ulation carries the gene HLA-DQB1*06:02, but less than 1% of them will develop narcolepsy as additional factors are needed to trigger an attack on the orexin neurons. Secondly, though it seems very likely that Pandemrix triggered narcolepsy in certain children, this vaccine was unusually potent, and future vaccines most likely will be designed differently now that this risk is known. There is no compelling evidence that other vaccines cause or worsen narcolepsy, so it is fine for people with narcolepsy and their families to receive all routine vaccinations.
Narcolepsy was first described by doctors in the 1870s, but only in the past 15 years has the underlying cause become clear. Some of the greatest insights about narcolepsy have come from the laboratories of Dr. Emmanuel Mignot of Stanford University and Dr. Jerome Siegel of the University of California, Los Angeles. In 2000, each group independently discovered that narcolepsy with cataplexy is caused by a loss of orexins in the brain. These and other valuable insights have revealed much about how the brain normally functions, as well as what goes wrong in narcolepsy.
Current theories about the role of orexins in narcolepsy are based on research findings that include the following:
Research in animals was the first to shed light on the connection between narcolepsy and loss of orexins. Just like people with narcolepsy, dogs, rats, and mice with disrupted orexin signaling fall asleep frequently and often have episodes of cataplexy.9, 10, 11, 12 In addition, tasty food can trigger cataplexy in dogs and mice with narcolepsy, suggesting that their cataplexy is triggered by positive emotions.13, 14
Researchers then examined the brains of people with narcolepsy with cataplexy and consistently found a 90–95% decrease in the number of orexin-producing neurons.15, 16, 17 orexin-1 can also be measured in cerebrospinal fluid, the liquid that surrounds the brain, and about 90% of people with narcolepsy with cataplexy have very low or undetectable levels of orexin-1.18 Thus, it seems likely that some process kills the orexin neurons, resulting in narcolepsy with cataplexy.
Thus far, the cause of narcolepsy without cataplexy is less clear. Researchers have examined the brains of only a few people with this type of narcolepsy, and these seem to have only a moderate loss of the orexin neurons.19 orexin-1 levels in spinal fluid are usually normal, although about 30% of these individuals have low or undetectable levels.18, 20 Among these people with low orexin, about one-third may develop cataplexy years later,20 suggesting that there may be some ongoing injury to the orexin neurons. Thus, narcolepsy without cataplexy may be caused by a less severe injury to the orexin neurons, but because so little is known about this form of narcolepsy, it remains possible that it has an entirely different cause.
See Developing New Treatments for the latest findings on potential new treatments for narcolepsy.
- de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95:322–7.
- Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92:573–85.
- Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 1998; 51:96–100.
- Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K, Zeitzer J, Mignot E. Elevated anti-streptococcal antibodies in patients with recent narc