Does streptococcal infection cause narcolepsy?

Narcolepsy is a lifelong neurological disorder which manifests as a problem with sleep; too much sleep. The hallmark symptom of this condition is 'cataplexy', which describes a sudden loss of muscle tone triggered by strong emotions. Narcolepsy affects around one in two-thousand people in our community. Most GPs will have one patient in their patient population with bona-fide narcolepsy.

As with many disorders, as the genetic and cellular basis of narcolepsy has become better understood, the tools upon which we rely for diagnosis have begun to look increasingly clumsy. The standard diagnostic test is a multiple sleep latency test; performed in the sleep lab, we essentially invite our patient to prove how sleepy they are by taking multiple naps during the course of the day. In the last decade, however, it has become apparent that:

1. There is a very tight genetic association with narcolepsy, with almost all patients demonstrating a particular HLA profile (HLA-DQB1*0602).
2. Narcolepsy is caused by the loss of hypocretin secreting neurons in the hypothalamus

To date, only five patients with narcolepsy worldwide have not demonstrated these associations. These findings have led to the hypothesis that narcolepsy is an autoimmune disorder. A recent study has tested the hypothesis that perhaps narcolepsy is a condition in which an infective organism triggers a destructive immune response.

Why should we consider that possibility? We already know, and have known for a long time, that the immune response associated with - for example -streptococcal infection can cause secondary damage in organs not related to the initial infection. Streptoccal antigens can mimic cardiac tissue, leading to rheumatic fever and valvular heart disease. A similar process affecting the brain may cause Sydenhams chorea, and post-strep glomerulonephritis is well described. Could narcolepsy be a manifestation of post-streptococcal neurological damage in the hypothalamus?

What evidence is there for this in narcolepsy? Well, til recently not much. However, with the publication of the study mentioned above - in Sleep Journal in August - the landscape has changed a little.

What did they do? The study involved multiple centres in North America, Europe and Asia. All patients had the HLA type mentioned above and were hypocretin deficient, or had the HLA type and clear cataplexy. Patients were divided into four groups according to the duration of their disease (less than one year, one to three years, three to ten years or more than10 years). They also studied age matched, healthy controls. Amongst other things, serological evidence of streptococcal infection was sought, with anti-streptolysin O and anti DNAseB antibody assays measured.

What did they find? They found that the more recent the onset of the narcolepsy the more likely a patient was to have serological evidence of streptococcal infection as follows (patients vs controls):

• 43% vs 4.5% of the 'less than one year group' had evidence of both ASO and antiDNAseB. 65% vs 26% had one or the other;
• 33% vs 9.5% of the 1-3 yr group had both, 57% vs 30% had one or the other

These differences were statistically significant. There was no significant difference in the other groups. This level of serological evidence of infection is comparable to what is seen in rheumatic fever and Sydenham's chorea.

What does this mean? This is very interesting evidence. If repeated in other populations of well selected narcolepsy it could have significant implications. There may turn out to be a place for immunotherapy or antibiotics in the management of narcolepsy - if the diagnosis is made early. (At present, the only treatments available are medications that help people stay awake, such as modafinil or dexamphetamine)

Andrew