SEX AND RACE DISPARITIES IN IH DIAGNOSES

  According to insurance databases, IH appears to be slightly more common in women than men: 11.1 versus 9.5 diagnoses per 100,000 people in 2016. Yet the IH CoRDS registry is almost 85 percent female, reflecting a combination of factors. For cultural reasons, men may be less likely to volunteer personal information for a chronic illness registry. In sleep apnea studies, men were less likely to report symptoms of sleepiness or fatigue than women, despite similar levels of physiological sleepiness.33

  It is possible that biological differences may be driving higher underlying rates of IH in women, but we can only speculate about mechanisms. Obstructive sleep apnea is more common in men and generally should be absent for an IH diagnosis. Clinicians may be more willing to consider IH for a slender young woman than for an overweight man. Narcolepsy diagnoses, both with and without cataplexy, are also more common among women than men in the United States.34 More women than men have autoimmune diseases, probably because of endocrine influences on the immune system.35

  Variations in the prevalence of narcolepsy and IH by race in the United States are currently unknown. One recent effort in addressing this issue was a 2015 analysis of the Stanford Center for Narcolepsy’s patient database.36 This found that African Americans with narcolepsy type 1 were more likely to have low hypocretin CSF levels but at the same time were less likely to display cataplexy. This suggests that hypocretin testing may be more important for accurate narcolepsy diagnosis in African Americans.

  For comparison, obstructive sleep apnea is thought to be more prevalent among African Americans and Latinos than among whites, partly because of differences in rates of obesity.37 Among autoimmune diseases, systemic lupus erythematosus is more likely to affect African Americans and Latinos than whites, while multiple sclerosis appears more among whites.

  So far, the population captured by the Hypersomnia Foundation’s CoRDS registry appears to be disproportionately white, with more than 90 percent of participants identified as white as of 2020.38 In a statement on its website, the Hypersomnia Foundation attributed the disparity primarily to racial minorities experiencing barriers to diagnosis of sleep disorders—a reasonable assumption that could be investigated in more detail. Discrimination and inclusion are issues that rare disease advocacy groups have been paying more attention to, and it comes down to making more effort to listen to people and meet them where they are. At a 2021 diversity-, equity-, and inclusion-oriented workshop held by the foundation, a few participants recalled carefully choosing their clothes, so that physicians would listen to what they said about their hypersomnia symptoms and take them seriously.

  An essay by James Stevens, a young African American man who was diagnosed with IH in high school in New Jersey, indicates that lack of social support made his experience dealing with IH worse.39 One of his teachers suspected he was smoking too much marijuana. The vice-principal at his high school told him, “Look, I know it’s hard to get up in the morning, but we’re all tired.” His mother, who had grown up “poor and angry” in Atlantic City, called him lazy and eventually kicked him out of the house in an attempt at tough love.

  James did find a neurologist and was diagnosed with IH after a sleep study. He tried a long list of medications, which didn’t help. Adderall gave him headaches that felt like “beads of sand whishing around my brain.” He lost several jobs because of oversleeping. In many ways, James’s narrative is archetypical for IH, except that he experienced remission, regaining a typical sleep schedule in 2017. “The lack of support I needed at such a vulnerable time was closer to killing me than hypersomnia ever had,” he concluded.

  His essay is another reminder of young people who may be struggling and require more understanding and recognition. The hypersomnia community can both learn from and expand to include others’ stories.

  A CHALLENGE OF RISK INTERPRETATION

  In 2019, the narcolepsy and hypersomnia communities were jolted by news about modafinil. For several medications commonly prescribed for sleep disorders, solid information is scarce about the risks of exposure during pregnancy, such as an elevated probability of miscarriage or birth defects. This encapsulates the uncertainty that many with narcolepsy and hypersomnia have to deal with if they are planning for pregnancy.

  Isabelle Arnulf has given an example of a woman with narcolepsy who was then taking modafinil and the antidepressant venlafaxine and had contacted her for advice: “My neurologist said I should stop taking my medication immediately. I use a computer for work, and without the medication, I would be unable to do my job. I am also worried I would be depressed if I have to go off my meds and stay at home during the pregnancy.” Previously, expert opinion held that modafinil would pose less risk, in comparison to conventional stimulants. For several years, Arnulf had recommended that her patients switch to modafinil from other stimulants before pregnancy—and other specialists followed her lead.40

  The Food and Drug Administration has been requiring drug manufacturers to establish pregnancy registries to gather data on newly approved medications’ safety. However, participation in registries is voluntary, and with medications for neurological disorders, the number of mothers involved is often low enough to make statistical analyses difficult.

  In 2019, an interim report from the Provigil/Nuvigil Pregnancy Registry revealed a rate of 15 percent for major malformations, in comparison to a rate of 3 percent in the general population. A rate of cardiac anomalies of 5 percent was also higher than expected for infants exposed to modafinil during pregnancy. The number of modafinil-exposed pregnancies on which the interim report was based was small (78),41 but it took almost a decade since the registry’s establishment to say anything at all. Around the same time, a Danish study also reported an increased risk of malformations with modafinil, compared to either methylphenidate or nonexposed pregnancies.42 This shows that expert opinion sometimes has to catch up to real-world data; earlier unpublished safety data had been reassuring. Health officials in France and Canada promptly recommended that pregnant women and those trying to become pregnant not take modafinil. Arnulf has agreed with this assessment, and Trotti told me that her recommendations to patients have also changed as a result.

  An analysis of the full registry report, with a larger number of prospective pregnancies, was published in 2021. It confirmed the increased risk, although the mechanism was unclear because several types of adverse outcomes were reported.43 As of 2022, the U.S. FDA has not updated modafinil’s label.

  A surprising counterpoint came in the International Pregnancy Safety Study consortium, which included investigators from Harvard and several Nordic countries. This reported that neither methylphenidate nor amphetamines were associated with an increased risk of malformations. Compared with the registry report for modafinil, this study included a much larger number of pregnancies exposed to the drugs in question: several thousand.44 This study does not mean that conventional stimulants are risk-free during pregnancy, since other long-range outcomes were not tracked. More such studies are needed on pregnancy outcomes with medications for neurological disorders.

  THE FUTURE OF PTZ, FLUMAZENIL, AND CLARITHROMYCIN

  One of the patients featured in Jazz’s 2021 awareness campaign was Meghan Mallare (from chapter 10). As the campaign started, sleep continued to take up more than one hundred hours of Meghan’s week. She made no testimonial for Xywav because she had not tried it yet. Out of many medications she did try, one of the few that made her feel truly awake was the experimental drug PTZ, which she was able to access as part of Balance Therapeutics’ clinical trial. “I woke up in the morning on my own and felt awake for the first time. It was such an incredible feeling,” she said.

  At that time, Balance Therapeutics had been dissolved. It was one more disappointment for proponents of the GABA hypothesis of IH. Jenkins and Rye’s search for the GABA-enhancing peptide they detected in Anna and other patients remained inconclusive, and they were not able to announce their findings. Jenkins had been contributing to efforts to automate old-school patch clamp experiments, an advance that sped up his research.45 In 2019, Jenkins acquired sophisticated equipment that would allow him to use smaller volumes of precious CSF and process many more samples per day. But after the end of the federal grant he and Rye were awarded, he had to transition to a smaller laboratory space. By mid-2022, Jenkins had left Emory for a position in Connecticut.

  After the challenge from Dauvilliers, Rye and Jenkins’s findings did not get much respect from some experts in sleep medicine. Their critics seemed to assume: if they were right, they should have found the somnogen by now. Emmanuel Mignot was more generous when asked for his opinion of their work.46 He said that excessive GABA signaling as an explanation for hypersomnia was a reasonable hypothesis. However, one attempt to replicate Jenkins’s laboratory results was unsuccessful, and the placebo effect might explain flumazenil’s apparent clinical benefits, he said. Mignot left the door open: “Flumazenil is a relatively safe medication, why not try it? … I think it could help some people.”

  Other sleep researchers have told me they thought a GABA-based mechanism for hypersomnia was appealing or had prescribed some of their patients clarithromycin when more conventional medications were unsatisfactory.

  A possibility to repurpose flumazenil is still open. Researchers at the University of Michigan have been testing whether the drug could be used for Parkinson’s disease.47 Starting in 2018, they have been investigating intravenous flumazenil’s effects on motor symptoms of Parkinson’s, such as postural instability and gait impairment. The results have not yet been reported.

  A FEW COMPARISONS

  The number of people in the hypersomnia community who use flumazenil may diminish. Some report that its efficacy has faded over time. However, I predict that some will stay with it, despite the expense and inconvenience. One woman told me that before trying flumazenil, she had progressed from working as a full-time lawyer and active mother to only having a few hours a day when she wasn’t sleeping or resting. Stimulants had helped a bit, but nothing else had come close to restoring “normal” for her. Before, it was almost impossible to get out of bed until noon or later. She said: “The benefit of flumazenil is that I feel normal. I do not feel anything unusual or different: I am just awake like a normal person.”

  Despite anecdotal evidence for flumazenil’s efficacy, the drug has not been tested for IH in the same rigorous clinical trial format as modafinil or other medications. Determining who is likely to respond positively to it remains difficult; CSF patch clamp assays do not predict response. Someone has to try it to find out if it works for them. “These medicines work—but who is the target population?” David Rye once asked me. He compared successfully treating hypersomnia to harpooning a swordfish—with Anna as the swordfish. “Now we’re trawling the whole North Atlantic.”

  Without a corporate or university sponsor, a trial of flumazenil for idiopathic hypersomnia is not currently on the horizon. The drug is available for off-label prescriptions through a few compounding pharmacies in the United States, an intermediate state between FDA approval and complete scarcity.

  Members of the hypersomnia community embraced Rye’s “sleepy juice” theory even though the biochemical evidence for it was incomplete, because his explanation for their sleepiness was appealing and he voiced the frustration that many of them felt. A pertinent comparison for Rye might be to Martin Scharf, who pioneered the use of GHB as a treatment for narcolepsy in the United States in the 1980s.48 Scharf may have tripped over the FDA’s documentation requirements, but he helped demonstrate that GHB for narcolepsy was clinically feasible, paving the way for Xyrem and Xywav.

  The community of IHers and others who find benefit from flumazenil, along with the physicians who prescribe it, might evolve into something like the Low-Dose Naltrexone Trust, whose annual conference is sponsored by compounding pharmacies.49 Naltrexone is FDA approved for the treatment of alcohol and opioid use disorders and has also been prescribed at lower doses for the off-label treatment of inflammation and pain. A clear mechanistic explanation for its anti-inflammatory properties is lacking, and low-dose naltrexone’s activity has been described as “paradoxical.”50

  Clarithromycin’s future is also uncertain. IHers’ experimentation with it might remind some observers of the subculture of “Lyme-literate” doctors willing to treat Lyme disease patients with antibiotics over long periods.51 However, enthusiasm for clarithromycin was never that great—it literally left a bad taste in IHers’ mouths. Cautious clinicians such as Trotti, as much as they wanted to give their patients more options, did not want to lead them astray. Trotti’s work on clarithromycin continued with a clinical study, funded by the National Institute of Neurological Disorders and Stroke. She and her team planned to measure clarithromycin’s effects on GABA signaling, as well as probing inflammation and changes in the intestinal microbiome as possible explanations for how the antibiotic may act against excessive daytime sleepiness.

  Rye and Jenkins may still find the hidden treasure they were looking for, but it is equally likely that other researchers will transform our understanding of IH and its pathophysiology. IH could splinter into more than one category as a result. The rewards of studying IH will include a deeper knowledge of why we sleep and how it restores us. People with IH can advise others and contribute to research on why sleep is consuming their lives. The next person to write a chapter in the story of IH may be someone who lives with it every day.

  POSTSCRIPT ON COVID-19

  Most of the events in this book took place before COVID-19, a global challenge for public health whose effects continue to unfold. At the beginning of the pandemic, I wondered whether the world might see an eerie repeat of encephalitis lethargica and the variety of neurological injuries that resulted. Some sleep researchers had proposed that COVID-19 might offer an opportunity to understand better how narcolepsy develops, in a way analogous to what occurred with the 2009 H1N1 influenza pandemic.52 While life altering for those involved, the surge in European narcolepsy diagnoses did help investigators clarify the autoimmune mechanism behind the disease.

  Instead, a new category of postviral chronic illness has emerged: postacute sequelae of COVID-19, or “long COVID,” which may eventually imprint itself upon millions of people around the world.53 Patient groups have pushed officials at the National Institutes of Health and elsewhere to fund research on long COVID. The similarities between long COVID and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) could end up propelling advances in the understanding of ME/CFS.

  Where does that leave IH and narcolepsy type 2? It depends whether we view neurological sleep disorders such as IH and narcolepsy in a silo or as part of a broader continuum of chronic illnesses, such as autoimmune disorders.54 Long COVID can have neurological components, but it varies from individual to individual and extends far beyond a disturbance of sleep. It can include brain fog and postural orthostatic tachycardia, symptoms that people with IH experience as well.

  Narcolepsy and IH are studied by a relatively small group of investigators around the world. Yet IH may have elements in common with disorders that are not usually considered sleep disorders, such as myotonic dystrophy and hepatic encephalopathy. Mapping the common elements may yield insights both in patient care and in research. Similarly, mutual benefits could come from exchanges with other fields, such as psychiatry, rheumatology, and addiction medicine.

  ACKNOWLEDGMENTS

  This section highlights my thanks to more than one hundred people who made this book possible. The writing of this book was generously supported by a 2019 grant from the Alfred P. Sloan Foundation. I am grateful to Chris Gunter and Andrew Miller for early encouragement, to Tom Scammell for allowing me to attend the seventh International Symposium on Narcolepsy, and to Holly Korschun and Vince Dollard at Emory’s Division of Communications and Public Affairs for tolerating my work on this book. Special thanks to Alexander Bieri and Svenja Egli at the Roche archive in Basel and National Institutes of Health and Food & Drug Administration staff responsible for Freedom of Information Act requests. Additional thanks to Jordan Tomes and Blanka Owensova for Czech translations and to Tara Coyt, Chuck Clark, and Glenn Hutchinson for English critique. In the text, IH and narcolepsy patients are identified by their first name; researchers and clinicians by last name.

  THE STARTING POINT

  Anna Sumner Pieschel, James and Ward Sumner, and James Sumner III.

  MEMBERS OF THE ATLANTA HYPERSOMNIA SUPPORT GROUP, NARCOLEPSY ATLANTA, AND THE BROADER HYPERSOMNIA COMMUNITY

  Diana Kimmel, Saraiah Naps, Julie Flygare, Thomas Fast, Diane Powell, Betsy Ashcraft, Evelyn Honig, Keith Harper, Michelle Chadwick, Matt Baker, Dean Jordheim, Danielle Hulshizer, Kristin Loomis, Michelle Emrich, Michael Sparace, Linda Johnson, David Kellogg, Meghan Mallare, Amy Desmarais, Romy Baudois, Stacy Erickson Edwards, Cate Murray, Catherine Page-Rye, Rebecca King, James Stevens, Alex Haagaard.

  SOURCES

  David Rye, Andrew Jenkins, Kathy Parker, Lynn Marie Trotti, Prabhjyot Saini, Bob Baker, Karel Šonka, Soňa Nevšímalová, Jan Roth, Anniki Rothova, Evžen Růžička, Donald Bliwise, Amanda Freeman, Glenda Keating, Gillian Hue, Paul Garcia, Mike Owens, Olivia Moody, Carol Clark, Allan Rechtschaffen, Bruce Wainer, Allan Levey, John Roback, Cliff Saper, Clete Kushida, Mahlon DeLong, Mary Carskadon, Tom Roth, Jim Krueger, Jamie Zeitzer, Phyllis Zee, Emmanuel Mignot, Richard Bogan, Amita Sehgal, Robert Thomas, George O’Neil, Erin Kelty, Luis de Lecea, Jerry Siegel, Tom Kilduff, Gary Aston-Jones, Mehdi Tafti, Giuseppe Plazzi, Hanns Möhler, Alessandro Guidotti, Phil Skolnick, Steven Paul, Roger Butterworth, Giuseppe Scollo-Lavizzari, William Ondo, Thien Thanh Dang Vu, David Plante, Jesse Cook, and Morgan Lam (to whom I owe a beer). Informal discussions with Isabelle Arnulf, Yves Dauvilliers, Todd Swick, Roger Broughton, Peter Young, Anne Heidbreder, Markku Partinen, Guy Leschziner, Ramin Khatami, Birgitte Kornum, Geert Mayer, Makoto Honda, and Kiran Maski.