110 Chapter 4 Several participants in our study who received an H1N1 influenza vaccination also reported an infection directly linked to the onset of their narcolepsy type 1. It remains unclear why immunological events rapidly trigger the onset of hypersomnolence symptoms in some, whereas, in others who experienced the same trigger, narcolepsy symptoms take many years to arise in individuals with delayed onset. It could be that the initial trigger induced a slow-paced autoimmune process that remained asymptomatic at first, or that additional triggers, closer to symptom onset or in different environmental circumstances, were needed to trigger the onset of the hypersomnolence disorder. This idea aligns with the multiple-hit model in which people with a specific genetic predisposition must experience multiple environmental triggers to develop narcolepsy [4]. In our sample, flu and other respiratory infections were frequently associated with the rapid development of narcolepsy type 1 with short delays between EDS and cataplexy. This suggests that these infections are relatively strong triggers for developing narcolepsy type 1 in genetically susceptible people. Longer delays between EDS and cataplexy were generally seen after EBV infection, implying that it is a weaker potential trigger. This aligns with a recent genome-wide association study (GWAS) that suggests that genetic polymorphisms in narcolepsy type 1 lead to increased influenza viral uptake by dendritic cells and antigen presentation to CD4+ T-cells [157]. This strong immune response to influenza infection could play a crucial role in the autoimmune attack leading to hypocretin deficiency. Interestingly, no genetic associations were found related to bacterial infection clearance. The genetic relationship between respiratory infections (such as streptococcus pyogenes) and narcolepsy type 1 development remains unclear. The higher prevalence of infections in people with narcolepsy type 2 and idiopathic hypersomnolence than in people with narcolepsy type 1, should not be overinterpreted. In people with EDS without cataplexy, physicians are more likely to check the medical history to rule out other potential causes for excessive sleepiness, potentially leading to increased identification of preceding infections. In many people with narcolepsy type 2 or idiopathic hypersomnia, the reported infections occurred long before onset of their hypersomnolence disorders. This was seen less in narcolepsy type 1. In cases where no infection was identified in narcolepsy type 2 and idiopathic hypersomnia, we believe the opposite may be true, leading to an overestimation of infection prevalence in these diagnoses. As narcolepsy type 2 and idiopathic hypersomnia had so far not been associated with immunological triggers, we think that physicians could have been more prone to not document absence of an infection compared to presence of an infection. This could explain why missing reports
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