The mechanisms underlying NT2 are less clear. Another suggestion is that deficient hypocretin signalling causes more frequent sleep–wake transitions, including brief transitions to REM sleep and partial REM states during wakefulness. Furthermore, because hypocretin-producing neurons stimulate brain areas that inhibit REM sleep, extensive loss of these neurons causes dissociated REM sleep, which may manifest as cataplexy. The pathophysiology of cataplexy is not well-established, but evidence suggests mechanisms that are common to cataplexy and REM sleep paralysis. Lack of hypocretin reduces excitatory signalling to neurons involved in synthesis of the wake-promoting neurotransmitters norepinephrine (NE), dopamine (DA), serotonin (5-hydroxytryptamine ) and histamine, and may lead to a subsequent reduction in activation of the cortex, basal forebrain, hypothalamus and brainstem. In NT1, EDS is a consequence of the loss of hypocretin-producing cells and the resulting hypocretin deficiency. ![]() infection) can contribute to the development of NT1. human leukocyte antigen class II polymorphisms in closely linked loci DQB1*06:02 and DQA1*01:02, which together form the DQ0602 heterodimer) and environmental factors (e.g. The pathophysiologic mechanism underlying NT1 is deficiency of hypocretin signalling, caused by selective loss of hypocretin-producing neurons in the hypothalamus, likely a result of autoimmune-related destruction. NT2 criteria include absence of cataplexy normal or unmeasured CSF levels of hypocretin 1 and no other condition (including the effect of medication or of its withdrawal) that better explains the EDS and/or MSLT findings. ![]() (A nocturnal polysomnographic test finding of a SOREMP within < 15 min of sleep onset may replace one SOREMP on the MSLT.) NT1 diagnostic criteria also include presence of cataplexy, and/or reduced cerebrospinal fluid (CSF) levels of hypocretin 1 (orexin A). Criteria common to both types include (1) chronic daily excessive sleepiness lasting ≥ 3 months and (2) mean sleep latency ≤ 8 min and two or more sleep-onset rapid eye-movement (REM) periods (SOREMPs) on the Multiple Sleep Latency Test (MSLT). The International Classification of Sleep Disorders–Third Edition (ICSD-3) diagnostic criteria for narcolepsy include two types: narcolepsy type 1 (NT1) and type 2 (NT2). Other symptoms are disturbed night-time sleep hypnagogic and hypnopompic hallucinations, which occur while falling asleep and waking up, respectively and sleep paralysis. Cataplexy, an involuntary loss of muscle tone during wakefulness that is typically evoked by strong emotions, occurs in up to 60% of patients. Symptoms of narcolepsy include excessive daytime sleepiness (EDS), which, although not specific to narcolepsy, is a characteristic of the disorder present in all patients, as it is a requirement for diagnosis. The onset of narcolepsy most commonly occurs in the second decade of life, though diagnosis is often delayed by several years. Narcolepsy, a chronic, disabling neurologic disorder of hypersomnolence, affects an estimated 20–67 people per 100,000 worldwide. This review summarises the mechanisms of action, pharmacokinetics, efficacy, and safety/tolerability of recently approved and emerging treatments for narcolepsy. ![]() Several new agents are being developed and tested as potential treatments for EDS and cataplexy associated with narcolepsy these agents include novel oxybate formulations (once-nightly low sodium ), a selective norepinephrine reuptake inhibitor (AXS-12), and a product combining modafinil and an astroglial connexin inhibitor (THN102). Pitolisant, an H3R antagonist, and solriamfetol, a dopamine and norepinephrine reuptake inhibitor, are the most recently approved treatments for EDS associated with narcolepsy in the European Union (pitolisant) and the USA (pitolisant and solriamfetol). Modulation of γ-aminobutyric acid B (GABA B) receptors or histamine H 3 receptors (H3Rs) has effects on both EDS and cataplexy. In general, medications that increase the release, or inhibit the reuptake, of norepinephrine or dopamine have wake-promoting effects and are useful in managing EDS, whereas medications that inhibit serotonin or norepinephrine reuptake have anticataplectic effects. ![]() sodium oxybate, venlafaxine), and treating the symptoms of disturbed nocturnal sleep, sleep paralysis and sleep-related hallucinations (e.g. modafinil, armodafinil, stimulants), reducing cataplexy attacks (e.g. Treatments for narcolepsy are aimed at improving wakefulness (e.g. Narcolepsy is a chronic, disabling neurologic disorder characterised by excessive daytime sleepiness (EDS) and, in up to 60% of patients, cataplexy.
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