| Idiopathic hypersomnia | |
|---|---|
| Specialty | Sleep medicine,Neurology,Psychiatry |
| Symptoms | Difficulty staying awake,mental fog,persistent sleepiness |
| Usual onset | Adolescence |
| Duration | Chronic |
| Medication | Stimulants (modafinil,methylphenidate,amphetamine,solriamfetol,pitolisant),sodium oxybate,mixed oxybate salts |
Idiopathic hypersomnia (IH) is aneurological disorder which is characterized primarily byexcessive sleep andexcessive daytime sleepiness (EDS).[1] Idiopathic hypersomnia was first described by Bedrich Roth in 1956,[2] and it can be divided into two forms: polysymptomatic and monosymptomatic.[3][4] The condition typically becomes evident in early adulthood and most patients diagnosed with IH will have had the disorder for many years prior to their diagnosis.[5] As of August 2021[update], anFDA-approved medication exists for IH calledXywav, which is an oral solution of calcium, magnesium, potassium, andsodium oxybates;[6] in addition to several off-label treatments (primarily FDA-approved narcolepsy medications).[7]
Idiopathic hypersomnia may also be referred to as IH, IHS, or primary hypersomnia,[8] and belongs to a group ofsleep disorders known as central hypersomnias, central disorders of hypersomnolence, orhypersomnia of brain origin.[9]Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) defines idiopathic hypersomnia as EDS withoutnarcolepsy or the associated features of other sleep disorders.[10] It occurs in the absence of medical problems or sleep disruptions, such assleep apnea, that can cause secondary hypersomnia.
Individuals with IH share common symptoms includingexcessive daytime sleepiness,sleep inertia,brain fog, and long sleep periods.[11][12][13]
Some studies have shown increased frequencies of palpitations, digestive problems, difficulty with body temperature regulation, and other symptoms in patients with IH.[16][17] Anxiety and depression are frequent, and are likely to be a response to chronic illness.[16] A case series in 2010 found that peripheral vascular symptoms, such as cold hands and feet (e.g.,Raynaud syndrome), were more common in people with IH than in controls.[18]
Otherautonomic dysfunctional symptoms, such asfainting episodes,dizziness upon arising, possiblymigrainous headaches, food cravings, andimpotence may also be correlated with IH.[17][19] Researchers have found that people reporting IH symptoms report high levels of autonomic dysfunction on par with other conditions of autonomic failure (i.e.,MSA anddiabetes). As of 2019[update] there is no evidence that such symptoms are related to IH.[20]
Unlikenarcolepsy withcataplexy, which has a known cause (autoimmune destruction of hypocretin-producing neurons), the cause of IH is largely unknown. As of 2012[update], researchers have identified a few abnormalities associated with IH, which with further study may help to clarify the etiology.[21]
Destruction ofnoradrenergic neurons has produced hypersomnia in experimental animal studies, and injury toadrenergic neurons has also been shown to lead to hypersomnia. IH has also been associated with a malfunction of thenorepinephrine system and decreasedcerebrospinal fluid (CSF)histamine levels.[22]
Researchers have recently found an abnormal hypersensitivity toGABA (the major brain chemical responsible forsedation) in a subset of patients with central hypersomnia i.e.: IH, narcolepsy without cataplexy and long sleepers. They have identified a small (500 to 3000daltons) naturally occurring bioactive substance (most likely apeptide as it istrypsin-sensitive) in the CSF of affected 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 ofGABAA receptors, which leads to increased sedation or somnolence. In essence, it is as though these patients are chronically sedated with abenzodiazepine (medication which acts through the GABA system) such asmidazolam oralprazolam, even though they do not take these medications.[23][24]
Idiopathic hypersomnia lacks a clearly defining biological marker (i.e.,HLA-DQB1*0602genotype in narcolepsy). Doctors can more carefully exclude these causes of EDS in order to more correctly diagnose IH.[19] 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 IH should be considered."[25]
The severity of EDS can be quantified by subjective scales, such as theEpworth Sleepiness Scale and theStanford Sleepiness Scale, and also by objective tests, likeactigraphy,psychomotor vigilance task, maintenance of wakefulness test (MWT),[26]multiple sleep latency test (MSLT) although as per latest research studies, the effectiveness of MSLT has been called into question.[27][28] Several groups of researchers have found normal MSLT results in patients who otherwise seem to have IH. Therefore, when IH is suspected, researchers suggest appending a 24-hour continuouspolysomnography to the standard overnight/MSLT study in order to record total sleep time.[29]
The recent studies have also found that reports of sleepiness in IH relate more to mental fatigue rather than physiological sleepiness per se and the subjective scales like ESS, IH symptom diary (IHSD) and PGIC better captures the severity of symptoms consistently.[30]
It is also important to note that whereas narcolepsy is strongly associated with theHLA-DQB1*0602genotype,[21] "HLA typing is of no help in the positive diagnosis of idiopathic hypersomnia."[19] This is "despite some reports that suggest an increase [sic] frequency of HLA Cw2 and DRS in idiopathic hypersomnia subjects."[19]
In patients with IH, 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."[31] Despite this, one study has found increased sleep fragmentation in patients with IH without long sleep time, suggesting multiple possible presentations.[32]
PerICSD-3, five criteria[clarification needed] must be met for a diagnosis of IH:
The latestICD-10 defines IH with long sleep time as a neurological disorder that is a rare sleep disorder characterized by prolonged sleep at night and extreme sleepiness during the day. There are no apparent causes. This disorder affects the ability to function. It is ofcentral nervous system origin characterized by prolonged nocturnal sleep and periods of daytime drowsiness. Affected individuals experience difficulty with awakening in the morning and may have associated sleep drunkenness, automatic behaviors, and memory disturbances. This condition differs from narcolepsy in that daytime sleep periods are longer, there is no association with cataplexy, and the multiple sleep latency onset test does not record sleep-onset rapid eye movement sleep.[36]
Since the underlying mechanism is not yet fully understood, treatment efforts have usually focused on symptom management. In August 2021, low-sodium oxybate (Xywav) became the first U.S. FDA-approved treatment for idiopathic hypersomnia.[6]Wake-promoting medications used in narcolepsy are also commonly usedoff-label to help manage the excessive daytime sleepiness of IH.Stimulants tend to be less effective for IH than they are for narcolepsy and may be less well tolerated.[29]
The main treatment of excessive daytime sleepiness is done through central nervous system stimulants. However, no stimulant medication has receivedFDA orEMA approval for the treatment of EDS in IH. As such, stimulants are usedoff-label in the treatment of IH.[37]
Modafinil andArmodafinil are non-amphetamine wake-promoting agents often used in the treatment of IH.[38] They are thought to work by binding to the dopamine transporter, thereby inhibiting dopamine reuptake and increasing its availability. Modafinil can cause uncomfortable side effects, includingnausea,headache, and adry mouth for some patients, while other patients report no noticeable improvement even on relatively high dosages.[39] 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."[21]
Methylphenidate anddextroamphetamine are psychostimulants with long histories of use in the treatment of hypersomnolence.[40][41] Increased extracellular dopamine availability is thought to be the main property explaining wake-promotion from these medications, although effects on norepinephrine also likely contribute.[21]Insomnia is another common side effect and may require additional treatment.[42]
Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (NDRI) used to treat excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea.[43]
Pitolisant, a selective histamine 3 (H3) receptor antagonist/inverse agonist.[44] It works by increasing the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain.[45]
Sodium oxybate (Xyrem) is anorphan drug which was designed specifically for the treatment of narcolepsy. Common side effects includenausea,dizziness, andhallucinations.[46] A 2016 study by Leu-Semenescu et al. found sodium oxybate reduced daytime sleepiness in IH to the same degree as in patients with narcolepsy type 1, and the drug improved severe sleep inertia in 71% of the hypersomnia patients.[47] In July 2020, the FDA approvedXywav™ (calcium, magnesium, potassium, and sodium oxybates), an oral solution for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.[48]
Although behavioral approaches have not been demonstrated to improve clinical markers of IH,cognitive behavioral therapy (CBT) has been found to potentially reduce depressive symptoms and improveself-efficacy in people with hypersomnia.[49]
IH can profoundly affect work, education, and quality of life due to excessive daytime somnolence. Patients will often need to adapt their lifestyle to avoid situations that might be dangerous while sleepy, such as high risk work, or driving. The risks associated with these activities have been found to be higher for patients with hypersomnias than for those with sleep apnea or severe insomnia.[7]
Typically, the symptoms of IH begin in adolescence or young adulthood, although they can begin at a later age.[50][16] After onset, hypersomnia often worsens over several years,[16] but it is often stable by the time of diagnosis and appears to be a lifelong condition.[5] Spontaneous remission is only seen in 10–15% of patients.[31][51]
According to the limited epidemiological data that exists, IH "has more of a female preponderance (1.8/1)."[52] Family cases are frequent, in a range from 25% to 66% without any clear mode of inheritance."[27]
IH has long been considered arare disease, believed to be 10 times less frequent than narcolepsy.[27] The prevalence of narcolepsy (with cataplexy) is estimated between 1/3,300 and 1/5,000.[53] Although the true prevalence of IH is unknown, it is estimated at 1/10,000 to 1/25,000 for the long sleep form and 1/11,000 to 1/100,000 without long sleep.[54] A more precise estimate "is complicated by a lack of clear biologic markers" and a lack of "unambiguous diagnostic criteria."[55]
Because of the rarity of IH, research into the condition is limited "Patients are rare, researchers and scientists involved in the field are few and research findings are therefore scarce."[7] "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."[7]
There is ongoing research into the efficacy of gamma aminobutyric acid A (GABAA) receptor antagonists for the treatment of IH.[56] 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.[57] Given the possible role of hyperactive GABAA receptors in IH, medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently includeclarithromycin andflumazenil.[23][24]
Flumazenil, a GABAA receptor antagonist is approved by the FDA for use in anesthesia reversal andbenzodiazepine overdose. Research has shown that flumazenil provides relief for most patients whose CSF contains the unknown "somnogen" that enhances the function ofGABAA 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.[23] A 2014 case report also showed improvement in IH symptoms after treatment with a continuous subcutaneous flumazenil administration. The patient was treated with a short-term subcutaneous administration through 96-hour continuous low dose (4 mg/day) infusion of flumazenil, followed by a slow-release long term subcutaneous administration through flumazenil implant.[58]
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 IH. In the pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia.[59] In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of patients with GABA-related hypersomnia.[60] A 2021Cochrane study determined that the evidence is inadequate to definitively determine the efficacy of clarithromycin in the management of idiopathic hypersomnia.[61] TheAmerican Academy of Sleep Medicine's 2021 clinical practice guidelines conditionally suggested its use, especially for those who don't respond to other therapies.[62][63]
Dr. Ferini-Strambi and his colleagues in Milan, Italy, performed neurologic examinations by applying anodal tDCS by placing one electrode over the left dorsolateral prefrontal cortex, with the cathode over the contralateral orbit over 3 weeks period and found that seven of the eight participants (87.5%) reported improvement in their daytime sleepiness, including for up to two weeks after the end of the study.[64][65]
Neural networks that regulate arousal and sleep comprise a bottom-up (from the brainstem to the cortex) pathway and a top-down (corticothalamic) pathway. The bottom-up pathway emerges from the ascending reticular arousal system (ARAS) and activates the cortex via well-characterized thalamic and nonthalamic pathways through cholinergic and aminergic neurotransmission. The bottom-up pathway represents the leverage point for pharmaceutical interventions. It is complemented by a corticothalamic top-down pathway, which appears to be modifiable throughnoninvasive brain stimulation (NIBS) techniques.[66]A single case report study indicates that high-frequency repetitive transcranial magnetic stimulation (HF rTMS) over the left dorsolateral prefrontal cortex (DLPFC) might represent an alternative choice for symptom control in narcoleptic patients with cataplexy. rTMS may also exert intrinsic effects on hypersomnia in depressed adolescents.[67]
Mazindol is a stimulant similar toamphetamine that "has been shown to be effective in treating hypersomnia in narcoleptics." However, it is not currently approved in the US.[68]
Selegiline, amonoamine oxidase B (MAO-B) inhibitor, works by slowing the breakdown of certain substances in the brain (mostly dopamine, but also serotonin and norepinephrine). It may also be useful, as it is also a metabolic precursor of amphetamine and exerts most of its therapeutic effects through amphetamine metabolism. It is not commonly prescribed for people with narcolepsy because of the high dosage required and potential for severe side effects.[21]
Atomoxetine is anorepinephrine reuptake inhibitor (NRI) 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."[21]
Ritanserin is aserotonin 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.[68]
Antidepressants seems to have some therapeutic effects as they enhance synaptic levels of norepinephrine and serotonin. Further, different medicines are known to augment the activity of one another like as seen in the case offluoxetine which augmented the activity of methylphenidate when taken together.
Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), which works by inhibiting the reabsorption of two important brain chemicals – norepinephrine and dopamine, is known to have wake-promoting effects.[citation needed]
Fluoxetine, an antidepressant of theselective serotonin reuptake inhibitor (SSRI) class is also known to have mild stimulating effects. It is also known to augment the activity of methylphenidate.[69]
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."[21] Although it is commonly used by people with IH or narcolepsy, many people with these disorders report that it has only limited benefit on their sleepiness.
Melatonin is a hormone that the body produces to help regulate sleep. One small study, which used a dose of 2 mg slow-release melatonin at bedtime, found that 50% of participants had "shortened nocturnal sleep duration, decreasedsleep inertia, and relieved daytime sleepiness." Other studies have shown that melatonin synchronizes the circadian rhythms, and improves the "onset, duration and quality of sleep."
There have been some studies suggestinglevothyroxine as a possible treatment for IH, especially for patients withsubclinical hypothyroidism.[70][71] This treatment does carry potential risks (especially for patients withouthypothyroidism or subclinical hypothroidism), which include cardiac arrhythmia.[72]
Orexin-A has been shown to be strongly wake-promoting in animal models, but it does not cross theblood–brain barrier.Suvorexant, aorexin receptor antagonist, has been developed to limit the natural effects of orexin in patients with insomnia. It is therefore possible that a orexinagonist may be similarly developed for the treatment of hypersomnia.[21]
Levodopa (L-DOPA) is an amino acid and is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). As per a study of six narcoleptic patients it was found thatL-DOPA improvedvigilance and performance as evaluated by the AVS and the FCRTT, while the capacity to fall asleep rapidly remained unchanged as evaluated by the MSLT. It raises the hypothesis that dopamine may play a role in the physiopathology of excessive daytime sleepiness of this condition.[73]
Carnitine has also been shown to improve narcolepsy symptoms (including daytime sleepiness) by increasing fatty-acid oxidation.[74] Abnormally low levels of acylcarnitine have been observed in patients with narcolepsy.[75] 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 ofacetyl-L-carnitine was shown to improve these symptoms in mice.[76] A subsequent human trial found that narcolepsy patients givenL-carnitine spent less total time in daytime sleep than patients who were given placebo.[77]
There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia.
Recommendation 9: We suggest that clinicians use clarithromycin (vs no treatment) for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL)
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