If or when narcolepsy type 2 and IH are redefined, some open questions for research are: How many people have these disorders? What co-morbidities, such as depression or cardiovascular disease, do they have? What is their life expectancy? In population studies, researchers have observed increased mortality for people who report extra short or extra-long habitual sleep duration—the so-called U-shaped curve.12 Does that increased mortality apply to people with IH? What are the risk factors, such as viral infections (including COVID-19), anesthesia, or environmental exposures?

  The classic way of determining the prevalence of a disease is to examine everyone, without selecting people who are already in the doctor’s office. The subjective symptom of excessive daytime sleepiness is common among the general population, and a substantial fraction of people may appear to have narcolepsy or IH if they go through an MSLT. A rigorous study would require more than asking people about their sleep habits. It might involve administering the MSLT or other more invasive procedures such as lumbar puncture and eliminating common causes of sleepiness such as sleep apnea or hypothyroidism. This may be impractical on a large scale.

  So far, a workaround has been to examine health insurance databases, catching the people who have already gone through the process of diagnosis under current categories. This type of analysis has its limitations, because insurance coverage has provided a disincentive for the IH diagnosis. Some people may be uncounted because they lack access to health care or because their condition is obscured by other diagnoses. Even so, in the United States, the number of people with IH diagnoses has been rising in recent years (2013–2016), reaching one in ten thousand people.13 IH’s prevalence is about a quarter of narcolepsy’s, but that could change if narcolepsy type 2 and IH without long sleep are merged.

  ALL THAT JAZZ

  The study on the prevalence of IH did not materialize out of thin air. Jazz Pharmaceuticals was releasing a flurry of research on IH at the same time as it was mounting its awareness campaign, in anticipation of an expected FDA approval for the company’s drug Xywav—the first ever for the indication of IH.

  The results of a trial of Xywav and IH, conducted by investigators in Europe and the United States, were presented at neurology and sleep research conferences that spring. Xywav showed strong effects on daytime sleepiness as well as sleep inertia, an outcome measured for the first time in any industry-sponsored clinical trial.14 Lead author Yves Dauvilliers and his colleagues had developed a composite measure of IH symptoms, the Idiopathic Hypersomnia Severity Scale, which included questions about sleep inertia. The IHSS was similar to the questionnaire Tom Roth and colleagues created for Balance Therapeutics’ IH trial.

  In the Xywav clinical trial, most of the participants had the form of IH without long sleep. The short-term efficacy for both groups was about the same. The study was set up so that all participants received the drug first and were able to grow accustomed to it over a few months. Then half the group was put on placebo for two weeks, to see how much their symptoms worsened. Because Xywav has acute sedative effects, a truly blind placebo would be difficult to implement.

  The “randomized discontinuation” or “maintenance of effect” study design was previously used to test medications for restless leg syndrome, as well as antidepressants and antipsychotics. The format weeds out patients who can’t tolerate the tested medication, but some experts have questioned the format, arguing that classic randomized controlled trials are more valid.15

  In the Xywav study, more than half of the participants had been taking stimulant medications and were allowed to continue using those drugs. Common adverse events included nausea, headache, dizziness, anxiety, and vomiting, which can be experienced with Xyrem as well. Some people who reported sleep inertia or long sleep time were advised to try a once-per-night regimen, a more flexible arrangement than the standard two doses per night for narcolepsy. More follow-up was needed to determine whether Xywav’s benefits are stable over time.

  The FDA was willing to approve Xywav for IH based on subjective outcome measures only. With the wake-promoting medication pitolisant, the FDA had softened its previous requirement for objective outcome measures because there was relevant backup data. However, for Xywav and IH, all the outcomes for establishing success were subjective, nonphysiological measures of sleepiness, such as the Epworth Sleepiness Scale and the Idiopathic Hypersomnia Severity Scale. This is not to say that the Idiopathic Hypersomnia Severity Scale is faulty or unreliable—but it is not an objective, physiological measure of sleepiness the field has previously relied on. Sleep specialists and IHers are still figuring out the best ways to measure the symptoms of IH, both objectively and subjectively, and how to gauge success. What is more important: a boost in the number of hours awake during the day or the quality of wakefulness during that time?

  ONE APPROVED, MORE TO COME?

  In August 2021, the FDA announced its approval of Xywav for the indication of IH. The approval was celebrated by the Hypersomnia Foundation, as well as by many people with IH, because it sent a signal of legitimacy and recognition for IH to the medical community. It was expected to encourage other pharmaceutical companies, such as Takeda and Harmony Biosciences, to follow.

  Takeda had already initiated a pilot study for people with IH in 2020, testing one of its hypocretin receptor agonists. A Takeda spokesperson declined to discuss the company’s decision making, but they did acknowledge the Hypersomnia Foundation as a partner. The company’s representatives have appeared at foundation events to recruit study participants. In 2021, the company announced plans to move a related drug into clinical trials for narcolepsy type 2 and IH together, after narcolepsy type 1. Later that year, Takeda halted its clinical research program studying hypocretin receptor agonists because of liver toxicity concerns.16

  Harmony’s narcolepsy drug pitolisant became available in the United States in 2020. At the end of 2021, Harmony announced plans for a study of pitolisant for people with IH, after beginning studies on pitolisant for people with myotonic dystrophy and Prader-Willi syndrome.17 Jazz appeared to have more expansive aims for its drug solriamfetol, having previously revealed discussions with regulators regarding excessive daytime sleepiness in the context of depression, potentially a large market that could overlap with IH.18 Jazz later sold the rights to solriamfetol to another company.

  The recent approval of medications such as Aduhelm for Alzheimer’s disease has led some critics to charge that the FDA’s rigorous standards for clinical trial efficacy have slipped.19 With Xywav and IH, the FDA’s relaxation of its previous preference for “objective” outcome measures in sleep disorders could be seen as part of this pattern. However, it is difficult to see how the agency could have proceeded otherwise, when experts in the sleep medicine field are still figuring out appropriate outcome measures for IH. An FDA spokesperson confirmed that the agency has sought advice on sleep disorder outcomes through informal meetings with advisors such as Trotti and Mignot, but the agency declined to answer questions about how outcome measures for Xywav and IH were set.20

  A SUBJECTIVE SUCCESS

  Despite the possibility of greater acceptance of IH, the prospect of Xywav as the only FDA-approved medication for idiopathic hypersomnia raises concerns. Before 2021, Xywav’s predecessor Xyrem had been the expensive and intimidating option, only tried after other medications were unsatisfactory. In Europe, Xywav and IH may face more obstacles because of preferences for objective outcome measures. And while the establishment of Xywav as “on label” for IH may facilitate IH patients’ access and insurance coverage in the United States, it was unclear how the change might affect coverage for other medications, which would continue to be off label.

  For Xywav and IH, there was no advisory committee meeting, which might have allowed discussion of safety issues. For example, Jazz’s data indicates that half of all newly diagnosed IH patients in the United States had been previously diagnosed with sleep apnea.21 It is not surprising that IHers are often diagnosed with other conditions first, but in 2012, the FDA had warned against Xyrem’s use in people with sleep apnea because of the risk of respiratory depression.22 Some clinicians prescribe Xyrem for people with dual diagnoses of narcolepsy and sleep apnea if they are successfully treated through CPAP, but the safety of this practice is debatable.23 Lynn Marie Trotti signaled some ambivalence about Xywav in her comments to the New York Times, saying: “If you gave me a list of medicines and said, ‘Which one do you want approved for idiopathic hypersomnia?’ I don’t know that I would have picked Xywav.”24

  That same year, Trotti and others had finished an update of the American Academy of Sleep Medicine’s practice guidelines for narcolepsy and IH. The update had recommended modafinil as a first-line treatment for IH, based on clinical trials from Europe and Japan. Still, Trotti said an FDA-approved drug for IH was a positive change: “For some patients, it is going to be the right medication, and they should be able to access it.”

  Despite fears expressed before it was approved for narcolepsy, the availability of Xyrem has not contributed to widespread diversion or abuse. Xyrem did not become “the next OxyContin,” partly because it was so expensive. Xyrem and Xywav represent a more restrictive model for the controlled distribution of abuse-prone drugs. Some 40 percent of newly approved drugs include REMS (Risk Evaluation and Mitigation Strategies) programs such as Xyrem/Xywav’s, although the FDA has mostly let pharmaceutical companies such as Jazz grade and police themselves on their implementation. A 2013 inspector general’s report for the Department of Health and Human Services concluded: “FDA lacks comprehensive data to determine whether risk evaluation and mitigation strategies improve drug safety.”

  Recognition of IH and a better public understanding of it continue as works in progress. Whether someone’s family member or friend recognizes IH as something real won’t change overnight. Awareness will take time to build, through media campaigns and more targeted outreach to medical schools and professional groups such as pharmacists and school nurses.

  Jazz’s sponsorship of a joint awareness campaign with the Hypersomnia Foundation meant that the company was able to play a role in defining how IH was perceived by the wider public. To its credit, Jazz avoided disease mongering Cephalon-style by not blending together IH with everyday sleepiness or fatigue. (In contrast, marketing for Sunosi was broader.) On a Jazz-sponsored website designed for health care professionals, one of the videos showed a man in his thirties with severe sleep inertia, whose partner struggles to have him wake up at around 3 pm.25 After almost twenty minutes, the man is sitting up but can barely speak. This is not an experience most people have.

  Through insurance database research, Jazz has sketched a picture of how people with IH pass through the health care system. One of the company’s abstracts revealed that only a minority of new IH patients in the United States were diagnosed after an overnight sleep study and MSLT. It was more common for the diagnosing physician to document long sleep time in an unspecified way.26 Balance Therapeutics–associated investigators had encountered a similar phenomenon, finding that a majority of patients with a preliminary diagnosis of IH failed study screening “due to inability to meet inclusion criteria necessary for the IH diagnosis.”27

  DO NARCOLEPSY OR IH HAVE A SILVER LINING?

  Anna Sumner Pieschel’s story, detailed at the beginning of this book, still stands as part of an inspirational, hopeful strand of communication about IH and other sleep disorders. Her progress through family and professional milestones—baby, marriage, law partnership—after her recovery demonstrated that IH did not curtail her life. In a Georgia Public Broadcasting video, as her young son was seen running around her backyard, she told an interviewer: “If you told me six years ago that this would be my life, I wouldn’t have thought it was possible.… Today I have everything I never thought I would have.”

  In a similarly optimistic tone, beginning in 2018, other people with IH have been part of a scholarship program sponsored by the patient advocacy group Project Sleep, in which young people with narcolepsy and IH receive $1,000 scholarships. Smiling students explain that they have idiopathic hypersomnia—and they are managing it well enough to attend college. According to their online biographies, they were able to get good grades in high school and participate in sports, band, and church mission trips. “We can do it, despite how debilitating IH can be,” they are saying.

  In serving their communities, patient advocacy groups like Project Sleep and the Hypersomnia Foundation have to balance how they display examples of people who are successfully navigating challenges such as college or career and, on the other hand, provide resources for those who are encountering obstacles or may need to apply for disability from Social Security or private insurance. The foundation has held informational sessions on the process of applying for disability, in an effort to destigmatize the process. “Our role is to be an empathetic resource and also to be realistic about what people need,” Diane Powell told me. “We recognize that IH can make ordinary things difficult to navigate. I don’t know how many other places have a guide on how to take a nap in your car.”

  In the narcolepsy community, the positive, optimistic mode has extended to the point where a few people with narcolepsy say that it provides them with an advantage. One proponent of this view has been the Harvard geneticist George Church, who has narcolepsy type 1. Church, an innovator in the field of DNA sequencing, is also known for nodding off during conferences and discussion panels. He told me that while narcolepsy affects him every day, cataplexy for him is “infrequent and mild—usually laughter-induced.” In interviews, Church has said that many ideas and solutions to scientific problems have come to him while he was dreaming or almost asleep. However, it took him until he was in his fifties to realize that narcolepsy is “a feature not a bug,” as he told the science writer Sharon Begley.28 To be sure, Church’s personal choices may not be practical for others. He did not take medication and managed his sleepiness partly by not eating during daylight hours.

  Church has suggested that people with narcolepsy could be seen as part of the neurodiversity movement, which holds that brains different from the typical are not necessarily in need of medication or correction. Neurodiversity is usually defined as the idea that neurological differences such as autism, ADHD, and dyslexia are the result of natural variation in human brain development, which may be advantageous in specific situations.29 In particular, some autistic people have championed neurodiversity, saying that they don’t need to be “fixed.”

  Parallel to this line of thinking are studies of creativity among people with narcolepsy. Arnulf and colleagues in France found that people with narcolepsy type 1 and 2 displayed higher creativity scores than a demographically matched control group.30 The study included questionnaires assessing personality and formal tests of creativity, such as drawing and making up stories. Arnulf’s paper attributes higher creativity in people with narcolepsy to lucid dreaming and “life-long privileged access to rapid eye movement sleep and dreams.” “One may wonder whether the frequent sleep bouts that subjects with narcolepsy perform in passive conditions offer them the opportunity to mind wander and to incubate complex problems,” the authors write.

  Within the hypersomnia community, I haven’t heard much enthusiasm for this idea. Diana Kimmel and others told me that the neurodiversity/creativity tune did not resonate with them, while a few people said they had come up with creative ideas while sleepy. This brings us to more pessimistic modes of communication. When sleep and brain fog consume a larger and larger proportion of the hours and days in someone’s life, there is no bright side. In a video posted online by the Hypersomnia Foundation in 2020, board member Michelle Emrich argued forcefully that IH severely limits her life without enhancing any corner of it.31 Emrich had to give up her medical practice in 2012 after an IH diagnosis the year before, and she decided not to have children because she was too sick to care for them.

  At the suggestion of her therapist, Emrich said she “set my baseline minimum for a successful day at feeding myself. That’s it. No showering, no getting dressed, no washing the dishes, no paying the bills, no calling a friend. I can’t predictably do any of these things.” “It is a testament both to an excellent therapist and my immense willpower that I have learned to cope with IH well enough to want to remain alive,” she said in the video. “My entire world revolves around sleep need.… Because of my sleep schedule and severe brain fog, I only have a few hours in which to live my life.”

  Talk therapy can have a role in the management of IH, even if many IHers want to draw a distinction between sleepiness and mood. Investigators in Illinois have developed an adaptation of cognitive behavioral therapy for hypersomnia, and discussing coping strategies with a therapist who understands IH can mitigate depressive symptoms.32

  Left untreated, people with IH may be impaired in their ability to drive safely, support their families around the house, or sustain enjoyable activities such as watching a movie. The standard for successful treatment must go beyond medication to include peer support, coping strategies, and accommodations.

  FIGURE 17.2. Cartoon depicting daily life with idiopathic hypersomnia.

  Source: Milo Hiisikolo.