Levetiracetam May Improve Cognition in Patients With Alzheimer Disease and Epileptiform Activity

Keith Vossel, MD, MSc

Findings from the phase 2a Alzheimer’s Disease-Associated Network Hyperexcitability (LEV-AD) clinical trial (NCT02002819) showed that treatment with levetiracetam did not improve cognition in patients with Alzheimer disease (AD); however, a subset of those who had AD with epileptiform activity demonstrated improved performance on tasks of spatial memory and executive function.

Lead author Keith Vossel, MD, MSc, director, Mary S. Easton Center for Alzheimer’s Disease Research, University of California, Los Angeles, and colleagues evaluated whether levetiracetam could improve executive function in 34 patients with AD using the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) composite score as primary analysis.

Patients were randomly assigned to 2 different treatment groups with study visits that occurred between October 16, 2014, and July 21, 2020. Those in group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then levetiracetam 125 mg twice daily for 4 weeks. Participants assigned to group B received this treatment sequence in reverse order.

In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. At the conclusion of the study, overall cognitive performance did not differ on the NIH-EXAMINER (mean score difference, 0.07 points [95% CI, –0.18 to 0.32 points]; P = .55) between those who received levetiracetam vs placebo. Additionally, no differences were observed on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog; mean score difference, –1.0 points [95% CI, –3.4 to 1.5 points]; P = .43), or the Stroop interference naming scale (mean score difference, 2.9 points [95% CI, –1.0 to 6.8 points]; P = .14).

READ MORE: Fenfluramine Continues to Show Meaningful Seizure Reduction in Lennox-Gastaut Syndrome

However, in a subset of levetiracetam-treated patients with epileptiform activity (n = 9), improvements on the Stroop interference naming subscale (net performance vs placebo, 7.4 points [95% CI, 0.2-14.7 points]; F = 5.54; Cohen f = 0.83; P = .046) were observed, compared with no change in performance for the 13 participants without epileptiform activity (net difference vs placebo, –0.3 points [95% CI, –4.5 to 3.9 points; P = .88 [P = .04 vs participants with epileptiform activity]).

"These findings could lead to future personalized approaches to AD, in which patients with the epileptic variant of AD will receive different treatments than those without the epileptic variant," Vossel et al concluded. "The implications are substantial when considering that an estimated 60% or more of patients with AD experience seizures and subclinical epileptiform activity."

Investigators also observed improvements in learning rates on the virtual route learning test among those with epileptiform activity (n = 5; t = 2.36; Cohen f2= 0.11; P = .02) compared with those without epileptiform activity (n = 7; t = 0.04; P = .97). Additionally, levetiracetam-treated patients with epileptiform activity showed net improvements in accuracy on the virtual route learning test (improvement vs placebo, 17.4 correct turns [95% CI, –0.6 to 34.4 correct turns]; P = .03).

While patients without epileptiform activity demonstrated no improvement on NIH-EXAMINER, most participants (6 of 8 [75%]) with epileptiform activity showed improved scores (Cohen f = 0.72) after treatment with levetiracetam. Additionally, most patients (7 of 9 [77.8%]) in this subset also experienced improvements on ADAS-Cog (Cohen f = 0.39); however, investigators deemed that the P values for these group comparisons were not significant.

Vossel et al also evaluated the impact of levetiracetam on cognitive measures in participants with early-onset AD (n = 20; symptom onset at age <65 years). In this subset, treatment with levetiracetam only improved scores on Stroop interference naming subscale (net improvement, 4.0 points [95% CI, 0-7.9 points]; F = 4.41; Cohen f = 0.48; P = .049).

No participants discontinued the trial due to adverse events (AEs). In total, 21.2% and 18.8% of those in the levetiracetam and placebo groups experienced mild AEs, respectively. Patients treated with the study drug also did not report changes in performance on the Neuropsychiatric Inventory, indicating no measurable effects on mood.

"Future AD clinical trials would benefit from including neurophysiological assessments whenever possible and adding antiseizure drugs when epileptic or epileptiform activity is detected," the study authors concluded.

REFERENCE

Vossel K, Ranasinghe KG, Beagle AJ, et al. Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity. JAMA Neurol. Published online September 27, 2021. doi:10.1001/jamaneurol.2021.3310