107 Potential Immunological Triggers for Central Disorders of Hypersomnolence Discussion Immunological events before disease onset were frequently reported across central disorders of hypersomnolence. The distribution of immunological events differed between people with narcolepsy type 1, and those with narcolepsy type 2 or idiopathic hypersomnia. In people with narcolepsy type 1, flu infections and H1N1 influenza vaccinations were most common, but other infection types were also reported. In people with narcolepsy type 2 or idiopathic hypersomnia, EBV, other respiratory and non-respiratory infections were often reported, while influenza vaccinations were uncommon. Onset within one year of the potential trigger was frequently reported in both groups but tended to be more common in people with narcolepsy type 1. Flu infection, in particular, was associated with rapid onset of EDS and cataplexy, often within a month. The variety of immunological events in narcolepsy type 1 replicate previously associated H1N1 infection [60, 136, 137, 189], streptococcal infection [10, 63-67, 180], and Pandemrix vaccination [56, 57, 134, 159] as potential immunological triggers. New potential triggers were also identified, including EBV and other upper respiratory and non-respiratory infections. These infections are common in the general population, but in our data, they frequently occurred within days to weeks before the onset of narcolepsy type 1. Thus, a direct relationship seems plausible. If we look for immunological commonalities among these infections, most involved the respiratory system and febrile illnesses were frequently seen. Reports of flu infections directly before narcolepsy type 1 onset in years where H1N1 was not the dominant flu strain within the Netherlands raise the question whether other flu strains (such as type B influenza or type A H3N2) could also be responsible for triggering narcolepsy type 1. More recently, questions have also arisen about the potential of COVID-19 infection and/or vaccination to trigger narcolepsy type 1. Future research should unravel this relationship and identify specific pathogens responsible for triggering narcolepsy type 1. Surprisingly, we found frequent infections before the onset of narcolepsy type 2 and idiopathic hypersomnia. This provides new insights into the potential of immunological pathophysiology underlying these non-hypocretin-1 deficient hypersomnolence forms. In some people with narcolepsy type 2 (but not in idiopathic hypersomnia), there have been reports of moderate loss of hypothalamic hypocretin-1 cells, while CSF-derived hypocretin-1 levels remain close to normal [29, 190, 191]. It is hypothesized that hypocretin-1 levels in CSF (derived through lumbar punctures) lack the sensitivity needed to detect such partial loss of hypocretin-1 neurons [39]. Partial hypocretin-1 neuron loss may therefore remain unnoticed in narcolepsy type 2. This suggests 4
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