Summary Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that over-activity in selective hippocampal circuits contributes to cognitive impairment. Here we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.

Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures.Methods: This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (Ն12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration. Results:Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was Ϫ21.0%, Ϫ26.3%, and Ϫ34.5% for placebo and perampanel 8 and 12 mg, respectively (p ϭ 0.0261 and p ϭ 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p ϭ 0.0760) or 12 mg (p ϭ 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia. Conclusions:This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable. Classification of evidence:This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures. Neurology ® 2012;79:589-596 GLOSSARY AE ϭ adverse event; AED ϭ antiepileptic drug; AMPA ϭ ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; ANCOVA ϭ analysis of covariance; CGIC ϭ Clinical Global Impression of Change; CI ϭ confidence interval; EU ϭ European Union; ITT ϭ intent-to-treat; PGIC ϭ Patient Global Impression of Change; QOLIE-31-P ϭ Quality of Life in Epilepsy questionnaire; SAE ϭ serious adverse event; TEAE ϭ treatment-emergent adverse event.Perampanel is an orally active, noncompetitive ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist under development for the treatment of epilepsy. AMPA receptors, a class of ionotropic glutamate receptors, are localized at excitatory synapses in the CNS where they serve as the principal mediators of fast excitatory postsynaptic neurotransmission and are critical to the generation and spread of epileptic activity.

This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

SUMMARYPurpose: To assess the efficacy and safety of once-daily doses of perampanel 8 and 12 mg when added to 1-3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: Study 305 was a multicenter, double-blind, placebo-controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1-3 AEDs. Equal randomization to once-daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19-week double-blind treatment phase comprising a 6-week titration period, with weekly 2-mg dose increments, followed by a 13-week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ‡50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre-perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty-six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent-to-treat analysis) was )9.7%, )30.5%, and )17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was )32.7% (8 mg), )21.9 (12 mg), and )8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ‡10% of patients in any treatment group) treatment-emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once-daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial-onset seizures. These study results also demonstrated that once-daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.

Rufinamide was an effective and well-tolerated treatment for seizures associated with Lennox-Gastaut syndrome.