Breakthroughs in Narcolepsy: A Postinfectious Autoimmune Syndrome?

Narcolepsy is a syndrome in which patients rapidly transition into sleep states from wakefulness and have excessive daytime sleepiness. Patients also frequently have cataplexy triggered by strong emotions or surprise.

A major breakthrough in narcolepsy came from studies demonstrating that the syndrome most typically is associated with particular human leukocyte antigen (HLA) haplotypes in patients. Patients with these HLA haplotypes are susceptible to narcolepsy on a sporadic basis, suggesting that there may be an autoimmune basis for narcolepsy in many patients.

The next significant breakthrough was the linkage of a distinct genetic form of narcolepsy identified in experimental animals with mutations in the orexin/hypocretin ligand receptor. This linkage suggested that there may be a defect in the orexin/hypocretin-controlled hypothalamic circuit regulating sleep and arousal.

Indeed, authors have shown in pathologic studies that the hypocretin receptor expressing hypothalamic neurons are lost in patients with sporadic narcolepsy, suggesting the possibility of an autoimmune attack on these cells leading to the loss of these neurons and the onset of clinical symptoms.

What is the inciting event that leads to the loss of these neurons in patients with narcolepsy? Recent studies have suggested that H1N1 influenza might be the trigger for some patients in whom narcolepsy develops. One indication of this was epidemiologic data showing that narcolepsy has a seasonal incidence and that there were increases in incidence after H1N1 outbreaks. Interestingly, there also were outbreaks associated with H1N1 vaccination in Scandinavian countries.

To complete the story, at least for now, recent studies have shown that there are shared epitopes between the H1N1 influenza virus and the hypocretin receptor and that patients have T-cell clones directed at these shared epitopes. This strongly suggests that a cytologic T-cell response triggered by H1N1 influenza can target hypocretin expressing cells and can be associated with the onset of narcolepsy in susceptible patients.

A number of interesting questions remain:

• Is narcolepsy triggered by influenza in all patients or are there other inciting environmental triggers?

• Can other influenza types trigger the disorder in susceptible patients?

• Is the risk higher for infection or vaccination?

• Should patients be screened for risk in some manner before influenza vaccination?

I’m sure readers will have other interesting thoughts on this topic. Please share your comments below.