Treatment with antiseizure drug levetiracetam was well-tolerated and associated with improvements in spatial memory and executive function tasks in patients with Alzheimer disease (AD) and epileptiform activity, according to findings from a phase 2a placebo-controlled randomized trial published in JAMA Neurology.

Patients with AD and seizures or subclinical epileptiform activity tend to experience a faster decline in cognitive function. It’s not clear whether epileptiform activity is associated with cognitive worsening, but previous research has suggested that the use of antiseizure medications could be beneficial for this patient population. At low doses, levetiracetam has been found to be well-tolerated and successful at seizure reduction in patients with AD with seizure disorders.

The objective of the current study was to assess whether a low-dose treatment of levetiracetam can lead to a favorable response among patients with AD those with AD with epileptiform activity.


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The trial, dubbed Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study (NCT02002819), included 34 adult patients with AD (mean age, 62.3 years).

All patients in the study were required to present with a Mini-Mental State Examination score of  ≥18 points and/or a Clinical Dementia Rating score of <2 points. At screening, researchers performed overnight video electroencephalography as well as a 1-hour resting magnetoencephalography examination.

Patients randomized to group A (n=17) received placebo twice daily for a total of 4 weeks followed by a subsequent 4-week washout period and then 125 mg levetiracetam twice daily for 4 weeks. In group B (n=17), patients received the same treatment but in a reverse sequence.

Researchers assessed whether levetiracetam improved executive function, as measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) composite score. Additional secondary outcomes included improvements in cognition, as measured by the Stroop Color and Word Test (Stroop) interference naming subscale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, as well as disability.

Approximately 38.2% (n=13) of the overall cohort had epileptiform activity. The majority of the study population (82.4%; n=28) completed the study, including 10 (35.7%) with epileptiform activity.

Treatment with levetiracetam was not associated with a significant change in NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, −0.18-0.32 points; P =.55). There was also no change in improvements in cognition (Stroop interference naming, 2.9 points; 95% CI, −1.0-6.8; P =.14) or disability (Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory, 0.1 points; 95% CI, −1.1-1.3; P =.90).

In the subgroup of patients with epileptiform activity, treatment with levetiracetam was associated with improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P =.046) as well as the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P =.02). No treatment discontinuations due to adverse events were reported in the overall cohort.

Study limitations included its small sample size as well as the “lack of correction for multiple comparisons in the exploratory analysis,” which may have led to the generation of false-positive results as well as possible subgroup confounders, the researchers noted.

They concluded that their “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.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.

Reference

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



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