The onset of narcolepsy during a 10-year period in China was highly correlated with seasonal and annual patterns of upper airway infections, and was generally independent of H1N1 influenza vaccination, contrary to reports of narcolepsy following H1N1 vaccination in northern Europe and other areas.
Self-reported data on the month and year of narcolepsy onset in 629 patients who were diagnosed between September 1998 and February 2011 indicate that onset is most frequent in April and least frequent in November in this population, with a nearly sevenfold increase from trough to peak, Dr. Fang Han of Peking University People’s Hospital, Beijing, and colleagues reported.
A greater-than-threefold increase in narcolepsy onset occurred about 6 months following the 2009 H1N1 winter influenza pandemic, but interviews with 142 patients who recalled whether they were vaccinated against H1N1 revealed that vaccination was not likely related to the increase, because only 8 (5.6%) of the patients reported having been vaccinated, the investigators said (Ann. Neurol. 2011;70:410-7).
Furthermore, about 25% of 150 patients recalled having been sick with an infection within a few months of narcolepsy onset, and 85% of those reported symptoms of upper airway infection, including 2 who reported "flu" and 2 who reported "strep throat."
Animal studies suggest that about 80% of hypocretin/orexin–producing neurons must be lost before symptoms of narcolepsy are exhibited, which could explain the 6-month delay between winter airway infection and narcolepsy onset occurrence, they noted.
The findings show that narcolepsy onset in China is strongly seasonal, and suggest that it is not related to H1N1 vaccination. The occurrence of narcolepsy onset was more than threefold greater than expected following the 2009-2010 H1N1 pandemic, but 96% of new narcolepsy patients in 2010 did not report being vaccinated. This is in contrast with reports of narcolepsy in Finland, the United States, France, and Canada following H1N1 vaccination with adjuvanted vaccine (particularly Pandemrix), which had caused alarm in those countries.
Indeed, the findings suggest that winter airway infections – such as those caused by influenza A (including H1N1) and/or Streptococcus pyogenes – are triggers for narcolepsy, the investigators wrote, adding that "winter infections would initiate or reactivate an immune response that leads to hypocretin cell loss and narcolepsy in genetically susceptible individuals."
About two-thirds of subjects in prior studies of narcolepsy onset had high titers of ASO (antistreptolysin O) antibody, which is a marker of S. pyogenes infection, primarily strep throat, they explained, noting that those findings are complemented by epidemiologic findings showing a 5.4-fold higher risk of narcolepsy in those reporting physician-diagnosed strep throat before age 21 years.
"As S. pyogenes is known to be associated with the onset of other autoimmune disease, notably rheumatic heart fever and [Sydenham’s] chorea, it was a prime candidate as a potential autoimmune trigger for narcolepsy," they said.
It is difficult to determine, however, whether streptococcus is involved, or is an associated infection, particularly because numerous studies have shown that upper airway infections often involve multiple viral and bacterial coinfections or superinfections, including S. pyogenes.
Available data suggest that two factors may be needed for narcolepsy development, including "a specific immune-mimicry component, mediated through the presentation by DQB1*06:02/DQA1*01:02 of a particular autoantigen to a specific [T-cell receptor] idiotype," and "nonspecific factors such as adjuvants, influenza, or strep infections, streptococcus superantigens and other factors," the investigators wrote, noting that studies are currently ongoing to evaluate this.
Although limited by the single-center and retrospective nature of the data, this study nonetheless supports the concept that H1N1 – either alone or with other winter infections – is associated with narcolepsy onset in a temporal manner, which suggests causality, they said.
The new finding of an association with infection – and not vaccination – is important because it suggests that limiting vaccination out of fear of narcolepsy could actually increase overall risk, they added.
Furthermore, the findings regarding winter upper airway infection as a trigger for narcolepsy also may have implications for other diseases of the central nervous system; a range of autoimmune pathologies of the brain may follow winter infections, they said.
In an accompanying commentary, Dr. Stephen L. Hauser and Dr. S. Claiborne Johnston of the University of California, San Francisco, noted that there is little evidence to support the claims by the authors of this study that the H1N1 pandemic flu virus accounts for the surge of narcolepsy seen in 2009-2010, other than the fact that the infection had been prevalent the previous winter (Ann. Neurol. 2011 Aug. 22 [doi:10.1002/ana.22590]). However, they thought that the data, which they said need to be replicated and confirmed, "add to evidence of a possible association between infection and narcolepsy, and could point to pandemic H1N1 – in addition to streptococcal infection – as a potential environmental culprit."