109 Potential Immunological Triggers for Central Disorders of Hypersomnolence their sleep disorder. Symptomatic EBV infection is known to cause complaints of fatigue, pharyngitis, tonsillitis, fever, and cervical lymphadenopathy [194]. Fatigue could be mistaken for expressing a central disorder of hypersomnolence leading to a test bias. Long-lasting EBV symptoms are rare but have been described and may include EDS [195, 196]. EDS complaints (and cataplexy in narcolepsy type 1) were continuously present in our study for multiple years in people who reported EBV infection. EBV has been associated with the onset of other (presumed) autoimmune disorders, including multiple sclerosis and multiple haematological malignancies [197-199]. A potential role for EBV in triggering hypersomnolence should be further assessed. 2009–2010H1N1 influenza vaccination was commonly reported as a trigger in people with narcolepsy type 1. No relationship was seen for influenza vaccination in other years. Influenza vaccinations have consistently included H1N1 since 2009. Pandemrix employed a novel adjuvant (AS03) that elicited a potentiated immune response, hypothesized as the primary factor for developing narcolepsy type 1 [200]. Discontinuation of this adjuvant after 2010 could explain why we found no association between influenza vaccination and narcolepsy type 1 onset outside 2009–2010. Multiple influenza vaccine brands were administered in the Netherlands during 2009–2010. Eight individuals with narcolepsy type 1 said they had received Pandemrix and two Focetria. Without a national vaccination registry, we could not trace the type of vaccination in other individuals. All children from six months to five years old and people living in their households, paediatric at-risk populations, soldiers on foreign deployments and pregnant women were offered 2009–2010H1N1 influenza vaccination with Pandemrix in the Netherlands [201]. Eleven children in our sample between six months and five years old were reported to have received H1N1 influenza vaccination. More than one-year latency between H1N1 influenza vaccination and narcolepsy type 1 symptom onset was frequently seen and is in line with previous reports in the United Kingdom [186]. Our sample’s latency was up to ten years, making a direct relationship unlikely. Why Pandemrix could have resulted in rapid onset of narcolepsy type 1 in some but not in others remains unknown. These others have possibly experienced additional triggers closer to narcolepsy type 1 onset. Other vaccinations unrelated to influenza were also reported before narcolepsy type 1 onset and included HPV, hepatitis A and hepatitis B vaccination. Routine HPV vaccination has only recently been introduced and is normally administered around the same age as when narcolepsy symptoms generally arise. Previous studies have also not found increased narcolepsy incidence rates following HPV vaccination [202, 203], so this finding should not be over-interpreted. 4
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