Examining Clinical Considerations for Diagnosis, Management of Idiopathic Hypersomnia

Idiopathic hypersomnia (IH) is a sleep disorder of neurologic origin that is characterized by excessive daytime sleepiness (EDS), a common symptom present in 15% to 33% of the general population. EDS is a core diagnostic feature of IH, but its prevalence in other more commonly known sleep disorders, such as narcolepsy, has contributed to misdiagnosis and years of inadequate management for patients with IH.

Findings of a recent survey launched as part of a campaign called I Have IH showed that more than half (57%) of health care providers reported personally misdiagnosing IH, with 86% saying that patients are often misdiagnosed with depression and/or anxiety. Furthermore, 39% of respondents reported that they believe it can take between 2 to 5 years to receive an accurate diagnosis of IH. And evidence shows a further delay in diagnosis of between 10 to 15 years.

For patients who are diagnosed, difficulties have been reported with treatment as well. There currently exists 1 treatment approved by the FDA for IH, Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution. And prior to 2021, there were no approved indications for adults with the condition.

In seeking to improve comprehension of IH, authors of a review published in Sleep Medicine Reviews explored clinical considerations related to the pathogenesis, diagnosis, and management of the sleep condition, including perspectives from the European Union and United States.

IH Diagnostic Criteria, Challenges, and Considerations

Diagnosis of IH is based on objective sleep testing and the presence of associated clinical features. However, due to its low prevalence, clinical heterogeneity, and symptoms, which are similar to those of other sleep disorders, IH may be difficult for clinicians to recognize and correctly diagnose, noted researchers.

Moreover, they said that testing required for diagnosis of IH presents logistical barriers, and reliability of objective sleep measures is suboptimal. Current International Classification of Sleep Disorders, 3rd Edition (ICSD-3) diagnostic criteria require the presence of EDS for 3 months, absence of cataplexy, and confirmatory objective sleep testing, including mean sleep latency (MSL) of 8 minutes on the multiple sleep latency test (MSLT) and/or 24-hour total sleep time (TST) of 660 min on polysomnography (PSG) or wrist actigraphy.

“Because of frequently normal MSLT findings in IH with long sleep time (LST) and low MSLT test-retest reliability, researchers have proposed objective evidence of LST as a more reliable endpoint,” said the study authors. “However, 2014 ICSD-3 criteria remain the standard for diagnosis.”

Per ICSD-3 criteria, sleep inertia is also not required for diagnosing IH, but it is an important, common symptom that clinicians should recognize and quantify, noted researchers.

Pathogenesis of IH

A major barrier to IH management is the lack of knowledge regarding its pathophysiology. There remain no known consistent abnormalities in the key wakefulness-promoting or sleep-wake circuit neurotransmitters.

However, the frequent family history of IH symptoms suggest genetic predisposition. Family history of excessive sleepiness, IH, or another disorder of hypersomnolence is seen in 34% to 37% of patients with IH. No specific genetic locus or inheritance pattern has been demonstrated, however.

“The heterogeneous nature of symptoms belonging to currently broadly defined IH suggests the possibility of different etiologies,” said researchers.

Notable findings of a cluster analysis including nighttime and daytime symptoms, nocturnal PSG, and MSLT in 96 patients with central hypersomnolence disorders differentiated 3 main clusters, including narcolepsy type 1, narcolepsy type 2 (NT2) and IH without LST, and IH with LST, suggesting that this last category has a homogeneous phenotype.

“Distinguishing these phenotypes will likely require novel discoveries providing better insight into the underlying neurobiology and pathophysiology.”

Treatment of IH and Further Considerations

As mentioned prior, Xywav serves as the sole therapeutic option approved by the FDA for the treatment of adult patients with IH. Phase 3 findings have shown that Xywav provided clinically meaningful improvements in symptoms of IH compared with placebo, including in the primary end point of Epworth Sleepiness Scale (P < .0001) and secondary end points of Patient Global Impression of Change (P < .0001) and IH Severity Scale (P < .0001).

However, there remain no treatments approved for use in pediatric patients, and no clinical studies of pediatric IH have been performed. Xywav is only approved in the United States, indicating that patient care needs worldwide are largely unmet.

For patients with IH outside the United States, treatments typically used off label include alerting agents (wake-promoting agents or stimulants), despite limited evidence for efficacy in this population.

Ultimately, researchers noted that thoughtful application of both clinical judgment and appropriate testing by health care providers is necessary to decide on the most effective treatment for this debilitating sleep disorder.

“More research is needed into protocols for diagnostic testing to improve accuracy, reliability, and convenience, especially approaches for in-laboratory and in-home recordings for extended sleep duration,” they concluded.

“The degree of distinction and possible overlap between IH and NT2, both in terms of pathophysiology and diagnostic features, should be further examined. Better understanding of IH as a disease state would lead to the identification of reliable biomarkers and inform rational treatment strategies.”

Reference

Dauvilliers Y, Bogan RK, Arnulf I, Scammell TE, St Louis EK, Thorpy MJ. Clinical considerations for the diagnosis of idiopathic hypersomnia. Sleep Med Rev. 2022;66:101709. doi:10.1016/j.smrv.2022.101709