Idiopathic hypersomnia is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS). 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. There is a very low level of public awareness of idiopathic hypersomnia, which often leads to stigma for those who suffer from it. There is currently no cure, but there are several off-label treatments, which are primarily FDA-approved narcolepsy medications.
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. It occurs in the absence of medical problems or sleep disruptions, such as sleep apnea, that can cause secondary hypersomnia.
Signs and symptoms
Excessive daytime sleepiness, which is 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 are compelled to nap repeatedly during the day; fighting off increasingly strong urges to sleep during inappropriate times such as while driving, while at work, during a meal, or in conversations.
Sleep inertia (also known as sleep drunkeness), which is characterized by having extreme difficulty waking up and feeling an uncontrollable desire to go back to sleep.
Clouding of consciousness (also known as brain fog or mental fog), which is characterized by inattention, thought process abnormalities, comprehension abnormalities, and language abnormalities. This may affect performance on virtually any cognitive task. Cognition includes perception, memory, learning, executive functions, language, constructive abilities, voluntary motor control, attention, and mental speed. Sufferers may complain of forgetfulness, being "confused", or being "unable to think straight".
Long sleep periods with patients sleeping 9 hours or more over 24-hour periods, yet not feeling refreshed upon waking from nighttime sleep or naps. Daytime naps are generally very long (up to several hours) and are also unrefreshing.
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. These symptoms include palpitations, digestive problems, difficulty with body temperature regulation, and cognitive problems, especially deficits in memory, attention, and concentration. Anxiety and depression are often increased in idiopathic hypersomnia, most likely as a response to chronic illness. 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). Food cravings and impotence have also been reported. The researchers found that people with IH reported extremely high levels of autonomic dysfunction, on par with other conditions of severe autonomic failure, like MSA (multiple system atrophy) and diabetes.
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.
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.
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.
People with idiopathic hypersomnia often live without a correct diagnosis for a long time, blaming themselves and struggling to maintain work, studies, and relationships. Idiopathic hypersomnia has historically been difficult to diagnose at an early stage, especially due to low awareness and therefore, at the time of presentation, most patients have had the disorder for many years.
Further complicating the diagnostic process, idiopathic hypersomnia lacks a clearly defining biological marker like HLA-DQB1*0602 genotype in narcolepsy. Doctors can more carefully exclude these causes of EDS in order to more correctly diagnose idiopathic hypersomnia. 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."
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 actigraphy, maintenance of wakefulness test (MWT), multiple sleep latency test (MSLT) although as per latest research studies, the effectiness of MSLT has been called into question." 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.
It is also important to note that whereas narcolepsy is strongly associated with the HLA-DQB1*0602 genotype, "HLA typing is of no help in the positive diagnosis of idiopathic hypersomnia." This is "despite some reports that suggest an increase [sic] frequency of HLA Cw2 and DRS in idiopathic hypersomnia subjects."
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." Despite this, one study has found increased sleep fragmentation in patients with idiopathic hypersomnia without long sleep time, suggesting multiple possible presentations.
As per ICSD-3, six criteria must be met for a diagnosis of idiopathic hypersomnia. First is daytime lapses into sleep or an irrepressible need to sleep on a daily basis, for at least 3 months, second is absence of insufficient sleep syndrome, third is absence of cataplexy, fourth is absence of other causes of hypersomnia and fifth and sixth is presence of positive MSLT tests.
The latest ICD 10 defines Idiopathic hypersomnia 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 of central 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.
Since the underlying disease mechanism is not yet fully understood, treatment efforts have usually focused on symptom management. There are no FDA-approved medicines for idiopathic hypersomnia. The wake-promoting medications used in narcolepsy are also commonly used off-label to help manage the excessive daytime sleepiness of idiopathic hypersomnia. However, the medications currently used for idiopathic hypersomnia 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. Different medications could be administered in combination to address different symptoms like it is found that methylphenidate is effective in addressesing EDS while pemoline is more effective in addressing brain fog. 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.
In addition to medications, "behavioral approaches and sleep hygiene techniques are recommended, although they have little overall positive impact on this disease." "Planned naps are unhelpful, as they are both long and unrefreshing." 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."
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. Insomnia is another common side effect and may require additional treatment.
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."
Non-stimulant wake-promoting medications
Modafinil and Armodafinil elevate hypothalamic histamine levels, 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. 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."
Solriamfetol is the first and only dual-acting dopamine and norepinephrine reuptake inhibitor approved by the FDA to improve wakefulness in adults living with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea.
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."
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.
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.
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.
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. 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. FDA approved Xywav™ (calcium, magnesium, potassium, and sodium oxybates) oral solution on July 2020 for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. 
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, decreased sleep drunkenness and relieved daytime sleepiness.” Other studies have shown that melatonin synchronizes the circadian rhythms, and improves the “onset, duration and quality of sleep.”
Antidepressants seems to have some therapeutic effects as they enhance synaptic levels of noradrenaline and serotonin.
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.
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.
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.
Flumazenil, a GABAA receptor antagonist is approved by the FDA for use in anesthesia reversal and benzodiazepine overdose. Research has shown 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. A 2014 case report also showed improvement in idiopathic hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion.
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. In the pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia.  In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of patients with GABA-related hypersomnia.
Carnitine, has also been shown to improve narcolepsy symptoms (including daytime sleepiness) by increasing fatty-acid oxidation. Abnormally low levels of acylcarnitine have been observed in patients with narcolepsy. 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. A subsequent human trial found that narcolepsy patients given L-carnitine spent less total time in daytime sleep than patients who were given placebo.
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.
The disorder is chronic, and the symptoms can be relentless. If an effective medication to control symptoms cannot be found, it can be extremely difficult for people with IH to hold down jobs, remain in school, maintain marriages, and fully engage with their family and friends. Even with medication, patients may struggle with these activities. Many patients are chronically tardy to work, school or social engagements and, over time, may lose the ability to function in family, social, occupational or other settings altogether.
Idiopathic hypersomnia profoundly affects work, education, and quality of life. Patients often need to drastically adapt their lifestyle after diagnosis. Avoiding situations that might be dangerous while sleepy, such as driving. It is not safe to drive a car unless the symptoms are under control with medication. 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." 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." Surprisingly, excessive daytime sleepiness is even more handicapping than the cataplectic attacks of narcolepsy.
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.
Typically, the symptoms of idiopathic hypersomnia begin in adolescence or young adulthood, although they can begin at a later age. After onset, hypersomnia often worsens over several years, but it is often stable by the time of diagnosis and appears to be a lifelong condition. Spontaneous remission is only seen in 10–15% of patients.
According to the limited epidemiological data that exists, IH "has more of a female preponderance (1.8/1)." Family cases are frequent, in a range from 25% to 66% without any clear mode of inheritance."
Idiopathic hypersomnia has long been considered a rare disease, believed to be 10 times less frequent than narcolepsy. The prevalence of narcolepsy (with cataplexy) is estimated between 1/3,300 and 1/5,000. 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. A more precise estimate "is complicated by a lack of clear biologic markers" and a lack of "unambiguous diagnostic criteria."
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." "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." (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 isolated and misunderstood. Therefore, the education of relatives, friends, and colleagues helps the patient to function much better with this incurable disease.
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. 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.
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.
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. 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.
There have been some studies suggesting levothyroxine as a possible treatment for idiopathic hypersomnia, especially for patients with subclinical hypothyroidism. This treatment does carry potential risks (especially for patients without hypothyroidism or subclinical hypothroidism), which include cardiac arrhythmia.
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.
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.  Memantine has also shown some positive effect on a patient suffering from narcolepsy.
Levodopa 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 that L-dopa improved vigilance 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.
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