Narcolepsy with Cataplexy: Hypocretin and Immunological Aspects

  • Yves Dauvilliers


Narcolepsy is a disabling sleep disorder characterized by severe excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations including cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep onset REM periods (American Academy of Sleep Medicine 2005; Dauvilliers, Billiard, and Montplaisir 2003b; Scammell 2003). Recent advances in pathophysiology demonstrated that narcolepsy is caused by the loss of hypothalamic neurons producing hypocretin (Mignot et al. 2002; Dauvilliers et al. 2003a; Peyron et al. 2000; Thannickal et al. 2000; Crocker et al. 2005; Blouin, Thannickal, Worley, Baraban, Reti, and Siegel 2005). Epidemiological data with a young and bimodal age at onset, frequent triggering factors and a tight HLA DQB1*0602 association, suggest an autoimmune hypothesis (Mignot, Tafti, Dement, and Grumet 1995; Carlander, Dauvilliers, and Billiard 2001; Chabas, Taheri, Renier, and Mignot 2003). Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons, in response to yet unknown environmental factors, is the most probable hypothesis. The treatment of narcolepsy has evolved significantly over the last few years, but current therapies are only symptom-based. Hypocretin-based therapies and immune-based therapies are part of the research projects for the development of new treatments in narcolepsy (Dauvilliers and Tafti 2006).


Sodium Oxybate Multiple Sleep Latency Test Sleep Paralysis Labrador Retriever Narcoleptic Patient 
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  1. Abad, V.C., and Guilleminault, C. (2004) Emerging drugs for narcolepsy. Expert Opin Emerg Drugs 9, 281–291.PubMedCrossRefGoogle Scholar
  2. American Academy of Sleep Medicine (2005) The International Classification of Sleep Disorders—Revised. American Academy of Sleep Medicine, Chicago, IL.Google Scholar
  3. Billiard, M., Pasquie-Magnetto, V., Heckman, M. et al. (1994) Family studies in narcolepsy. Sleep 17, S54–S59.PubMedGoogle Scholar
  4. Billiard, M., and Seignalet, J. (1985) Extraordinary association between HLA-DR2 and narcolepsy. Lancet 1, 226–227.CrossRefGoogle Scholar
  5. Black, J.L., Avula, R.K., Walker, D.L. et al. (2005a) HLA DQB1*0602 positive narcoleptic subjects with cataplexy have CSF lgG reactive to rat hypothalamic protein extract. Sleep 28, 1191–1192.Google Scholar
  6. Black, J.L., Silber, M.H., Krahn, L.E. et al. (2005b) Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep 28, 427–431.Google Scholar
  7. Blouin, A.M., Thannickal, T.C., Worley, P.F., Baraban, J.M., Reti, I.M., and Siegel, J.M. (2005) Narp immunostaining of human hypocretin (orexin) neurons, loss in narcolepsy. Neurology 65, 1189–1192.PubMedCrossRefGoogle Scholar
  8. Carlander, B., Dauvilliers, Y., and Billiard, M. (2001) Immunological aspects of narcolepsy. Rev Neurol 157, S97–S100.PubMedGoogle Scholar
  9. Chabas, D., Taheri, S., Renier, C., and Mignot, E. (2003) The genetics of narcolepsy. Annu Rev Genom Hum Genet 4, 459–483.CrossRefGoogle Scholar
  10. Chemelli, R.M., Willie, J.T., Sinton, C.M. et al. (1999) Narcolepsy in orexin knockout mice, molecular genetics of sleep regulation. Cell 98, 437–451.PubMedCrossRefGoogle Scholar
  11. Chen, W., Black, J., Call, P., and Mignot, E. (2005) Late-onset narcolepsy presenting as rapidly progressing muscle weakness, response to plasmapheresis. Ann Neurol 58, 489–490.PubMedCrossRefGoogle Scholar
  12. Crocker, A., Espana, R.A., Papadopoulou, M. et al. (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65, 1184–1188.PubMedCrossRefGoogle Scholar
  13. Dauvilliers, Y. (2006) Follow-up of four narcolepsy patients treated with intravenous immunoglobulins. Ann Neurol 26, 153.CrossRefGoogle Scholar
  14. Dauvilliers, Y., Baumann, C.R., Carlander, B. et al. (2003a) CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 74, 1667–1673.CrossRefGoogle Scholar
  15. Dauvilliers, Y., Billiard, M., and Montplaisir, J. (2003b) Clinical aspects and pathophysiology of narcolepsy. Clin Neurophysiol 114, 2000–2017.CrossRefGoogle Scholar
  16. Dauvilliers, Y., Blouin, J.L., Neidhart, E. et al. (2004a) A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q. Ann Neurol 56, 382–388.CrossRefGoogle Scholar
  17. Dauvilliers, Y., Carlander, B., Molinari, N. et al. (2003c) Month of birth as a risk factor for narcolepsy. Sleep 26, 663–665.Google Scholar
  18. Dauvilliers, Y., Carlander, B., Rivier, F., Touchon, J., and Tafti, M. (2004a) Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol 56, 905–908.CrossRefGoogle Scholar
  19. Dauvilliers, Y., Gosselin, A., Paquet, J., Touchon, J., Billiard, M., and Montplaisir, J. (2004b) Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 62, 46–50.Google Scholar
  20. Dauvilliers, Y., Maret, S., Bassetti, C. et al. (2004c) A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1. Neurology 62, 2137–2138.Google Scholar
  21. Dauvilliers, Y., Montplaisir, J., Molinari, N. et al. (2001a) Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 57, 2029–2033.Google Scholar
  22. Dauvilliers, Y., Neidhart, E., Billiard, M., and Tafti, M. (2002) Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenom J 2, 65–68.CrossRefGoogle Scholar
  23. Dauvilliers, Y., Neidhart, E., Lecendreux, M., Billiard, M., and Tafti, M. (2001b) MAO-A and COMT polymorphisms and gene effects in narcolepsy. Mol Psychiatry 6, 367–372.CrossRefGoogle Scholar
  24. Dauvilliers, Y., and Tafti, M. (2006) Molecular genetics and treatment of narcolepsy. Ann Med 38, 252–262.PubMedCrossRefGoogle Scholar
  25. de Lecea, L., Kilduff, T.S., Peyron, C. et al. (1998) The hypocretins, hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95, 322–327.PubMedCrossRefGoogle Scholar
  26. Dement, W., Carskadon, M., and Ley, R. (1973) The prevalence of narcolepsy II. Sleep Res 2, 147.Google Scholar
  27. Fredrikson, S., Carlander, B., Billiard, M., and Link, H. (1990) CSF immune variables in patients with narcolepsy. Acta Neurol Scand 81, 253–254.PubMedCrossRefGoogle Scholar
  28. Gencik, M., Dahmen, N., Wieczorek, S., Kasten, M., Gencikova, A., and Epplen, J.T. (2001) ApoE polymorphisms in narcolepsy. BMC Med Genet 2, 9.PubMedCrossRefGoogle Scholar
  29. Hara, J., Beuckmann, C.T., Nambu, T. et al. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345–354.PubMedCrossRefGoogle Scholar
  30. Hinze-Selch, D., Wetter, T.C., Zhang, Y. et al. (1998) In vivo and in vitro immune variables in patients with narcolepsy and HLA-DR2 matched controls. Neurology 50, 1149–1152.PubMedGoogle Scholar
  31. Hohjoh, H., Terada, N., Kawashima, M., Honda, Y., and Tokunaga, K. (2000) Significant association of the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy. Tissue Antigens 56, 446–448.PubMedCrossRefGoogle Scholar
  32. Honda, Y. (1979) Census of narcolepsy, cataplexy and sleep life among teenagers in Fujisawa city. Sleep Res 8, 191.Google Scholar
  33. Honda, Y., Asaka, A., Tanaka, Y., and Juji, T. (1983) Discrimination of narcolepsy by using genetic markers and HLA. Sleep Res 12, 254.Google Scholar
  34. Hublin, C., Kaprio, J., Partinen, M. et al. (1994) The prevalence of narcolepsy, an epidemiological study of the Finnish Twin Cohort. Ann Neurol 35, 709–716.PubMedCrossRefGoogle Scholar
  35. Hungs, M., Lin, L., Okun, M., and Mignot, E. (2001) Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy. Neurology 57, 1893–1895.PubMedGoogle Scholar
  36. Khatami, R., Maret, S., Werth, E. et al. (2004) Monozygotic twins concordant for narcolepsycataplexy without any detectable abnormality in the hypocretin (orexin) pathway. Lancet 363, 1199–1200.PubMedCrossRefGoogle Scholar
  37. Koch, H., Craig, I., Dahlitz, M., Denney, R., and Parkes, D. (1999) Analysis of the monoamine oxidase genes and the Norrie disease gene locus in narcolepsy. Lancet 353, 645–646.PubMedCrossRefGoogle Scholar
  38. Kotagal, S., Krahn, L.E., and Slocumb, N. (2004) A putative link between childhood narcolepsy and obesity. Sleep Med 5, 147–50.PubMedCrossRefGoogle Scholar
  39. Lavie, P., and Peled, R. (1987) Narcolepsy is a rare disease in Israel. Sleep 10, 608–609.PubMedGoogle Scholar
  40. Lecendreux, M., Maret, S., Bassetti, C., Mouren, M.C., and Tafti, M. (2003) Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 12, 347–348.PubMedGoogle Scholar
  41. Lin, L., Faraco, J., Li, R. et al. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376.PubMedCrossRefGoogle Scholar
  42. Lin, L., Hungs, M., and Mignot, E. (2001) Narcolepsy and the HLA region. J. Neuroimmunol 117, 9–20.PubMedCrossRefGoogle Scholar
  43. Mieda, M., Willie, J.T., Hara, J., Sinton, C.M., Sakurai, T., and Yanagisawa, M. (2004) Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A 101, 4649–4654.PubMedCrossRefGoogle Scholar
  44. Mignot, E. (1998) Genetic and familial aspects of narcolepsy. Neurology 50, S16–S22.PubMedGoogle Scholar
  45. Mignot, E., Lammers, G.J., Ripley, B. et al. (2002) The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurology 59(10), 1553–1562.CrossRefGoogle Scholar
  46. Mignot, E., Lin, L., Rogers, W. et al. (2001) Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 68, 686–699.PubMedCrossRefGoogle Scholar
  47. Mignot, E., and Nishino, S. (2005) Emerging therapies in narcolepsy-cataplexy. Sleep 28, 754–763.PubMedGoogle Scholar
  48. Mignot, E., Tafti, M., Dement, W.C., and Grumet, F.C. (1995) Narcolepsy and immunity. Adv Neuroimmunol 5, 23–37.PubMedCrossRefGoogle Scholar
  49. Mignot, E., Wang, C., Rattazzi, C. et al. (1991) Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment. Proc Natl Acad Sci U S A 88, 3475–3478.PubMedCrossRefGoogle Scholar
  50. Nakayama, J., Miura, M., Honda, M., Miki, T., Honda, Y., and Arinami, T. (2000) Linkage of human narcolepsy with HLA association to chromosome 4p13-q21. Genomics 65, 84–86.PubMedCrossRefGoogle Scholar
  51. Nishino, S., and Kanbayashi, T. (2005) Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 9, 269–310.PubMedCrossRefGoogle Scholar
  52. Ohayon, M.M. (2000) Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 97, 153–164.PubMedCrossRefGoogle Scholar
  53. Ohayon, M.M., Priest, R.G., Zulley, J., Smirne, S., and Paiva, T. (2002) Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 58, 1826–1833.PubMedGoogle Scholar
  54. Orellana, C., Villemin, E., Tafti, M., Carlander, B., Besset, A., and Billiard, M. (1994) Life events in the year preceding the onset of narcolepsy. Sleep 17, S50–S53.PubMedGoogle Scholar
  55. Overeem, S., Dalmau, J., Bataller, L. et al. (2004) Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 62, 138–140.PubMedGoogle Scholar
  56. Overeem, S., Geleijns, K., Garssen, M.P., Jacobs, B.C., van Doorn, P.A., and Lammers, G.J. (2003) Screening for anti-ganglioside antibodies in hypocretin-deficient human narcolepsy. Neurosci Lett 341, 13–16.PubMedCrossRefGoogle Scholar
  57. Overeem, S., Verschuuren, J.J., Fronczek, R. et al. (2006) Immunohistochemical screening for autoantibodies against lateral hypothalamic neurons in human narcolepsy. J Neuroimmunol 174, 187–191.PubMedCrossRefGoogle Scholar
  58. Pelin, Z., Guilleminault, C., Risch, N., Grumet, F.C., and Mignot, E. (1998) HLADQB1* 0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 51, 96–100.PubMedCrossRefGoogle Scholar
  59. Peyron, C., Faraco, J., Rogers, W. et al. (2000) 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.PubMedCrossRefGoogle Scholar
  60. Peyron, C., Tighe, D.K., van den Pol, A.N. et al. (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18, 9996–10015.PubMedGoogle Scholar
  61. Picchioni, D., Mignot, E.J., and Harsh, J.R. (2004) The month-of-birth pattern in narcolepsy is moderated by cataplexy severity and may be independent of HLA-DQB1*0602. Sleep 27, 1471–1475.PubMedGoogle Scholar
  62. Ripley, B., Fujiki, N., Okura, M., Mignot, E., and Nishino, S. (2001) Hypocretin levels in sporadic and familial cases of canine narcolepsy. Neurobiol Dis 8, 525–534.PubMedCrossRefGoogle Scholar
  63. Sakurai, T., Amemiya, A., Ishii, M. et al. (1998) Orexins and orexin receptors, a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585.PubMedCrossRefGoogle Scholar
  64. Scammell, T.E. (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 53, 154–166.PubMedCrossRefGoogle Scholar
  65. Siebold, C., Hansen, B.E., Wyer, J.R. et al. (2004) Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc Natl Acad Sci U S A 101, 1999–2004.PubMedCrossRefGoogle Scholar
  66. Silber, M.H., Krahn, L.E., Olson, E.J., and Pankratz, V.S. (2002) The epidemiology of narcolepsy in Olmsted County, Minnesota, a population-based study. Sleep 25, 197–202.PubMedGoogle Scholar
  67. Smith, A.J., Jackson, M.W., Neufing, P., McEvoy, R.D., and Gordon, T.P. (2004) A functional autoantibody in narcolepsy. Lancet 364, 2122–2124.PubMedCrossRefGoogle Scholar
  68. Taheri, S., and Mignot, E. (2002) The genetics of sleep disorders. Lancet Neurol 1, 242–250.PubMedCrossRefGoogle Scholar
  69. Tanaka, S., Honda, Y., Inoue, Y., and Honda, M. (2006) Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy, anti-Hcrt system antibody in narcolepsy. Sleep 29, 633–638.PubMedGoogle Scholar
  70. Thannickal, T.C., Moore, R.Y., Nienhuis, R. et al. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474.PubMedCrossRefGoogle Scholar
  71. Wieczorek, S., Gencik, M., Rujescu, D. et al. (2003) TNFA promoter polymorphisms and narcolepsy. Tissue Antigens 61, 437–442.PubMedCrossRefGoogle Scholar
  72. Wieczorek, S., Jagiello, P., Arning, L., Dahmen, N., and Epplen, J.T. (2004) Screening for candidate gene regions in narcolepsy using a microsatellite based approach and pooled DNA. J Mol Med 82, 696–705.PubMedCrossRefGoogle Scholar
  73. Willie, J.T., Chemelli, R.M., Sinton, C.M. et al. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice, molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 38, 715–730.PubMedCrossRefGoogle Scholar

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  • Yves Dauvilliers

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