331 Discussion idiopathic hypersomnia, similar results between both groups were found in our exploratory post-hoc analyses. There are differences with narcolepsy type 1 that should be considered and may be linked to HLA-DQB1*0602-related susceptibility, which is relatively absent in narcolepsy type 2 and idiopathic hypersomnia. We identified different distributions of potential triggers prior to onset of excessive daytime sleepiness with relatively fewer reports of H1N1 influenza vaccination and more non-flu infections in narcolepsy type 2 and idiopathic hypersomnia. There also was no significant association with preceding type B Victoria influenza season severity. The regular reports of Epstein-Barr virus (EBV) are in line with a recent report of uniform positive EBV serology in ten individuals with idiopathic hypersomnia [187]. EBV has been associated with the onset of other (presumed) autoimmune disorders, including multiple sclerosis and multiple haematological malignancies [197, 198, 394]. Long-lasting EBV symptoms are rare but may include excessive daytime sleepiness [195, 196]. A potential role for EBV in triggering central disorders of hypersomnolence should therefore be assessed in future studies. The significant association with preceding type A H1N1 influenza season severity (Chapter 3) contradicts the relatively fewer self-reported influenza infections in narcolepsy type 2 and idiopathic hypersomnia compared to narcolepsy type 1 (Chapter 4). This could be explained by the notably weaker association with preceding type A H1N1 influenza season severity in narcolepsy type 2 and idiopathic hypersomnia compared to narcolepsy type 1, and the relatively small sample of individuals with narcolepsy type 2 and idiopathic hypersomnia that were included in our study described in Chapter 4. Future replications of these findings in larger samples are necessary, and our results on narcolepsy type 2 and idiopathic hypersomnia should mainly be considered hypothesis-generating. Methodological considerations Section A provides important new associations between central disorders of hypersomnolence and immunological events as potential triggers. Association should however not be mistaken for causation. Our results require replication with independent control groups and follow-up laboratory testing is warranted to unravel possible underlying cellular immunological mechanisms. The main challenge for such studies will be to obtain biosamples within the window of an ongoing autoimmune attack (preferably days to weeks of onset of central disorders of hypersomnolence). Another obstacle for future antigen/ antibody studies will be managing the frequent circulation of influenza and 11
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