Concept of activity-induced cell death in epilepsy: historical and contemporary perspectives

Selective neuronal loss following status epilepticus was first described just under 100 years ago. The acute pathology following status epilepticus was shown to be 'ischemic cell change' and was assumed to arise through hypoxia/ischemia. Less than 30 years ago it was proposed, from experiments in primates, that the selective neuronal loss in hippocampus and cortex resulted from the abnormal electrical discharges. Selectively vulnerable neurons show swollen, calcium-loaded mitochondria in the soma and focally in dendrites. Burst firing with a massive Ca2+ entry needs to be sustained for 30-120 min to produce necrotic cell death. Lesser stress may produce apoptosis or immediate early gene expression with enhanced expression of many enzymes and receptor subunits. Changes in enzyme, transporter, ion-channel or receptor function or in network properties may lead to altered vulnerability to the effects of seizures. This type of modification and the cumulative effect of oxidative damage to proteins and lipids may explain the long-term consequences of repetitive brief seizures.