Idiopathic Hypersomnia: The History and Future of Narcolepsy’s Shadowy Sibling
Quinn Eastman
What makes a disease or disorder “real”? More precisely, what attributes allow medical professionals to take a condition — and the people living with it — seriously?
My book, The Woman Who Couldn’t Wake Up, explores the history of idiopathic hypersomnia (IH), a rare sleep disorder. Recently IH has been getting more attention from sleep researchers and the pharmaceutical industry, but until about a decade ago, IH was obscure—and it didn’t get much respect. As one industry consultant told me, IH was considered a “garbage can diagnosis,” either too rare or too vague to be worth the investment of a clinical study. Until 2021, there was no FDA-approved medication for the IH indication. My book is a look at how that situation changed.
IH is characterized by persistent and excessive daytime sleepiness, along with sleep inertia or “sleep drunkenness.” Some people with IH need to sleep more than eleven hours out of every twenty-four, eating up time during which they can work, attend school, or care for a family. Sleep takes over an abnormally large chunk of their lives, and their friends and family come to wonder if they’re depressed or simply lazy, not putting enough effort.
Currently, the prevalence of IH in the United States is estimated at about 1 in 10,000. While a large percentage of adults (more than 20 percent) report experiencing excessive daytime sleepiness, most of those people don’t have IH. Instead, they are likely to have obstructive sleep apnea or other conditions. People with IH are often diagnosed with depression or obstructive sleep apnea first. A thorough examination, eliminating other possible causes of excessive sleepiness, is necessary for the proper diagnosis of IH.
Experts have criticized the Multiple Sleep Latency Test because it often provides divergent results when performed a second time on the same person.
Bedrich Roth, a neurologist and sleep researcher in Czechoslovakia, first described IH in the 1950s and later named it in the 1970s. IH was thought to have a neurological cause or causes, but its underlying biology was unclear. Despite the uncertainty, IH was not a “contested illness,” dismissed by mainstream physicians in the same way as chronic Lyme disease or ME/CFS (myalgic encephalomyelitis /chronic fatigue syndrome). Sleep medicine specialists acknowledged IH as a diagnostic category, but the people with the IH label felt neglected and overlooked. IH was hidden behind a sleep disorder that was more well known: narcolepsy.
The French neurologist Isabelle Arnulf portrayed the imbalance in this way to her fellow sleep researchers last year: “Narcolepsy is like the big brother, attracting all the attention of the parents, while idiopathic hypersomnia is like the little sister.”
The sleep medicine field is largely oriented around sleep apnea and narcolepsy, which has an extensive history in the medical literature. The most distinctive form of narcolepsy, known as narcolepsy type 1, has been linked to genetic risk factors and an autoimmune mechanism. Scientists have developed a good picture of how narcolepsy type 1 occurs and what is missing in the brains of the people who have it (the wake-promoting neuropeptide hypocretin). At the same time, the pathophysiology for narcolepsy type 2, a more prevalent diagnosis in the United States, is murkier.
As diagnostic categories, narcolepsy and IH have a close relationship. The symptoms overlap, and the standard procedures for evaluating people suspected of having either disorder are the same. They involve the Multiple Sleep Latency Test, in which someone is asked to take five short naps during the day. If someone falls asleep quickly enough and enters REM sleep a couple times, they meet criteria for narcolepsy. If they fall asleep quickly, but they don’t enter REM sleep, they meet criteria for idiopathic hypersomnia.
Objective measurements are critical for convincing physicians or researchers that a disorder is genuine.
Experts have criticized the Multiple Sleep Latency Test because it often provides divergent results when performed a second time on the same person. It can be a headache for the people who have to go through it. Antidepressants, many of which suppress REM sleep, and other confounding factors can distort MSLT results. So it’s worth asking why sleep specialists have stuck with the MSLT.
Part of the answer is because the MSLT is noninvasive and relatively safe, but another reason is because it is considered objective, rather than subjective. Developed in the 1970s by two pioneers of the field, the MSLT supposedly provides a measurement of someone’s physiological state. It separates sleep specialists from psychiatrists, who ask their patients to quantify how miserable they feel.
Objective measurements are critical for convincing physicians or researchers that a disorder is genuine. They are thought to be more reliable and less subject to bias. And in a way, the gravitational pull exerted by objective measurements and physiological mechanisms explains IH’s trajectory. Like a distant comet nudged into an orbit that will send it closer to the sun, IH was diverted onto a different path.
My book opens with the story of Anna, a young lawyer diagnosed with idiopathic hypersomnia at a medical center in Atlanta. Her doctors prescribed her stimulants, which were unsatisfactory and propelled her into periodic crashes. Running out of options, her doctors tried something unconventional: flumazenil, an antidote against benzodiazepine overdose.
Although hundreds of people with sleep disorders later tried flumazenil, the science supporting this “sleepy stuff” theory remains incomplete.
Because of Anna’s positive response to flumazenil, her doctors believed that her brain was under the influence of a benzodiazepine-like substance. Researchers detected signs that such a substance—informally named “sleepy stuff”—was present in her cerebrospinal fluid and in samples from others with similar symptoms. Although hundreds of people with sleep disorders later tried flumazenil, the science supporting this “sleepy stuff” theory remains incomplete. Rivals of the Atlanta-based researchers were unable to reproduce their results.
The proposed mechanism, while controversial, and the narrative surrounding it had two important effects. They triggered the coalescence of the hypersomnia community in the United States, and they led to the first industry-supported clinical trials focusing on people with idiopathic hypersomnia. A cynical view of idiopathic hypersomnia’s 2021 recognition by the FDA is that Jazz Pharmaceuticals wanted to expand the market for one of its products—and the company was successful. However, this view would unfairly diminish the role of patient advocacy organizations, such as the Hypersomnia Foundation and Hypersomnolence Australia. As a result of these organizations’ efforts, people with IH have obtained some of the recognition that they sought. Research, patient advocacy, and shifts in expert opinion, along with external recognition, all had a role in IH’s maturation.
The prospects for future research on IH are bright. A hot topic in idiopathic hypersomnia research now is the search for biomarkers, such as slow reaction time or the pupil’s impaired response to light. The ultimate objective marker, a likely genetic cause, has been identified for a small fraction of IH cases in Japan. At the same time, sleep medicine specialists have been discussing how to reclassify or even rename narcolepsy type 2 and idiopathic hypersomnia diagnoses. An upcoming revision of the ICSD (International Classification of Sleep Disorders) may incorporate additional ways of gauging a patient’s sleepiness and need for sleep.
Quinn Eastman is a technical editor at Emory University School of Medicine and the author of The Woman Who Couldn’t Wake Up: Hypersomnia and the Science of Sleepiness.
