Animal Models of Drug‐Resistant Epilepsy

It is not known why and how epilepsy becomes drug resistant in 20-30% of patients, while other patients with seemingly identical seizure types can achieve control of seizures with medication. An animal model of epilepsy allowing selection of pharmacoresistant and pharmacosensitive subgroups of animals would be a valuable tool to study mechanisms of pharmacoresistance and to develop more effective treatment strategies. Only a few models are available which mimic patterns of drug resistance in humans with epilepsy. One model seems to be particularly interesting: amygdala-kindled rats. In this model in Wistar rats, animals which do not respond to repeated or chronic administration of anti-epileptic drugs (non-responders) can be separated from animals in whom anti-epileptics are effective (responders). Hence, pharmacoresistant subgroups of kindled rats provide a unique tool to study why seizures become intractable, particularly because pathophysiological processes in these resistant rats can be directly compared with those of kindled rats that respond to treatment. By using this model, we have recently shown that both the individual genetic background and kindling-induced processes determine whether a rat becomes a responder or a non-responder to anticonvulsant treatment after kindling. We are currently studying the cellular mechanisms underlying the development of drug-resistant kindled seizures.