NASHVILLE, Tennessee ― Targeting relevant sleep problems for patients with refractory temporal lobe epilepsy (TLE) improves cognition, results of a new, double-blind, randomized controlled trial suggested.
Study findings show significant improvement in REM sleep and language scores for patients with TLE who took the cholinesterase inhibitor donepezil and better slow-wave sleep and memory scores for those who took the sleep aid zolpidem.
The results are “intriguing and surprising” and should encourage clinicians to “look for sleep abnormalities” in patients with uncontrolled epilepsy, study investigator Garima Shukla, MBBS, MD, DM, professor, Division of Neurology, Department of Medicine, Queens University, Kingston , Ontario, Canada, told Medscape Medical News.
Daytime sleepiness could be a red flag in these patients, although it could mean they just have treatable sleep apnea, said Shukla. “But if they have very poor slow-wave sleep, we could try increasing its percentage by prescribing zolpidem.”
The findings were presented here at the American Epilepsy Society (AES) 2022 Annual Meeting.
Sleep, Cognitive Disturbances Common
Sleep disturbances and cognitive disturbances are common among patients with TLE. Executive function is affected in almost all patients with refractory epilepsy, and it’s “super common” that TLE patients have memory disturbances, Shukla said.
The study included 108 patients with refractory TLE who were awaiting surgery. The patients, who had no severe comorbidities, were randomly assigned to three groups; the final number in each group was 36.
Patients in group 1 received donepezil 10 mg in the morning and a placebo at night. (Donepezil is used to treat memory loss associated with Alzheimer’s disease.)
Those in group 2 received a placebo in the morning and zolpidem 6.25 mg at night. Group 3 patients received a placebo in the morning and again at night.
The mean age of the patients was 25.4, 27.1, and 27.6 years, and the percentage of men was 63.8%, 72.2%, and 63.8% in groups 1, 2, and 3, respectively.
In all groups, patients had been experiencing about three seizures per month. The median number of antiseizure medications were two in group 1 and three in both groups 2 and 3.
Researchers evaluated sleep using the Pittsburgh Sleep Quality Index, the Epsworth Sleepiness Scale, and video polysomnography and electroencephalography.
To assess executive function, they used the Trail A & B, Stroop, and forward and backward Digit Span tests. For memory, they used the Weschler Memory Scale, and for language, the Western Aphasia Battery. They conducted follow-up evaluations at 6 months.
The results showed significant improvement in the percentage of rapid eye movement (REM) sleep in group 1 (from 14.81 at baseline to 18.21 at 6 months). In this group, the number of patients whose REM sleep percentage was less than 15 dropped significantly—from 29 (of 36) to 10.
In group 2, sleep onset latency significantly improved, and the percentage of N3 (slow-wave) sleep stage increased significantly — from 25.27 to 28.74.
Regarding cognitive outcomes, backward Digit Span was significantly improved for patients in group 1. In this group, there was also a significant reduction in the time taken for the Stroop A test, and there was significant improvement in language.
In group 2, there was a significant improvement in verbal and visual memory scores. There were no significant changes in group 3.
The increase in REM sleep percentage in group 1 strongly correlated with increased language and executive function scores. Similarly, in group 2, the increase in N3 sleep score strongly correlated with an increase in verbal memory scores.
On the basis of these observations, giving a small dose of zolpidem to a patient with “acceptable” REM sleep but very little slow-wave sleep may boost the patient’s non-REM sleep, Shukla said. “By improving non-REM sleep percentage, we will possibly help memory consolidation.”
Shukla sees this study as “a stepping-stone” to larger, multicenter trials testing “the effect of zolpidem through its impact on improving non-REM sleep percentage consolidation and its impact on memory.”
This idea is somewhat different from the traditional idea that REM sleep plays a greater role in memory consolidation, she said. “We actually found it correlates very well with language, which we have also seen in some of our anecdotal case reports.”
Patients whose language scores are very poor are “the population I would pick to target REM sleep through donepezil,” said Shukla.
Commenting for medical News, Daniel Goldenholz, MD, PhD, assistant professor, Harvard Beth Israel Deaconess Medical Center, praised the study design.
“It allows for comparison between different treatments, as well as a placebo control group,” said Goldenholz, who added, “There appears to be good follow-up” as well.
The fact that medication may provide some cognitive benefit for patients with TLE is “very encouraging,” he said.
He noted many patients with TLE complain of memory or language problems. So, this is a major concern.
However, he is careful about side effects. “Putting all temporal-lobe epilepsy patients who say that they have memory problems or language problems on these medications could have some serious consequences.”
The study was funded by a Department of Health Research grant from the government of India. Goldenholz is on the advisory board for epilepsy AI, Eyzs and Magic Leap.
American Epilepsy Society (AES) 2022 Annual Meeting: Abstract 1.229. Presented December 3, 2022.
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