Abstracts

Rationale: SGTCS arise from partial seizures and engage widespread cortical and subcortical networks. Generalization presents as a loss of consciousness plus vegetative and motor manifestations involving the entire body. A number of AEDs, including levetiracetam (LEV), lacosamide (LCM), lamotrigine (LTG), and carbamazepine (CBZ), are approved for the treatment of partial seizures with or without SGTCS. PER is a non-competitive AMPA receptor antagonist approved for adjunctive treatment of partial seizures, with or without SG seizures, and primary generalized tonic-clonic seizures. In Phase III trials, adjunctive PER conferred greater seizure control than placebo in patients with SG seizures (Steinhoff et al. Epilepsia 2013;54:1481–1489). Here, we investigate the effect of PER compared with common-use AEDs on SGTCS. Methods: On Day 1, male Wistar-Kyoto rats (n=50) received gradually increasing levels of electrical stimulation of the basolateral amygdala until the after-discharge threshold (ADT) was reached. The rats then received daily stimulation at their ADT until three Racine score 5 seizures occurred consecutively. PER (0.2–1.5 mg/kg), LEV (6.25–100 mg/kg), LCM (7.5–30 mg/kg), LTG (5–20 mg/kg), CBZ (3.75–30 mg/kg), or vehicle were administered intraperitoneally. Their effects were assessed by measuring seizure score, duration of Racine score 4/5 (S4/5D; duration of generalized seizure), and score 4 latency (S4L; an index of generalization rate) with stimulation at either the ADT or three times the ADT (3xADT). Results: Compared with vehicle, PER, LEV, LCM, LTG, and CBZ significantly reduced seizure score (P < 0.05) with stimulation at the ADT; LEV and LTG lost this effect with stimulation at 3xADT (Table). Only PER (1.5 mg/kg) reduced seizure score to 1.8 at the ADT and 2.1 at 3xADT, indicating a potent effect regardless of stimulation intensity (Table). A significant effect (P < 0.05 compared with vehicle) was observed in S4/5D reduction for 1.5 mg/kg PER at both the ADT and 3xADT (reduced to < 30%) and 30 mg/kg CBZ at 3xADT (reduced to < 50%) (Table). PER significantly and dose-dependently increased S4L with stimulation at both the ADT (0.4–0.75 mg/kg, doses ineffective for seizure reduction) and 3xADT (0.75–1.5 mg/kg) (P < 0.05 compared with vehicle) (Table). LEV (25 and 100 mg/kg) and LTG (20 mg/kg) only showed this effect with stimulation at the ADT (P < 0.05 compared with vehicle), whereas LCM and CBZ did not significantly increase S4L at any dose tested (Table). Conclusions: In a rat amygdala kindling model, only PER was effective in all three parameters of SG seizures regardless of stimulation intensity. PER significantly reduced seizure severity and SG seizure duration, and increased latency to SG seizures at doses that were suboptimal for reducing seizure severity. These results may suggest that AMPA receptor antagonists are more effective than common-use AEDs in preventing SG seizures and that AMPA receptors play an important role in secondary generalization. Funding: Eisai Co., Ltd.