Seizures, brain damage and brain development.

Abstract

Recent evidence suggests that hippocampal damage can be both the result of seizure activity and the cause of further chronic epilepsy. A review of current models of status epilepticus-induced brain damage reveals that excitotoxic mechanisms probably mediate the lesions in most brain regions. NMDA receptors appear to play a dominant role, although non-NMDA glutamate receptors are important in several specific neuronal populations. In the immature brain, a number of unique metabolic features determine a different set of vulnerabilities, resulting in a brain which is more resistant than the adult's to certain mechanisms of brain damage, but quite vulnerable to others. The inhibition of growth by severe seizure activity has implications for the developing brain that have not yet been fully explored. The mechanisms by which seizure-induced hippocampal lesions cause chronic epilepsy have been explored in several recent animal models. A rearrangement of hippocampal circuits may result from death of selected populations of inhibitory neurons, or from misdirected regeneration by excitatory neurons. It could lead to chronic epilepsy through loss of normal inhibition, through sprouting of new excitatory connections, through conservation of excitatory connections which in a healthy brain would be pruned during development, or through facilitation of kindling by one of these mechanisms. These recent results are beginning to reconcile the pathology seen in human hippocampi ablated for intractable epilepsy with that observed in experimental animals, and offer the promise of even greater advances in the future. They suggest a mechanism for Gower's dictum that "seizures beget seizures" and highlight the importance of the interneurons of the dentate gyrus in epileptogenesis.