Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy

Abstract

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for pediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with e developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers’ global impression, serum inflammatory markers, and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a “responder,” defined as ≥ 2 of: > 50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement, or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (p < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (p < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (p < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

A hyperthermic seizure unleashes a surge of spreading depolarizations in Scn1a-deficient mice

“…Maximal suppression was found when memantine was administered before the hyperthermia episode. This effect is consistent with a recent randomized placebo-controlled clinical trial in which chronic memantine treatment reduced seizure frequency in pediatric developmental epileptic encephalopathy (DEE) patients (66). The prolonged suppression of SD/seizure frequency by memantine administration seen in our study suggests that memantine may have a potential role in DEE therapy when carefully administered.…”

A hyperthermic seizure unleashes a surge of spreading depolarizations inScn1adeficient mice

“…Maximal suppression was found when memantine was administered before the hyperthermia episode. This effect is consistent with a recent randomized placebo-controlled clinical trial in which chronic memantine treatment reduced seizure frequency in pediatric DEE patients 61 . The prolonged suppression of SD/seizure frequency by memantine administration seen in our study suggests memantine may have a potential role in DEE therapy when carefully administered.…”

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

“…In our report, a favorable response to memantine treatment was not observed. Memantine may exert a beneficial effect on seizure control and cognitive function in patients with DEE, 58 in addition to its low to moderate N‐methyl‐D‐aspartate (NMDA) receptor antagonist activity which may explain the limited evidence of favorable response to memantine in patients with GoF GRIN2B variants observed in the previous reports 57,59 …”