15 Introduction and idiopathic hypersomnia has so far hindered scientific and therapeutic breakthroughs. Environmental triggers The aetiopathogenesis of hypocretin deficiency in narcolepsy type 1 is currently thought to have an autoimmune basis with roots in both genetic and environmental factors. Genetic predisposition of the human leukocyte antigen (HLA) complex HLA-DQB1*06:02 increases susceptibility to develop narcolepsy type 1 by over 200-fold, and up to 98% of patients carry this haplotype [51-53]. HLA-DQB1*06:02 has been considered a genetic factor that is essential but not sufficient to develop narcolepsy type 1 as 20-30% of the general European population also carries this haplotype. Associations with other HLA classes have been reported (such as HLA-DR and HLA-A) albeit not as strong as HLA-DQ, and HLA-DQB1*06:02 in particular [51-53]. The onset of narcolepsy type 1 most commonly manifests during adolescence and young adulthood [54, 55] and has been associated with immunological life events. In the winter of 2009-2010 the influenza A virus subtype H1N1 resurfaced through a pandemic, after which clearly increased incidence rates of narcolepsy type 1 were quickly reported in Scandinavian children [56, 57]. The H1N1 vaccine named Pandemrix® (GlaxoSmithKline Biologicals, Wavre, Belgium) that was frequently administered in these countries, was initially deemed to be the culprit. Not long after, research groups from countries with low vaccination grades (such as China, the United States, Taiwan, and several other European countries) also reported a more modest increase in narcolepsy type 1 incidence [57-61]. A possible role for the H1N1 virus itself was thus emphasized. The discovery that immune system-related triggers such as Pandemrix vaccination and H1N1 infection are associated with narcolepsy type 1 development, in combination with the H1N1 virus not circulating for decades before its reintroduction in 2009-2010 [62], has sparked interest into the possibility of other triggers also causing narcolepsy type 1. Mainly streptococcal infections have been associated with onset of narcolepsy type 1 but direct causal evidence of underlying pathophysiological mechanisms [10, 63-67], and assessment of other potential triggers remains limited. Non-flu potential triggers remain poorly studied, also in the context of narcolepsy type 2 and idiopathic hypersomnia. In Chapter 2 we present narcolepsy incidence rates before and after the 2009-2010 H1N1 pandemic using the EU-NN database. Our analyses in Chapter 3 additionally provide correlations with local severity data of the preceding flu season to identify whether particular influenza strains are attributable to 1
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