Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment

Abstract

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep–wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep–wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.

Key points

  • Narcolepsy is a rare and often disabling hypothalamic disorder that presents with sleep–wake dysregulation (excessive daytime sleepiness (EDS), cataplexy, hallucinations, sleep paralysis and disturbed sleep) and motor, cognitive, psychiatric, metabolic and autonomic disturbances.

  • Narcolepsy arises from the interaction of genetic and environmental factors, which lead to an immune-mediated selective loss or dysfunction of orexin neurons in the lateral hypothalamus.

  • Patients with narcolepsy type 1 have cataplexy and little or no orexin in cerebrospinal fluid; narcolepsy type 2 is a diagnosis of exclusion requiring ancillary tests ruling out other causes of EDS.

  • Several drugs (including modafinil, sodium oxybate, pitolisant, solriamfetol and methylphenidate) improve narcoleptic symptoms in most patients.

  • More research is needed to understand the clinical spectrum of narcolepsy, the exact mechanisms leading to orexin neuronal loss and the value of new treatments, including orexin agonists and immunomodulation.

  • Awareness of narcolepsy, assessments of treatment efficacy, treatment of children or during pregnancy and management of comorbidities are still suboptimal in narcolepsy and require improvement.

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Fig. 1: Excessive daytime sleepiness in a patient with narcolepsy.
Fig. 2: Cataplexy in patients with narcolepsy.
Fig. 3: The multiple-hit model of narcolepsy involves genetic, environmental and triggering factors.

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Acknowledgements

The authors thank the Klaus-Grawe Foundation and the European Sleep Foundation (formerly the Alpine Sleep Summer School) for enabling the Think Tank, which formed the basis of this article. They also thank A. Blank of Inselspital Bern for preparation of the original figures accompanying this article.

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Nature Reviews Neurology thanks M. Honda, G. Plazzi, M. Partinen and other anonymous reviewer(s) for their contribution to the peer review of this work.

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All authors contributed to researching data for the article and discussions of its content. C.L.A.B. and Y.D. prepared the first draft of the manuscript. All authors participated in review and revision of the manuscript before submission.

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Correspondence to Claudio L. A. Bassetti.

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C.L.A.B. declares that he is a member of the advisory boards of Idorsia, Jazz, Takeda and UCB. R.K. and M.T. declare that they are members of the advisory board of UCB. G.J.L. and G.M. declare that they are members of the advisory boards of Bioproject and UCB. T.S. declares that he is a member of the advisory board of Jazz. Y.D. declares that he is a member of the advisory boards of Bioproject, Harmony Biosciences, Idorsia, Jazz, Takeda and UCB. R.L. has received a research grant from GSK. UK declares that he is a member of the advisory boards of AOP Orphan Pharmaceuticals, Bioprojet, Harmony Biosciences, Jazz, and UCB. T.E.S. has received research grant support from Takeda and Merck. T.E.S. declares that he is a member of the advisory board of Avadel, Harmony Biosciences, Idorsia, Jazz and Takeda. The other authors declare no competing interests.

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Bassetti, C.L.A., Adamantidis, A., Burdakov, D. et al. Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol 15, 519–539 (2019). https://doi.org/10.1038/s41582-019-0226-9

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