21 Introduction Treatment options No curative treatments are currently available for any of the central disorders of hypersomnolence. Across the diagnoses, the non-pharmacological options include regular bedtimes, scheduled daytime napping, patient education and psychotherapy. Various wake-promoting agents are effective against EDS and include methylphenidate, dexamphetamine, modafinil/armodafinil, pitolisant and solriamfetol. These compounds act on dopamine, histamine, noradrenaline and other systems [4, 121-123]. Commonly used compounds for treating cataplexy are sodium oxybate or antidepressants like clomipramine or venlafaxine [121, 123]. As a GABAB receptor agonist, sodium oxybate leads to more consolidated nocturnal sleep and is effective against all major narcolepsy symptoms, even though its exact mode of action remains largely unknown [124]. Pitolisant is also effective against cataplectic attacks, but its effect is usually weaker than sodium oxybate. Based on individuals’ symptoms, different combinations of sodium oxybate, wake-promoting agents and antidepressants may be used. The currently available treatments often have adverse side effects and incompletely alleviate excessive daytime sleepiness, which are essential considerations in finding the optimal treatment regimen [123]. A recent study in rodents and postmortem human brain tissue has suggested that opioids interact with the hypocretin system and could hereby possibly relieve narcolepsy type 1 symptoms [125]. Mainly case reports have been reported and no structured assessment has been conducted on this potential new treatment option in humans with narcolepsy type 1 [126-131]. In Chapter 10 we assess the possible effects of opioid use on narcolepsy type 1 symptomatology. Outline of the thesis This thesis assesses the past (Section A), present (Section B) and future (Section C) of central disorders of hypersomnolence. Section A on the origin of central disorders targets the role of immunological triggers in developing central disorders of hypersomnolence. We studied annually fluctuating incidence rates of narcolepsy type 1 (Chapter 2) in the EU-NN database, annual incidence rates of all central disorders of hypersomnolence in relation to preceding flu season severity in multiple complete European centres (Chapter 3) and realworld insights on immunological events that people with a central disorder of hypersomnolence reported prior to disease onset (Chapter 4). The chapters on the present in Section B first focus on brain morphology of people with 1
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