Continuing Education Activity

Idiopathic hypersomnia (IH) is a central disorder of hypersomnolence, with the primary complaint being the irresistible need to sleep and waking up non-refreshed despite the prolonged duration of sleep. The subtypes and diagnostic criteria for the diseases have been debated in the past. Current subtypes are based on the length of total sleep time- Idiopathic Hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time. Although IH is a diagnosis of exclusion, electrophysiological testing, including polysomnography and mean sleep latency test remain crucial to establish the diagnosis. This activity highlights the role of the interprofessional team in evaluating and managing patients with idiopathic hypersomnia.

Objectives:

• Describe signs and symptoms of idiopathic hypersomnia.
• Outline differential diagnoses of hypersomnolence.
• Summarize the diagnostic criteria.
• Review treatment options for idiopathic hypersomnia.

Introduction

Idiopathic hypersomnia (IH) is a rare chronic sleep disorder introduced by Bedrich Roth in Prague in 1956.[1] Idiopathic hypersomnia is characterized by excessive daytime sleepiness, uncontrollable need to sleep with long unrefreshing naps, and difficulty waking up from sleep in most instances despite average or longer amounts of nocturnal sleep for at least three months.[2]

Idiopathic hypersomnia is considered a disorder of neurological origin, classified as a central disorder of hypersomnolence; others include narcolepsy, type 1 and type 2, and Kleine-Levin syndrome.[2] The condition's pathophysiology is poorly understood, making diagnosing and managing to challenge for clinicians. This article will review etiology, epidemiology, clinical manifestations, and the treatment of IH in adults.

Etiology

The etiology of IH is unclear. Triggers include Abrupt change in sleep-wake habits, overexertion, general anesthesia, Viral illness, and mild head trauma. Rare genetic predisposition was recently suggested to play a role in the pathogenesis of IH.[3] Specifically, it was found that subgroups of IH are associated with reduced signaling of orexin via variant in the cleavage site of prepro-orexin.[4] Another genetic variant thought to play a role is the homozygous PER2 variant.[5] 

Furthermore, dysregulation of micro RNA (miRNAs) has been reported to play a role in the etiology of central hypersomnias, including IH.[6]. In addition, recent studies linked IH to immune reactivity between a vaccine antigen and antigen on neural cells, suggesting an abnormal immune process playing a role in the etiology of IH mimicking narcolepsy.[7]

Epidemiology

Although central hypersomnia is considered a continuum, the rate of its subtypes differs. IH has the lowest rate compared to narcolepsy type 1 and type 2 (approximately 82%, 13%, and 5%, respectively).[8] Usually, idiopathic hypersomnia is considered a disorder of neurological origin, classified as a central disorder of hypersomnolence; others include narcolepsy, type 1 and type 2, and Kleine-Levin syndrome, which commonly occurs in the young or teenagers, with the mean age of symptom onset being 17 years and the mean age of diagnosis being 30 years.

Approximately one-third of cases have a positive family history, with family members having IH or other central disorders of hypersomnolence such as narcolepsy.[1] The prevalence of IH increased in the last decade by 32% (from 7.8 to 10.3 per 100,000 persons) in both men and women equally.[9]

Pathophysiology

Neurochemical studies are inconclusive. The main pathophysiologic feature of central hypersomnias is a defect in the arousal CNS system rather than hyperactivity of sleep centers.[10] 

Impairment in the neurotransmission of orexin (a neuropeptide produced mainly by neurons in the lateral hypothalamus) is the hallmark pathology in narcolepsy with cataplexy (narcolepsy type 1), possibly due to an autoimmune process.[11] However, the pathophysiology of the other central hypersomnias like IH remains unknown.

History and Physical

The usual presentation is chronic and disabling excessive daytime sleepiness in an adolescent or young adult, with the majority complaining of "sleep drunkenness" as difficulty waking up from sleep with transient confusion upon awakening. The onset of the disease is insidious, with symptoms appearing over weeks to months, making it difficult to elucidate any specific triggering factors.[12] 

Patients commonly endorse symptoms of long daytime naps (>1 hour) which are typically non-refreshing but sleep attacks are not frequently reported. Two clinical subtypes of IH have been previously reported as IH with long sleep time (IHwLST, >10 hours) and IH without long sleep time (IHwoLST) in the second edition of ICSD. Individuals with long sleep time (>10 to 11 hours) tend to be younger at the time of disease onset, thinner, and have higher sleep efficiency.[13] 

Age at disease onset is usually reported to be younger in the IHwLST group, and MSLT latency is longer, with naps that are non-refreshing.[14]

Although sleepiness is the hallmark of IH, symptoms of this condition are not limited to excessive daytime sleepiness and are frequently persistent despite treatment. Specifically, individuals with IHwLST can present with a history of severe sleep inertia, fatigue, and evening chronotype tendency. Furthermore, a study of five-hundred sixty-three participants with idiopathic hypersomnia, brain fog, and sleep drunkenness were more common in IH associated with long sleep durations.[12] Other symptoms such as automatic behaviors,  sleep paralysis, and hypnogogic hallucinations- are common but non-specific. 

Compared to narcolepsy, individuals with IH were more likely to have prolonged and unrefreshing daytime naps and have a family history of sleepiness. On polysomnography, they are more likely to have increased slow-wave sleep and present with a longer sleep latency on the multiple sleep latency test.[15]

Evaluation

The diagnosis of IH is by excluding other reasons and causes of hypersomnia. However, history alone is insufficient to make the diagnosis of idiopathic hypersomnia.[16] Therefore, objective tests such as polysomnography (PSG) followed by multiple sleep latency tests (MSLT ) are very important to measure the mean sleep latency and the number of sleep onset REM periods (SOREMs) in addition to the use of a wrist actigraphy in association with a sleep log are essential to distinguish IH from other disorders that cause similar symptoms including depression, insufficient sleep, sedating medication, and sleep-related breathing disorders.

A total sleep time must be longer than or equal to 66O minutes, especially when the mean sleep latency on the MSLT is longer than 8 min. However, MSLT is not a sensitive diagnostic test for IH.[1] Other common findings on PSG include a short sleep latency, increased total sleep time (TST), spindles, and increased sleep efficiency. In addition, PSG can help in ruling out sleep-disordered breathing (SDB) and the presence of SOREMs in narcolepsy.

Valid MSLT requires that it is performed on the day following nocturnal PSG (with sufficient sleep >6 hours). Usually, the MSLT should have five daytime nap opportunities in IH, and the mean sleep latency is less than 8 minutes with SOREMPs or less than two. 

Actigraphy can be helpful as multiple-day recordings occur in a home environment and can corroborate the history with sleep logs- at least over seven days with unrestricted sleep.

The CSF hypocretin is usually unnecessary and can be used to confirm the diagnosis of narcolepsy but not IH. When suspicion of accurate diagnosis remains, repeating MSLT would be needed. 

According to the International Classification of Sleep Disorders (ICSD) -the third edition, the diagnostic criteria are as follows:

• Daily periods of irrepressible need to sleep 
• No cataplexy
• MSLT  with mean sleep latency <8 minutes or TST >660 minutes on 24-hour PSG or actigraphy with a sleep log.
• No evidence of insufficient sleep (from the sleep diary).
• MSLT findings or symptoms of hypersomnolence are not better explained by alternate etiology.[2]

Treatment / Management

Non-pharmacological treatments such as prolonging sleep times, scheduled naps, and behavioral therapy are not generally effective.

Pharmacological therapy is effective and includes medications that promote alertness:

Modafinil: Modafinil is considered the first-line treatment option for idiopathic hypersomnia per the latest clinical practice guidelines from the American Academy of Sleep Medicine.[17] The efficacy in IH is similar to narcolepsy cases and very safe, including those without long sleep time [Level I].[18][19] 

The most frequently reported adverse events were headaches and gastrointestinal disorders. Modafinil significantly improved self-reported sleepiness on the Epworth Sleepiness Scale by 5.08 points more than placebo (95% confidence interval (CI) 3.01 to 7.16). Furthermore, the ability to remain awake on the Maintenance of Wakefulness Test was significantly improved with modafinil by 4.74 minutes more than with placebo (95% CI 2.46 to 7.01).

Other Medications for Idiopathic Hypersomnia

• Oxybate in phase 3, multicentre (six EU countries and the USA), placebo-controlled, double-blind, randomized withdrawal study showed that low dose oral solution once or twice nightly (with dose adjustment between 2·5 to 9·0 g/night) was effective in improving sleepiness (ESS decreased from mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0)) [Level I].[20] 

  • The reported adverse events included nausea (22%), headache (18%), dizziness (12%), anxiety (11%), and vomiting (11%). Mixed oxybate salts were FDA approved in 2021.[21]  
  • The drug is recommended to be titrated slowly and started at a low dose of < 3g and increased by no more than 1.5 g per night per week.
• Amphetamines like central nervous system stimulants (such as methylphenidate).[22]
• Other stimulates: Pitolisant is a selective histamine H3 receptor antagonist approved for the treatment of narcolepsy with or without cataplexy. It can have some role in some cases of IH [Level V].[23] 
• Clarithromycin: One trial studying 20 participants with different disorders of sleepiness included 10 participants with idiopathic hypersomnia, with or without long sleep time, and compared clarithromycin to placebo.[24] [Level 5] There were no significant differences between clarithromycin and placebo for the Epworth Sleepiness Scale, psychomotor vigilance testing, sleep inertia, other subjective ratings, or side effects.
• Flumazenil: In a retrospective chart review study, sublingual and transdermal flumazenil (through its effect as GABA-A receptor antagonist) led to improved sleepiness in refractory cases of hypersomnia [Level V].[24]

According to the recent American Academy of Sleep Medicine (AASM) clinical practice guidelines for treating central disorders of hypersomnolence, modafinil is strongly recommended as the first-line option for treating idiopathic hypersomnia in adults. Other options for treating idiopathic hypersomnia in adults (such as clarithromycin, methylphenidate, pitolisant, and sodium oxybate had a conditional recommendation.[17]

Differential Diagnosis

• Insufficient sleep: therefore, extending sleep before testing is a helpful technique
• Drugs/ substance use
• Sleep-related breathing disorder. Polysomnography confirms this diagnosis, and idiopathic hypersomnia should not be considered before adequate treatment and adherence are established
• Narcolepsy type 2 (without cataplexy): SOREMPs may be absent during MSLT early in the development of narcolepsy
• Psychiatric disorders, typically depression. In psychiatric disorders, the mean sleep latency is within normal
• Movement disorders such as periodic limb movement disorder
• Chronic fatigue syndrome- persistent fatigue, does not improve with rest or sleep
• Medical disorders: Chronic medical conditions, hypercapnia, and Trypanosomiasis differentiate with history, physical exam, and labs
• Neurological disorders: Alzheimer and Parkinson disease

Prognosis

Most patients with IH remain stable; approximately 1 in 10 experience spontaneous improvement, which is more common than narcolepsy.[25] In a recent study on a cohort of individuals with IH from Japan older than 35, the only period was associated with the increased incidence of metabolic syndrome among several demographic variables.[26] 

Daytime naps longer than an hour have been linked to a higher rate of stroke and hypertension after adjusting for risk factors for cardiovascular disease and stroke. For individuals younger than 60 years of age, napping most days raises the risk of developing high blood pressure by 20% compared with people who never or rarely nap.[27]

Complications

Excessive daytime sleepiness and associated symptoms (such as automatic behaviors) can lead to danger to self and others, including an increased risk of motor vehicle accidents. Due to the potential for diversion as a "date rape" drug, access to oxybate is regulated in the United States and is controlled under Schedule III.[28]

Deterrence and Patient Education

Patients with IH should be counseled on the risk of driving and operating heavy machines. Regular follow-up to assess for side effects of medications and monitor adherence. In our practice, we follow patients with IH every six months or more frequently to assess for adverse effects of the treatment, renew their controlled substance refills, assess any occupational or social needs, the adequacy of control for their daytime sleepiness, and adherence to medications.

Enhancing Healthcare Team Outcomes

An interprofessional team (nursing, primary care clinician, psychiatrist or specialty physicians, and social worker/case manager) that provides an evidence-based approach to refractory daytime sleepiness is essential to achieving a satisfactory outcome. If side effects of treatment adherence occur, prompt follow-up with the patient is necessary.

If medication is used to manage idiopathic hypersomnia, the pharmacist should provide input to verify appropriate dosing, perform medication reconciliation, and offer patient counsel.

Finally, counseling patients and working with employers to accommodate patient schedules and safety is vital to prevent accidents and productivity issues.

All interprofessional team members must document their patient interactions and interventions so that everyone on the care team has the latest and most accurate data. They also need to have open communication lines between themselves and other team members so that appropriate action can occur if any changes in patient status require intervention. This interprofessional approach will optimize patient care for idiopathic hypersomnia. [Level 5]

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Disclosure: Kunwardeep Dhillon declares no relevant financial relationships with ineligible companies.

Disclosure: Abdulghani Sankari declares no relevant financial relationships with ineligible companies.