In this issue of Neurology, a cross-sectional study by Fuerst et al. 1 and case studies by Schulz and Ebner2 and Briellmann et al. 3 address a controversy unresolved after more than 100 years: Are hippocampal sclerosis and brain damage a cause or effect of seizures? The question is important because patients with epilepsy not only have seizures, but face the possibility that recurring seizures damage the brain and cause progressive decline in cognition and quality of life.

Epidemiologic studies indicate that many cases of epilepsy have a favorable long-term outcome, and both animal and human studies demonstrate that damage is most obvious after intense or continuous seizures (status epilepticus). Thus, physicians have generally reassured patients that brief seizures (typically lasting 2 minutes) probably have minimal or no long-term effects. This reassurance has been challenged by recent studies in animal models, 4-6 which have shown that repeated brief seizures induce neuronal loss and cumulatively produce a pattern of hippocampal damage and cognitive decline like that in drug-refractory patients. Concern about progressive seizure-induced damage is supported by highresolution imaging studies of patients with intractable temporal lobe epilepsy, which have demonstrated progressive hippocampal volume loss that correlates with hippocampal sclerosis, 7 and neuropsychological studies revealing cumulative cognitive dysfunction increasing with the duration of poorly controlled epilepsy. 8 It has been anticipated that serial MRI examinations, with the capability to detect evolving hippocampal atrophy, would provide an opportunity to address the long-standing question of whether hippocampal sclerosis is a cause or an effect of repeated seizures.