Kindling in humans: Does secondary epileptogenesis occur?

The relevance of secondary epileptogenesis for human epilepsy remains a controversial subject decades after it was first described in animal models. Whether or not a previously normal brain region can become independently epileptogenic through a kindling-like process has not, and cannot, be definitely proven in humans. Rather than reliance on direct experimental evidence, attempts to answering this question must depend on observational data. In this review, observations based largely upon contemporary surgical series will advance the case for secondary epileptogenesis in humans. As will be argued, hypothalamic hamartoma-related epilepsy provides the strongest case for this process; all the stages of secondary epileptogenesis can be observed. Hippocampal sclerosis (HS) is another pathology where the question of secondary epileptogenesis frequently arises, and observations from bitemporal and dual pathology series are explored. The verdict here is far more difficult to reach, in large part because of the scarcity of longitudinal cohorts; moreover, recent experimental data have challenged the claim that HS is acquired consequent to recurrent seizures. Synaptic plasticity more than seizure-induced neuronal injury is the likely mechanism of secondary epileptogenesis. Postoperative running-down phenomenon provides the best evidence that a kindling-like process occurs in some patients, evidenced by its reversal. Finally, a network perspective of secondary epileptogenesis is considered, as well as the possible role for subcortical surgical interventions.