Phenytoin and carbamazepine, alone and in combination: anticonvulsant and neurotoxic effects.

Comedication with phenytoin and carbamazepine is frequently used in patients with refractory seizures, although the benefit of this strategy has not been established. To assess whether the combination is a rational anticonvulsant treatment, we determined the therapeutic index (toxicity:efficacy ratio) for the drugs, alone and together, in mice, The individual agents were virtually identical in anticonvulsant and neurotoxic activity, and combined use had no additional therapeutic advantage. Analysis of drug concentrations in brain showed an additive pharmacodynamic interaction for phenytoin and carbamazepine, indicating that the combination is unlikely to be superior to either drug alone. Thus, we find no experimental justification for the simultaneous use of phenytoin and carbamazepine in the treatment of epilepsy.

Kindling with rapidly recurring hippocampal seizures.

Bipolar electrodes, stereotactically implanted in the hippocampus of adult rats, were used to deliver 10 s trains of suprathreshold tetanic electrical stimuli every few minutes. As indices of seizure intensity, durations of the afterdischarges triggered by these stimuli were measured, and the accompanying behaviors were scored on a 5-point scale. After 2-3 h, prolonged afterdischarges appeared in conjunction with severe limbic seizures, separated by periods of approximately 60 min. After 3-9 h, the stimulation was withheld until the following day. Upon reinstitution of the stimuli, intense seizures were seen at the onset, and the cycle time between them was shortened. Enhanced responsiveness to a fixed stimulus persisted for several months, the longest period tested. In addition, the enhanced epileptogenicity showed transference and was not stimulus-specific. These studies, using stimuli with low intertrain frequency and short interstimulus intervals, establish a robust and rapidly-developing model of epileptogenesis in the hippocampus that is comparable to traditional kindling.

Functional mapping of limbic seizures originating in the hippocampus: a combined 2-deoxyglucose and electrophysiologic study.

The pathways by which seizures spread from the hippocampus were studied both with multiple electroencephalographic recordings and 2-deoxyglucose autoradiography. The rapid kindling model described in the previous report was employed to compare mild versus severe limbic seizures. Seizures were accompanied by an increased glucose utilization in localized brain areas. The transition from mild to severe limbic seizures involved a greater spatial extent of paroxysmal electroencephalographic activity and metabolic signals. However, electrical recordings proved more sensitive in mapping seizures, as regions shown to be involved in mild or severe limbic seizures with electrical recordings did not necessarily show an increased glucose metabolism. Three types of circuits are important in dissemination of these seizures: interhippocampal connections, pathways leading out of the hippocampus to other limbic regions, and connections to certain extralimbic areas. The nucleus accumbens, amygdala, and substantia nigra emerge as important relay points in the spread of hippocampal-based seizures.