Emmanuel Mignot^a, Jamie Zeitzer^a, Fabio Pizza^{b, c}, Giuseppe Plazzi^{c, d}

^a Center for Narcolepsy, Stanford University, Palo Alto, CA, USA; 
^b Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 
^c IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; 
^d Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy

© 2021 The Author(s)
Published by S. Karger AG, Basel

• Chapter 9 graphical abstract

Since its description in the 19th century, narcolepsy type 1 (NT1) has been considered as a model sleep disorder, and after the discovery of rapid eye movement (REM) sleep onset in the disorder, a gateway to understanding REM sleep. The discovery that NT1 is caused by hypocretin/orexin deficiency, together with neurochemical studies of this system, has helped to establish how this neuropeptide regulates the organization of sleep and wake in humans. Current analyses suggest that the main functions of the hypocretin/orexin system are (1) maintenance of wakefulness in the face of moderate sleep deprivation; (2) passive wake promotion, especially in the evening, driven by the circadian clock; (3) inhibition of REM sleep, with possible differential modulating effects on various subcomponents of the sleep-stage, explaining REM sleep dissociation events in NT1. Narcolepsy is also associated with an inability to consolidate sleep, a more complex phenotype that may result from secondary changes or be central to the role of hypocretin in coordinating the activity of other sleep- and wake-promoting systems. Novel technologies, such as the use of deep learning analysis of electroencephalographic signals, is revealing a complex pattern of sleep abnormalities in human narcolepsy that can be used diagnostically. The availability of novel devices measuring sleep 24 h per day also holds promise to provide new insights into how brain electrical activity and muscle tone are regulated by hypocretin.

• Hypocretin/orexin deficiency in NT1 is associated with complex sleep-wake abnormalities that change from onset to established cases.
• Hypocretin/orexin deficiency is best defined by a decreased wake drive and a disinhibition of REM sleep occurrence, which can occur as normal REM sleep or as wake-REM sleep dissociated events (sleep paralysis hallucinations, and maybe cataplexy). These disrupt both sleep and wake.
• Once established, disturbed nocturnal sleep in narcolepsy is best described as an inability to stay asleep for a long period of time accompanied by dissociated sleep stages such as vivid dreams with partial remembrance and consciousness, REM sleep behavior disorder and sleep paralysis.
• The peak of circadian alertness in the evening is likely blunted in NT1.
• The standard diagnostic test, the MSLT, although specific and sensitive for NT1, is now overused. It has lost its ability to diagnose hypocretin deficiency when cataplexy is not present. Better sleep recording techniques, such as continuous PSG recordings during 24–48 h need to better differentiate the cause of disorders of hypersomnolence. Novel sleep analytics, such as deep learning-based technology, are likely to play a critical role in the diagnosis of narcolepsy and other disorders with a centrally mediated hypersomnolence.

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