Primary Hypersomnias of Central Origin

Review Article

Address correspondence to Dr Clete A. Kushida, Stanford Primary Hypersomnias University Center for Human Sleep Research, 780 Welch Rd, Suite 203, Palo Alto, CA of Central Origin 94304, [email protected]. Relationship Disclosure: Samit Malhotra, MD; Clete A. Kushida, MD, PhD, RPSGT Dr Kushida has consulted for Apnex Medical, Inc, and Seven Dreamers Laboratories and has received royalties ABSTRACT from Philips Respironics. Dr Kushida has received Purpose of Review: This review discusses the various causes of primary hyper- research support from somnias with emphasis on clinical recognition, diagnosis, and treatment options. Apnex Medical, Inc; Recent Findings: Narcolepsy is probably the most fascinating syndrome causing GlaxoSmithKline; Impax Laboratories, Inc; Merck & Co, excessive daytime sleepiness. With increasing understanding of the hypocretin/orexin Inc; Pacific Medico Co, Ltd; pathways and the neurotransmitters that subserve the role of wakefulness and sleep, ResMed; and XenoPort, Inc. newer therapeutic modalities with promising results are being investigated and Dr Malhotra reports no disclosure. opening new frontiers in the treatment of this rare but devastating disease. Unlabeled Use of Summary: This article reviews the primary hypersomnias of central origin. Where Products/Investigational possible, clinical cases that highlight and explain the clinical syndromes are included. Use Disclosure: Treatment modalities and future directions are also discussed to help the clinician Dr Kushida discusses the unlabeled use of selective identify and treat the underlying disorder. serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and Continuum (Minneap Minn) 2013;19(1):67–85. tricyclic antidepressants for the treatment of narcolepsy with cataplexy; melatonin for the treatment of idiopathic INTRODUCTION Classification of Sleep Disorders, Sec- hypersomnia; and amantadine, lithium, The symptom of hypersomnia is com- ond Edition: Diagnostic and Coding lamotrigine, valproic acid, Manual (ICSD-2) lists a number of and modafinil for the monly encountered in clinical practice treatment of Kleine-Levin and can occur as a result of a sleep- conditions that are grouped under this syndrome. Dr Malhotra 2 related breathing disorder, or it may also category of sleep disorders (Table 4-1). reports no disclosure. It may be normal for a preschooler * 2013, American Academy occur secondary to a circadian rhythm of Neurology. disorder or other causes of disturbed to sleep 12 hours a night, but the same nocturnal sleep. When hypersomnia does amount of nocturnal sleep with symp- not result from the aforementioned con- toms of EDS in an adult may raise sus- ditions, it is termed hypersomnia of picion for a sleep disorder. Sleep needs central origin. It is defined as an inability are individual, and the National Sleep to maintain an alert state during the Foundation provides an outline of nor- major waking episodes of the day. mal sleep time based on the age of the 1 Excessive daytime sleepiness (EDS) person (Table 4-2). is the cardinal manifestation common Supplemental digital content: Videos accompanying this ar- to all types of hypersomnia. In com- NARCOLEPSY ticle are cited in the text as parison to hypersomnia due to various Introduction Supplemental Digital Content. Videos may be accessed by pathologies, such as sleep-disordered A disorder of REM sleep, narcolepsy is clicking on links provided in breathing, hypersomnia of central ori- the classic hypersomnia of central origin. the HTML, PDF, and iPad versions of this article; the gin is a rare cause of EDS. It is im- EDS and episodic loss of muscle tone URLs are provided in the print 3 portant for the treating clinician to be were identified in 1877 by Westphal, version. Video legends begin cognizant of disease entities that con- and 3 years later, Gelineau coined the on page 83. stitute the umbrella term ‘‘hypersomnia term narcolepsy. Subsequently, Adie of central origin,’’ to be able to diagnose recognized the loss of muscle tone as them, and, most importantly, to manage part of the constellation of the disease them appropriately. The International and named it cataplexy. Investigation

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KEY POINT h Most whites and African TABLE 4-1 International Classification of Sleep Disorders, Second Americans who have Edition: Diagnostic and Coding Manual Diagnostic narcolepsy with Criteria for Hypersomniaa cataplexy are positive for HLA-DQB1*0602, b Narcolepsy With Cataplexy showing a strong b Narcolepsy Without Cataplexy association with this Narcolepsy due to medical condition human leukocyte Narcolepsy, unspecified antigen type. b Recurrent Hypersomnia Kleine-Levin syndrome Menstrual-related hypersomnia b Idiopathic Hypersomnia With Long Sleep Time b Idiopathic Hypersomnia Without Long Sleep Time Behaviorally induced insufficient sleep syndrome Hypersomnia due to medical condition Hypersomnia due to drug or substance Hypersomnia not due to substance or known physiologic condition (nonorganic hypersomnia) Physiologic (organic) hypersomnia, unspecified

a Modified from American Academy of Sleep Medicine.2 Used with permission of the American Academy of Sleep Medicine, Darien, IL, 2012.

into the etiology of this disorder es- Additional research identified the tablished an association with HLA-DR2 hypocretin/orexin pathway and its abil- in the Japanese population with narco- ity to regulate sleep and wakefulness.6 lepsy.4 Most whites and African Americans The finding of undetectable CSF levels who have narcolepsy with cataplexy of hypocretin-17 and hypothalamic were also positive for HLA-DQB1*0602, hypocretinergic cell dropout in patients showing a strong association with this with narcolepsy and cataplexy further human leukocyte antigen (HLA) type.5 confirmed this association.

TABLE 4-2 Age-Specific Sleep Needs as Recommended by the National Sleep Foundationa

Age Sleep Newborns (0Y2 months) 12Y18 hours Infants (3Y12 months) 14Y15 hours Toddlers (1Y3 years) 12Y14 hours Preschoolers (3Y5 years) 11Y13 hours School-aged children (5Y10 years) 10Y11 hours Preteenaged and teenaged children (10Y17 years) 8.5Y9.25 hours Adults 7Y9 hours a Reprinted with permission from National Sleep Foundation.1 www.sleepfoundation.org/article/ how-sleep-works/how-much-sleep-do-we-really-need.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 4-3 International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual Diagnostic Criteria for Narcolepsy With Cataplexya

A. Excessive daytime sleepiness present for at least 3 months. B. Definite history of cataplexy, ie, loss of muscle tone triggered by laughter or strong emotions. C. Should be confirmed by multiple sleep latency test preceded by an overnight polysomnogram consisting of at least 6 hours of sleep. A sleep latency of 8 minutes or less plus two or more sleep-onset REM periods are considered abnormal. Alternatively, a decreased CSF hypocretin level (G110 pg/mL) can be used. D. The hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder. a Modified from American Academy of Sleep Medicine.2 Used with permission of the American Academy of Sleep Medicine, Darien, IL, 2012.

Epidemiology or CNS trauma or disease before mak- The prevalence of this disease is between ing a diagnosis of narcolepsy without 0.03% and 0.05% of the population.8 cataplexy. First-degree relatives of Both sexes are equally affected, with patients with narcolepsy have a 1% to mean age at onset in the mid-twenties. 2% risk of developing this disorder. The A peak occurs around 15 years and ICSD-2 diagnostic criteria for narco- another near 35 years, suggesting a lepsy with and without cataplexy are bimodal distribution. Narcolepsy with- outlined in Table 4-3 and Table 4-4. out cataplexy is comparatively less common than narcolepsy with cata- Clinical Symptoms plexy. It is prudent to exclude secon- The classic symptoms of narcolepsy in- dary hypersomnia resulting from clude EDS, cataplexy, hypnagogic hallu- systemic disease, drugs or medications, cinations, and sleep paralysis.

TABLE 4-4 International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual Diagnostic Criteria for Narcolepsy Without Cataplexya

A. Excessive daytime sleepiness present for at least 3 months. B. Cataplexy is absent or very doubtful. C. Must be confirmed by multiple sleep latency test preceded by an overnight polysomnogram consisting of at least 6 hours of sleep. A sleep latency of 8 minutes or less plus two or more sleep-onset REM periods are considered abnormal. D. The hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder. a Modified from American Academy of Sleep Medicine.2 Used with permission of the American Academy of Sleep Medicine, Darien, IL, 2012.

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KEY POINTS h Naps are usually Excessive daytime sleepiness. EDS than a few minutes. Subsequent recur- refreshing and often is usually the heralding feature of ring attacks are deemed less stressful recommended as part of narcolepsy, manifesting as episodes as patients readily recognize the phe- the treatment plan for of an inadvertent and irresistible urge nomenon and its transient nature. narcolepsy. Short to sleep that appears without warning. Sleep paralysis, which occurs in two- daytime naps lasting These may last seconds to minutes and thirds of patients with narcolepsy, is about 30 minutes can are known as sleep attacks. Sedentary not pathognomonic of narcolepsy as result in the attenuation and boring settings may predispose to it can be present even in the healthy of the sleep drive for a and enhance the symptom of EDS. population,9 commonly in the setting few hours. Naps are usually refreshing and often of sleep deprivation. h Symptoms of subtle recommended as part of the treatment Hallucinations. Simple or complex muscle weakness in plan. Short daytime naps lasting about visual hallucinations are experienced cataplexy include 30 minutes can result in the attenuation by approximately two-thirds of patients slurring of speech, of the sleep drive for a few hours.9 with narcolepsy. These may either buckling of knees, jaw Cataplexy. Cataplexy is defined as occur during the period of transition dropping, or even the sudden, involuntary loss or decrease from wakefulness to sleep (hypnagogic) nodding of the head and should be of muscle tone. Episodes are most com- or from sleep to wakefulness (hypno- specifically elicited monly precipitated by laughter; how- pompic) with the former being typical of during history taking. ever, other intense positive emotions narcolepsy. Other forms, such as audi- such as joy, elation, and even surprise tory and tactile hallucinations, may also h A rare sustained cataplectic episode, can be potential triggers. These attacks be experienced. It is imperative to ex- status cataplecticus, may either be profound, with general- clude an underlying psychiatric condi- may occur following ized atonia resulting in falls and injuries, tion as a cause of the hallucinations that abrupt discontinuation or consist of localized loss of muscle do not occur exclusively during sleep. of medications used to tone that may be missed if this diag- Hallucinations during sleep stage tran- treat cataplexy. This is nosis is not considered (Supplemental sitionarealsoreportedinhealthy also referred to as Digital Content 4-1, links.lww.com/ people9 and, therefore, are also not rebound cataplexy. CONT/A16). Symptoms of subtle mus- pathognomonic of narcolepsy. cle weakness include slurring of speech, Disturbed nighttime sleep. Al- buckling of knees, jaw dropping, or though not a part of the classic tetrad, even nodding of the head and should nighttime sleep disturbance is an es- be specifically elicited during history sential symptom of narcolepsy, and for taking. The diagnosis may be delayed this reason several efforts at character- by several years if these key symptoms izing the nocturnal sleep of these pa- are not elicited on initial evaluation. Most tients have been made. A large number cataplectic attacks last a short duration, of patients with narcolepsy experience a few seconds to a few minutes.10 How- vivid dreams, sleep fragmentation due ever, a rare sustained cataplectic episode, to multiple arousals, early morning status cataplecticus, may occur follow- awakenings, nocturnal eating, and unre- ing abrupt discontinuation of medica- freshing nocturnal sleep.11 tions used to treat cataplexy. This state is Automatic behavior. Nearly half of also referred to as rebound cataplexy. all patients with narcolepsy experience Sleep paralysis. A terrifying experi- automatic behavior,11 which is described ence when it occurs for the first time, as the act of pursuing a purposeful be- sleep paralysis is characterized by an havior with no reminiscence of it. Pa- inability to move while being totally tients either seem awake and alert or aware of one’s surroundings. Typically may appear inattentive during an epi- occurring either at arousal or at sleep sode. Intrusion of microsleep into wake- onset, these events rarely last more fulness is believed to account for this

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 11 KEY POINTS symptom. Sleep deprivation may precip- onset of symptoms of EDS. Case 4-1 h The presence of a itate automatic behavior in normal indi- demonstrates a typical presentation of sleep-onset REM period viduals and therefore this symptom is narcolepsy. on an overnight sleep also not pathognomonic of narcolepsy. study of a patient with Pathophysiology a history of excessive Associated Conditions The connection between major histo- daytime sleepiness and Periodic limb movements of sleep. compatibility complex and narcolepsy muscle atonia that Very common in the narcoleptic pa- was initially reported in the Japanese occurs in the setting of tient, periodic limb movements of sleep population and led to the consider- an emotional outburst (PLMS) may occur in 60% of these pa- ation of an autoimmune basis in the may be suggestive of a tients. These are characterized as a development of narcolepsy. An asso- diagnosis of narcolepsy with cataplexy. cluster of limb movements occurring ciation of HLA-DR with narcolepsy was during sleep that resemble a triple flexion reported in the Japanese population, h Hypocretin-1 and response.Thisisapolysomnographic and subsequently other HLA types hypocretin-2 are the finding and it should be remembered were also associated with narcolepsy, two peptides that result from the splitting of that patients with PLMS may or may not with the most closely linked being their precursor, have symptoms of restless legs during HLA-DQB1*0602. Twelve percent to preprohypocretin. wakefulness. PLMS are more prevalent 34% of the general population has this Hypocretin-1 is as the patient gets older, tend to be allele, and more than 90% of patients implicated in human more prevalent in REM sleep, and are with narcolepsy and cataplexy test pos- narcolepsy. associated with more sleep disruption itive for this HLA type.12 The HLA link is than in controls, most likely because of less certain in patients with narcolepsy the PLMS-associated arousals. without cataplexy, although more than REM sleep behavior disorder. REM 40% of these patients are positive for sleep behavior disorder is an associated this HLA.12 Additionally, up to 30% of condition present in 7% to 36% of pa- patients positive for HLA-DQB1*0602 tients with narcolepsy (Supplemental do not have narcolepsy.5,12 Digital Content 4-2, links.lww.com/ The discovery of the hypocretin/ CONT/A17). The term REM sleep orexin neurons in the lateral hypothal- behavior disorder may be misleading, amus furthered understanding of the since patients with narcolepsy may dem- pathophysiology of this disorder.6 onstrate an increase in phasic and/or Hypocretin-1 and hypocretin-2 are tonic muscle activity in nocturnal REM the two peptides that result from the sleep without the associated behavioral splitting of their precursor, preprohy- component needed to make a diagno- pocretin. Hypocretin-1 is implicated in sis of REM sleep behavior disorder. human narcolepsy. These hypocretin peptides bind to their own specific Presentation receptors, which are found in the his- Both EDS and cataplexy will be present taminergic tuberomamillary nucleus, in about half of the patients when the the ventrolateral preoptic nucleus, the diagnosis of narcolepsy is made, and cholinergic pedunculopontine nucleus, about 40% will progress and show symp- the brainstem monoaminergic system, toms of cataplexy later in the course of and also diffusely in the basal forebrain.13 their disease. Occasionally, the onset of As previously mentioned, patients who REM-related muscle atonia (cataplexy) have narcolepsy with cataplexy show precipitated by intense emotions occurs low or undetectable CSF hypocretin more than 40 years later, although most levels, with most patients testing pos- patients will experience their first epi- itive for HLA-DQB1*0602.7 Addition- sode of cataplexy within 10 years of the ally, histologic examination on brain

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Case 4-1 An 8-year-old boy was brought to the office by his parents because of a 2-week history of abrupt onset of overwhelming sleepiness. He was inappropriately falling asleep in the day despite getting over 10 hours of uninterrupted nocturnal sleep. No history of sleep paralysis or visual hallucinations could be elucidated from the patient or his family. He described an episode of falling off his bicycle without any clear reason, and another episode when his knees buckled and he fell to the ground after hearing his brother tell a joke. (The accompanying video [Supplemental Digital Content 4-3, links.lww.com/CONT/A18] demonstrates a different patient with similar clinical history and presentation.) He had an unexplained weight gain of about 3 kg (6 lbs) over 2 months. He had nothing remarkable in his medical or psychiatric history and no history of recent trauma or medication use. His routine blood work and EEG were normal, as was the MRI of the brain with and without gadolinium. An overnight polysomnogram (PSG) was normal, with a subsequent multiple sleep latency test (MSLT) showing a mean sleep-onset latency of 2.3 minutes and a sleep-onset REM period (SOREMP) on each of the five naps. Human leukocyte antigen typing was positive for HLA-DQB1*0602, and CSF hypocretin level was undetectable. Comment. The patient’s history of a rather abrupt onset of excessive daytime sleepiness (EDS) and episodes of muscle atonia that occurred during an emotionally charged situation was highly suggestive of narcolepsy with cataplexy. This diagnosis was confirmed with a normal PSG and a MSLT positive for multiple SOREMPs and a sleep-onset latency shorter than 8 minutes. HLA typing for HLA-DQB1*0602 and abnormal CSF hypocretin levels may help confirm the diagnosis if the MSLT results are equivocal, unlike in this case. Additionally, the presence of a SOREMP on an overnight sleep study with a history of EDS and muscle atonia that occurs in the setting of an emotional outburst may also be suggestive of a diagnosis of narcolepsy with cataplexy. An MSLT is still necessary to confirm this diagnosis since the presence of a SOREMP on an overnight PSG is not included in the diagnostic criteria outlined in the International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual. Treatment was initiated with sodium oxybate 3 g in two divided doses, resulting in improvement of the patient’s symptoms of EDS and cataplexy. The sodium oxybate dose was increased to 4.5 g in three divided doses a few months later.

tissue in patients with narcolepsy affected during a cataplectic episode. showed evidence of hypocretin neuro- Since magnetic stimulation via the nal cell loss in the lateral hypothalamus transcranial route is not impaired in (Figure 4-1). cataplexy, presynaptic inhibition of the The inhibition of the motor effector afferent sensory neuron has been pro- of the H reflex is the proposed mech- posed as an alternative mechanism for anism for the development of the atonic the development of cataplexy.15 process encountered in cataplexy. This mirrors the mechanism that explains the Diagnostic Tools atonia normally seen in REM sleep.14 Epworth Sleepiness Scale. The Epworth However, this theory cannot explain the Sleepiness Scale (Appendix A) assesses general loss of muscle tone and areflexia subjective daytime sleepiness through seen in muscles that are not clinically a short and simple questionnaire. The

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 4-1 Prehypocretin messenger RNA in the lateral hypothalamus stains darkly in the control subject (B), but is undetectable in the patient with narcolepsy (A). f = fornix.

Modified from Nishino S, et al, Sleep Med Clin.19 B 2012, with permission from Elsevier. www.sciencedirect.com/science/article/pii/S1556407X12000434.

chance of falling asleep in eight com- bed and try to fall asleep during each mon situations is graded from 0 to 3. A of the five naps. Sleep onset as well as total score greater than 10 is indicative the presence of REM sleep during the of EDS.16 nap is noted. REM sleep occurring within Multiple sleep latency test. The 15 minutes of sleep onset is deemed a multiple sleep latency test (MSLT) SOREMP. A short sleep-onset latency of was designed to record the physio- less than 8 minutes is considered ab- logic tendency to fall asleep in the abnormal. If this short sleep-onset latency sence of external alerting factors.17 To is accompanied by at least two SOR- be considered valid, the MSLT has to be EMPs, a diagnosis of narcolepsy may be preceded by an overnight sleep study made in the right clinical setting.18 If polysomnogram (PSG), essentially to the patient does not sleep during a nap, ensure that the patient is not sleep the nap is interrupted after 20 minutes deprived and has slept sufficiently. and the patient waits for the next nap Sleep-disordered breathing that may time.17 account for the symptom of EDS and Polysomnogram. Patients with nar- may give a false-positive MSLT is also colepsy often show abnormalities on ruled out with the PSG. Although a the PSG that include a decrease in total diagnosis of sleep-disordered breathing sleep time, a short sleep-onset latency, does not rule out narcolepsy, it makes it sleep fragmentation, REM without ato- less likely to be the sole cause of the nia, and PLMS. Often, the presence of a EDS. Avoidance of all medications influ- SOREMP on the PSG may alert a phy- encing sleep from 2 weeks before the sician to consider narcolepsy in the dif- test is necessary, although sometimes ferential diagnosis in a patient with EDS. impractical. HLA. Testing for serum HLA-DQB1* For the MSLT, five 20-minute naps 0602 typing is available and more com- at 2-hour intervals are scheduled dur- monly seen in patients with narcolepsy ing the day, and the patient, dressed and cataplexy. However, there is a in street clothes, is instructed to lie in higher chance for narcolepsy patients

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KEY POINT h A finding of low (less without cataplexy to be HLA negative pending on the presence or absence than 110 pg/mL) or than positive, and upward of 30% of of cataplexy. These criteria take into undetectable CSF the general population may be positive consideration the duration of symp- hypocretin levels will for this HLA type without having symptoms, the presence or absence of 5,12 nearly always be seen in toms of narcolepsy. cataplectic events, and specific diag- patients with true Hypocretin. CSF measurement of nostic modalities used to make the narcolepsy with hypocretin is commercially available, distinction between narcolepsy with cataplexy. and the finding of low (less than 110 cataplexy and narcolepsy without cata- pg/mL) or undetectable CSF hypocre- plexy (Tables 4-3 and 4-4). tin levels will nearly always be seen Another issue that a clinician may in patients with true narcolepsy with face is whether to draw blood for HLA cataplexy.7 typing and/or CSF analysis for hypocretin levels. In the presence of cata- Diagnostic Criteria plexy with a positive MSLT, these tests The ICSD-2 has developed slightly may not be necessary. However, they different criteria for narcolepsy, de- may help to confirm the diagnosis

TABLE 4-5 Pharmacologic Treatment of Excessive Daytime Sleepiness

Drug Dosage Common Side Effects Stimulants d-Amphetamine 5Y10 mg once or twice daily Palpitations, tachycardia, elevated (morning and noon) blood pressure, anorexia, weight loss, insomnia, psychosis (rare), potential Maximum daily dose 60 mg for abuse

Methamphetaminea 5Y10 mg once or twice daily Same as d-amphetamine, more (morning and noon) anorexigenic, very high abuse potential Maximum daily dose 60 mg Methylphenidate HCl 10Y20 mg once or twice daily Same as d-amphetamine, less (morning and noon) anorexigenic, less abuse potential Maximum daily dose 60 mg Wake-Promoting Agents Modafinil 100Y200 mg once or twice daily Headache, nausea, insomnia (morning and noon) Maximum daily dose 400 mg, although 600 mg has been used Armodafinil 150Y250 mg once or twice daily Similar to modafinil Other Sodium oxybateb Starting dose 1.5 g taken at Headache, nausea, dizziness, bedtime and again 2Y4 hours enuresis, worsened sleep-disordered after sleep onset breathing Usual effective dose 4.5Y6g per night Maximum daily dose 9 g a Methamphetamine is not approved by the US Food and Drug Administration (FDA) for narcolepsy. b Sodium oxybate is also FDA-approved for treatment of cataplexy.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. in the presence of equivocal MSLT the serotonin transporter.20 The first results. accounts of methylphenidate usage at doses up to 300 mg in treating EDS in Treatment patients with narcolepsy date back to Excessive daytime sleepiness. Stimu- 1959. lantshavebeenthemainstayoftreatment, Wake-promoting agents. Modafinil but with the advent of wake-promoting is a nonamphetamine wake-promoting agents and the availability of sodium agent whose mechanism of action is oxybate, additional treatment options not yet fully elucidated. However, it are now available for the treatment of is thought to not only increase the EDS (Table 4-5). release of monoamines, such as nor- Stimulants. Various amphetamines epinephrine and dopamine, but also (eg, d-amphetamine, methamphetamine) elevate hypothalamic histamine levels. and methylphenidate are included in this Wake-promoting agents have become class of medications that have been used the favored medication and are the for the treatment of EDS. Pemoline was first-line agents for treating EDS in taken off the market by the US Food and narcolepsy,21 and modafinil may be Drug Administration (FDA) because of used at up to 400 mg in divided doses. its association with idiosyncratic liver Armodafinil is an active enantiomer of failure leading either to transplantation the racemic drug modafinil and has the or death and therefore will not be same indications for use as modafinil. discussed here. However, it has a considerably longer The initial reports of amphetamine half-life and a longer wake-promoting use for the treatment of EDS dates back effect than modafinil.22 It was approved to 1935, when nine patients with narco- by the FDA for treating EDS in narcolepsy were treated with Benzedrine.5 lepsy in June 2007. The dose is either Amphetamines, therefore, were the prin- 150 mg or 250 mg given daily in the cipal agents used for the treatment of morning. the symptom of EDS associated with The use of +-hydroxybutyrate, also narcolepsy. Amphetamines alleviate known as sodium oxybate, for treat- sleepiness by blocking dopamine reup- ment of narcolepsy dates back to take at the nerve terminal and revers- 1979. +-Hydroxybutyrate became infa- ing its transporter action at the synaptic mous as the ‘‘date rape drug’’ and cleft. Amphetamines also facilitate the subsequently went into medical obliv- free cytosolic movement of dopamine ion. A renewed interest in sodium contained in storage vesicles and its oxybate led to well-designed random- release in the synaptic region by inter- ized double-blind studies comparing acting with the vesicular monoamine different doses of sodium oxybate to transporter 2. Additionally, at higher placebo in the treatment of EDS, cata- doses, these compounds prevent deg- plexy, and overall sleep efficiency.23 radation of the catecholamines by act- Although its exact mechanism of ac- ing as an inhibitor of monoamine tion remains unclear, it is known that oxidase.10 Divided doses of up to 60 sodium oxybate is naturally occurring mg of d-amphetamine are given on and has its own receptors as well as an waking up and at noon. Methamphet- affinity for activating +-aminobutyric amine shares a mechanism of action acid B receptors.10 Its efficacy for day- similar to all amphetamines, as does time alertness in combination with mod- methylphenidate, except that methyl- afinil is superior to either drug taken phenidate has a weak binding effect on alone.21 Sodium oxybate consolidates

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and counters sleep fragmentation seen norepinephrine uptake inhibitors, were in patients with narcolepsy by signifi- investigated. Table 4-6 lists the medi- cantly increasing slow-wave sleep. It is cations that are prescribed for the treat- available as a liquid formulation and ment of cataplexy along with their doses prescribed to be taken at bedtime and and notable side effects. Currently, none about 2 to 4 hours later. The patients of these medications is FDA-approved set an alarm and take the medication 2 for the treatment of cataplexy.10 to 4 hours after bedtime. Based on the Tricyclic antidepressants. This was dosing studies, the recommended the first class of medications available starting dose is 3 g in divided doses to for the treatment of cataplexy, and imipr- a maximum of 9 g a night. amine was the first drug used for this Cataplexy. Treatment is directed purpose. Protriptyline and clomipramine toward prevention of the occurrence are probably the most widely used drugs of muscle atonia and thereby prevent- from this class and share the common ing falls and injuries. Various medica- mechanism of action of blocking norepi- tions were tried with this goal in mind, nephrine reuptake to improve cata- and the first observed improvement in plexy.10 Although these medications treatment of cataplectic events dates belong to the class of antidepressants, back to 1960 with imipramine. This the doses needed to treat cataplexy effe- paved the way for other tricyclic anti- ctively are well below those used for the depressants to become the drugs of treatment of depression, with anticholi- choice for treating cataplexy. Subse- nergic side effects remaining the same. quently, other agents that alter the Selective serotonin reuptake inhib- metabolism of norepinephrine, namely itors. The most commonly prescribed the selective serotonin reuptake inhib- medication from this class is fluoxe- itors (SSRIs) and the selective serotonin tine. It is inferior in efficacy to the

TABLE 4-6 Medications Used in the Treatment of Cataplexy

Drug Dosage Common Side Effects Tricyclic Imipramine Start with 10Y25 mg given at bedtime Dry mouth, constipation, drowsiness Maximum effective dose 125Y150 mg Protriptyline Start with 5Y10 mg given at bedtime Same as imipramine Maximum effective dose 60 mg Clomipramine Start with 10Y25 mg given at bedtime Same as imipramine Maximum effective dose 10Y150 mg Selective serotonin reuptake inhibitor Fluoxetine Start with 10Y20 mg in the morning Nausea, insomnia, diarrhea Maximum dose 60 mg Fluvoxamine Start with 25Y50 mg in the morning Nausea, diarrhea, headache Can be given in divided doses (morning/lunch) to a maximum of 300 mg Serotonin-norepinephrine reuptake inhibitor Venlafaxine Start with 75 mg in the morning Nausea, constipation, somnolence, Can be given in divided doses dry mouth, dizziness (morning/lunch) to a maximum of 375 mg

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS tricyclics in its anticataplectic effect mal studies have demonstrated en- h Various medications largely because of the affinity of the hanced histaminergic neurotransmission treat the individual 10 SSRIs toward the serotonin pathway. as well as stimulation of the H1 receptors symptoms of narcolepsy Therefore, higher doses of the SSRIs postsynaptically with H3 autoreceptor in- with cataplexy, but 25 are usually required to see similar ther- verse agonists and antagonists. With the sodium oxybate is apeutic effects. current understanding of the hypocretin/ favored over the Selective serotonin norepinephrine orexin pathway in regulating wakeful- others because of its uptake inhibitors. The most frequently ness, and knowledge regarding the effectiveness in treating used medication in this class is venla- association of narcolepsy in patients the primary symptoms, faxine, which is effective in doses lower with low or undetectable hypocretin including excessive than those used to treat depression. levels and hypocretin cell destruction, daytime sleepiness and REM-related atonia Venlafaxine along with modafinil and it is intuitive that hypocretin replace- (cataplexy), sodium oxybate are the most used and ment therapy would be the most ratio- simultaneously. continued medications for treatment of nal approach for treatment of narcolepsy. h narcolepsy and cataplexy when compared This has been tried, with encouraging Idiopathic hypersomnia has an unknown to stimulants and TCAs, as well as SSRIs, results, in animal studies with central ad- 26 etiology and is typified which are tried but rarely continued. ministration of hypocretin-1. An intra- by symptoms of nasal hypocretin delivery method has nonrefreshing sleep Management Considerations also been tried. Gene therapy and cell with difficulty waking Management is symptomatic rather transplantation have been investigated up, which could either than curative. Although various medi- as therapeutic options in animal mod- be in the morning or cations treat the individual symptoms, els. Additionally, in their review of the after a nap. sodium oxybate is favored over the orexin receptors, Scammell and Winrow27 others because of its effectiveness in have suggested the possibility of de- treating the primary symptoms, includ- veloping orexin receptor agonists that ing EDS and REM-related atonia (cata- may promote wakefulness in narcolepsy plexy), simultaneously. If EDS persists, patients with EDS. Since more and more the addition of a wake-promoting agent evidence indicates an immune-mediated or stimulant is advisable. In narcolepsy death of the hypocretin-secreting neu- without cataplexy, either a wake-promoting rons in the development of narcolepsy, agent or a stimulant, or even sodium focus has shifted to immunotherapy, oxybate, may be tried as first-line ther- although without much success. Plasma apy. To help the treating physician make exchange, immunoglobulins, and ste- therapeutic choices, practice parameters roids have been tried with no clear have been published by the American benefits. Academy of Sleep Medicine.24 Treatment directed specifically for associated disor- IDIOPATHIC HYPERSOMNIA ders (such as REM sleep behavior dis- Introduction order, sleep-disordered breathing, and Idiopathic hypersomnia (IH) was first PLMS) should be used. described in the 1950s by Roth to dis- tinguish patients with EDS who were Future Directions not narcoleptics.28 It has an unknown Since antihistamine agents cause drow- etiology and is typified by symptoms siness, various manipulations of the his- of nonrefreshing sleep with difficulty tamine receptor have been attempted waking up, which could either be in the in order to develop therapeutic targets morning or after a nap. IH continues to for the treatment of EDS. Stimulation of be a poorly understood entity, and a postsynaptic H1 receptors has been diagnosis of IH is made only after other shown to increase wakefulness, and ani- causes of EDS have been excluded. It is

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therefore a diagnosis of exclusion and an inability to perform mental or phys- must be made with caution. ical tasks immediately upon waking up is commonly encountered but is not Epidemiology pathognomonic of IH and therefore not Since IH is a poorly understood entity, considered as part of the diagnostic the precise prevalence of this disorder criteria. Inappropriate sleep intrusion is remains unknown. Patients with nar- commonly seen. This can be disturbing colepsy outnumber patients with IH and also dangerous. Patients also fre- by a ratio of 10:1 based on a general quently show a depressed mood, but survey of sleep clinics, with both sexes the diagnostic criteria for mood disor- being equally affected.29 A familial pre- der as laid out in the Diagnostic and disposition has been noted with symp- Statistical Manual of Mental Disor- toms typically starting in the teenage ders, Fourth Edition for mood disorder years or as a young adult. CSF hypo- must not be met.29 Case 4-2 describes a cretin levels are normal, and an HLA typical presentation. association is inconclusive.30 Pathophysiology Clinical Manifestations The cause of IH is speculative, as little is The cardinal manifestation of IH is known of its pathophysiology. Abnormal EDS despite a normal total sleep time melatonin secretion and a circadian dys- and an absence of sleep-disordered function have been postulated. Aberrant breathing and normal sleep architec- homeostatic sleep drive has also been ture in an overnight sleep study. suggested based on the finding of a Clinically, patients report difficulty lesser quantity of slow-wave sleep in these waking up in the morning, feel sleepy patients. Additionally, an association during the day, and typically want to with the hypocretin/orexin system and return to sleep. Naps are not refresh- hypothalamic dysfunction has been ing, even if they last a few hours. Sleep proposed, but evidence in this regard inertia or a feeling of grogginess and is lacking.

Case 4-2 A 22-year-old woman presented to the sleep clinic with abrupt-onset sleepiness following a week of flulike symptoms. She had an unremarkable medical and psychiatric history and was employed as a cashier in a local bank. Three months before her presentation, her total sleep time was about 9 to 11 hours per night and she took no daytime naps. Meticulous history elucidated no cataplectic events. Routine laboratory and imaging studies were normal. An overnight polysomnogram showed a prolonged sleep time of more than 10 hours. The multiple sleep latency test showed a mean sleep-onset latency of 0.6 minutes and no sleep-onset REM period on any of the five naps. Human leukocyte antigen typing was negative for HLA-DQB1*0602; CSF hypocretin level was not checked. After ruling out medication or substance abuse, a diagnosis of idiopathic hypersomnia (IH) was made. Wake-promoting agents were started, and the patient responded well to therapy. Comment. IH is one of the most baffling conditions encountered by the sleep physician. As the name suggests, the cause is unknown, and at this time IH tends to be a catch-all diagnosis after other causes of hypersomnia have been effectively ruled out. Treatment is symptomatic with stimulants and wake-promoting agents.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 4-7 International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual Diagnostic Criteria for Idiopathic Hypersomnia With Long Sleep Timea

A. Almost daily excessive daytime sleepiness occurring for at least 3 months. B. Documented prolonged nocturnal sleep of at least 10 hours with laborious morning or end-of-nap arousals. C. Nocturnal polysomnogram (PSG) excludes other causes of daytime sleepiness. D. PSG documents a short sleep latency and a prolonged sleep period of greater than 10 hours. E. A multiple sleep latency test performed after the overnight PSG will show a mean sleep latency of less than 8 minutes and fewer than two sleep-onset REM episodes. F. The condition is not explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder. a Modified from American Academy of Sleep Medicine.2 Used with permission of the American Academy of Sleep Medicine, Darien, IL, 2012.

Diagnosis diaries are powerful tools to document 31 The diagnostic criteria as laid out by the sleep-wake schedule. the ICSD-2 are presented in Table 4-7 and Table 4-8. Subjective sleepiness is Differential Diagnosis estimated using the Epworth Sleepi- Other causes of hypersomnia (Table 4-1) ness Scale and objectified with the need to be meticulously considered and MSLT. To help differentiate circadian excluded before a diagnosis of IH can rhythm disorder, actigraphy and sleep be made.

TABLE 4-8 International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual Diagnostic Criteria for Idiopathic Hypersomnia Without Long Sleep Timea

A. Almost daily excessive daytime sleepiness occurring for at least 3 months. B. Normal nocturnal sleep of at least 6 hours and less than 10 hours with laborious morning or end-of-nap arousals. C. Nocturnal polysomnogram (PSG) excludes other causes of daytime sleepiness. D. PSG documents a normal sleep period of greater than 6 hours but less than 10 hours. E. A multiple sleep latency test performed after the overnight PSG will show a mean sleep latency of less than 8 minutes and fewer than two sleep-onset REM episodes. F. The condition is not explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder. a Modified from American Academy of Sleep Medicine.2 Used with permission of the American Academy of Sleep Medicine, Darien, IL, 2012.

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KEY POINTS h Treatment first patients in Germany and New Naps are usually not 33 refreshing in patients It is advisable to try behavioral interven- York, respectively. The syndrome with idiopathic tions even if they are of unclear value in consists of symptoms of hyperphagia, hypersomnia, in treatment of IH. Issues pertaining to hypersomnia, and hypersexuality. contrast to patients sleep hygiene need to be emphasized, Case 4-3 outlines the typical presenta- with narcolepsy, who including planning or taking naps if tion of this condition. find scheduled naps possible. Naps, however, are usually Epidemiology. KLS is a rare cause very rewarding. not refreshing in patients with IH, in of hypersomnia, with an estimated h Kleine-Levin syndrome contrast to patients with narcolepsy, prevalence of 1 in 1 million. Although consists of symptoms who find scheduled naps very reward- the peak age at initial presentation is of hyperphagia, ing. Increasing the total time spent in usually in the second decade of life, hypersomnia, bed is also not useful and should not be patients 4 years old and 80 years old and hypersexuality. recommended. Approach to pharma- have been reported in the literature. h Kleine-Levin syndrome is cologic treatment is similar to that of nar- KLS is more common in men, who a clinical diagnosis, and colepsy. Stimulants and wake-promoting outnumber women by a ratio of 2:1. A the investigations are agents are the mainstay of treatment. disproportionately large number of done merely to rule out Treatment with melatonin as well as cases are found in the Ashkenazi Jewish other causes of hyper- levothyroxine has also been tried with population compared to patients of somnia. some success.32 Antidepressants have other ethnicities. No clear association no role in the treatment of IH. has been demonstrated to suggest an inheritable trait or genetic susceptibility RECURRENT HYPERSOMNIA for the development of KLS, although Kleine-Levin Syndrome one-third of patients with KLS report Introduction. Kleine-Levin syndrome associated birth or developmental (KLS) is a classic, but rare, cause of issues.34,35 Familial cases have also recurrent hypersomnia. The eponym been reported, but these are rare. was coined by Critchley and Hoffman Clinical presentation. The initial in 1942, recognizing the work of episode in KLS is frequently preceded Kleine and Levin, who reported the by a precipitating factor in 9 of 10

Case 4-3 A 23-year-old man experienced multiple episodes, each lasting a few days, of hypersomnolence, binge eating, and excessive and inappropriate sexual arousal occurring intermittently during the past 2 years. During these episodes he was sleeping 18 to 20 hours a day. When awake, he would go on an eating binge or report inappropriate sexual arousals. These episodes would last days to weeks and be followed by spontaneous and complete resolution of symptoms. He did not report any prodromal symptoms and often had partial amnesia for his behavior during these episodes. During one of these episodes he had an overnight polysomnogram which showed increased sleep time but was otherwise normal. Other laboratory and imaging studies were also normal. Comment. Kleine-Levin syndrome is a clinical diagnosis, and the investigations are done merely to rule out other causes of hypersomnia. As in this case, a history of recurrent episodes of excessive daytime sleepiness with binge eating and hypersexuality are key features of Kleine-Levin syndrome. Various medications have been tried to treat this condition, but none has been consistently effective.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS patients. Infection or high fever is the Diagnosis. The diagnostic criteria are h Most episodes of most common complaint. Stress, alco- outlined in the ICSD-2 with an empha- Kleine-Levin syndrome hol use, travel, and sleep deprivation sis on the recurrence of the disorder resolve spontaneously have also been reported to precipitate (Table 4-9). within a 30-day period, symptoms of this syndrome. Less than Polysomnogram. Studies evaluat- and the interepisode 15% of patients can identify a prodromal ing PSGs done during and between hiatus almost never event to account for recurrent episodes. episodes of hypersomnia show a tre- surpasses 15 months. Clinically, patients report periods of mendous amount of discrepancy when h SPECT has demonstrated excessive sleepiness that may last 2 days the results are compared. Therefore, no a reduced perfusion of to4weekswithrecurrenceofsymptoms clear and beneficial conclusions can be the thalamus during an at least once per year. Patients typically drawn. Sleep study evaluation done by active Kleine-Levin have normal cognitive functioning with Huang and colleagues showed no dif- syndrome episode that normal alertness between episodes. ferences between PSG done during and eventually reversed to EDS is explained by no other medical, between episodes. However, when the normal as the symptoms neurologic, sleep, or psychiatric disor- results were divided into the start and resolved. der, nor by substance abuse or medica- end of episodes and analyzed sepa- tion use. Few symptoms differ between rately, slow-wave sleep increased and the sexes, although men present with REM sleep decreased significantly dur- significantly more symptoms of hyper- ing the later half.36 MSLT performed in sexuality than women. During an active patients with KLS has also shown episode, the sleep needs increase dras- inconsistent results and is therefore tically, with patients sleeping in excess of not used as a diagnostic criterion, em- 12 hours over a 24-hour period. Most phasizing the point that KLS is a clinical episodes resolve spontaneously within diagnosis. a 30-day period, and the interepisode Imaging studies. CT and MRI scans hiatus almost never surpasses 15 months. have always been normal in patients Therecurrenceofepisodesbecomesless with idiopathic KLS.33 SPECT, however, frequent, less severe, and shorter in has demonstrated a reduced perfusion duration as time passes. Persistent re- of the thalamus during an active KLS missions have been reported in patients episode that eventually reversed to when the disease started before adult- normal as the symptoms resolved. This hood and when hypersexuality was not was the most reliable finding, present present.34,35 in all subjects investigated.37

TABLE 4-9 International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual Diagnostic Criteria for Recurrent Hypersomnia (Kleine-Levin Syndrome and Menstrual-Related)a

A. Recurrent episodes of excessive sleepiness last 2 days to 4 weeks. B. The episodes recur at least once a year. C. The patient has normal alertness, cognitive functioning, and mental status between attacks. D. The hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder. a Modified from American Academy of Sleep Medicine.2 Used with permission of the American Academy of Sleep Medicine, Darien, IL, 2012.

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KEY POINT h Women with CSF analysis. One study demonstra- associationofdepressioninuptoone- menstrual-related ted a decrease in the CSF hypocretin third of women with menstrual-related hypersomnia experience level during a KLS episode when com- hypersomnia. No familial cases of this episodes of recurrent pared with the baseline during an disorder have been identified. Some sleepiness coinciding asymptomatic period and suggested a case reports indicate that treatment with with their menstrual hypothalamic dysfunction that is inter- oral contraceptives may be effective. It is cycles. mittent.38 It is not clear whether this suggested that the episodes of hyper- decline in CSF hypocretin occurs as a somnia are triggered by progesterone, cause or an effect of a KLS episode, or and the instigation of anovulatory cycles even whether it occurs consistently. with oral contraceptive treatment causes Pathology. Because KLS is a rare dis- an inhibitory effect on progesterone order, brain tissue analysis is uncom- secretion, resulting in resolution of symp- mon. No specific abnormalities of the toms. However, this concept is purely hypothalamus have been demonstrated, hypothetic with no conclusive evidence however.39 supporting or refuting it. Treatment. Various treatments In addition to the primary hyper- have been tried in patients with KLS. somnias described above, other causes Only a limited number of patients have of hypersomnia as classified by the demonstrated a major response to treat- ICSD-2 are briefly discussed below. ment with valproic acid, lithium, amantadine, or lamotrigine.35,40Y42 Modafinil BEHAVIORALLY INDUCED has been tried and showed a decrease INSUFFICIENT SLEEP SYNDROME in the duration of the episodes but had Classified under the category of hyper- no effect on recurrence. Since the con- somnia of central origin, this cause of dition is intermittent, the clinician has hypersomnia occurs as a result of sleep to be careful before reporting a certain deprivation and is most commonly seen treatment option successful, as it may among adolescents. It usually does not in reality only coincide with the end of need intense investigation because the an episode. history of sleep deprivation and of patients catching up on their sleep on MENSTRUAL-RELATED weekends makes the diagnosis obvious. HYPERSOMNIA If a sleep study is done, it will show a Menstrual-related hypersomnia is a short sleep-onset latency and high sleep very rare condition. Women with this efficiency and may occasionally also disorder experience episodes of recur- reveal a SOREMP. Sleep deprivation rent sleepiness coinciding with their may be a result of social or work-related menstrual cycles. A diagnostic crite- factors, and patients may report neu- rion, similar to one recommended for rocognitive impairment as a result of KLS, has been put forth in the ICSD-2 insufficient sleep time. Stimulant med- (Table 4-9). A review by Billiard and ications are not recommended, since colleagues43 compared occurrence of behavioral modifications are sufficient this disorder with other forms of to treat this condition. recurrent hypersomnias, such as KLS, in women and found that the onset of HYPERSOMNIA DUE TO hypersomnia may occur at menarche, OTHER CAUSES during menstruation alone, or during Metabolic syndromes, toxic or infec- menstruation in conjunction with other tious disease processes, and drugs may factors such as alcohol use or a bout of cause hypersomnia by depressing CNS influenza. This review also noted the alerting centers. Traumatic brain injury

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT (TBI) and neurodegenerative processes conducting an orchestra. The patient becomes h excited, has loss of muscle tone with unbuck- Posttraumatic that directly affect the CNS are also hypersomnia is known to cause hypersomnia. When ling of the knees, and falls to the ground. Consciousness is preserved completely, and he prevalent and often evaluating a patient with hypersomnia, never loses awareness. He recovers quickly, missed as a cause the history of medical conditions, such regaining his muscle strength and standing up of unexplained as Niemann-Pick type C disease, Prader- as if he never experienced the episode. hypersomnia. Willi syndrome, myotonic dystrophy, links.lww.com/CONT/A16 Parkinson disease, cervical spine or B 2013 Geert Mayer, MD, PhD. Used with whiplash injury, and TBI, should either permission. be specifically asked for or investigated, Supplemental Digital Content 4-2 as deemed necessary. Posttraumatic REM sleep behavior disorder in a child. Video hypersomnia is prevalent and often demonstrates REM sleep behavior disorder missed as a cause of unexplained hyper- (RBD) in a child. RBD in children is narcolepsy somnia. Other causes include multiple unless proven otherwise. Although the electro- sclerosis, vascular disorders, and ence- graphic recordings are blurry, the video shows phalitis. Patients with EDS and symp- the patient exhibiting dream enactment behavior with loss of muscle tone during REM sleep. Pa- toms of neuromyelitis optica who are tients with RBD require in-depth review and positive for antiYaquaporin 4 antibody assessment for CNS hypersomnia, which is also a (AQP4) have also been reported, sug- manifestation of anomalous REM sleep control. gesting an immunologic attack to AQP4 links.lww.com/CONT/A17 resulting in damage to hypocretin- B 2013 Sonˇ a Nevsˇı´malova´ , MD, DSc. Used with secreting neurons and the develop- permission. ment of secondary narcolepsy. Reports Supplemental Digital Content 4-3 of moderately decreased hypocretin Child cataplexy. Video demonstrates laughter- levels in patients with secondary narco- induced cataplexy in a child. This child has the lepsy exist in the literature. There are hypocretin gene defect leading to narcolepsy also reports of improvement in symp- with cataplexy. He is dancing and playing, and toms of hypersomnia in secondary children are laughing in the background, narcolepsy with improvement in the which leads him to become excited and lose muscle tone in the legs. While the condition is causative neurologic disorder and con- exclusively genetically based in animals, it is not comitant improvement in hypocretin the case in humans, and was not the case in this levels. In addition to medical causes, a patient. complete list of all current medications links.lww.com/CONT/A18 should be reviewed, since a simple mea- B 2013 Sonˇ a Nevsˇı´malova´ , MD, DSc. Used with sure of discontinuing a medication known permission. to cause hypersomnia may be sufficient to treat the patient effectively. The use of REFERENCES over-the-counter medication and illicit 1. National Sleep Foundation. How much sleep drug use must be elicited. When the cause do we really need? www.sleepfoundation. of hypersomnia cannot be explained on org/article/how-sleep-works/how-much- sleep-do-we-really-need. Accessed the basis of an underlying medical con- December 5, 2012. dition, medication, or drug use, the pos- 2. American Academy of Sleep Medicine. sibility of a psychiatric disorder should International classification of sleep be considered and investigated. disorders, second edition: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005. VIDEO LEGENDS 3. Schenck CH, Bassetti CL, Arnulf I, Mignot E. Supplemental Digital Content 4-1 English translations of the first clinical Adult cataplexy. Video demonstrates cataplexy reports on narcolepsy and cataplexy by elicited by the strong emotional stimulus of Westphal and Ge´lineau in the late 19th

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