335 Discussion and identifying any autoreactive T cells and/or autoantibodies present within the hypothalamus. Given the segregating nature of the blood-brain barrier, forthcoming studies should prioritize examining the immunological composition of cerebrospinal fluid close to disease onset rather than solely relying on blood samples. The multiple-hit model of narcolepsy type 1 It remains unclear why immunological events rapidly trigger the onset of narcolepsy type 1 symptoms in some (typically within weeks to months). In others that experienced the same trigger, narcolepsy symptoms take many years to arise. In delayed onset cases, it could be that the initial stimulus induced a slow-paced autoimmune process that remained asymptomatic at first or that additional triggers, closer to narcolepsy symptom onset, were needed to trigger onset. A first trigger could not have been strong enough or occurred under different environmental circumstances and did not directly trigger symptomatic narcolepsy. This idea aligns with the multiple-hit model [4] in which people with a specific genetic predisposition must experience (possibly multiple) environmental triggers to develop narcolepsy. Except for the descriptive case reports fitting the multiple-hit hypothesis, there so far was limited pathophysiological evidence that supports this theory. Extended evidence for the multiple-hit model is already obtained within other fields, for example, for developing various cancer types [428, 429]. Given its strong association with the type A H1N1 influenza pandemic in 2009-2010, the scientific field has recently hotly debated whether COVID19 infection and/or vaccination could be a potential trigger for developing narcolepsy type 1 [430-435]. On the contrary, in case COVID-19 is not a trigger of central disorders of hypersomnolence, it could be that the COVID-19 pandemic has resulted in a protective environment for those prone to develop narcolepsy or idiopathic hypersomnia. COVID-19 pandemic control measures (such as lockdowns, social distancing and hygiene measures) have resulted in near absence of influenza infections, presenting a unique epidemiological opportunity to investigate the relationship between influenza circulation and onset of trigger-related autoimmune disorders. Sporadic evidence has been published on a possible relationship [430, 433, 435] and the COVID-19 pandemic provides the perfect test case for future investigations. The “limited pool” hypothesis of narcolepsy type 1 In the EU-NN database, we documented new peaks in narcolepsy type 1 incidence during 2013 in the Netherlands, Italy, and France, whereas the 2010 11
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