Ending the big sleep
By By Quinn Eastman, Illustrations by Christiane Beauregard
Sleep was consuming Anna Sumner's life. The Atlanta attorney routinely slept 16 hours every day, and it never felt like quite enough. She needed multiple alarms to wake up and could sleep through a phone ringing or someone shaking her. When she came to Emory Sleep Center in 2005, she told doctors there that she "craved" sleep all the time. "It came to the point when faced with a choice between sleeping and eating, I would rather sleep," she recalls. "But when I did sleep it was not restorative."
Sumner's care team had considered and ruled out common causes of sleepiness, such as sleep apnea and narcolepsy. The typical drugs of choice to combat sleepiness, prescription stimulants, didn't help. This was a type of sleep disorder that they did not know how to treat.
"It required a shift in thinking," says neurologist David Rye, who has led the effort to understand Sumner's mysterious condition. "Usually if people are having trouble staying awake, the conventional thought is that their brains are deficient in excitatory monoamines, like histamine or dopamine, and are in need of a jolt from these wake-promoting neurochemicals. In Anna's case, giving her extraordinary doses of stimulants was like trying to drive a car with the parking brake on. We needed to release the brake, rather than push the gas harder."
Sumner's condition would lead Rye and his team on one of the most demanding—and rewarding—scientific journeys they've had. In the end, they were able to put a name to her condition and track down the world's first treatment for it. But along the way, Rye discovered the scientific community wasn't as convinced as he was about his discovery.
The 'Sumner stupor'
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Sumner says her sleep demands increased in high school. While she was studying at Princeton, her parents in Mississippi became more concerned because she'd spend much of her holidays at home asleep. During law school, a flexible schedule allowed her to conceal her sleep requirements. As an attorney, she says she never missed a critical legal appointment, although the strain became difficult to bear. Over the years, she kept a list of "things I slept through," like a friend's wedding she had traveled across the country for. She managed to keep a sense of humor about her situation, joking with her brothers about the "Sumner stupor."
When Sumner came to Emory's sleep clinic, Rye and his team diagnosed idiopathic hypersomnia and prescribed her stimulants, such as modafinil and amphetamines. These drugs proved beneficial for a while. However, the increasing doses needed to sustain the effect made Sumner feel "twitchy," elevated her blood pressure, and suppressed her appetite. And she began experiencing crashes. Unpredictably, she would sleep for 30, even 57 hours at a stretch.
"That was the scary part," she says. "If I went to bed, I didn't know if I'd fall off the map and wake up two days later."
She took a leave of absence from her job, and her mother had to move in with her to wake her so she could eat.
"We had never had a patient quite like her before," says former Emory nursing sleep specialist Kathy Parker, who is now at the University of Rochester. "I thought to myself that she's going to sleep her life away if we don't do something."
Hey, GABA
Parker made a chart of all the signaling molecules in the brain, checking off each one as she and Rye tried different drugs to alter Sumner's brain chemistry. With the list of untried neurotransmitters growing very short, they decided to look at the brain chemical GABA (gamma-amino butyric acid), an amino acid that calms the nervous system for sleep. Sleep-promoting circuits in the brain are thought to use GABA. Barbiturates and benzodiazepines, such as Valium and Ambien, make neurons respond more strongly to GABA.
Parker enlisted anesthesiology researcher Andrew Jenkins, who has been studying since the 1990s how GABA affects brain cells, to look at Sumner's cerebrospinal fluid (CSF). He found a normal level of GABA in her CSF, but her CSF contained a substance with an amount of GABA-enhancing activity comparable to someone undergoing oral surgery or a colonoscopy who had received a strong sedative. (He did not find any synthetic benzodiazepines in her CSF.)
The mystery substance appeared to be working with her GABA to tamp down her brain's activity, like an ever-present sleeping pill. But neither Jenkins nor Rye could figure out what the substance was in her CSF.
"Sleep and anesthesia may share some features in common, but they're not the same thing," Jenkins says. "You don't wake up feeling satisfied after general anesthesia."
Jenkins wanted to see if the substance was similar to a benzodiazepine and tested it against flumazenil, an antidote kept on hand in emergency departments for benzodiazepine overdoses. When Jenkins added the flumazenil on top of Sumner's sample, it nearly reversed the effects. That led to the question: would it accomplish the same feat in Sumner?
The eye-opening moment
Flumazenil is known to provoke seizures in people going through benzodiazepine withdrawal, so the team decided to give Sumner the drug in Emory University Hospital's epilepsy unit over the course of two days in June 2007. Sumner occupied herself with "the world's most boring video game," a psychomotor vigilance test that measured her alertness by timing how fast she could react to numbers on a screen. The team monitored her vital signs and brain waves. When the dose reached two milligrams, she exclaimed, "I feel alive!"
"The best way to describe it is that my eyes opened, after being half-closed for so long. It was as if a force grabbed my eyelids and pulled them upwards," she says.
For the researchers gathered around, the moment was dramatic as well.
"In a matter of days, we went from a biophysical experiment in the lab to having a real impact on a patient's life," Jenkins says. "It was certainly one of the highest points in my career."
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As exciting as the test result was, the drug's effect wore off after a few hours. Since flumazenil rapidly metabolizes if swallowed whole, it is usually given intravenously, but Sumner would need a formulation that was more convenient. Parker wanted to reformulate the drug, but it was only approved to counter overdoses, and there was little supply of the drug. It had not been manufactured since 2004.
Parker worked with the FDA to secure a compassionate-use exemption for Sumner and with drug patent holder Roche to tap the last flumazenil supply, held in Roche's laboratory in Switzerland. Parker also worked with a compounding pharmacy to develop a 6-milligram flumazenil lozenge for Sumner to put under the tongue throughout the day. Sumner discovered that having the level of flumazenil in her system swing too drastically made her nauseous or groggy. Along with the lozenges, a flumazenil-containing cream applied to her forearms before bedtime helped her wake up in the morning.
Sumner reported that this regimen finally worked, with few side effects. She could drive, something that didn't feel safe when sleep was such an overpowering urge. She could watch entire television shows for the first time in years. In short, she had her life back.
Finding others…and skepticism
His success with Sumner led Rye and his team to examine CSF samples from other patients who had experienced daytime sleepiness. The sleepiness was severe enough that some had applied for disability and others needed leaves of absence from school or work. Sleep apnea and other conditions that cause daytime sleepiness had been ruled out.
"Even when they're ostensibly awake, these patients report that they feel as if they are walking around in a fog," Rye says. "They have the reaction times of someone who has stayed up all night, all the time."
Rye found enhanced GABA activity similar to that in Sumner in their CSF samples. He tested Sumner and six others in a clinical study on the effects flumazenil could have on their alertness, measured by a psychomotor vigilance test. Flumazenil improved reaction times and perceived alertness in all seven, although their responses were not uniform.
When Rye wrote up the results of his clinical study, his quest to get his paper published proved to be as long as finding a treatment for Sumner. A number of journals turned him down, citing skepticism about his results. The journals' goodwill had been tainted by a similar, but bogus, study in Italy in the 1990s.
The Italian neurologists reported that they had identified patients experiencing a "recurrent stupor" because their bodies produced benzodiazepine-like substances. It was later revealed that the Italian patients were being given the benzodiazepine drug Ativan covertly.
Rye's study was finally published in the Nov. 21, 2012, issue of Science Translational Medicine, but not before he and Jenkins went to great lengths to show that the unknown substance was not an artificial benzodiazepine drug taken by the patients. Using the latest technology, they scoured patients' CSF samples for benzodiazepines. They also showed that the sleep-inducing substance works in situations where benzodiazepines don't. In the lab they demonstrated that the substance still works upon GABA receptors that were mutated and rendered insensitive to synthetic benzodiazepines.
The still unknown substance
Rye and Jenkins' next quest is developing new tests to look for the unknown sleep-inducing substance. What they have determined so far is that based on its size and sensitivity to certain enzymes, the substance could be a peptide, similar to the hormone oxytocin. While the substance is detectable in blood, its concentrations are much higher in CSF, suggesting that it is synthesized in the brain.
"I think the 'sleepy stuff' is something that is made by everyone's brain in some amount," Jenkins says. "Either Anna and other people like her make more of it, or what they make is more potent, which is the direction I'm leaning now."
If the substance is present in all of us, would flumazenil wake up sleep deprived healthy people? If so, could truck drivers, airplane pilots, and medical residents use it to stay awake? Presented with this idea, Rye threw cold water on it.
"We are not the first to think that if you muck around with GABA, you can wake people up," he says. "The military tried out flumazenil on sleep-deprived recruits years ago and seems to have abandoned it."
Several studies with flumazenil indicate that for most people it has no stimulant effects, even if it has now been shown to restore alertness in a handful. Rye says this variability may have something to do with a patient's sensitivity to sleep deprivation, possibly genetic—his hypersomnia patients often have a close relative with similar experiences.
Although flumazenil has helped Sumner, it may not be a practical long-term treatment for others. The supply of the drug is limited. Sumner has about a year's supply left, and no manufacturers so far have expressed interest in taking up flumazenil.
Rye's other hypersomnia patients are taking the antibiotic clarithromycin. (Sumner says she will probably transition to this drug once her flumazenil runs out.) This drug came by way of Sumner herself. After contracting bronchitis in 2010 and taking clarithromycin, she found herself with insomnia. She called Emory, and soon thereafter, clarithromycin's effects on GABA were tested in the laboratory. The results were promising, and clarithromycin is now the focus of another clinical study, supervised by neurologist Lynn Marie Trotti.
Rye and Jenkins say they still have some work to do in convincing their peers that hypersomnia has genuine biology behind it, judging from an experience of Sumner's parents. They approached a prominent neurologist [not at Emory] and described their daughter's condition, only to be told that she was probably taking drugs recreationally. Some of Rye's other hypersomnia patients have received diagnoses of narcolepsy or depression, but hypersomnia may be more common than narcolepsy, he says.
"Looking back on it, it just demonstrates the good luck that I had to be dealing with doctors who listened to me," Sumner says. "I am grateful for their perseverance." EM
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