ATS CORE CURRICULUM ATS Core Curriculum 2014: Part III. Adult Sleep Medicine Series Editor: Carey Thomson Part III Editor: Grace W. Pien Grace W. Pien1, Ronald Szymusiak2,3,4, Armand M. Ryden5,6, Alon Y. Avidan7,8, Robert C. Stansbury9, Patrick J. Strollo, Jr.10, Barry G. Fields11, Ilene M. Rosen12, and Kingman P. Strohl13 1

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; 2Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; Departments of 3Medicine, 4Neurobiology, and 8Neurology, 6Pulmonary, Critical Care and Sleep Medicine, and 7Sleep Disorders Center, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California; 5Pulmonary, Critical Care and Sleep Medicine, Veterans Affairs West Los Angeles Medical Center, Los Angeles, California; 9Section of Pulmonary and Critical Care Medicine, Department of Medicine, West Virginia University, Morgantown, West Virginia; 10Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 11Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; 12Division of Sleep Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and 13Department of Medicine, Pulmonary, Critical Care, and Sleep Medicine Division, Case Western Reserve University School of Medicine, Cleveland, Ohio Keywords: sleep/physiology; rapid eye movement sleep; sleep apnea syndromes; obstructive sleep apnea; restless legs syndrome

The American Thoracic Society (ATS) Core Curriculum updates clinicians annually in adult and pediatric pulmonary diseases, medical critical care, and sleep medicine in a 3-year recurring cycle of topics. The 2014 course was presented in May during the annual International Conference, and is published monthly in four parts beginning with the September issue of the Journal. Part III covers advances in adult sleep medicine. An American Board of Internal Medicine Maintenance of Certification module and a Continuing Medical Education exercise covering the contents of the CORE Curriculum can be accessed online at www.thoracic.org until November 2017.

Neurobiology/Neurochemistry of Sleep and Wakefulness Ronald Szymusiak Ascending Arousal Systems

Electrographic and behavioral arousal in mammals is achieved by the actions of multiple ascending arousal systems (Table 1; reviewed in References 1 and 2). These include acetylcholine (ACH) neurons in the laterodorsal tegmentum (LDT) and basal forebrain, noradrenalin (NA) neurons in the locus coeruleus, histamine (HA) neurons in the tuberomammillary nucleus, and serotonergic (5HT) neurons in the dorsal raphe nucleus. Orexin (ORX)-containing neurons in the lateral hypothalamus are key regulators of arousal by virtue of direct projections to the cortex and projections to monaminergic and

cholinergic arousal systems. Monoamine and ORX neurons exhibit maximal discharge rates during waking, reduced discharge during non–rapid eye movement (non-REM) sleep, and minimal or no activity during REM sleep (REM-off discharge). ACH neurons exhibit a wake-REM on discharge pattern, with minimal discharge rates during non-REM sleep. Preoptic Sleep-Regulatory Neurons and Homeostatic Regulation of Arousal States

The ventrolateral preoptic area (VLPO) and the median preoptic nucleus (MnPO) contain populations of sleep-active neurons that exhibit increased activity during non-REM and REM sleep compared with waking (reviewed in References 1–3). Sleep-active neurons are GABAergic. VLPO neurons express both GABA and the inhibitory neuropeptide, galanin. VLPO and MnPO neurons project to the tuberomammillary nucleus, dorsal raphe nucleus, locus coeruleus, LDT, and to ORX neurons. Activation of MnPO/ VLPO neurons at the wake–sleep transition results in rapid and coordinated suppression of neuronal activity of arousal systems through GABA/galanin–mediated inhibition. Prolonged wakefulness causes increases in sleep pressure through increased expression of endogenous sleep factors, including adenosine, IL-1b, and TNF-a, occurring as a result of waking brain activity and metabolism. These factors act as sensors of prior waking time, and exert inhibitory effects on multiple

(Received in original form August 5, 2014; accepted in final form October 19, 2014 ) The American Thoracic Society CORE Curriculum updates clinicians annually in adult and pediatric pulmonary diseases, medical critical care, and sleep medicine in a 3-year recurring cycle of topics. The 2014 course was presented in May during the annual International Conference and is published monthly in four parts beginning with the September issue of the journal. Part II covers advances in adult critical care medicine. An ABIM Maintenance of Certification (MOC) module covering the contents of the CORE Curriculum can be accessed online at: http://www.atsjournals.org/page/ats_core_curriculum_2014, and a Continuing Medical Education (CME) exercise is available at www.atsjournals.org. Correspondence and requests for reprints should be addressed to Grace W. Pien, M.D., M.S.C.E., Division of Pulmonary and Critical Care Medicine, Johns Hopkins Allergy and Asthma Center, Room 5B 77, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 9, pp 1480–1487, Nov 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201408-356CME Internet address: www.atsjournals.org

1480

AnnalsATS Volume 11 Number 9 | November 2014

ATS CORE CURRICULUM Table 1. Neurotransmitter activity profiles across sleep and wakefulness Neurotransmitter Acetylcholine Monoamines

Orexin/hypocretin VLPO/MNPO

Location (Type) BF, LDT/PPT LC (NA) DRN, MRN (5HT) TMN (HA) SN, VTA/vPAG (DA) LH, PH VLPO/MnPO

Wakefulness

NREM Sleep

REM Sleep

↑↑ ↑↑

— ↑

↑↑ —

↑↑ —

— ↑↑

— ↑↑

Definition of abbreviations: 5HT = serotonin; BF = basal forebrain; DA = dopamine; DRN = dorsal raphe nucleus; HA = histamine; LC = locus coeruleus; LDT = laterodorsal tegmentum; LH = lateral hypothalamus; MnPO = median preoptic nucleus; MRN = median raphe nucleus; NA = noradrenalin; NREM = non-REM; PH = posterior hypothalamus; PPT = pedunculopontine tegmentum; REM = ; SN = substantia nigra; TMN = tuberomammillary nucleus; VLPO = ventrolateral preoptic area; vPAG = ventral periaqueductal gray; VTA = ventral tegmental area. Adapted from Espana RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep 2011;34:845–858.

arousal systems. Adenosine is a potent endogenous somnogen, and extracellular levels of adenosine in the brain increase during sustained waking (4). Adenosine promotes sleep through inhibitory effects on arousal systems mediated by A1 adenosine receptors and excitation of MnPO/VLPO neurons via A2A receptors. Role of the Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN) generates a self-sustaining rhythm of approximately 24 hours through autoregulatory feedback loops in which protein products of circadian clock genes regulate their own expression. The activity of the SCN is entrained to the external light–dark cycle and to melatonin secretion by the pineal gland. The SCN actively promotes wakefulness during the daily active phase by activating neuronal circuits mediating arousal, including those involving ORX and NA neurons (2, 3).

References 1 Szymusiak R, McGinty D. Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 2008;1129:275–286. 2 Espana RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep 2011;34:845–858. 3 Amlaner CJ, Fuller PM. Basics of sleep guide. 2nd ed. Westchester, IL: Sleep Research Society; 2009. 4 Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol 2004;73:379–396. 5 Hasegawa E, Yanagisawa M, Sakurai T, Mieda M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest 2014;124:604–616.

Sleep-Related Movement Disorders Armand M. Ryden and Alon Y. Avidan

Control of REM Sleep

Restless Legs Syndrome

REM sleep control involves interactions among cholinergic and monoaminergic systems (reviewed in References 2 and 3). REM-on neurons in the LDT project to glutamatergic REM effector neurons located in the pons. These REM effector neurons project to GABA/glycine neurons in the ventromedial medulla and spinal cord to evoke muscle atonia. NA and 5HT inhibit ACH neurons in the LDT. At the non-REM–REM sleep transition, reduced activity of NA and of 5HT neurons (REM-off) leads to disinhibition of ACH REM-on neurons. Drugs that promote 5HT and NA release can suppress REM sleep. Activation of ORX neurons suppresses REM sleep through excitation of 5HT and NA neurons (5). Loss of ORX neurons leads to expression of REM sleep features from a background of wakefulness (cataplexy, sleep onset REM sleep) in narcolepsy.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is characterized by the urge to move the legs and sometimes the arms, and is usually accompanied by uncomfortable or unpleasant sensations that are partially or wholly relieved with motion, such as walking or stretching. Symptoms generally worsen with rest or inactivity, and are worse in the evening or at night compared with daytime (1). In making the diagnosis of RLS, all of these essential diagnostic criteria should be present, and other medical or behavioral conditions that can cause similar symptoms should be excluded. The discomfort often results in difficulty sleeping. Because 80% of patients with RLS have periodic leg movements (PLMs) on polysomnography (PSG), the presence of PLMs is supportive, but not necessary, for an RLS diagnosis. Iron deficiency, pregnancy, and many psychotropic medications may cause or contribute to RLS.

Table 2. Key updates: sleep-related movement disorders The two major RLS phenotypes are based on age of onset, with early-onset RLS (,45 yr) more likely to be familial and to progress slowly. The pathophysiology of RLS likely involves a brain iron deficiency, leading to CNS dopaminergic abnormalities. First-line therapies include dopamine agonists and gabapentin. d In the absence of arousals, periodic limb movements can be an incidental finding. Making the diagnosis of periodic limb movement disorder of sleep requires at least 15 PLMs/h during sleep and that the patient’s complaints are not explained by another sleep disorder. d Rhythmic movement disorder is common in children, but rare in adults. Injuries are rare, but have been reported. d d

Definition of abbreviations: CNS = central nervous system; PLMs = periodic leg movements; RLS = restless legs syndrome.

ATS Core Curriculum

1481

ATS CORE CURRICULUM Table 3. Key updates: sleep-related breathing disorders Epidemiology and pathophysiology Current prevalence of OSA has likely increased, due to greater obesity and aging of the population worldwide. Overall prevalence is estimated at 10% of the general population for moderate to severe OSA. Redistribution of extracellular fluid occurring in the supine position during sleep leads to increased airway collapsibility and smaller upper airway cross-sectional area. However, treatment to reduce nocturnal fluid shifts reduced absolute AHI only modestly. A novel, state-sensitive, motor-inhibitory cholinergic channel within the hypoglossal motor pool has been identified as the principal mechanism of genioglossus muscle suppression during REM sleep Diagnosis of sleep-related breathing disorders Unattended cardiopulmonary sleep studies are coming into more widespread use and are required by some third-party payers. Patients with a high pretest probability and no significant cardiopulmonary comorbidities are most appropriate for unattended studies. Treatment of sleep-related breathing disorders Effective treatment of moderate to severe OSA (AHI > 15 events/h) reduces cardiovascular risk, improves neurobehavioral performance, and enhances quality of life. CPAP remains the mainstay of therapy for most patients with OSA. Based on randomized trials, oral appliances are a reasonable alternative to CPAP, particularly for mild to moderate OSA. Nasal EPAP devices are a novel device with a one-way mechanical valve that stents open the upper airway. These devices provide an alternative for individuals with mild to moderate OSA who cannot tolerate CPAP. Definition of abbreviations: AHI = apnea–hypopnea index; CPAP = continuous positive airway pressure; EPAP = expiratory positive airway pressure; NREM = non–rapid eye movement; OSA = obstructive sleep apnea; REM = rapid eye movement.

There are two major phenotypes based on age of onset of RLS. Early-onset RLS (age , 45 yr) is more likely to be familial and to have an underlying genetic association, and progresses more slowly. In contrast, late-onset RLS (age . 45 yr) may be either primary or secondary, and tends to occur sporadically and to progress rapidly. The prevalence of RLS increases with age, affecting up to 4–5% in patients over age 60 years, and affecting women more frequently than men (2). The pathophysiology of RLS appears to involve a brain iron deficiency, which may lead to central nervous system dopaminergic abnormalities (3). RLS is a clinical diagnosis, and does not require formal diagnostic testing, except to rule out suspected comorbid sleep disorders or neuropathy. Treatment should address potential aggravators, including iron deficiency, sleep deprivation, and use of alcohol, caffeine, selective serotonin reuptake inhibitors, tricyclic antidepressants, dopamine antagonists, and antihistamines. First-line pharmacotherapy for primary moderate to severe RLS includes the dopamine agonists, rotigotine, ropinirole, and pramipexole, as well as an alpha-2-delta ligand, gabapentin enacarbil. Levodopa/carbidopa can be used for intermittent RLS in an “on demand fashion.” Second-line agents include pregabalin, opiates, and clonidine; a recent randomized controlled trial demonstrates that pregabalin may be as effective as pramipexole (4, 5). Opiates, particularly methadone, can be used in refractory cases. Side effects of the dopamine agonists include irresistible sleep attacks, behaviors of impaired impulse control, and augmentation of RLS. Augmentation is defined as the development of more severe symptoms in the setting of pharmacologic treatment of RLS (usually with dopamine agonists), occurring earlier in the day, with geographical spread to other body parts. Periodic Limb Movement Disorder of Sleep

PLMs are defined by PSG criteria of leg movements lasting from 0.5 to 10 seconds, occurring with a regular period ranging between 5 and 90 seconds in a train of at least four movements. Movements associated with respiratory events are not counted (6). PLMs are rhythmic, stereotyped movements that can lead to arousals. In the 1482

absence of arousals, PLMs may be an incidental finding. PLM disorder of sleep (PLMDS) requires that there be at least 15 PLMs/h and that the patient’s sleep complaints are not explained by another sleep disorder. Approximately 30% of patients with PLMs have RLS. Individuals with PLMs who meet the diagnostic criteria for RLS should receive the diagnosis of RLS rather than PLMDS. Treatment for PLMSD is similar to that for RLS, but, as of July 2014, no drug has been approved by the U.S. Food and Drug Administration specifically for PLMDS. Bruxism

Bruxism is defined as a rhythmic and repetitive grinding or clenching of the teeth during sleep. The potential consequences of bruxism include temporomandibular joint pain and dental pathology. Patients may present with bed partner complaints of grinding/clenching sounds. The patient’s dentist may note abnormal wear on the teeth, and masseter muscle hypertrophy may be present. Psychological stress has been implicated. Rhythmic artifacts in the chin electromyogram are typically seen Table 4. Key updates: sleepy driving A total of 2.5% of fatal motor vehicle crashes involve drowsy drivers, with deaths and serious injuries more likely to occur in drowsy driving crashes. d Having OSA increases the risk for a motor vehicle crash for both noncommercial and commercial drivers. d Insufficient sleep , 6 hours is another major risk factor for drowsy driving. d All patients being evaluated for known or suspected OSA should be asked about recent motor vehicle crashes or near misses attributable to sleepiness, fatigue, or inattention, and about daytime sleepiness. Patients with these characteristics are deemed high-risk drivers. d High-risk drivers should be warned immediately about the potential risk of driving until effective treatment is instituted. These patients should undergo expedited evaluation and treatment for OSA. d

Definition of abbreviation: OSA = obstructive sleep apnea.

AnnalsATS Volume 11 Number 9 | November 2014

ATS CORE CURRICULUM with a characteristic “checkerboard” artifactual spread in a periodic pattern involving the electroencephalogram leads on PSG. Protective night guards are generally the treatment of choice for preventing dental damage. For refractory cases, benzodiazepines, clonidine, and localized injection of botulinum toxin are used occasionally (7). Rhythmic Movement Disorder

These are rhythmic, repetitive, stereotyped movements during sleep that occur in up to 20% of children, but are exceedingly rare in adults. The movements usually involve the head or torso (i.e., head/body banging/rolling). Injuries are rare, but skull callus, carotid dissection, and retinal bleeds have been reported (8). Treatment includes reassurance, bed padding, helmets, and, rarely, benzodiazepines. Nocturnal Leg Cramps

Nocturnal leg cramps are painful sensations described as muscle contractions in the lower extremities that disturb sleep. Cramps can be relieved by forceful stretching of the muscles. It can be challenging to distinguish nocturnal leg cramps from RLS. The etiology of leg cramps is not known. Treatment is focused on stretching and treatment of any underlying cause (9). Pharmacological therapy has not been shown to be effective in clinical trials, but may include gabapentin and verapamil. Quinine is not a safe option given its side effects profile (Table 2).

References 1 Panossian LA, Avidan AY. Review of sleep disorders. Med Clin North Am 2009;93:407–425, ix. 2 Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, FeriniStrambi L. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–1292. 3 Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61:304– 309. 4 Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, Lamm CI, Tracy SL, Rosenberg RS; American Academy of Sleep Medicine. The treatment of restless legs syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039–1062. 5 Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, Knapp L, Winkelman JW. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621–631. 6 Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, Marcus CL, Mehra R, Parthasarathy S, Quan SF, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597–619. 7 Walters AS. Clinical identification of the simple sleep-related movement disorders. Chest 2007;131:1260–1266. 8 Khan A, Auger RR, Kushida CA, Ramar K. Rhythmic movement disorder. Sleep Med 2008;9:329–330. 9 Coppin RJ, Wicke DM, Little PS. Managing nocturnal leg cramps—calfstretching exercises and cessation of quinine treatment: a factorial randomised controlled trial. Br J Gen Pract 2005;55:186–191.

ATS Core Curriculum

Epidemiology and Pathophysiology of Sleep-Related Breathing Disorders Grace W. Pien Epidemiology of Obstructive Sleep Apnea

In the United States, the landmark Wisconsin Sleep Cohort Study (published in 1993) reported the prevalence of obstructive sleep apnea (OSA) with daytime sleepiness to be 4% in men and 2% in women between ages 30 and 60 years. Subsequent studies have estimated the prevalence of symptomatic OSA to be 3–8% in men and 1–5% in women. Current prevalence is likely higher, given rising rates of obesity and population aging worldwide, and has been estimated at 26% for overall prevalence of at least mild sleep-disordered breathing (SDB) (apnea–hypopnea index [AHI] > 5 events/h) and 10% for moderate or severe SDB (AHI > 15 events/h) (1). The prevalence of OSA defined by SDB events alone, without daytime symptoms, is also considerably higher than the prevalence of symptomatic OSA. Age. The prevalence of OSA increases through mid-life, but plateaus after age 60–65 years. Nevertheless, several studies have observed that the prevalence of SDB is greater than 50% in those at least 65 years of age (2). Sex. OSA is two to three times more prevalent in men than in women. Postmenopausal women are at a threefold risk for OSA compared with premenopausal women, likely related to lower levels of reproductive hormones (2). Among women, pregnancy poses an additional period of vulnerability for SDB, with important potential consequences for maternal/fetal well being (3). Ethnicity. Several recent studies have sought to define the burden of OSA among non-white populations. In Hong Kong, India, and Korea, the prevalence of OSA is similar to white population samples. After controlling for age and obesity, OSA severity appears to be higher among Asians, perhaps because of craniofacial characteristics. Among middle-aged African Americans, OSA prevalence is similar to that in whites. OSA is more prevalent, however, among younger African Americans compared with either whites or African Americans in other age groups (3). Among Hispanics in the United States, emerging data suggest that OSA prevalence may be higher compared with nonHispanic whites (4). Common Risk Factors. In the general population, the strongest risk factor for OSA is obesity. Other risk factors include neck size (collar size . 17 inches in males, .16 inches in females), genetic factors/family history, specific genetic disorders (e.g., Down’s syndrome), and endocrine disorders, including hypothyroidism and polycystic ovarian syndrome. Upper airway and craniofacial anatomic features, such as macroglossia, enlargement of the soft palate or tonsils, retrognathia, and micrognathia, also increase the risk for OSA (3). Pathophysiology of OSA

The pathogenesis of OSA involves both anatomic and neurologic components. Collapse of the upper airway reduces its airway intraluminal diameter and increases airways resistance, leading to the apneas and hypopneas that characterize OSA. During wakefulness, upper airway caliber is smaller in patients with sleep apnea compared with that in normal individuals. Individuals 1483

ATS CORE CURRICULUM with OSA demonstrate an excess of upper airway soft tissue within the craniofacial structures that envelop the pharyngeal lumen, with a recent study demonstrating that fat deposition within the tongue is greater in apneic individuals compared with body mass index–matched normal subjects (5). Variations in craniofacial morphology also influence upper airway configuration. Several recent studies have demonstrated that redistribution of extracellular fluid can occur during sleep and in the supine position, leading to significant increases in neck circumference and airway collapsibility, and a reduction in upper airway crosssectional area. Nevertheless, absolute AHI fell only modestly when patients wore compression stockings to reduce nocturnal fluid shifts, suggesting that this mechanism does not play a major role in OSA pathogenesis (6). During sleep, the balance in transpharyngeal pressure shifts toward upper airway collapse due to reduced upper airway dilator muscle activity for several reasons. First, the negative airway pressure reflex that activates the genioglossus is diminished during non-REM sleep compared with wakefulness, and is further reduced during REM sleep, placing the airway at risk for collapse. Recently, a novel, state-sensitive, motor-inhibitory cholinergic channel that operates at the hypoglossal motor pool has been identified as the principal mechanism of REM sleep pharyngeal motor inhibition (7). Patients with OSA have reduced upper airway reflexes during sleep compared with normal individuals. Next, because upper airway muscle activity increases and decreases in proportion to input from the respiratory control center in the medulla, situations of ventilatory control instability can precipitate airway collapse. Third, during episodes of upper airway collapse, arousal from sleep in response to respiratory activation helps to restore airway patency. Patients with OSA have a reduced ability to restore ventilation without cortical arousal compared with nonsnorers (8) (Table 3).

References 1 Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013;177:1006–1014. 2 Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5:136–143. 3 Pien GW, Rosen IM, Fields BG. Sleep apnea syndromes. In: Grippi MA, Elias JA, Fishman JA, Pack AI, Senior RM, Kotloff RM, editors. Fishman’s pulmonary diseases and disorders. 5th ed. New York: McGraw-Hill (In press) 4 Loredo JS, Soler X, Bardwell W, Ancoli-Israel S, Dimsdale JE, Palinkas LA. Sleep health in US Hispanic population. Sleep 2010;33: 962–967. 5 Kim AM, Keenan BT, Jackson N, Chan EL, Staley B, Poptani H, Torigian DA, Pack AI, Schwab RJ. Tongue fat and its relationship to obstructive sleep apnea. Sleep 2014;37:1639–1648. 6 Redolfi S, Arnulf I, Pottier M, Bradley TD, Similowski T. Effects of venous compression of the legs on overnight rostral fluid shift and obstructive sleep apnea. Respir Physiol Neurobiol 2011;175: 390–393. 7 Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med 2013;187:311–319. 8 Jordan AS, Wellman A, Heinzer RC, Lo YL, Schory K, Dover L, Gautam S, Malhotra A, White DP. Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans. Thorax 2007;62:861–867.

1484

Clinical Manifestations and Diagnosis of Sleep-Related Breathing Disorders Robert C. Stansbury and Patrick J. Strollo, Jr. Sleep-related breathing disorders (SRBDs) encompass a spectrum of respiratory abnormalities that are associated with sleep. The initial clinic evaluation of a patient with suspected SRBD is extremely important in determining: (1) whether treatment is appropriate; (2) what diagnostic study should be performed to assess SRBD; and (3) which therapy is best suited to the patient. Clinical Presentation

During the initial clinical assessment, patients may relate one or more classic symptoms that may have been present for years. These symptoms include snoring, witnessed apneas, difficulty sleeping, excessive daytime sleepiness, morning headache, dry mouth, night sweats, nocturia, arousals related to snoring or gasping, depression, irritability, erectile dysfunction, and impaired memory or concentration (1). Individual symptoms vary with regard to sensitivity and/or specificity for SRBD. Nocturnal choking or gasping is the most suggestive individual finding for OSA (2). Physical Exam

Some patients with OSA may have a relatively normal physical exam (3). In other patients, the suspicion of OSA may only arise after abnormalities are detected on physical exam. Evaluation of craniofacial features and the upper airway anatomy is important, not only in the risk stratification of patients with suspected SRBD, but also in directing treatment decisions. Many anatomical abnormalities encroach on the pharyngeal airway, predisposing patients to SDB (4). Morbid obesity and/or an enlarged neck circumference are commonly encountered in patients with SRBD. The presence of a retrognathic mandible and/or dental overjet can suggest a small oral cavity that is predisposed to collapse. Macroglossia may also lead to airway occlusion. Clinical scales are frequently used in the oropharyngeal evaluation, and are somewhat predictive of the presence of SRBDs (5). The Mallampati scale assigns a score between 1 and 4 based on visual assessment of the oropharynx. A score of 1 reflects no significant obstruction, whereas a score of 4 indicates a crowded and obstructed oropharynx. Assessment of the tonsils has a similar score, with “0” indicating the absence of tonsils and a score of “4” indicating complete obstruction of the airway. Evaluation of the nares should also be included as part of the evaluation in patients with suspected SRBDs. Assessment for an abnormality leading to increased airway resistance (i.e., nasal deviation, trauma, or inflammation) should be documented. Although nasal pathology is rarely the sole cause of SRBDs, medical and/or surgical treatment may enhance tolerance of therapy or significantly improve disruptive snoring. Signs/symptoms suggestive of heart failure or neurologic disease should also be noted and considered when planning diagnostic testing. Diagnostic Testing

The decision to order a diagnostic sleep study is based on the clinician’s suspicion of disease presence (6). Home testing (unattended cardiopulmonary sleep studies) are being used more commonly, and are now required by some third-party payers. AnnalsATS Volume 11 Number 9 | November 2014

ATS CORE CURRICULUM Current practice guidelines suggest that patients with a high pretest probability and no significant cardiopulmonary comorbidities are most appropriate for unattended studies. Full-night attended PSG provides the most comprehensive evaluation. Attended testing should be used in patients with intermediate pretest probability (e.g., those who deny daytime sleepiness), those who have significant cardiopulmonary comorbidities, in patients who are frail or otherwise unable to perform home testing, and in cases where there is diagnostic uncertainty regarding OSA as a primary cause of daytime sleepiness. Split-night attended PSG should be reserved for patients with high pretest probabilities who are willing to be treated with positive pressure via a mask and need expedited treatment (e.g., who report sleepy driving) (Table 3).

References 1 Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, et al.; Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5:263–276. 2 Myers KA, Mrkobrada M, Simel DL. Does this patient have obstructive sleep apnea?: The Rational Clinical Examination systematic review. JAMA 2013;310:731–741. 3 Patil SP, Schneider H, Schwartz AR, Smith PL. Adult obstructive sleep apnea: pathophysiology and diagnosis. Chest 2007;132:325–337. 4 White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363–1370. 5 Kryger MH. Examination of the patient with suspected sleep apnea. In: Kryger MH, editor. Atlas of clinical sleep medicine. Philadelphia, PA: Elsevier and Saunders; 2010. pp. 149–166. 6 Collop NA, Anderson WM, Boehlecke B, Claman D, Goldberg R, Gottlieb DJ, Hudgel D, Sateia M, Schwab R. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737–747.

Treatment of Sleep-Related Breathing Disorders Barry G. Fields and Ilene M. Rosen Positive Airway Pressure Therapies

The decision to treat OSA should be based on its severity, related symptoms, and medical and psychiatric comorbidities. Treatment of moderate to severe OSA (AHI > 15 events/h), particularly with positive airway pressure (PAP) therapy, reduces cardiovascular risk, improves neurobehavioral performance, and enhances quality of life (1, 2). Continuous PAP (CPAP) delivers a fixed pressure throughout inspiration and expiration, providing a pneumatic splint for the airway that prevents its collapse during sleep. It remains the mainstay of therapy for most patients with OSA. CPAP usually reduces the AHI to the normal range, and is noninvasive. It clearly improves daytime sleepiness in patients with OSA in numerous studies, with greater improvements among those with the highest AHIs (2). CPAP use is also associated with a modest reduction in blood pressure among hypertensive patients with OSA, and with a reduced risk of motor vehicle crashes among drivers with OSA (1).

ATS Core Curriculum

Over the past 2 decades, CPAP machines and masks have become increasingly user friendly. CPAP use is associated with few serious side effects. Adherence to CPAP therapy generally ranges from 60 to 85%. A dose–response relationship has been observed between duration of use and daytime alertness and functional status (3). PAP can also be delivered via bilevel systems and automatically titrating systems. Bilevel systems deliver higher pressures during inspiration and lower pressures during expiration, and may be used when patients report difficulty with exhaling against PAP. However, they are more expensive, and evidence of better adherence and outcomes compared with CPAP is lacking. Autotitrating CPAP (auto-CPAP) adjusts the pressure level in response to snoring, apneas, and inspiratory flow limitation. Auto-CPAP can be used for chronic treatment of OSA or in the shorter term to determine the optimal setting for conventional fixed CPAP after a trial period. Patient adherence does not appear to be significantly improved with auto-CPAP compared with fixed CPAP therapy (1). Weight Loss

Weight loss has been associated with significant reductions in SDB. The extent of weight loss and degree of improvement are not always directly related, although it has been shown, on average, that a 1% change in weight is associated with a 3% change in AHI (4). AHI changes associated with weight loss (or weight gain) are stronger in men than in women (1). Mandibular Repositioning Devices

Although CPAP remains the gold standard for OSA treatment, adherence is challenging for many patients. Thus, increasing attention has focused on intraoral devices (oral appliances) as an alternative treatment. Oral devices alter the position of the upper airway structures, enlarging airway caliber and/or reducing airway collapsibility during sleep. Based on randomized trials, oral appliances are a reasonable alternative to CPAP, particularly for mild to moderate OSA (5). Individuals with lower body mass index and positional OSA are likely to be good candidates for these devices. Position Therapy

For patients with positional OSA, symptoms may be alleviated by sleeping in the lateral decubitus position, creating increased crosssectional upper airway area and lower closing pressure of the passive pharyngeal airway compared with the supine position. However, a recent meta-analysis concluded that positional therapy was inferior to CPAP for reducing AHI and increasing oxyhemoglobin saturation (6). Nasal Expiratory Airway Pressure

Nasal expiratory PAP (EPAP) is delivered via a novel device with a one-way mechanical valve that provides high expiratory resistance in conjunction with low inspiratory resistance, stenting open the upper airway. Nasal EPAP reduces AHI and improves subjective sleepiness in patients with mild-moderate OSA (7). Currently, nasal EPAP can be considered as an alternative for individuals with mild-moderate OSA who cannot tolerate CPAP. Surgical Treatment of Obstructive Sleep Apnea

Although multiple surgical options are available to correct upper airway abnormalities leading to obstruction during sleep, the success

1485

ATS CORE CURRICULUM of these treatments is generally less well established and less effective than PAP therapy. A recent systematic review noted that uvulopalatopharyngoplasty with or without tonsillectomy does not have a consistent effect on AHI, and therefore cannot be recommended as a stand-alone treatment for OSA (8). Use of a multilevel surgical approach involving uvulopalatopharyngoplasty and mandibular advancement may be beneficial for some patients. Oxygen Therapy

Although oxygen desaturation may be mitigated by oxygen therapy, supplemental oxygen can increase the arousal threshold and thereby prolong apneic events. Among patients with a relatively unstable ventilatory control system, supplemental oxygen may stabilize ventilation, thus reducing AHI (1). The role of supplemental oxygen alone in the treatment of OSA remains unclear; at a minimum, it improves nocturnal oxygen saturation during use without significant adverse consequences. However, in a recent randomized trial, nocturnal supplemental oxygen for treatment of OSA failed to lower blood pressure (9) (Table 3).

References 1 Pien GW, Rosen IM, Fields BG. Sleep apnea syndromes. In: Grippi MA, Elias JA, Fishman JA, Pack AI, Senior RM, Kotloff RM, editors. Fishman’s pulmonary diseases and disorders. 5th ed. New York: McGraw-Hill (In press) 2 Chai CL, Pathinathan A, Smith B. Continuous positive airway pressure delivery interfaces for obstructive sleep apnoea. Cochrane Database Syst Rev 2006;(4):CD005308. 3 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;30:711–719. 4 Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284:3015–3021. 5 Lim J, Lasserson TJ, Fleetham J, Wright J. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2004;(4): CD004435. 6 Ha SC, Hirai HW, Tsoi KK. Comparison of positional therapy versus continuous positive airway pressure in patients with positional obstructive sleep apnea: a meta-analysis of randomized trials. Sleep Med Rev 2014;18:19–24. 7 Berry RB, Kryger MH, Massie CA. A novel nasal expiratory positive airway pressure (EPAP) device for the treatment of obstructive sleep apnea: a randomized controlled trial. Sleep 2011;34:479–485. 8 Caples SM, Rowley JA, Prinsell JR, Pallanch JF, Elamin MB, Katz SG, Harwick JD. Surgical modifications of the upper airway for obstructive sleep apnea in adults: a systematic review and metaanalysis. Sleep 2010;33:1396–1407. 9 Gottlieb DJ, Punjabi NM, Mehra R, Patel SR, Quan SF, Babineau DC, Tracy RP, Rueschman M, Blumenthal RS, Lewis EF, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370: 2276–2285.

2% of all nonfatal crashes involve drowsy drivers. Furthermore, deaths and serious injuries are more likely to occur in drowsy driving crashes than other crashes, with some studies suggesting that 15–33% of fatal crashes involve drowsy drivers (1). Insufficient or poorquality sleep and untreated sleep disorders have been identified as causal factors in a growing number of crashes. Sleep Disorders, Fatigue, and Drowsy Driving

OSA confers a moderately increased risk for a motor vehicle crash in noncommercial drivers (ztwo- to threefold higher) and a slightly increased risk (z1.3-fold higher) for commercial drivers (2). Nevertheless, the ascertainment of driving risk in an individual patient upon initial presentation can be difficult, especially because only a small proportion of patients presenting to physicians for evaluation of OSA have excessive sleepiness that rises to the level of concern for driving risk. In a survey of primary care patients in the United States and Europe, nearly 4% of participants endorsed drowsy driving at least three to four times weekly. However, although the pretest probability of at least mild OSA was high (38%), approximately one-quarter of those reporting sleepiness resulting in impairment in activities of daily living did not meet criteria for high OSA risk (3). Other factors alone or in combination with SDB can amplify daytime sleepiness and, implicitly, increase crash risk. The most important of these factors is insufficient sleep, with individuals who usually sleep less than 6 hours being more likely to report falling asleep while driving (1). Shift workers are at increased risk for drowsy driving (4). Other contributors to drowsy driving include use of sedative drugs, alcohol (5), and anti-HA, antidepressant, or anxiolytic medications. In addition, all these interact with sleep fragmentation or sleep restriction to increase sleepiness (6). Sleep apnea syndrome and narcolepsy are the two most common medical causes of severe sleepiness. However, many other medical and psychiatric disorders produce excessive sleepiness. Hence, clinical assessment of patients for drowsy driving risk requires knowledge and experience other than the ability to identify sleep apnea. Factors such as insufficient sleep and alcohol and sedative drug use can be addressed to reduce sleepiness and drowsy driving risk even in the presence of OSA and other sleep disorders. New ATS Clinical Practice Guideline for Sleep Apnea and Driving Risk

Kingman P. Strohl

The ATS recently updated its clinical practice guideline on sleep apnea, sleepiness, and driving risk in noncommercial drivers (7). The report committee reaffirmed that individuals with known or suspected OSA who report severe daytime sleepiness and a history of a previous motor vehicle accident (including near-miss events) are at particularly high risk for drowsy driving crashes. Identification of such individuals should compel the physician to immediately warn the patient of the potential risk of driving until effective therapy is instituted. Counseling to family members and exploration of alternatives to driving may be needed. Not all patients suspected of having sleep apnea will present with this level of risk. However, those with lesser degrees of sleepiness should also be educated about the hazards of drowsy driving (Table 4).

A recent estimate from the National Highway Traffic Safety Administration suggests that 2.5% of fatal motor vehicle crashes and

Author disclosures are available with the text of this article at www.atsjournals.org.

Drowsy Driving

1486

AnnalsATS Volume 11 Number 9 | November 2014

ATS CORE CURRICULUM References 1 Centers for Disease Control and Prevention (CDC). Drowsy driving—19 states and the District of Columbia, 2009–2010. MMWR Morb Mortal Wkly Rep 2013;61:1033–1037. 2 Ellen RL, Marshall SC, Palayew M, Molnar FJ, Wilson KG, Man-SonHing M. Systematic review of motor vehicle crash risk in persons with sleep apnea. J Clin Sleep Med 2006;2:193–200. 3 Netzer NC, Hoegel JJ, Loube D, Netzer CM, Hay B, Alvarez-Sala R, Strohl KP; Sleep in Primary Care International Study Group. Prevalence of symptoms and risk of sleep apnea in primary care. Chest 2003;124:1406–1414. 4 Scott LD, Hwang WT, Rogers AE, Nysse T, Dean GE, Dinges DF. The relationship between nurse work schedules, sleep duration, and drowsy driving. Sleep 2007;30:1801–1807.

ATS Core Curriculum

5 Vakulin A, Baulk SD, Catcheside PG, Antic NA, van den Heuvel CJ, Dorrian J, McEvoy RD. Effects of alcohol and sleep restriction on simulated driving performance in untreated patients with obstructive sleep apnea. Ann Intern Med 2009;151: 447–455. 6 Smolensky MH, Di Milia L, Ohayon MM, Philip P. Sleep disorders, medical conditions, and road accident risk. Accid Anal Prev 2011; 43:533–548. 7 Strohl KP, Brown DB, Collop N, George C, Grunstein R, Han F, Kline L, Malhotra A, Pack A, Phillips B, et al.; ATS Ad Hoc Committee on Sleep Apnea, Sleepiness, and Driving Risk in Noncommercial Drivers. An official American Thoracic Society clinical practice guideline: sleep apnea, sleepiness, and driving risk in noncommercial drivers. An update of a 1994 statement. Am J Respir Crit Care Med 2013;187:1259–1266.

1487

ATS Core Curriculum 2014: part III. Adult sleep medicine.

ATS Core Curriculum 2014: part III. Adult sleep medicine. - PDF Download Free
490KB Sizes 2 Downloads 7 Views