Mechanisms of epilepsy progression: current theories and perspectives from neuroplasticity in adulthood and development.

Clinical and epidemiological studies have repeatedly demonstrated that a subset of patients with epilepsy have progressive syndromes with increasing seizure frequency and cumulative adverse effects despite optimal anticonvulsant therapy. Recent longitudinal imaging studies and long-term neuropsychological studies have confirmed that a substantial subset of people with epilepsy undergo progressive brain atrophy accompanied by functional declines that worsen with duration of epilepsy. As further evidence of the progressive and adverse effects of inadequately controlled epilepsy, chronic experimental models of epilepsy and the phenomenon of kindling have provided abundant evidence that neural circuits undergo long-term progressive structural and functional alterations in response to seizures. This long-term seizure-induced plasticity in neural circuits appears to be "bidirectional", inducing progressive damage while also inducing resistance to additional damage, as a function of timing or inter-seizure interval. Seizure-induced plasticity has pronounced age-dependence, and influences long-term cognitive consequences of seizures during early life and acquired susceptibility to epilepsy in adulthood. While it is clear from clinical and epidemiological studies that human epilepsy is a heterogeneous disorder and that not all epileptic syndromes are progressive, emerging results from studies of activity-dependent and seizure-induced plasticity and perspectives from "complex systems" analysis are providing new insights into systematic neurobiological processes that are likely to influence the progressive features of epileptic syndromes and patterns of progression in individual patients. The emerging perspective is that phenomena of plasticity and genetic background exert powerful effects in development and adulthood through regulation of activity-dependent structural and functional remodeling of neural circuitry, and that these effects not only influence progression and consequences of seizures, but also offer new opportunities for therapeutic intervention.