Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep.
[8] Proposed pathophysiology as an autoimmune disease suggest antigen presentation by DQ0602 to specific CD4+ T cells resulting in CD8+ T-cell activation and consequent injury to orexin producing neurons.
[medical citation needed] Excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that do not require much interaction.
[15] The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy", are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness.
There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals.
When a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement (NREM) sleep.
People with narcolepsy fall quickly into what appears to be very deep sleep, and they wake up suddenly and can be disoriented when they do (dizziness is a common occurrence).
[1] There is a strong link with certain genetic variants,[27] which may make T-cells susceptible to react to the orexin-releasing neurons (autoimmunity)[30] after being stimulated by infection with H1N1 influenza.
[15][27] The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex.
[27][32] These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.
T-cells have been demonstrated to be cross-reactive to both a particular piece of the hemagglutinin flu protein of the pandemic 2009 H1N1 and the amidated terminal ends of the secreted hypocretin peptides.
[36][37] In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by molecular mimicry with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy.
[12] Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes.
During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway.
When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night.
[citation needed] The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy.
However, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans.
[52][53] General strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful.
Ongoing communication between the health care provider, person, and their family members is important for optimal management of narcolepsy.
[63] Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.
[71] Narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits or recreational drug use, making misdiagnosis likely.
[73] In 2015, it was reported that the British Department of Health was paying for sodium oxybate medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the Pandemrix swine flu vaccine.
This research showed that flumazenil provides relief for most people whose CSF contains the unknown "somnogen" that enhances the function of GABAA receptors, making them more susceptible to the sleep-inducing effect of GABA.
For one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years.
[81] In a test tube model, clarithromycin (an antibiotic approved by the FDA for the treatment of infections) was found to return the function of the GABA system to normal in people with primary hypersomnias.
In order to help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012.
"Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity."
[92] The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder.
[91] Narcolepsy with cataplexy was identified in a few breeds like Labrador retrievers or Doberman pinschers where it was investigated the possibility to inherit this disorder in the autosomal recessive mode.
Rats who lost the majority of their orexinergic neurons exhibited multiple SOREMPs as well as less wakefulness during nocturnal hours, shortened REM latency, and brief periods of cataplexy.