Despite more than 20 clinically approved
antiepileptic drugs (AEDs), there remains a substantial unmet clinical need for patients with refractory (AED-resistant)
epilepsy. Animal models of
refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory
seizures. It is only incompletely understood why two patients with seemingly identical types of
epilepsy and
seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we previously evaluated whether epileptic rats respond differently to AEDs and discovered AED responsive and resistant animals in the same models. In the present study, we used the same approach for the widely used intrahippocampal
kainate mouse model of mesial
temporal lobe epilepsy. In a first step, we examined anti-seizure effects of 6 AEDs on spontaneous recurrent focal electrographic
seizures and secondarily generalized convulsive
seizures in epileptic mice, showing that the focal nonconvulsive
seizures were resistant to
carbamazepine and
phenytoin, whereas
valproate and
levetiracetam exerted moderate and
phenobarbital and
diazepam marked anti-seizure effects. All AEDs seemed to suppress generalized convulsive
seizures. Next we investigated the inter-individual variation in the anti-seizure effects of these AEDs and, in case of
focal seizures, found responders and nonresponders to all AEDs except
carbamazepine. Most nonresponders were resistant to more than one AED. Our data further validate the intrahippocampal
kainate mouse model as a model of difficult-to-treat
focal seizures that can be used to investigate the determinants of AED efficacy.