Narcolepsy and Other Central Hypersomnias

Home , Cataplexy, Narcolepsy, Sleepwalking

Review Article

Address correspondence to Dr Yves Dauvilliers, Centre Narcolepsy and Other National de Re´fe´rence Narcolepsie Hypersomnies, INSERM U1061, De´partement Central Hypersomnias de Neurologie, CHRU Gui de Chauliac, 80 avenue Augustin Fliche, 34295 Montpellier Yves Dauvilliers, MD, PhD; Lucie Barateau, MD Cedex 5, France, [email protected]. Relationship Disclosure: ABSTRACT Dr Dauvilliers has received personal compensation for Purpose of Review: This article focuses on the clinical presentation, pathophys- speaking engagements and iology, diagnosis, differential diagnosis, and management of narcolepsy type 1 and travel expenses, served as narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, and other consultant for, and received research/grant support central disorders of hypersomnolence, as defined in the International Classification from Bioprojet Pharma, of Sleep Disorders, Third Edition (ICSD-3). Flamel Technologies, Jazz Recent Findings: In ICSD-3, the names of some central disorders of hypersomnolence Pharmaceuticals, Theranexus, and UCB SA. Dr Dauvilliers have been changed: narcolepsy with cataplexy and narcolepsy without cataplexy have serves as specialty chief been renamed narcolepsy type 1 and narcolepsy type 2, respectively. A low level of editor of the Sleep and hypocretin-1/orexin-A in the CSF is now theoretically sufficient to diagnose narcolepsy Chronobiology section of Frontiers in Neurology. type 1, as it is a highly specific and sensitive biomarker. Conversely, other central Dr Barateau has received hypersomnias are less well-defined disorders with variability in the phenotype, and few reimbursement for travel reliable biomarkers have been discovered so far. The epidemiologic observation that expenses from Laidet Me´dical and has received personal influenza A (H1N1) infection and vaccination are potential triggering factors of compensation as a speaker narcolepsy type 1 (discovered during the 2009 H1N1 pandemic) has increased interest for UCB SA. in this rare disease, and progress is being made to better understand the process Unlabeled Use of (highly suspected to be autoimmune) responsible for the destruction of hypocretin Products/Investigational Use Disclosure: neurons. Treatment of narcolepsy remains largely symptomatic, usually initially with Drs Dauvilliers and Barateau modafinil or armodafinil or with higher-potency stimulants such as methylphenidate or report no disclosures. amphetamines. Several newer wake-promoting agents and psychostimulants have * 2017 American Academy also been developed, including sodium oxybate, which has a role in the treatment of of Neurology. cataplexy and as an adjunctive wake-promoting agent, and pitolisant, a selective histamine H3 receptor inverse agonist that is currently only available in Europe. Summary: Although far less common than many other sleep disorders, central hypersomnias are among the most severe and disabling diseases in the field of sleep medicine, and their early recognition is of major importance for patients, especially children, to maximize their quality of life and functioning in activities of daily living.

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INTRODUCTION hypersomnias has improved consider- Excessive daytime sleepiness is the ably over the past 2 decades because most common presenting symptom of of the integration of data from human rare sleep diseases, the hypersomnia and animal models. The diagnostic disorders of central origin. These in- workup includes medical history, sleep clude narcolepsy type 1 and narcolepsy logs, and polysomnography, followed type 2, idiopathic hypersomnia, Kleine- by the multiple sleep latency test in Levin syndrome, and other hyper- most patients and, in some, additional somnias (eg, due to a medical disorder evaluation with actigraphy, human leu- or substance or associated with psychi- kocyte antigen (HLA) genotyping, and atric disorders). Our understanding CSF examination for hypocretin. The of the pathophysiology of central current management of hypersomnias of

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KEY POINT h Narcolepsy type 1 is a central origin remains symptomatic, and conversation, writing something inap- well-defined entity good evidence for treatment (Level A) propriate or illegible, or doing an characterized by currently exists only for narcolepsy. This activity such as driving to an inappro- excessive daytime article reviews the clinical features, priate location with no memory of the sleepiness and pathophysiology, diagnostic criteria, event) can be seen. cataplexy, whereas and treatment options for narcolepsy Cataplexy is the pathognomonic narcolepsy type 2 is a and other primary hypersomnias. symptom of narcolepsy type 1, de- syndrome of sleepiness fined by a loss of muscle tone in full without cataplexy and NARCOLEPSY TYPE 1 AND consciousness triggered by emotions, is a considerably less TYPE 2 particularly positive ones such as specific and more Narcolepsy is classified into two dis- laughter or surprise (Case 3-1).5 Cat- heterogeneous syndrome. tinct disorders according to the In- aplexy can either be generalized and ternational Classification of Sleep lead to falls or partial, with lower limb Disorders, Third Edition (ICSD-3): collapse, head dropping, or dysarthria. narcolepsy type 1, formerly called Muscle stretch reflexes are abolished narcolepsy with cataplexy, and nar- during generalized cataplexy, since colepsy type 2.1 Narcolepsy type 1 the pathophysiology of cataplexy affects about 1 in 2000 people in the seems mediated by an intrusion of world, with a bimodal age at onset, physiologic rapid eye movement usually between 15 and 35 years of (REM) sleep atonia into wakefulness, age.2 The prevalence of narcolepsy thereby interrupting conscious volun- type 2 remains unclear, as this disorder tary motor activity and waking muscle is more heterogeneous, with an un- tone. Cataplectic attacks can be dif- known pathophysiologic mechanism.3,4 ferent in children. Sometimes they appear without a specific triggering Clinical Features factor; they can also arise in anticipa- Excessive daytime sleepiness is the tion of a strong emotion to come and major and most frequent initial symp- sometimes even during movement. Chil- tom of narcolepsy. Excessive daytime dren can also present with cataplectic sleepiness arises preferentially in mo- facial expressions, such as generalized notonous situations or during periods face hypotonia, abnormal movements, of relative inactivity. Typically, naps and tongue protrusion.6 Clinical signs are short and considered to be re- and biological markers that should freshing by patients, who may also make the physician reconsider the recall the experience of dream activity diagnosis of supposed cataplectic at- just after falling asleep. Similarly, noc- tacks are listed in Table 3-1. turnal sleep is usually considered Other symptoms are often asso- refreshing, and morning waking is ciated with narcolepsy, but they are usually not difficult. In children, the not specific to the condition. Sleep phenotype can be slightly different: paralysis is a transient paralysis lasting naps are inconsistently refreshing, pa- a few seconds or minutes while falling tients sometimes fight against sleepi- asleep or upon awakening. Hypna- ness and do not fall sleep, and they gogic (ie, while falling asleep) and may present with hyperactive behav- hypnopompic (ie, upon awakening) ioral symptoms that can mimic atten- hallucinations can occur at the same tion deficit hyperactivity disorder. time as the paralysis and can be very During episodes of sleepiness, auto- frightening. These symptoms are also matic activities (ie, saying something reported in the general population but inappropriate or out of context in a are more frequent and severe in

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 3-1 An 18-year-old man presented with a 2-year history of severe excessive daytime sleepiness that began a few months after a vaccination for influenza A (H1N1). He had to repeat a school year because of the excessive daytime sleepiness. He was overweight and had frequent sleep paralysis and nightmares. Six months after the onset of excessive daytime sleepiness, he developed episodes of weakness in his limbs and neck triggered by various emotional stimuli, especially when he laughed with his brother. The frequency was variable, from several episodes per day to several per week, depending on exposure to the stimuli. His brother had made a cell phone video that the neurologist was able to view, which led to the diagnosis of typical cataplectic attacks. After reviewing the patient’s sleep diary to ensure he was getting adequate nocturnal sleep, polysomnography was performed, followed by a multiple sleep latency test that showed fragmented sleep with no apnea, short sleep latency (2 minutes), and four sleep-onset rapid eye movement (REM) periods, confirming a clear-cut diagnosis of narcolepsy type 1. Human leukocyte antigen genotyping was positive for the DQB1*0602 allele, and CSF hypocretin-1 levels in the CSF were undetectable (less than 10 pg/mL). A modafinil treatment trial was started, with the dosage gradually increased to 200 mg in the morning and 200 mg at noon. Anticataplectic treatment (venlafaxine 37.5 mg/d) was introduced a few weeks later, with excellent efficacy. Comment. In this case, the patient’s cataplectic attacks were typical, but sometimes the recognition of this pathognomonic symptom can be more difficult. Identification of cataplexy during consultation or hospitalization or video recorded by relatives helps determine if the phenotype is typical or atypical. The first-line option for excessive daytime sleepiness should be modafinil (doses from 100 mg/d to 400 mg/d). Once adequate improvement of excessive daytime sleepiness is obtained, the cataplexy severity is evaluated and treatment started, if needed. The management of excessive daytime sleepiness alone sometimes improves cataplexy. This case also illustrates the burden of narcolepsy and the impact of a delayed diagnosis on scholastic performance. patients with narcolepsy. Nighttime of children with narcolepsy are sleep is altered and fragmented, with obese). Children may also experience multiple nocturnal arousals and some- precocious puberty. times significant sleep maintenance Narcolepsy type 1 is a chronic insomnia. REM sleep behavior disor- disease with an often stable clinical der, a parasomnia characterized by a course. The severity of cataplexy and loss of normal skeletal muscle atonia sleepiness may improve with age, during REM sleep, has an increased whereas nighttime sleep may worsen. frequency in narcolepsy type 1, lead- In contrast, the clinical course of ing to abnormal behaviors and dream narcolepsy type 2 remains unclear. enactment. An increase in weight is Some patients may later develop cat- frequent at disease onset, especially aplexy and be reclassified as having in children (30% of all patients with narcolepsy type 1; other patients with narcolepsy are obese, and up to 50% narcolepsy type 2 may have a chronic

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KEY POINT h Pathophysiologic studies TABLE 3-1 Clinical Signs and Biological Markers of Typical Cataplexy have shown that and Atypical Attacks Suggesting an Alternative Diagnosis narcolepsy type 1 is caused by the early b Typical Cataplexy loss of neurons in Clinical signs the hypothalamus Clear positive emotional trigger (eg, laughter, telling a joke, surprise) that produce hypocretin/orexin. Frequent attacks (multiple times per day or week) Brief duration (seconds to 1Y2 minutes) Consciousness preserved Generalized or segmental (face, head/neck, knee dropping/buckling with or without falling) Biological markers Presence of HLA DQB1*0602 allele Low hypocretin-1 levels in the CSF (G110 ng/L) b Atypical Attacksa Clinical signs Rarity of attacks (G1/year) Nonrecurrence despite the absence of treatment Long lasting (92 minutes) Alteration of consciousness Unilateral or asymmetric localization Affecting only the upper limbs (not the face, neck, or lower limbs) No association with emotional triggers (except in children) Relatives and people nearby do not notice the episodes Only triggered by negative stimuli and emotion (eg, anger, fear, stress) Prodromal symptoms or occurrence of symptoms after the episode of any kind (eg, warm feeling, sweat, dizziness, tinnitus, visual and auditory impairment, nausea, tingling sensation in the extremities) Biological markers Absence of HLA DQB1*0602 allele Normal hypocretin-1 levels in the CSF (9200 ng/L)

CSF = cerebrospinal fluid; HLA = human leukocyte antigen. a These clinical signs and biomarkers suggest an alternative diagnosis.

stable condition. In approximately peptides.8 Hypocretin-1/orexin-A and one-half of patients with narcolepsy hypocretin-2/orexin-B are neurotrans- type 2, excessive daytime sleepiness mitters that were discovered 20 years may improve spontaneously, without ago.9,10 Several genetic animal models the persistent neurophysiologic hall- of the disease exist, as across species marks of narcolepsy.7 (in both mice and dogs), disrupted hypocretin signaling leads to a nar- Pathophysiology coleptic phenotype with excessive Narcolepsy type 1 is caused by a daytime sleepiness and cataplexy.11 selective loss of a small population of Recently, hypocretin neurons were neurons in the lateral hypothala- shown to be particularly susceptible mus that synthesize hypocretin neuro- to influenza A (H1N1) viral infection in

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS mice lacking B and T cells, and sleep and project to brain regions that h The etiology of hypocretin neurons were destroyed regulate metabolism, motivated be- narcolepsy type 1 is after injection of autoreactive cyto- haviors such as reward seeking, and not yet completely + toxic CD8 T cells in transgenic mice the autonomic system. In narcolepsy, understood, but an expressing influenza virus protein hem- the loss of hypocretin signaling re- autoimmune process is agglutinin in the hypocretin cells.12,13 In sults in excessive daytime sleepiness, highly suspected, with a some cases, narcolepsy type 2 may be dysregulation of REM sleep, and obe- role of genetic (human caused by a less extensive loss of these sity in many patients, but with a large leukocyte antigen neurons, but this disorder is probably intervariability in symptom frequency DQB1*0602 allele) heterogeneous, and knowledge about and intensity. During cataplexy, posi- and environmental its pathophysiology is still limited. tive emotions relayed through the (influenza A vaccination) factors. An autoimmune process probably amygdala and medial prefrontal cortex mediates the selective destruction of probably activate circuits in the dorsal h Narcolepsy type 1 is hypothalamic hypocretin neurons in pons responsible for muscle weakness associated with a narcolepsy type 1. This hypothesis is in the absence of hypocretin, includ- wide range of sleep abnormalities and supported by many epidemiologic and ing the sublateral dorsal nucleus. metabolic, cardiovascular, clinical findings: rare family cases, autonomic, and Diagnosis frequent discordance in monozygotic psychiatric consequences, 1 twins, young and bimodal age at In ICSD-3, narcolepsy type 1 is defined in which the direct role onset, and a strong association with as the presence of excessive daytime of the hypocretin system the 2009 H1N1 influenza pandemic sleepiness for more than 3 months, remains to be defined. and its vaccine (Case 3-1) and with associated with either (1) the presence streptococcal infections. However, no of cataplexy, a mean sleep latency of specific antibodies against hypocretin 8 minutes or fewer on the multiple neurons have yet been discovered, sleep latency test, and at least two possibly because of very small amounts sleep-onset REM periods during the of antibodies or due to a specific T-cell multiple sleep latency test or polysom- activation. Genetic background is of nography or (2) a hypocretin-1 level major importance, as more than 98% of 110 pg/mL or less in the CSF, which of patients with narcolepsy type 1 carry is a highly specific biological measure. the HLA class II HLA-DQB1*0602 Narcolepsy type 2 is defined by the allele,14 compared to only 12% to presence of excessive daytime sleepi- 30% of the general population. More ness without cataplexy for longer than recently, the role of HLA class I15 3 months, with a mean sleep latency of and other immune gene variants, such 8 minutes or fewer on the multiple as the purinergic receptor P2RY11 sleep latency test, at least 2 sleep-onset and T-cell receptor alpha locus TRA, REM periods on the multiple sleep was revealed. latency test or polysomnography, and Hypocretin neurons are normally a hypocretin-1 level of higher than active during wakefulness and func- 110 pg/mL, if measured. Excessive day- tion to stimulate other neurons in time sleepiness must not be better the cerebral cortex, basal forebrain, explained by another cause, such as sleep brainstem, and hypothalamus, produc- deprivation, obstructive sleep apnea syn- ing norepinephrine, dopamine, sero- drome, circadian rhythm disorders, or tonin, and histamine, which allow the the effect of a medication or substance maintenance of wakefulness through abuse. If cataplexy appears over time, the day.16 Hypocretin neurons also or if a hypocretin-1 measurement of increase activity in the lateral pon- 110 pg/mL or less is found, the condi- tine tegmentum that suppresses REM tion is reclassified as narcolepsy type 1.

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KEY POINT h Treatment of narcolepsy Narcolepsy type 1 is a chronic amphetamines should have ECG mon- is symptomatic disease requiring lifelong treatment, itoring to evaluate for QTc prolongation and focuses on as the destruction of hypocretin neu- when target dosages are reached. improving sleepiness rons is irreversible. On the other Sodium oxybate is the only medi- and cataplexy. hand, narcolepsy type 2 has a variable cation approved for both sleepiness phenotype and evolution, with im- and cataplexy in adults. Specific anti- provement or even disappearance of cataplectic treatment should depend the symptoms, the development of on the severity of this symptom, as cataplexy, or a change in the pheno- mild cataplexy frequently improves type to idiopathic hypersomnia (refer with increased alertness following the to the section on clinical features of initiation of wake-promoting therapies. idiopathic hypersomnia). Antidepressants (selective serotonin reuptake inhibitors [SSRIs] and seroto- Treatment Options nin norepinephrine reuptake inhibitors Narcolepsy treatment is symptomatic [SNRIs]) are commonly used for cata- and varies from a single drug targeting plexy based on expert consensus since several symptoms to multiple drugs to no controlled trial evidence exists for address different symptoms.17 Recent this use. An algorithm for the manage- clinical trials and practice guidelines ment of the main symptoms of narco- have confirmed that stimulants such lepsy type 1 is presented in Figure 3-1. as modafinil, armodafinil, or sodium A list of common comorbidities and oxybate (as first line); methylpheni- signs associated with narcolepsy type 1 date and pitolisant (as second line and strategies for managing them are [pitolisant is currently only available in presented in Table 3-2. Europe]); and amphetamines (as third Medications and guidelines for ex- line) are appropriate medications for excessive daytime sleepiness in narco- cessive daytime sleepiness.17 Women lepsy type 2 should be the same of childbearing potential receiving as for narcolepsy type 1. However, modafinil or armodafinil should be the treatment and phenotype should forewarned about the potential for be regularly reassessed because of reduced efficacy of hormonal contra- the variability of the narcolepsy type 2 ceptives while receiving these drugs, phenotype and the possible evolution which induce hepatic cytochrome sys- toward a normal condition. tems and reduce serum concentra- Good sleep hygiene is also rec- tions of estrogenic drugs, possibly ommended, including avoiding sleep leading to increased risk of contracep- deprivation, maintaining a regular night- tive failure and unintended pregnancy. time sleep schedule, and scheduling Use of barrier contraceptives, increased short naps. As most of the symptoms in dose of hormonal contraceptives, or narcolepsy type 1 are directly explained an alternative noninducing psycho- by hypocretin deficiency, hypocretin stimulant such as methylphenidate replacement could be an ideal specific should be considered. Typical psychotherapy for narcolepsy type 1, but the stimulant adverse effects include tremor, development of a clinical formulation is palpitations, and jitteriness. Patients limited by the impermeability of the receiving psychostimulants should blood-brain barrier to this large neuro- also be instructed to carefully monitor peptide. Immune-based therapies, ad- their blood pressure to avoid the ministered very close to disease onset, development of hypertension, and could modify the natural history and the those receiving methylphenidate or clinical course of the disease, although

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 3-1 Decision tree for managing excessive daytime sleepiness and cataplexy in narcolepsy type 1.

EDS = excessive daytime sleepiness; IR = immediate release; XR = extended release. a Pitolisant is currently only available in European Union countries. Modified with permission from Barateau L, et al, CNS Drugs.17 B 2016 Springer International Publishing. link.springer.com/article/10.1007%2Fs40263-016-0337-4.

TABLE 3-2 Management of Symptoms and Comorbidities in Narcolepsy Type 1a

Symptoms and Comorbidities Management Strategies Disturbed nighttime sleep Sodium oxybate; regular sleep-wake schedule; avoid long naps late in the day; avoid psychostimulant intake during the afternoon; hypnotic medications may be considered Sleep paralysis/hypnagogic Sodium oxybate, antidepressants and hypnopompic (eg, venlafaxine, fluoxetine); provide hallucinations information, education, and reassurance Unpleasant dreams/ Antidepressants; cognitive-behavioral therapy recurrent nightmares Continued on page 996

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TABLE 3-2 Management of Symptoms and Comorbidities in Narcolepsy Type 1a Continued from page 995

Symptoms and Comorbidities Management Strategies Neuropsychiatric disorders Mood disorders/ Antidepressants; psychotherapy; avoid sodium anxiety disorders oxybate if possible Psychotic symptoms Consider antipsychotic drugs such as aripiprazole; use psychostimulants with caution (except pitolisantb, which is a new psychostimulant without dopaminergic activity, thus without any deleterious impact suspected on positive psychotic symptoms) Attention deficit Methylphenidate; psychotherapy hyperactivity disorder Cardiovascular and metabolic disorders Overweight/obesity Sodium oxybate, most psychostimulants; dietary measures and exercise; avoid tricyclic antidepressants; prescribe antidepressants at minimal doses Type 2 diabetes mellitus Sodium oxybate, most psychostimulants; dietary measures and exercise; avoid tricyclic antidepressants; prescribe antidepressants at minimal doses Obstructive sleep Continuous positive airway pressure; loss of apnea syndrome weight; use sodium oxybate with cautionc Cardiovascular diseases Use all psychostimulants with caution (eg, cardiac rhythm (except pitolisantb, which is a good abnormalities, palpitations) alternative in case of cardiovascular disorder) Other sleep disorders Rapid eye movement (REM) Melatonin, clonazepam, possibly sodium oxybate sleep behavior disorder (RBD) (if already indicated for cataplexy or excessive daytime sleepiness symptoms); antidepressants can worsen RBD and should be avoided or given at minimal doses if RBD is severe Non-REMYrelated parasomnias Clonazepam; avoid sodium oxybate when possible (eg, sleepwalking, sleep terrors, enuresis) Restless legs syndrome (RLS), Sodium oxybate and antidepressants may worsen periodic leg movements RLS and periodic leg movements and should be avoided or given at minimal doses if RLS is severe; check ferritin/transferrin saturation percentage to exclude iron deficiency; sometimes specific treatment of RLS is required a Managing excessive daytime sleepiness and cataplexy should be a clinician’s priority because they are often the most severe and disabling symptoms. This table provides management strategies for other symptoms and comorbidities usually associated with narcolepsy type 1. The medications used for excessive daytime sleepiness and cataplexy can improve some of those comorbidities, but the same medications can also worsen others. In these conditions, the drugs are not necessarily contraindicated, but should be used with caution, at minimal doses if required, and benefit-risk balance should be well assessed. b Pitolisant is currently only available in European Union countries. c Note that sodium oxybate has a sedative effect along with a theoretic risk of hypoventilation, but can also reduce weight and thus improve obstructive sleep apnea syndrome.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS no current evidence exists to guide such Safety and Fitness to Drive in Sleep h All patients with an approach, and future controlled trials Disorders” by Jon Tippin, MD, FAAN, narcolepsy and central will be necessary to determine if immu- FAASM, and Mark Eric Dyken, MD, hypersomnias with 20 nomodulatory approaches could impact FAHA, FAASM, FANA, in this issue uncontrolled sleepiness the natural history or clinical symp- of Continuum. should be warned about tom burden in narcolepsy. Other new the possible risks of psychostimulants are expected to IDIOPATHIC HYPERSOMNIA driving while impaired emerge within the next few years: Idiopathic hypersomnia is another and instructed not to JZP-110 (a phenylalanine derivative with rare central hypersomnia that has drive when drowsy. dopaminergic and noradrenergic activ- been identified more recently than h Idiopathic hypersomnia ity), longer-acting formulations of sodi- narcolepsy type 1 and is probably is another rare central um oxybate, and a combination of even more rare, although no epidemi- hypersomnia that has modafinil with connexin inhibitors are ologic studies are available to date. been identified more currently in development. The sex ratio seems to be in favor of recently than narcolepsy A recent valid, reliable, and informa- women, and the age at onset of the type 1 and is probably even more rare. tive narcolepsy-specific instrument re- disease is often after puberty but ferred to as the Narcolepsy Severity Scale under 30 years old.21 was developed to monitor symptom severity and changes after treatment.18 Clinical Features Physicians can use this brief scale to Two idiopathic hypersomnia pheno- assess narcolepsy type 1 symptom types have been described, one with frequency, severity, and consequences; prolonged nighttime sleep and the to detect changes in symptoms after other without long nighttime sleep.22,23 treatment; and to provide guidance on A pervasive excessive daytime sleepi- whether treatment goals are met. ness characterizes the first form, with a Clinical evidence shows that medi- prolonged nocturnal sleep duration of cations approved for adults are also more than 10 or 11 hours and good- effective in children,19 but specific quality nighttime sleep with few guidelines are still lacking. Several arousals. It is associated with difficul- multicenter clinical trials are currently ties in waking up in the morning, a ongoing in the pediatric narcolepsy symptom known as sleep inertia and type 1 population. defined by reduced vigilance during All patients with narcolepsy and the minutes or hours following arousal central hypersomnias with uncontrolled in the morning or from daytime naps. sleepiness should be warned about the Patients describe an excessive time to possible risks of driving while impaired be fully operational and sometimes and instructed not to drive when describe mental confusion.24 Daytime drowsy. Sleepiness and vigilance under naps are typically long, lasting up to medication can be objectively mea- several hours, and unrefreshing in sured with the maintenance of wakeful- quality. In the form of idiopathic hyper- ness test, which may be important in somnia called idiopathic hypersomnia assessing the capacity to drive. In some without long sleep time, the nighttime cases, medical restriction of driving sleep is of normal quantity and quality privileges may need to be considered, (more than 6 hours and fewer than depending on the severity of excessive 10 hours), without sleep inertia, and daytime sleepiness symptoms and pre- sleepduringthedaytimeisshort vious reported history of near misses or and refreshing. These two phenotypes motor vehicle collisions. For more of idiopathic hypersomnia some- information, refer to the article “Driving times overlap and are pooled as one

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KEY POINT h The etiology of diagnosis in ICSD-3. Hypnagogic hallu- and severity of symptoms, the diagno- idiopathic hypersomnia cinations and sleep paralysis are sis, and management (Case 3-2). is still unknown, but rare in idiopathic hypersomnia, and homeostatic and the workup must exclude the presence Pathophysiology circadian disturbances of cataplexy. Idiopathic hypersomnia is probably a and a deficient Idiopathic hypersomnia is a disorder heterogeneous disease, and this could arousal system have with frequent phenotype variation, and a explain why its physiopathology re- been suggested. continuum may exist between the forms mains largely unknown. No biomarker with and without long sleep time and specific to idiopathic hypersomnia has narcolepsy type 2. Indeed, the presence yet been identified. A circadian or of one sleep-onset REM period is the homeostatic dysregulation or a dis- only different diagnostic criterion be- turbance in brain arousal systems tween narcolepsy type 2 and idiopathic is suspected. A dysfunction of the hypersomnia, and this electrophysio- ,-aminobutyric acidYmediated (GABA- logic biomarker is unstable and some- ergic) signaling pathway was reported times not reproducible. The symptoms in 2012,25 but no active component in of idiopathic hypersomnia can be severe the CSF has been found and no differ- and chronic, but it is also important to ence with other central hypersomnias inform patients that idiopathic hyper- has been shown. Moreover, these re- somnia symptoms disappear over time sults were not replicated in a 2016 in up to 50% of patients. Clinicians study.26 No genetic factor has yet been must regularly reevaluate the presence identified in idiopathic hypersomnia.

Case 3-2 A 25-year-old woman presented with a 1-year history of hypersomnolence, without mood disorders or any comorbid conditions. She slept an average of 11 hours at night and needed a 2-hour nap every afternoon. She lost her job because she was always late, as awakening in the morning and after the nap was extremely difficult, and she had major sleep inertia. Brain MRI was normal. Polysomnography followed by a multiple sleep latency test showed normal sleep at night, with high efficiency (95%) and a mean sleep latency of 7 minutes, without any sleep-onset rapid eye movement (REM) periods. She was diagnosed with idiopathic hypersomnia. Modafinil was started but was not effective for her hypersomnolence and sleep inertia at a maximal dose of 600 mg/d. A second-line therapy, methylphenidate, was introduced; however, it was not well tolerated, with resultant irritability and palpitations. She was lost to follow-up but returned to the clinic 3 years later. She had stopped the medication during her pregnancy and felt no rebound of excessive daytime sleepiness. Polysomnography was again performed and showed normal mean sleep latency on the multiple sleep latency test (15 minutes). The psychostimulant did not need to be renewed. Comment. This case illustrates the difficulty in managing hypersomnolence and sleep inertia symptoms in idiopathic hypersomnia and the variability of the idiopathic hypersomnia phenotype with possible evolution toward a normal condition, which is a relatively common phenomenon in clinical practice. Women of childbearing age must be informed that modafinil could decrease the efficiency of contraceptive agents, so another contraceptive method should be employed.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Diagnosis KEY POINTS the date of onset of every symptom, h The differential The diagnosis of idiopathic hyper- the evolution of excessive daytime diagnosis of idiopathic somnia must be established according sleepiness depending on mood, and hypersomnia must 1 to ICSD-3, with the presence of all of the effect of the treatment of depres- exclude chronic the following criteria: (1) excessive sive symptoms on excessive daytime insufficient sleep daytime sleepiness, irrepressible need sleepiness. An evaluation by a psychia- syndrome, especially in to sleep, or daytime lapses into sleep trist or a therapeutic trial with antide- long sleepers. The for the past 3 months without cata- pressants is sometimes needed before diagnosis of idiopathic plexy; (2) a mean sleep latency on the further investigations are carried out. hypersomnia requires multiple sleep latency test of 8 or fewer the exclusion of other minutes and/or a total sleep time on a Treatment Options sleep, medical, and psychiatric comorbidities. continued 24-hour polysomnography Modafinil is effective in the treatment recording of more than 11 hours, after of excessive daytime sleepiness in h Idiopathic hypersomnia correction of chronic sleep depriva- idiopathic hypersomnia and should be is most frequently tion; (3) no more than one sleep-onset the first-line therapeutic option.27,28 managed with psychostimulants, but REM period on polysomnography Methylphenidate is the second-line 29 evidence for their use in and the multiple sleep latency test. treatment, and amphetamines or idiopathic hypersomnia In ICSD-3, wrist actigraphy and a pitolisant (currently available only in remains poor, and sleep diary over 1 week preceding European Union countries) can be medications are usually polysomnography can be used to proposed when idiopathic hyper- unsatisfactory in demonstrate the prolonged sleep somnia is resistant to modafinil and managing sleep inertia. time and exclude insufficient night- methylphenidate or if those medica- time sleep duration. It is important to tions are not well tolerated. Some confirm the persistence of excessive studies have suggested that sodium daytime sleepiness after a period of oxybate could be effective for excessive sleep extension, and excessive daytime daytime sleepiness and sleep inertia in sleepiness must not be explained more idiopathic hypersomnia.30 However, clearly by another sleep disorder (such systematic studies of the use of sodium as circadian rhythm disturbances), en- oxybate in idiopathic hypersomnia docrine or neurologic disorders (in with a strong methodology are lacking. particular, vascular, tumor-associated, Dextroamphetamine can also be used infectious, or neurodegenerative le- in the case of treatment-resistant idio- sions affecting the arousal circuits), pathic hypersomnia.29 Sleep inertia is psychiatric disorders, or use of drugs difficult to manage, and available med- or sedating medications. ications are still unsatisfactory to re- The most challenging differential duce that symptom. Planned naps are diagnosis is probably major depressive seldom indicated in idiopathic hyper- disorder, as hypersomnolence and somnia, as they are often of long fatigue can be among the first or main duration and not refreshing. It is also symptoms in mood disorders. Fur- important to counsel patients with thermore, patients with idiopathic hy- idiopathic hypersomnia about planning persomnia can present with depressive appropriate school and university symptoms, probably because of disease- schedules that allow for therapeutic related impairment in function and napping, and, if possible, to plan for quality of life. When a patient presents career work that is active and engaging. with depressive symptoms and a sus- Clinicians must also frequently advo- picion of idiopathic hypersomnia, the cate for appropriate school and work- physician should carefully evaluate place accommodation for patients with

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KEY POINTS h idiopathic hypersomnia, and avoiding gions (thalamus, hypothalamus, mesial Kleine-Levin syndrome is 34,35 a recurrent hypersomnia early morning starts to better enable temporal and frontal lobes). The associated with adequate sleep can be beneficial. young age at onset and triggering behavioral, psychological, factors, such as infection, suggest a and cognitive KLEINE-LEVIN SYNDROME possible autoimmune process. The disturbances during Kleine-Levin syndrome is a recurrent hypothesized etiology that is most episodes, with strictly hypersomnia with an estimated preva- likely is a recurrent, transient, multi- normal sleep lence of about 1 to 2 per million that focal encephalopathy.33 and functioning affects young people during the sec- between episodes. ond decade of life, especially young Diagnosis h Diagnostic criteria for men (male to female ratio of 2:1). Diagnostic criteria for Kleine-Levin syn- Kleine-Levin syndrome drome are only clinically defined, with- are only clinically Clinical Features out any reliable biomarker yet identified. defined, and no reliable Kleine-Levin syndrome is character- According to ICSD-3,1 Kleine-Levin syn- biomarker has yet ized by relapsing-remitting episodes drome is diagnosed by the presence of been identified. of severe hypersomnolence associated all the following criteria: with behavioral and psychiatric disturbances, cognitive abnormalities, and & The patient experiences at least hyperphagia or hypersexuality.31,32 two recurrent episodes of The median duration of an episode is excessive daytime sleepiness 10 days, recurring every 1 to 12 months. lasting 2 days to 5 weeks that recur A triggering factor, such as infection or usually more than once a year alcohol intake, is often reported. Dur- and at least every 18 months. ing episodes, patients can sleep for & Between episodes, mood, 16 to 20 hours per 24 hours and are alertness, cognitive function, and irritable if prevented from doing so. behavior are strictly normal. During their wake period, they are & During episodes, the patient has apathetic, confused, and slow in speak- at least one of the following ing and may have variable anterograde symptoms: cognitive dysfunction, amnesia. Derealization is also typical altered perception, eating disorder (dreamlike and altered perception of (anorexia or hyperphagia), or the environment) as are hallucinations disinhibited behavior (such as and delusions. Sleep, cognition, mood, hypersexuality). eating, and sexual behavior are usually & The symptoms are not explained normal between episodes. by another sleep disorder, other medical or psychiatric disorder Pathophysiology (especially bipolar disease), or Kleine-Levin syndrome is likely a het- use of substance or medication. erogeneous disease, with the underly- If performed, 24-hour polysomnog- ing pathophysiology remaining unclear; raphy shows prolonged total sleep time however, some studies suggest recur- during episodes, and CSF cytology and rent primary hypothalamic dysfunction protein are normal.36 However, some mediated by immune mechanisms.33 studies showed that intraepisodic levels Postmortem examinations have re- of CSF hypocretin-1 can be lower than vealed inflammation of the hypothala- interepisodic levels.36 mus, amygdala, temporal lobes, and thalamus. During episodes, functional Treatment Options brain imaging is abnormal, with meta- No medication has clearly demonstrat- bolic changes in several brain re- ed its efficacy in the treatment of

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS Kleine-Levin syndrome, and most Some examples include brain tumors, h The prognosis for practices are based on case reports, residual excessive daytime sleepiness Kleine-Levin syndrome is 31 case series, or open-label trials. in patients with adequately treated generally good, with a Placebo-controlled trials are extremely sleep apnea, genetic disorders such as spontaneous resolution difficult to perform because of the Niemann-Pick disease type C, or hyper- of the symptoms after a rarity of the disease. Symptomatic somnolence secondary to Parkinson median of 14 years. treatments are based on stimulants disease. If criteria for narcolepsy are h Hypersomnia due to a such as modafinil but can induce fulfilled, the diagnosis is narcolepsy type medication or a paradoxical agitation; they are of poor 1 or narcolepsy type 2 due to a medical substance, sleep efficacy since cognitive and behavioral condition. Indeed, on rare occasions, deprivation, or a problems will remain despite improve- narcolepsy can be caused by a broad psychiatric disorder ment in the vigilance state. Moreover, injury of the hypothalamus or of the must always be the spontaneous disappearance of projections of the hypocretin neurons considered in the symptoms after a few days of evolution as a consequence of a cerebral lesion differential diagnosis of leads to difficulties in proper evaluation (tumor, stroke, sarcoidosis, demyelin- narcolepsy type 2 and idiopathic hypersomnia. of the potential benefit of these drugs. ation) or paraneoplastic disorder.39 Prophylactic treatments based on mood Patients with myotonic dystrophy have stabilizers such as lithium37 or anti- a narcolepsy type 2 phenotype in 30% epileptic drugs (valproic acid, carba- of cases.40 mazepine, phenytoin, gabapentin, and The diagnosis of hypersomnia due lamotrigine)38 may be prescribed and to a medication or a substance or to have reportedly been effective to de- stimulant withdrawal should be consid- crease the frequency and duration of ered when daytime sleepiness occurs episodes. The prognosis for Kleine- in the setting of current medication Levin syndrome is generally good, with or substance abuse or withdrawal a spontaneous resolution of the symp- from a wake-promoting medication or toms after a median of 14 years; substance. Indeed, the chronology of therefore, routine pharmacologic man- the onset of excessive daytime sleepi- agement is sometimes not needed, ness needs to be compatible with such especially when episodes are rare or conditions of drug intake or with- lack major social impact. Patients should drawal. Stimulant abuse and the exces- beallowedtorestinasafeandstress- sive daytime sleepiness due to their free environment during an episode. withdrawal is more frequent among adolescents and young adults. OTHER CENTRAL Hypersomnia associated with a psy- HYPERSOMNIAS chiatric disorder is a complex entity In ICSD-3, three other central disor- and subject to controversy. The mean ders of hypersomnolence are also sleep latency on the multiple sleep defined: hypersomnia due to a medi- latency test is fewer than 8 minutes, and cal disorder, hypersomnia due to a the patient also presents with a psy- medication or substance or to stimu- chiatric condition. Hypersomnolence is lant withdrawal, and hypersomnia as- indeed frequent in the context of sociated with a psychiatric disorder.1 mood disorders; however, the sleep In hypersomnia due to a medical latency on multiple sleep latency test disorder, the mean sleep latency on is often normal.41 A challenge for the multiple sleep latency test is fewer sleep specialists and psychiatrists is to than 8 minutes, and excessive daytime differentiate psychiatric hypersom- sleepiness occurs as a consequence of nolence from a central hypersomnia a medical or neurologic condition. disorder with comorbid psychiatric

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symptoms. The current diagnostic markers have not yet been discovered. tools seem to be limited in this It is important for clinicians to recog- combination of conditions, and further nize the manifestations of central research is warranted.42 hypersomnia and to accurately diagnose and efficiently manage excessive DIFFERENTIAL DIAGNOSIS daytime sleepiness to maximize the patient’s quality of life and daily school The differential diagnoses of excessive or work performance and to minimize daytime sleepiness are numerous, and the risk of accidents. the most important and correctable is likely insufficient sleep syndrome. The clinician must carefully establish pa- REFERENCES tients’ sleep time on weekdays and 1. American Academy of Sleep Medicine. weekends by personal or collateral International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of history, sleep logs, or, sometimes, Sleep Medicine, 2014. actigraphy, if needed. Extension of 2. Dauvilliers Y, Montplaisir J, Molinari N, total sleep time during holidays or et al. Age at onset of narcolepsy in two sometimes even on weekends results large populations of patients in France and in resolution of symptoms. In a nor- Quebec. Neurology 2001;57(11):2029Y2033. doi:10.1212/WNL.57.11.2029. mal variant known as a long sleeper, habitual sleep is reported as refresh- 3. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007;369(9560): ing, with normal daytime functioning, 499Y511. doi:10.1016/S0140-6736(07)60237-2. when the subject is allowed to sleep at 4. Scammell TE. Narcolepsy. N Engl J Med least 9 or 10 hours per night, yet such 2015;373(27):2654Y2662. doi:10.1056/ individuals often report sleepiness NEJMra1500587. when they are relatively sleep de- 5. Dauvilliers Y, Siegel JM, Lopez R, et al. prived and sleep less than their sleep CataplexyYclinical aspects, pathophysiology and management strategy. Nat Rev Neurol requirement of 9 or 10 hours or 2014;10(7):386Y395. doi:10.1038/ longer. Shift workers may also present nrneurol.2014.97. with excessive daytime sleepiness, 6. Plazzi G, Pizza F, Palaia V, et al. Complex even mimicking a narcolepsy type 2 movement disorders at disease onset in phenotype.43 It is also important to childhood narcolepsy with cataplexy. Brain 2011;134(pt 12):3477Y3489. doi:10.1093/ rule out other sleep disorders, such as brain/awr244. obstructive sleep apnea or periodic 7. Trotti LM, Staab BA, Rye DB. Test-retest limb movement disorder, or circadian reliability of the multiple sleep latency test disorders (such as delayed sleep-wake in narcolepsy without cataplexy and phase disorder), which can be respon- idiopathic hypersomnia. J Clin Sleep Med Y sible for excessive daytime sleepiness. 2013;9(8):789 795. doi:10.5664/jcsm.2922. 8. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy CONCLUSION and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Central disorders of hypersomnolence Med 2000;6(9):991Y997. doi:10.1038/79690. are rare but disabling diseases, with a 9. de Lecea L, Kilduff TS, Peyron C, et al. The long delay before diagnosis, sometimes hypocretins: hypothalamus-specific peptides reaching several years (a median of with neuroexcitatory activity. Proc Natl Acad 10 years for narcolepsy type 1).44 The Sci U S A 1998;95(1):322Y327. categorization is often difficult for 10. Sakurai T. Roles of orexin/hypocretin in sleep specialists, especially for hy- regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev persomnias outside the spectrum of 2005;9(4):231Y241. doi:10.1016/ narcolepsy type 1, as reliable bio- j.smrv.2004.07.007.

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