Narcolepsy and the Flu

Narcolepsy, an interesting disorder where patients exhibit excessive sleepiness, cataplexy, and sleep paralysis, has long fascinated neuroscientists. Important genetic studies demonstrated the importance of hypocretin/orexin receptors in pedigrees of narcoleptic dogs and goats, and revealed the central role for these receptors and the neurons that express them in the hypothalamus in the induction of sleep and maintenance of arousal. However, most patients with narcolepsy, unlike the dog models, don’t have mutations in these receptors or a strict Mendelian inheritance of narcolepsy.

Other studies established, long before the involvement of hyocretin receptors was known, that there is an inherited basis for narcolepsy in humans, but one that it is associated with a particular HLA haplotype (HLA-DQB1), suggesting a role for autoimmunity in narcolepsy. Interestingly, in patients with narcolepsy who have been autopsied, there is a loss of the cells expressing the hypocretin receptors in the hypothalamus (unlike in the receptor mutation cases where the cells are there but the receptors aren’t). This suggests that some sort of immune process leads to the loss of these cells in susceptible individuals. But what is the inciting event that leads to this autoimmune process?

Several observations over the last few years have indicated that one of the inciting events may be infection with influenza or vaccination with particular influenza vaccines. Finally, a recent study has pretty much nailed down this hypothesis with some molecular detail.  In this paper the authors demonstrate that there is sequence homology between one of the proteins expressed by the H1N1 influenza virus, and also in the H1N1 vaccine that was used for a time in Europe, and the human hypocretin-2 receptor. This is the specific receptor previously demonstrated to be associated with narcolepsy. The authors also showed that antibodies in the serum of patients who were administered this vaccine and who developed narcolepsy bind to this receptor expressed in cell culture. This finding provides a satisfying end to the associations previously found between an “epidemic” of narcolepsy in Scandinavia after H1N1 vaccination and also with the previously noted seasonal association with narcolepsy in China.

What remains to sort out is whether all cases of narcolepsy (other than cases with Mendelian inheritance) are post-infectious (or post-vaccination) and whether there are viruses other than H1N1 that are associated. Studies in this area are important because it may be possible to design vaccines that will avoid this problem entirely in the future and also to determine who is at risk for this type of unfortunate post-infectious/vaccination complication.