The effect of repeated seizures on anticonvulsant drug response in the kindling model

Clinical reports suggest that the occurrence of numerous seizures prior to the onset of anticonvulsant therapy is associated with a poor prognosis for drug control. This seems to imply that seizures become harder to suppress as they recur--a possibility which argues for the early initiation of anticonvulsant therapy. The present study attempted to determine whether this effect could be demonstrated under controlled laboratory conditions. The kindling preparation, an animal model involving the elicitation of repeated focal seizures, was used. Drug response (ED50) was measured in Royal Victoria hooded rats after either a small or a large number of pretreatment seizures, administered in the kindling paradigm. A variety of experiments were performed, involving: different drugs (phenobarbital, phenytoin, and carbamazepine), different seizure types (amygdala focal seizure, cortical focal seizure, generalized convulsion), and different stimulation parameters (0, 20, 40 or 100 pretreatment seizures: 'near-threshold' vs. 'standard' stimulation). In no case were seizures found to be harder to suppress following repeated pretreatment seizures. After large numbers of pretreatment seizures (40, 100), drug response was actually enhanced. These data indicate that the mere repetition of seizures does not automatically lead to a decrease in anticonvulsant effectiveness. They offer no particular rationale for the early initiation of anticonvulsant therapy in clinical situations.