Narcolepsy

This article is about the medical condition. For other uses, see Narcolepsy (disambiguation).

Narcolepsy

The concentration of orexin-A neuropeptides in the cerebrospinal fluid of narcoleptic individuals is usually very low
Pronunciation|

* /ˈnɑːrkəˌlɛpsi/

Specialty| Sleep medicine, neurology
Symptoms| Excessive daytime sleepiness, involuntary sleep episodes, sudden loss of muscle strength, hallucinations[1]
Complications| Motor vehicle collisions, falls[1]
Usual onset| Childhood[1]
Duration| Long term[1]
Causes| Unknown[1]
Risk factors| Family history, brain injury[1]
Diagnostic method| Based on the symptoms and sleep studies[1]
Differential diagnosis| Sleep apnea, major depressive disorder, anemia, heart failure, drinking alcohol, not getting enough sleep[1]
Treatment| Regular short naps, sleep hygiene[1]
Medication| Modafinil, sodium oxybate, stimulants, antidepressants[1]
Frequency| 0.2 to 600 per 100,000[2]

Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep-wake cycles.[1] Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes.[1] About 70% of those affected also experience episodes of sudden loss of muscle strength, known as cataplexy.[1] These experiences can be brought on by strong emotions.[1] Less commonly, there may be vivid hallucinations or an inability to move (sleep paralysis) while falling asleep or waking up.[1] 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.[1]

The exact cause of narcolepsy is unknown, with potentially several causes.[1][3] In up to 10% of cases, there is a family history of the disorder.[1] Often, those affected have low levels of the neuropeptide orexin, which may be due to an autoimmune disorder.[1] Trauma, infections, toxins or psychological stress may also play a role.[1] Diagnosis is typically based on the symptoms and sleep studies, after ruling out other potential causes.[1] 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.[1] Cataplexy may be mistaken for seizures.[1]

While there is no cure, a number of lifestyle changes and medications may help.[1] Lifestyle changes include taking regular short naps and sleep hygiene.[1] Medications used include modafinil, sodium oxybate and methylphenidate.[1] While initially effective, tolerance to the benefits may develop over time.[1] Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) may improve cataplexy.[1]

Estimates of frequency range from 0.2 to 600 per 100,000 people in various countries.[2] The condition often begins in childhood, with males and females being affected equally.[1] Untreated narcolepsy increases the risk of motor vehicle collisions and falls.[1]

## Contents

* 1 Signs and symptoms
* 2 Causes
* 2.1 Genetics
* 2.2 H1N1 vaccine
* 3 Pathophysiology
* 4 Diagnosis
* 4.1 Tests
* 5 Treatment
* 5.1 Children
* 6 Epidemiology
* 7 Society and culture
* 7.1 Name
* 8 Research
* 8.1 Histamine-directed medications
* 8.2 GABA-directed medications
* 8.2.1 Flumazenil
* 8.2.2 Clarithromycin
* 8.3 Orexin receptor agonists
* 8.4 L-carnitine
* 8.5 Animal models
* 8.5.1 Dog models
* 8.5.2 Rodent models
* 9 References
* 10 External links

## Signs and symptoms[edit | edit source]

There are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal REM sleep.[4] 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 times and places, or just be very tired throughout the day. Narcoleptics are not able to experience the amount of restorative deep sleep that healthy people experience – they are not "over-sleeping". In fact, narcoleptics live their entire lives in a constant state of extreme sleep deprivation.

Excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that don't require much interaction.[5] 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.[4]

The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy," are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness.[6] Other symptoms may include automatic behaviors and night-time wakefulness.[4][7][8] These symptoms may not occur in all people with narcolepsy.

* Cataplexy is an episodic loss of muscle function, 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",[9] 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.[10] 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.[citation needed]
* Periods of wakefulness at night[4]
* Sleep paralysis is the temporary inability to talk or move when waking (or less often, when falling asleep). It may last a few seconds to minutes. This is often frightening but is not dangerous.[citation needed]
* Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep. Hypnopompic hallucinations refer to the same sensations while awakening from sleep. These hallucinations may manifest in the form of visual or auditory sensations.[4]
* Automatic behaviors occur when a person continues to function (talking, putting things away, etc.) during sleep episodes but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes.[citation needed]

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 suffer from 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.[11][12]

## Causes[edit | edit source]

The exact cause of narcolepsy is unknown, and it may be caused by several distinct factors.[1][3] The mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus.[13][14]

In up to 10% of cases there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy.[1] There is a strong link with certain genetic variants.[13] In addition to genetic factors, low levels of orexin peptides have been correlated with a past history of infection, diet, contact with toxins such as pesticides, and brain injuries due to, head trauma, brain tumors or strokes.[4][13] Autoimmunity may also play a role.[15]

### Genetics[edit | edit source]

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.[13][16] Specific variations in HLA genes are strongly correlated with the presence of narcolepsy;[13] however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy.[13][17] 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.[13][14][17]

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).[18] A 2013 review article reported additional but weaker links to the loci of the genes TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795).[19] Another gene locus that has been associated with narcolepsy is EIF3G (rs3826784).[20]

### H1N1 vaccine[edit | edit source]

A link between GlaxoSmithKline's H1N1 flu vaccine Pandemrix and narcolepsy has been found in both children and adults.[21] Finland's National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy.[22][23] This vaccine was available only in Europe.

## Pathophysiology[edit | edit source]

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.[13][24][25] While there are billions of cells in the human brain, only 10,000–20,000 neurons secrete orexin peptides;[4] all of these neurons project out of the lateral hypothalamus.[13] Loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains.[13][14][17]

The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal REM sleep.[1]

The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus.[14] In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals.[14] Those with narcolepsy generally experience the REM stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived)[26] do not experience REM until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle.[1]

## Diagnosis[edit | edit source]

The third edition of the International Classification of Sleep Disorders (ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder.[27] The most recent edition of the International Classification of Diseases, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy.[28]

ICSD-3 diagnostic criteria posits that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy.[27] This symptom must last for at least three months. For a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean sleep latency of less than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL.[27] A diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL. In addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes.[27]

DSM-5 narcolepsy criteria requires that the person to display recurrent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over a period of three months.[27] The individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/mL, REM sleep latency of less than 15 minutes, or a multiple sleep latency test (MSLT) showing sleep latency of less than 8 minutes and two or more SOREMPs.[27] For a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. In addition, the hypersomnolence must occur at least three times a week for a period of three months, and must be accompanied by significant distress or impairment. It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication.[29]

### Tests[edit | edit source]

Diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist.[citation needed]

Polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during night time sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.[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.[citation needed]

The multiple sleep latency test is performed after the person undergoes an overnight sleep study. The person will be asked to sleep once every 2 hours, and the time it takes for them to do so is recorded. Most individuals will fall asleep within 5 to 8 minutes, as well as display REM sleep faster than non-narcoleptic people.[30]

Measuring orexin levels in a person's cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder.[31] This test can be useful when MSLT results are inconclusive or difficult to interpret.[32]

## Treatment[edit | edit source]

People with narcolepsy can be substantially helped, but not cured. Treatments have a general formula but the best attempt is made to tailor it to the individual, based on symptoms and therapeutic response. The time required to achieve optimal control of symptoms is highly variable and may take several months or longer. Medication adjustments are frequently necessary, and complete control of symptoms is seldom possible. While oral medications are the mainstay of formal narcolepsy treatment, lifestyle changes are also important but secondary as no amount of lifestyle changes will solve the underlying biological problem.[medical citation needed] General strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful. Potential side effects of medication can also be addressed.[5] Regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues.[5]

The main treatment of excessive daytime sleepiness in narcolepsy is central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil. In late 2007 an alert for severe adverse skin reactions to modafinil was issued by the FDA.[33]

Modafinil and sodium oxybate are the most effective treatment of sleepiness although they are only moderately effective.[5] Several studies also showed that sodium oxybate is effective to treat cataplexy.[5]

Another drug that is used is atomoxetine, a non-stimulant and a norepinephrine reuptake inhibitor (NRI), which has no addiction liability or recreational effects. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3 hours in the person's alertness whereas a 15-minute nap provided no benefit.[34] Daytime naps are not a replacement for night time sleep. Ongoing communication between the health care provider, person, and their family members is important for optimal management of narcolepsy.

Another FDA-approved treatment option for narcolepsy is sodium oxybate,[35] also known as sodium gamma-hydroxybutyrate (GHB). It can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy.[35][36][5][37]

Narcolepsy has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress REM sleep.[38] Venlafaxine, an antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy,[39] however, it has notable side-effects including sleep disruption.[40] The antidepressant class is used mainly for the treatment of cataplexy, for people with narcolepsy without cataplexy these are usually not used.[41]

### Children[edit | edit source]

Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.[42]

There are no approved medications in the United States for narcolepsy in children. However, many medications are used in treating adults and may be used to treat childhood. These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine.[43] Other medications, such as sodium oxybate or atomoxetine may also be used to counteract sleepiness. Medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy.[44]

## Epidemiology[edit | edit source]

Estimates of frequency range from 0.2 per 100,000 in Israel to 600 per 100,000 in Japan.[2] These differences may be due to how the studies were conducted or the populations themselves.[2]

In the United States, narcolepsy is estimated to affect as many as 200,000 Americans, but fewer than 50,000 are diagnosed. The prevalence of narcolepsy is about 1 per 2,000 persons.[45] Narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits, recreational drug use, or laziness, making misdiagnosis likely.[citation needed] While narcolepsy symptoms are often confused with depression, there is a link between the two disorders. Research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50%.[46]

Narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in adolescence and young adulthood. There is about a ten-year delay in diagnosing narcolepsy in adults.[12] Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially devastating. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence.[47]

## Society and culture[edit | edit source]

See also: List of people with narcolepsy

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. Sodium oxybate is not available to people with narcolepsy through the National Health Service.[48]

### Name[edit | edit source]

The term "narcolepsy" is from the French narcolepsie.[49] The French term was first used in 1880 by Jean-Baptiste-Édouard Gélineau, who used the Greek νάρκη (narkē), meaning "numbness", and λῆψις (lepsis) meaning "attack".[49]

## Research[edit | edit source]

### Histamine-directed medications[edit | edit source]

It remains to be seen whether H3 antagonists (i.e., compounds such as pitolisant that promote the release of the wakefulness-promoting molecule amine histamine) will be particularly useful as wake-promoting agents.[50] However, usage now does exist in various nations such as in France, United Kingdom's (NHS as of September 2016[51][52][53][54]) after being given marketing authorisation by European Commission on the advice of the European Medicines Agency and in the United States by the approval of the Food and Drug Administration (FDA) as of August 2019.[55]

### GABA-directed medications[edit | edit source]

Given the possible role of hyper-active GABAA receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil.[56][57]

#### Flumazenil[edit | edit source]

Flumazenil is the only GABAA receptor antagonist on the market as of Jan 2013, and it is currently manufactured only as an intravenous formulation. Given its pharmacology, researchers consider it to be a promising medication in the treatment of primary hypersomnias. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. 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.[56][58] A 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion.[59] The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias.[60] However, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label.[61]

#### Clarithromycin[edit | edit source]

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. Investigators therefore treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. 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.[57] "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted."[62] In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of people with GABA-related hypersomnia.[63] “It is important to note that the positive effect of clarithromycin is secondary to a benzodiazepine antagonist-like effect, not its antibiotic effects, and treatment must be maintained.”[50]

### Orexin receptor agonists[edit | edit source]

See also: Orexin receptor

Orexin-A (a.k.a. hypocretin-1) has been shown to be strongly wake-promoting in animal models, but unfortunately it does not cross the blood-brain barrier. Therefore, companies have developed orexin receptor antagonists, like suvorexant, for the treatment of insomnia. It is also likely that an orexin-A receptor agonist will be found and developed for the treatment of hypersomnia.[50]

### L-carnitine[edit | edit source]

Abnormally low levels of acylcarnitine have been observed in people with narcolepsy.[64] These same low levels have been associated with primary hypersomnia in general in mouse studies. “Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.” Administration of acetyl-L-carnitine was shown to improve these symptoms in mice.[65] A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo.[66]

### Animal models[edit | edit source]

Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide.[67] An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy.[68] More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience.[69]

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.[68]

#### Dog models[edit | edit source]

Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the one reported in humans. The attacks of cataplexy in dogs can involve partial or full collapse.[68] 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.[70] According to [67] a reliable canine model for narcolepsy would be the one in which the narcoleptic symptoms are the result of a mutation in the gene HCRT 2. The animals affected exhibited excessive daytime sleepiness with a reduced state of vigilance and severe cataplexy resulted after palatable food and interactions with the owners or with other animals.[67]

#### Rodent models[edit | edit source]

Mice that are genetically engineered to lack orexin genes demonstrate many similarities to human narcolepsy. During nocturnal hours, when mice are normally present, those lacking orexin demonstrated murine cataplexy and displayed brain and muscle electrical activity similar to the activity present during REM and NREM sleep. This cataplexy is able to be triggered through social interaction, wheel running, and ultrasonic vocalizations. Upon awakening, the mice also display behavior consistent with excessive daytime sleepiness.[68]

Mice models have also been used to test whether the lack of orexin neurons is correlated with narcolepsy. Mice whose orexin neurons have been ablated have shown sleep fragmentation, SOREMPs, and obesity, similar to what is seen in humans.[68]

Rat models have been used to demonstrate the association between orexin deficiency and narcoleptic symptoms. 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.[68]

## References[edit | edit source]

1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 "Narcolepsy Fact Sheet". NINDS. NIH Publication No. 03-1637. Archived from the original on 27 July 2016. Retrieved 19 August 2016.
2. ↑ 2.0 2.1 2.2 2.3 Goswami M, Thorpy MJ, Pandi-Perumal SR (2016). Narcolepsy: A Clinical Guide (2nd ed.). Springer. p. 39\. ISBN 9783319237398. Archived from the original on 23 August 2016. Retrieved 19 August 2016.
3. ↑ 3.0 3.1 "Narcolepsy Information Page". NINDS. Archived from the original on 7 January 2017. Retrieved 7 January 2017.
4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Green, Simon (2011). Biological rhythms, sleep, and hypnosis. Basingstoke, Hampshire, England: Palgrave Macmillan. ISBN 9780230252653.
5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Wise, Merrill S.; Arand, Donna L.; Auger, R.Robert; Brooks, Stephen N.; Watson, Nathaniel F. (2007). "Treatment of Narcolepsy and other Hypersomnias of Central Origin. An American Academy of Sleep Medicine Review". Sleep. 30 (12): 1712–27. doi:10.1093/sleep/30.12.1712. PMC 2276130. PMID 18246981.
6. ↑ Kandel, Eric R.; Schwartz, James H.; Jessell, Thomas M., eds. (2000). Principles of Neural Science (4th ed.). McGraw-Hill. p. 949. ISBN 978-0-8385-7701-1.
7. ↑ Cunha, John P. Shiel, William C., Jr. (ed.). "Narcolepsy". MedicineNet. Archived from the original on 24 March 2016. Retrieved 15 March 2016.
8. ↑ Zorick FJ, Salis PJ, Roth T, Kramer M (April 1979). "Narcolepsy and automatic behavior: a case report". The Journal of Clinical Psychiatry. 40 (4): 194–7. PMID 422531.
9. ↑ "About Narcolepsy". Stanford Center for Narcolepsy. Archived from the original on 18 March 2016. Retrieved 15 January 2016.
10. ↑ Dunham CK (2010). "Narcolepsy presenting as pseudoseizures". Primary Care Companion to the Journal of Clinical Psychiatry. 12 (2). doi:10.4088/PCC.09l00793whi. PMC 2910991. PMID 20694129.
11. ↑ Scammell TE (December 2015). "Narcolepsy". The New England Journal of Medicine. 373 (27): 2654–62. doi:10.1056/NEJMra1500587. PMID 26716917.
12. ↑ 12.0 12.1 Nevsimalova S (August 2014). "The diagnosis and treatment of pediatric narcolepsy". Current Neurology and Neuroscience Reports. 14 (8): 469. doi:10.1007/s11910-014-0469-1. PMID 24954623.
13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9 Mahlios J, De la Herrán-Arita AK, Mignot E (October 2013). "The autoimmune basis of narcolepsy". Current Opinion in Neurobiology. 23 (5): 767–73. doi:10.1016/j.conb.2013.04.013. PMC 3848424. PMID 23725858. "Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns."
14. ↑ 14.0 14.1 14.2 14.3 14.4 Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 12: Sleep and Arousal". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 294–296, 303. ISBN 9780071481274. "the loss of orexin neurons raise the interesting possibility that narcolepsy may be caused by an autoimmune mediated destruction of these neurons in analogy with the autoimmune destruction of insulin-secreting β-islet cells in type I diabetes."
15. ↑ "Narcolepsy Fact Sheet". Nature. 2013. doi:10.1038/nature.2013.14413. Archived from the original on 22 March 2019. Retrieved 25 November 2018.
16. ↑ Klein J, Sato A (September 2000). "The HLA system. Second of two parts". The New England Journal of Medicine. 343 (11): 782–6. doi:10.1056/NEJM200009143431106. PMID 10984567.
17. ↑ 17.0 17.1 17.2 Mignot E (November 2001). "A commentary on the neurobiology of the hypocretin/orexin system". Neuropsychopharmacology. 25 (5 Suppl): S5–13. doi:10.1016/S0893-133X(01)00316-5. PMID 11682267.
18. ↑ Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, Mayer G, Plazzi G, Nevsimalova S, Bourgin P, Hong SC, Hong SS, Honda Y, Honda M, Högl B, Longstreth WT, Montplaisir J, Kemlink D, Einen M, Chen J, Musone SL, Akana M, Miyagawa T, Duan J, Desautels A, Erhardt C, Hesla PE, Poli F, Frauscher B, Jeong JH, Lee SP, Ton TG, Kvale M, Kolesar L, Dobrovolná M, Nepom GT, Salomon D, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Young T, Peppard P, Tokunaga K, Kwok PY, Risch N, Mignot E (June 2009). "Narcolepsy is strongly associated with the T-cell receptor alpha locus". Nature Genetics. 41 (6): 708–11. doi:10.1038/ng.372. PMC 2803042. PMID 19412176. `{{cite journal}}`: Unknown parameter `|displayauthors=` ignored (help)
19. ↑ Singh AK, Mahlios J, Mignot E (June 2013). "Genetic association, seasonal infections and autoimmune basis of narcolepsy". Journal of Autoimmunity. 43: 26–31. doi:10.1016/j.jaut.2013.02.003. PMC 4118764. PMID 23497937.
20. ↑ Holm A, Lin L, Faraco J, Mostafavi S, Battle A, Zhu X, Levinson DF, Han F, Gammeltoft S, Jennum P, Mignot E, Kornum BR (November 2015). "EIF3G is associated with narcolepsy across ethnicities". European Journal of Human Genetics. 23 (11): 1573–80. doi:10.1038/ejhg.2015.4. PMC 4613472. PMID 25669430.
21. ↑ Sarkanen T, Alakuijala A, Julkunen I, Partinen M (June 2018). "Narcolepsy Associated with Pandemrix Vaccine". Current Neurology and Neuroscience Reports. 18 (7): 43. doi:10.1007/s11910-018-0851-5. hdl:10138/302445. PMID 29855798.
22. ↑ "The MPA investigates reports of narcolepsy in patients vaccinated with Pandemrix". Swedish Medical Products Agency. 18 August 2010. Archived from the original on 17 February 2011. Retrieved 19 August 2010.
23. ↑ "Terveyden ja hyvinvoinnin laitos suosittaa Pandemrix-rokotusten keskeyttämistä". National Institute of Health and Welfare. 24 August 2010. Archived from the original on 20 July 2011. Retrieved 24 August 2010.
24. ↑ Li J, Hu Z, de Lecea L (January 2014). "The hypocretins/orexins: integrators of multiple physiological functions". British Journal of Pharmacology. 171 (2): 332–50. doi:10.1111/bph.12415. PMC 3904255. PMID 24102345. "The analgesic properties of orexin peptides have been well-established"
25. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 179\. ISBN 9780071481274. "Orexinergic projections in the CNS. Orexin neurons with cell bodies in the lateral hypothalamic area (LHA) and posterior hypothalamus (PH) project throughout the brain (excluding the cerebellum) with dense projections to the noradrenergic locus ceruleus (LC), histaminergic tuberomamillary nucleus (TMN), serotonergic raphe nuclei, cholinergic laterodorsal and pedunculopontine nuclei (LDT and PPT), and the dopaminergic ventral tegmental area (VTA)."
26. ↑ Beersma DG, Dijk DJ, Blok CG, Everhardus I (August 1990). "REM sleep deprivation during 5 hours leads to an immediate REM sleep rebound and to suppression of non-REM sleep intensity". Electroencephalography and Clinical Neurophysiology. 76 (2): 114–22. doi:10.1016/0013-4694(90)90209-3. PMID 1697239. Archived from the original on 24 September 2014.
27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 Ruoff, Chad; Rye, David (2 October 2016). "The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality". Current Medical Research and Opinion. 32 (10): 1611–1622. doi:10.1080/03007995.2016.1208643. ISSN 0300-7995. PMID 27359185.
28. ↑ World Health Organization (2018). "International Classification of Diseases" (11th ed.). Archived from the original on 27 November 2021.
29. ↑ American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Association.
30. ↑ Rahman, Touseef; Farook, Omer; Heyat, Md Belal Bin; Siddiqui, Mohd Maroof (March 2016). "An overview of narcolepsy". International Advanced Research Journal in Science, Engineering and Technology. 3 (3). doi:10.17148/IARJSET.2016.3320 (inactive 12 May 2020).`{{cite journal}}`: CS1 maint: DOI inactive as of May 2020 (link)
31. ↑ "Narcolepsy Research - FAQs". Stanford Center for Narcolepsy. Archived from the original on 13 November 2015. Retrieved 15 January 2016.
32. ↑ Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S (October 2002). "The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias". Archives of Neurology. 59 (10): 1553–62. doi:10.1001/archneur.59.10.1553. PMID 12374492.
33. ↑ "Modafinil (marketed as Provigil): Serious Skin Reactions". Postmarketing Reviews. 1 (1). Fall 2007. Archived from the original on 4 March 2016. Retrieved 15 March 2016.
34. ↑ Helmus, Todd; Rosenthal, Leon; Bishop, Christopher; Roehrs, Timothy; Syron, Mary Lou; Roth, Thomas (April 1997). "The Alerting Effects of Short and Long Naps in Narcoleptic, Sleep-Deprived, and Alert Individuals". Sleep. 20 (4): 251–257. doi:10.1093/sleep/20.4.251. PMID 9231950.
35. ↑ 35.0 35.1 "XYREM® (sodium oxybate)" (PDF). United States Food and Drug Administration. Jazz Pharmaceuticals, Inc. 11 April 2014. Archived (PDF) from the original on 4 March 2016. Retrieved 9 August 2015.
36. ↑ "FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 Jul 2002" (PDF). Archived (PDF) from the original on 17 October 2012.
37. ↑ Boscolo-Berto, Rafael; Viel, Guido; Montagnese, Sara; Raduazzo, Daniella I.; Ferrara, Santo D.; Dauvilliers, Yves (October 2012). "Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): A systematic review and meta-analysis of randomized controlled trials". Sleep Medicine Reviews. 16 (5): 431–443. doi:10.1016/j.smrv.2011.09.001. PMID 22055895.
38. ↑ Gowda, Chandan R.; Lundt, Leslie P. (18 November 2014). "Mechanism of action of narcolepsy medications" (PDF). CNS Spectrums. 19 (S1): 25–34. doi:10.1017/S1092852914000583. PMID 25403789. Archived from the original (PDF) on 9 July 2020. Retrieved 6 August 2020.
39. ↑ Caputo, Fabio; Zoli, Giorgio (March 2007). "Treatment of narcolepsy with cataplexy". The Lancet. 369 (9567): 1080–1081. doi:10.1016/S0140-6736(07)60522-4. PMID 17398302.
40. ↑ "NAMI, National Alliance on Mental Illness, Effexor, Common Side Effects". Archived from the original on 18 July 2012. Retrieved 23 September 2019.
41. ↑ Alexandre, Chloé; Scammell, Thomas E. (2011). "The Serotoninergic System in Sleep and Narcolepsy". In Baumann, Christian R.; Bassetti, Claudio L.; Scammell, Thomas E. (eds.). Narcolepsy: Pathophysiology, Diagnosis, and Treatment. Springer. pp. 73–84. doi:10.1007/978-1-4419-8390-9_7. ISBN 978-1-4419-8390-9.
42. ↑ Postiglione, Emanuela; Antelmi, Elena; Pizza, Fabio; Lecendreux, Michel; Dauvilliers, Yves; Plazzi, Giuseppe (April 2018). "The clinical spectrum of childhood narcolepsy". Sleep Medicine Reviews. 38: 70–85. doi:10.1016/j.smrv.2017.04.003. PMID 28666745.
43. ↑ Peterson, Paul C.; Husain, Aatif M. (November 2008). "Pediatric narcolepsy". Brain and Development. 30 (10): 609–623. doi:10.1016/j.braindev.2008.02.004. PMID 18375081.
44. ↑ Guilleminault, Christian; Fromherz, Scott (2005). "Narcolepsy: Diagnosis and Management". In Kryger, Meir H.; Roth, Thomas; Dement, William C. (eds.). Principles and Practice of Sleep Medicine (4th ed.). W.B. Saunders. pp. 780–790. doi:10.1016/B0-72-160797-7/50072-0. ISBN 978-0-7216-0797-9.
45. ↑ "Who Is At Risk for Narcolepsy?". Archived from the original on 22 September 2008.
46. ↑ "Link Between Narcolepsy and Mental Health". Archived from the original on 9 August 2014. Retrieved 6 June 2014.
47. ↑ Thorpy MJ, Krieger AC (May 2014). "Delayed diagnosis of narcolepsy: characterization and impact". Sleep Medicine. 15 (5): 502–7. doi:10.1016/j.sleep.2014.01.015. PMID 24780133.
48. ↑ "DH funds private prescriptions for drug denied to NHS patients". Health Service Journal. 20 July 2015. Archived from the original on 24 September 2015. Retrieved 20 July 2015.
49. ↑ 49.0 49.1 Harper, Douglas (2010). "Narcolepsy". Dictionary.com. Online Etymology Dictionary. Archived from the original on 8 March 2016. Retrieved 19 August 2016.
50. ↑ 50.0 50.1 50.2 Mignot, Emmanuel J. M. (11 October 2012). "A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes". Neurotherapeutics. 9 (4): 739–752. doi:10.1007/s13311-012-0150-9. PMC 3480574. PMID 23065655.
51. ↑ "Archive copy". Archived from the original on 7 July 2020. Retrieved 6 August 2020.`{{cite web}}`: CS1 maint: archived copy as title (link)
52. ↑ https://www.ema.europa.eu/en/news/narcolepsy-treatment-recommended-approvall[permanent dead link]
53. ↑ "Archive copy" (PDF). Archived (PDF) from the original on 7 July 2020. Retrieved 6 August 2020.`{{cite web}}`: CS1 maint: archived copy as title (link)
54. ↑ "Archive copy". Archived from the original on 6 July 2020. Retrieved 6 August 2020.`{{cite web}}`: CS1 maint: archived copy as title (link)
55. ↑ Syed, Yahiya Y. (20 July 2016). "Pitolisant: First Global Approval". Drugs. 76 (13): 1313–1318. doi:10.1007/s40265-016-0620-1.
56. ↑ 56.0 56.1 Lynn Marie Trotti, MD (9 August 2010). "Flumazenil for the Treatment of Primary Hypersomnia". Emory University - Georgia Research Alliance. ClinicalTrials.gov. Archived from the original on 28 October 2012.
57. ↑ 57.0 57.1 Lynn Marie Trotti, MD (15 June 2010). "Clarithromycin for the Treatment of Primary Hypersomnia". Emory University - Georgia Research Alliance. ClinicalTrials.gov. Archived from the original on 1 December 2012.
58. ↑ Rye DB, Bliwise DL, Parker K, Trotti LM, Saini P, Fairley J, Freeman A, Garcia PS, Owens MJ, Ritchie JC, Jenkins A (November 2012). "Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors". Science Translational Medicine. 4 (161): 161ra151. doi:10.1126/scitranslmed.3004685. PMID 23175709.
59. ↑ Kelty E, Martyn V, O'Neil G, Hulse G (July 2014). "Use of subcutaneous flumazenil preparations for the treatment of idiopathic hypersomnia: A case report". Journal of Psychopharmacology. 28 (7): 703–6. doi:10.1177/0269881114523865. PMID 24554692.
60. ↑ Beck, Melinda (10 December 2012). "Scientists Try to Unravel the Riddle of Too Much Sleep". The Wall Street Journal. Archived from the original on 8 August 2017.
61. ↑ "Hypersomnia Update". Emory University. Archived from the original on 31 May 2014. Retrieved 22 April 2014.
62. ↑ Trotti, L (June 2013). "Clarithromycin for the Treatment of Hypersomnia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial". Sleep. 36 (Abstract Supplement): A248.
63. ↑ Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB (July 2014). "Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: Clinical experience". Journal of Psychopharmacology. 28 (7): 697–702. doi:10.1177/0269881113515062. PMID 24306133.
64. ↑ Miyagawa T, Miyadera H, Tanaka S, Kawashima M, Shimada M, Honda Y, Tokunaga K, Honda M (March 2011). "Abnormally low serum acylcarnitine levels in narcolepsy patients". Sleep. 34 (3): 349–53A. doi:10.1093/sleep/34.3.349. PMC 3041711. PMID 21358852.
65. ↑ Miyagawa T, Honda M, Kawashima M, Shimada M, Tanaka S, Honda Y, Tokunaga K (30 April 2009). "Polymorphism located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype confer susceptibility to CNS hypersomnias (essential hypersomnia)". PLOS ONE. 4 (4): e5394. Bibcode:2009PLoSO...4.5394M. doi:10.1371/journal.pone.0005394. PMC 2671172. PMID 19404393.
66. ↑ Miyagawa T, Kawamura H, Obuchi M, Ikesaki A, Ozaki A, Tokunaga K, Inoue Y, Honda M (2013). "Effects of oral L-carnitine administration in narcolepsy patients: a randomized, double-blind, cross-over and placebo-controlled trial". PLOS ONE. 8 (1): e53707. Bibcode:2013PLoSO...853707M. doi:10.1371/journal.pone.0053707. PMC 3547955. PMID 23349733.
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## External links[edit | edit source]

Classification|

* ICD-10: G47.4
* ICD-9-CM: 347
* OMIM: 161400
* MeSH: D009290
* DiseasesDB: 8801

|

External resources|

* MedlinePlus: 000802
* eMedicine: neuro/522

* "Narcolepsy Information Page". National Institute of Neurological Disorders and Stroke. Archived from the original on 7 January 2017. Retrieved 6 August 2020.

* v
* t
* e

Diseases of the nervous system, primarily CNS

Inflammation|

| Brain|

* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic

|

Brain and spinal cord|

* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis

Brain/
encephalopathy|

| Degenerative|

| Extrapyramidal and
movement disorders|

* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA

* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia

* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person

|

Dementia|

* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy

* Vascular dementia

Mitochondrial disease|

* Leigh syndrome

Demyelinating|

* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS

Episodic/
paroxysmal|

| Seizures and epilepsy|

* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy

|

Headache|

* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache

Cerebrovascular|

* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases

Other|

* Sleep disorders
* For more detailed coverage, see Template:Sleep

CSF|

* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension

Other|

* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy

Both/either|

| Degenerative|

| SA|

* Friedreich's ataxia
* Ataxia–telangiectasia

|

MND|

* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia

* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy

* both:
* Amyotrophic lateral sclerosis

* v
* t
* e

Sleep and sleep disorders

Stages of sleep cycles|

* Rapid eye movement (REM)
* Quiescent sleep
* Slow-wave

Brain waves|

* Alpha wave
* Beta wave
* Delta wave
* Gamma wave
* K-complex
* Mu rhythm
* PGO waves
* Sensorimotor rhythm
* Sleep spindle
* Theta wave

Sleep disorders|

| Anatomical|

* Bruxism
* Mouth breathing
* Sleep apnea
* Catathrenia
* Central hypoventilation syndrome
* Obesity hypoventilation syndrome
* Obstructive sleep apnea
* Periodic breathing
* Snoring

|

Dyssomnia|

* Excessive daytime sleepiness
* Hypersomnia
* Insomnia
* Kleine–Levin syndrome
* Narcolepsy
* Night eating syndrome
* Nocturia
* Sleep state misperception

Circadian rhythm
disorders

* Advanced sleep phase disorder
* Cyclic alternating pattern
* Delayed sleep phase disorder
* Irregular sleep–wake rhythm
* Jet lag
* Non-24-hour sleep–wake disorder
* Shift work sleep disorder

Parasomnia|

* Nightmare disorder
* Night terror
* Periodic limb movement disorder
* Rapid eye movement sleep behavior disorder
* Sleepwalking
* Sleepdriving
* Sleep-talking

Benign phenomena|

* Dreams
* Exploding head syndrome
* Hypnic jerk
* Hypnagogia / Sleep onset
* Hypnopompia
* Sleep paralysis
* Sleep inertia
* Somnolence
* Nocturnal clitoral tumescence
* Nocturnal penile tumescence
* Nocturnal emission

Treatment|

* Sleep diary
* Sleep hygiene
* Sleep induction
* Hypnosis
* Lullaby
* Somnology
* Polysomnography

Other|

* Sleep medicine
* Behavioral sleep medicine
* Sleep study

Daily life|

* Bed
* Bunk bed
* Daybed
* Four-poster bed
* Futon
* Hammock
* Mattress
* Sleeping bag
* Bed bug
* Bedding
* Bedroom
* Bedtime
* Bedtime story
* Biphasic and polyphasic sleep
* Chronotype
* Comfort object
* Dream diary
* Microsleep
* Nap
* Nightwear
* Power nap
* Second wind
* Siesta
* Sleep and creativity
* Sleep and learning
* Sleep deprivation / Sleep debt
* Sleeping while on duty
* Sleepover

*[a.k.a.]: also known as
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template