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  THE WOMAN WHO COULDN’T WAKE UP

  THE WOMAN WHO COULDN’T WAKE UP

  Hypersomnia and the Science of Sleepiness

  QUINN EASTMAN

  Columbia University Press

  New York

  Columbia University Press

  Publishers Since 1893

  New York    Chichester, West Sussex

  cup.columbia.edu

  Copyright © 2023 Quinn Eastman

  All rights reserved

  E-ISBN 978-0-231-55091-8

  Library of Congress Cataloging-in-Publication Data

  Cataloging-in-Publication Data is available from the Library of Congress.

  ISBN 9780231194648 (hardback)

  LCCN 2023002759

  A Columbia University Press E-book.

  CUP would be pleased to hear about your reading experience with this e-book at cup-ebook@columbia.edu.

  Cover design: Henry Sene Yee

  Cover images: Shutterstock

  CONTENTS

  Introduction

  1. Anna Sleeps a Lot, and We Don’t Know Why

  2. The Doctors and GABA

  3. The Antidote

  4. Rye Versus MSLT

  5. Behind the Curtain

  6. The Essence of Sleepiness

  7. My Favorite Mistake

  8. The Atlanta Sleepers Club

  9. The Story of Flumazenil

  10. Weird Drugs

  11. The Heart of the Brain

  12. Immobilized by Happiness

  13. Frustrating and Mostly Fruitless

  14. Everything Off Label

  15. Knock Yourself Out

  16. Biomarkers of Sleepiness—and IH

  17. The FDA Opens a Door

  Acknowledgments

  Notes

  Index

  INTRODUCTION

  The first time I experienced having my eyes close and legs buckle while standing up, I was an undergraduate working in a biochemistry lab. The night before, I had stayed up late to finish assignments for my classes. After I nodded off a few times, even while someone was speaking to me, I was jokingly accused of having narcolepsy. It was the first time I can remember anyone using the word in a conversation; I had never met anyone with narcolepsy.

  What I actually had is called “insufficient sleep syndrome,” which goes away after enough rest. I can remember a fender bender in graduate school after a late night in the lab and another time falling asleep at a stoplight, releasing the brakes just enough to nudge the car in front of me. My wife recalls my falling asleep during a scientific lecture and then audaciously asking a detailed question when the lights were turned on. None of this makes me special—many people have had similar experiences. In my late thirties, I was diagnosed with obstructive sleep apnea, a common sleep disorder among Americans. When I visit support groups for people with rarer sleep disorders, I tell them that I view what they have through a keyhole; I’ve experienced “sleepy,” but not to the same degree. This book is about people dealing with something more extreme than what I have.

  Just before I started working at Emory University in 2007, the nursing professor Kathy Parker gave a lecture describing her patient Anna, a young lawyer whose life was being taken over by sleep. Despite powerful stimulants and multiple alarm clocks, Anna could sleep more than thirty hours at a stretch. Forced to stop working, she was losing weight because she didn’t stay awake long enough to eat. The resulting headline in the university newspaper was: “ ‘Sleeping Beauty’ Case Awakens Hope for Disorder.”

  Baffled, Parker and other researchers searched for an explanation. They had ruled out conditions such as sleep apnea and narcolepsy and diagnosed Anna with idiopathic hypersomnia, a poorly understood neurological sleep disorder. Following a hunch of Parker’s, they glimpsed signs of something in Anna’s spinal fluid, which they thought might be causing her sleepiness. This substance’s chemical effects resembled those of benzodiazepines, the class of antianxiety and anti-insomnia drugs that includes Valium and Xanax. With that clue, the researchers found a treatment for Anna and convinced the pharmaceutical company Roche to help. Soon afterward, Parker left for another university, and it took years for the remaining group at Emory to publish their work.

  I eventually met Anna at a talk given by the neurologist David Rye. When the findings of Rye, Parker, and colleagues appeared in a scientific journal in 2012, it was my job to explain them in an announcement aimed at news organizations. For me, what caused idiopathic hypersomnia or how to treat it didn’t matter so much at the time. What changed my mind were the emails and phone calls: “Is there a study I can be part of?” or “My daughter has this. Can you help her?”

  I was seeing a small fraction of the avalanche of pleas that Rye and his colleagues were receiving. It went on for months. Then I learned that people with conditions resembling Anna’s had organized online and were planning a conference in Atlanta. They had formed a community on social media based on what they shared: debilitating sleepiness that wasn’t explained by some other medical condition.

  The 2014 Living with Hypersomnia conference was my first contact with this irreverent, often frustrated group. Members bonded over feeling misunderstood by friends and coworkers. They traded morbid jokes and recommendations for alarm clocks. Because of their chronic sleepiness, some were reluctant to drive more than a few miles or had given up driving entirely. A substantial number of people with idiopathic hypersomnia (abbreviated as IH) had to abandon their jobs or school or had applied for disability benefits. Once awake, people with IH don’t often fall asleep suddenly, but more than one told me: “Waking up is the hardest thing I do all day.”

  If you don’t know someone with IH, you may be thinking: “Sometimes I have trouble getting out of bed,” or, “My teenager moans and groans almost every morning.” People with IH get dismissive reactions all the time, even from their families. The father of one teenager with IH described being in denial, considering his son “just a lazy kid.” What changed his mind was finding out his son fell asleep not only during lectures in school but also while passing papers back to a classmate. The father, a Lutheran minister, took his son to the family doctor. To better understand his son’s condition, the doctor urged the father to try to take three naps in one day. “I couldn’t do it, as much as I loved sleep,” he said.1

  As a neurochemical state, sleepiness continues to be difficult to pin down and dissect. EEG (electroencephalography) can indicate with high confidence whether someone is asleep or awake, so you might think that concerns about subjective symptoms that emerge when studying conditions like depression don’t apply. But even though being asleep can be determined objectively, sleepiness cannot. There is no rapid biological test for sleepiness. In the doctor’s office, it is measured by questionnaire: Do you often fall asleep while watching television or at stoplights? In the clinic, the standard test for narcolepsy or IH involves having someone take five naps throughout the day. The variable measured is the speed at which someone enters sleep. A large number of people in our sleep-deprived society will meet the criteria for this test by dozing off quickly enough each time, but people with IH can do so even after a week of apparently sufficient rest.

  At the 2014 conference, I could see that Rye and his colleagues had given people with IH energy, hope, and some new options. Their research also contained a potential explanation for why some people with IH were sleepy: the “somnogen” in their spinal fluid. At that time, it had not been identified. It was known informally as “sleepy stuff” or even “sleepy juice.” Rye’s collaborator Andy Jenkins was in the process of figuring out what the somnogen was.

  This puzzle intrigued me. I had spent a large part of my time as a graduate student in a walk-in refrigerator purifying proteins—the same task facing Jenkins. I wasn’t working in the laboratory anymore, but maybe I could give the search for the somnogen a nudge. Perhaps assembling the clues and presenting them to the professionals, like a private investigator does for the police in the movies, would help. More realistically, I could be there when they resolved the mystery. My postdoctoral supervisor once told me: “You can follow a disease, or you can follow the molecules. The molecules may lead you to unexpected places.”

  For a century, the molecules that make us and our animal relatives sleepy have captured the scientific imagination. As one early example, French scientists reported in 1913 that spinal fluid from sleep-deprived dogs induced sleep when injected into another animal; spinal fluid from rested dogs did not. Today, the roles of several molecules that regulate sleep are well worked out.

  Reading the literature told me that what Parker, Rye, and Jenkins had stumbled upon was weirder. A tantalizing hint toward the origins of Anna’s sleepiness came from flu
mazenil, the antidote to benzodiazepines that she relied upon every day. Since its discovery almost four decades ago, doctors have tried using flumazenil to wake up other sleepy people, with little consistency. What flumazenil was counteracting was neuroscience’s equivalent of sunken pirate gold: once glittering and glamorous, but later obscured by the complexity of the brain. It was striking how researchers from different fields—hepatology, addiction medicine, and neurology—had become champions of this odd, obscure drug.

  I learned that IH occupied an awkward place in sleep medicine. Neurologists who study sleep are accustomed to thinking about narcolepsy, a disorder with a longer history. They tend to regard IH as part of the “narcoleptic borderland.” Narcolepsy was their homeland, and other disorders were viewed in relation to it.

  Rye was arguing that some people diagnosed with narcolepsy should be grouped together with those with IH. He wanted to redraw the map of how those disorders were classified, based on the mechanism he proposed to explain Anna’s and others’ sleepiness. His ideas about IH were at the edge of mainstream sleep medicine; his peers didn’t think there was enough solid evidence behind them.

  Doctors have used many drugs without knowing exactly how they worked. But to convince neurologists and sleep specialists that Anna’s case was not an anomaly, someone would have to identify the sleepy stuff. They’d have to demonstrate that it was abnormally active in some people with IH. A rigorous study would have to show that enough of them responded to an agent that counteracted it. That might take years. I realized that Rye’s ideas could be wrong, and I had to evaluate alternative explanations for IH that did not depend on his theories.

  By the time I started collecting material for this book, organizations such as the Hypersomnia Foundation and Hypersomnolence Australia had been established to advocate for people with IH. Drawn by this activity, pharmaceutical companies had begun clinical trials that included people with IH, but the companies’ success wouldn’t necessarily show that Rye was correct. The medications that helped Anna didn’t always work for others. Anna told me: “My story may be inspiring, but it’s not everybody’s story.”

  For me, writing this book started out as a scientific detective story, but it turned into something that was more about the coalescence of a community. As a former lab rat, I’m more comfortable discussing molecules rather than personal identity. But I learned that names people give to their conditions are important. At a support group meeting in Atlanta, I asked people with IH what they wanted to be called and what they thought were the important aspects of their symptoms. A few people with IH had embraced the term “sleepyhead”; others disliked it. One said: “It sounds like something you’d say to a toddler.” The organizer of the support group argued that “sleepyhead” did not capture the full extent of the condition. In particular, it doesn’t include the “brain fog” that can envelop people with IH, making them indecisive and prone to mishaps. Brain fog also seems to respond less to stimulants; combining the two leads to a “fake awake” situation, in which someone’s eyes are open but they are not alert. Still, brain fog is not specific to IH. The symptom appears in depression, multiple sclerosis, and other disorders, including long COVID. In comparison, IH seemed to be purer than other neurological or psychiatric disorders because it involved excessive sleepiness and sleep duration, without other prominent symptoms.

  Many IHers (an agreed-upon term) experience something objective but difficult to verify quickly: they need considerably more hours asleep every week than the average person. Moment-to-moment sleepiness is more subjective. It’s connected to many variables: lack of sleep, time of day, meals, position of the body, light, and temperature, as well as mental activity and effort. When nonspecialists talk about how they feel after a long day, sleepiness can blend together with tiredness and fatigue. Still, sleepiness is a different experience from the physical fatigue someone might feel after playing sports or climbing a mountain.

  Other neurological disorders characterized by subjective symptoms have had difficulty being recognized as something “real.” Earlier in the twentieth century, people with multiple sclerosis were misdiagnosed with hysteria because their symptoms were regarded as psychosomatic.2 According to the sociologist Joanna Kempner, migraine headache once had a “legitimacy deficit” because of the subjective aspect of headache pain and because the stereotypical migraine patient was female.3 Perhaps IH will undergo a similar evolution. A molecular marker for migraine-related pain called CGRP (calcitonin gene-related peptide) could present a possible parallel with the “sleepy stuff” somnogen.4

  Recently, the COVID-19 pandemic and the phenomenon of long COVID have led to renewed attention to postviral chronic illnesses and other conditions with uncertain status, such as myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). IH has followed a different course because of its historical relationship with narcolepsy—it was acknowledged within mainstream medicine yet received little attention.

  Does discussion of IH take something that everyone experiences sometimes—drowsiness or feeling groggy after waking up—and turn it into a disease, requiring treatment? On the margins, maybe. Debate continues among sleep medicine specialists on the proper borders between everyday sleepiness and IH or narcolepsy. Consider how much persistence it often takes for someone to receive an IH diagnosis. Those years of asking doctors for help should not be seen as simply a ploy to obtain stimulants. While many physicians are comfortable prescribing conventional stimulants, the need for alternatives is clear.

  Looking ahead, the pharmaceutical industry has been developing several newer wake-promoting medications—an emerging arms race of weapons against sleep. In a sense, we are all struggling against the environment we created. Chronic sleep deprivation leads to long-term health consequences: higher rates of cardiovascular disease, metabolic problems, and cancer. People in industrialized societies have collectively lost sleep since the appearance of artificial lighting and electricity, and that loss has accelerated in recent decades. We can learn from IHers, who need more of a scarce commodity.

  This book follows the emergence of IH as a diagnosis, a sleep disorder, and an FDA indication. At the same time, the value of focusing on the “sleepy stuff” (or stuffs)—the physical currency of extreme sleepiness—is that it might cut through concern about disease mongering and uncertainty about how IH should be defined and is thus potentially relevant to a wider population: all of us.

  CHAPTER 1

  ANNA SLEEPS A LOT, AND WE DON’T KNOW WHY

  Some syndromes have languished for an appreciable time for lack of a satisfactory name. An unfortunate consequence of naming can be the mistaken impression that we understand the condition.

  —Victor A. McKusick, 1969

  Anna Sumner knew she was taking a risk. She was in the epilepsy monitoring unit of a university hospital, ready to try a medicine suspected of provoking seizures. Her doctors were prepared, just in case. She had EEG electrodes attached to her head, and her nervous parents were waiting outside.

  The medicine was flumazenil, an antidote against an overdose of sleeping pills. But Anna had not taken any sleeping pills. Instead, her doctors thought her body was making its own. This might explain why she needed multiple alarm clocks in the mornings and why she could doze through a phone ringing or someone shaking her. How did she get here?

  In 2004, after finishing law school, Anna started working at a respected law firm in Atlanta. There she had difficulty managing her body’s extraordinary requirements for sleep. She could routinely sleep for twelve or fourteen hours and still wake up without feeling refreshed. “It came to the point where if I had a choice between sleeping or eating, I would rather sleep,” she said later. “At the same time, when I did, it was not restorative or satisfying.” Anna recalled her predicament in an interview recorded at Emory, the medical center in Atlanta where she sought treatment. “I was always thinking, how can I get more sleep?” she said in her faintly Southern-accented voice. “If I don’t wash my hair this morning, can I get thirty minutes more sleep? If I don’t eat lunch today at work, can I come home early and go to sleep?”1