332 Chapter 11 other infections in society, as this will result in high rates of positivity for these infections within control groups. Cross-reactivity of involved immune cell populations to hypocretin should therefore be standardly assessed. Direct evidence on the relationship between influenza and onset of central disorders of hypersomnolence remains limited. The study presented in Chapter 2 did not directly incorporate data on relevant environmental factors and only included partial samples as most of the EU-NN expert centres had not included their complete populations in the database. In the analyses in Chapter 3 we aimed to overcome these limitations by incorporating full samples and preceding influenza seasons severity data. We modelled frequent environmental events such as influenza infection with incidence rates of the relatively rare disorders narcolepsy and idiopathic hypersomnia. Despite our large European samples, future studies should aim for even larger ones. Since reliable influenza monitoring data for type B Victoria influenza was only available for the Netherlands, these results require replication in independent samples. Our analyses described in Chapters 3 and 4 also were insufficiently powered to perform detailed subgroup analyses on narcolepsy type 2 and idiopathic hypersomnia. Despite exploratory post-hoc analyses suggesting similar results in narcolepsy type 2 and idiopathic hypersomnia in both chapters, similar larger analyses should be repeated in future studies. The immunological events that were reported in Chapter 4 are retrospective and an influence of recall bias should be considered. We gathered detailed self-reported immunological history of infections and vaccinations before the onset of hypersomnolence through consistent questioning during the intake visits and confirmed events via medical records from general practitioners whenever available. Apart from EBV, many of the infections were not laboratory confirmed, which could have led to misdiagnosis in our results. Future perspectives Box 1 – Research agenda Section A • Is narcolepsy type 1 an autoimmune disorder? • The multiple-hit model of narcolepsy type 1 • The “limited pool” hypothesis of narcolepsy type 1 • Possible immunological origin of narcolepsy type 2 and idiopathic hypersomnia without long sleep time?
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