Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

REVIEWS

Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

Ethan M.Goldberg and Douglas A.Coulter

Abstract | Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause. The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis. Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge. Recent work has yielded important conceptual advances in this field. We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction.

Dravet syndrome

Previously referred to as severe myoclonic epilepsy of infancy, Dravet syndrome is a spectrum of severe infantile-onset epileptic encephalopathy that is due to an underlying genetic cause, most commonly mutation of the voltage-gated sodium channel subunitNa 1.1. Typically, infants are initially normal, then develop febrile and afebrile seizures, progressing to myoclonus and multiple seizure types, and cognitive impairment.

Epilepsy (BOX1) is a common end point of many forms of acquired brain pathology (such as tumours, infection, stroke and traumatic brain injury). Epilepsy can also be the result of the mutation of a single gene (genetic epilepsy), and it can be one component of a neurodevelop-mental disorder. The most common epilepsy syndrome in adults mesial temporal lobe epilepsy (TLE; see

BOX2) is typically considered to be an acquired disorder, resulting from injury to a previously normal brain. However, there are also familial (presumed genetic) forms of TLE. Although usually applied to the acquired epilepsies, the concept of epileptogenesis might also be relevant to the genetic epilepsies. An anti-epileptogenic intervention could be used in the context of a broader neurodevelopmental abnormality that includes epilepsy if an underlying defect could be identified and modulated before seizures began. Conversely, there could be potentially modifiable genetic contributions to what are classically considered to be acquired epilepsies, including TLE14. For example, an individual might have a genetic predisposition to risk factors for epilepsy, such as status epilepticus or hippocampal sclerosis, which in turn drive epileptogenesis.

In this Review, rather than attempting to provide a broad overview of epileptogenesis, we restrict our...