Primary and secondary mechanisms of epileptogenesis in the temporal lobe: there is a before and an after

Abstract

Extensive data involving several animal models of temporal lobe epilepsy highlight synaptic alterations that likely act synergistically during acquired epileptogenesis. Most of this research has utilized experimental models in which intense electrical activity in adult animals, primarily involving status epilepticus, causes variable neuronal death in the hippocampus and other temporal lobe structures. Neuronal death, including principal cells and specific interneurons, likely has several roles in epileptogenesis after brain injury. Both reduction of GABA-mediated inhibition from selective interneuron loss and the progressive formation of new recurrent excitatory circuits after death of principal neurons enhance excitability and promote seizures during the development of epilepsy. These epileptogenic circuits hypothetically continue to undergo secondary epileptogenesis, which involves further modifications that contribute to a progressive, albeit variable, increase in the frequency and severity of spontaneous recurrent seizures.

FIGURE 1

Loss of interneurons and decreased GABAergic inhibition in the hippocampus during epileptogenesis. Schematic diagram showing hippocampal CA1 pyramidal cells and interneurons before (A) and after (B) epileptogenesis has occurred. The diagrams illustrate the hypothesis that the hippocampus either from the brain of a patient or from an animal model of temporal lobe epilepsy loses specific, but not all, interneurons.

FIGURE 2

Axon sprouting and increased recurrent excitation in the hippocampus during epileptogenesis. The diagram shows glutamatergic pyramidal cells (e.g., CA1 area of the hippocampus) before (A) and after (B) epileptogenesis. The diagrams illustrate the hypothesis that although recurrent excitation is normally present among some pyramidal cells before epileptogenesis, recurrent excitation increases during epileptogenesis (B).

FIGURE 3

Step-function and continuous-function hypotheses of the time course of epileptogenesis. (A) A hypothetical graph illustrates the step-function hypothesis, involving two discrete states. The first state is a seizure-free period, which follows immediately after the initial brain insult (i.e., the latent period, when the process of epileptogenesis occurs and the brain does not experience spontaneous recurrent seizures). The second state is a period during which spontaneous recurrent seizures occur (i.e., epileptogenesis is mature). In the step-function hypothesis, the mechanisms responsible for generation of spontaneous recurrent seizures (i.e., epileptogenesis) are essentially complete by the time the first seizure has occurred. In this hypothesis, seizure rate abruptly reaches a steady state but may be variable, once reached. (B) A hypothetical graph illustrates the continuous-function hypothesis, which is consistent with but does not prove secondary epileptogenesis. In the continuous-function hypothesis, seizure frequency or probability continuously increases after a brain insult, until a steady state is achieved.