The neurobiology of epilepsy

Abstract

Epilepsy is a complex disease with diverse clinical characteristics that preclude a singular mechanism. One way to gain insight into potential mechanisms is to reduce the features of epilepsy to its basic components: seizures, epileptogenesis, and the state of recurrent unprovoked seizures that defines epilepsy itself. A common way to explain seizures in a normal individual is that a disruption has occurred in the normal balance of excitation and inhibition. The fact that multiple mechanisms exist is not surprising given the varied ways the normal nervous system controls this balance. In contrast, understanding seizures in the brain of an individual with epilepsy is more difficult because seizures are typically superimposed on an altered nervous system. The different environment includes diverse changes, making mechanistic predictions a challenge. Understanding the mechanisms of seizures in an individual with epilepsy is also more complex than understanding the mechanisms of seizures in a normal individual because epilepsy is not necessarily a static condition but can continue to evolve over the lifespan. Using temporal lobe epilepsy as an example, it is clear that genes, developmental mechanisms, and neuronal plasticity play major roles in creating a state of underlying hyperexcitability. However, the critical control points for the emergence of chronic seizures in temporal lobe epilepsy, as well as their persistence, frequency, and severity, are questions that remain unresolved.

Figure 1

A timeline for epileptogenesis in temporal lobe epilepsy. Acquired epilepsy, using temporal lobe epilepsy as an example, can be simplified as three stages: an initial insult, followed by epileptogenesis, and ultimately ending in a state of recurrent, spontaneous seizures (epilepsy). The initial insult can take several forms and is followed by both rapid and slower progressive changes with rapid and slower durations. Rapid changes in animal models include neuronal excitation and calcium influx, triggering a cascade of events that include second messenger and immediate early gene responses, modifications to pre-existing proteins, and protein synthesis. Within days, there can be cell death and proliferation as well as inflammatory, glia, and vascular responses. Slower responses include growth (eg, axon outgrowth, synaptogenesis, angiogenesis), leading to synaptic reorganization, and this may in turn cause other changes. Over time, seizure threshold is lowered by a growing increase in excitability, and the risk of a seizure increases. These changes may be sufficient to cause epilepsy or may stall until a second “hit” occurs. The second hit could be environmental, or it could be due to time-dependent gene expression or co-morbidity. Therefore, genes, development, and the responses to the initial insult are likely to act together to result in a state of chronic seizures.