Cause, Treatment Found for Excessive Sleepiness

Primary hypersomnia is defined by excessive daytime sleepiness in the absence of known causes of sleepiness.

An abnormal protein in cerebrospinal fluid appears to cause hypersomnia, a form of excessive daytime sleepiness, and an off-the-shelf drug effectively treated it, researchers said.

Extracted from patients with primary hypersomnia, the elusive substance, which was not fully isolated in the study, enhanced the sensitivity of subtype A gamma-aminobutyric acid (GABA) receptors, reported David Rye, MD, PhD, of Emory University in Atlanta, and colleagues.

Moreover, seven patients treated with a drug that inhibits GABA receptor signaling — flumazenil, currently approved as a benzodiazepine antidote — showed marked reductions in daytime sleepiness, the researchers reported online in Science Translational Medicine.

Rye and colleagues noted that flumazenil is not known to promote alertness or wakefulness in healthy controls. But in what they called the “unique population” of patients recruited for the study, the drug’s effects were clinically meaningful.

The only downside is that the currently approved drug must be given intravenously. But the researchers indicated that they had a solution to that problem as well.

Primary hypersomnia has been a diagnosis of exclusion — excessive daytime sleepiness and lethargy for which no specific cause can be identified. It is distinct from narcolepsy in that patients do not necessarily fall totally to sleep. Rather, they are more in a half-awake state, often reporting a subjective mental-fog sensation.

The authors suspected that GABAA receptors might play a role in the condition, because agents that increase their function are well known to promote sleep and even anesthesia. Moreover, previous studies have suggested that flumazenil improves alertness in a variety of pro-sleepiness conditions such as hepatic encephalopathy as well as simple sleep deprivation.

The evidence in primary hypersomnia, they wrote, “suggested to us a pathogenesis rooted in a naturally occurring excess in GABAergic signaling.”

For the current study, they recruited 32 patients diagnosed with primary hypersomnia. Cerebrospinal fluid (CSF) samples were taken from them and from a group of healthy controls.

In vitro experiments showed that, when exposed to GABA at 10 micromolar and CSF from the patients, GABAA receptor signaling was increased by 84 percent (SD 41 percent), compared with a stimulation of 36 percent (SD 8 percent) with controls’ CSF (P<0.0001). The researchers then identified the component in the patients' CSF responsible for the extra GABAA receptor stimulation as a substance with a molecular weight of 500 to 3,000 daltons. Rye and colleagues did not report further efforts to characterize the substance, except to say its activity at the receptors was abolished when treated with a protein-digesting enzyme. Another set of in vitro experiments showed that flumazenil blocked the GABAA receptor enhancement seen with the CSF from hypersomnia patients. Armed with these results, the researchers then administered IV flumazenil to seven patients. Alertness was evaluated with a psychomotor vigilance test, in which patients had to respond to a visual stimulus, with reaction time as the outcome measure. Patients also reported their own subjective assessments of their alertness. One patient was relatively unresponsive to the drug. But in the other six, lapses in attention fell nearly to zero after treatment and the slowest 10 percent of reaction times in the tests became significantly faster relative to baseline. Rye and colleagues recognized that an IV drug with a short half-life is not very practical for a chronic condition. Consequently, they said, they developed sublingual and transdermal formulations that they gave to one patient over a 4-year period. This patient was a 34-year-old woman with a 15-year history of sleeping an average of 12 hours nightly and still showing daytime sleepiness. The researchers said that, after 4 years of treatment with the novel flumazenil formulations, she was sleeping 8 to 10 hours nightly but reported awakening refreshed and with "marked" reduction in daytime symptoms. Studies in a sleep lab confirmed that, when the drug was withheld, signs of hypersomnia returned, and were abolished again when the treatment was restarted. By John Gever