65 Incidence Peaks and the Role of Influenza Introduction Narcolepsy type 1 (NT1) is a neurological disorder characterized by excessive daytime sleepiness (EDS) and cataplexy, resulting from the loss or dysfunctioning of hypocretin (or orexin) neurons [45]. A connection with environmental events triggering NT1 gained interest after increased incidence rates were reported in children in North European countries with widespread use of Pandemrix (GlaxoSmithKline Biologicals, Wavre, Belgium), a type A H1N1 influenza vaccine, during the 2009-2010 type A H1N1 influenza pandemic (pH1N1) [56, 57]. Subsequent data from France suggested that the use of Pandemirix was associated with increased NT1 incidence rates in both children and adults [134]. Also in East Asia and the United States where Pandemrix was not used, incidence increases were noted, leading to the hypothesis that the type A H1N1 influenza virus itself may also trigger NT1 [58-60, 136, 137]. Later genetic evidence further supported this hypothesis [157]. It seems plausible that various triggers must already have been present before the recirculation of type A H1N1 in 2009. Streptococcus pyogenes infections have been associated with onset of NT1 but supporting evidence remains limited [63-65, 67, 158]. The concept of the multiple-hit hypothesis emerged, suggesting that immunemediated narcolepsy might not be specific to type A H1N1 influenza infection or Pandemrix vaccination but involves various triggers, potentially combined, to induce NT1 in genetically susceptible individuals [4, 72]. Within multiple European countries, a second NT1 incidence peak was discovered for 2013 using the European Narcolepsy Network (EU-NN) database [159]. Most interestingly, this peak was child-specific. These fluctuating narcolepsy incidence rates suggest a temporal relationship between narcolepsy development and environmental fluctuations, such as influenza type and season severity. Influenza seasons differ heavily geographically and on an annual basis in regards to duration, severity and dominance of particular influenza strains. Since the recirculation of type A H1N1 after the pH1N1, four regularly circulating influenza strains are generally identified, type A H3N2, type A H1N1, type B Victoria and type B Yamagata. Where re-assortment in type A influenza is much faster, type B influenza generally affects younger individuals and less frequently requires medical consultation [160, 161]. In the United States and China, NT1 incidence rates were only weakly correlated to type A H1N1 influenza season severity [59, 162]. This could be driven by geographic differences within these large countries in influenza season severity and strain dominance, or the influence of other, still unknown triggers. Whether the temporal relationship between type A H1N1 influenza 3
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