What is the evidence for the efficacy of treatments for idiopathic hypersomnia and their proposed mechanism of action?


Idiopathic hypersomnia (IH) is a poorly understood neurological disorder that was only recently described in 1976 by Roth et al (1). The symptoms of excessive daytime sleepiness, prolonged nocturnal sleep or daytime naps, difficulty waking with cognitive impairment can frequently overlap with symptoms of other causes of hypersomnia such as sleep deprivation, narcolepsy type 1 and 2, psychiatric illnesses and delayed sleep phase sleep syndrome. Therefore the International Classification of Sleep Disorders 3rd Edition has laid out specific criteria for the diagnosis of IH (2). These are at least 3 months of daytime sleepiness, absence of cataplexy, less than 2 sleep onset REM periods on an overnight polysomnogram (PSG) and daytime multiple sleep latency test (MSLT) considered together, either a mean sleep latency of less than 8 minutes on MSLT or a minimum of 11 hours recorded sleep on a 24 hour PSG and the exclusion of insufficient sleep, other disorders or substance use. As the pathophysiology of this disorder is unclear, the treatment strategy relies largely on reducing symptoms of the disease. In this essay, we will look at the current treatment modalities and their reported efficacies.

Before defining efficacy of treatment, we will have to define the aim of treatment, which is to reduce the symptom burden on the patient. Vernet et al described the heterogenous symptom variability in patients with IH, but categorised them into 3 major groups (3). These are: excessive daytime sleepiness, prolonged night time and/or daytime sleep periods and increased sleep inertia with difficulty waking from sleep. An efficacious treatment outcome would be symptom reduction in these 3 groups. A quantifiable, reliable and validated scoring tool for IH symptom severity would be useful to evaluate treatment efficacy. However, while such a clinical tool exists for narcolepsy (4), one does not currently exist for IH. Other non-specific measures are, therefore, commonly used to assess treatment outcomes in IH. The Epworth Sleepiness Scale (ESS) is frequently used to assess excessive daytime sleepiness (EDS) severity in IH and response to treatment (5). MSLT and maintenance of wakefulness test (MWT) provide objective measures of EDS (6). MSLT is a required assessment in the diagnosis of IH while MWT is used to measure changes in EDS after treatment (7). As for measures of prolonged sleep duration and sleep inertia, no standardised tools exist for their assessment. Total sleep time can be estimated with the use of a sleep diary or actigraphy (8). 24 hour PSG assessments can also be used to objectively quantify sleep durations both in the day and at night (9). Sleep inertia measurements include a recently developed sleep inertia questionnaire. This was designed for use in clinical depression and not for hypersomnia disorders but could be adopted as an outcome measure (10). Similarly, objective testing of sleep inertia including measuring event-related potentials during forced awakening were not specifically designed for IH and remain to be validated as an outcome measure (11). When evaluating the evidence for treatment efficacy, it would be useful to consider the outcome measures used in each setting.

Non-pharmacological Treatments:


Neikrug at al recently performed an internet based survey with 371 participants (129 with IH). One of the survey sections looked at the endorsement of non-pharmacological strategies to cope with their symptoms (12). Only 3.9% of surveyed participants reported not using any non-pharmacological treatment. Non-pharmacological treatments include the use of caffeine (82.2%), daytime naps (81.4%), scheduled nocturnal sleep (75.2%), exercise (58.1%), temperature manipulations (47.3%), diet (39.5%) amongst others. However, when asked to rate the effectiveness of these strategies from 0-10 (10 being most effective), all strategies were rated as below 4. Caffeine rated an average of 3.3, daytime naps was rated at 2.7, scheduled nocturnal sleep rated at 3.0, exercise 2.2, temperature manipulation 2.7 and diet 1.9. 57% of those surveyed reported that they were informed about non-pharmacological methods by a medical doctor, either a sleep specialist or a primary care physician. This data shows that non-pharmacological treatments, although widely adopted, fail to provide consistent subjective effectiveness for controlling symptoms in IH. The authors did not use the ESS or any other of the outcome measures that were mentioned earlier. It is also worthwhile noting that 79.1% of IH patients surveyed were on medications that included stimulants and modafinil. They were not asked to rate the subjective effectiveness of any of the drugs. This would have been a useful comparison.

Pharmacological Treatments:


There are numerous agents that have been used in the treatment of IH. These drugs are  used off-label as there are no specifically FDA approved drugs for the treatment of IH. Only 3 recent randomised controlled trials have been conducted for the pharmacological treatment of IH. The majority of investigations conducted have been observational studies or case studies. We will look at some of the commonly used drugs and the evidence behind them. One common thread that will be noticed is the paucity of data on all these drugs.

Modafinil is one of the most widely used drugs in the treatment of IH (13). It is considered to be effective and is used as a first-line therapeutic option. The mechanism of action is thought to be from the inhibition of dopamine transporters that prevents dopamine reuptake with the resultant increase in the extracellular concentration of dopamine in certain brain regions (14). However, the exact mechanism is unclear. Two recent randomised, double-blind, placebo controlled trials have showed positive results in treatment of IH. Mayer et al conducted a multicentric study on 31 IH patients which showed a reduction of ESS scores by 6 points in patients given modafinil versus a placebo group (15). There was, however, no corresponding improvement in MWT measured mean sleep latency between the groups. Philip et al (13) performed a crossover trial on 14 patients with IH and 13 patients with narcolepsy and found that modafinil increased simulated driving performance as compared to placebo. There was an improvement in MWT sleep latencies as well. However, no segregation of results of the IH group was provided. Anderson et al reviewed the pharmacotherapy responses of 61 patients with IH over 3.8 years. Modafinil was given to 54 patients but 39 patients received modafinil monotherapy treatment with 24 (60%) resultant responders as assessed by the ESS (16).

Dextroamphetamine has been studied in 2 retrospective studies and has been shown to  improve EDS in IH in 1 of these studies. It is a central nervous system stimulant and a sympathomimetic. The mechanisms of action of dextroamphetamine include blocking uptake of adrenergic and dopamine, stimulating release of monoamines, and inhibiting monoamine oxidase. In 2007, Anderson et al performed a retrospective review of 77 IH patients. He found that 8 patients were treated with dextroamphetamine with 5 showing a response (ESS reduction of >4) (16). In Moshin et al’s study in 2009, 7 patients with IH were given dextroamphetamine but none reported significant improvement in ESS scores (17).

Methylphenidate is a stimulant that acts by blocking the reuptake of dopamine. In Moshin et al’s study, 61 patients with IH were given methylphenidate with 38 responding to the drug as reflected in the ESS scores (17). 25 (41%) reported good response (mean ESS reduction of 9) and 13 (21%) reported partial response (mean ESS reduction of 6) to the drug.

Mazindol was studied by Nittur et al in 2013 as a treatment option in narcoleptics and IH patients refractory to treatment with modafinil, methylphenidate and sodium oxybate. 37 IH patients were included in this retrospective review. Mazindol administered over an average of 30 months showed an average ESS reduction of 4.6 in all groups (18). Mazindol is a sympathomimetic amine and is thought to act as a reuptake inhibitor of norepinephrine.

Pitolisant is a histamine H3 receptor inverse agonist, increasing arousals through histaminergic pathways. A retrospective review of the efficacy of pitolisant in 78 drug resistant IH patients was performed in 2014. There was a 36% response rate (ESS reduction of >3) but 63% of patients stopped pitolisant due to the lack of efficacy (19).

In 2012, Rye et al showed that cerebrospinal fluid (CSF) from subjects with hypersomnias of unknown cause stimulated in vitro GABAergic transmission relative to the stimulation obtained with CSF from control subjects (20). They proposed a new possible pathophysiological pathway in the generation of excessive daytime sleepiness. These findings were not replicated in a subsequent study which did not find in vitro GABA-A receptor potentiation with CSF from patients with central hypersomnolence disorders (21). Nonetheless, this pathway was evaluated clinically with drugs that inhibit or enhance GABA transmission. Clarithromycin, a negative modulator of GABA-A receptor, was used in a crossover trial in 2015. 20 patients with hypersomnia syndromes without cataplexy (not specifically IH) were studied. The findings showed that although subjective measures of sleepiness improved (ESS reduction of >4), objective psychomotor vigilance tasks scores were not changed between the groups (22). Flumezanil, a GABA-A receptor antagonist, was retrospectively studied in 153 patients with central hypersomnolence who were refractory to medical treatment. 62.8% of patients reported response with an average ESS reduction of 4.7. 39% had sustained clinical benefit. Sodium oxybate is a GABA-B agonist used in the treatment of narcolepsy (23). Leu-Semenescu et al retrospectively examined the efficacy of sodium oxybate in 46 patients with IH. They found an average ESS reduction of 3.5 as well as an improvement of morning sleep inertia in 71% of patients.


As previously mentioned, there is paucity of data on the treatment response of IH. Only 2 randomised control trials were performed using modafinil and one using clarithromycin. The rest of the data on the treatment of IH comes from retrospective observational studies. Understandably, there is no standardised consensus on any one drug or treatment protocol. Most studies focus on excessive daytime sleepiness as measured with the ESS. However, the other symptoms of IH, including sleep inertia, prolonged daytime and night-time sleep need to be evaluated in order to make a meaningful assessment of clinical efficacy of treatment. As such, validated assessment tools will be required to quantify these symptoms.


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