Idiopathic hypersomnia has arrived

Quinn Eastman
6 min readJun 16, 2022

At the recent SLEEP 2022 conference in Charlotte, I saw signs that idiopathic hypersomnia had arrived, as a focus of both scientific inquiry and patient advocacy.

More posters focused on (or even mention) idiopathic hypersomnia than ever before.* There was continued interest from pharma, following the 2021 FDA approval of Jazz Pharmaceuticals’ Xywav — the agency’s first approval of any medication for idiopathic hypersomnia (IH). It is thanks to Jazz that we now have an estimate of how many people have IH in the United States, based on insurance data: 1/10,000.

The spike in 2003 was partly a hangover from the discovery of hypocretin/orexin — patients with IH have tended to serve as controls when investigators study narcolepsy type 1.

To be sure, IH existed decades before a pharmaceutical company decided to count those diagnosed with it (don’t get me started on the history of Xywav/Xyrem). Now people with IH have independently organized themselves, and others are beginning to take notice. The Hypersomnia Foundation — established in 2015 — held its in-person conference for the first time in four years, and was the recipient of a “Sleep Champion” award from the American Association of Sleep Medicine.

For me, it was satisfying to touch base with experts in the field and make new contacts. This year’s meeting didn’t bring earth-shaking news on par with last year’s FDA approval, although separately, Japanese researchers have reported the first genetic study of IH to identify a mutation with a strong connection to the disorder. While the mutation may account for just a sliver of IH diagnoses, the Japanese study was significant because it was the first to find anything at all. More below.

Isabelle Arnulf, a leading IH researcher based in Paris, gave a lecture in which she described IH as having attracted little attention in comparison with narcolepsy, and invited others to help advance the field.

“It’s not that rare of a disorder and it’s a neglected disorder,” Arnulf said. “Narcolepsy is like the big brother, attracting all the attention of the parents, while idiopathic hypersomnia is like the little sister.”

In her talk, Arnulf included unpublished 10 year follow up data on Parisian IH patients, showing that a few experienced remission, but a majority continued to experience daytime sleepiness and excessive need for sleep.

Additional highlights

In the posters, researchers at Stanford provided confirmation that a majority of IHers tested experience disturbances of autonomic nervous system function. This finding was with physiological tests, rather than online surveys, but in a small number of people (20). Robert Thomas’s group at Beth Israel reported intriguing investigations of IHers’ sleep characteristics, measuring EEG sleep depth, “brain age” or cardiopulmonary coupling.

For the Hypersomnia Foundation, Emory’s David Rye provided a sneak peek of data on the mysterious GABA-enhancing peptide in CSF samples from hypersomnia patients — but did not reveal its identity. In my opinion, two critical steps for the future will be 1) confirmation of Rye’s CSF peptide data in patients diagnosed elsewhere and 2) a repeat of the work of Sonka and Nevsimalova on altered melatonin rhythms in IH.

Dauvilliers/Plante debate

At the conference, two respected clinicians, David Plante from University of Wisconsin and Yves Dauvilliers from University of Montpellier, held a debate on the proposition: “Idiopathic Hypersomnia is a Distinct Clinical Condition.” Their positions may seem counter-intuitive, given the two men and their work in the field. In particular, Dauvilliers, senior author of a proposal to redefine idiopathic hypersomnia more narrowly based on increased need for sleep, was arguing the “Pro” side! His debate position was more accurately described as: “IH is distinct — if we reorganize the categories in the way I am advocating.”

Dauvilliers has published his team’s protocol for rigorous IH diagnosis, including two nights of ad libitum slumber in the sleep laboratory. (He poked at the idea that similar procedures would be impractical in the United States because of cost.) His arguments for redefining IH more narrowly are based on research from Czechoslovak sleep neurology pioneer Bedrich Roth and his scientific heirs. But they are also based on the goal of discovering IH biomarkers and its pathophysiology. That goal will be more readily achievable if the group of patients labeled with IH is as homogeneous as possible.

“Today we say the patient has IH,” Dauvilliers said. “Tomorrow, I would like to say there is something wrong in the brain, whether it is with histamine or GABA or something else.”

It was also surprising to see Plante, current head of the medical advisory board for the Hypersomnia Foundation, speaking against the proposition that IH is a distinct clinical condition. He pointed to IH’s history of having been split into two categories (with and without long sleep) and joined together again. And he said that an overly strict approach will leave clinicians with patients that are “very sleepy, but we can’t give them a diagnosis.”

“Casting a wider net and focusing research on more measurable phenotypes will be more helpful in the long term,” he told me. “If we had a known pathophysiology, we could segregate some patients based on that. But we don’t.”

We can hear echoes of Plante’s arguments for a more inclusive approach in his recent paper on multimodal assessment. He also cited a recent paper from the Czech National Institute of Mental Health (not the Department of Neurology in Prague) comparing patients diagnosed with IH and with hypersomnia associated with a psychiatric disorder. It demonstrates that the division of patients into IH and psychiatric hypersomnolence categories is somewhat arbitrary. Those with IH displayed higher total sleep time and shorter MSLT sleep latency, yet there was considerable overlap — more than a third of those in the psychiatric group would qualify for an IH diagnosis based on total sleep time, and the two groups did not differ in terms of Beck Depression Inventory scores.

Japanese genetic study

Japanese researchers led by Taku Miyagawa and Makoto Honda recently published the first genetic study of IH to identify an apparently causative mutation. The mutation was in the prepro-orexin gene, encoding the neuropeptide orexin, also known as hypocretin. Autoimmune elimination of orexin/hypocretin-producing neurons is responsible for narcolepsy type 1.

Mutation carriers, all heterozygotes, have a change in the amino acid sequence that is predicted to impair processing of the peptide. It’s puzzling why the mutation does not lead to a narcolepsy-like phenotype (that is, sleep onset REM), since the overall effect of an orexin mutation would be like a mild version of narcolepsy type 1. The prepro-orexin mutation also shows up in patients with narcolepsy type 2, but the frequency is less than in IH (>1%).

Under ICSD-3 criteria, IH can be diagnosed as a result of high sleep propensity — falling asleep quickly on the MSLT — or long sleep duration of >11 hours. The paper does not contain information about total sleep time, so it is unclear what type of IH the patients with prepro-orexin mutations have. I would be surprised if they had long sleep IH. The authors suggest that cholinergic and/or anti-adrenergic drugs might be able to provoke cataplexy-like symptoms in mutation carriers, as seen in canine models of narcolepsy, but this would be a cruel experiment!

Keep in mind: only 20 out of 598 IH-diagnosed patients had mutations in prepro-orexin, and the mutation may be relevant only in Asian populations. Still, this finding supports the idea that more genetic studies of IH would be productive. Ideally, this could be based on whole-exome or whole-genome sequencing of multiplex families, along with sleep phenotyping. A similar proposal earned support from the National Institutes of Health a few years ago. New work in this space could mirror the success of Ptacek and Fu in understanding the origins of inherited short sleep duration.

I do not mean to dismiss Plante’s 2021 report on PAX8 DNA methylation and its association with sleep duration, but the authors do note that the effect size is modest (10%). I think that more work needs to be done correlating PAX8 expression and thyroid hormone levels in hypersomnolent patients.

*I searched through 2000–2022 APSS abstract supplements on the phrases “idiopathic hypersomnia” or “essential hypersomnia” or “primary hypersomnia”. I omitted abstracts that only mention IH in passing.



Quinn Eastman

Quinn was trained as a biochemist and then as a science journalist. His book on idiopathic hypersomnia will be published by Columbia University Press in 2023.