328 Chapter 11 This thesis was divided in three sections where Section A targets identification of potential triggers for developing narcolepsy and idiopathic hypersomnia, Section B focusses on brain structure and functioning in narcolepsy type 1 and Section C on future prospects that could improve the diagnostic classification and identify new treatment options. Section A – The past: Identifying Potential Immunological Triggers for Central Disorders of Hypersomnolence Narcolepsy type 1 is hypothesised to be an autoimmune disorder and to develop according to the multiple-hit model in which genetically susceptible individuals undergo environmental triggers before developing excessive daytime sleepiness [4]. The spectrum of environmental triggers that could potentially induce narcolepsy type 1 remained poorly understood and no studies have yet systematically assessed potential triggers for narcolepsy type 2 and idiopathic hypersomnia. Chapter 2 shows us that narcolepsy type 1 incidence rates fluctuate annually within Europe with replication of the 2010 peak and identification of a new incidence peak in 2013 that is specific to children. These fluctuating incidence rates further substantiate the hypothesis that narcolepsy type 1 onset is subject to environmental factors. Given the previous association with Pandemrix vaccination and type A H1N1 influenza and streptococcus pyogenes infections, it seems plausible that these environmental factors are constituted by immunological triggers that lead to an autoimmune reaction disrupting hypocretin synthesis. Chapter 3 covers extension of our work with replication of the incidence peaks in narcolepsy type 1 using large-scale complete datasets from multiple sleep-wake centres across Europe. Notably, the 2013 incidence peak also occurred in adults. We observed similar incidence peaks in 2010 and 2013 in narcolepsy type 2 and idiopathic hypersomnia, independent of HLADQB1*06:02 status and robust for resampling analyses. These findings suggest shared environmental influences among central disorders of hypersomnolence. The severity of preceding type A H1N1 influenza seasons correlated significantly with incidence rates across age groups in narcolepsy type 1 and childonset narcolepsy type 2 and idiopathic hypersomnia. In narcolepsy type 1 we additionally identified a new and stronger predictor in the Netherlands, preceding type B Victoria influenza season severity. A negative association was found with preceding influenza season severity for type A H3N2 influenza, which was strongest in children with narcolepsy type 1. This could be explained
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