake after sleep onset time: N/A

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Wake time: Rise time: Naps: Total sleep time:

7:00 AM 7:15 AM (with multiple alarms and assistance from her husband) Daily, usually 1–2 hours’ duration between 12 and 2 PM. Naps are not refreshing. Approximately 12 hours per 24-hour period

Scales/Questionnaires STOP-BANG Scale: 1 points (low risk of obstructive sleep apnea) Epworth Sleepiness Scale: 17 points (excessive daytime sleepiness) Patient Health Questionnaire-9: 7 points (mild depression)

Past Medical History • • • • • • •

Seasonal allergies Asthma Eczema Chronic nasal congestion Atypical depression Obstructive sleep apnea during childhood Frequent upper respiratory infections during childhood

Past Surgical History • Adenotonsillectomy at age 7 years • Bilateral wisdom tooth extraction at age 12 years

Allergies • Pollen • Cat dander • Strawberry

Medications •  Albuterol inhaler • Sertraline • Cetirizine • Fluticasone

2 puffs PO BID PRN wheezing 50 MG PO QAM 10 MG PO QAM during PRN for nasal irritation 1 spray in each nostril at bedtime during allergy season

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Family History • • • • •

Fibromyalgia, mother Chronic insomnia, mother Depression, mother and father Coronary artery disease, maternal grandfather Breast cancer, paternal grandmother

Social History She is married and does not have children. She works at a university library, where she is helping to grow the digital archive and increase its accessibility and usefulness for students. She lives with her husband in a 2-level townhome. The patient does not smoke cigarettes and rarely drinks a glass of wine on special occasions. She does not use recreational drugs.

Review of Systems All systems were reviewed, and all concerns are noted above in the patient’s history.

Vital Signs Blood pressure: 123/82 mmHg Heart rate: 73 beats per minute Respiratory rate: 16 breaths per minute Height: 5 feet 8 inches Weight: 170 pounds BMI: 25 kg/m2

Physical Examination General: Eyes: ENT:

Neck: Respiratory:

Slightly overweight body habitus. No apparent distress. No conjunctival erythema, no scleral icterus. Ears unremarkable, hearing intact, nasal airflow mildly restricted bilaterally, nasal septum midline, inferior nasal turbinates unremarkable, tongue normal without scalloping, somewhat high-arched hard palate, soft palate unremarkable, uvula normal, Friedman Class 2 airway. 13.5-inches neck circumference, no cervical lymphadenopathy. Clear to auscultation bilaterally, no wheezing/rhonchi/crackles.

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Cardiovascular:

Regular rate and rhythm, no murmur, rubs or gallops. No carotid bruit. Musculoskeletal: Normal gait and station. Extremities: No cyanosis, clubbing, or edema. Skin: No rash, lesions ulcers, induration, or nodules in visible regions. Neurologic: Cranial nerves II–XII are intact. Mental status: Alert and fully oriented, judgment and insight are good, and she describes her mood as “Fine.”

Differential Diagnosis • Idiopathic hypersomnia • Narcolepsy type 2 • Obstructive sleep apnea

Diagnostic Testing Note  Sertraline was discontinued 2 weeks prior to actigraphy and 4 weeks prior to the polysomnogram and multiple sleep latency test shown below. Actigraphy and Sleep Diary (2 Weeks) • Regular bedtimes (average 8:30 PM) and get-up times (average 7:10 AM) without circadian rhythm abnormality, and with an average estimated total sleep time of 11 hours per 24-hour period. • Average estimated sleep onset latency of 8 minutes and sleep efficiency of 89%. • Actigraphy supported the content of the sleep diary without significant discrepancies. Diagnostic Polysomnogram (PSG) Total sleep time: 423.5 minutes Latency to sleep: 4.5 minutes Rapid-eye-movement (REM) latency: 140.5 minutes Wake after sleep onset: 63.5 minutes Sleep efficiency: 86.2% Apnea-hypopnea index (AHI): 2.3 events per hour of sleep REM AHI: 3.6 events per hour of sleep 0.0 events per hour AHI with 4% O2 desaturation: Obstructive apnea index: 0.0 events per hour Central apnea index: 0.0 events per hour Hypopnea index: 2.3 events per hour Mean sleep % SpO2: 95%

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Min sleep % SpO2: 92% Periodic limb movement index: 17.3 limb movements per hour Urine toxicology screen (the morning preceding the multiple sleep latency test): Negative Multiple Sleep Latency Test (MSLT)

Assessment Symptoms of excessive daytime sleepiness (not due to medical illness, psychiatric illness, or sedating substances), total sleep time in excess of 12  hours, unrefreshing naps with burdensome sleep inertia, and hypnagogic hallucinations in this non-­obese young woman with a history of depression are strongly suggestive of idiopathic hypersomnia (IH). Idiopathic hypersomnia was confirmed by studies that showed long total sleep time (often >12 hours per 24-hour period), a normal circadian rhythm, the absence of sleep-disordered breathing (Fig. 1.5), and one sleep-­ onset REM period (SOREMP) on MSLT with a mean sleep latency of 1.6 minutes (Table 1.2 and Fig 1.6). Periodic limb movements of sleep (PLMS), seen during this patient’s PSG, are not strongly associated with sleepiness and have been linked to higher rates of insomnia [47, 48]. Diagnosis  Idiopathic hypersomnia

Treatment Modafinil reduced the patient’s daytime sleepiness at a dose of 200 MG in the morning, and was subsequently increased to 200 MG twice per day due to residual sleepiness in the early afternoon. Modafinil enabled the patient to remain alert throughout her work day without a mid-day nap. While she continued CBT twice per year, the patient did not reinitiate sertraline after her MSLT and her mood remained stable. She exercises after work three times per week at the local gymnasium, and maintains a regular sleep-wake schedule, sleeping approximately 10–12 hours per 24-hour period. She continues to require multiple alarms and assistance from her husband to wake up on time in the morning.

Discussion The pathophysiology and genetic mechanisms underlying idiopathic hypersomnia are unknown. Nonetheless, much research has illuminated neurochemical differences between patients with IH, narcolepsy, and controls. For example, a study of CSF monoamine metabolites in humans showed a lack of correlation between a

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norepinephrine metabolite (3-methoxy-4-hydroxyphenylethylene glycol) and other monoamine metabolites in IH patients, suggesting an abnormality of norepinephrine processing in patients with IH [49]. This finding is compelling in light of prior research showing that bilateral destruction of the dorsal norepinephrine bundle in the isthmus or midbrain of cats causes hypersomnia with a significant increase in both REM and slow-wave sleep [50]. CSF dopamine and indoleacetic acid were shown in one study to be lower in patients with IH and narcolepsy compared to controls; however, this result has not been convincingly replicated [51]. A Japanese study showed CSF histamine levels to be significantly lower in patients with narcolepsy and IH compared to control patients and patients with OSA; however, a later study found no significant difference in levels of CSF histamine (or its major metabolite) in patients with narcolepsy or IH compared to controls [52, 53]. Contradictory results have also been found in studies of gamma-aminobutyric acid (GABA) receptor potentiation in the CSF of patients with IH, and the role of GABA in the pathogenesis of IH remains unclear [54, 55]. Contrary to low or absent CSF orexin (hypocretin) levels in patients with narcolepsy type 1, CSF orexin levels are normal in patients with IH [56]. Compared to control patients, patients with IH have been found to have a phase delay (as measured by salivary melatonin and serum cortisol) and a longer duration melatonin signal (not statistically significant), which could contribute to difficulty awakening in the morning [57]. The patient in the above case has idiopathic hypersomnia. In order to diagnose IH, a patient must have the following: • Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months • No cataplexy • A multiple sleep latency test (MSLT) showing fewer than two sleep-onset rapid eye movement periods (SOREMPs), or no SOREMPs if the REM sleep latency on the preceding polysomnogram was ≤15 minutes • At least one of the following: –– MSLT with a mean sleep latency of ≤8 minutes. –– Total 24-hour sleep time ≥660 minutes (typically 12–14 hours) on 24-hour polysomnography or by wrist actigraphy in association with a sleep log [58]. Therefore, the above patient meets diagnostic criteria for idiopathic hypersomnia based upon a daily irrepressible need to sleep for more than 3 months, the absence of cataplexy, a mean sleep latency of 1.6 minutes, and one SOREMP on an MSLT. In addition, there is not a better explanation for the patient’s sleepiness (e.g., insufficient sleep or psychiatric disease), and the SOREMP is not better explained by sleep deprivation or circadian disruption. While this patient’s very brief mean sleep latency may be more consistent with narcolepsy than IH, this result must be interpreted in the context of the patient’s clinical symptoms, which are more strongly suggestive of IH [59]. That said, narcolepsy type 2 and IH share clinical

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features, and a second PSG/MSLT could be considered in the future if disease re-­ classification is likely to result in more effective treatment [60]. The prevalence of idiopathic hypersomnia is unknown due in part to diagnostic challenges and clinical heterogeneity. The frequency of IH relative to narcolepsy in cohorts of patients with disorders of hypersomnolence has been reported by a number of sleep medicine clinics and ranges widely from 5% to 50% [61–64]. As stated above, no consistent genetic or immunologic (including human leukocyte antigen) markers of IH have been identified to date. That said, some studies have found immunologic differences (e.g., IgG profiles) in IH patients compared to narcolepsy and control patients, and research is ongoing [65]. In addition, many studies have reported a family history of IH in up to 40% of IH patients, and the pedigree from one study was consistent with an autosomal dominant inheritance pattern [59, 63, 66–68]. Therefore, an underlying genetic predisposition to IH is likely and warrants further investigation. With the exception of a family history, no other predisposing or precipitating factors for IH have been clearly established. Cases of hypersomnia developing after head trauma and viral illness may mimic clinical features of IH, but are unique clinical entities with different prognostic implications. IH usually begins in the second or third decade of life. While there is not a robust gender association in IH, analysis of some study cohorts has found a slightly higher prevalence of IH in women than in men [62, 63, 69]. The principal clinical feature of IH is excessive daytime sleepiness (EDS), sometimes referred to as hypersomnolence, which can worsen slowly for months before reaching peak severity. Initial studies of the Epworth Sleepiness Scale (ESS) showed a mean score of approximately 18 points for patients with IH, indicative of severe EDS and on par with the average ESS score of patients with narcolepsy [70]. IH patients often have a long total sleep time in excess of 11 hours per 24-hour period, which includes long nocturnal sleep and prolonged daytime naps. Contrary to patients with narcolepsy, the daytime naps of patients with IH are classically unrefreshing and are characterized by disabling sleep inertia and “sleep drunkenness” upon awakening [71]. While a long sleep time and sleep drunkenness are relatively specific for IH, the absence of these symptoms does not rule out IH, a diagnosis that encompasses significant clinical heterogeneity [59, 69]. The EDS of IH causes patients to experience functional decline (which may be occupational, social, etc.) and reduced quality of life [72]. Given the higher risk of accidents in patients with EDS, clinicians should counsel all IH patients about safe driving practices. In addition to the above clinical features, patients with IH may suffer from myriad other symptoms at rates higher than control groups; these include hypnagogic hallucinations, sleep paralysis, cognitive (including memory and attention) problems, depression, anxiety, and fatigue. Symptoms suggestive of autonomic dysfunction (e.g., temperature dysregulation, palpitations, syncope, and digestive problems) also may be more common in IH patients than in matched controls [69, 73]. Patients with IH do not experience cataplexy and usually do not suffer from sleep attacks.

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The treatment of IH consists primarily of the use of wake-promoting medications to reduce EDS and improve functionality and quality of life. Non-pharmacologic, behavioral treatments for IH such as increased total sleep time and scheduled naps do not ease symptoms of EDS and sleep inertia. Of the stimulants (amphetamine, mazindol, methylphenidate) and wake-­ promoting agents (modafinil, armodafinil) used to treat IH, the efficacy of modafinil is supported by the strongest evidence with two randomized double-blind placebo-­ controlled trials showing that it reduced sleepiness (ESS declined by more than 5 points), reduced the number of daytime naps, and improved driving performance in patients with IH compared to placebo [74, 75]. The most frequent adverse effects of modafinil were headache (26%) and gastrointestinal discomfort (20%) [74]. Other alerting medications that have shown promise for the treatment of EDS in patients with IH include flumazenil (selective GABA-A antagonist), clarithromycin (antibiotic with possible GABA modulation), and pitolisant (selective histamine-3 receptor inverse agonist), all of which have been studied retrospectively in relatively small cohorts. Both flumazenil (N = 153) and clarithromycin (N = 23) reduced sleepiness by an average of 4–5 points on the ESS in nearly 40% of patients with drug-resistant IH, an effect size comparable to that of modafinil in patients with narcolepsy [76–78]. In these studies, dizziness (13%) and anxiety (7%) were the most common reported side effects of flumazenil, while altered taste/smell perception (68%) and nausea (32%) were the most common reported side effects of clarithromycin. More than half of patients with idiopathic hypersomnia or symptomatic hypersomnia (N = 78) and drug-resistant EDS who were treated with pitolisant discontinued treatment due to lack of efficacy; the most common pitolisant side effects in this retrospective study were gastrointestinal discomfort (15%) and weight gain (14%) [79]. Solriamfetol (a norepinephrine-dopamine reuptake inhibitor), recently approved for the treatment of hypersomnolence in narcolepsy, has not been adequately tested in patients with IH. Sodium oxybate and melatonin also have been shown to reduce sleepiness in patients with IH. In a retrospective review of 42 IH patients, treatment with sodium oxybate reduced the ESS by an average of 3–4 points in more than half of IH patients and improved morning sleep inertia in 71% of patients. However, 40% of patients in this review eventually discontinued sodium oxybate due to adverse effects, the most common being nausea (40%) and dizziness (34%) [80]. In a brief report of 10 patients treated with 2 milligrams of slow-release melatonin at bedtime, 5 patients experienced benefit in the form of reduced daytime sleepiness, less sleep drunkenness upon awakening, and shortened nocturnal sleep time [81]. If IH patients have refractory EDS despite optimal treatment, other causes of EDS should be reconsidered and treated if present (Fig. 1.7). Despite uncertainty regarding the pathogenesis of IH and significant heterogeneity in clinical presentation, studies have shown that stimulants and wake-promoting agents successfully treat EDS in up to 72% of patients with IH, and in up to one-quarter of IH patients, symptoms such as EDS and sleep drunkenness may spontaneously resolve [59, 61, 82].

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Key Learning Points • The pathophysiology and genetic mechanisms underlying idiopathic hypersomnia are unknown. • Cerebrospinal fluid (CSF) orexin levels are normal in patients with IH. • Some patients with IH may have a family history of the same, and more studies are needed to determine the genetic mechanisms and inheritance patterns underlying this familial predisposition. • The age of onset of IH is usually in one’s late teens or early twenties, though symptomatic hypersomnia (e.g., following head trauma or viral illness) can occur later in life. • The principal clinical feature of IH is excessive daytime sleepiness (EDS), which can worsen slowly for months before reaching peak severity; the corresponding ESS score is usually >15 points. • IH patients often have a long sleep time in excess of 11 hours per 24-hour period, though a long sleep time is not required to diagnose IH. • Contrary to patients with narcolepsy, the daytime naps of patients with IH are classically unrefreshing and are characterized by disabling sleep inertia and “sleep drunkenness” upon awakening. In addition, IH patients do not experience cataplexy and usually do not suffer from sleep attacks. • Patients with IH may suffer from other symptoms at rates higher than control groups; these include hypnagogic hallucinations, sleep paralysis, cognitive (including memory and attention) problems, depression, anxiety, autonomic dysfunction, and fatigue.

Fig. 1.5  A hypnogram shows the absence of sleep-disordered breathing, periodic limb movements of sleep, and a very brief sleep onset latency

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• Non-pharmacologic, behavioral treatments for IH such as increased total sleep time and scheduled naps do not ease symptoms of EDS and sleep inertia. All IH patients should be counselled about the risk of injury at work and when operating a motor vehicle. • Wake-promoting and stimulant medications are the mainstay of pharmacologic treatment for EDS in IH patients; of these, the efficacy of modafinil is supported by the strongest evidence.

Table 1.2  A chart of five naps shows a mean sleep onset latency of 1.6 minutes and one sleep-­ onset REM period (SOREMP), occurring in first nap (but not during the patient’s habitual sleep period) Results Time test began Time to bed (min) Latencies to (min)  First sleep epoch  Three consecutive sleep epochs  Stage 2 REM sleep Number of REM periods = 1

NAP1 07:58 16.5

NAP2 9:56 16.5

NAP3 11:57 16.5

NAP4 14.05 16.0

NAP5 16:05 17.5

Mean

1.5 1.5 3.5 3.0

1.5 1.5 4.0 None

1.5 1.5 4.5 None

1.0 1.0 2.0 None

2.5 2.5 4.0 None

1.6 1.6 3.6

Fig. 1.6  A hypnogram from the multiple sleep latency test (MSLT) shows sleep during all five naps and a SOREMP during the first nap

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Excessive Daytime Sleepiness (EDS)

History, Physical Exam, Scales, Safety Counseling

Insufficient sleep most likely cause?

YES

Increase total sleep time

YES

Identify and treat underlying cause

Evaluation unremarkable, or persistent EDS despite optimal treatment

NO Medical/psychiatric illness or substance/medication most likely cause?

EDS improved or resolved; continue current treatment and monitor

NO Sleep disorder most likely cause, and greatest suspicion for:

Sleep apnea (obstructive or central) or sleeprelated hypoventilation

Home sleep apnea test or polysomnogram (+/CO2 monitoring)

Identify and treat underlying cause (e.g. positive airway pressure)

Narcolepsy, idiopathic hypersomnia, or Kleine-Levin syndrome

Restless legs syndrome or periodic limb movement disorder

Circadian rhythm sleep-wake disorders

Sleep diary/ actigraphy for 2 weeks, stop stimulant and REM-suppressing meds

Polysomnogram if suspect periodic limb movement disorder

Sleep diary/actigraphy for 2-4 weeks

Polysomnogram, urine toxicology screen, multiple sleep latency test

Identify and treat underlying cause (e.g iron supplementation)

Identify and treat underlying cause (e.g. melatonin)

Identify and treat underlying cause (e.g. wake-promoting meds)

EDS improved or resolved; continue current treatment and monitor

Evaluation unremarkable, or persistent EDS despite optimal treatment

Fig. 1.7  A general approach to the assessment and treatment of excessive daytime sleepiness (EDS)

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References Case 1: Obstructive Sleep Apnea 1. American Academy of Sleep Medicine, editor. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine; 2014. 2. Punjabi NM.  The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008;5(2):136–43. 3. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-­ disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–14. 4. Dancey DR, Hanly PJ, Soong C, Lee B, Hoffstein V. Impact of menopause on the prevalence and severity of sleep apnea. Chest. 2001;120(1):151–5. 5. Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med. 2003;167(9):1181–5. 6. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540–5. 7. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea: the Epworth Sleepiness Scale. Chest. 1993;103(1):30–6. 8. Chervin RD, Aldrich MS. The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea. Neurology. 1999;52(1):125. 9. Horstmann S, Hess C, Bassetti C, Gugger M, Mathis J. Sleepiness-related accidents in sleep apnea patients. Sleep-New York. 2000;23(3):383–92. 10. Roth T, Hartse KM, Zorick F, Conway W. Multiple naps and the evaluation of daytime sleepiness in patients with upper airway sleep apnea. Sleep. 1980;3(3–4):425–39. 11. Guilleminault C, Partinen M, Antonia QS, Hayes B, Dement WC, Nino-Murcia G. Determinants of daytime sleepiness in obstructive sleep apnea. Chest. 1988;94(1):32–7. 12. Gonsalves MA, Paiva T, Ramos E, Gseuilleminault C.  Obstructive sleep apnea syndrome, sleepiness, and quality of life. Chest. 2004;125(6):2091–6. 13. Colt HG, Haas H, Rich GB. Hypoxemia vs sleep fragmentation as cause of excessive daytime sleepiness in obstructive sleep apnea. Chest. 1991;100(6):1542–8. 14. Seneviratne U, Puvanendran K. Excessive daytime sleepiness in obstructive sleep apnea: prevalence, severity, and predictors. Sleep Med. 2004;5(4):339–43. 15. Roure N, Gomez S, Mediano O, Duran J, de la Peña M, Capote F, Teran J, Masa JF, Alonso ML, Corral J, Sánchez-Armengod A. Daytime sleepiness and polysomnography in obstructive sleep apnea patients. Sleep Med. 2008;9(7):727–31. 16. Chervin RD.  Sleepiness, fatigue, tiredness, and lack of energy in obstructive sleep apnea. Chest. 2000;118(2):372–9. 17. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med. 2003;163(5):565–71. 18. Bennett LS, Langford BA, Stradling JR, Davies RJ. Sleep fragmentation indices as predictors of daytime sleepiness and nCPAP response in obstructive sleep apnea. Am J Respir Crit Care Med. 1998;158(3):778–86. 19. Sforza E, Krieger J. Daytime sleepiness after long-term continuous positive airway pressure (CPAP) treatment in obstructive sleep apnea syndrome. J Neurol Sci. 1992;110(1–2):21–6. 20. Kribbs NB, Pack AI, Kline LR, Getsy JE, Schuett JS, Henry JN, Maislin G, Dinges DF. Effects of one night without nasal CPAP treatment on sleep and sleepiness in patients with obstructive sleep apnea. Am Rev Respir Dis. 1993;147(5):1162–8. 21. Weaver TE, Maislin G, Dinges DF, Bloxham T, George CF, Greenberg H, Kader G, Mahowald M, Younger J, Pack AI. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–9.

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22. Mcardle N, Devereux G, Heidarnejad H, Engleman HM, Mackay TW, Douglas NJ.  Long-­ term use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med. 1999;159(4):1108–14. 23. Santamaria J, Iranzo A, Montserrat JM, de Pablo J. Persistent sleepiness in CPAP treated obstructive sleep apnea patients: evaluation and treatment. Sleep Med Rev. 2007;11(3):195–207. 24. Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med. 2001;164(9):1675–81. 25. Black JE, Hirshkowitz M.  Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep. 2005;28(4):464–71.

Case 2: Narcolepsy Type 1 26. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM.  Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–74. 27. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39–40. 28. American Academy of Sleep Medicine, editor. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine; 2014. 29. Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, Van Belle G. The epidemiology of narcolepsy. Sleep. 2007;30(1):13–26. 30. Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1* 0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997;20(11):1012–20. 31. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–62. 32. Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, Karle A, Rigat F, Rappuoli R, Narasimhan V, Julkunen I. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015;7(294):294ra105. 33. Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX, An P, Zhao L, Wang LH, Li QY, Yan H. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410–7. 34. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–5. 35. Aldrich MS. Automobile accidents in patients with sleep disorders. Sleep. 1989;12(6):487–94. 36. Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med. 2004;5(1):37–41. 37. Hishikawa Y, Shimizu T.  Physiology of REM sleep, cataplexy, and sleep paralysis. Adv Neurol. 1995;67:245–71. 38. Schuld A, Hebebrand J, Geller F, Pollmächer T. Increased body-mass index in patients with narcolepsy. Lancet. 2000;355(9211):1274–5. 39. Frauscher B, Ehrmann L, Mitterling T, Gabelia D, Gschliesser V, Brandauer E, Poewe W, Högl B. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck narcolepsy cohort. J Clin Sleep Med. 2013;9(08):805–12. 40. Ruoff CM, Reaven NL, Funk SE, McGaughey KJ, Ohayon MM, Guilleminault C, Black J. High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J Clin Psychiatry. 2017;78(2):171–6. 41. Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep. 2001;24(4):385–91. 42. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88–97.

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43. Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin. 2006;22(4):761–74. 44. Thorpy MJ, Shapiro C, Mayer G, Corser BC, Emsellem H, Plazzi G, Chen D, Carter LP, Wang H, Lu Y, Black J. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019;85(3):359–70. 45. US Xyrem® Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25(1):42–9. 46. Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, Lehert P, Ding CL, Lecomte JM, Schwartz JC, HARMONY I Study Group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068–75.

Case 3: Idiopathic Hypersomnia 47. Chervin RD. Periodic leg movements and sleepiness in patients evaluated for sleep-disordered breathing. Am J Respir Crit Care Med. 2001;164(8):1454–8. 48. Scofield H, Roth T, Drake C. Periodic limb movements during sleep: population prevalence, clinical correlates, and racial differences. Sleep. 2008;31(9):1221–7. 49. Faull KF, Thiemann S, King RJ, Guilleminault C. Monoamine interactions in narcolepsy and hypersomnia: a preliminary report. Sleep. 1986;9(1):246–9. 50. Petitjean F, Sakai K, Blondaux C, Jouvet M. Hypersomnie par lésion isthmique chez le chat. II. Etude neurophysiologique et pharmacologique. Brain Res. 1975;88(3):439–53. 51. Montplaisir J, De Champlain J, Young SN, Missala K, Sourkes TL, Walsh J, Remillard G.  Narcolepsy and idiopathic hypersomnia: biogenic amines and related compounds in CSF. Neurology. 1982;32(11):1299. 52. Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S, Shimizu T, Nishino S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep. 2009;32(2):181–7. 53. Dauvilliers Y, Delallée N, Jaussent I, Scholz S, Bayard S, Croyal M, Schwartz JC, Robert P. Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. Sleep. 2012;35(10):1359–66. 54. Rye DB, Bliwise DL, Parker K, Trotti LM, Saini P, Fairley J, Freeman A, Garcia PS, Owens MJ, Ritchie JC, Jenkins A. Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Sci Transl Med. 2012;4(161):161ra151. 55. Dauvilliers Y, Evangelista E, Lopez R, Barateau L, Jaussent I, Cens T, Rousset M, Charnet P. Absence of γ-aminobutyric acid-a receptor potentiation in central hypersomnolence disorders. Ann Neurol. 2016;80(2):259–68. 56. Dauvilliers Y, Baumann CR, Carlander B, Bischof M, Blatter T, Lecendreux M, Maly F, Besset A, Touchon J, Billiard M, Tafti M. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry. 2003;74(12):1667–73. 57. Nevšímalová S, Blažejová K, Illnerova H, Hajek I, Vaňková J, Pretl M, Šonka K. A contribution to pathophysiology of idiopathic hypersomnia. In: Supplements to clinical neurophysiology, vol. 53. Amsterdam: Elsevier; 2000. p. 366–70. 58. American Academy of Sleep Medicine, editor. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine; 2014. 59. Anderson KN, Pilsworth S, Sharples LD, Smith IE, Shneerson JM. Idiopathic hypersomnia: a study of 77 cases. Sleep. 2007;30(10):1274–81. 60. Aldrich MS.  The clinical spectrum of narcolepsy and idiopathic hypersomnia. Neurology. 1996;46(2):393–401.

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61. Bassetti C, Aldrich MS.  Idiopathic hypersomnia. A series of 42 patients. Brain J Neurol. 1997;120(8):1423–35. 62. Dauvilliers Y, Paquereau J, Bastuji H, Drouot X, Weil JS, Viot-Blanc V.  Psychological health in central hypersomnias: the French Harmony study. J Neurol Neurosurg Psychiatry. 2009;80(6):636–41. 63. Ali M, Auger RR, Slocumb NL, Morgenthaler TI. Idiopathic hypersomnia: clinical features and response to treatment. J Clin Sleep Med. 2009;5(06):562–8. 64. Roth B. Narcolepsy and hypersomnia: review and classification of 642 personally observed cases. Schweiz Arch Neurol Neurochir Psychiatr. 1976;119(1):31–41. 65. Tanaka S, Honda M. IgG abnormality in narcolepsy and idiopathic hypersomnia. PLoS One. 2010;5(3):e9555. 66. Nevšímalová-Bruhova S, Roth B.  Heredofamilial aspects of narcolepsy and hypersomnia. Schweiz Arch Neurol Neurochir Psychiatr. 1972;110(1):45–54. 67. Billiard M, Dauvilliers Y. Idiopathic hypersomnia. Sleep Med Rev. 2001;5(5):349–58. 68. Janáčková S, Motte J, Bakchine S, Sforza E.  Idiopathic hypersomnia: a report of three adolescent-­onset cases in a two-generation family. J Child Neurol. 2011;26(4):522–5. 69. Vernet C, Arnulf I.  Idiopathic hypersomnia with and without long sleep time: a controlled series of 75 patients. Sleep. 2009;32(6):753–9. 70. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–5. 71. Roth B, Nevšímalová S, Rechtschaffen A.  Hypersomnia with sleep drunkenness. Arch Gen Psychiatry. 1972;26(5):456–62. 72. Ozaki A, Inoue Y, Hayashida K, Nakajima T, Honda M, Usui A, Komada Y, Kobayashi M, Takahashi K. Quality of life in patients with narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia without long sleep time: comparison between patients on psychostimulants, drug-naive patients and the general Japanese population. Sleep Med. 2012;13(2):200–6. 73. Vernet C, Leu-Semenescu SM, Buzare MA, Arnulf I.  Subjective symptoms in idiopathic hypersomnia: beyond excessive sleepiness. J Sleep Res. 2010;19(4):525–34. 74. Mayer G, Benes H, Young P, Bitterlich M, Rodenbeck A. Modafinil in the treatment of idiopathic hypersomnia without long sleep time—a randomized, double-blind, placebo-controlled study. J Sleep Res. 2015;24(1):74–81. 75. Philip P, Chaufton C, Taillard J, Capelli A, Coste O, Leger D, Moore N, Sagaspe P. Modafinil improves real driving performance in patients with hypersomnia: a randomized double-blind placebo-controlled crossover clinical trial. Sleep. 2014;37(3):483–7. 76. Trotti LM, Saini P, Koola C, LaBarbera V, Bliwise DL, Rye DB.  Flumazenil for the treatment of refractory hypersomnolence: clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389–94. 77. Trotti LM, Saini P, Bliwise DL, Freeman AA, Jenkins A, Rye DB.  Clarithromycin in γ-aminobutyric acid–related hypersomnolence: a randomized, crossover trial. Ann Neurol. 2015;78(3):454–65. 78. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88–97. 79. Leu-Semenescu S, Nittur N, Golmard JL, Arnulf I. Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med. 2014;15(6):681–7. 80. Leu-Semenescu S, Louis P, Arnulf I. Benefits and risk of sodium oxybate in idiopathic hypersomnia versus narcolepsy type 1: a chart review. Sleep Med. 2016;17:38–44. 81. Montplaisir J, Fantini L.  Idiopathic hypersomnia: a diagnostic dilemma. A commentary of “idiopathic hypersomnia” (M. Billiard and Y. Dauvilliers). Sleep Med Rev. 2001;5(5):361–2. 82. Bruck D, Parkes JD. A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary data. J Neurol Neurosurg Psychiatry. 1996;60(5):576–8.

2

Insomnia Sabra M. Abbott

Case 1: Difficulty Staying Asleep A 52 -year-old woman presents with a history of difficulty maintaining sleep. She reports that symptoms have been present since the birth of her first child when she was 35; however, they have worsened since menopause started 2 years ago.

Sleep Routine Weekdays: • Bedtime: She typically is able to fall asleep easily around 10 pm. • Number of awakenings  – She finds herself waking up approximately every 2 hours. • Wake after sleep onset – Earlier in the evening, she is able to fall back to sleep within about 10 minutes; however, on most nights she will wake up around 3 am, and it will take her at least 2 hours to fall back to sleep. Some mornings she does not fall back to sleep at all, and will eventually just give up and get up for the day. • Wake up time – On weekdays her alarm is set for 6 am, though she typically is awake before the alarm goes off.

S. M. Abbott (*) Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 A. S. Sahni et al. (eds.), Sleep Disorders, https://doi.org/10.1007/978-3-030-65302-6_2

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On weekends, she notes that she is often exhausted. • Bedtime – falls asleep on the couch around 9 pm. • Wake up time – stays in bed until 8 am in order to get more sleep, however feels like she is generally just tossing and turning, and not actually sleeping for the last 2–3 hours. If she is unable to sleep, she will generally just lay in bed trying to relax and make herself fall back to sleep. Initial sleep logs are provided in Fig. 2.1. She reports daytime sleepiness, with an Epworth Sleepiness Scale score of 12. She drinks two cups of coffee in the morning, nothing after noon. She works full time, so generally does not have time to nap, and is not aware of whether she would be able to fall asleep if she did try. She notes that she used to enjoy exercising, but has been finding it harder to motivate herself to do it recently. She has gained ~20 pounds in the past year, which she attributes to a combination of decreased exercise and poor diet choices.

Past Medical History • Hypertension • Occasional migraine headaches • Seasonal allergies

M Tu W Th F

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Fig. 2.1  Example sleep log from case 1, prior to initiating treatment. Black shaded boxes indicate subjective reports of sleep time. Down arrows indicate the time of getting into bed, and up arrows indicate the time of getting out of bed. A = alcohol, C = caffeine

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Past Surgical History • None

Allergies • None

Medications • Metoprolol • Multivitamin

Family History • Insomnia in her mother, and sleep apnea in her father. • She also notes that she comes from a family of “early birds.”

Social History • Two glasses of wine/night, one with dinner, and one while reading before bed.

Review of Symptoms • Mild snoring • Occasional morning headaches

Vital Signs Blood pressure 120/80 mmHg Heart rate 70/minute Respiratory rate 14/minute BMI 29 kg/m2

Physical Examination She has mild nasal congestion and a Mallampati III airway. Neck circumference is 16 inches. Rest of the exam was unremarkable.

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Differential Diagnosis • • • •

Chronic Insomnia Obstructive sleep apnea Untreated depression Advanced sleep wake phase disorder

Assessment At this point, she presents with symptoms of chronic insomnia, with difficulty maintaining sleep, and waking up earlier than desired that have been present for greater than 3 months. Initial precipitating factors appear to be the birth of her son, with perpetuating factors including spending excessive amount of time in bed on weekends to try to “catch up” sleep. However in addition to the typical symptoms of insomnia, she has several other factors that merit further evaluation. First, she does note excessive daytime sleepiness, snoring, and morning headaches in the context of recent weight gain, and is now post-menopausal, so it is possible that untreated sleep apnea may be contributing to her difficulty maintaining sleep. Many women also experience an increase in insomnia symptoms following menopause. In addition, she recently started taking metoprolol, which can be associated with sleep difficulties. She also notes a loss of interest in activities that she previously enjoyed, so it will be important to explore whether untreated depression is contributing to her symptoms. She also notes alcohol intake immediately prior to bed, which could be causing rebound insomnia. Finally, she does note that she comes from a family of “early birds” so it is important to consider whether her difficulty with sleep maintenance may be secondary to advanced sleep-wake phase disorder.

Management The patient was counselled to get into bed when sleepy (rather than falling asleep on the couch), to not stay in bed if she is unable to sleep, to maintain consistent sleep-wake times on work days and non-work days. In addition, she was advised to limit alcohol intake before bedtime. Additional screening for depressive symptoms with the Patient Health Questionnaire (PHQ-9) showed a score of only 4, suggesting a low likelihood for major depression. On discussion with her primary care doctor, she was switched from metoprolol to lisinopril for her blood pressure control. She was also referred for home sleep apnea testing, with the results shown in Fig. 2.2. As the home sleep apnea testing indicated mild sleep apnea (AHI = 12) and the patient has hypertension and daytime sleepiness, she was started on CPAP.  At a follow-up visit 1 month after initiating PAP therapy, she notes significant improvement in her daytime sleepiness, and a decrease in some of her middle of the night awakenings, however continues to find it difficult to fall back to sleep after 3 am, noting that after that time she found herself lying awake with racing thoughts. She

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Fig. 2.2  Example sleep log from case 1 after limiting alcohol intake and working to make sleep-­ wake times more consistent. Black shaded boxes indicate subjective reports of sleep time. Down arrows indicate the time of getting into bed, and up arrows indicate the time of getting out of bed. C = caffeine

was referred for cognitive behavioral therapy for insomnia (CBT-I) and sleep logs from that initial appointment are presented in Fig. 2.3. Based on her sleep logs demonstrating a slightly earlier bedtime after being instructed to get into bed when sleepy, and her reported family history, there was concern for a component of advanced sleep-wake phase disorder contributing to her early morning awakenings. Evening bright light therapy was recommended. However, in addition, she did also report times of lying awake in bed with racing thoughts, so was also instructed on strategies for stimulus control and scheduled worry. Sleep logs from 2 months later are shown in Fig. 2.4.

Case 2: Difficulty Falling Asleep A 25-year-old man who was referred to the sleep clinic by his human resources department at work, due to sleep problems. He reports that he first noted difficulty with his sleep when he started his first job after graduating from college, which required him to be at work by 8 am every morning. He needs to get up for work at 6 am on weekdays, so will try to get into bed by 10 pm. It will typically take several hours to fall asleep, and he has found himself getting increasingly more anxious about getting into bed at night because he finds it so challenging to fall asleep. Once he finally does fall asleep, he notes that he sleeps “too well” having slept through his alarm several times, resulting in difficulty making it to work on time, resulting in

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Fig. 2.3  Example sleep log from case 1 after initiating therapy for obstructive sleep apnea. Black shaded boxes indicate subjective reports of sleep time. Down arrows indicate the time of getting into bed, and up arrows indicate the time of getting out of bed. C = caffeine

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Fig. 2.4  Example sleep log from case 1 after initiating evening bright light therapy and cognitive behavioral therapy for insomnia. Black shaded boxes indicate subjective reports of sleep time. Down arrows indicate the time of getting into bed, and up arrows indicate the time of getting out of bed. L = light, C = caffeine

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disciplinary action. In the past, he has been prescribed several hypnotics to try to help him fall asleep more easily, including zolpidem and trazodone. While they do make it slightly easier to fall asleep, they have not helped with his difficulty sleeping through his alarm. On weekends he will frequently stay out with his friends, going to bed between 2 and 4 am, and notes that it is much easier to fall asleep on those nights. He will typically wake up between 11  am and noon and generally feels refreshed. He does not typically nap on weekends, though will sometimes fall asleep for 1–2 hours after getting home from work.

Sleep Routine Weekdays: • Bedtime – 10:00 pm • SOL – several hours • wake up time – 6 am, with an alarm Weekends: • Bedtime – 2:00 am and 4:00 am • SOL – less than 30 minutes • wake up time – 11:00 am to 12:00 pm On further history, he notes that he may have had similar problems with his sleep during college, but was able to adapt to this. During his first semester of school, he failed out of an 8  am class because he slept through too many of the lectures. However for the rest of his undergraduate time, he was able to schedule classes that started later in the day, and did well in his classes. During this time, he would typically sleep from 2 am to 10 am without difficulty.

Review of Symptoms • Denies snoring, witnessed apneas or symptoms of restless legs syndrome.

Past Medical History • Mild depression

Medications • None now, though he has tried several hypnotics in the past.

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Family History • Similar sleep problems in his older brother. His father is a shift worker, and has always preferred to work third shift, so primarily sleeps during the daytime.

Physical Examination Vital signs – stable. BMI of 22 kg/m2. He has a Mallampati I airway. Neck circumference is 14 inches.

Differential Diagnosis • • • • •

Delayed sleep wake phase disorder Sleep initiation insomnia Comobid anxiety Central hypersomnia Obstructive sleep apnea

Assessment At this point, the patient is presenting with symptoms of difficulty with sleep initiation and anxiety related to bedtime. More concerning, he also has difficulty waking up in time for work, resulting in disciplinary action and concerns about his ability to be able to maintain his job. The early morning sleepiness could raise concerns for an underlying disorder of hypersomnia, though he has minimal risk factors for obstructive sleep apnea, and denies any symptoms to suggest a diagnosis of narcolepsy. More importantly, when allowed to sleep during his preferred schedule he denies any sleep complaints. Of note, his family history suggests similar symptoms in his brother, and possibly his father who has self-selected for a third shift position, working at night and sleeping during the daytime. As the primary concern at this point is for delayed sleep-wake phase disorder, the patient was instructed to complete 2 weeks of sleep logs, shown in Fig. 2.5.

Management Based on the clinical history and actigraphy results, the patient was diagnosed with delayed sleep-wake phase disorder, and was given instructions to take a low dose of melatonin and avoid bright light exposure in the evening, in conjunction with morning bright light therapy to gradually advance his sleep-wake schedule. In addition,

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A A A C

Fig. 2.5  Example sleep log from case 2, prior to initiating treatment. Black shaded boxes indicate subjective reports of sleep time. Down arrows indicate the time of getting into bed, and up arrows indicate the time of getting out of bed. A = alcohol, C = caffeine

after discussion of his diagnosis with his work place, he was able to arrange for a more flexible start time. On initial follow-up, while he was able to fall asleep and wake up earlier, he was still experiencing significant anxiety related to bedtime, given his history of difficulty falling asleep in the past. He was referred for cognitive behavioral therapy for insomnia, with significant improvement in his bedtime anxiety. He is now able to sleep from midnight to 8 am and is working from 10 am to 7  pm. His productivity at work has improved significantly, and both he and his employer are pleased with his progress. Figure  2.6 demonstrates the response to treatment.

Discussion For most individuals, the symptoms of insomnia are likely multifactorial and require evaluation of multiple factors that may be contributing to the inability to all asleep and stay asleep. A flow chart demonstrating a general approach to insomnia symptoms is presented in Fig. 2.7. As a first step in evaluating patients with insomnia, it is important to screen for the presence of daytime sleepiness. While many patients with insomnia will present with symptoms of daytime fatigue related to difficulty sleeping, the classic description is of someone who is “tired but wired” who would love to be able to nap, but is unable to fall asleep when given the opportunity. The presence of actual daytime sleepiness raises the question of whether additional sleep disorders may be present, with the most common being obstructive sleep apnea. In addition, patients with narcolepsy can present with fragmented nocturnal sleep, in addition to the more

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M M

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M M M

L L L L

M

L L L L

M M

Tu

M

W Th

M

F Sa Su

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L L L L L L L L L L L L L L

Fig. 2.6  Example sleep log from case 2, demonstrating the use of light and melatonin to advance (week 1) and then stabilize (week 2) the sleep-wake schedule at the desired time. Black shaded boxes indicate subjective reports of sleep time. Down arrows indicate the time of getting into bed, and up arrows indicate the time of getting out of bed. A = alcohol, M = melatonin

classic daytime symptoms of sleep attacks and cataplexy. Patients should also be screened for symptoms of restless legs syndrome, as this can exacerbate difficulties with sleep initiation, and associated periodic limb movements of sleep can potentially disrupt the ability to stay asleep [1]. In patients with insomnia who do not also present with daytime sleepiness, the next step will be to screen for other precipitating factors. A careful history should be taken of daytime behaviors, including caffeine and alcohol intake, exercise (regularity, proximity to bedtime), and bedtime behaviors. All patients should be counseled on good sleep hygiene, including maintaining regular sleep-wake times, avoiding the use of electronics or bright light prior to bedtime, limiting caffeine and alcohol intake prior to bedtime and making sure the bedroom is a cool quiet environment conducive to sleep. In addition, medications should be reviewed, with attention particularly given to those the timing of administration of sedating and alerting medications. In case 1 the patient was taking a beta-blocker, which has been demonstrated to be associated with poor sleep quality, though at least in part to be related to suppression of melatonin production. A small study has demonstrated that administration of a low dose of melatonin at bedtime can improve sleep quality in these individuals [2]. However, in our patient the addition of evening melatonin in a patient who may

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also have comorbid advanced sleep-wake phase disorder can potentially result in even further phase advances, so the decision was instead made to switch her to an alternate anti-hypertensive. As demonstrated in both cases, it is important for all patients with insomnia to screen for the presence of circadian rhythm disorders, which may contribute to overall symptoms. Up to 10% of patients presenting to the sleep clinic with complaints of insomnia actually have delayed sleep-wake phase disorder [3]. In the clinical history, it will be important to ask about factors such as duration of symptoms. Patients with ASWPD and DSWPD will often note sleep patterns that have been present since childhood, and will also frequently note a family history of symptoms [4, 5]. In addition, questioning patients about their preferred sleep habits while on vacation or otherwise during times where they have no time obligations can be insightful. A patient with a circadian rhythm sleep-wake disorder may have much less difficulty sleeping when allowed to sleep at their preferred times, but will develop symptoms of insomnia when required to sleep at conventional times. Sleep logs and/or actigraphy can be useful for helping to distinguish individuals with a circadian disorder. In addition, while not readily available, other measures of circadian timing such as salivary dim light melatonin onset can also be useful in distinguishing patients with a circadian rhythm disorder [3]. It is also important to recognize that while the focus of treatment for the CRSWDs is primarily on adjusting circadian timing, many of these individuals will also have developed primary insomnia symptoms, and may also benefit from elements of cognitive behavioral therapy for insomnia, including stimulus control and sleep restriction, with a focus on centering their sleep window around their optimal circadian time for sleep. Another important factor to consider is the role of depression/anxiety in the presentation of insomnia. Early morning awakenings are a common presenting symptom of depression, and the severity of insomnia often correlates with the severity of depression. In turn, insomnia can be associated with worsening depressive symptoms, with severe insomnia having demonstrated to be an independent risk factor for suicide [6]. Similarly among patients with insomnia, 13% report symptoms consistent with generalized anxiety disorder [7]. Cognitive behavioral therapy for insomnia can be effective at treating the sleep symptoms in comorbid insomnia, and in some cases has also been demonstrated to improve some depressive symptoms [8]. Finally, once other comorbid factors have been addressed, one can move to focusing on addressing the primary insomnia symptoms. Current recommendations are to focus on cognitive behavioral therapy for insomnia. If medications are included in a treatment regimen, treatment should focus on the specific characteristics of the patient’s insomnia (e.g., difficulties with sleep initiation vs. maintenance) and the presence of any comorbid conditions, as this can guide treatment selection. Based on weighing risks and benefits, the American Academy of Sleep Medicine currently recommends the use of either suvorexant, benzodiazepine receptor agonists (eszopiclone, zaleplon or zolpidem), benzodiazepines (triazolam or temazepam), ramelteon, or

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doxepin. They advise against the use of trazodone, tiagabine, diphenhydramine, melatonin, l-tryptophan, or valerian as a primary treatment for insomnia [9]. Overall, it is important to recognize that the approach to insomnia must be individualized. While CBT-I is often an effective component of treatment for individuals with difficulty falling and staying asleep, it is also important to evaluate and address other factors that may be contributing to a patient’s symptoms.

Key Points • Sleep disorders are often multifactorial. Even if the primary presenting complaint is insomnia, it is important to evaluate for other factors that may also be impacting a patient’s sleep • Up to 10% of patients presenting to a clinic with complaints of insomnia may have delayed sleep-wake phase disorder Difficulty Falling or Staying Asleep

No

Daytime Yes sleepiness?

• Screen for OSA • Evaluate for symptoms of narcolepsy

Complete Sleep Logs No

Yes Circadian disorder?

• Actigraphy • Chronotype Questionnaires • Consider melatonin testing

Address Sleep Hygiene • • • •

Caffeine Alcohol Medication (type and timing) Bedtime activities

No

Psychiatric symptoms?

• Cognitive Behavioral Therapy for Insomnia • Consider Addition of a Hypnotic

Timed Light and melatonin

Yes Treat co-morbid depression/anxiety

Fig. 2.7  Flow chart demonstrating the process for evaluating a patient with symptoms of insomnia

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References 1. ICSD-3. The international classification of sleep disorders: diagnostic and coding manual. 2nd ed. Darien: American Academy of Sleep Medicine; 2014. 2. Scheer FA, Morris CJ, Garcia JI, Smales C, Kelly EE, Marks J, et  al. Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. Sleep. 2012;35(10):1395–402. 3. Flynn-Evans EE, Shekleton JA, Miller B, Epstein LJ, Kirsch D, Brogna LA, et al. Circadian phase and phase angle disorders in primary insomnia. Sleep. 2017;40(12):zsx163. 4. Reid KJ, Chang AM, Dubocovich ML, Turek FW, Takahashi JS, Zee PC. Familial advanced sleep phase syndrome. Arch Neurol. 2001;58(7):1089–94. 5. Patke A, Murphy PJ, Onat OE, Krieger AC, Ozcelik T, Campbell SS, et  al. Mutation of the human circadian clock gene CRY1  in familial delayed sleep phase disorder. Cell. 2017;169(2):203–15 e13. 6. Woznica AA, Carney CE, Kuo JR, Moss TG.  The insomnia and suicide link: toward an enhanced understanding of this relationship. Sleep Med Rev. 2015;22:37–46. 7. Belanger L, Morin CM, Langlois F, Ladouceur R.  Insomnia and generalized anxiety disorder: effects of cognitive behavior therapy for gad on insomnia symptoms. J Anxiety Disord. 2004;18(4):561–71. 8. Geiger-Brown JM, Rogers VE, Liu W, Ludeman EM, Downton KD, Diaz-Abad M. Cognitive behavioral therapy in persons with comorbid insomnia: a meta-analysis. Sleep Med Rev. 2015;23:54–67. 9. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of sleep medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–49.

3

Nocturnal Awakenings Kenneth Lee

Case 1: Non-REM (NREM) Parasomnia History A 25-year-old right-handed male presents with episodes of complex nocturnal behaviors over the last 2 years. These night episodes consist of thrashing and flailing of his arms, along with sitting up and kicking of his legs, oftentimes associated with sleep talking, per his girlfriend’s report. The episodes tend to be most pronounced when he is under significant stress or becomes very anxious. For example, he recalled a time when his grandmother passed away and he was preparing for exams when he had an episode consisting of knocking over lamps, and accidently hitting his girlfriend, while asleep. The described episodes last 15–20 seconds but do not occur every night. As per his girlfriend, they may occur between 2 and 4 AM, and almost always occur in the first half of the night. His girlfriend has woken him up from the events, and he does not have significant recollection of the events the next morning. Although he does have vivid dreams at night, these are not associated or related to the events described. He believes that the episodes may occur more frequently when he is travelling or on vacation with his girlfriend or following a period of sleep deprivation. Upon further questioning, the patient has had episodes of “waking up screaming” a few times when he was a child, as described by his family. He also had instances of falling out of bed as a child. There is no significant neurologic or psychiatric disease in his medical history and no history of substance use. His girlfriend denies any nocturnal wandering, nor any sort of sleep eating. There is mild snoring, but no gasping arousals or witnessed apneas. He does not have any symptoms of restless leg. K. Lee (*) Department of Neurology, University of Chicago Medical Center, Chicago, IL, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 A. S. Sahni et al. (eds.), Sleep Disorders, https://doi.org/10.1007/978-3-030-65302-6_3

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Differential Diagnosis • Non-rapid eye movement (NREM) or rapid eye movement (REM) parasomnia • Nocturnal seizures • Secondary disruption from other sleep disorder, i.e., sleep disordered breathing, insufficient sleep, and circadian rhythm disorder • Non-epileptic event, i.e., psychogenic non-epileptic seizure (PNES)

History Continued On further history, our patient has had a few episodes of sleep paralysis in the past, seen during times of sleep deprivation, but none recently. He denies any sort of cataplectic attacks or hallucinations. He is not using hypnotics. He denies any history of seizures, or risk factors for seizures, such as prior nervous system infection, history of febrile seizures, or family history of seizures. He does not report any neurologic symptoms nor any psychiatric disorders. His father does have a history of sleepwalking as well when he was younger.

Sleep Schedule/Sleep Hygiene The patient sleeps in a full-size bed by himself on most nights, and with his girlfriend 2–3 nights per week. He denies using electronics such as television, phone, or tablet devices in bed. Time in bed/lights out: 11:00 PM–1:00 AM Sleep onset latency: 30–60 minutes Sleep aids: None Number of awakenings: Infrequent, only when experiencing said episode above Wake time: 7:30 AM Naps: None Total sleep time: Approximately 6–7 hours

Scales/Questionnaires STOP-BANG Scale: 3 points (intermediate risk of obstructive sleep apnea) Epworth Sleepiness Scale: 10 points (borderline excessive daytime sleepiness)

Past Medical and Surgical History • Seasonal allergies

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Allergies • None

Medications • Ibuprofen and loratadine as needed

Family History • Father with history of sleep walking, which resolved after age of 30 • No other family history of neurologic or sleep disorder

Social History He reports occasional alcohol usage (1–2 drinks several times per week). He denies current or former tobacco use and does not have any other illicit drug use.

Review of Systems All systems were reviewed and were negative unless reported above in history.

Vital Signs Blood pressure: 121/69 Heart rate: 81 beats per minute Respiratory rate: 18 breaths per minute Height: 6 feet 1 inches Weight: 190 pounds BMI: 25 kg/m2

Physical Exam General: HEENT:

Normal body habitus. No apparent distress. Mallampati Class II. Neck circumference 16 inches. No tonsillar hypertrophy. Funduscopic examination is normal, normal range of motion. No nasal flaring, no swelling of the turbinates, and no septal deviation.

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Respiratory: Clear to auscultation bilaterally, no wheezing/rhonchi/crackles. Cardiovascular: Regular rate and rhythm, no murmur, rubs, or gallops. No carotid bruit. Extremities: No cyanosis, clubbing, or edema. Neurologic: Alert and fully oriented. Cranial nerves II–XII are intact. Motor strength 5/5 in upper and lower extremities. Sensory exam intact to light touch, pinprick, and vibration. Reflexes 2+ throughout, normal gait.

Differential Diagnosis • NREM or REM parasomnia • Secondary disruption from other sleep disorder, i.e., sleep disordered breathing, insufficient sleep, and circadian rhythm disorder The further history and physical exam obtained are most suggestive of a parasomnia or awakening from another sleep disorder, such as sleep disordered breathing. A few key points from the history indicate that the events are not occurring nightly and do not appear to be stereotypical in nature, both features which are more common with nocturnal seizures. In addition, there are no abnormal neurologic symptoms or signs on exam, and no prior history of seizure or increased risk for seizure. The patient has been reported to have sleep talking, along with a childhood history suggestive of night terrors, and a family history of NREM parasomnia (sleepwalking in father). Together, these elements also make nocturnal seizures less likely, and make parasomnia higher on the differential. Although his history and exam are not entirely consistent with a classic phenotype for sleep disordered breathing, he does have symptoms of snoring. Thus, as this point, a diagnostic evaluation with polysomnogram would be helpful, to rule out sleep disordered breathing, and to assess for other sleep disorders. Although nocturnal seizures are lower on the differential list, an extended EEG montage would be helpful to assess for epileptiform activity.

Diagnostic Testing Diagnostic Polysomnogram (PSG) Total sleep time: 455 minutes Latency to sleep: 12.4 minutes REM latency: 98 minutes Wake after sleep onset: 40 minutes Sleep efficiency: 86% Apnea-hypopnea index (AHI): 1.2 events per hour of sleep

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REM AHI: 4.8 events per hour of sleep Mean sleep % SpO2: 97% Min sleep % SpO2: 92% Periodic limb movement index: 7.5 limb movements per hour

Assessment The PSG of the patient did not show any evidence of sleep disordered breathing but did reveal multiple transitions to wake from NREM sleep, specifically from stages N2 and N3. Figure 3.1 demonstrates an arousal out of N3 slow wave sleep, while Fig. 3.2 demonstrates the overall hypnogram with multiple arousals out of NREM sleep. Notably, no clear epileptiform discharges or seizures were seen. The patient also had one episode of sleep talking seen during a transition from N3 sleep to wakefulness. This abrupt transition from slow wave sleep to wakefulness is a classic sign of NREM instability, and coupled with the history of sleepwalking and sleep talking, supports our clinical diagnosis of NREM parasomnia. Diagnosis  NREM parasomnia

Fig. 3.1  A 30-second window of an abrupt transition from stage N3 sleep to wakefulness. The patient was talking during this time. When awoken, he had no recollection of this event

MT W R N1 N2 N3

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Fig. 3.2  Hypnogram of the entire night showing significant disruption of sleep, and multiple transitions from NREM sleep (N2 and N3) to wakefulness

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Treatment After completion of the study, the results were discussed with the patient. The patient was counseled on safety precautions, particularly on the importance of removing sharp objects from his bed area and ensuring that his doors are locked to prevent injury and harm with future episodes of sleepwalking. He was also encouraged to modify his sleep environment to minimize disruptions to sleep, which may trigger parasomnia episodes. The patient was interested in pharmacotherapy and was prescribed clonazepam at a dose of 0.5 mg at night, which provided near resolution of episodes without significant side effects.

Discussion The AASM defines parasomnias as sleep disorders involving undesirable physical experiences that occur while falling asleep, sleeping, or waking from sleep [1]. Events can range from sleep enuresis to full formed violent complex actions, which have resulted in lawsuits within the specific forensic section of parasomnology [2]. Parasomnias mostly reflect a benign process, but in some cases such as in REM sleep behavior disorder, may be a harbinger of a neurodegenerative disorder. Classification of parasomnias is primarily based upon the stage of sleep from which the abnormal behaviors arise from. In normal sleep architecture, NREM sleep consists of approximately 60–70% of total sleep in children and 70–80% of sleep in adults with the remainder of sleep time consisting of REM sleep [3]. In general, parasomnias that encompass NREM sleep include sleepwalking, confusional arousals, sleep terrors, sleep-related eating disorder, sleep sexual behavior (termed “sexsomnia”), and exploding head syndrome. Sleep enuresis in children also occurs in NREM sleep. REM parasomnias compose of REM sleep behavior disorder, isolated sleep paralysis, nightmares, and catathrenia. NREM parasomnia tends to be more prevalent in children. Discounting the high prevalence of sleep enuresis, sleep terrors occur at a prevalence of 6.5% in children and 1% in adults [4]. Sleepwalking occurs with a prevalence of 5–15% of children and 1.5–4% in adults [5]. Confusional arousals can occur with about a 2.9% prevalence in the general population. As can be inferred from the epidemiological data, many people tend to outgrow parasomnias as they enter adulthood; however, there is still a small population of patients that will continue to struggle with parasomnias. There also is a genetic predisposition for NREM parasomnia with an association with HLA DQB1*05:01. A study demonstrated that this allele was present in 41% of patients with NREM parasomnia compared to 24.2% of controls, irrespective of the type of NREM parasomnia [6]. In addition, sleep terrors and sleepwalking have a strong family history with one study demonstrating up to a 57% concordant family history [7]. The pathophysiology of NREM sleep is secondary to sleep dissociation and may also involve autonomic dysfunction as see in sleep terrors. Essentially, as sleep is not completely dissociated during wakefulness, skeletal muscle movements are

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seen while still in a sleep state. This finding on a polysomnogram can be seen with abrupt transition from N2 or N3 to wakefulness as seen in Fig. 3.1. A change in rate of specific cyclic alternating patterns (CAPs) of the EEG has also been implicated in the pathophysiology of decreased NREM parasomnia. The CAP is a marker of cerebral activity under states of decreased level of global consciousness. Each CAP is composed of an “A” phasic sleep phase and “B” phase with return to baseline background rhythm. The A phase is divided into further phases of A1, A2, and A3 with A2 and A3 demonstrating increasing desynchrony as evidenced by increasing amounts of low-amplitude fast activity [8] (Fig. 3.3). A study from Guilleminault in 2006 demonstrated a difference in parasomnia patients with a decrease in phase A1 and increase in phase A2 and A3, which may be indicative of increased instability of NREM sleep [9]. However, while this trend is seen, its use in the clinical setting is limited as it is a non-specific EEG marker. In addition to intrinsic NREM sleep state instability, other primary medical issues that affect sleep and cause sleep disruption can also potentiate NREM parasomnias. For example, sleeping in new environments has been a known precipitant of somnambulism. Sleep insufficiency or deprivation can cause a worsening of the frequency of episodes due to the increased presence of N3 sleep during recovery. Stress and anxiety, as in our patient, can also be disruptive to sleep causing more arousals, as can other primary sleep disorders such as sleep disordered breathing, circadian rhythm disorders such as a delayed sleep phase or shift work disorder, periodic limb movements, or narcolepsy, which can fragment sleep as well. Specific medications can also disrupt sleep, which can then also cause worsening episodes. Notoriously, zolpidem has been known to precipitate episodes of NREM parasomnias. For this reason, it is important to rule out other causes of sleep disruption in addition to identifying and treating the parasomnia.

CAP cycle

A

A B

A B

C4-A1 CAP sequence 10 sec

Fig. 3.3  Example of cyclic alternating pattern with the A and B phases

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The specific semiology of parasomnia can vary, but there may be significantly complex actions as evidenced by the eating, sexual activity, and violence accompanying many parasomnia episodes. The leading theory is that this may be related to what is termed central pattern generators [10]. This theory, both implicated in seizures and parasomnias, suggests that central pattern generators networks within levels of the brainstem including the midbrain, pons, and spinal cord produce self-­ sustaining patterns for survival. These are suppressed by higher cortical function, but when the higher cortex is suppressed (i.e., sleep) there can be emergence of the more basic functions such as feeding and intrinsic autonomic function (i.e., fight or flight) reproduction. The same process is thought to occur in post-ictal psychosis and agitation, wherein after a seizure, epileptic patients can often times flail, kick, and bite. The descriptions of the types of NREM parasomnias are as follows: • Confusional Arousals: Also described as sleep inertia or sleep drunkenness, these are episodes of acute confusion upon awakening. During these episodes, the patients may have confusion about their surroundings. Their response to the environment may be decreased, and they may have associated difficulty with speech or articulation, and subsequent amnesia about details of the event. The duration of confusional arousals can vary from a few seconds to 20  minutes, though most tend to be no more than 1 minute. Unlike sleep terrors, there is usually no accompanying autonomic dysfunction. Confusional arousals can derive from N2 or N3 sleep and are not necessarily limited to the first third of night, as is the case for other NREM parasomnias. • Sleep Terrors: More commonly seen in children, sleep terrors tend to be very dramatic events for parents to witness. They usually occur in the first third of sleep, as they tend to arise from N3 slow wave sleep during homeostatic recovery. However, sleep terrors can also occur out of N2 sleep. Episodes are usually very sudden events whereby the individual will sit up, crying or screaming. The individual will seem inconsolable and will also have adrenergic symptoms such as diaphoresis, tachycardia, dilated pupils, and rapid breathing. Individuals may appear awake, but are typically not responsive to environmental cues and if woken will become confused, agitated, and perhaps even violent. Unlike nightmares, these patients are largely amnestic to these events (though may report vague recollection without clear description of details). • Sleep Talking/Sleepwalking/Sleep-Related Eating Disorder (SRED): These parasomnias tend to encompass more complex actions. Sleep talking/somniloquy can occur both in NREM and REM sleep, though in NREM there is no association with dream imagery, and rarely any recollection. The talking itself can vary between single mumbled words to full sentences and conversations. Sleepwalking (somnambulism) typically occurs out of stage N3 sleep and usually last less than 15  minutes, though there have been reports of events lasting up to hours. Clinically, the individual will have what appears to be an arousal though with some confusion and at times even automatism with repetitive motions. The individual then may walk around the room, outside the room and in some cases may

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perform significantly complex tasks, such as sleep driving [11]. More concerning, there have been cases of violence, sexual assault, and even homicide reported with somnambulism [12]. Patients with these types of complex NREM parasomnias have minimal awareness of their environment and are at high risk for injury and falls; thus, it is important to modify the sleep environment to minimize this risk. • Sleep-related eating disorder or SRED is a subtype of sleepwalking wherein the person will typically go to the kitchen and consume food, usually in high amounts. A distinctive feature of SRED is the ingestion of atypical and oftentimes inedible products such as pet food, cigarettes, frozen foods, and toxic substances such as detergents. There may be some clues in the household such as signs of food left out on tables or counters and crumbs of food that the patient cannot remember. Sex-related parasomnias, or sexsomnia, have also been described with bizarre sexual activity, initiation of sexual activity with partners, oftentimes with no knowledge of the events afterwards. Much of the assessment of NREM parasomnia can be determined from detailed history, and clinical history alone is sufficient to make a diagnosis of NREM parasomnia. Video obtained by family or bed partner can also be helpful and supportive of the diagnosis. An extensive evaluation of other causes of nocturnal arousals is indicated, such as evaluation for insufficient sleep, circadian rhythm disorders, hypersomnias, periodic limb movements/restless legs syndrome, and sleep disordered breathing. Obtaining a history of epilepsy, and medication history (especially with usage of hypnotics such as zolpidem) is also helpful. Many uncomplicated cases of NREM parasomnia do not require additional workup. However, in complicated cases polysomnogram with extended EEG montage may be warranted. This is most useful when the diagnosis is uncertain and there is difficulty differentiating between nocturnal seizures and parasomnias. The polysomnographic features of a NREM parasomnia include abrupt transition from N3 sleep to wakefulness as in our patient. There also may be a mixed slow theta frequency during the arousal. Autonomic features can potentially be seen such as increase in EMG tone, and increased heart rate. In addition, cyclical alternating pattern (CAP) may indicate NREM instability and can be seen in NREM parasomnias but is largely not specific. One study did demonstrate a high predictive ability of polysomnogram, with 65% of suspected patients having confirmatory testing [13]. However, the primary purpose of polysomnography is to rule out other sleep disorders and causes of sleep disruption. NREM parasomnias do not always necessitate pharmacologic treatment. Treatment of any underlying sleep disorder, which may cause sleep disruption, is important. However, in primary parasomnias without an underlying trigger, lifestyle modifications are typically sufficient. This involves keeping the bedroom free of clutter, restricting amount of furniture in the bedroom, and providing safeguards against nocturnal wandering, such as complex locks on the bedroom door. Extreme precaution should also be taken if firearms are present in the house, to ensure they are properly locked and not easily accessible. Cognitive behavioral therapy can also

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be considered for positive imagery and relaxation techniques, though supporting evidence for this is limited. In addition, anticipatory guidance for patients should also be discussed, such as possible increase in frequency when outside of normal sleep environments. Pharmacologic intervention is not indicated often, as most events will resolve over time, however if needed low-dose clonazepam at 0.5–1.0 mg is considered first-line therapy, with response rates as high as 73.7% in one study [14].

Key Learning Points • NREM parasomnia is fairly common in childhood, and less so in adulthood. • Semiology of NREM parasomnia can vary from mild sleep talking and brief confusional arousals, to complex motor actions or dysautonomia episodes as seen in sleep terrors and somnambulism. • Majority of NREM parasomnias can be determined from history, but polysomnography with extended EEG montage should be considered in difficult or unclear cases. • Treatment of NREM parasomnias is primarily directed towards safety measures and behavioral interventions. Low-dose clonazepam can be considered in severe or refractory cases.

Case 2: Nocturnal Frontal Lobe Seizures History A 20-year-old left-handed male presents to the sleep clinic for complaints of abnormal laughter episodes during the night. The majority of the history is provided by his girlfriend, who is his bed partner. These episodes have been occurring over the last several years, which have been gradually increasing in frequency, and are now occurring nightly during the first third of the night and are almost identical in character. His girlfriend describes a fit of laughter and giggling, sometimes so forceful that he will wake himself up. This episode itself is brief, and the patient will then arouse from them with some awareness, often asking his girlfriend if “it happened again, right?” He denies any sort of dream mentation when awoken from these episodes. His girlfriend does say that he snores, though this is not a constant issue, and there are no clear witnessed apneas or gasping arousals. The patient has not wandered outside the bedroom, and there are no episodes of sleep eating. There have been no overt episodes of talking during the night, but he has had infrequent episodes of thrashing of his arms and legs, which can last for about 1 minute. There are also less severe leg movements at night, which are different from these trashing episodes, without any internal sense of restlessness. The patient does endorse excessive daytime sleepiness and difficulty with his job, having nodded off during a few office meetings.

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Differential Diagnosis • • • •

Parasomnia (NREM, REM, or overlap) Catathrenia Nocturnal seizures Sleep disruption secondary to periodic limb movements and/or obstructive sleep apnea • Non-epileptic event, i.e., psychogenic non-epileptic seizure (PNES)

History Continued On further questioning, our patient reports a history of one generalized tonic-clonic seizure in the past, which occurred several years ago after he had been sleep deprived while studying for an exam in college. He was evaluated at the time with an MRI of the brain and an EEG, both of which were normal. He was not started on an antiepileptic medication at the time. He also has a history of minor head trauma when he fell on his head in gym class with loss of consciousness for 1–2 minutes. Aside from these incidents, he has had no other neurologic history, and denies any sort of staring episodes, abnormal occurrences where he has lost a substantial amount of time and has never woken up with any incontinence episodes nor tongue biting.

Sleep Schedule/Sleep Hygiene The patient sleeps in bed with his girlfriend on most nights out of the week. He denies using any electronics in bed. Time in bed: 10:45 PM Lights out: 11:00 PM Sleep onset latency: 15 minutes Number of awakenings: 3–4 per night, usually in the first half of the night Cause of awakenings: Due to episodes of laughter described above Wake after sleep onset time: 5–10 minutes per awakening Wake time: 7:30 AM; a few times per week, he wakes at 6:30 AM Naps: Occasionally in the afternoon, 1–2 times per week Total sleep time: Approximately 7–8 hours per 24-hour period

Scales/Questionnaires Epworth Sleepiness Scale: 13 points (excessive daytime sleepiness) Patient Health Questionnaire-9: 8 points (mild depression)

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Past Medical History • None

Past Surgical History • None

Allergies • No known allergies

Medications • Multivitamin daily

Family History • Cousin with history of obstructive sleep apnea • No known family history of narcolepsy, parasomnias, or epilepsy

Social History He reports rare alcohol use (few drinks per year during social events) and has no history of tobacco use or other non-prescription drug use. He works as a software engineer.

Review of Systems All systems were reviewed and were negative unless reported above in history.

Vital Signs Blood pressure: 118/60 mmHg Heart rate: 65 beats per minute Respiratory rate: 16 breaths per minute Height: 5 feet 9 inches Weight: 162 pounds BMI: 24 kg/m2

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Physical Examination General: HEENT:

Normal body habitus. No apparent distress. Mallampati Class I. Neck circumference 15 inches. No tonsillar hypertrophy. Funduscopic examination is normal, normal range of motion. No nasal flaring, no swelling of the turbinates, and no septal deviation. Respiratory: Clear to auscultation bilaterally, no wheezing/rhonchi/crackles. Cardiovascular: Regular rate and rhythm, no murmur, rubs or gallops. No carotid bruit. Extremities: No cyanosis, clubbing, or edema. Skin: No rash, lesions ulcers, induration, or nodules in visible regions. Neurologic: He is alert and fully oriented. Cranial nerves II–XII are intact. Motor strength 5/5 in upper and lower extremities. Sensory exam intact to light touch, pinprick, and vibration. Reflexes 2+ throughout, normal gait.

Differential Diagnosis • NREM parasomnia • Nocturnal seizure The differential diagnosis is very similar to the previous case due to similar elements of the clinical presentation. The episodes tend to occur earlier in the night, and the lack of dream mentation is more suggestive of a non-REM-related event (i.e., NREM parasomnia vs. nocturnal seizure). The description of thrashing may be suggestive of either condition. However unlike NREM parasomnia, there appears to be some stereotypy of the laughing episodes that occur almost nightly. This feature may be more consistent with a seizure rather than a parasomnia, which tends to have a more varied behavioral semiology. Also, unlike the first case, there is at least some minimal awareness of the events at night, which can be seen with seizures. Catathrenia and OSA are lower on our differential list, as the physical exam and history is less suggestive of sleep disordered breathing. Psychogenic non-epileptic seizure (PNES) is a diagnosis of exclusion and should not be entertained until there has been diagnostic testing ruling out other organic conditions.

Diagnostic Testing A polysomnography with extended EEG montage is ordered to differentiate between the most likely disorders listed above. Diagnostic Polysomnogram (PSG) Total sleep time: 479 minutes Latency to sleep: 10.4 minutes

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REM latency: 102 minutes Sleep efficiency: 86% Apnea-hypopnea index (AHI): 2.2 events per hour of sleep REM AHI: 3.8 events per hour of sleep Mean sleep % SpO2: 98% Min sleep % SpO2: 90% Periodic limb movement index: 8.5 limb movements per hour

Assessment Polysomnography with an extended EEG montage demonstrated normal sleep transitions; however, there were multiple events with clinical correlation as seen in Figs. 3.4, 3.5, and 3.6. Frontal rhythmic activity is seen very briefly maximally over the F3–C3 leads. This finding is consistent with very brief seizure activity. Coupled

Fig. 3.4  A 30-second window of N2 sleep with an extended EEG montage. Note the tech comment of stiffening and laughing

Fig. 3.5  This figure is the subsequent 30-second epoch demonstrating frontal repetitive theta frequency activity maximal over the left frontal leads F3–C3. The overall period of time is brief lasting only 9 seconds, though there is a clear clinical correlation with this event

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Fig. 3.6  A 10-second window with only the EEG leads showing the frontal repetitive theta frequency waveforms

with the history of stereotypical events, occurring nightly in the first half of the night, the patient was diagnosed as most likely having nocturnal frontal lobe seizures. Diagnosis  Nocturnal frontal lobe seizures

Treatment After diagnosis, the patient was referred to an epileptologist. MRI of the brain revealed no abnormal findings; however, the patient was started on oxcarbazepine and responded with remission of seizure activity.

Discussion Continuing the discussion on the evaluation of nocturnal awakenings, frontal lobe seizures are one of the main items in the differential diagnoses along with NREM parasomnia. Seizure activity is defined by hypersynchronous electrical cortical activity of neuronal networks then manifesting as alteration of motor, behavioral, or sensory pathways depending on the location of the seizure focus. Seizures are the fourth most common neurologic disorder, affecting up to 8–10% of the population at some point in their life. The prevalence of seizures follows a bimodal distribution with peaks during childhood/adolescence and over the age of 60 [15]. Seizures are subdivided into primary generalized or secondary/focal seizures. Primary seizures are typically seen in childhood and are usually caused by an inherent disturbance of the neural network, such as a channelopathy. Nocturnal frontal lobe seizures were first described in 1981 by Lugaresi and Cirignotta, with patients described as having a clustering of posturing and movements during sleep. However, surface EEG did not capture any epileptiform abnormalities, and it took many years later until the pathophysiology of mechanisms of nocturnal seizures was more fully understood.

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Though the term “nocturnal frontal lobe epilepsy/seizures” (NFLE) is still used, the term “sleep-related hypermotor epilepsy” (SHE) has been used more frequently since 2014. The change occurred as the events are not inherently nocturnal and can occur during diurnal sleep periods. In addition, while the frontal lobe is implicated in the majority of cases, extrafrontal epileptogenic foci from the temporal lobe and insular cortex have been implicated in up to 30% of cases [16–18]. In general, nocturnal seizures are a NREM phenomenon. NREM sleep is modulated by thalamocortical oscillatory projections and promotes hypersynchrony, which allows for interical discharges to increase in frequency. Herman et al. studied 133 patients with a total of 613 seizures and noted seizures starting in N1 and N2 sleep (91%) with rare seizures in N3 sleep and none in REM sleep. Frontal lobe seizures were also the most likely to occur in sleep as well [19]. Frontal lobe seizures have a peak age of onset of age 14, with a 7:3 male: female ratio [20]. While most cases are idiopathic, multiple genetic components have been discovered. Sheffer published his findings of an Australian family with 25% prevalence of nocturnal frontal lobe epilepsy with an autosomal dominant pattern [21]. Genetic studies revealed a mutation in the CHRNA4 gene coding in the alpha4 subunit of the nicotinic acetylcholine receptor nAChR, and further mutations have since been discovered in CHRNA2 and CHRNB2 [22, 23]. This also has importance as the hyperexcitable potential of the nAChR may decrease arousal threshold and cause NREM destabilization. In fact, NREM parasomnia and frontal lobe seizures have a strong concordance with one study demonstrating 34% of NFLE patients having NREM parasomnia, and a 39% concordance with first-degree relatives [24]. What further complicates this pattern is that interictal discharges are inherently disruptive to sleep, which again promotes NREM instability in and of itself as seen in Fig. 3.7 [25]. Nocturnal frontal lobe seizures have variable clinical presentations and can often be mistaken for NREM parasomnias, psychogenic non-epileptic seizures (PNES, or formerly pseudoseizures), other dystonic movements disorders and other psychiatric manifestations. This is further complicated as frontal seizures can be very difficult to capture electrographically even with a clinical event if the seizure focus is an area which cannot be recorded via surface electrodes. This can often lead to the misdiagnosis of PNES or some sort of other movement disorder. In fact, the history of SHE has been complicated with debates of whether they truly represent an epileptic event as electrographic seizures oftentimes were not captured on EEG.  However historically, patients did tend to respond to antiepileptic medications. The semiology of the epileptic events can be delineated in three distinct types though can be considered on a spectrum of epileptic events: • Paroxysmal Arousals (PA): Paroxysmal arousals account for approximately 75% of SHE seizures [20]. These events are very brief, usually lasting less than 30  seconds in duration and are characterized by vocalizations, or stereotyped movements. Common behavior observed include automatisms, such as picking at clothes or picking at leads, gelastic (laughing) events, profanities, and other

3  Nocturnal Awakenings Fig. 3.7  Cycle of sleep-related epileptic discharges, which acts as a trigger for micro-arousal increasing sleep instability and causing risk of other sleep disorders and NREM instability and in turn becomes a risk for further interictal discharges and seizures. Ref. [25], modified with permission

67 Ictal discharges / seizures

Interictal epileptiform discharges

Micro-arousals and sleep instability

Minor motor events (epileptic or not), other sleep-related motor events (PLMS, bruxism, parasomnias)

such stereotyped movements. These tend to occur several times a night and are often clustered together during stage N2 sleep. The patient may have awareness of the event but is unable to control them. This paroxysmal arousal is the type of brief seizure event that our patient had. • Nocturnal Paroxysmal Dystonias (NPD): Preceded by paroxysmal arousals, these events account for approximately 23% of nocturnal seizures and usually last less than 2 minutes. The initial arousal is followed by more complex movements, such as flailing of the arms or legs, bicycling of the legs, pelvic thrusting, vocalizations, or dystonic posturing. The prevalence of these events are less than PA, and are often accompanied with minimal awareness (usually only ~30%) [26]. Unlike NREM parasomnias, these episodes tend to occur nightly, and may also be part of a constellation of other behaviors such as automatisms and other seizure types. Our patient in this case may have also had some component of this based on the description of his limb movements. • Episodic Nocturnal Wandering (ENW): Preceded by both PA and NPD, episodic nocturnal wandering results in agitated wandering outside the bed. These episodes are the rarest nocturnal seizure subtype, only occurring in ~2% of nocturnal seizures. There may be some symptoms resembling dysautonomia with screaming, yelling, or talking and there still may be persistence of dystonia. However, this does appear to be more of an epileptic event rather than a post-ictal

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phenomenon; in cases where ambulatory EEG was performed, ictal activity is seen [27]. Unlike pure NREM parasomnia, there is an “agitated” component to the seizure in that the patient tends to be distressed at the start of the episode, which is rare for NREM parasomnia. Differences Between NREM Parasomnia and Nocturnal Seizure Distinguishing between a NREM parasomnia and nocturnal seizure, such as frontal lobe epilepsy, can prove challenging. While polysomnography and capturing an event with an epileptic correlation can be helpful, frontal lobe seizures can oftentimes be elusive. If initial clinical suspicion is higher for epileptic spells, then long-­ term monitoring (LTM) with video EEG is preferred to maximize opportunities for observing a clinical event. Despite advanced modalities for evaluation, frontal lobe patients have low yield on EEG with ictal discharges reported in only 10–56% of cases [24]. In addition, the classic hypersynchronous theta activity consistent with seizure may not be seen, and an underlying seizure may solely be represented as a burst of repetitive slow waves, abrupt transitions in sleep to wake or even a simple K complex. Despite the genetic discoveries in ADNFLE, genetic testing is still not routinely recommended at this time as the ADNFLE families are still relatively rare and idiopathic NFLE is far more common. Further complicating the matter is the fact that NREM parasomnia and NFLE have a high concordance rate and patients with overlap of the two processes may simply be diagnosed as having NREM parasomnia. Similar to NREM parasomnia, clinical history can be very helpful. In 2006, Derry created the frontal lobe epilepsy scale [28]. This scale from −10 to +11 assesses likelihood of frontal lobe seizure vs. parasomnia. Scores from −10 to 0 are more suggestive of a parasomnia and 1 to 11 are more suggestive of frontal lobe seizures. The scale assesses age of onset, duration, number of events, and other clinical characteristics. The scale itself has a specificity of 90–100% and a sensitivity of 71.4%. Other clinical features differentiating parasomnia and epilepsy are presented in Table 3.1. Specifically, NFLE patients will tend to have multiple attacks at night and have the repetitive stereotypy to the episodes. Table 3.2 also represents features that can be helpful in distinguishing whether an event is characteristic of a parasomnia. Patient and family reporting may not be as helpful as video evidence either by home video by a family member or with PSG/ long-term video EEG monitoring. Treatment options for frontal lobe seizures include antiepileptic medications including carbamazepine, oxcarbazepine, levetiracetam, valproic acid, phenytoin, lamotrigine, etc. The remission rate of frontal lobe seizures remains relatively high with about 70–73% remission with medication therapy [30]. Neuroimaging may be beneficial as well with MRIs assessing for cortical dysplasia or other structural lesions. Refractory cases may require referral to an epileptologist specifically trained in more invasive intracranial monitor and assessment for possible surgical ablation or resection. The workup of NREM parasomnia vs. frontal lobe seizures should begin with the clinical history. If there is a strong suspicion for epilepsy, it is highly recommended

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Table 3.1  General features of Parasomnias vs. Nocturnal frontal lobe seizures Age of onset

Parasomnias 10/hour), patients can be symptomatic even with less severe objective markers (i.e., lower AHI) or with primary snoring alone (a syndrome designed as “upper airway resistance syndrome” or UARS). Treatment of UARS, or milder forms of sleep disordered breathing, can be oftentimes done non-­ surgically and more specifically with a nasal corticosteroid and oral leukotriene inhibitor [6, 13]. This combination allows for a decrease in the size of inflamed tissues in the airway, decreasing the amount of obstruction in these already narrow airways. This will theoretically decrease the resistance in his airway, improving the quality of his breathing in sleep and allowing for more consolidated and restorative sleep, overall (especially compared to the low sleep efficiency and high WASO (wake after sleep onset) index seen on the sleep study night). Highlights • Sleep disordered breathing is a spectrum that spans from mouth breathing, snoring, increased upper airway resistance syndrome (UARS), and finally is most severe in obstructive sleep apnea. • Snoring is a common pediatric finding and can be a clue to the presence of more severe sleep disordered breathing. It should prompt further history taking and physical examination to determine a patient’s risk for having obstructive sleep apnea. • Pediatric sleep disordered breathing has negative neurocognitive implications for pediatric patients, including diminished attention span and concentration in school, hyperactivity, and restlessness during the day and night. • Polysomnography is the primary objective method to evaluate for sleep disordered breathing and grade its severity. • In pediatric patients, OSA severity is broken down as follows: Mild: AHI 1–5/hour Moderate: AHI >5–10/hour Severe: AHI >10/hour • UARS and mild pediatric sleep apnea can be treated in largely the same way, with a trial of intranasal corticosteroids and an oral leukotriene receptor antagonist.

Case 2: Treatment of Pediatric OSA History Anna is an 11-year-old girl with 5–6 years of snoring, witnessed apneas, and diaphoresis noted in her sleep by her mother. While she continues to do well in school, she is feeling tired throughout the school day, yawning, and having trouble keeping

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her eyes open as the day progresses. She tries to limit napping afterschool, but sometimes needs to rest in order to finish her homework afterwards. She was seen by ENT several years ago who recommended a PSG but parents declined at that time. She has been seeing an orthodontist and is planning on wearing braces, but no palatal expansion has been started yet. She has no other unusual behaviors in her sleep: no kicking, sleepwalking, sleep talking, or screaming out in sleep. No reported head banging or body rocking. No bed wetting.

Sleep Schedule/Sleep Hygiene Anna sleeps in a full-size bed by herself. Her bedroom is on the other side of the house from her mother’s bedroom. Time in bed: 11:00 pm on weekdays, 11:00 pm–1:00 am on weekends Sleep onset latency: 10–30 minutes Number of awakenings: None that she specifically recalls, but may have 1–2 per week Weekday wake time: 5:30–6:15 am Weekend wake time: 10:00 am Naps on weekdays: Rare, 1–2 hours between 6 and 7 pm Naps on weekends: Often, 2–3 hours around 4 pm, which she finds refreshing Total sleep time: Approximately 7–8 hours per 24-hour period

Past Medical and Surgical History • Seasonal allergies

Medications and Allergies • Cetirizine as needed • Multivitamin

Family History and Social History Mother and MGM with OSA, both with BMI in normal range and both on CPAP

Review of Systems Review of medical systems was unremarkable.

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Vital Signs Blood pressure: Heart rate: Respiratory rate: BMI:

131/74 mmHg 73 beats per minute 16 breaths per minute Noted to be in the 13th percentile

Physical Exam General: HEENT:

Friendly, talking appropriately, in no apparent distress or pain. Palate intact with high-arched palate, along with crowded teeth and cross bite. Tonsils 1+ bilaterally, with Mallampati III sitting and supine. Nasal turbinates appeared erythematous and inflamed bilaterally. Respiratory: Clear to auscultation bilaterally, no wheezing/rhonchi/crackles. Cardiovascular: Regular rate and rhythm, no murmur, rubs, or gallops. No carotid bruit. Neurologic: Alert and fully oriented. Cranial nerves II–XII are intact. Motor and sensory exam grossly intact.

Differential Diagnosis • • • • •

Upper airway resistance syndrome Pediatric obstructive sleep apnea Periodic limb movement disorder Narcolepsy Circadian rhythm disorder

Diagnostic Testing Polysomnogram #1: • Sleep latency 40.2 minutes • REM latency 99 minutes • Sleep efficiency 56.1% • WASO 170 minutes • Normal EEG • Normal chin EMG • Limbs 8.3/hour • Normal sinus rhythm • AHI 31.3/hour

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• • • •

REM AHI 40/hour Supine AHI 58/hour (non-supine AHI 4.9/hour) SpO2 nadir 84% Max EtCO2 50  mmHg (7 years), obese, or have an underlying syndrome. Further studies performed on one of the cohorts included in the meta-analysis demonstrated that in children with an AHI of 2.5 or lower, there was over 75% rate of spontaneous resolution with watchful waiting for 7 months. Once the AHI was greater than 2.5/hour, the rate of resolution fell to approximately 50%, and with AHIs above 4.6 and 9.1, the rates fell to approximately 25% and 20%, respectively. This suggests that pediatric sleep apnea with an initially higher severity has a lower likelihood of resolving without intervention. As operative intervention is not without risks (most commonly poor oral intake and pain but also possibly infection, bleeding, etc.), understanding which cohort of patients have the highest likelihood to benefit from “watchful waiting” is important. It is also important to keep in mind that these analyses did not include children younger than 5 years old, so these outcomes cannot necessarily be applied to younger patients. In this particular case, the decision was made to pursue adenotonsillectomy given the severity of Anna’s initial OSA. She was likely monitored closely postoperatively given the AAP recommendation for children to have inpatient postoperative monitoring in cases of AHI ≥ 24/hour and/or SpO2 5-10

Trial of ICS & leukotriene receptor antagonist

AHI  95% percentile for age and gender) in the early 1990s, but more than 50% of children referred to the sleep center for suspected SDB in early 2000s fulfilled the criteria for obesity [33]. Subsequently there has been a shift from the classic presentation of children with OSA, ATH, and FTT to children with obesity with and without ATH. This epidemiological change triggered an intense interest in exploring the relationship between OSA and weight gain and OSA and obesity in particular [20]. Obesity is defined as a BMI at or above the 95th percentile for children and teens of the same age and sex; being overweight is defined as a BMI at or above the 85th percentile and below the 95th percentile for children and teens of the same age and sex. BMI is calculated as weight in kilograms divided by the height in meters squared (CDC website [16]). BMI is a simple yet imperfect tool for evaluation of obesity. It does not distinguish excessive weight due to abundance of fat mass from being overweight due to excess lean mass. BMI is the most commonly used measure for assessing obesity in adults. Despite the likelihood of misclassification of the small percentage of individuals whose high BMI is due to lean muscle mass (e.g., athletes), the vast majority of individuals with high BMI have excess body fat. BMI estimation in children is more complicated as an individual child’s BMI score has to be compared to the BMI of other children of the same age and gender. The BMI-for-­ age reference in the United States is based on nationally representative data from boys and girls ages 2–20 years collected between 1963 and 1980 available through the CDC website (CDC website). Morbidly obese children’s BMI could not be plotted on the standard CDC BMI percentile chart because their BMI points were above the chart cutoff. Conversely, children with low BMI were also difficult to track on the standard percentile chart. BMI z-scores, also called BMI standard deviation scores, were later introduced to measure relative weight adjusted for child age and sex. Z-scores are particularly useful to monitor changes in patients with extreme BMIs, that is, BMI above the 99th percentile or below the first percentile. A z-score describes how far a child’s BMI is from the population mean for his/her age and sex, expressed as a multiple of the population standard deviation. The value of a z-score can be negative or positive depending on whether a child’s BMI is smaller or larger than the population mean for his/her age and sex. The further a child’s BMI is away from the population mean for his/her age and sex, the larger the absolute value of his/her z-score [5]. Most early studies [14, 27, 55] reporting association between OSA and weight abnormalities focused on children’s weight and height; however, recent studies also take into consideration BMI z-scores [24, 47, 63, 90]. Obese

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children are at a higher risk for OSA as the prevalence of OSA among obese children and adolescents can be as high as 60% [85]. The severity of OSA seems to be proportional to the degree of obesity [43, 69, 76]. At any level of OSA severity, the likelihood of excessive daytime sleepiness for obese children is greater when compared to non-obese children [20]. Many obese children with OSA have ATH [74]; however, the pathophysiology of OSA in obese children is complex and cannot be explained by ATH alone. Other proposed mechanisms include genetic predisposition, race [71], increased deposition of fat in the parapharyngeal fat pads near and within the soft palate contributing to airway obstruction (although, no consistent relationship between measures of fat distribution and pediatric OSA in children has been found to date) [84], local upper airway inflammation and mucosal swelling from recurrent vibration, and elevated levels of inflammatory cytokines. Other contributing factors include systemic inflammation, elevated leptin level, lower lung volumes, increased airway collapsibility, and gas exchange abnormalities [9, 46]. There appears to be a reciprocal relationship between OSA and obesity in adults [42]. In obese adults, OSA causes dysregulation of hunger/satiety-regulating hormones, sleep disruption, fatigue, and sleepiness as well as behavioral changes such as poor dietary choices and lack of physical activity, as well as an alteration of energy balance between energy intake and energy expenditure [42, 72]. There is a considerable similarity between adult OSA and pediatric OSA profiles. As in adults with OSA, pediatric OSA with obesity is associated with insulin resistance, hypertension, and an increase in inflammatory markers [9, 50]. There is now a plethora of evidence suggesting that OSA in adults contributes to or exacerbates cardiovascular disease, especially in the context of obesity [42, 65]. Although long-term data on childhood obesity and OSA-related effects on cardiovascular structure and function are currently not available, data from short-term studies focusing on blood pressure regulation, cardiac function, autonomic dysfunction, and endothelial properties suggest a similar pattern in obese children and obese adults with OSA [4, 23, 73, 79, 83]. Therefore, some investigators speculated that OSA associated with obesity is a different entity than OSA associated with FTT and subsequently proposed to divide OSA in children into type I (OSA without associated obesity) and type II pediatric OSA (OSA with associated obesity) [20, 50]. As opposed to children with ATH and FTT, obese children with OSA may not have adenotonsillar hypertrophy, often present at a slightly later age, and are more likely to have a clinical presentation resembling the adult OSA phenotype [32]. There has been accumulating evidence of metabolic sequelae of OSA and obesity in children such as insulin resistance and diabetes [18, 49], dyslipidemia [18, 75], cardiovascular morbidity including hypertension [3, 35, 39, 60], endothelial dysfunction [31], right ventricular hypertrophy [21], and left ventricular remodeling hypertrophy [4] as well as systemic inflammation [9]. These complications resemble findings in adults with OSA and are now recognized as important public health issues.

 denotonsillectomy and Weight Gain A AT is recommended as the first step in the management of pediatric OSA in both non-obese and obese children with ATH by the American Academy of Pediatrics

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[1]. In the United States, the number of tonsillectomies has actually declined significantly since the 1970s. In the past, approximately 90% of AT in children were performed for recurrent infection; now 80% of AT are performed for obstructive sleep problems (American Academy of otolaryngology-head and neck surgery). The first documented case of improved growth after AT in a child with FTT was reported in 1893 [41]. Since then, there have been multiple reports demonstrating postsurgical weight gain and GF resolution in children undergoing AT [13, 19, 25, 37, 47, 70]. Interestingly, the research suggests that AT can not only lead to normalization of weight in children with GF but also increases the risk of obesity in overweight and obese patients [13, 15, 47, 78, 83]. Most studies have focused on evaluating growth and obesity after AT based on anthropometric measurements such as BMI. Although BMI is a simple method to evaluate obesity, it does not distinguish between lean body mass and body fat [51]. This would be an important consideration as obesity is defined by an abnormal percentage of adipose tissue in the body, and children have a higher percentage of lean body mass than adults [52]. Bioelectrical impedance analysis (BIA) appears to be a relatively reliable, simple, and noninvasive method evaluating body fat and lean body mass [87]. One prospective study [54] used BIA to evaluate the difference between the rate of weight increase among children ages 6–9 with chronic tonsillitis and adenotonsillar hypertrophy following adenoidectomy or AT versus healthy controls. This study demonstrated an improvement in BMI in the surgical group without an increase in body fat percentage. However, children in this study were not screened for OSA [54]. Resolution of GF in children with OSA undergoing AT is attributed to increased postoperative levels of circulating IGF-1 and IGFBP-3 [7, 44, 53, 54, 89], reduced upper airway and systemic inflammation [53], increased caloric intake [62] due to unhealthy food choices [29], decreased nocturnal caloric expenditure due to lower work of breathing during sleep, resolution of intermittent hypoxemia, and reduction in wakefulness caloric expenditure due to reduction and/or resolution of hyperactivity [44, 70].

Key Learning Points • Obese children with OSA may not have ATH but do have pathophysiological changes and metabolic derangements similar to adults with OSA. • Obese children with OSA are more likely to develop excessive daytime sleepiness than non-obese children with OSA. • Although normalization of growth post-AT is beneficial in the setting of GF, an exaggerated increase in weight gain in overweight and obese children could increase their risk for OSA recurrence and obesity-related morbidity.

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 creening Children for Obstructive Sleep Apnea, Proposed S Algorithm Based on American Academy of Pediatrics Clinical Practice Guideline: Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome, 2012 Screening all children for OSA during well child visits (history and exam)

History or physical examination findings concerning for OSAa

Complex high-risk patientsb without cardiovascular compromise – refer to a sleep specialistc

Low-risk patients without cardiovascular compromise

Patients with cardiorespiratory failurerefer for urgent in hospital evaluation

Consider a polysomnography (gold standard) to evaluate for OSA presence and severity, especially if symptoms are concerning for OSA and physical exam findings are unremarkable

Consider audiovisual recording at home, overnight pulse oximetry, or home sleep study (for post pubertal teenagers)d

Consider direct referral to otolaryngologist for otherwise healthy children over 2 years of age when polysomnography is unavailable or the child is unable to sleep during the study [2]

Confirmed or highly suspected diagnosis of OSA

Consultation with otolaryngologist

Non-surgical candidates: refer to the specialists for the following options: CPAP, orthodonture, treatment of allergies, or conservative therapy, weight loss

The patient is a candidate for surgery (i.e. AT)

High-risk patients should be monitored as inpatients postoperatively. Clinical reevaluation 2–3 months after surgical intervention. Repeat sleep study for patients with symptoms suggestive of persistent OSA or patient with

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• aHistorical findings associated with OSA include habitual snoring with labored breathing, observed apnea, mouth breathing, sleep with an arched back, parasomnia, restless sleep, daytime neurobehavioral abnormalities or sleepiness, and others. Physical findings may include growth abnormalities, obesity, mouth breathing, malocclusion, signs of nasal obstruction, adenoidal facies, enlarged tonsils, hypertension, and others. Note that some patients may have no abnormalities on examination. • bComplex, high-risk patients include infants younger than 12 months and children with craniofacial disorders, Down syndrome, neuromuscular disorders (including cerebral palsy), chronic lung disease, sickle cell disease, central hypoventilation syndromes, persistent asthma, or genetic, metabolic, or storage disease. • cSubspecialist refers to a physician with expertise in sleep disorders in children. This physician may be a pulmonologist, neurologist, or other physician with experience in the management of sleep-disordered breathing in children. • dAASM: does not recommend home sleep apnea testing for OSAS diagnosis in children (AASM Practice Parameters 2017; Kirk et al. 2017).

References 1. American Academy of Pediatrics. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012;130(3):576–84. 2. American Academy of Otolaryngology-Head and Neck Surgery. Tonsillectomy facts in the US: from ENT doctors. Available from: https://www.entnet.org/content/ tonsillectomy-facts-us-ent-doctors. 3. Amin RS, Carroll JL, Jeffries JL, et al. Twenty-four-hour ambulatory blood pressure in children with sleep-disordered breathing. Am J Respir Crit Care Med. 2004;169(8):950–6. 4. Amin RS, Kimball TR, Bean JA, et al. Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165(10):1395–9. 5. Anderson S.  Body mass index in children and adolescents: considerations for population-­ based applications. Int J Obes. 2006;30(4):590–4. 6. Assadi MH, Shknevsky E, Segev Y, Tarasiuk A. Abnormal growth and feeding behavior persist after removal of upper airway obstruction in juvenile rats. Sci Rep. 2017;7(1):2730. 7. Bar A, Tarasiuk A, Segev Y, Phillip M, Tal A.  The effect of adenotonsillectomy on serum insulin-like growth factor-I and growth in children with obstructive sleep apnea syndrome. J Pediatr. 1999;135:76–80. https://doi.org/10.1016/S0022-3476(99)70331-8. 8. Bate TW, Price DA, Holme CA, McGucken RB. Short stature caused by obstructive apnoea during sleep. Arch Dis Child. 1984;59(1):78–80. 9. Bhattacharjee R, Kim J, Kheirandish-Gozal L, Gozal D. Obesity and obstructive sleep apnea syndrome in children: a tale of inflammatory cascades. Pediatr Pulmonol. 2011;46:313–23. 10. Bland R, Bulgarelli S, Ventham J, Jackson D, Reilly J, Paton J. Total energy expenditure in children with obstructive sleep apnoea syndrome. Eur Respir J. 2001;18:164–9. 11. Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB. Serum levels of insulin-like growth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab. 1993;76:1610–6. 12. Brandenberger G, Weibel L. The 24-h growth hormone rhythm in men: sleep and circadian influences questioned. J Sleep Res. 2004;13:251–5.

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Index

A Actigraphy and sleep diary, 214 idiopathic hypersomnia, 24 narcolepsy type 1, 15 Acting out dreams, 145, 146 allergies, 147 assessment, 149 diagnostic testing, 148, 149 differential diagnosis, 145, 148 epworth sleepiness scale, 146 family history, 147 medications, 147 past medical history, 146 past surgical history, 146 physical examination, 147 review of systems, 147 sleep schedule/sleep hygiene, 146 social history, 147 treatment, 149, 150 vital signs, 147 Adaptive servo-ventilation (ASV), 109, 177, 182 Adenotonsillectomy (AT), 256, 267, 268 Amphetamines, 19 Apnea-hypopnea index (AHI), 9, 64, 103, 105–107, 206 Armodafinil, 19 Assured pressure support mode (AVAPS), 178 Attention-deficit hyperactivity disorder (ADHD), 225, 228, 247 Atypical antipsychotics, 164 Augmentation, 91 Automatic titrating continuous positive airway pressure (Auto-CPAP) machine, 204 Average volume-assured pressure support mode (AVAPS), 177

B Benzodiazepines, 91, 157 Berlin Questionnaire (BQ), 202, 211 Bilevel positive airway pressure (BPAP), 108, 109, 177 Bioelectrical impedance analysis (BIA), 268 BMI standard deviation scores, 266 BMI z-scores, 266 Body mass index (BMI), 266 C Cardiac resynchronization therapy, 111 Cardiovascular disease, 195 Cataplexy, 19 Catathrenia, 63 Central sleep apnea, due to congestive heart failure and stroke assessment, 181 chest radiography, 181 CPAP therapy, 183 diagnosis, 181 diagnostic testing, 181 differential diagnosis, 181 echocardiogram, 180 laboratory findings, 180 medications, 180 PAP therapy, 183 past medical/surgical history, 179–180 patient history, 179 physical examination, 180 social history, 180 treatment, 182 vital signs, 180

The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 A. S. Sahni et al. (eds.), Sleep Disorders, https://doi.org/10.1007/978-3-030-65302-6

275

Index

276 Central sleep apnea with Cheyne-Stokes breathing (CSA-CSB) cardiac resynchronization therapy, 111 diagnostic testing, 111 differential diagnosis, 110 medications, 110 past medical history, 110 physical examination, 110 social history, 110 Central sleep apneas, 117 Channelopathy, 65 Cheyne-Stokes breathing, 109, 117, 182, 183 Chiari malformations, 179 Childhood Adenotonsillectomy Trial (CHAT), 238 Circadian rhythm sleep-wake disorder, 47 Clarithromycin, 29 Clinical Video Telehealth (CVT), 207 Clomipramine, 141 Clonazepam, 88, 149 Cognitive behavioral therapies (CBT), 21, 59, 141, 216, 217 Cognitive behavioral therapy for insomnia (CBT-I), 41, 42, 45, 48, 196, 217 Complex sleep apnea, 106 Confusional arousals, 58, 158 Continuous positive airway pressure (CPAP), 7, 10, 87, 97, 146, 182, 183, 192, 195, 256, 257 assessment and plan, 107 diagnosis, 107 past medical history, 106 physical examination, 107 Cyclic alternating patterns (CAPs), 57, 59 D DEA, 218 Disturbed sleep, 160 allergies, 161 assessment, 163 diagnostic testing, 163 differential diagnosis, 160, 163 epworth sleepiness scale, 161 family history, 161 medications, 161 past medical history, 161 past surgical history, 161 patient history, 159–160 physical examination, 162 review of systems, 162 sleep schedule/sleep hygiene, 160 social history, 162 treatment, 163–165

vital signs, 162 Dopamine receptor antagonists, 90 Dopaminergic therapy, 90 E Echocardiogram, 180 EDS, 30 Electroencephalography (EEG), 195 Elevated systolic pulmonary artery pressure, 182 Episodic nocturnal wandering (ENW), 67 Epworth sleepiness scale (ESS), 9, 28, 129, 202, 211, 261 acting out dreams, 146 disturbed sleep, 161 idiopathic hypersomnia, 22 narcolepsy, 125 narcolepsy type 1, 13 night terrors, 153 nightmares, 131 nocturnal frontal lobe seizures, 61 non-REM (NREM) parasomnia, 52 obstructive sleep apnea, 5, 96 sleep deprivation, 136 treatment-emergent central sleep apnea, 102 Escitalopram, 194 Excessive daytime sleepiness (EDS), 9, 18, 28, 127 Expiratory positive airway pressure (EPAP), 178 F Failure to thrive (FTT), 257 Fatigue severity scale (FSS), 5, 125, 202, 211 Flumazenil, 29 Frontal lobe seizures, 66, 68, 70 G Gabapentin enacarbil, 88 Gamma-aminobutyric acid (GABA) receptor, 27 Growing pains, 247 Growth failure (GF), 257 H Home sleep apnea testing (HSAT), 101, 182, 204–206 Hyperarousal, 166 Hypercapnia, 186

Index Hypersomnia, 28 Hypersomnolence, 28 Hypocretin, 17 Hypopneas, 117 I Idiopathic hypersomnia allergies, 23 assessment, 25 CSF dopamine, 27 diagnosis, 27 diagnostic testing actigraphy and sleep diary, 24 polysomnogram, 25 urine toxicology screen, 25 differential diagnosis, 21, 24 EDS, 30 epworth sleepiness scale, 22 excessive daytime sleepiness, 28 family history, 23 gamma-aminobutyric acid receptor, 27 indoleacetic acid, 27 medications, 23 melatonin, 29 past medical history, 22 past surgical history, 22 patient health questionnaire-9, 22 patient history, 20, 21 physical examination, 24 review of systems, 23 sleep schedule/sleep hygiene, 22 social history, 23 sodium oxybate, 29 STOP-BANG Scale, 22 symptoms, 29 treatment, 25, 29 vital signs, 23 Image rehearsal therapy (IRT), 134, 164 Imipramine, 141 Impaired ventilation, 176 Indoleacetic acid, 27 Inpatient sleep consultation central sleep apnea, due to congestive heart failure and stroke (see Central sleep apnea, due to congestive heart failure and stroke) obesity hypoventilation syndrome (see Obesity hypoventilation syndrome) obstructive sleep apnea (see Obstructive sleep apnea) parasomnia secondary to neurologic disorder (see Parasomnia secondary to neurologic disorder)

277 restrictive thoracic disorder (see Restrictive thoracic disorder) Insomnia circadian rhythm disorders, 47 cognitive behavioral therapy for insomnia, 48 depression/anxiety, 48 difficulty falling asleep, 41, 43 assessment, 44 differential diagnosis, 44 family history, 44 management, 44, 45 medications, 43 past medical history, 43 physical examination, 44 sleep routine, 43 symptoms, 43 difficulty staying asleep, 37 allergies, 39 assessment, 40 differential diagnosis, 40 family history, 39 management, 40, 41 medications, 39 past medical history, 38 past surgical history, 39 physical examination, 39 review of symptoms, 39 sleep routine, 37, 38 social history, 39 vital signs, 39 symptoms, 46 telemedicine allergies, 212 assessment, 213 CBT-I, 217 diagnostic testing, 214 differential diagnosis, 213 family history, 212 management/treatment, 214 medications, 212 past medical history, 212 past surgical history, 212 patient history, 210, 211 physical examination, 213 review of systems, 212 scales/questionnaires, 211 sleep schedule/sleep hygeine, 211 social history, 212 vital signs, 213 Insomnia Severity Index (ISI), 211 Inspiratory positive airway pressure (IPAP), 178 Insulin-like growth factor (IGF-1), 259

278 Intelligent volume assured pressure support (iVPAPS), 178 International restless leg syndrome study group (IRLSSG), 247 Iron, 248 Iron replacement therapy, 90 Iron therapy, 249 K Kyphoscoliosis, 176, 179 L Lucid dreaming therapy, 164 M Mallampati score, 100, 208 Mandibular advancing device (MAD), 107, 108 Medicaid, 209 Medicare, 209 Melatonin, 29, 46, 75, 85, 150 Methadone, 114 Methylphenidate, 19 Metoprolol, 40 Modafinil, 10, 17, 19, 29 Mood disorders, 159 Multiple sleep latency test (MSLT), 10, 26–28, 213, 217 narcolepsy, 127–129 narcolepsy type 1, 17 N Narcolepsy, 141 allergies, 125 assessment, 129 differential diagnosis, 124, 127 epworth sleepiness scale, 125 family history, 125 fatigue severity scale, 125 multiple sleep latency test, 127–129 past medical history, 125 past surgical history, 125 patient health questionnaire-9, 125 physical exmination, 126 polysomnogram, 128, 129 review of systems, 126 sleep schedule/sleep hygiene, 124 social history, 126 STOP-BANG Scale, 125 treatment, 129

Index vital signs, 126 Narcolepsy type 1 actigraphy and sleep diary, 15 allergies, 13 assessment, 16 depression and anxiety, 19 differential diagnosis, 15 DQB1*0602 haplotype, 18 epworth sleepiness scale, 13 excessive daytime sleepiness, 18 family history, 13 medications, 13 non-pharmacologic and pharmacologic treatments, 19 past medical history, 13 past surgical history, 13 patient health questionnaire-9, 13 patient history, 11, 12 physical examination, 14 polysomnogram with end-tidal CO2 monitoring, 15 review of systems, 14 sleep schedule/sleep hygiene, 12, 13 social history, 14 sodium oxybate, 19 SOREMPs, 18 STOP-BANG Scale, 13 treatment, 17 urine toxicology screen, 15 vital signs, 14 Nasal continuous positive airway pressure, 239 Nasal expiratory positive airway pressure, 108 Nicotinic acetylcholine receptor (nAChR), 66 Night terrors, 153, 165 allergies, 154 assessment, 156 differential diagnosis, 152, 155, 156 epworth sleepiness scale, 153 family history, 154 medications, 154 NREM parasomnias, 157 past medical history, 154 past surgical history, 154 patient health questionnaire-9, 153 patient history, 152 physical examination, 155 polysomnogram, 156 review of systems, 154 sleep schedule/sleep hygiene, 153 social history, 154 STOP-BANG scale, 153 treatment, 157 vital signs, 155 Nightmare disorder, 165

Index Nightmares, 130 acting out dreams, 145, 146 allergies, 147 assessment, 149 diagnostic testing, 148, 149 differential diagnosis, 145, 148 epworth sleepiness scale, 146 family history, 147 medications, 147 past medical history, 146 past surgical history, 146 physical examination, 147 review of systems, 147 sleep schedule/sleep hygiene, 146 social history, 147 treatment, 149, 150 vital signs, 147 allergies, 131 assessment, 134 diagnostic testing, 133 differential diagnosis, 130, 133 disorder, 165 disturbed sleep (see Disturbed sleep) epworth sleepiness scale, 131 family history, 132 medications, 131 night terrors (see Night terrors) past medical history, 131 past surgical history, 131 patient health questionnaire-9, 131 physical exmination, 132 review of systems, 132 sleep schedule/sleep hygiene, 130, 131 social history, 132 STOP-bANG scale, 131 treatment, 134 vital sign, 132 Nocturnal awakenings nocturnal frontal lobe seizures (see Nocturnal frontal lobe seizures) non-REM (NREM) parasomnia (see Non-REM (NREM) parasomnia) Nocturnal frontal lobe epilepsy/seizures (NFLE), 66 allergies, 62 assessment, 64 diagnostic testing, 63, 64 differential diagnosis, 61, 63 episodic nocturnal wandering, 67 epworth sleepiness scale, 61 family history, 62 medication, 62 nocturnal paroxysmal dystonias, 67 paroxysmal arousals, 66

279 past medical history, 62 past surgical history, 62 patient health questionnaire-9, 61 patient history, 60, 61 physical examination, 63 review of systems, 62 sleep schedule/sleep hygiene, 61 social history, 62 treatment, 65 vital signs, 62 vs. NREM parasomnia, 68–70 Nocturnal panic attack (NPA), 163, 165 Nocturnal paroxysmal dystonias (NPD), 67 Noninvasive positive pressure ventilation (NPPV), 176–178 Non-invasive therapy, 108 Non-REM (NREM) parasomnia, 55, 66, 67, 70, 82, 84, 155, 157, 158 allergies, 53 assessment, 55 confusional arousals, 58 cyclic alternating pattern, 57 diagnostic testing, PSG, 54 differential diagnosis, 52, 54 epidemiology, 84 epworth sleepiness scale, 52 family history, 53 management, 85 medications, 53, 57 vs. nocturnal frontal lobe seizures, 68–70 past medical and surgical history, 52 pathophysiology of, 56, 84 patient history, 51, 52 physical examination, 53, 54 review of systems, 53 SERD, 58–60 sleep schedule/sleep hygiene, 52 sleep terrors, 58 social history, 53 STOP-BANG scale, 52 treatment, 56 vital signs, 53 NREM slow wave sleep (SWS), 157 O Obesity, definition of, 266 Obesity hypoventilation syndrome (OHS), 186, 187 assessment, 185 diagnostic testing, 115, 116, 185 differential diagnosis, 116, 185 laboratory findings, 185 medications, 115, 184

280 Obesity hypoventilation syndrome (OHS) (cont.) past medical history, 114 past medical/surgical history, 184 patient history, 114, 183, 184 physical examination, 115, 184 social history, 115, 184 Stop-bang questionnaire, 184 symptoms, 116 treatment, 186 vital signs, 184 Obstructive hypopnea, 8 Obstructive sleep apnea, 19, 42, 45, 108, 118, 186, 187 allergies, 5 apnea-hypopnea index, 9 assessment, 7, 97, 185 caused by, 9 complaints in patients, 99 CPAP, 10 diagnostic testing, 185 differential diagnosis, 3, 7, 96, 185 EDS, 9 epworth sleepiness scale, 5, 9, 96 family history, 5 fatigue severity scale, 5 home sleep apnea testing, 101 laboratory findings, 185 medical history, 4 medications, 5, 96, 184 past medical history, 5, 95 past medical/surgical history, 184 past surgical history, 5 patient health questionnaire-9, 5, 97, 100 patient history, 3, 4, 95, 183, 184 physical examination, 6, 96, 184 prevalence of, 119 PSG, 101 review of systems, 6 risk for, 9 sleep habit review, 96 sleep schedule/sleep hygiene, 4 social history, 6, 184 STOP-Bang scale, 5, 96, 100, 184 telemedicine allergies, 203 assessment, 204 Clinical Video Telehealth, 207 diagnostic testing, 204 differential diagnosis, 204 family history, 203

Index management, 206 medications, 203 PAP, 206, 209 past medical history, 202 past surgical history, 202 patient history, 201, 202 physical examination, 204 review of systems, 203 scales/questionnaires, 202 sleep schedule/sleep hygeine, 202 social history, 203 telehealth, 207–209 vital signs, 203 treatment, 7, 186 vital signs, 6, 184 Obstructive sleep apnea and weight ­abnormalities in children behavioral therapy, 107 classification of severity of, 105 non-invasive therapy, 108 in obese teenager adenotonsillectomy and weight gain, 267, 268 allergies and medications, 261 assessment, 263 differential diagnosis, 260, 262 Epworth Sleepiness Scale, 261 family history, 261 past medical and surgical history, 261 patient history, 260 physical examination, 262 polysomnogram, 262, 263 sleep schedule/sleep hygiene, 261 social history, 261 STOP-BANG Scale, 261 treatment, 264, 265 vital signs, 262 toddler presenting with failure to thrive, 258, 259 assessment, 255 diagnostic testing, 255, 256 differential diagnosis, 255 family and social history, 254 medications and allergies, 254 past medical and surgical history, 254 patient history, 254 physical examination, 255 review of system, 254 treatment, 256, 258 Oral appliances therapy (OAT), 108 Orexin, 17 Oxycodone-naloxone, 91

Index P Parasomnia overlap disorder, 79, 81 description, 81 diagnosis, 82–84 differential diagnosis, 79 medications, 80 past medical history, 80 past surgical history, 80 pathophysiology, 85 physical examination, 80 social history, 80 work-up, 81 Parasomnia secondary to neurologic disorder, 188, 194–196 assessment, 193 diagnostic testing, 191, 192 differential diagnosis, 188, 191 family history, 190 medications, 189 past medical and surgical history, 189 patient history, 188 physical examination, 190, 191 review of systems, 190 sleep schedule/sleep hygiene, 189 social history, 190 treatment, 193 vital signs, 190 Paroxysmal arousals (PA), 66 Patient health questionnaire-9 (PHQ-9), 40 idiopathic hypersomnia, 22 narcolepsy, 125 narcolepsy type 1, 13 night terrors, 153 nightmares, 131 nocturnal frontal lobe seizures, 61 obstructive sleep apnea, 5, 97, 100 Pediatric limb movement disorder, 246 Pediatric obstructive sleep apnea, 230, 232, 264 assessment, 237 associated with growth failure, 256 differential diagnosis, 236 family and social history, 235 medications, 235 past medical and surgical history, 235 patient history, 234 physical examination, 236 polysomnogram, 236, 237 review of systems, 235 sleep schedule/sleep hygiene, 235 treatment, 238–240 vital signs, 236

281 Periodic leg movements during sleep (PLMS), 75 Periodic limb movement disorder (PLMD), 247–250 Peripheral arterial tonometry (PAT), 101 Pharmacotherapy, 164 Pickwickian syndrome, see Obesity hypoventilation syndrome (OHS) Pitolisant, 19, 29 Polysomnogram (PSG), 11, 101, 177, 217, 233, 236, 237, 262, 263 with end-tidal CO2 monitoring, 15 idiopathic hypersomnia, 25 narcolepsy, 128, 129 night terrors, 156 nocturnal frontal lobe seizures, 63 for NREM parasomnia, 54 obstructive sleep apnea, 7 restless sleeper, 245, 246 sleep deprivation, 139 snoring, 229–231 toddler presenting with failure to thrive, 255 Positive airway pressure therapy, 108, 114, 117, 151, 182, 206 Post-traumatic stress disorder (PTSD), 141, 164, 166 Pramipexole, 87 Pregabalin, 91 Primary care providers (PCPs), 218 Primary enuresis, 228 Primary insomnia, 214 Primary seizures, 65 Pseudo-RBD, 148, 151 Pseudoseizures, 66 Psychogenic non-epileptic seizure (PNES), 52, 63, 66 Q Quality of life (QOL), 101 R Rapid eye movement (REM) sleep, 8, 106 Rapid maxillary expansion (RME), 240 Rapid response team (RRT), 187 RBD Screening Questionnaire, 76 Recurrent isolated sleep paralysis (RISP), 140, 141 REM-predominant obstructive sleep apnea, 8

282 REM sleep behavior disorder (RBD), 19, 73, 74, 81, 149–151, 163, 165, 193 association with neurodegenerative disorders risk, 77 characterization, 75 diagnosis, 76 differential diagnosis, 75 epidemiology, 77 management, 78, 79 past surgical history, 74 pathophysiology, 77 physical examination, 74 secondary, 78 social history, 74 REM sleep without atonia (RSWA), 75, 148, 149 Respiratory assist device (RAD), 177, 178 Respiratory event index (REI), 97, 101 Restless leg syndrome (RLS), 19, 86, 87, 247 diagnosis, 88 epidemiology, 88, 89 laboratory tests, 87, 88 management, 90, 91 pathophysiology, 89, 90 physical examination, 87 sleep routine, 87 Restless sleep parasomnia overlap disorder, 79, 81 description, 81 diagnosis, 82–84 differential diagnosis, 79 medications, 80 past medical history, 80 past surgical history, 80 pathophysiology, 85 physical examination, 80 social history, 80 work-up, 81 REM sleep behavior disorder, 73, 74 association with neurodegenerative disorders risk, 77 characterization, 75 diagnosis, 76 differential diagnosis, 75 epidemiology, 77 management, 78, 79 past surgical history, 74 pathophysiology, 77 physical examination, 74 secondary, 78 social history, 74 restless leg syndrome, 86, 87 diagnosis, 88 epidemiology, 88, 89 laboratory tests, 87, 88

Index management, 90, 91 pathophysiology, 89, 90 physical examination, 87 sleep routine, 87 Restless sleeper, 244 assessment, 246 differential diagnosis, 243 family and social history, 244 medications and allergies, 244 past medical and surgical history, 244 patient history, 243 physical examination, 245 PLMD, 247–250 polysomnogram (PSG), 245, 246 review of systems, 245 sleep schedule/sleep hygeine, 244 treatment, 246 vital signs, 245 Restrictive thoracic chest wall disease, 177 Restrictive thoracic disorder assessment, 176 assured pressure support mode, 178 chest radiography, 175 differential diagnosis, 175 laboratory findings, 175 medications, 174 NIPPV, 177 noninvasive positive pressure ventilation, 177 NPPV, 177, 178 past medical history, 174 patient history, 173 physical examination, 175 social history, 175 vital signs, 175 Rotigotine, 88 S Scoliosis, 176 Seizures, 65, 195 Selective serotonin reuptake inhibitors (SSRI), 78, 85, 141 Self-exposure therapy, 164 Serotonin norepinephrine reuptake inhibitors, 78 Sexsomnia, 56, 59 Sleep apnea, 187 Sleep attacks, 19 Sleep deprivation, 158 assessment, 138 diagnostic testing, 138 differential diagnosis, 135, 137 epworth sleepiness scale, 136 family history, 136

Index medications and allergies, 136 past medical history, 136 past surgical history, 136 patient history, 134 physical examination, 137 review of systems, 136 sleep schedule/sleep hygiene, 135 social history, 136 STOP-BANG Scale, 136 treatment, 139 vital signs, 137 Sleep disordered breathing (SDB), 218, 233 Sleep drunkenness, 28 Sleepiness idiopathic hypersomnia (see Idiopathic hypersomnia) narcolepsy type 1 (see Narcolepsy type 1) obstructive sleep apnea (see Obstructive sleep apnea) Sleep-onset REM periods (SOREMPs), 18, 26, 28 Sleep paralysis narcolepsy allergies, 125 assessment, 129 differential diagnosis, 124, 127 epworth sleepiness scale, 125 family history, 125 fatigue severity scale, 125 multiple sleep latency test (MSLT), 127–129 past medical history, 125 past surgical history, 125 patient health questionnaire-9, 125 physical examination, 126 polysomnogram, 128, 129 review of systems, 126 sleep schedule/sleep hygiene, 124 social history, 126 STOP-BANG Scale, 125 treatment, 129 vital signs, 126 nightmares (see Nightmares) sleep deprivation (see Sleep deprivation) Sleep paralysis (SP), 139, 140, 142 flowchart/algorithm, 143 sleep disorders associated with, 141 Sleep-related breathing disorders, 119 Sleep related eating disorder (SRED), 58–60, 118 Sleep-related hypermotor epilepsy (SHE), 66, 70 Sleep related hypoventilation diagnostic testing, 112 differential diagnosis, 112

283 medications, 112 methadone, 114 past medical history, 112 patient history, 112 physical examination, 112 Sleep talking, 58–60 Sleep terrors, 58, 158, 165 Sleepwalking (somnambulism), 58–60, 158 Snoring, 97, 241 lack of concentration, 225 assessment, 230 differential diagnosis, 226, 228 family and social history, 227 medications and allergies, 227 past medical and surgical history, 226 patient history, 226 pediatric obstructive sleep apnea, 230, 232 physical examination, 227 polysomnogram, 229–231 review of systems, 227 sleep schedule/sleep hygiene, 226 treatment, 231 vital signs, 227 pediatric OSA assessment, 237 differential diagnosis, 236 family and social history, 235 medications, 235 past medical and surgical history, 235 patient history, 234 physical examination, 236 polysomnogram, 236, 237 review of systems, 235 sleep schedule/sleep hygiene, 235 treatment, 238–240 vital signs, 236 Sodium oxybate (Xyrem), 19, 29, 129, 141 Solriamfetol, 19, 29 Spina bifida, 179 Stanford sleepiness scale, 10 STOP-BANG questionnaire/scale, 5, 13, 186, 261 idiopathic hypersomnia, 22 narcolepsy, 125 nightmares, 131 night terrors, 153 non-REM parasomnia, 52 obesity hypoventilation syndrome, 184 obstructive sleep apnea, 184 obstructive sleep apnea, 96, 100 sleep deprivation, 136 treatment-emergent central sleep apnea, 102 Synucleinopathy, 151

Index

284 T Telehealth, 207–209, 211, 217, 218 Telemedicine, 207, 218, 219 advantages, 208 insomnia allergies, 212 assessment, 213 CBT-I, 217 diagnostic testing, 214 differential diagnosis, 213 family history, 212 management/treatment, 214 medications, 212 past medical history, 212 past surgical history, 212 patient history, 210, 211 physical examination, 213 review of systems, 212 scales/questionnaires, 211 sleep schedule/sleep hygeine, 211 social history, 212 vital signs, 213 obstructive sleep apnea allergies, 203 assessment, 204 Clinical Video Telehealth, 207 diagnostic testing, 204 differential diagnosis, 204 family history, 203 management, 206 medications, 203 PAP, 206, 209 past medical history, 202 past surgical history, 202 patient history, 201, 202 physical examination, 204 review of systems, 203 scales/questionnaires, 202 sleep schedule/sleep hygeine, 202 social history, 203 telehealth, 207–209 vital signs, 203 Telesleep, 201, 209 Temazepam, 81 Toddler presenting with failure to thrive, 258, 259 assessment, 255 diagnostic testing, 255, 256 differential diagnosis, 255 family and social history, 254

medications and allergies, 254 past medical and surgical history, 254 patient history, 254 physical examination, 255 review of system, 254 treatment, 256, 258 Tramadol, 88 Transdermal rotigotine, 90 Transient ischemic attacks (TIAs), 182, 193 Traumatic brain injury (TBI), 195 Trazodone, 43 Treatment-emergent central sleep apnea differential diagnosis, 102, 103 epworth sleepiness scale, 102 initial phase-baseline portion of “Split” polysomnogram, 103 medications, 102 past medical history, 109 patient medical history, 102 physical examination, 102 second phase-treatment portion of “Split” polysomnogram, 103 STOP-Bang score, 102 titration PSG starting with BPAP therapy, 109 Tricyclic antidepressants (TCA), 141 U Upper airway resistance syndrome (UARS), 234 Urine toxicology screen, 15 V Venlafaxine, 214 Video polysomnography (vPSG), 75, 76, 81, 151 Volume-assured pressure support (VAPS), 108 W Watch-PAT, 101 Willis-Ekbom disease, see Restless legs syndrome Z Zolpidem, 43, 57, 59 Zolpidem tartrate, 159