Idiopathic hypersomnia
Idiopathic Hypersomnia | |
---|---|
Specialty | Sleep medicine, Neurology, Psychiatry |
Idiopathic hypersomnia (IH) is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS).[1] Idiopathic hypersomnia was first described by Bedrich Roth in 1976, and it can be divided into two forms: polysymptomatic and monosymptomatic.[2][3] 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.[4] As of August 2021[update], an FDA-approved medication exists for IH called Xywav, which is oral solution of calcium, magnesium, potassium, and sodium oxybates;[5] in addition to several off-label treatments (primarily FDA-approved narcolepsy medications).[6]
Idiopathic hypersomnia may also be referred to as IH, IHS, or primary hypersomnia[7] and belongs to a group of sleeping disorders known as central hypersomnias, central disorders of hypersomnolence, or hypersomnia of brain origin.[8] 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.[9] It occurs in the absence of medical problems or sleep disruptions, such as sleep apnea, that can cause secondary hypersomnia.
Signs and symptoms
This section needs additional citations for verification. (June 2021) |
Individuals with IH share common symptoms including excessive daytime sleepiness, sleep inertia, brain fog, and long sleep periods.[10][11][12]
- Excessive daytime sleepiness, characterized by persistent sleepiness throughout the day and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. People with EDS nap repeatedly throughout the day and have strong urges to sleep while driving, working, eating, or conversing with others.[13]
- Sleep inertia (also known as sleep drunkenness), characterized by having extreme difficulty waking up and feeling an uncontrollable desire to go back to sleep.[13]
- Clouding of consciousness characterized by inattention, thought process abnormalities, comprehension abnormalities, and language abnormalities. These symptoms may affect performance on perception, memory, learning, executive functions, language, constructive abilities, voluntary motor control, attention, and mental speed. Affected individuals can complain of forgetfulness, confusion, or inability to think clearly.[14]
- Excessive sleep (9 hours or more over a full 24-hour period), without feeling refreshed after waking. Daytime naps can be up to several hours and are also unrefreshing.[13]
Some studies have shown increased frequencies of palpitations, digestive problems, difficulty with body temperature regulation, and other symptoms in patients with IH.
Other
Causes
Unlike
Destruction of
Researchers have recently found an abnormal hypersensitivity to
Diagnosis
Idiopathic hypersomnia lacks a clearly defining biological marker (i.e. HLA-DQB1*0602 genotype in narcolepsy). Doctors can more carefully exclude these causes of EDS in order to more correctly diagnose IH.[18] 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."[24]
The severity of EDS can be quantified by subjective scales, such as the
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.[29]
It is also important to note that whereas narcolepsy is strongly associated with the HLA-DQB1*0602 genotype,[20] "HLA typing is of no help in the positive diagnosis of idiopathic hypersomnia."[18] This is "despite some reports that suggest an increase [sic] frequency of HLA Cw2 and DRS in idiopathic hypersomnia subjects."[18]
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."[30] Despite this, one study has found increased sleep fragmentation in patients with IH without long sleep time, suggesting multiple possible presentations.[31]
Per ICSD-3, five criteria[clarification needed] must be met for a diagnosis of IH:
- Daytime lapses into sleep or an irrepressible need to sleep on a daily basis, for at least 3 months
- Absence of insufficient sleep syndrome
- Absence of cataplexy
- Absence of other causes of hypersomnia
- The presence of positive MSLT tests.[32][33][34]
The latest
Management
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.[5] Wake-promoting medications used in narcolepsy are also commonly used
Stimulants
The main treatment of excessive daytime sleepiness is done through central nervous system stimulants.
Methylphenidate and Dextroamphetamine are most used stimulants to controlled EDS. Increased dopamine release is felt to be the main property explaining wake-promotion from these medications.[20] Insomnia is another common side effect and may require additional treatment.[36]
Non-stimulant wake-promoting medications
Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (NDRI) used to treat excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea.[37]
Pitolisant, a selective histamine 3 (H3) receptor antagonist/inverse agonist, was approved by FDA during August 2019. It works by increasing the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain.
Sleep promoting medications
Sodium oxybate is an orphan drug which was designed specifically for the treatment of narcolepsy. Common side effects include nausea, dizziness, and hallucinations.[40] 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.[41] In July 2020, the FDA approved Xywav™ (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.[42]
Cognitive Behavioral Therapy
Although behavioral approaches have not been demonstrated to improve clinical markers of IH, cognitive behavioral therapy has been found to potentially reduce depressive symptoms and improve self-efficacy in people with central disorders of hypersomnolence.[43]
Prognosis
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.[6]
Epidemiology
Typically, the symptoms of IH begin in adolescence or young adulthood, although they can begin at a later age.[44][15] After onset, hypersomnia often worsens over several years,[15] but it is often stable by the time of diagnosis and appears to be a lifelong condition.[4] Spontaneous remission is only seen in 10–15% of patients.[30][45]
According to the limited epidemiological data that exists, IH "has more of a female preponderance (1.8/1)."[46] Family cases are frequent, in a range from 25% to 66% without any clear mode of inheritance."[26]
IH has long been considered a rare disease, believed to be 10 times less frequent than narcolepsy.[26] The prevalence of narcolepsy (with cataplexy) is estimated between 1/3,300 and 1/5,000.[47] 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.[48] A more precise estimate "is complicated by a lack of clear biologic markers" and a lack of "unambiguous diagnostic criteria."[49]
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."[6] "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."[6]
Research
GABA-directed medications
There is ongoing research into the efficacy of gamma aminobutyric acid A (GABAA) receptor antagonists for the treatment of IH.[50] 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.[51] 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 include clarithromycin and flumazenil.[22][23]
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.[53] In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of patients with GABA-related hypersomnia.[54] A 2021 Cochrane study determined that the evidence is inadequate to definitively determine the efficacy of clarithromycin in the management of idiopathic hypersomnia.[55] The American Academy of Sleep Medicine's 2021 clinical practice guidelines conditionally suggested its use, especially for those who don't respond to other therapies.[56][57]
Transcranial direct-current stimulation (tDCS)
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.[58][59]
Transcranial magnetic stimulation (TMS)
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 through noninvasive brain stimulation (NIBS) techniques.[60] 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.[61]
Mazindol
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.[62]
Selegiline
Selegiline, monoamine oxidase type 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.[20]
Atomoxetine
Ritanserin
Antidepressants
Antidepressants seems to have some therapeutic effects as they enhance synaptic levels of noradrenaline and serotonin. Further, different medicines are known to augment the activity of one another like as seen in the case of Fluoxetine 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 the selective serotonin reuptake inhibitor (SSRI) class is also known to have mild stimulating effects. It is also known to augment the activity of methylphenidate.[63]
Caffeine
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."[20] 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
Levothyroxine
There have been some studies suggesting
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.[20]
Acetylcholinesterase inhibitor
Antidepressants seems to have some therapeutic effects as they enhance synaptic levels of noradrenaline and serotonin and for same reason enhancing the levels of acetylcholine may have some therapeutic effect. Donepezil showed improvement in one patient by decreasing ESS score from 20 up to 14.[67] Memantine has also shown some positive effect on a patient with narcolepsy.[68]
Levodopa
Carnitine
Carnitine, has also been shown to improve narcolepsy symptoms (including daytime sleepiness) by increasing fatty-acid oxidation.[70] Abnormally low levels of acylcarnitine have been observed in patients with narcolepsy.[71] 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.[72] A subsequent human trial found that narcolepsy patients given L-carnitine spent less total time in daytime sleep than patients who were given placebo.[73]
See also
- List of investigational sleep drugs
- Altered level of consciousness
- Wakefulness
- Sleep study
- Sleep medicine
- Sleep hygiene
- Sleep
- Neuroscience of sleep
- Ascending reticular activating system
- Circadian rhythm
- Somnology
- Stimulant
- Nootropic
- Doping in sport
- List of drugs banned by WADA
References
- ^ Narcolepsy and hypersomnia: review and classification of 642 personally observed cases. Roth B. Schweiz Arch Neurol Neurochir Psychiatr. 1976;119(1):31-4
- PMID 35450222.
- PMID 11924018.
- ^ a b "International classification of sleep disorders, revised: Diagnostic and coding manual" (PDF). American Academy of Sleep Medicine. 2001. Archived from the original (PDF) on 26 July 2011. Retrieved 25 January 2013.
- ^ a b "FDA Approves First Drug for Idiopathic Hypersomnia". Archived from the original on 12 August 2021. Retrieved 2021-08-12.
- ^ PMID 19493688.
- ^ "Idiopathic Hypersomnia (GARD)". Archived from the original on 8 December 2021. Retrieved 2021-08-12.
- PMID 32901432.
- ISBN 0-89042-025-4.
- PMID 28778232.
- ^ "Idiopathic hypersomnia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov.
- ^ "About Idiopathic Hypersomnia". Hypersomnia Foundation.
- ^ a b c Moawad H (23 August 2023). "Rapid Rx Quiz: Idiopathic Hypersomnia". Medscape.
- ^ John Noble, Harry L. Greene (1996). Textbook of Primary Care Medicine. Mosby. p. 1325.
- ^ PMID 9278632.
- ^ S2CID 26085500.
- S2CID 26085500.
- ^ PMID 12530998.
- S2CID 190873732.
- ^ PMID 23065655.
- ^ Preda A. "Primary Hypersomnia: Etiology". Medscape. Retrieved 25 January 2013.
- ^ a b c Lynn Marie Trotti, MD (August 9, 2010). "Flumazenil for the Treatment of Primary Hypersomnia". Emory University – Georgia Research Alliance. ClinicalTrials.gov. Retrieved 2013-01-25.
- ^ a b Lynn Marie Trotti, MD (June 15, 2010). "Clarithromycin for the Treatment of Primary Hypersomnia". Emory University – Georgia Research Alliance. ClinicalTrials.gov. Retrieved 2013-01-25.
- PMID 12530999.
- ^ "Maintenance of Wakefulness Test". Hypersomnia Foundation.
- ^ S2CID 43410010.
- ^ "Quantifying sleepiness". Retrieved 2013-07-23.
- ^ a b Michel Billiard, MD. "Idiopathic Hypersomnia". Sleep Disorders I. Gui-de-Chauliac Hospital, Neurology B Department, 34295 Montpellier, Cedex 05, France. pp. 573–582.
- S2CID 213214852.
- ^ PMID 17969461.
- S2CID 205353142.
- ^ "Idiopathic Hypersomnia (IH) Characteristics".
- ^ "About Idiopathic Hypersomnia".
- ^ "Classification of Hypersomnias". Hypersomnia Foundation.
- ^ "2021 ICD-10-CM Diagnosis Code G47.11: Idiopathic hypersomnia with long sleep time". www.icd10data.com.
- ^ "Epocrates – Adderall". Retrieved 2013-07-19.
- ^ "Jazz Pharmaceuticals Announces U.S. FDA Approval of Sunosi™ (solriamfetol) for Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea | Jazz Pharmaceuticals plc". investor.jazzpharma.com.
- PMID 17920581.
- ^ "Epocrates – Provigil". Retrieved 2013-01-29.
- ^ "Epocrates – Xyrem". Retrieved 2013-01-29.
- PMID 26847972.
- ^ "Jazz Pharmaceuticals Announces U.S. FDA Approval of Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Cataplexy or Excessive Daytime Sleepiness Associated with Narcolepsy | Jazz Pharmaceuticals plc". investor.jazzpharma.com.
- PMID 32804069.
- ^ National Institutes of Health (June 2008). "NINDS Hypersomnia Information Page". Archived from the original on 2012-03-30. Retrieved 2009-01-23.
- PMID 26599679.
- PMID 24956068.
- ^ "Narcolepsy-cataplexy". Retrieved 2014-08-14.
- ^ "Idiopathic hypersomnia". Retrieved 2014-08-14.
- ^ "Primary hypersomnia epidemiology". Retrieved 2014-08-14.
- ^ "A Randomized, Placebo-Controlled, Double-Blind, Crossover Study of Oral BTD-001 in Adults with Idiopathic Hypersomnia". 28 April 2020.
- PMID 17858587.
- S2CID 31846588.
- ^ Trotti, L, et al. (June 2013). "CLARITHROMYCIN FOR THE TREATMENT OF HYPERSOMNIA: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSSOVER TRIAL". Sleep. 36 (Abstract Supplement): A248.
- S2CID 13121904.
- PMID 34031871.
There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia.
- PMID 34743789.
Recommendation 9: We suggest that clinicians use clarithromycin (vs no treatment) for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL)
- ^ "Treatment of Central Disorders of Hypersomnolence: An American Academy of Sleep Medicine Clinical Practice Guideline - Guidelines at a Glance" (PDF). American Academy of Sleep Medicine. 2021. Archived (PDF) from the original on 25 February 2024. Retrieved 25 February 2024.
- ^ "A Pilot Study of tDCS Looks Promising for the Treatment of IH". Hypersomnia Foundation. 1 November 2016.
- PMID 27548094.
- PMID 26883160.
- S2CID 212729744.
- ^ S2CID 207342823.
- PMID 21430816.
- ^ "Successful treatment with levothyroxine for idiopathic hypersomnia patients with subclinical hypothyroidism". General Hospital Psychiatry – Elsevier Inc. Retrieved 2010-08-05.
- ^ H. Shinno et al. (June 2011). "Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia." Sleep Medicine Vol. 12 6: 578–583
- ^ "Epocrates – levothyroxine". Retrieved 2013-01-29.
- PMID 17557440.
- S2CID 145515017.
- S2CID 11487907.
- ^ "Summary of Rationale Behind and Research Studies into L-carnitine as a Treatment for Narcolepsy". Hypersomnia Foundation. 19 January 2016.
- PMID 21358852.
- PMID 19404393.
- PMID 23349733.