narcolepsy narcolepsy narcolepsy is a chronic neurological disorder that involves a decreased ability to regulate sleep–wake cycles. symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. about 70% of those affected also experience episodes of sudden loss of muscle strength, known as cataplexy. narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. these experiences of cataplexy can be brought on by strong emotions. less commonly, there may be vivid hallucinations or an inability to move (sleep paralysis) while falling asleep or waking up. people with narcolepsy tend to sleep about the same number of hours per day as people without, but the quality of sleep tends to be lessened. narcolepsythe concentration of orexin-a neuropeptides in the cerebrospinal fluid of narcoleptic individuals is usually very lowpronunciation/ˈnɑːrkəˌlɛpsi/ specialtysleep medicine, neurologysymptomsexcessive daytime sleepiness, involuntary sleep episodes, sudden loss of muscle strength, hallucinationscomplicationsmotor vehicle collisions, fallsusual onsetchildhooddurationlong termcausesorexin deficiencyrisk factorsfamily history, brain injurydiagnostic methodbased on the symptoms and sleep studiesdifferential diagnosissleep apnea, major depressive disorder, anemia, heart failure, drinking alcohol, idiopathic hypersomnia, not getting enough sleeptreatmentmedication, regular short naps, sleep hygienemedicationmodafinil, sodium oxybate, wakix, methylphenidate, amphetamine, stimulants, antidepressantfrequency0.2 to 600 per 100,000 narcolepsy is a clinical syndrome of hypothalamic disorder, however, the exact cause of narcolepsy is unknown, with potentially several causes. in up to 10% of cases, there is a family history of the disorder. often, those affected have low levels of the neuropeptide orexin, which may be due to an autoimmune disorder triggered in genetically susceptible individuals by infection with h1n1 influenza. in rare cases, narcolepsy can be caused by traumatic brain injury, tumors, or other diseases affecting the parts of the brain that regulate wakefulness or rem sleep. diagnosis is typically based on the symptoms and sleep studies, after ruling out other potential causes. excessive daytime sleepiness can also be caused by other sleep disorders such as sleep apnea, major depressive disorder, anemia, heart failure, drinking alcohol and not getting enough sleep. the accompanying cataplexy may be mistaken for seizures. while there is no cure, a number of lifestyle changes and medications may help. lifestyle changes include taking regular short naps and sleep hygiene. medications used include modafinil, sodium oxybate and methylphenidate. while initially effective, tolerance to the benefits may develop over time. tricyclic antidepressants and selective serotonin reuptake inhibitors (ssris) may improve cataplexy. estimates of frequency range from 0.2 to 600 per 100,000 people in various countries. the condition often begins in childhood, with males and females being affected equally. untreated narcolepsy increases the risk of motor vehicle collisions and falls. narcolepsy generally occurs anytime between early childhood and 50 years of age, and most commonly between 15 and 36 years of age. however, it may also rarely appear at any time outside of this range. signs and symptoms there are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal rem sleep. excessive daytime sleepiness occurs even after adequate night time sleep. a person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate or undesired times and places, or just be very tired throughout the day. narcoleptics may not be able to experience the amount of restorative deep sleep that healthy people experience due to abnormal rem regulation – they are not "over-sleeping". narcoleptics typically have higher rem sleep density than non-narcoleptics, but also experience more rem sleep without atonia. many narcoleptics have sufficient rem sleep, but do not feel refreshed or alert throughout the day. this can feel like living their entire lives in a constant state of sleep deprivation. excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that don't require much interaction. daytime naps may occur with little warning and may be physically irresistible. these naps can occur several times a day. they are typically refreshing, but only for a few hours or less. vivid dreams may be experienced on a regular basis, even during very brief naps. drowsiness may persist for prolonged periods or remain constant. in addition, night-time sleep may be fragmented, with frequent awakenings. a second prominent symptom of narcolepsy is abnormal rem sleep. narcoleptics are unique in that they enter into the rem phase of sleep in the beginnings of sleep, even when sleeping during the day. the classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy," are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. other symptoms may include automatic behaviors and night-time wakefulness. these symptoms may not occur in all people with narcolepsy. an episodic loss of muscle function, known as cataplexy, ranging from slight weakness such as limpness at the neck or knees, sagging facial muscles, weakness at the knees often referred to as "knee buckling", or inability to speak clearly, to a complete body collapse. episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear. the person remains conscious throughout the episode. in some cases, cataplexy may resemble epileptic seizures. usually speech is slurred and vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. cataplexy also has a severe emotional impact on narcoleptics, as it can cause extreme anxiety, fear, and avoidance of people or situations that might elicit an attack. cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis in that the usually protective paralysis mechanism occurring during sleep is inappropriately activated. the opposite of this situation (failure to activate this protective paralysis) occurs in rapid eye movement behavior disorder. periods of wakefulness at night the temporary inability to talk or move when waking (or less often, when falling asleep), known as sleep paralysis. it may last a few seconds to minutes. this is often frightening but is not dangerous. vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep, known as hypnagogic hallucinations. hypnopompic hallucinations refer to the same sensations while awakening from sleep. these hallucinations may manifest in the form of visual or auditory sensations. in most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. the other symptoms may begin alone or in combination months or years after the onset of the daytime naps. there are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. only about 20 to 25 percent of people with narcolepsy experience all four symptoms. the excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not. many people with narcolepsy also have insomnia for extended periods of time. the excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a person's social, personal, and professional life. normally, when an individual is awake, brain waves show a regular rhythm. when a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement (nrem) sleep. after about an hour and a half of nrem sleep, the brain waves begin to show a more active pattern again, called rem sleep (rapid eye movement sleep), when most remembered dreaming occurs. associated with the eeg-observed waves during rem sleep, muscle atonia is present called rem atonia. in narcolepsy, the order and length of nrem and rem sleep periods are disturbed, with rem sleep occurring at sleep onset instead of after a period of nrem sleep. also, some aspects of rem sleep that normally occur only during sleep, like lack of muscular control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy. for example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is an intrusion of rem atonia during wakefulness. sleep paralysis and vivid dreams can occur while falling asleep or waking up. simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (rem) sleep. as a consequence night time sleep does not include as much deep sleep, so the brain tries to "catch up" during the day, hence excessive daytime sleepiness. people with narcolepsy may visibly fall asleep at unpredicted moments (such motions as head bobbing are common). 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). they have very vivid dreams, which they often remember in great detail. people with narcolepsy may dream even when they only fall asleep for a few seconds. along with vivid dreaming, people with narcolepsy are known to have audio or visual hallucinations prior to falling asleep. narcoleptics can gain excess weight; children can gain 20 to 40 lb (9 to 18 kg) when they first develop narcolepsy; in adults the body-mass index is about 15% above average. causes the exact cause of narcolepsy is unknown, and it may be caused by several distinct factors. the mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus (about 70,000 neurons). some researches indicated that people with type 1 narcolepsy (narcolepsy with cataplexy) have a lower level of orexin (hypocretin), which is a chemical contributing to the regulation of wakefulness and rem sleep. it also acts as a neurotransmitter to enable nerve cells to communicate. in up to 10% of cases there is a family history of the disorder. family history is more common in narcolepsy with cataplexy. there is a strong link with certain genetic variants, which may make t-cells susceptible to react to the orexin-releasing neurons (autoimmunity) after being stimulated by infection with h1n1 influenza. in addition to genetic factors, low levels of orexin peptides have been correlated with a history of infection, diet, contact with toxins such as pesticides, and brain injuries due to head trauma, brain tumors or strokes. genetics 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. specific variations in hla genes are strongly correlated with the presence of narcolepsy (hla dqb1*06:02, frequently in combination with hla drb1*15:01); however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. 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. the allele hla-dqb1*06:02 of the human gene hla-dqb1 was reported in more than 90% of people with narcolepsy, and alleles of other hla genes such as hla-dqa1*01:02 have been linked. a 2009 study found a strong association with polymorphisms in the trac gene locus (dbsnp ids rs1154155, rs12587781, and rs1263646). a 2013 review article reported additional but weaker links to the loci of the genes tnfsf4 (rs7553711), cathepsin h (rs34593439), and p2ry11-dnmt1 (rs2305795). another gene locus that has been associated with narcolepsy is eif3g (rs3826784). h1n1 influenza type 1 narcolepsy is caused by hypocretin/orexin neuronal loss. 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. genes associated with narcolepsy mark the particular hla heterodimer (dq0602) involved in presentation of these antigens and modulate expression of the specific t cell receptor segments (traj24 and trbv4-2) involved in t cell receptor recognition of these antigens, suggesting causality. a link between glaxosmithkline's h1n1 flu vaccine pandemrix and narcolepsy has been found in both children and adults. in 2010, finland's national institute of health and welfare recommended that pandemrix vaccinations be suspended pending further investigation into narcolepsy. 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. pathophysiology loss of neurons 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. loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains. selective destruction of the hcrt/ox neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology. cerebrospinal fluid hcrt-1/ox-a is