Present and Future of Central Disorders of Hypersomnolence

Central disorders of hypersomnolence (CDH) are rare neurological conditions lumped by excessive daytime sleepiness (EDS) as primary complaint mostly arising at young age, including narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS). Advances in clinical and translational research have deepened our understanding of NT1, particularly the loss of hypothalamic hypocretin/orexin-producing neurons, establishing hypocretin deficiency as a reliable disease specific biomarker, although the exact mechanisms of neuronal loss remain unknown. Conversely, the pathophysiological mechanisms underlying NT2, IH, and KLS are still poorly understood, as well as their natural course. Standard diagnostic evaluation primarily relies on clinical symptoms, polysomnography and the multiple sleep latency test, with alternative neurophysiological markers (long term polysomnographic recordings), quantitative signal analysis, and wearables technologies being explored as potential innovative tools. Management remains symptomatic, combining pharmacological treatments such as stimulants, sodium oxybate, and emerging hypocretin/orexin receptor agonists, with nonpharmacological strategies tailored to improve patient quality of life. Notably, new therapies targeting orexin signalling offer promising avenues for transforming treatment approaches, particularly in NT1. Looking ahead, advancing precision medicine approaches and addressing unmet needs in CDH are essential to improve patient outcomes. This review summarises current knowledge and highlights future research directions in CDH pathophysiology, diagnostic approaches and pharmacological management.