Abstracts

Rationale: Clinical trials have demonstrated the efficacy of lacosamide (LCM) in focal seizures. With the exception of some indirect evidence from animal models of generalized epilepsies little is known about LCM s effect on generalized seizures. We sought to examine the effect of LCM in an established animal model of symptomatic generalized seizures, and compare it to that of levetiracetam (LEV) a medication with a distinctly different mechanism of action that shows clear efficacy in generalized epilepsies.Methods: We used a two-hit model, in which a pro-epileptic substrate of multifocal cortical dysplasia is first induced via in utero irradiation. Adult rats are known to exhibit seizures following a subsequent single, subconvulsive dose of (pentylenetetrazol) PTZ injection. Cortical dysplasia was induced in utero using 145cGy of irradiation (XRT) on E17 pregnant rats (XRT: first-hit ). After PND-55 we divided the experimental animals into two groups that had (+XRT) or had not (-XRT) received irradiation in utero. All rats were implanted with 5 epidural electrodes: one reference above the frontal sinus, and 2 in the frontal and the parietal bones bilaterally. Rats were allowed 72 hours to recover from surgery before commencing video-EEG monitoring. Rats were observed for baseline EEG and then treated with LCM, LEV or Placebo. +LCM or +LEV rats were given a single i.p. dose of LCM 25mg/kg or LEV 60mg/kg. Placebo (PBO) rats received saline. Thirty minutes later, all rats received a single sub-convulsive dosage of PTZ 40 mg/kg i.p. (PTZ: second-hit ). Their behavior and EEG were monitored for 24 hours. Seizure severity was assessed using a standard scale (Veliskova et al., 1990), which divides PTZ-induced seizures into those having minimal versus major manifestations.Results: We enrolled a total of 50 animals, of which 4 died prior to video-EEG monitoring. Remaining rats were divided in the following 6 groups: +XRT+LCM n=10; +XRT+LEV n=5; +XRT/+PBO n=9; -XRT+LCM n=8; -XRT+LEV n=3; -XRT+PBO n=11. Control (non-irradiated) animals had less severe seizures, as compared to XRT animals. Almost all of the untreated (PBO) irradiated animals exhibited major seizures associated with loss of righting ability. On the other hand, irradiated animals that had received LCM or LEV, only exhibited minimal seizures without losing their righting ability and without progressing to generalized tonic-clonic seizures. Myoclonic seizures were seen in both LCM and LEV pre-treated groups although the frequency of these seizures appeared lower in LEV+ animals.Conclusions: Treatment with LCM impedes acute generalized convulsive seizures induced by a second-hit in a rat model of in utero radiation induced cortical dysplasia. Both LCM and LEV eliminated progression into GTC seizures. LEV may be more effective in eliminating myoclonic seizures in this model. This data suggests that LCM may have a role in the treatment of some (symptomatic) generalized seizures. Comparisons with different doses and other medications with different seizure-suppressing mechanisms are warranted.