Therapeutic approaches to epileptogenesis--hope on the horizon

Abstract

Prevention of epileptogenesis is an unmet need in medicine. During the last 3 years, however, several preclinical studies have demonstrated remarkable favorable effects of novel treatments on genetic and acquired epileptogenesis. These include the use of immunosuppressants and treatments that modify cellular adhesion, proliferation, and/or plasticity. In addition, the use of antiepileptic drugs in rats with genetic epilepsy or proconvulsants in acquired epilepsy models has provided somewhat unexpected favorable effects. This review summarizes these studies, and introduces some caveats when interpreting the data. In particular, the effect of genetic background, the severity of epileptogenic insult, the method and duration of seizure monitoring, and size of animal population are discussed. Furthermore, a novel scheme for defining epileptogenesis-related terms is presented.

Figure 1

A schematic drawing showing the different outcomes after epileptogenic brain insults. The blue boxes on the right indicate the natural outcome. Green boxes show the possible treatment effects.

Figure 2

Partitioning of disease or syndrome modification into antiepileptogenesis, co-morbidity modification, and reversal of pathology. Antiepileptogenesis can be further divided into prevention, seizure modification, and cure. See the definitions of each term in Table 1. At the bottom of the page there are examples of the indicators for seizure modification and co-morbidity modification.

Figure 3

Variability in the severity of status epilepticus (SE). (A) A dot-plot demonstrating the variability in the severity of SE that was induced by electrical stimulation of the amygdala. The severity of SE (y-axis) in individual animals randomized to different treatments is shown as the number of epileptiform spikes per 24 h after the initiation of electrographic SE. Note the remarkable variability within each treatment group (Veh, vehicle; CBZ, carbamazepine; VPA, valproate; LEV, levetiracetam). (B) A bar graph showing the percentage of rats that developed epilepsy (number of animals is in parenthesis). When the severity of SE (number of spikes/24 h) was taken as a covariate, there was no difference between the treatment groups.