If someone who was otherwise resistant to high doses of stimulants developed insomnia, that seemed significant. In medical literature, clarithromycin had been connected with occasional reports of delirium in hospitalized elderly patients and “agitation, euphoria, and insomnia” in otherwise healthy young people with acute infections.2 How an antibiotic produced these effects was unknown. In some cases, it might have been interfering with the metabolism of other drugs.

  Rye and Trotti took what was considered a nuisance or harmful side effect, and turned it into the main effect. Clarithromycin was available outside of the practical and regulatory constraints surrounding flumazenil. It only took a short time for Rye to try clarithromycin with some of his hypersomnia patients. He prescribed it to Valerie, who texted him that she felt surprisingly energetic and that her daughter had to coax her out of the garden in the evening.

  Trotti followed in Rye’s footsteps a few months later. Initially, she was concerned that the antibiotic would trigger seizures or some other adverse event, such as diarrhea caused by Clostridium difficile, a stubborn type of bacterial infection that can colonize the intestines following antibiotic treatment.

  In the laboratory, Jenkins and Garcia were inspired by Anna’s experience to investigate clarithromycin’s effects on GABA signaling via patch clamp. Garcia tried clarithromycin himself after a residency shift; it had some kick, he said. The pair presented their results at an October 2009 anesthesiology conference.3 They showed that clarithromycin acts on GABA-A receptors, but in a different mode than flumazenil. Clarithromycin blocked those receptors’ ionic gates, even if hypersomnia patients’ CSF is absent. In Anna’s case, what tipped the balance toward insomnia was probably the combination of clarithromycin and flumazenil together.

  Trotti and Rye have continued to hold open the possibility that clarithromycin works through some other mechanism besides GABA receptors. At first Rye was uncertain whether clarithromycin even entered the brain, so he had CSF samples sent to an outside chemist to check. In terms of molecular size, clarithromycin was larger and clunkier than flumazenil. Was it perhaps indirectly reducing sleepiness, by acting as an anti-inflammatory agent or altering intestinal bacteria?

  Trotti and Rye prescribed clarithromycin to more than fifty of their patients with refractory hypersomnia over the next four years.4 Almost two-thirds experienced subjective improvements in sleepiness, they reported in Journal of Psychopharmacology. This paper is a snapshot of the Emory Sleep Center hypersomnia population before the influx triggered by media attention in 2012. Most patients had tried and rejected two or three other wake-promoting medications, such as modafinil, before being prescribed clarithromycin. More than 40 percent had a history of depression. In terms of formal diagnoses, the patients were a mix of narcolepsy without cataplexy and “primary hypersomnia”—not idiopathic, since they were all positive for GABA-enhancing CSF. The patch clamp assay didn’t predict who was likely to respond well to clarithromycin. The only strong predictor was age; nonresponders were older.

  Most of those who reported a benefit from a two-week trial of clarithromycin continued to take it. Some people did not tolerate the antibiotic because of side effects, such as abdominal cramping, diarrhea, and nausea. Commonly reported was a lingering metallic taste, sometimes described as like “a rusty sink” or “like sucking on quarters all day.” Valerie, for example, said that she used clarithromycin intermittently, only when she really needed it, partly because of the side effects and also because she was concerned about growing tolerant and wanted to keep it in reserve.

  Although it was readily available from pharmacies, Rye and Trotti did not consider clarithromycin an ideal solution for people with hypersomnia. Prolonged use might promote antibiotic resistance or have other harmful effects on intestinal bacteria. A Danish study of people with heart disease detected an increased risk of mortality connected with clarithromycin, prompting anxiety from Emory patients.5

  For these reasons, Rye pushed ahead with a clinical trial of flumazenil in its sublingual form. To find commercial partners, he worked with Emory’s Office of Technology Transfer, without success. The language around what Anna and others had and who the target market might be remained confusing. An OTT PowerPoint presentation from that time promoting the project was titled “Sublingual Flumazenil Treatment for Recurring Stupor.”6

  Rye and Jenkins drew up plans for a company called Somnolytics, meaning “dissolving sleep.” A January 2010 application to the Georgia Research Alliance (a state government–private partnership promoting research) for $50,000 in seed money emphasized the possible advantages of flumazenil. It would be presumably nonaddictive and not subject to restrictions by the Drug Enforcement Administration, in contrast to traditional stimulants. Cephalon’s modafinil was described as a model because it was first approved for narcolepsy, then more prevalent conditions such as shift work and sleep apnea.

  The scale of the clinical trial was small: ten people received either flumazenil or placebo for a day. Rye intended this study as a first step, which he could use to convince investors or a larger pharmaceutical company to do business. The primary outcome, what researchers tested as a gauge of success, was reaction time measured through the psychomotor vigilance test. The results were disappointing: no obvious differences between flumazenil and placebo for reaction time or subjective sleepiness.7

  In a presentation he gave afterward, Rye listed several lessons learned. Possibly because there was no adjustment for Anna’s small size, the doses of flumazenil in the trial may have been too low. Most participants did not reach the same level of flumazenil in their blood that Anna had. Also, participants were still using other medications, and a single day of treatment spent lying in bed was probably insufficient to assess changes in symptoms. Overall, the scale of the study, limited by financial constraints, was too small.

  CAPTAIN OF THE SHIP

  For the flumazenil clinical trial, Trotti was listed as the principal investigator. A condition for the Georgia Research Alliance funding was that Rye not have that role, to avoid conflict of interest with his status as a potential beneficiary of flumazenil’s commercialization. For studies of clarithromycin, Trotti took the lead in seeking support from the American Academy of Sleep Medicine (AASM) Foundation and then in being principal investigator for the study. “I was captain of that ship,” she said.

  Trotti started out in a trainee relationship with Rye but has developed her own expertise and preferences. In comparison with him, she was more cautious and less eager for media attention. She was less likely to tell stories about her unnamed patients. Also, she was less openly critical in relations with their peers and more willing to work within organizations such as the AASM to change guidelines and policy.

  Growing up in Canada and then upstate New York, Trotti had wanted to be a psychologist or family physician, having little personal experience with neurology or sleep medicine. She gained some neurology research experience over the summers while attending Rice University in Houston. In addition, she was attracted to the field because of instructors she admired at Baylor, where she attended medical school, and because neurology practice would call for her to maintain ongoing relationships with patients. “I could have gone somewhere else after residency, but I knew that it would be foolish to leave,” she said. “What was happening here was too important, too unique.”

  Trotti has occasionally mentioned being influenced by her father, Lorne Becker, a proponent of down-to-earth family medicine. When she was in high school, she and her family moved from Toronto to Syracuse so her father could become chair of the family medicine department at the state university there. He has been active in the Cochrane Collaboration, an organization that organizes systematic reviews, an effort to squeeze out wishful thinking and industry spin. Becker and Trotti have collaborated on Cochrane reviews related to restless leg syndrome and, more recently, wake-promoting medications for IH.8

  FIGURE 7.1. Lynn Marie Trotti (seated) and Prabhjyot Saini (standing).

  Source: Photo courtesy of Diana Kimmel.

  After he returned to Toronto, Becker told another author that his experience in the United States made him appreciate Canadian health care: “The overwhelming good thing about this system is never having your hands tied by the patient’s financial status. It’s a relief not having to fight with patients to get mammograms because they cost too much.”9 In her own practice in Atlanta, Trotti has struggled against insurance companies’ restrictions on her patients’ behalf. She told an audience of other doctors that her time in the sleep clinic made her worry about how many people are driving while drowsy: “There are days when I think I’ll never get on the highway again.”10

  WHY YOU AND NOT ME?

  After the clarithromycin episode, Anna said that she was starting to feel a bit sleepier: “She complained of mild difficulties with sustaining vigilance.” As a result, modafinil was added to her daily regimen. Although modafinil had been insufficient for Anna back in 2005, the combination of flumazenil and modafinil worked well for her, and she returned to work full time. Although Anna was thereafter less of a source of drama, she continued to be a reference point for the Emory researchers.

  Anna did not come into contact with others with similar sleep disorders until a couple years later. In October 2010, she attended the Narcolepsy Network national conference in Virginia, along with her parents. For people with narcolepsy in the United States, the conference was a chance to meet others who understand their struggles. In the absence of organizations focused on IH, narcolepsy organizations and support groups often seemed like the best fit for IHers. Some had been previously diagnosed with narcolepsy or told others they had “something related to narcolepsy.” At the conference, Anna told her story of getting her life back. Some people who were listening to her talk had tears in their eyes.11 “I was amazed at the community,” Anna said. “Some people said, ‘Finally, someone is studying this.’ But others had some uncomfortable questions, like, ‘What makes you so special that you got this treatment, and others won’t? Why you and not me?’ ”

  The 2010 Narcolepsy Network conference was one of the first occasions when Rye told his sleep medicine peers about what was going on at Emory. In Narcolepsy Network’s newsletter, he shared an update on his research. He mentioned the flumazenil clinical study and vented about how his National Institutes of Health grant applications had been reviewed unfavorably. Rye was quoted as saying: “We have determined that greater than two thirds of patients presenting to us with one of these diagnoses are essentially making their own endogenous anesthetic, i.e. they’re making their own Valium, so to speak.”

  ANECDOTAL ANNA

  The manuscript on Anna’s case encountered difficulties when it was sent to the New England Journal of Medicine, because reviewers associated it with the “idiopathic recurring stupor” research at the University of Bologna from more than a decade before. “One reviewer used a kind of ‘straw man’ argument,” Rye recalled. “They said: ‘You haven’t explained this other thing, which happened in Italy. So I don’t understand what you’re telling me here.’ ” Another referee called the report “merely anecdotal.” Rye told Anna, and she was offended at the thought of being anecdotal. To show that his patients weren’t sleepy because of known drugs, Rye and the pathologist Jim Ritchie paid thousands of dollars to have urine and blood samples tested by outside forensic laboratories. They also looked for newer drugs, ones not commercially available in the 1990s. All samples were negative.

  Nature Medicine rejected the manuscript without outside review. When preparing to try again with Science Translational Medicine, the Emory team wanted to give their submission a little more heft. They asked Anna, then back at work, to abstain from flumazenil and other medications for several days and come back to the hospital. At that point, her doctors felt like family, and she was willing to make an extra effort to help. She and Rye had been discussing a documentary about the chess player Bobby Fischer, so they watched it together, ordering takeout over a weekend in April 2012. Coming back to the sleep laboratory was not especially fun. Having to stop flumazenil made her feel grumpy and sleepy all over again. “It reminded me how debilitating this condition actually was,” she said. “I felt like a pin cushion because they drew blood every hour.”

  Anna’s alertness responses had already been tested twice, but a third time could remove lingering doubts. The aim was to test whether she had undergone a remission or if the findings were spurious, Rye told the editors. When they gave Anna flumazenil again, they measured her reaction time and EEG responses before and after. Just like four years prior, her reaction time went from slower than average to faster. This extra effort may have put the manuscript over the top.

  When he was getting ready to publicize his upcoming paper, Rye did not want to confuse matters by comparing the GABA-enhancing sleepy stuff seen in Anna and others to what had been published before. He said emphatically: “Don’t call it an endozepine.”

  MY BED WAS MY HOME

  When the paper highlighting Anna’s case was finally published in Science Translational Medicine in November 2012, it aroused interest from news organizations and also in people with sleep disorders around the world. Anna’s recovery was highlighted on NBC’s Today Show. “My bed was my home. It was everything,” she told NBC. “It was like an addiction. I would hit a point in the day where I thought: ‘If I do not go to sleep right now, I will literally not survive.’ ” A voiceover intoned, “She’s able to do tasks she could never finish before.” Anna was shown in the Emory sleep lab, at her Midtown Atlanta law office, raking leaves outside her house, and unloading her dishwasher.12

  In an interview for the program, Rye said: “We’ve discovered that the body seems to be producing a substance that acts very much like a sedative.” The unidentified sedative-like substance had been detected in thirty-one others, and the Science Translational Medicine paper included descriptions of several people who had responded well to flumazenil in the hospital, displaying improvements in reaction time and subjective sleepiness. Just two of this group fit then-current diagnostic criteria for idiopathic hypersomnia; others were long sleepers or had narcolepsy without cataplexy or Kleine-Levin syndrome. This group appears to include those described in the 2009 patent and NINDS grant application.

  NBC pointed out that Anna was currently the only person with a sleep disorder taking flumazenil long term but that her supply could run out in a year. The alternative of clarithromycin wasn’t mentioned, even though more people were taking it at the time. “There is a huge unmet need of people who identify with Anna,” Rye told the Wall Street Journal, in an article that appeared a couple weeks after the paper’s publication.13 He added that Emory’s sleep center had received a wave of calls from interested patients and other sleep clinics—ninety-five in one week. One concerned mother of a college student with IH contacted Emory after reading the Journal article and was not able to secure an appointment with Rye until a year later.14 (The mom was Betsy Ashcraft, who later became a board member of the Hypersomnia Foundation.)

  Again, there was confusion about what to call Anna’s condition. The Journal called it “primary hypersomnia,” while the Today Show said it didn’t even have a name. A Fox News headline writer misled readers with “ ‘Sleeping Beauty’ Gene Proves Beastly for Sufferers,” since no specific gene was in sight.15

  Science asked Rye’s friend Cliff Saper about the Emory research, and he referred back to the Bolognese fumble with idiopathic recurring stupor. But Saper said the new paper made a strong case that alterations in GABA signaling had a role in hypersomnia. Rye had his work cut out for him: “Identify the mystery compound, figure out a faster way to detect it, and conduct a larger clinical trial to test the benefits of flumazenil.”16

  PASSING THE TORCH

  It’s time to introduce someone else who played a pivotal role in forming the hypersomnia community. Like Anna, she has appeared on television and in news articles as a spokesperson. For many people, her experiences may be more relatable than Anna’s. Instead of elite law firms, her stories involve feeling extremely sleepy while driving her kids to soccer practice. They also include a long period when doctors thought her sleepiness was something else.

  In the 1990s, Diana Kimmel was living in Rockland County, north of New York City. She worked in medical billing and had a side gig in photography. Diana began to perceive that she was “more tired than most people.” She would take naps, but she felt embarrassed about it, jumping up when someone came to visit.

  Doctors checked her thyroid and iron levels, sometimes her vitamin B12. They would attribute her fatigue to her hectic schedule or her two children or advise her to lose weight. A few offered her conventional stimulants, which made her feel shaky or jittery. Modafinil made her feel like she was having a heart attack. “I stopped complaining to doctors for a while, because I wasn’t getting anywhere,” she said.

  Around 2006, Diana was preparing to move to Georgia to be closer to her parents. While she still had good insurance coverage through work, she decided to have a few tests performed to check out her persistent sleepiness. She recalled that at the time, she felt foggy and would nap during the day, while being unable to sleep at night. An MRI scan discovered a pituitary tumor, which was removed surgically in 2007. “After that was taken out, I thought everything was going to be fine,” she said—but she felt worse.

  During the day, she would experience recurrent sleep paralysis: she would wake up from a nap and find she couldn’t move. While driving, she would lose chunks of time. She would emerge from a mental fog and not realize how she got to where she was. An endocrinologist thought her potassium was low. She bounced from doctor to doctor. Her need for sleep increased. “I would be up to fifteen, sixteen [hours],” she later told a television interviewer.17 “I would sleep all night long. I would wake up and by nine, ten o’clock, I was back in bed.”