Behavioral Sleep Medicine Services for Hypersomnia Disorders: A Survey Study Wednesday February 22, 2016 12:00PM EDT Presented by Dr. Suzie Bertisch Beth Israel Deaconess Medical Center Harvard Medical School

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Behavioral Sleep Medicine Services for Hypersomnia Disorders: A Survey Study Behavioral Sleep Medicine, Vol 15 (2017) Ariel Neikrug, PhD, Megan Crawford, PhD, Jason Ong, PhD

Hypersomnias of Central Origin Narcolepsy type 1 (with cataplexy) or type 2 Idiopathic hypersomnia Kleine-Levin syndrome Studies on the epidemiology of narcolepsy show an incidence of 0.2 to 1.6 per thousand in Europe Narcolepsy is a clinical syndrome of daytime sleepiness with cataplexy, hypnagogic hallucinations, and sleep paralysis. Must be distinguished from other causes of hypersomnolence: Insufficient sleep, other sleep disorders (e.g., obstructive sleep apnea), circadian rhythm disorders, medical disorders that causes sleepiness, psychiatric disorders, medications and substance abuse

Etiology: Narcolepsy Loss of orexin (hypocretin) Genetic factors Brain lesions (rare) Narcolepsy can be conceptualized as a disorder of sleep-wake control in which elements of sleep intrude into wakefulness and elements of wakefulness intrude into sleep Targets of the orexin-producing neurons include monoaminergic areas such as the locus coeruleus, raphe nuclei, ventral tegmental area, periaqueductal grey, and tuberomammillary nucleus as well as cholinergic areas such as the basal forebrain and pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT). Increased activity in these monoaminergic areas promotes wakefulness, inhibits REM sleep, and suppresses REM sleep-related phenomena including cataplexy. Genetic factors — Narcolepsy usually occurs sporadically, but genetic factors play an important role. The DQB1*0602 haplotype (a subtype of DR2) is present in 95 percent of patients with cataplexy and in 96 percent of those with orexin deficiency [27,31,38-41]. Some additional human leukocyte antigen (HLA) haplotypes may further increase the risk of narcolepsy, while others appear protective [42,43]. Though these and other genetic factors may predispose some people to develop narcolepsy, environmental factors appear to be even more important, as only about 25 percent of affected monozygotic twins are concordant for narcolepsy [44]. (See "Human leukocyte antigens (HLA): A roadmap".) On rare occasions, narcolepsy runs in families. Affected individuals often lack DQB1*0602 and have normal orexin-A levels [27,45]. Some family members lacking definite narcolepsy may have isolated sleepiness, hallucinations, or sleep paralysis, suggesting incomplete penetrance. The genes underlying these familial cases are generally unknown, but eight Japanese families with narcolepsy showed linkage to a site on chromosome 4p13-q21, which may act in concert with the HLA-influenced predisposition [46]. Other families have been reported with linkage to the myelin oligodendrocyte glycoprotein gene and sites on chromosome 6 (near the HLA region) and chromosome 21 [47-49].  2000, hypocretin deficiency was discovered to be the basic cause of narcolepsy cataplexy.[6] This followed the discovery of hypocretin (also called orexin) neurons in the 1990s. It has been hypothesized that this is an autoimmune-mediated destruction of hypocretin neurons, although this is yet to be definitively proved. In light of the positive HLA associations, there is also an assumption of a genetic component that may predispose individuals to the development of narcolepsy. Orexin neurons in the lateral hypothalamus innervate and excite many wake-promoting brain Orexin neurons in the lateral hypothalamus innervate and excite many wake-promoting brain ©2017 UpToDate®

Narcolepsy: Classic Tetrad Chronic, excessive daytime sleepiness Cataplexy Hypnagogic/pompic hallucinations Sleep paralysis Associated symptoms: restorative daytime naps; disturbances in nocturnal sleep Only about 15% of patients experience full tetrad  Narcolepsy can be conceptualized as a disorder of sleep-wake control in which elements of sleep intrude into wakefulness and elements of wakefulness intrude into sleep. The result is the classic tetrad of chronic daytime sleepiness with varying amounts of cataplexy, hypnagogic hallucinations, and sleep paralysis. Only one-third of patients will have all of these symptoms; thus, the diagnosis of narcolepsy should be considered even among patients with chronic daytime sleepiness alone. The features of narcolepsy frequently worsen during the first few months to years and then persist for life [86].Only one-third of patients will have all of these symptoms; thus, the diagnosis of narcolepsy should be considered even among patients with chronic daytime sleepiness alone. The features of narcolepsy frequently worsen during the first few months to years and then persist for life [86].  Cataplexy is emotionally-triggered transient muscle weakness. Most episodes are triggered by strong, generally positive emotions such as laughter, joking, or excitement [93]. Episodes may also be triggered by anger or grief in some individuals. Cataplexy develops within three to five years of the onset of sleepiness in 60 percent of people with narcolepsy [86]. he second symptom of the tetrad is cataplexy; this is the sudden loss of muscle tone, which in adults is almost always precipitated by emotion, especially positive emotions such as laughter. As we will discuss later, in children this may not be as typical. The third symptom is sleep paralysis, which is the loss of muscle tone and inability to move on transitioning from waking to sleep or from sleep to waking. The fourth symptom is hypnagogic hallucinations that occur at sleep onset. (Enlarge Slide)In addition to the classic tetrad of narcolepsy symptoms, there are several associated characteristics. The first of these is restorative daytime naps. Most narcoleptics will feel reasonably alert for a period of time following their overnight sleep or even a brief daytime nap. About half of the narcolepsy population experiences disturbances of nocturnal sleep.[8] 

Narcolepsy, Type 1: Diagnosis Daily periods of irrepressible need to sleep or daytime lapses into sleep for at least 3 months.* B. Presence of one or both: Cataplexy and a mean SOL of ≤8 minutes and ≥ 2 SOREMPs on an MSLT CSF hypocretin-1 concentration, measured by immunoreactivity, is either ≤110 pg/mL or <1/3 of mean values.  * In young children, narcolepsy may sometimes present as excessively long night sleep or as resumption of previously discontinued daytime napping.  International Classification of Sleep Disorders, 3rd ed, American Academy of Sleep Medicine, Darien, IL 2014. Copyright © 2014 American Academy of Sleep Medicine.

Narcolepsy, Type 2: Diagnosis Daily periods of irrepressible need to sleep or daytime lapses into sleep for at least 3 months.* B. Presence of one or both: Mean SOL of ≤8 mins and ≥ 2 SOREMPs on an MSLT CSF hypocretin-1 not measured or >110 pg/mL or >1/3 of mean values. Hypersomnolence not explained by another causes  A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.B. A mean sleep latency of ≤8 minutes and two or more SOREMPs are found 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.C. Cataplexy is absent.*D. Either CSF hypocretin concentration has not been measured or CSF hypocretin concentration measured by immunoreactivity is either >110 pg/mL or >1/3 of mean values obtained in normal subjects with the same standardized assay.¶E. The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.  International Classification of Sleep Disorders, 3rd ed, American Academy of Sleep Medicine, Darien, IL 2014. Copyright © 2014 American Academy of Sleep Medicine.

Idiopathic Hypersomnia Daily periods of irrepressible need to sleep or daytime lapses into sleep for at least 3 months.* Cataplexy is absent Mean < 2 SOREMPs on an MSLT AND presence of one : Mean SOL of ≤8 mins on MSLT Total 24hr sleep time >660 min (12-14 hours) Hypersomnolence not explained by another cause Daily periods of irrepressible need to sleep or daytime lapses into sleep for at least three months ●Cataplexy is absent ●A multiple sleep latency test (MSLT) documents 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 (see 'Multiple sleep latency test' above) ●The presence of at least one of the following: •MSLT shows a mean sleep latency of ≤8 minutes •Total 24-hour sleep time is ≥660 minutes (typically 12 to 14 hours) on 24-hour polysomnography or by wrist actigraphy in association with a sleep log ●Insufficient sleep syndrome is ruled out (if deemed necessary, by lack of improvement of sleepiness after an adequate trial of increased nocturnal time in bed, preferably confirmed by at least a week of wrist actigraphy) ●No better explanation by another sleep disorder, medical or psychiatric disorder or use of drugs or medications Daytime sleepiness leads to naps that tend to be long (an hour or more) and unrefreshing. Many patients take naps on five or more days per week. Unlike patients with narcolepsy, patients with idiopathic hypersomnia do not generally have sleep attacks (instances of irresistible sleep). (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Daytime sleepiness'.) Total 24-hour sleep time and nocturnal sleep time are often, but not always, prolonged in patients with idiopathic hypersomnia. The 24-hour sleep duration is often 12 to 14 hours. Sleeping longer at night does not appear to improve the EDS. Another common feature of idiopathic hypersomnia can be difficulty arousing from nocturnal sleep periods or daytime naps. Patients often report transient periods of confusion and "sleep drunkenness" upon awakening. Other features that are common but nonspecific in patients with hypersomnolence include automatic behaviors during wakefulness, sleep paralysis (complete inability to move for several minutes upon awakening), and hypnagogic hallucinations (vivid visual, tactile, or auditory dream-like experiences that occur as the patient is falling asleep) [15]. In a prospective study of 75 patients referred to a sleep disorders unit for EDS and who met diagnostic criteria for idiopathic hypersomnia, sleep drunkenness was reported by 36 percent of patients, sleep paralysis by 28 percent, and hypnagogic hallucinations by 24 percent [16].  International Classification of Sleep Disorders, 3rd ed, American Academy of Sleep Medicine, Darien, IL 2014. Copyright © 2014 American Academy of Sleep Medicine.

Treatment Excessive daytime sleepiness Cataplexy Structured nocturnal sleep* Times daytime naps*(narcolepsy) Avoiding sedating medications* Wake promoting medications Stimulants Sodium oxybate (narcolepsy) Psychotherapy * Cataplexy Sodium oxybate Antidepressants (SSRI, SNRI, NERI)  Cataplexy Sodium oxybate Antidepressants (SSRI, SNRI, NERI) One or two well-timed 20 minute naps will often improve sleepiness for one to three hours though some patients only benefit from long naps [4]. If it can be arranged, a brief nap at work or school is often helpful. Sleep deprivation may worsen narcolepsy symptoms and therefore patients should be counseled to maintain a regular and adequate sleep schedule [5]. ●Psychosocial support – Patients with narcolepsy face various psychosocial and work-related problems throughout their lives; as a result, they may have difficulty meeting economic and social responsibilities [6]. They also have the additional burden of coping with misperceptions about the causes and the involuntary nature of their symptoms. Common misconceptions, even among medical caregivers, are that sleep attacks and cataplexy (emotionally triggered muscle paralysis resulting in partial or complete collapse) are manifestations of poor motivation, denial, or avoidance. Thus, patients often benefit from participation in support groups that focus on coping skills and identification of community resources to assist with administrative and medical issues. sodium salt of gamma hydroxybutyrate (GHB) http://julieflygare.com/narcolepsy-not-alonematters/

Behavioral Sleep Medicine Services for Hypersomnia Disorders: A Survey Study Aim Examine the concept viability of delivering behavioral sleep medicine (BSM) services to patients with hypersomnia disorders Phase 1, with longer term of development of BSM intevention, establish main outcome measures, prelim data to test efficacy, and intervention Goal was to gather data on the need for cognitive and behavioral therapy interventions, the potential treatment targets, and patient acceptability of these approaches

Study Overview Population, internet-based survey Open for 1 month (August 8-Sept 5, 2014) 33 questions queried on: Diagnosis Symptoms Treatment Perceived effectiveness Acceptability Conducted in Europe an Australia TIDY UP

Sample Characteristics (n=371) 65.2% with narcolepsy (2/3 with cataplexy) 97.6% reported currently experiencing significant daytime sleepiness 86.3% female; 89% white Mean age about 37 years (+/- 11 yrs) Mean age of symptoms 18 yrs (+/- 9 yrs) >60% college graduates 45% “professionals”; 15% disability Cowie, NEJM 2015;doi10.1056

Sample Selection: Inclusion Patients with HD identified through Wake Up Narcolepsy network ≥ 17 yrs Self reported diagnosis of narcolepsy or idiopathic hypersomnia

Treatment Strategies 86% used pharmacologic medications (Table 3) Effectiveness rate 6/10, slightly higher in narcolepsy >90% nonpharmacologic strategies (Table 4A) Most common: daytime naps, scheduled nocturnal sleep, caffeine, exercise, diet, temperature manipulations Information sources: 78% trial and error, 44% internet, 38% other patients, 33% sleep physician, 25% patient organizations, 24% primary care physicians

Perceived Effectiveness

Mental Health and Social Impact Respondants reoprted that the disease symptoms have had a significant impact on their quality of life. Difficulties in work or school (8 high), family relationships, social relationships, avoiding symptoms due to their symptoms.

Interest in BSM Services 86% some interest in support groups 74% interested at least some in CBT 72% endorsed interest in yoga and mindfulness 62% interested in working with BSM provider Considerations: effectiveness, time, satisfied with current regimen Cowie, NEJM 2015;doi10.1056

Conclusions Medications relatively effective, more in persons with narcolepsy Patient engagement was high for behavioral therapies, though with more modest improvements, particularly among patients with IH Only 1/3 of patients learned about nonpharm strategies from sleep physician Nearly 2/3 of patients interested in working with BSM provider, in a variety of formats

Discussion How can we improve management of patients with HD? What are the current limitations (and future targets) for treatment? What does the study suggest about how can we utilize BSM to improve management of patients with HD? What are potential barriers? What is the role, including future roles for BSM providers in treating HD? How do we engage patients with PD to develop and expand BSM services for HD? Goal was to gather data on the need for cognitive and behavioral therapy interventions, the potential treatment targets, and patient acceptability of these approaches What about patients with HD not included in this sample?

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