356 Chapter 11 Conclusions This dissertation explores the past, present, and future of central disorders of hypersomnolence. In Section A we examine the role of immunological triggers in these disorders. We found fluctuating annual incidence rates of narcolepsy type 1, type 2 and idiopathic hypersomnia with peaks in 2010 and 2013. These fluctuations correlated with severe type A H1N1 influenza seasons and, for narcolepsy type 1, type B Victoria influenza in the Netherlands. Selfreported immunological triggers were frequent, diverse, and often closely preceded the onset of excessive daytime sleepiness. In Section B we present the effects of narcolepsy type 1 on brain structure and functioning. Multimodal studies revealed lower axonal density in hypocretin pathways and lower activity in attention and arousal regions during a vigilance task, and visual activation during active sleep resistance. In Section C we use unsupervised machine learning to identify reliable subgroups within central disorders of hypersomnolence with different subgrouping of those without cataplexy, and further explore the potential of opioids as a treatment for narcolepsy type 1. Distinct clusters were found, suggesting the need to include biomarkers like sleep drunkenness in future diagnostic criteria. The multimodal assessment implemented in this dissertation has provided important insights into the possible trigger-related origin, neural correlates and future diagnostic and therapeutic perspectives of central disorders of hypersomnolence. In an era of rapidly advancing understanding of narcolepsy type 1, it is crucial for the scientific community to utilize recent findings to also uncover the pathophysiologies of central hypersomnolence disorders in absence of cataplexy. First, re-evaluation of current classifications of narcolepsy type 2 and idiopathic hypersomnia is necessary, as accurate resemblance of underlying phenotypes will prove essential for identifying meaningful disease mechanisms. This should be followed by international collaboration to amass sufficient data of these orphan disorders to carefully investigate the trigger-related pathophysiologies and brain profiles of all central disorders of hypersomnolence. Adapting translational approaches at various stages will illuminate their underlying aetiologies and disease courses, ultimately aiming to develop new, potentially disease-modifying or preventive treatment strategies for all central disorders of hypersomnolence.
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