Abstracts

Rationale: Excitotoxic injury involving N-methyl-D-aspartate (NMDA) receptor hyperactivity contributes to epilepsy-related memory dysfunction (ERMD). Current treatment strategies for ERMD have limited efficacy and fail to target the underlying pathophysiology. This pilot study evaluated the efficacy of memantine, an NMDA receptor antagonist, for treatment of ERMD in adults with focal-onset seizures. Methods: In this randomized, double-blind, parallel-group study, subjects underwent cognitive testing at baseline, after a 13 week blinded phase (of memantine titrated to 10mg bid or placebo), and following a 13 week open label extension period (of memantine titrated to 10mg bid). The Selective Reminding Test continuous long-term retrieval (CLTR) score and 7/24 Spatial Recall Test learning score served as the primary outcome measures. Secondary measures included assessments of attention span, fluency, visual construction, response inhibition, quality of life (QOL), depression, sleepiness, and side effects. Results: Twenty subjects completed the blinded phase (n=10 memantine, n=10 placebo). Mean age was 44.9 years (range 22-62) and 48.6 years (range 31-62) in the memantine and placebo groups, respectively. Educational level was similar across groups, with mean 16 years (range 11-20) in the memantine group and 15.6 years (range 12-20.5) in the placebo group. Mean duration of epilepsy was 15.9 years (range 0.8-41) in the memantine group and 20.0 years (0.9-42.7) in the placebo group. In the memantine group, seven subjects had left-sided seizure onset, one had bilateral independent onsets, and two had unknown lateralization. In the placebo group, six subjects had left-sided seizure onset, two had right-sided onset, and two had unknown lateralization. None of the group differences in primary or secondary outcome measures reached statistical significance (Table 1).At the end of the open label phase, pooled data from 10 subjects (initially randomized to memantine n=3 or placebo n=7) demonstrated statistically significant improvement from baseline in CLTR score, memory-related QOL, spatial span, and response inhibition (Table 2). No significant changes were evident in depression, sleepiness, side effects, or seizure frequency throughout the trial. Conclusions: Results demonstrated no significant effect of memantine on cognition when assessed at the end of the blinded period. Pooled data at the end of the open label phase showed significant improvement over baseline performance in measures of verbal memory, frontal-executive function, and memory-related QOL. These improvements, however, may be due to practice effects and should be interpreted cautiously. Findings suggest a favorable safety profile of memantine in the setting of epilepsy. Funding: This study was supported by a grant from the American Academy of Neurology and American Brain Foundation (BAL). This work was also supported in part by Career Development Award IK2 CX-001255-01 from the U.S. Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service (BAL).