Medicine:Idiopathic hypersomnia

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Idiopathic hypersomnia is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS).[1] It has historically been rarely diagnosed and is often very difficult to diagnose at an early stage; it is usually a lifelong chronic disease, which is often debilitating.[2] There is a very low level of public awareness of idiopathic hypersomnia, which often leads to stigma for those who suffer from it.[3] There is currently no cure, but there are several off-label treatments, which are primarily FDA-approved narcolepsy medications.[4]

In the medical literature, idiopathic hypersomnia may also be referred to as IH, IHS, primary hypersomnia, central hypersomnia, or hypersomnia of brain origin. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defines idiopathic hypersomnia as EDS without narcolepsy or the associated features of other sleep disorders.[5] It occurs in the absence of medical problems or sleep disruptions, such as sleep apnea, that can cause secondary hypersomnia.

Signs and symptoms

Those who suffer from idiopathic hypersomnia have recurring episodes of excessive sleep and daytime sleepiness (EDS). Sleep is usually deep, with significant difficulty arousing from sleep, even with use of several alarm clocks. In fact, patients with IH often must develop elaborate rituals to wake, as alarm clocks and even physical attempts by friends/family to wake them may fail. Despite getting more hours of sleep than typically required by the human body, patients awake unrefreshed and may also suffer sleep inertia, known more descriptively in its severe form as sleep drunkenness (significant disorientation upon awakening).[6] Daytime naps are generally very long (up to several hours) and are also unrefreshing, as opposed to the short refreshing naps associated with narcolepsy.

Some studies have shown increased frequencies of other symptoms in patients with idiopathic hypersomnia, although it is not clear whether these symptoms are caused by the idiopathic hypersomnia.[7][8] These symptoms include palpitations, digestive problems, difficulty with body temperature regulation, and cognitive problems, especially deficits in memory, attention, and concentration.[8] Anxiety and depression are often increased in idiopathic hypersomnia, most likely as a response to chronic illness.[7] A case series in 2010 found that peripheral vascular symptoms, such as cold hands and feet (Raynaud's-type phenomena) were more common in people with idiopathic hypersomnia than in controls. In addition to difficulty with temperature regulation and Raynaud's type symptoms, other symptoms associated with autonomic dysfunction were noted to occur in idiopathic hypersomnia. These included: fainting episodes (syncope); dizziness upon arising (orthostatic hypotension); and headaches (possibly migrainous in quality).[8] Food cravings and impotence have also been reported.[9]

Many patients are chronically tardy to work, school or social engagements[10] and, over time, may lose the ability to function in family, social, occupational or other settings altogether.[11] (See Prognosis section below).


Unlike narcolepsy with cataplexy, which has a known cause (autoimmune destruction of hypocretin-producing neurons), the cause of idiopathic hypersomnia has, until recently, been largely unknown, hence its name. However, researchers have identified a few abnormalities associated with IH, which with further study may help to clarify the etiology.[12]

Destruction of noradrenergic neurons has produced hypersomnia in experimental animal studies, and injury to adrenergic neurons has also been shown to lead to hypersomnia. Idiopathic hypersomnia has also been associated with a malfunction of the norepinephrine system and decreased cerebrospinal fluid (CSF) histamine levels.[13]

Researchers have recently found an abnormal hypersensitivity to GABA (the major brain chemical responsible for sedation) in a subset of patients with central hypersomnia i.e.: idiopathic hypersomnia, narcolepsy without cataplexy and long sleepers. They have identified a small (500 to 3000 daltons) naturally occurring bioactive substance (most likely a peptide as it is trypsin-sensitive) in the CSF of afflicted patients. Although this substance requires further identification of its chemical structure, it is currently referred to as a "somnogen" because it has been shown to cause hyper-reactivity of GABAA receptors, which leads to increased sedation or somnolence. In essence, it is as though these patients are chronically sedated with a benzodiazepine (medication which acts through the GABA system) such as Versed or Xanax, even though they do not take these medications.[14][15]


Idiopathic hypersomnia has historically been "difficult to diagnose at an early stage," especially because many other disorders can cause symptoms of excessive daytime sleepiness (EDS). Therefore, "at the time of presentation, most patients have had the disorder for many years."[2]

Further complicating the diagnostic process, idiopathic hypersomnia lacks a clearly defining clinical feature. Whereas narcolepsy is associated with cataplexy and sleep-onset REM episodes, and Kleine-Levin syndrome is associated with megaphagia (compulsive food cravings) and hypersexuality, idiopathic hypersomnia has no such dramatic associated features, except perhaps sleep drunkenness. "Consequently there has been an unfortunate tendency to label all difficult-to-classify cases of excessive daytime sleepiness as idiopathic hypersomnia." For example, upper airway resistance syndrome and delayed sleep phase disorder were formerly confused with idiopathic hypersomnia, but now that they have been more clearly defined, doctors can more carefully exclude these causes of EDS in order to more correctly diagnose idiopathic hypersomnia.[9] However, "even in the presence of other specific causes of hypersomnia, one should carefully assess the contribution of these etiological factors to the complaint of EDS and when specific treatments of these conditions fail to suppress EDS, the [additional] diagnosis of idiopathic hypersomnia should be considered."[16]

The severity of EDS can be quantified by subjective scales, such as the Epworth sleepiness scale and the Stanford sleepiness scale (SSS), and also by objective tests, like the multiple sleep latency test (MSLT)."[17][18]

In 2001, the ICSD (International Classification of Sleep Disorders) updated their criteria for the diagnosis of idiopathic hypersomnia. Essentially, EDS must be present for at least 6 months, sleep studies (polysomnography and multiple sleep latency test) must show certain characteristics, and all other known causes for long sleep time and EDS must be considered (see hypersomnia).[2] For the patient, this diagnostic process is often tedious, expensive and time-consuming, as other than the sleep studies, it is still basically a diagnosis of exclusion.

In patients with idiopathic hypersomnia, polysomnography typically shows short sleep latency, increased mean slow wave sleep, and a high mean sleep efficiency. "Latency to REM sleep and percentages of light sleep and REM sleep were normal, compared with normal ranges."[19] Despite this, one study has found increased sleep fragmentation in patients with idiopathic hypersomnia without long sleep time, suggesting multiple possible presentations.[20]

It is important to note that although sleep latencies are typically short in idiopathic hypersomnia, the clinical severity may not correlate closely with the MSLT results. In fact, "latencies above 5 minutes are not uncommon in patients with clinically severe hypersomnia."[2] When sleep latency is below 10 minutes, the presence of sleep-onset REM periods (SOREMPs) in two or more of the MSLT naps suggests a diagnosis of narcolepsy, whereas sleep periods lacking rapid eye movement (NREM sleep) in the various naps suggests a diagnosis of idiopathic hypersomnia.[11] However, the importance of this differentiation between REM and NREM has been called into question.[12] (See Classification.)

Although the MSLT is currently the best available test to diagnose EDS in general, the MSLT protocol lacks the ability to document the extended, unrefreshing daytime naps that often occur in idiopathic hypersomnia. Complicating the matter, several groups of researchers have found normal MSLT results in patients who otherwise seem to have idiopathic hypersomnia. Therefore, when idiopathic hypersomnia is suspected, researchers suggest appending a 24-hour continuous polysomnography to the standard overnight/MSLT study in order to record total sleep time.[11]

It is also important to note that whereas narcolepsy is strongly associated with the HLA-DQB1*0602 genotype,[12] "HLA typing is of no help in the positive diagnosis of idiopathic hypersomnia."[9] This is "despite some reports that suggest an increase [sic] frequency of HLA Cw2 and DRS in idiopathic hypersomnia subjects."[9]


In addition to differentiating between the primary and secondary hypersomnias, the 2001 International Classification of Sleep Disorders (ICSD) further classified the primary hypersomnia syndromes. These included idiopathic hypersomnia, narcolepsy, and the recurrent hypersomnias (like Klein-Levin syndrome).

The 2001 ICSD defines idiopathic hypersomnia as "a disorder of presumed central nervous system cause that is associated with a normal or prolonged major sleep episode and excessive sleepiness consisting of prolonged (1- to 2-hour) sleep episodes of N-REM"(non-rapid eye movement sleep). The ICSD initially described two clinical forms of idiopathic hypersomnia: "1) a polysymptomatic form with nocturnal sleep and naps of abnormally long duration with 'sleep drunkenness' on awakening, and 2) a monosymptomatic form manifested by isolated EDS." These forms were later described as idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time, respectively.[17]

This classification has steadily evolved, as further research has shown overlap between narcolepsy and idiopathic hypersomnia.[7] The 3rd edition of the ICSD labels narcolepsy caused by hypocretin deficiency as "type 1 narcolepsy", which is almost always associated with cataplexy. The other hypersomnias remain subdivided based on the presence of sleep-onset rapid eye movement periods (SOREMPs). They are labeled: "type 2 narcolepsy", with 2 or more SOREMPs on multiple sleep latency testing (MSLT); and "idiopathic hypersomnia," with less than 2 SOREMPS.[12] However, "there is no evidence that the pathophysiology or therapeutic response is substantially different for hypersomnia with or without SOREMPs on the MSLT."[12]

The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders also updated its classification of the primary hypersomnias. It reclassified both idiopathic hypersomnia with and without long sleep time as hypersomnolence disorder. In general, anyone who meets ICSD-3 criteria for IH would meet criteria for DSM-5 hyper somnolence disorder, but not vice versa.[21]

Further complicating these updated classification schemes, overlap between narcolepsy with cataplexy and idiopathic hypersomnia has also been reported. A subgroup of narcoleptics with long sleep time, comprising 18% of narcoleptics in one study, had symptoms of both narcolepsy with cataplexy and idiopathic hypersomnia (long sleep time and unrefreshing naps). It is felt that this subgroup might have dysfunction in multiple arousal systems.[22] (See Causes section below).


Currently, there is no cure for idiopathic hypersomnia. Also, because the underlying disease mechanism is not yet fully understood (see Causes), treatment efforts have usually focused on symptom management. Although there are several FDA-approved medications for use in narcolepsy, there are no FDA-approved medicines for idiopathic hypersomnia. Therefore, the wake-promoting medications used in narcolepsy are also commonly used off-label to help manage the excessive daytime sleepiness of idiopathic hypersomnia.

In addition to medications, "behavioral approaches and sleep hygiene techniques are recommended, although they have little overall positive impact on this disease."[23] "Planned naps are unhelpful, as they are both long and unrefreshing."[19] Although behavioral approaches have not been shown to improve EDS, the goal, as in CBT (cognitive behavioral therapy), is often to help patients learn to reduce their negative emotional responses (e.g. frustration, anger, depression) to their disease symptoms. Furthermore, because idiopathic hypersomnia "may lead to marriage breakdown, extensive counseling for the patient's partners, educating them about the symptomatology and treatment options, must be part of a comprehensive management plan... Education of relatives, friends, and colleagues helps the patient to function much better with this incurable disease."[3]

Although management of idiopathic hypersomnia is not well codified, it is recommended that initial therapy be conservative, focusing on behavioral modifications and medications such as modafinil and atomoxetine. However, treatment "may have to be more aggressive (high-dose stimulants, sodium oxybate, etc.) on a case-by-case, empirical trial basis. As cause and evolution are unknown in these conditions, it is important to challenge diagnosis and therapy over time."[12]

Overall, the medications currently used for idiopathic hypersomnia (all off-label) are far from satisfactory. CNS stimulants tend to be less effective for idiopathic hypersomnia than they are for narcolepsy and may be less well tolerated.[11]


There are several stimulants approved by the FDA for treatment of excessive sleepiness due to narcolepsy. These include methylphenidate (e.g., Ritalin) and dextroamphetamine, among others. Selegiline may also be useful, as it is "primarily a metabolic precursor of amphetamine and exerts most of its therapeutic effects through amphetamine metabolism."[12] Increased dopamine release is felt to be the main property explaining wake-promotion from these medications.[12] Insomnia is another common side effect and may require additional treatment.[24]

Mazindol is a stimulant similar to amphetamines that "has been shown to be effective in treating hypersomnia in narcoleptics." However, it is not currently approved in the US.[25]

Caffeine is one of the safer nondopaminergic wake-promoting compounds. It is widely used but "has intolerable side effects at high doses (including cardiovascular), and it is generally not efficient enough for patients with hypersomnia or narcolepsy."[12]

Wakefulness promoting medications

The non-stimulant wake-promoting medications approved for use in narcolepsy include modafinil and armodafinil. They elevate hypothalamic histamine levels,[26] and they are known to bind to the dopamine transporter, thereby inhibiting dopamine reuptake. Modafinil can cause uncomfortable side effects, including nausea, headache, and a dry mouth for some patients, while other patients report no noticeable improvement even on relatively high dosages.[27] They may also "interact with low-dose contraceptives, potentially reducing efficacy, although the scientific data supporting this claim is weak and rests on poorly documented anecdotes."[12] New histamine-directed wake-promoting medications are currently under development (see Histamine-directed medications).

Atomoxetine (or reboxetine in Europe) is an adrenergic reuptake inhibitor which increases wakefulness (generally less strongly than the medications which act on dopamine) and which has been argued to have a "clear use in the therapeutic arsenal against narcolepsy and hypersomnia although undocumented by clinical trials."[12]

Ritanserin is a serotonin antagonist that has "been shown to improve daytime alertness and subjective sleep quality in patients on their usual narcolepsy medications." It is intended as an adjunct (supplement to another main therapeutic agent), and although it is not available in the US, it is available in Europe.[25]

Although anti-depressants, in general, have not been found to be helpful for treatment of idiopathic hypersomnia, bupropion specifically is known to have wake-promoting effects. Bupropion is a relatively weak inhibitor of the neuronal uptake of 29 norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase.(FDA Prescribing Information)

Sleep promoting medications

Sleep promoting medications can help by ensuring effective sleep as well as sleep at an appropriate time.

Sodium oxybate is an orphan drug which was designed specifically for the treatment of narcolepsy. Common side effects include nausea, dizziness, and hallucinations.[28] A 2016 study by Leu-Semenescu et al. found sodium oxybate improved daytime sleepiness in idiopathic hypersomnia to the same degree as in patients with narcolepsy type 1, and the drug improved severe sleep inertia in 71% of the hypersomnia patients.[29]

Histamine-directed medications

It remains to be seen whether H3 antagonists (i.e., compounds such as pitolisant that promote the release of the wake-promoting amine histamine) will be particularly useful as wake-promoting agents in the treatment of idiopathic hypersomnia.[12]

GABA-directed medications

Given the possible role of hyperactive GABAA receptors in idiopathic hypersomnia, medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil.[14][15]


Flumazenil is the only GABAA receptor antagonist on the market as of Jan 2013. Flumazenil is currently available in lozenge and topical cream form from the Pavilion Compounding pharmacy in Atlanta It is also currently manufactured as an intravenous formulation. It is approved by the FDA for use in anesthesia reversal and benzodiazepine overdose. However, given its pharmacology, researchers consider it to be a promising medication in the treatment of idiopathic hypersomnia. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. This research showed that flumazenil provides relief for most patients 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 patient, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years.[10][14] A 2014 case report also showed improvement in idiopathic hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion.[30] The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of idiopathic hypersomnia.[31] However, this scarcity has eased, and dozens of patients are now being treated with flumazenil off-label.[32]


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 patients with idiopathic hypersomnia. Investigators therefore treated a few patients 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 idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012.[15] "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted."[33] In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of patients with GABA-related hypersomnia.[34] "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."[12]


Idiopathic hypersomnia is a lifelong disorder (with only rare spontaneous remissions) whose symptoms typically begin in adolescence or young adulthood. It is initially progressive, but may stabilize, and its main consequences are professional and social.[2][35]

Idiopathic hypersomnia profoundly affects work, education, and quality of life. Patients are often too sleepy to work or attend school regularly, and they are predisposed "to develop serious performance decrements in multiple areas of function as well as to potentially life-threatening domestic, work-related and driving accidents."[4] Furthermore, these risks are higher for idiopathic hypersomnia patients than for those with sleep apnea or severe insomnia. In fact, "the most severe cases of daytime somnolence are found in patients affected by narcolepsy or idiopathic hypersomnia."[4] Surprisingly, excessive daytime sleepiness is even more handicapping than the cataplectic attacks of narcolepsy.[4]

Due to the consequences of their profound EDS, both idiopathic hypersomnia and narcolepsy can often result in unemployment. Several studies have shown a high rate of unemployment in narcoleptics (from 30–59%), which was felt to be related to the severe symptoms of their illness.[36][37]


Typically, the symptoms of idiopathic hypersomnia begin in adolescence or young adulthood, although they can begin at a later age.[38][7] After onset, hypersomnia often worsens over several years,[7] but it is often stable by the time of diagnosis and appears to be a lifelong condition.[2] Spontaneous remission is only seen in 10–15% of patients.[19][39]

According to the limited epidemiological data that exists, IH "has more of a female preponderance (1.8/1)."[40] Family cases are frequent, in a range from 25% to 66% without any clear mode of inheritance."[17]

Idiopathic hypersomnia has long been considered a rare disease, believed to be 10 times less frequent than narcolepsy.[17] The prevalence of narcolepsy (with cataplexy) is estimated between 1/3,300 and 1/5,000.[41] Although the true prevalence of idiopathic hypersomnia is unknown, it is estimated at 1/10,000 – 1/25,000 for the long sleep form and 1/11,000 to 1/100,000 without long sleep.[42] A more precise estimate "is complicated by a lack of clear biologic markers" and a lack of "unambiguous diagnostic criteria."[43]

Because idiopathic hypersomnia has been considered a rare disease, it has not received enough attention from authorities and researchers. "Patients are rare, researchers and scientists involved in the field are few and research findings are therefore scarce."[4] "In Europe and in North America there is now a public health concern about helping patients and families affected by these rare diseases. Due to the complexity of the disease, they often experience difficulties to be diagnosed and often face social and professional consequences."[4] (see Prognosis)

Society and culture

Idiopathic hypersomnia is a rarity in the public eye and has a very low level of public awareness.

Because of this low awareness, patients with idiopathic hypersomnia "often need significant support because they are at risk of being misunderstood as being incompetent or slothful. Therefore, education of relatives, friends, and colleagues helps the patient to function much better with this incurable disease."[3]


Gamma aminobutyric acid A antagonist

There is ongoing research into the efficacy of gamma aminobutyric acid A (GABAA) receptor antagonists for the treatment of idiopathic hypersomnia.[44] Research findings suggest that the GABA neurotransmitter system plays a significant role in the etiology of primary hypersomnias, such as IH and Narcolepsy Type 2.[45]


Abnormally low levels of acylcarnitine have been observed in patients with narcolepsy.[46] 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.[47] A subsequent human trial found that narcolepsy patients given L-carnitine spent less total time in daytime sleep than patients who were given placebo.[48]


There have been some studies suggesting levothyroxine as a possible treatment for idiopathic hypersomnia, especially for patients with subclinical hypothyroidism.[49][50] This treatment does carry potential risks (especially for patients without hypothyroidism or subclinical hypothroidism), which include cardiac arrhythmia.[51]


There have been a few studies suggesting melatonin could be helpful in the treatment of idiopathic hypersomnia.[12] One small study used a dose of 2 mg slow release melatonin at bedtime and showed 50% of patients with "shortened nocturnal sleep duration, decreased sleep drunkenness and relieved daytime sleepiness."[16]

Hypocretin agonists

Hypocretin-1 has been shown to be strongly wake-promoting in animal models, but it does not cross the blood-brain barrier. Suvorexant, a hypocretin receptor antagonist, has been developed to limit the natural effects of hypocretin in patients with insomnia. It is therefore possible that a hypocretin agonist may be similarly developed for the treatment of hypersomnia.[12]


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