Abstracts

Rationale: The new antiepileptic medication Lacosamide (LCM) has been shown to be effective in various animal epilepsy models. Its efficacy is demonstrated in clinical trials for partial-onset seizures as adjunctive therapy. In contrast, there is only indirect evidence for efficacy in animal models of generalized epilepsy. To further explore the potential effects of LCM in rodents we completed a preliminary series of experiments utilizing an established animal model for symptomatic epilepsy, whereby a pro-epileptic substrate of multifocal cortical dysplasia is induced via in utero irradiation. Adult rats are known to exhibit seizures following a single subconvulsive dose of PTZ injection. Thus, we measured the effect of LCM on seizure activity provoked by a systemic PTZ injection in these animals. Methods: Following a standard protocol that has been developed and utilized in our laboratory, 13 Sprague-Dawley rats were divided into 4 experimental groups: 1)-XRT/-LCM (n=4); 2)-XRT/ LCM (n=4); 3) XRT/-LCM (n=2) ;4) XRT/ LCM (n=3). Five rats were irradiated with 145cGy in utero on E17 (XRT; first hit ).All rats were implanted with epidural electrodes on PND 55. On PND 60 rats were given a single dose of LCM (25mg/kg i.p.) 30 minutes before receiving a single subconvulsive dose (40 mg/kg s.c.) of pentylenetetrazol (PTZ; second hit ). Their behavior and EEG were monitored for a subsequent 8 hours. Seizure severity was assessed using a standard scale (Veliskova et al. 1989). Results: All control animals (-XRT/ LCM) had less severe seizures (Grade1 n=7; Grade 2 n=2) as compared to XRT animals. The two untreated irradiated animals ( XRT/-LCM) had severe generalized seizures (Grade 4). Treated irradiated animals ( XRT/ LCM) were observed to have less severe seizures (Grade 1, 2, 3, n=1 respectively). Interestingly the ictal EEG analyses showed that the frequency of spike wave complexes during generalized seizures was lower (~4-5Hz) in animals treated with LCM, as compared to untreated animals (~6-7Hz) regardless of XRT allocation. Conclusions: Treatment with LCM impedes acute generalized convulsive seizures induced by a 2nd hit in a rat model of in utero radiation induced cortical dysplasia. These experiments are ongoing. If confirmed, this preliminary data would suggest that LCM may be effective in some (symptomatic) generalized seizures. Comparisons with other sodium channel blockers (such as CBZ) are also under way in our laboratory.