Winter 2008: Of Note
‘Sleeping Beauty’ Case Awakens Hope for Cure
By Carol Clark
It was the most baffling case that Kathy Parker, an expert in sleep disorders, had ever encountered. “Anna,” a thirty-two-year-old attorney, came to the Emory Healthcare Sleep Program in June 2005 because her excessive need for sleep—as many as fifty-seven hours at a stretch—had put her career, and her life, on hold. “She reported that she craved sleep,” said Parker, codirector of the Emory Healthcare Sleep Program. “In fifteen years, I have never had a patient tell me that. They’ll say, ‘I can’t stay awake,’ or ‘I struggle to stay awake,’ but Anna described it as this crazy compulsion to sleep.”
Parker enlisted an interdisciplinary team of Emory scientists to investigate Anna’s case. The team not only diagnosed the rare condition that Anna is suffering from—endozepine-induced recurrent stupor—they also are developing what may be the first treatment for the devastating illness.
“We have a sleeping beauty here. She can’t stay awake for more than six hours. She can’t go out on a date. She had to take leave from her job,” said Parker, describing her hopes that the treatment trial will transform Anna’s life and lead to help for others as well.
Parker presented the findings of Anna’s case in October as the featured speaker for the ninth-annual Mary Lynn Morgan Lecture for Women in the Health Professions. Parker is Edith F. Honeycutt Professor in the Nell Hodgson Woodruff School of Nursing and one of five nurses in the nation certified in clinical sleep disorders. Her research at Emory has made significant contributions to understanding the connections between sleep, health, and illness.
The Emory team that worked on Anna’s case included specialists from neurology, pharmacology, anesthesiology, and nursing. A battery of tests ruled out narcolepsy, one of the most well-known sleep disorders, as the cause of Anna’s excessive sleeping. She was given an initial diagnosis of “idiopathic hypersomnia,” the term used “when we really don’t know what the issue is,” Parker said.
“Our ‘sleep’ and ‘awake’ brain mechanisms are very complex,” she added, explaining that the sleep-wake cycle is controlled by nerve-signaling chemicals called neurotransmitters. Some neurotransmitters are associated with alertness and wakefulness, while others are linked to calmness and sleep.
The Emory team first tried activating Anna’s “awake” neurotransmitters by giving her powerful stimulants such as dextroamphetamine. “She continued to sleep through everything,” Parker said.
They weaned her off the drugs and conducted a spinal tap to analyze her cerebral spinal fluid. That led to the diagnosis of endozepine-induced recurrent stupor—a condition so rare that only thirty-one cases have been confirmed in the world. Endozepine is an enzyme associated with the gamma-aminobutyric acid receptor (GABA), one of the neurotransmitters that help settle the brain down for sleep.
The cause of endozepine-induced recurrent stupor is not clearly understood, and no treatment exists. Sufferers have no recourse but to sleep their lives away.
Parker researched medical literature for clues to help Anna. One possibility was a drug called flumazenil, a benzodiazepine antagonist that inhibits the activity of GABA. It is used to treat patients who have overdosed on benzodiazepine-derivative drugs, such as Valium, since it blocks the activity of GABA and keeps patients awake and breathing. The problem: flumazenil is approved only for the treatment of overdoses and must be administered intravenously.
In the face of enormous regulatory hurdles, Parker moved to get flumazenil approved for treating Anna. She worked with executives at Roche, the drug’s manufacturer, and the FDA to gain a compassionate-use exemption for a controlled experiment.
“I’ve got a beautiful, intelligent, thirty-two-year-old woman here who will sleep most of the rest of her days if we don’t do something,” Parker said, explaining her persistence.
In June, Anna entered Emory University Hospital for the experiment, conducted in the epilepsy ward in case she experienced seizures. Over two days, flumazenil was slowly titrated into Anna’s veins while her response times and other vital signs were monitored. When the dosage reached two milligrams, Anna came out of her stupor, sat up, and told the research team, “I feel alive!”
“I will never forget those words,” Parker said. “The anesthesiologist in the room broke out in tears. He said, ‘I sit all day behind a bench with rats and finally I get to see my work make a difference for someone.’ We were all crying, it was so thrilling.”
The next task for the team is to develop a form of flumazenil that Anna can take safely and conveniently. Enzymes in the stomach and liver destroy the active ingredients in the drug so it is not effective when swallowed. The team wants to create a sublingual tablet that will slowly release optimal amounts of the drug.
Anna’s case prompted the Emory Healthcare Sleep Program to reanalyze other samples of cerebral spinal fluid in its case files. “We have already found another case of endozepine-induced recurrent stupor,” said Parker, who suspects that less-severe cases of the syndrome may be more common than previously thought. “Anna’s case could be leading us on a whole new journey.”