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. Continuum (Minneap Minn) 2017;23(4):989–1004. 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 Continuum (Minneap Minn) 2017;23(4):989–1004 ContinuumJournal.com 989 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Narcolepsy and Hypersomnias 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 990 ContinuumJournal.com August 2017 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