|Classification and external resources|
Idiopathic hypersomnia is a disease, thought to be a neurological disorder, which is characterized primarily by severe 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. Currently, there is no cure, there are no FDA-approved treatments, and research funding for its study is scarce.
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 that can cause secondary hypersomnia, and it occurs "despite normal quality and quantity of night time sleep (and sometimes despite exceptionally long periods of night time sleep). Primary Hypersomnia is thought to arise from problems with the brain’s systems that regulate sleep and wake."
- 1 Classification
- 2 Signs and symptoms
- 3 Causes
- 4 Diagnosis
- 5 Management
- 6 Prognosis
- 7 Epidemiology
- 8 Society and culture
- 9 Research
- 10 References
- 11 External links
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.
This classification has been steadily evolving, as further research has now shown overlap between narcolepsy and idiopathic hypersomnia. The 3rd edition of the ICSD is currently being finalized, and its new classification will label narcolepsy caused by hypocretin deficiency as “type 1 narcolepsy,” which is almost always associated with cataplexy. The other hypersomnias will remain subdivided based on the presence of sleep-onset rapid eye movement periods (SOREMPs). They will be labeled: “type 2 narcolepsy,” with 2 or more SOREMPs on mean sleep latency testing (MSLT); and “idiopathic hypersomnia,” with less than 2 SOREMPS.
However, “there is no evidence that the pathophysiology or therapeutic response is substantially different for hypersomnia with or without SOREMPs on the MSLT.” Given this currently understood overlap of idiopathic hypersomnia and narcolepsy, the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders has also updated its classification of the primary hypersomnias. It reclassified both idiopathic hypersomnia with and without long sleep time as major somnolence disorder (MSD). Additionally, MSD encompasses all syndromes of hypersomnolence not explained by low hypocretin, including not only idiopathic hypersomnia, but also narcolepsy without cataplexy, and long sleepers (patients requiring >10 hours sleep/day).
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. (See Causes section below).
Signs and symptoms
Those who suffer from idiopathic hypersomnia have recurring episodes of excessive daytime sleepiness (EDS). These occur in spite of “adequate, or more typically, extraordinary sleep amounts (e.g., greater than 10 hours per night).” Sleep is usually quite 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). Daytime naps are generally very long (up to several hours) and are also unrefreshing, as opposed to the short refreshing naps associated with narcolepsy. Sleep paralysis and hypnagogic hallucinations may also be seen, and these symptoms are as common in idiopathic hypersomnia as they are in narcolepsy without cataplexy.
Several studies have shown increased frequencies of other symptoms in patients with idiopathic hypersomnia, although it is not clear whether or not 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. Peripheral vascular symptoms, such as cold hands and feet (Raynaud’s-type phenomena) are quite common. In addition to difficulty with temperature regulation and Raynaud’s type symptoms, other symptoms associated with autonomic dysfunction are not uncommon in idiopathic hypersomnia. These may include: fainting episodes (syncope); dizziness upon arising (orthostatic hypotension); and headaches (possibly migrainous in quality). Food cravings and impotence can also be associated. In addition, some patients “exhibit hypersensitivity to sedating medications such as anesthetics, sleeping pills, or alcohol."
Patients with idiopathic hypersomnia display these symptoms continually for months or years. Symptom intensity often varies between weeks, months, or years, and symptoms sometimes worsen just prior to menses in women. 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. (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.
Destruction of nonadrenergic 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.
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."
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. 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 the multiple sleep latency test (MSLT)."
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). 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.”
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." 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. However, the importance of this differentiation between REM and NREM has been called into question. (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. Alternatively, an assay of the patient's cerebrospinal fluid (CSF) can be performed in order to test for an adequate level of hypocretin (to exclude narcolepsy with cataplexy) and to determine whether the patient’s CSF abnormally boosts GABAA receptor sensitivity (thought to underlie many cases of idiopathic hypersomnia and narcolepsy without cataplexy). Globally, there are very few labs capable of performing the CSF assays referenced above.
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 frequency of HLA Cw2 and DRS in idiopathic hypersomnia subjects.”
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. “These treatments have not been studied to nearly the same extent in patients with idiopathic hypersomnia, and some patients with idiopathic hypersomnia do not achieve adequate control of symptoms with these medications."
However, current research is raising the possibility of several other potential medication options for idiopathic hypersomnia. "As the brain systems regulating sleepiness and wakefulness are better understood, scientists will be in a better position to design treatments that target key portions of this system." (see Research)
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.”
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.”
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.
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.” Increased dopamine release is felt to be the main property explaining wake-promotion from these medications. Although stimulants can effectively reduce sleepiness in the short to medium term, they are rarely effective long-term, as patients frequently become resistant to their effects. In addition, there are unpleasant potential side effects, which include heart problems, aggressive behavior, and dependence. 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.”
The non-stimulant wake-promoting medications approved for use in narcolepsy include modafinil and armodafinil. Their pharmacology is not completely understood, but these medications “appear to influence brain chemistry that increases wakefulness.” They 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.” 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.”
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. “It is a low potency nonspecific monoamine reuptake inhibitor that also has DAT [dopamine-reuptake] inhibitory effects.”
Sodium oxybate is an orphan drug which was designed specifically for the treatment of narcolepsy. It has been shown to promote deep sleep and improve daytime sleepiness (as well as cataplexy) in patients with narcolepsy; however, “its effects in those with idiopathic hypersomnia are not well characterized." Common side effects include nausea, dizziness, and hallucinations.
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.
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." 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." And idiopathic hypersomnia is often as, if not more, disabling than narcolepsy; 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. The disorder usually develops slowly over a period of months and years, often worsening over that period. Although it is initially progressive, idiopathic hypersomnia 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.
There is no clear indication of gender predominance, although women may be slightly more affected than men. 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 and was believed to be 10 times less frequent than narcolepsy. The prevalence of narcolepsy is known to be about 1 in 2000. "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)
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." Because of the absence of a gold standard test for idiopathic hypersomnia and the diagnostic confusion (including the use of many different labels and names), a true prevalence for idiopathic hypersomnia has not, in fact, been determined. Researchers have recently suggested that the prevalence is higher, at least 1 in 800, which translates to about 400,000 in the U.S. alone.
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.”
"Based on the role of histamine in keeping people awake (and hence the common side effect of anti-histamines such as diphenhydramine causing sleepiness), medications that act on histamine are under development for the treatment of excessive sleepiness." It remains to be seen whether or not these 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.
Given the possible role of hyper-active 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 is the only GABAA receptor antagonist on the market as of Jan 2013, and it is currently manufactured only 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. A 2014 case report also showed improvement in idiopathic hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion. The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of idiopathic hypersomnia. However, this scarcity has eased, and dozens of patients are now being treated with flumazenil off-label.
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. "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted." In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of patients with GABA-related hypersomnia. “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.”
Hypocretin-1 has been shown to be strongly wake-promoting in animal models, but it unfortunately does not cross the blood brain barrier. Therefore, companies are currently developing hypocretin receptor antagonists, like almorexant, which is awaiting FDA approval for the treatment of insomnia. It is also likely that a hypocretin-1 agonist will be found and developed for the treatment of hypersomnia.
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.
There have been a few studies suggesting melatonin could possibly be helpful in the treatment of idiopathic hypersomnia. 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.”
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.
- "International classification of sleep disorders, revised: Diagnostic and coding manual". American Academy of Sleep Medicine. 2001. Retrieved 25 January 2013.
- "Medscape Overview#aw2aab6b2b5". Retrieved 2013-01-25.
- "Hypersomnia Foundation - Treatment". Retrieved 2013-01-25.
- Bayon V, Léger D, Philip P. (2009). "Socio-professional handicap and accidental risk in patients with hypersomnias of central origin". Sleep Med Rev 13 (6): 421–426. doi:10.1016/j.smrv.2009.02.001. PMID 19493688.
- Diagnostic and statistical manual of mental disorders : DSM-IV-. Washington, DC: American Psychiatric Association. 2000. ISBN 0-89042-025-4.
- "About Hypersomnia". Hypersomnia Foundation. Retrieved 2013-01-25.
- Dauvilliers, Yves et al (2006-04-01). "Differential Diagnosis in Hypersomnia". Current Neurology and Neuroscience Reports (Current Medicine Group) 6 (2): 156–162. doi:10.1007/s11910-996-0039-2. PMID 16522270.
- Bassetti, C (1997). "Idiopathic hypersomnia A series of 42 patients". Brain 120 (8): 1423. doi:10.1093/brain/120.8.1423.
- Mignot, Emmanuel J. M. (2012). "A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes". Neurotherapeutics 9 (4): 739–52. doi:10.1007/s13311-012-0150-9. PMC 3480574. PMID 23065655.
- "Diagnosis of Idiopathic Hypersomnia/ Major Hypersomnolence Disorder". Retrieved 2013-04-23.
- "Recent Updates to Proposed Revisions for DSM-5: Sleep-Wake Disorders". DSM-5 Development. American Psychiatric Association.
- Vernet, Cyrille (2009). "Narcolepsy with Long Sleep Time". Sleep.
- Bendrich Roth, MD; Sonia Nevsimalova, MD; Allan Rechtschaffen, PhD (May 1972). "Hypersomnia With "Sleep Drunkenness"". Arch Gen Psychiatry 26 (5): 456–462. doi:10.1001/archpsyc.1972.01750230066013. PMID 5019884.
- Vernet, C., Leu-Semenescu, S., Buzare, M.-A. and Arnulf, I. (2010). "Subjective symptoms in idiopathic hypersomnia: beyond excessive sleepiness". Journal of Sleep Research 19 (4): 525–534. doi:10.1111/j.1365-2869.2010.00824.x. PMID 20408941.
- Billiard, M. (2001). "Idiopathic Hypersomnia". Sleep Medicine Reviews 5 (5): 349–358. doi:10.1053/smrv.2001.0168. PMID 12530998.
- Michel Billiard, MD. "Idiopathic Hypersomnia". Sleep Disorders I. Gui-de-Chauliac Hospital, Neurology B Department, 34295 Montpellier, Cedex 05, France. pp. 573–582.
- D.B. Rye, D.L. Bliwise, K. Parker, L.M. Trotti, P. Saini, J. Fairley, A. Freeman, P.S. Garcia, M.J. Owens, J.C. Ritchie and A. Jenkins (2012). "Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors". Sci. Transl. Med. 4 (161): 161ra151. doi:10.1126/scitranslmed.3004685. PMID 23175709.
- Preda, Adrian. "Primary Hypersomnia: Etiology". Medscape. Retrieved 25 January 2013.
- 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.
- 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.
- Billiard, M.; Dauvilliers, Y. (Oct 2001). "Idiopathic Hypersomnia". Sleep Med Rev 5 (5): 349–358. doi:10.1053/smrv.2001.0168. PMID 12530998.
- Montplaisir, Jacques (2001). "Idiopathic hypersomnia: a diagnostic dilemma. A commentary of "Idiopathic hypersomnia" (M. Billiard and Y. Dauvilliers)". Sleep Medicine Reviews 5 (5): 361–362. doi:10.1053/smrv.2001.0216. PMID 12530999.
- "Quantifying sleepiness". Retrieved 2013-07-23.
- Anderson (2007). "Idiopathic hypersomnia: A study of 77 Cases". Sleep.
- "Medscape - Treatment". Retrieved 2013-01-25.
- "Epocrates - Adderall". Retrieved 2013-07-19.
- Ishizuka T, Murakami M, Yamatodani A (January 2008). "Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats". Eur. J. Pharmacol. 578 (2–3): 209–15. doi:10.1016/j.ejphar.2007.09.009. PMID 17920581.
- "Epocrates - Provigil". Retrieved 2013-01-29.
- "Epocrates - Xyrem". Retrieved 2013-01-29.
- "Primary Hypersomnia". Retrieved 2013-01-29.
- Gosmany M. "The influence of clinical symptoms on quality of life in patients with narcolepsy." Neurology 1998;50:S31–6
- Dodel R, Peter H, Walbert T, Spottke A, Noelker C, Berger K, et al. "The socio-economic impact of narcolepsy." Sleep 2004;27:1123–8
- National Institutes of Health (June 2008). "NINDS Hypersomnia Information Page". Retrieved 2009-01-23.
- Sharon L. Schutte-Rodin, MD (January 12, 2006). "Idiopathic Hypersomnia with Long Sleep Time". American Academy of Sleep Medicine.
- Vecchierini (2013). "Role and actions of the orphan rare diseases reference center for central hypersomnias in France". Revue Neurologique.
- "Hypersomnia Foundation Interview with David Rye". Retrieved 2013-01-25.
- E. Kelty, V. Martyn, G. O’Neil and G. Hulse (19 February 2014). "Use of subcutaneous flumazenil preparations for the treatment of idiopathic hypersomnia: A case report". Journal of Psychopharmacology. doi:10.1177/0269881114523865.
- Beck, Melinda (2012-12-10). "Scientists Try to Unravel the Riddle of Too Much Sleep". The Wall Street Journal.
- "Hypersomnia Update". Emory University. Retrieved 2014-04-22.
- 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.
- Trotti, L et al (December 3, 2013). "Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: Clinical experience". Journal of Psychopharmacology 27 (12).
- "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.
- 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): 349–353.
- Miyagawa T, Honda M, Kawashima M, Shimada M, Tanaka S, et al. (30 April 2009). "Polymorphism Located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)". In Rubinsztein, David C. PLoS ONE 4 (4): e5394. doi:10.1371/journal.pone.0005394. PMC 2671172. PMID 19404393.
- 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. doi:10.1371/journal.pone.0053707. PMC 3547955. PMID 23349733.
- Talk About Sleep - Idiopathic Hypersomnia
- Help: I can't stay awake! - Public Radio Interview with Dr. David Rye
- med/3129 at eMedicine - "Primary Hypersomnia"
- 06-081c. at Merck Manual of Diagnosis and Therapy Home Edition - "Circadian Rhythm Sleep Disorders"
- -483065848 at GPnotebook