354 Chapter 11 following daytime sleep or comparison with other vigilance tasks such as the SART [458]. Are there sex-specific subtypes of narcolepsy type 1? We identified a narcolepsy type 1 cluster with female predominance (Chapter 9), coupled with mild cataplexy, hypnagogic hallucinations, and sleep paralysis. The mild cataplexy with fewer triggers that we observed might more easily be overlooked by clinicians and could explain the longer diagnostic delays in females that have previously been reported [55, 342]. Automatic behaviours, depressive symptoms and official registrations as having a disability, have also been reported more frequently in women [459]. Animal studies using narcolepsy type 1 mice models have suggested female mice on average to have significantly more frequent and complete cataplexy attacks with younger onset compared to male mice [460-463]. These findings were related to oestrous cycle changes [461]. In summary, these recent studies have provided conflicting results suggesting different average narcolepsy type 1 disease burden in females compared to males. Future research should systematically assess sex-specific and hormonal influences on narcolepsy type 1 during different life stages, while also taking into account possible cross-cultural effects. Are hypocretin neurons destructed or is hypocretin deficiency reversible? The recently observed stimulating effects of opioids on hypocretin cell counts and functioning [125], and our self-reported narcolepsy type 1 symptom improvements during opioid use, suggest that opioids may directly induce alterations to the hypocretinergic system. Where early studies claimed destruction of hypocretin neurons since they were untraceable using postmortem hypothalamic immunohistochemistry [44, 45], more recent studies have provided clues that hypocretin deficiency might stem from a lack of hypocretin expression rather than from the death of neurons [125, 380]. Higher numbers of postmortem hypocretin neurons have been found in the hypothalamus of heroin addicts compared to healthy donors, and a relatively higher hypocretin cell count in an individual with narcolepsy type 1 with chronic opioid use (compared to other donors with narcolepsy type 1). Using animal models it has been shown that these increases were likely not due to neurogenesis [125]. Besides highlighting the potential of treatment with opioids, these results suggest that hypocretin deficiency in narcolepsy type 1 may be reversible. In future randomized controlled trials with opioids
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