Hypocretin deficiency treatment9/18/2023 ![]() ![]() The subject enters REM sleep (red bar) abnormally quickly, within 10 minutes of sleep onset, and thereafter has numerous awakenings from REM sleep, explaining the reported experience of numerous disturbing and vivid dreams. The sleep architecture is both severely fragmented and dysregulated. Time through the night is shown at the top. Nevertheless, study of the hypocretin system in the brain has provided significant insight into how the sleep-wake cycle is regulated as well as furthering the diagnostic process in narcolepsy.įigure 1: An example of a hypnogram that demonstrates the typical features of poor overnight sleep in severe narcolepsy. Furthermore, the remarkable landmark discovery that specific loss of around 70000 neurons in the lateral hypothalamus containing the neuropeptide hypocretin could cause human narcolepsy and cataplexy 1 has yet to lead to any significant therapeutic breakthroughs. The newest useful treatment to become available is a novel stimulant drug that increases cortical histaminergic transmission, Pitolisant.ĭespite major advances in our understanding of narcolepsy and its neurobiology over the last 15 years, many questions concerning its nature and causation remain. ![]() Future treatments are likely to focus on hypocretin replacement via oral or intra-nasal medication.A recent surge in incidence amongst children in particular following the swine ‘flu vaccination (Pandemrix) in 2009 has fuelled the notion of an autoimmune aetiology although many questions remain.In these latest guidelines, the multiple sleep latency test remains an important diagnostic tool despite its poor sensitivity and reliability. The most recent diagnostic classification divides narcolepsy into type 1 (with cataplexy and significant hypocretin deficiency) and type 2 (without cataplexy and normal or low hypocretin levels).Nocturnal sleep fragmentation is a key feature and helps to explain why the sedative agent, sodium oxybate, is the best available treatment.Its phenotype is wide and includes elements not directly related to sleep such as appetite control, perhaps reflecting hypothalamic dysfunction. The narcoleptic syndrome is best viewed as a disorder of sleep-wake regulation, particularly affecting the REM sleep stage.Powerful hypnotic agents, notably, sodium oxybate, consolidate the fragmented sleep frequently seen in narcolepsy and improve many of the daytime symptoms as a likely consequence. A new wake-promoting agent that increases brain histamine levels (pitolisant) has recently become available and will probably be used alongside modafinil and more traditional psychostimulants such as dexamphetamine. Treatment options remain symptomatic and are often only partially effective. However, it is likely the classification system will be further refined. Narcolepsy is now classed as either type 1 or type 2, depending on sleep investigation results and whether cataplexy and/or hypocretin deficiency is present. Several lines of evidence, including a causal link to the swine ‘flu vaccination, suggest autoimmune destruction of these neurons as an initial event. Typical cases are due to specific loss of a subset of hypothalamic neurons containing the neuropeptide, hypocretin (orexin). It is best viewed as a disorder of sleep-wake regulation with particular abnormalities of the rapid eye movement (REM). Narcolepsy is thought to affect 0.05% of Caucasian populations and frequently causes severe symptoms across the 24-hour period. ![]()
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