Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment

Nature Reviews Neurology volume 15, pages 519–539 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Bassetti, C. & Aldrich, M. Narcolepsy. Neurol. Clin. 14, 545–571 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Westphal, C. Eigentümliche mit Einschlafen verbundene Anfälle. Arch. Psychiatr. Nervenkr. 7, 631–635 (1877).

    Google Scholar 

  3. Gélineau, J. B. E. De la narcolepsie [French]. Gaz. Hop. 53–54, 626–637 (1880).

    Google Scholar 

  4. Fischer, F. Epileptoide Schlafzustände [German]. Arch. Psychiatr. Nervenkr. 8, 200–203 (1878).

    Article  Google Scholar 

  5. Henneberg, R. Über genuine Narkolepsie [German]. Neurol. Zbl. 30, 282–290 (1916).

    Google Scholar 

  6. Löwenfeld, L. Über Narkolepsie [German]. Münch. Med. Wochenschr. 49, 1041–1045 (1902).

    Google Scholar 

  7. Redlich, E. Zur Narkolepsiefrage [German]. Monatsschr. Psychiatr. Neurol. 37, 85 (1915).

    Article  Google Scholar 

  8. Redlich, E. Über Narkolepsie [German]. Z. Gesamte Neurol. Psychiatr. 95, 256–270 (1924).

    Article  Google Scholar 

  9. Daniels, L. E. Narcolepsy. Medicine 13, 1–122 (1934).

    Article  Google Scholar 

  10. Yoss, R. E. & Daly, D. D. Criteria for the diagnosis of the narcoleptic syndrome. Mayo Clin. Proc. 32, 320–328 (1957).

    CAS  Google Scholar 

  11. Wilder, J. in Handbuch der Neurologie Vol. 17 (eds Braun, E., Bumke, O. & Förster, O.) 87–141 (Springer, 1935).

  12. Adie, W. J. Idiopathic narcolepsy: a disease sui generis; with remarks on the mechanism of sleep. Brain 49, 257–306 (1926).

    Article  Google Scholar 

  13. Wilson, S. A. The narcolepsies. Brain 51, 63–109 (1928).

    Article  Google Scholar 

  14. Vogel, G. Studies in psychophysiology of dreams III. The dreams of narcolepsy. Arch. Gen. Psychiatry 3, 421–428 (1960).

    Article  CAS  PubMed  Google Scholar 

  15. Honda, Y., Asaka, A., Tanaka, Y. & Juji, T. Discrimination of narcolepsy by using genetic markers and HLA. Sleep Res. 12, 254 (1983).

    Google Scholar 

  16. Juji, T., Satake, M., Honda, Y. & Doi, Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 24, 316–319 (1984).

    Article  CAS  PubMed  Google Scholar 

  17. Nishino, N., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. American Academy of Sleep Medicine. International Classification of Sleep Disorders (ICSD-3) 3rd edn (AASM, 2014).

  19. Juji, T., Matsuki, L., Tokunaga, K., Naohara, K. & Honda, Y. Narcolepsy and HLA in the Japanese. Ann. NY Acad. Sci. 540, 106–114 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Hublin, S. et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann. Neurol. 35, 709–716 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Silber, M. H., Krahn, L. E., Olson, E. J. & Pankratz, V. S. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 25, (197–202 (2002).

    Google Scholar 

  22. Ohayon, M., Priest, R. G., Zulley, J., Smirne, S. & Paiva, T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 58, 1826–1833 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Wilner, A. et al. Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. Hum. Immunol. 21, 15–22 (1988).

    Article  CAS  PubMed  Google Scholar 

  24. al Rajeh, S. et al. A community survey of neurological disorders in Saudi Arabia: the Thugbah study. Neuroepidemiology 12, 164–178 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Jennum, J., Ibsen, R., Petersen, E. R., Knudsen, S. & Kjellberg, J. Health, social and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. Sleep Med. 13, 1086–1093 (2012).

    Article  PubMed  Google Scholar 

  26. Jennum, P., Thorstensen, E. W., Pickering, L., Ibsen, R. & Kjellberg, J. Morbidity and mortality of middle-aged and elderly narcoleptics. Sleep Med. 36, 23–28 (2017).

    Article  PubMed  Google Scholar 

  27. Dauvilliers, Y. et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 57, 2029–2033 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Rocca, F. L., Pizza, F., Ricci, E. & Plazzi, G. Narcolepsy during childhood: an update. Neuropediatrics 46, 181–198 (2015).

    Article  PubMed  Google Scholar 

  29. Yoss, R. & Daly, D. Narcolepsy in children. Pediatrics 25, 1025–1033 (1960).

    CAS  PubMed  Google Scholar 

  30. Challamel, M. J. et al. Narcolepsy in children. Sleep 17, 17–20 (1994).

    Article  Google Scholar 

  31. Guilleminault, C. & Pelayo, R. Narcolepsy in prepubertal children. Ann. Neurol. 43, 135–142 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Pizza, F. et al. Primary progressive narcolepsy type 1: the other side of the coin. Neurology 83, 2189–2190 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Luca, G. et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J. Sleep Res. 22, 482–495 (2013).

    Article  PubMed  Google Scholar 

  34. Sturzenegger, C. & Bassetti, C. L. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J. Sleep Res. 13, 395–406 (2004).

    Article  PubMed  Google Scholar 

  35. van Dijk, J. G., Lammers, G. J. & Blansjaar, B. A. Isolated cataplexy of more than 40 years’ duration. Br. J. Psychiatry 159, 719–721 (1991).

    Article  PubMed  Google Scholar 

  36. Andlauer, O. et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep 35, 1247–1255 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Trotti, L. M., Staab, B. A. & Rye, D. B. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J. Clin. Sleep Med. 9, 789–785 (2013).

    PubMed  PubMed Central  Google Scholar 

  38. Lopez, R. et al. Test-retest reliability of the multiple sleep latency test in central disorders of hypersomnolence. Sleep 40, 164–168 (2017).

    Google Scholar 

  39. Dauvilliers, Y., Abril, B., Mas, E., Michel, F. & Tafti, M. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology 73, 1333–1334 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Symonds, C. P. Narcolepsy as a symptom of encephalitis lethargica. Lancet 173, 1214–1125 (1922).

    Google Scholar 

  41. Mankowski, B. Zur Pathogenese kataplegisches Anfälle bei Narkolepsie (auf Grund eines Falls von Encephalitis epidemica) [German]. Monatschr. Psychiatr. Neurol. 61, 340–349 (1926).

    Article  Google Scholar 

  42. Langdon, N., Welsh, K. I., van Dam, M., Vaughan, R. W. & Parkes, D. Genetic markers in narcolepsy. Lancet 2, 1178–1180 (1984).

    Article  CAS  PubMed  Google Scholar 

  43. Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991–997 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Crocker, A. et al. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65, 1184–1188 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Krahn, L. E. Reevaluating spells initially identified as cataplexy. Sleep Med. 6, 537–542 (2005).

    Article  PubMed  Google Scholar 

  49. Desseilles, M. et al. Neuroimaging insights into the pathophysiology of sleep disorders. Sleep 31, 777–794 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Burgess, C. R. & Scammell, T. E. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J. Neurosci. 32, 12305–12311 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Broughton, R. et al. Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep 9, 205–215 (1986).

    Article  CAS  PubMed  Google Scholar 

  52. Nishino, S. & Kanbayashi, T. Symptomatic narcolepsy, cataplexy, and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med. Rev. 9, 269–310 (2005).

    Article  PubMed  Google Scholar 

  53. Baumann, C. R. et al. Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury. Neurology 65, 147–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Baumann, C. R. et al. Loss of hypocretin (orexin) neurons with trumatic brain injury. Ann. Neurol. 66, 555–559 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Baumann, C. R., Bassetti, C. L., Hersberger, M. & Jung, H. H. Excessive daytime sleepiness in Behçet’s disease with diencephalic lesions and hypocretin dysfunction. Eur. Neurol. 63, 190 (2010).

    Article  PubMed  Google Scholar 

  56. Mignot, E. et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol. 59, 1553–1562 (2002).

    Article  PubMed  Google Scholar 

  57. Bassetti, C. L. Selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies. Neurology 65, 1152–1153 (2005).

    Article  PubMed  Google Scholar 

  58. Latorre, D. et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 562, 63–68 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Lippert, J. et al. Specific T cell activation in peripheral blood and cerebrospinal fluid in central disorders of hypersomnolence. Sleep 42, zsy223 (2019).

    Article  Google Scholar 

  60. Luo, F. et al. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc. Natl Acad. Sci. USA 115, E12323–E12332 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pedersen, N. W. et al. CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nat. Commun. 10, 837 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Thannickal, T. C., Nienhuis, R. & Siegel, J. M. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 32, 993–998 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Valko, P. O. et al. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann. Neurol. 74, 794–804 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Honda, M. et al. Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy. Neurology 18, 511–517 (2009).

    Article  CAS  Google Scholar 

  65. Gerashchenko, D. et al. Relationship between CSF hypocretin levels and hypocretin neuronal loss. Exp. Neurol. 184, 1010–1016 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. John, J. et al. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann. Neurol. 74, 786–793 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Khatami, R. et al. Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway. Lancet 363, 1199–1200 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Dauvilliers, Y. et al. A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1. Neurology 62, 2137–2138 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Hor, H. et al. A missense mutation in myelin oligdendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am. J. Hum. Genet. 89, 474–479 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Degn, M. et al. Rare missense mutations in P2RY11 in narcolepsy with cataplexy. Brain 140, 1657–1668 (2017).

    Article  PubMed  Google Scholar 

  71. Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50, S16–S22 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Dauvilliers, Y. et al. A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q. Ann. Neurol. 56, 382–388 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Mignot, E. et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68, 686–699 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tafti, M. et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 37, 19–25 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Mignot, E., Young, T., Lin, L., Finn, L. & Palta, M. Reduction of REM sleep latency associated with HLA-DQB1*0602 in normal adults. Lancet 351, 727 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Ollila, H. M. et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am. J. Hum. Genet. 96, 136–146 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Han, F. et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLOS Genet. 9, e1003880 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Tafti, M. et al. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep 39, 581–587 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Hor, H. et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat. Genet. 42, 786–789 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Hallmayer, J. et al. Narcolepsy is strongly associated with the T cell receptor alpha locus. Nat. Genet. 41, 708–711 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Faraco, J. et al. Immunochip study implicates antigen presentation to T cells in narcolepsy. PLOS Genet. 9, e1003270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kornum, B. R. et al. Common variants in P2RY11 are associated with narcolepsy. Nat. Genet. 43, 66–71 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Singh, A. K., Mahlios, J. & Mignot, E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J. Autoimmun. 43, 26–31 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shimada, M., Miyagawa, T., Toyoda, H., Tokunaga, K. & Honda, M. Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach. Sleep 41, zsy019 (2018).

    Article  Google Scholar 

  85. Imlah, N. W. Narcolepsy in identical twins. J. Neurol. Neurosurg. Psychiatry 24, 158–160 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pollmächer, T. et al. DR2-positive monozygotic twins discordant for narcolepsy. Sleep 13, 336–343 (1990).

    Article  PubMed  Google Scholar 

  87. Partinen, M., Hublin, C., Kaprio, J., Koskenvuo, M. & Guilleminault, C. Twin studies in narcolepsy. Sleep 17, S13–S16 (1994).

    Article  CAS  PubMed  Google Scholar 

  88. Dahmen, N. & Tonn, P. Season of birth effect in narcolepsy. Neurology 61, 1016–1017 (2003).

    Article  PubMed  Google Scholar 

  89. Dauvilliers, Y. et al. Month of birth as a risk factor for narcolepsy. Sleep 26, 663–665 (2003).

    Article  PubMed  Google Scholar 

  90. Picchioni, D., Mignot, E. & Harsh, J. R. The month-of-birth pattern in narcolepsy is moderated by cataplexy severity and may be independent of HLA-DQB1*0602. Sleep 27, 1471–1475 (2004).

    Article  PubMed  Google Scholar 

  91. Donjacour, C. E., Fronczek, R., Le Cessie, Lammers, S., G. J. & Van Dijk, J. G. Month of birth is not a risk factor for narcolepsy with cataplexy in the Netherlands. J. Sleep Res. 20, 522–525 (2011).

    Article  PubMed  Google Scholar 

  92. von Economo, C. Sleep as a problem of localization. J. Nerv. Ment. Dis. 71, 249–259 (1930).

    Article  Google Scholar 

  93. Aran, A. et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32, 979–993 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Partinen, M. et al. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 13, 600–613 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Dauvilliers, Y. et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 136, 2486–2496 (2013).

    Article  PubMed  Google Scholar 

  96. Ahmed, S. S. et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl Med. 7, 294ra105 (2015).

    Article  PubMed  CAS  Google Scholar 

  97. Saariaho, A. H. et al. Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus. J. Autoimmun. 63, 68–75 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Han, F., Lin, L., Li, J., Dong, X. S. & Mignot, E. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann. Neurol. 73, 560 (2013).

    Article  PubMed  Google Scholar 

  99. Sarkanen, T., Alakuijala, A., Julkunen, I. & Partinen, M. Narcolepsy associated with Pandemrix vaccine. Curr. Neurol. Neurosci. Rep. 18, 43 (2018).

    Article  PubMed  CAS  Google Scholar 

  100. Heyck, H. & Hess, R. Some results of clinical studies on narcolepsy. Schweiz. Arch. Neurol. Psychiatr. 75, 401–402 (1955).

    CAS  PubMed  Google Scholar 

  101. Hidalgo, H., Kallweit, U., Mathis, J. & Bassetti, C. L. Post Tick-borne encephalitis virus vaccination narcolepsy with cataplexy. Sleep 39, 1811–1814 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Lankford, D. A., Wellmann, J. J. & O’Hara, C. Posttraumatic narcolepsy in mild to moderate closed head injury. Sleep 17, S25–S28 (1994).

    Article  CAS  PubMed  Google Scholar 

  103. Silber, M. H. Narcolepsy, head injury, and the problem of causality. J. Clin. Sleep Med. 1, 157–158 (2005).

    PubMed  Google Scholar 

  104. Cvetikovic-Lopes, V. et al. Elevated Tribbles homolog-2-specific antibody levels in narcolepsy patients. J. Clin. Invest. 120, 713–719 (2010).

    Article  CAS  Google Scholar 

  105. Bergman, H. et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc. Natl Acad. Sci. USA 111, E3735–E3744 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kallweit, U. et al. Co-existing narcolepsy (with and without cataplexy) and multiple sclerosis: six new cases and a literature review. J. Neurol. 265, 2071–2078 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Ekbom, K. Familial multiple sclerosis associated with narcolepsy. Arch. Neurol. 15, 337–344 (1966).

    Article  CAS  PubMed  Google Scholar 

  108. Tsutsui, K. et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry 12, 37 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Overeem, S. et al. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 62, 138–140 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Dauvilliers, Y. et al. Hypothalamic immunopathology in anti-Ma–associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol. 70, 1305–1310 (2013).

    PubMed  Google Scholar 

  111. Peraita-Adrados, R. et al. A patient with narcolepsy with cataplexy and multiple sclerosis: two different diseases that may share pathophysiologic mechanisms? Sleep Med. 14, 695–696 (2013).

    Article  PubMed  Google Scholar 

  112. Valko, P. O., Khatami, R., Baumann, C. R. & Bassetti, C. L. No effect of intravenous immunoglobulins in patents with narcolepsy with cataplexy. J. Neurol. 255, 1900–1903 (2008).

    Article  PubMed  Google Scholar 

  113. Chen, W., Black, J., Call, P. & Mignot, E. Late-onset narcolepsy presenting as rapidly progressing muscle weakness: response to plasmapheresis. Ann. Neurol. 58, 489–490 (2005).

    Article  PubMed  Google Scholar 

  114. Lecendreux, M., Maret, S., Bassetti, C., Mouren, M. C. & Tafti, M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J. Sleep Res. 12, 347–348 (2003).

    Article  PubMed  Google Scholar 

  115. Black, J. L. 3rd et al. Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep 28, 427–431 (2005).

    Article  PubMed  Google Scholar 

  116. Tanaka, S., Honda, Y., Inoue, Y. & Honda, M. Detection of autoantibodies against hypocretin, HCRTR1, and HCRTR2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep 29, 633–638 (2006).

    Article  PubMed  Google Scholar 

  117. Giannoccaro, M. P. et al. Antibodies against hypocretin receptor 2 are rare in narcolepsy. Sleep 40, zsw056 (2017).

    Article  Google Scholar 

  118. Langdon, N. et al. Immune factors in narcolepsy. Sleep 9, 143–148 (1986).

    Article  CAS  PubMed  Google Scholar 

  119. Fredrikson, S., Carlander, B., Billiard, M. & Link, H. CSF immune variables in patients with narcolepsy. Acta Neurol. Scand. 81, 253–254 (1990).

    Article  CAS  PubMed  Google Scholar 

  120. Hartmann, F. J. et al. High-dimensional single-cell analysis reveals the immune signature of narcolepsy. J. Exp. Med. 213, 2621–2633 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ramberger, M. et al. CD4+ T cell reactivity to orexin/hypocretin in patients with narcolepsy type 1. Sleep 40, zsw070 (2017).

    Article  Google Scholar 

  122. Lecendreux, M. et al. Impact of cytokine in type 1 narcolepsy: role of pandemic H1N1 vaccination? J. Autoimmun. 60, 20–31 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Lecendreux, M. et al. Narcolepsy type 1 is associated with a systemic increase and activation of regulatory T cells and with a systemic activation of global T cells. PLOS ONE 12, e0169836 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Khatami, R. et al. The European Narcolepsy Network (EU-NN) database. J. Sleep Res. 25, 356–364 (2016).

    Article  PubMed  Google Scholar 

  125. Kornum, B. R. et al. Narcolepsy. Nat. Rev. Dis. Primers 3, 16100 (2017).

    Article  PubMed  Google Scholar 

  126. Guilleminault, C., Philips, R. & Dement, W. C. A syndrome of hypersomnia with automatic behaviour. Electroencephalogr. Clin. Neurophysiol. 38, 403–413 (1975).

    Article  CAS  PubMed  Google Scholar 

  127. Valko, P. O., Bassetti, C. L., Bloch, K. E., Held, U. & Baumann, C. R. Validation of the fatigue severity scale in a Swiss cohort. Sleep 31, 1601–1607 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Droogleever Fortuyn, H. A. et al. Severe fatigue in narcolepsy with cataplexy. J. Sleep Res. 21, 163–169 (2012).

    Article  PubMed  Google Scholar 

  129. Overeem, S. et al. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med. 12, 12–18 (2011).

    Article  PubMed  Google Scholar 

  130. Pizza, F. et al. The distinguishing motor features of cataplexy: a study from video-recorded attacks. Sleep 41, zsy026 (2018).

    Article  Google Scholar 

  131. Serra, L., Montagna, P., Mignot, E., Lugaresi, E. & Plazzi, G. Cataplexy features in childhood narcolepsy. Mov. Disord. 23, 858–865 (2008).

    Article  PubMed  Google Scholar 

  132. Barateau, L. et al. Persistence of deep-tendon reflexes during partial cataplexy. Sleep Med. 45, 80–82 (2018).

    Article  PubMed  Google Scholar 

  133. Antelmi, E., Vandi, S., Pizza, Liguori, F., R. & Plazzi, G. Parkinsonian tremor persisting during cataplexy. Sleep Med. 17, 174–176 (2016).

    Article  CAS  PubMed  Google Scholar 

  134. Poryazova, R., Siccoli, M., Werth, E. & Bassetti, C. L. Unusually prolonged rebound cataplexy after withdrawal of fluoxetine. Neurology 65, 967–968 (2005).

    Article  PubMed  Google Scholar 

  135. Gelb, M. et al. Stability of cataplexy over several months — information for the design of therapeutic trials. Sleep 17, 265–273 (1994).

    Article  CAS  PubMed  Google Scholar 

  136. Rubboli, G. et al. A video-polygraphic analysis of the cataplectic attack. Clin. Neurophysiol. 111, S120–S128 (2000).

    Article  PubMed  Google Scholar 

  137. Plazzi, G. et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain 134, 3477–3489 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Redlich, E. Epilegomena zur Narkolepsie-Frage [German]. Z. Ges. Neurol. Psychiatr. 136, 129–173 (1931).

    Article  Google Scholar 

  139. Roth, B. Narcolepsy and Hypersomnia (Karger, 1980).

  140. Rüther, E., Meier-Ewert, K. & Gallitz, A. Zur Symptomatologie des narkoleptischen syndroms [German]. Nervenarzt 43, 640–643 (1972).

    PubMed  Google Scholar 

  141. Attarian, H. P., Schenck, C. H. & Mahowald, M. W. Presumed REM sleep behavior disorder arising from cataplexy and wakeful dreaming. Sleep Med. 1, 131–133 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Poryazova, R., Khatami, R., Werth, E. & Bassetti, C. L. Weak with sex: sexual intercourse as a trigger for cataplexy. J. Sex. Med. 6, 2271–2277 (2009).

    Article  PubMed  Google Scholar 

  143. Parkes, J. D., Chen, S. Y., Clift, S. J., Dahlitz, M. J. & Dunn, G. The clinical diagnosis of the narcoleptic syndrome. J. Sleep Res. 7, 41–52 (1997).

    Article  Google Scholar 

  144. Vgontzas, A. N., Sollenberger, S. E., Kales, A., Bixler, E. O. & Vela-Bueno, A. Narcolepsy-cataplexy and loss of sphincter control. Postgrad. Med. J. 72, 493–494 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Fortuyn, H. A. et al. Psychotic symptoms in narcolepsy: phenomenology and a comparison with schizophrenia. Gen. Hosp. Psychiatry 31, 146–154 (2009).

    Article  PubMed  Google Scholar 

  146. Wamsley, E., Donjacour, C. E., Scammell, T. E., Lammers, G. J. & Stickgold, R. Delusional confusion of dreaming and reality in narcolepsy. Sleep 37, 419–422 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Roth, T. et al. Disrupted nighttime sleep in narcolepsy. J. Clin. Sleep Med. 9, 955–965 (2013).

    PubMed  PubMed Central  Google Scholar 

  148. Gudden, H. Die physiologische und pathologische Schlaftrunkenheit [German]. Arch. Psychiat. 40, 989–1015 (1905).

    Article  Google Scholar 

  149. Mullington, J. & Broughton, R. Daytime sleep inertia in narcolepsy-cataplexy. Sleep 17, 69–76 (1994).

    CAS  PubMed  Google Scholar 

  150. Broughton, R., Dunham, W., Weisskopf, M. & Rivers, M. Night sleep does not predict day sleep in narcolepsy. Electroencephalogr. Clin. Neurophysiol. 91, 67–70 (1994).

    Article  CAS  PubMed  Google Scholar 

  151. Harsh, J., Peszka, J., Hartwig, G. & Mitler, M. Night-time sleep and daytime sleepiness in narcolepsy. J. Sleep Res. 9, 309–316 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Mayer, G. & Meier-Ewert, K. Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?). J. Sleep Res. 2, 143–148 (1993).

    Article  CAS  PubMed  Google Scholar 

  153. Nevsimalova, S., Prihodova, I., Kemlink, D., Lin, L. & Mignot, E. REM behavior disorder (RBD) can be one of the first symptoms of childhood narcolepsy. Sleep Med. 8, 784–786 (2007).

    Article  PubMed  Google Scholar 

  154. Pizza, F., Tartarotti, S., Poryazova, R., Baumann, C. R. & Bassetti, C. L. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur. Neurol. 70, 22–26 (2013).

    Article  PubMed  Google Scholar 

  155. Knudsen, S., Gammeltoft, S. & Jennum, P. J. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency. Brain 133, 568–579 (2010).

    Article  PubMed  Google Scholar 

  156. Dauvilliers, Y. et al. Periodic leg movements during sleep and wakefulness in narcolepsy. J. Sleep Res. 16, 333–339 (2007).

    Article  PubMed  Google Scholar 

  157. Plazzi, G. et al. Restless legs syndrome is frequent in narcolepsy with cataplexy patients. Sleep 33, 689–694 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Franceschini, C. et al. Motor events during REM sleep in patients with narcolepsy-cataplexy: a video-polysomnographic pilot study. Sleep Med. 12, S59–S63 (2011).

    Article  PubMed  Google Scholar 

  159. Nightingale, S. et al. The association between narcolepsy and REM behavior disorder (RBD). Sleep Med. 6, 253–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Chokroverty, S. Sleep apnea in narcolepsy. Sleep 9, 250–253 (1986).

    Article  CAS  PubMed  Google Scholar 

  161. Sansa, G., Iranzo, A. & Santamaria, J. Obstructive sleep apnea in narcolepsy. Sleep Med. 11, 93–95 (2010).

    Article  PubMed  Google Scholar 

  162. Dodet, P., Chavez, M., Leu-Semenescu, S., Golmard, J. L. & Arnulf, I. Lucid dreaming in narcolepsy. Sleep 38, 487–497 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Rak, M. et al. Increased lucid dreaming frequency in narcolepsy. Sleep 38, 787–792 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Bladin, P. F. Narcolepsy-cataplexy and psychoanalytic theory of sleep and dreams. J. Hist. Neurosci. 9, 203–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Willey, M. M. Sleep as an escape mechanism. Psychoanal. Rev. 11, 181–183 (1924).

    Google Scholar 

  166. Missriegler, A. On the psychogenesis of narcolepsy. J. Nerv. Ment. Dis. 93, 141–162 (1941).

    Article  Google Scholar 

  167. Pai, M. N. Hypersomnia syndromes. Br. Med. J. 1, 522–524 (1950).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Orellana, C. et al. Life events in the year preceding the onset of narcolepsy. Sleep 17, S50–S53 (1994).

    Article  CAS  PubMed  Google Scholar 

  169. Broughton, R. et al. Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can. J. Neurol. Sci. 8, 299–304 (1981).

    Article  CAS  PubMed  Google Scholar 

  170. Roth, B. & Nevsimalova, S. Depression in narcolepsy and hypersomnia. Schweiz. Arch. Neurol. Neurochir. Psychiatr. 116, 291–300 (1975).

    CAS  PubMed  Google Scholar 

  171. Vourdas, A. et al. Narcolepsy and psychopathology: is there an association? Sleep Med. 3, 353–360 (2002).

    Article  CAS  PubMed  Google Scholar 

  172. Ohayon, M. M. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 14, 488–492 (2013).

    Article  PubMed  Google Scholar 

  173. Ruoff, C. M. et al. High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J. Clin. Psychiatry 78, 171–176 (2017).

    Article  PubMed  Google Scholar 

  174. Cohen, A., Mandrekar, J., St Louis, E. K., Silber, M. H. & Kotagal, S. Comorbidities in a community sample of narcolepsy. Sleep Med. 43, 14–18 (2018).

    Article  PubMed  Google Scholar 

  175. Fortuyn, H. A., Mulders, P. C., Renier, Buitelaar, W. O., J. K. & Overeem, S. Narcolepsy and psychiatry: an evolving association of increasing interest. Sleep Med. 12, 714–719 (2011).

    Article  PubMed  Google Scholar 

  176. Rosenthal, C. Über das Auftreten von halluzinatorisch-kataplektischen Angstsyndrom, Wachanfällen und ähnlichen Störungen bei Schizophrenen [German]. Monatschr. Psychiatr. Neurol. 102, 11–38 (1939).

    Article  Google Scholar 

  177. Nissen, C. et al. Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine. J. Sleep Res. 14, 207–208 (2005).

    Article  PubMed  Google Scholar 

  178. Plazzi, G., Khatami, R., Serra, Pizza, L., F. & Bassetti, C. L. Pseudocataplexy in narcolepsy-cataplexy. Sleep Med. 11, 591–594 (2010).

    Article  PubMed  Google Scholar 

  179. Krahn, L. E., Hansen, M. R. & Shepard, J. W. Pseudocataplexy. Psychosomatics 42, 356–358 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Ponz, A. et al. Abnormal activitiy in reward brain circuits in human narcolepsy with cataplexy. Ann. Neurol. 67, 190–200 (2010).

    Article  PubMed  Google Scholar 

  181. Ponz, A. et al. Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann. Neurol. 67, 394–398 (2010).

    Article  PubMed  Google Scholar 

  182. Georgescu, D. et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J. Neurosci. 23, 3106–3111 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Broughton, R. J., Guberman, A. & Roberts, J. Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study. Epilepsia 25, 423–433 (1984).

    Article  CAS  PubMed  Google Scholar 

  184. Ohayon, M. M. et al. Increased mortality in narcolepsy. Sleep 37, 439–444 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Pizza, F. et al. Car crashes and central disorders of hypersomnolence: a French study. PLOS ONE 10, e0129386 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Blackwell, J. E., Alammar, H. A., Weighall, A. R., Kellar, I. & Nash, H. M. A systematic review of cognitive function and psychosocial well-being in school-age children with narcolepsy. Sleep Med. Rev. 34, 82–93 (2017).

    Article  PubMed  Google Scholar 

  187. Szakacs, Z., Hallbook, T., Tideman, P., Darin, N. & Wentz, E. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccnination. Sleep 38, 615–621 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Douglas, N. J. The psychosocial aspects of narcolepsy. Neurology 50, S27–S30 (1998).

    Article  CAS  PubMed  Google Scholar 

  189. Goswami, M. The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 50, S31–S36 (1998).

    Article  CAS  PubMed  Google Scholar 

  190. Oosterloo, M., Lammers, G. J., Overeem, S., de Noord, I. & Kooij, J. J. Possible confusion between primary hypersomnia and adult attention-deficit/hyperactivity disorder. Psychiatry Res. 143, 293–297 (2006).

    Article  PubMed  Google Scholar 

  191. Filardi, M. et al. Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiency. PLOS ONE 12, e0182085 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Naumann, A., Bellebaum, C. & Daum, I. Cognitive deficits in narcolepsy. J. Sleep Res. 15, 329–338 (2006).

    Article  CAS  PubMed  Google Scholar 

  193. Zamarian, L. et al. Subjective deficits of attention, cognition and depression in patients with narcolepsy. Sleep Med. 16, 45–51 (2015).

    Article  PubMed  Google Scholar 

  194. Bayard, S. et al. Executive control of attention in narcolepsy. PLOS ONE 7, e33525 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Jennum, J. et al. Cerebrospinal fluid biomarkers of neurodegeneration are decreased or normal in narcolepsy. Sleep 40, zsw006 (2017).

    Google Scholar 

  196. Economou, N. T., Manconi, M., Ghika, J., Raimondi, M. & Bassetti, C. L. Development of Parkinson and Alzheimer diseases in two cases of narcolepsy-cataplexy. Eur. Neurol. 67, 48–50 (2012).

    Article  PubMed  Google Scholar 

  197. Roberts, H. J. Obesity due to the syndrome of narcolepsy and diabetogenic hyperinsulinism: clinical and therapeutic observations on 252 patients. J. Am. Geriatr. Soc. 15, 721–743 (1967).

    Article  CAS  Google Scholar 

  198. Schuld, A., Hebebrand, J., Geller, F. & Pöllmächer, T. Increased body mass index in patients with narcolepsy. Lancet 355, 1274–1275 (2000).

    Article  CAS  PubMed  Google Scholar 

  199. Kok, S. W. et al. Reduction of plasma leptin levels and loss of its circadian rhythmicity in hypocretin (orexin)-deficient narcoleptic humans. J. Clin. Endocrinol. Metab. 87, 805–809 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Donjacour, C. E. et al. Glucose and fat metabolism in narcolepsy and the effect of sodium oxybate: a hyperinsulinemic-euglycemic clamp study. Sleep 37, 795–801 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Poli, F. et al. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 36, 175–181 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  202. van Holst, R. J. et al. Aberrant food choices after satiation in human orexin-deficient narcolepsy type 1. Sleep 39, 1951–1959 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Nishino, S. et al. Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann. Neurol. 50, 381–388 (2001).

    Article  CAS  PubMed  Google Scholar 

  204. Kok, S. W. et al. Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men. Am. J. Physiol. Endocrinol. Metab. 288, E892–E899 (2005).

    Article  CAS  PubMed  Google Scholar 

  205. Plazzi, G. et al. Autonomic disturbances in narcolepsy. Sleep Med. Rev. 15, 187–196 (2011).

    Article  PubMed  Google Scholar 

  206. Stiasny-Kolster, K. et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128, 126–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  207. Bayard, S. et al. Olfactory dysfunction in narcolepsy with cataplexy. Sleep Med. 11, 876–881 (2010).

    Article  PubMed  Google Scholar 

  208. Black, J. et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 33, 13–18 (2017).

    Article  CAS  PubMed  Google Scholar 

  209. Lecendreux, M. Pediatric narcolepsy: clinical and therapeutical approach. Handb. Clin. Neurol. 112, 839–845 (2013).

    Article  Google Scholar 

  210. Vandi, S. et al. A standardized test to document cataplexy. Sleep Med. 53, 197–204 (2017).

    Article  PubMed  Google Scholar 

  211. Baumann, C. R., Khatami, R., Werth, E. & Bassetti, C. L. Hypocretin (orexin) deficiency predicts severe objective excessive daytime sleepiness in narcolepsy with cataplexy. J. Neurol. Neurosurg. Psychiatry 77, 402–404 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Gerashchenko, D. et al. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J. Neurosci. 21, 7273–7283 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Baumann, C. R. & Bassetti, C. L. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol. 10, 673–682 (2005).

    Article  Google Scholar 

  214. Baumann, C. R., Dauvilliers, Y., Mignot, E. & Bassetti, C. L. Normal CSF hypocretin-1 (orexin-A) levels in dementia with Lewy bodies. Eur. Neurol. 52, 73–76 (2004).

    Article  CAS  PubMed  Google Scholar 

  215. Mayer, G. & Lammers, G. J. The MSLT: more objections than benefits as a diagnostic gold standard? Sleep 37, 1027–1028 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Sakai, N., Matsumura, M., Lin, L., Mignot, E. & Nishino, S. HLPC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy. Sci. Rep. 9, 477 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Mignot, E. et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain 129, 1609–1623 (2006).

    Article  PubMed  Google Scholar 

  218. Goldbart, A. et al. Narcolepsy and predictors of positive MSLTs in the Wisconsin sleep cohort. Sleep 37, 1043–1051 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Zhang, Z. et al. Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning. Sci. Rep. 8, 10628 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Bassetti, C. & Aldrich, M. S. Idiopathic hypersomnia. A series of 42 patients. Brain 120, 1423–1435 (1997).

    Article  PubMed  Google Scholar 

  221. Berti Ceroni, G., Coccagna, G., Gambi, D. & Lugaresi, E. Considerazioni clinico-poligrafiche sulla narcolessia essenziale “a sonno lento” [Italian]. Sist. Nerv. 2, 81–89 (1967).

    Google Scholar 

  222. Hishikawa, Y. et al. The nature of sleep attack and other symptoms of narcolepsy. Electroencephalogr. Clin. Neurophysiol. 24, 1–10 (1968).

    Article  CAS  PubMed  Google Scholar 

  223. Melberg, A. et al. Autosomal dominant cerebellar ataxia deafness and narcolepsy. J. Neurol. Sci. 134, 119–129 (1995).

    Article  CAS  PubMed  Google Scholar 

  224. Moghadam, K. K. et al. Narcolepsy is a common phenotype in HSAN IE and ADCA-DN. Brain 137, 1643–1655 (2014).

    Article  PubMed  Google Scholar 

  225. D’Cruz, O. F., Vaughn, B. V., Gold, S. H. & Greenwood, R. S. Symptomatic cataplexy in pontomedullary lesions. Neurology 44, 2189–2191 (1994).

    Article  PubMed  Google Scholar 

  226. Kanbayashi, T. Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications. Arch. Neurol. 66, 1563–1566 (2009).

    Article  PubMed  Google Scholar 

  227. Mathis, J., Hess, C. W. & Bassetti, C. Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder. J. Neurol. Neurosurg. Psychiatry 78, 427–429 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Schwartz, W. J., Stakes, J. W. & Hobson, J. A. Transient cataplexy after removal of a craniopharyngioma. Neurology 34, 1372–1375 (1984).

    Article  CAS  PubMed  Google Scholar 

  229. Bonduelle, M. & Degos, C. in Narcolepsy: Proceedings of the First International Symposium on Narcolepsy (eds Guilleminault, C. et al.) 313–332 (Spectrum, 1976).

  230. Stahl, S. M., Layzer, R. B., Aminoff, M. J., Townsend, J. J. & Feldon, S. Continuous cataplexy in a patient with a midbrain tumor: the limp man syndrome. Neurology 30, 1115–1118 (1980).

    Article  CAS  PubMed  Google Scholar 

  231. Fernandez, J. M., Sadaba, F., Villaverde, F. J., Alvaro, L. C. & Cortina, C. Cataplexy associated with midbrain lesion. Neurology 45, 393–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  232. Roehrs, T., Zorick, F., Sicklesteel, J., Wittig, R. & Roth, T. Excessive daytime sleepiness associated with insufficient sleep. Sleep 6, 319–325 (1983).

    Article  CAS  PubMed  Google Scholar 

  233. Baumann, C., Ferini-Strambi, L., Waldvogel, D., Werth, E. & Bassetti, C. L. Parkinsonism with excessive daytime sleepiness — a narcolepsy-like disorder? J. Neurol. 252, 139–145 (2005).

    Article  PubMed  Google Scholar 

  234. Kaplan, K. A. & Harvey, A. G. Hypersomnia across mood disorders: a review and synthesis. Sleep Med. Rev. 13, 275–285 (2009).

    Article  PubMed  Google Scholar 

  235. McLeod, S., Ferrie, C. & Zuberi, S. M. Symptoms of narcolepsy in children misinterpreted as epilepsy. Epileptic Disord. 7, 13–17 (2005).

    Google Scholar 

  236. Paskind, H. A. Effect of laughter on muscle tone. Arch. Neurol. Psychiatry 28, 623–628 (1932).

    Article  Google Scholar 

  237. Partinen, M. Sleeping habits and sleep disorders of Finnish men before, during and after military service. Ann. Med. Milit. Fenn. 57 (Suppl. 1), 1–96 (1982).

    Google Scholar 

  238. Overeem, S., Lammers, G. J. & van Dijk, J. G. Weak with laughter. Lancet 354, 838 (1999).

    Article  CAS  PubMed  Google Scholar 

  239. Kim, L. J. et al. Frequencies and associations of narcolepsy-related symptoms: a cross-sectional study. J. Clin. Sleep Med. 11, 1377–1384 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Parkes, J. D. Genetic factors in human sleep disorders with special reference to Norrie disease, Prader–Willi syndrome and Moebius syndrome. J. Sleep Res. 8 (Suppl. 1), 14–22 (1999).

    Article  PubMed  Google Scholar 

  241. Iranzo, A. & Santamaria, J. Hyperkalemic periodic paralysis associated with multiple sleep onset REM periods. Sleep 22, 1123–1124 (1999).

    Article  CAS  PubMed  Google Scholar 

  242. Hartse, K. M., Zorick, F., Sicklesteel, J. & Roth, T. Isolated cataplexy: a familial study. Henry Ford Hosp. Med. J. 36, 24–27 (1988).

    CAS  PubMed  Google Scholar 

  243. Kishi, Y. et al. Schizophrenia and narcolepsy: a review with a case report. Psychiatry Clin. Neurosci. 58, 117–124 (2004).

    Article  PubMed  Google Scholar 

  244. Bassetti, C. L. in Handbook of Clinical Neurology 169–190 (Elsevier, 2014).

  245. Antelmi, E., Pizza, F., Vandi, S. & Plazzi, G. Stereotyped episodes of aphasia and immobility: how cataplexy mimics stroke in an elderly patient. Sleep Med. 36, 122–124 (2017).

    Article  CAS  PubMed  Google Scholar 

  246. Leu-Semenscu, S. et al. Hallucinations in narcolepsy with and without cataplexy: contrasts with Parkinson’s disease. Sleep Med. 12, 497–504 (2011).

    Article  Google Scholar 

  247. Cheyne, J. A., Newby-Clark, I. R. & Rueffer, S. D. Relations among hypnagogic and hypnopompic experiences associated with sleep paralysis. J. Sleep Res. 8, 313–318 (1999).

    Article  CAS  PubMed  Google Scholar 

  248. Dahmen, N., Kasten, M., Müller, M. J. & Mittag, K. Frequency and dependence on body posture of hallucinations and sleep paralysis in a community sample. J. Sleep Res. 11, 179–180 (2002).

    Article  PubMed  Google Scholar 

  249. Ohayon, M. M. & Smirne, S. Prevalence and consequences of insomnia disorders in the general population of Italy. Sleep Med. 3, 115–120 (2002).

    Article  PubMed  Google Scholar 

  250. Kallweit, U., Schmidt, M. & Bassetti, C. L. Patient-reported measures of narcolepsy: the need for better assessment. J. Clin. Sleep Med. 13, 737–744 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Sturzenegger, C. et al. Swiss Narcolepsy Scale: a simple screening tool for hypocretin-deficient narcolepsy with cataplexy. Clin. Transl Neurosci. 2, 1–5 (2018).

    Article  Google Scholar 

  252. Aldrich, M. S., Chervin, R. D. & Malow, B. A. Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 20, 620–629 (1997).

    CAS  PubMed  Google Scholar 

  253. Dauvilliers, Y. et al. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 62, 46–50 (2004).

    Article  CAS  PubMed  Google Scholar 

  254. Singh, M., Drake, C. L. & Roth, T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 29, 890–895 (2016).

    Article  Google Scholar 

  255. Huang, Y. S. et al. Multiple sleep latency test in narcolepsy type 1 and narcolepsy type 2: a 5-year follow-up study. J. Sleep Res. 27, e12700 (2018).

    Article  PubMed  Google Scholar 

  256. Marti, I., Valko, P. O., Khatami, R., Bassetti, C. L. & Baumann, C. R. Multiple sleep latency measures in narcolepsy and behaviourally insufficient sleep syndrome. Sleep Med. 10, 1146–1150 (2009).

    Article  PubMed  Google Scholar 

  257. Drakatos, P. et al. First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias. Sleep Med. 14, 897–901 (2013).

    Article  PubMed  Google Scholar 

  258. Cairns, A. & Bogan, R. Prevalence and clinical correlates of a short onset REM period (SOREMP) during routine PSG. Sleep 38, 1575–1581 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Pizza, F. et al. Spectral electroencephalography profile of rapid eye movement sleep at sleep onset in narcolepsy type 1. Eur. J. Neurol. 24, 334–340 (2017).

    Article  CAS  PubMed  Google Scholar 

  260. Pizza, F. et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep 38, 1277–1284 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  261. Sakai, N., Mastsumura, M., Lin, L., Mignot, E. & Nishino, S. HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy. Sci. Rep. 9, 477 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  262. Bassetti, C., Aldrich, M. S. & Quint, D. J. MRI findings in narcolepsy. Sleep 20, 630–631 (1997).

    Article  CAS  PubMed  Google Scholar 

  263. Plazzi, G. et al. Pontine lesions in idiopathic narcolepsy. Neurology 46, 1250–1254 (1996).

    Article  CAS  PubMed  Google Scholar 

  264. Kaufmann, C., Schuld, A., Pöllmächer, T. & Auer, D. P. Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry. Neurology 58, 1852–1855 (2002).

    Article  PubMed  Google Scholar 

  265. Overeem, S. et al. Voxel-based morphometry in hypocretin-deficient narcolepsy. Sleep 26, 44–46 (2003).

    PubMed  Google Scholar 

  266. Poryazova, R. et al. Magnetic resonance spectroscopy in narcolepsy [abstract]. Sleep 29, A222 (2006).

    Google Scholar 

  267. Schaer, M., Poryazova, R., Schwartz, S., Bassetti, C. L. & Baumann, C. R. Cortical morphometry in narcolepsy with cataplexy. J. Sleep Res. 21, 487–494 (2012).

    Article  PubMed  Google Scholar 

  268. Wada, M. et al. Neuroimaging correlates of narcolepsy with cataplexy: a systematic review. Neurosci. Res. https://doi.org/10.1016/j.neures.2018.03.005 (2018).

    Article  PubMed  Google Scholar 

  269. Meletti, S. et al. The brain correlates of laugh and cataplexy in childhood narcolepsy. J. Neurosci. 35, 11583–11594 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Schwartz, S. et al. Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy. Brain 131, 514–522 (2008).

    Article  PubMed  Google Scholar 

  271. Reiss, A. L. et al. Anomalous hypothalamic response to humor in cataplexy. PLOS ONE 3, e2225 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  272. Siegel, J. M. et al. Neuronal-activity in narcolepsy: Identification of cataplexy-related cells in the medial medulla. Science 252, 1315–1318 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Aldrich, M. Narcolepsy. N. Engl. J. Med. 323, 389–394 (1990).

    Article  CAS  PubMed  Google Scholar 

  274. Apergis-Schoute, J. et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J. Neurosci. 35, 5435–5441 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Schöne, C., Apergis-Schoute, J., Sakurai, T., Adamantidis, A. & Burdakov, D. Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep. 7, 697–704 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  276. van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M. & Spanswick, D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat. Neurosci. 7, 493–494 (2004).

    Article  PubMed  CAS  Google Scholar 

  277. Belle, M. D. et al. Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. J. Neurosci. 34, 3607–3621 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Lee, M. G., Hassani, O. K. & Jones, B. E. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J. Neurosci. 25, 6716–6720 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  280. Lin, L. et al. The sleep disorder of canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  281. Hasegawa, E., Yanagisawa, M., Sakurai, T. & Mieda, M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J. Clin. Invest. 124, 604–616 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Irukayama-Tomobe, Y. et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc. Natl Acad. Sci. USA 114, 5731–5736 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Kaushik, M. K. et al. Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy. Proc. Natl Acad. Sci. USA 115, 6046–6051 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Black, S. W. et al. Partial ablation of the orexin field induces a sub-narcoleptic phenotype in a conditional mouse model of orexin neurodegeneration. Sleep 41, zsy116 (2018).

    Article  Google Scholar 

  285. Lin, J. S. Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on posterior hypothalamus and histaminergic neurons. Sleep Med. Rev. 4, 471–503 (2000).

    Article  CAS  PubMed  Google Scholar 

  286. Kanbayashi, T. et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 32, 181–187 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  287. Nishino, S. et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 32, 175–180 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  288. Bassetti, C. L. et al. Cerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin. J. Sleep Res. 19, 620–623 (2010).

    Article  PubMed  Google Scholar 

  289. Dauvilliers, Y. et al. Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. Sleep 35, 1359–1366 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  290. Lin, J. S. et al. An inverse agonist of the histamine H3 receptor improves wakefulnesss in narcolepsy: studies in orexin−/− mice and patients. Neurobiol. Dis. 30, 74–83 (2008).

    Article  PubMed  CAS  Google Scholar 

  291. Jordan, W. et al. Prostaglandin D synthase (beta-trace) in healthy human sleep. Sleep 27, 867–874 (2004).

    Article  PubMed  Google Scholar 

  292. Jordan, W. et al. Narcolepsy increased L-PGDS (beta-trace) levels correlate with excessive daytime sleepiness but not with cataplexy. J. Neurol. 252, 1372–1378 (2005).

    Article  CAS  PubMed  Google Scholar 

  293. Bassetti, C. L., Hersberger, M. & Baumann, C. R. CSF prostaglandin D synthase is reduced in excessive daytime sleepiness. J. Neurol. 253, 1030–1033 (2006).

    Article  CAS  PubMed  Google Scholar 

  294. Peyron, C. et al. Neurons containing hypocretin (orexin) project to multiple neuronal system. J. Neurosci. 18, 9996–10015 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Boissard, R. et al. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur. J. Neurosci. 16, 1959–1973 (2002).

    Article  PubMed  Google Scholar 

  296. Lu, J., Sherman, D., Devor, M. & Saper, C. B. A putative flip-flop switch for control of REM sleep. Nature 441, 589–594 (2006).

    Article  CAS  PubMed  Google Scholar 

  297. Okura, M., Riehl, J., Mignot, E. & Nishino, S. Sulpiride, a D2/D3 blocker reduces cataplexy but not REM sleep in canine narcolepsy. Neuropsychopharmacology 23, 528–538 (2000).

    Article  CAS  PubMed  Google Scholar 

  298. Vu, M. H., Hurni, C., Mathis, J., Roth, C. & Bassetti, C. L. Selective REM sleep deprivation in narcolepsy. J. Sleep Res. 20, 50–56 (2011).

    Article  PubMed  Google Scholar 

  299. Overeem, S., Lammers, G. J. & van Dijk, J. G. Cataplexy: ‘tonic immobility’ rather than ‘REM-sleep atonia’? Sleep Med. 3, 471–477 (2002).

    Article  PubMed  Google Scholar 

  300. Hishikawa, Y. et al. Characteristics of REM sleep accompanied by sleep paralysis and hypnagogic hallucinations in narcoleptic patients. Waking Sleeping 2, 113–123 (1978).

    Google Scholar 

  301. Terzaghi, M., Ratti, P. L., Manni, F. & Manni, R. Sleep paralysis in narcolepsy: more than just a motor dissociative phenomenon? Neurol. Sci. 33, 169–172 (2012).

    Article  PubMed  Google Scholar 

  302. Snow, M. B. et al. GABA cells in the central nucleus of the amygdala promote cataplexy. J. Neurosci. 37, 4007–4022 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Mahoney, C. E., Agostinelli, L. J., Brooks, J. N., Lowell, B. B. & Scammell, T. E. GABAergic neurons of the central amygdala promote cataplexy. J. Neurosci. 37, 3995–4006 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Gulyani, S., Wu, M. F., Nienhuis, R., John, J. & Siegel, J. M. Cataplexy-related neurons in the amygdala of the narcoleptic dog. Neuroscience 112, 355–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  305. Burgess, C. R., Oishi, Y., Mochizuki, T., Peever, J. H. & Scammell, T. E. Amygdala lesions reduce cataplexy in orexin knock-out mice. J. Neurosci. 33, 9734–9742 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Hong, S. B., Tae, W. S. & Joo, E. Y. Cerebral perfusion changes during cataplexy in narcolepsy patients. Neurology 66, 1747–1749 (2006).

    Article  PubMed  Google Scholar 

  307. Tucci, V. et al. Emotional information processing in patients with narcolepsy: a psychophysiologic investigation. Sleep 26, 558–564 (2003).

    Article  PubMed  Google Scholar 

  308. Khatami, R., Birkmann, S. & Bassetti, C. L. Amygdala dysfunction in narcolepsy-cataplexy. J. Sleep Res. 16, 226–229 (2007).

    Article  PubMed  Google Scholar 

  309. Oishi, Y. et al. Role of the medial prefrontal cortex in cataplexy. J. Neurosci. 33, 9743–9751 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. Vassalli, A. et al. Electroencephalogram paroxysmal θ characterizes cataplexy in mice and children. Brain 136, 1592–1608 (2013).

    Article  PubMed  Google Scholar 

  311. van der Heide, A. et al. Comparing treatment effect measurements in narcolepsy: the sustained attention to response task, Epworth sleepiness scale and maintenance of wakefulness test. Sleep 38, 1051–1058 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  312. Bogan, R. et al. Evaluation of quality of life in patients with narcolepsy treated with sodium oxybate: use of the 36-item short-form health survey in a clinical trial. Neurol. Ther. 5, 203–213 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  313. Filardi, M. et al. Physical activity and sleep/wake behavior, anthropometric, and metabolic profile in pediatric narcolepsy type 1. Front. Neurol. 9, 707 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  314. Yoss, R. E. & Daly, D. Treatment of narcolepsy with ritalin. Neurology 9, 171–173 (1959).

    Article  CAS  PubMed  Google Scholar 

  315. Hishikawa, Y., Ida, H., Nakai, K. & Kaneko, Z. Treatment of narcolepsy with imipramine (tofranil) and desmethylimipramine (pertofran). J. Neurol. Sci. 3, 453–461 (1966).

    Article  CAS  PubMed  Google Scholar 

  316. Frey, J. & Darbonne, C. Fluoxetine suppresses human cataplexy: a pilot study. Neurology 44, 707–709 (1994).

    Article  CAS  PubMed  Google Scholar 

  317. Kallweit, U. & Bassetti, C. L. Pharmacological management of narcolepsy with and without cataplexy. Expert Opin. Pharmacother. 18, 809–817 (2017).

    Article  CAS  PubMed  Google Scholar 

  318. Broughton, R. et al. Randomized, double blind, placebo-controlled cross-over trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 49, 444–451 (1997).

    Article  CAS  PubMed  Google Scholar 

  319. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann. Neurol. 43, 88–97 (1998).

    Article  Google Scholar 

  320. US Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 5, 119–123 (2004).

    Article  Google Scholar 

  321. US Xyrem Multicenter Study Group. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 26, 31–35 (2003).

    Google Scholar 

  322. Dauvilliers, Y. et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 12, 1068–1075 (2013).

    Article  CAS  PubMed  Google Scholar 

  323. Szakacs, Z. et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 16, 200–207 (2017).

    Article  CAS  PubMed  Google Scholar 

  324. Thannickal, T. C. et al. Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy. Sci. Transl Med. 10, eaao4953 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  325. Harper, J. M. Gelineau’s narcolepsy relieved by opiates. Lancet 10, 92 (1981).

    Article  Google Scholar 

  326. Fry, J. M., Pressman, M. R., DiPhilippo, M. A. & Forst-Paulus, M. Treatment of narcolepsy with codeine. Sleep 9, 269–274 (1986).

    Article  CAS  PubMed  Google Scholar 

  327. Billiard, M. et al. EFNS guidelines on management of narcolepsy. Eur. J. Neurol. 13, 1035–1048 (2006).

    Article  CAS  PubMed  Google Scholar 

  328. Mignot, E. J. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics 9, 739–752 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  329. Bogan, R. K., Roth, T., Schwartz, J. & Miloslavsky, M. Time to response with sodium oxybate for the treatment if excessive daytime sleepiness and cataplexy in patients with narcolepsy. J. Clin. Sleep Med. 11, 427–432 (2015).

    PubMed  PubMed Central  Google Scholar 

  330. Thorpy, M. J. et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann. Neurol. 85, 359–370 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  331. Ruoff, C. et al. Effect of oral JZP-110 (ADX-N05) on wakefulness and sleepiness in adults with narcolepsy: a phase 2b study. Sleep 39, 1379–1387 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  332. Mitler, M. M., Hajdukovic, R. & Erman, M. K. Treatment of narcolepsy with methamphetamine. Sleep 16, 306–317 (1993).

    Article  CAS  PubMed  Google Scholar 

  333. Jin, L. et al. Antidepressants for the treatment of narcolepsy: a prospective study of 148 patients in northern China. J. Clin. Neurosci. https://doi.org/10.1016/j.jocn.2019.02.014 (2019).

    Article  PubMed  Google Scholar 

  334. Lehert, P. & Falissard, B. Multiple treatment comparison in narcolepsy: a network meta-analysis. Sleep 41, zsy185 (2018).

    Article  PubMed Central  Google Scholar 

  335. Roth, T. et al. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J. Sleep Res. 26, 407–414 (2016).

    Article  PubMed  Google Scholar 

  336. Plazzi, G. et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc. Health 2, 483–494 (2018).

    Article  PubMed  Google Scholar 

  337. Calvo-Ferrandiz, E. & Peraita-Adrados, R. Narcolepsy with cataplexy and pregnancy: a case–control study. J. Sleep Res. 27, 268–272 (2017).

    PubMed  Google Scholar 

  338. Maurovich-Horvat, E. et al. Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies. J. Sleep Res. 22, 496–512 (2013).

    Article  PubMed  Google Scholar 

  339. Dauvilliers, Y., Carlander, B., Rivier, F., Touchon, J. & Tafti, M. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann. Neurol. 56, 905–908 (2004).

    Article  CAS  PubMed  Google Scholar 

  340. Miyata, R., Hayashi, M., Kohyama, J. & Honda, M. Steroid therapy ameliorated cataplexy in three children with recent-onset of narcolepsy. Sleep Med. 29, 86–87 (2017).

    Article  PubMed  Google Scholar 

  341. Donjacur, C. E. & Lammers, G. J. A remarkable effect of alemtuzumab in a patient suffering from narcolepsy with cataplexy. J. Sleep Res. 21, 479–480 (2012).

    Article  Google Scholar 

  342. Liblau, R. S., Vassalli, A., Seifinejad, A. & Tafti, M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol. 14, 318–328 (2015).

    Article  CAS  PubMed  Google Scholar 

  343. Bernard-Valnet, R. et al. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc. Natl Acad. Sci. USA 113, 10956–10961 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  344. Krahn, L. E., Boeve, B. F., Olson, E. J., Herold, D. L. & Silber, M. H. A standardized test for cataplexy. Sleep Med. 1, 125–130 (2000).

    Article  CAS  PubMed  Google Scholar 

  345. Olsen, A. V. et al. Diagnostic value of sleep stage dissociation as visualized on a 2-dimensional sleep state space in human narcolepsy. J. Neurosci. Methods 282, 9–19 (2017).

    Article  PubMed  Google Scholar 

  346. Hirtz, C. et al. From radioimmunoassay to mass spectrometry: a new method to quantify orexin-A (hypocretin-1) in cerebrospinal fluid. Sci. Rep. 6, 25162 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  347. Stephansen, J. B. et al. Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy. Nat. Commun. 9, 5229 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  348. Rosenberg, R. & Kim, A. Y. The AWAKEN survey: knowledge of narcolepsy among physicians and the general population. Postgrad. Med. 126, 78–86 (2014).

    Article  PubMed  Google Scholar 

  349. Maski, K. et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J. Clin. Sleep Med. 13, 419–425 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  350. Chaplin, J. E., Szakács, A. & Hallböök, Darin, T. N. The development of a health-related quality-of-life instrument for young people with narcolepsy: NARQoL-21. Health Qual. Life Outcomes 15, 135 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  351. Dauvilliers, Y. et al. Measurement of narcolepsy symptoms: the Narcolepsy Severity Scale. Neurology 88, 1358–1365 (2017).

    Article  PubMed  Google Scholar 

Download references

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.

Reviewer information

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.

Author information

Authors and Affiliations

  1. Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Claudio L. A. Bassetti, Antoine Adamantidis, Ulf Kallweit & Ramin Khatami

  2. The Francis Crick Institute, London, UK

    Denis Burdakov

  3. Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Denis Burdakov

  4. Department of Health Sciences and Technology, Swiss Federal Institute of Technology/ETH Zürich, Zurich, Switzerland

    Denis Burdakov

  5. Department of Pulmonary Medicine, Beijing University People’s Hospital, Beijing, China

    Fang Han

  6. Department of Rheumatology, University Hospital, Zurich, Switzerland

    Steffen Gay

  7. University of Witten/Herdecke, Institute of Immunology, Clinical Sleep and Neuroimmunology, Witten, Germany

    Ulf Kallweit

  8. Centre of Sleep Medicine and Sleep Research, Klinik Barmelweid AG, Barmelweid, Switzerland

    Ramin Khatami

  9. Department of Immunohaematology, and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands

    Frits Koning

  10. Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

    Brigitte R. Kornum

  11. Neurology Department, Leiden University Medical Centre, Leiden, Netherlands

    Gert Jan Lammers

  12. Sleep Wake Centre, Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands

    Gert Jan Lammers

  13. INSERM U1043 — Centre National de la Recherche Scientifique UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Université Toulouse III, Toulouse, France

    Roland S. Liblau

  14. Centre de Recherche en Neurosciences de Lyon (CRNL), INSERM, Lyon, France

    Pierre H. Luppi

  15. Université Claude Bernard Lyon 1, Lyon, France

    Pierre H. Luppi

  16. Hephata-Klinik, Schwalmstadt, Philipps-Universität Marburg, Department of Neurology, Marburg, Germany

    Geert Mayer

  17. Zentrum für psychische Gesundheit, Klinikum Ingolstadt, Ingolstadt, Germany

    Thomas Pollmächer

  18. Faculty of Medicine, University of Tsukuba, Ibaraki, Tsukuba, Japan

    Takeshi Sakurai

  19. Center of Medical Immunology, Institute for Research in Biomedicine, Bellinzona, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

    Federica Sallusto

  20. Institute of Microbiology, Eidgenössische Technische Hochschule, Zurich, Switzerland

    Federica Sallusto

  21. Department of Neurology, Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Thomas E. Scammell

  22. Department of Physiology, University of Lausanne, Lausanne, Switzerland

    Mehdi Tafti

  23. Center for Investigation and Research in Sleep, Vaud University Hospital, Lausanne, Switzerland

    Mehdi Tafti

  24. Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France

    Yves Dauvilliers

  25. National Reference Network for Narcolepsy, Montpellier, France

    Yves Dauvilliers

  26. Institut National de la Santé et de la Recherche Médicale (INSERM) U1061, Montpellier, France

    Yves Dauvilliers

Authors
  1. Claudio L. A. Bassetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antoine Adamantidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Denis Burdakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steffen Gay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulf Kallweit
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ramin Khatami
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Frits Koning
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Brigitte R. Kornum
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gert Jan Lammers
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Roland S. Liblau
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pierre H. Luppi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Geert Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas Pollmächer
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Takeshi Sakurai
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Federica Sallusto
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Thomas E. Scammell
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mehdi Tafti
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yves Dauvilliers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Claudio L. A. Bassetti.

Ethics declarations

Competing interests

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-019-0226-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing