Abstracts

Rationale: Humans with TLE are more likely to have focal seizures than status epilepticus (SE). Focal seizures are rapid, repetitive, and brief (? 5 minute) seizures that may or may not affect consciousness. In contrast, SE is a prolonged generalized seizures lasting more than 15 minutes. To gain a greater understanding of the damage following seizures that do not progress to SE, we infused a low dose of kainic acid (KA) to test, a) the extent of hippocampal damage from short duration seizures, b) the progression of cell loss over time, c) the relationship between behavioral manifestations of seizures and cell loss, and d) the functional consequences. Methods: Eight week old male Sprague-Dawley rats were implanted with cannula in the lateral ventricle at the anterior tip of the dorsal hippocampus. After two weeks of recovery, KA (0.55 g in 4.4 L saline) or saline were infused into the lateral ventricle. Seizures were coded for 3 hr using the modified Racine scale. Ketamine (100 mg/kg) was injected to stop all seizures after 3 hours. Subjects were euthanized at 1, 3 or 7 days after seizures. Coronal sections were stained for Nissl. Cell layer length and neuropil volume were measured with MCID.Results: Whereas prolonged generalized seizures (SE) produce complete cell loss in the CA3 subregion of the hippocampus, animals that had only brief seizures ranging from wet dog shakes to brief generalized seizures had highly variable amounts of cell loss in CA3. The amount of cell loss after 7 days was significantly correlated with the number of generalized seizures (p= .05). Cell loss increased from 1 to 7 days with relatively little loss seen after 1 day, and significantly more loss seen after day 7. At day 7, neuropil volume and working memory were unaffected despite the significant loss of cells.Conclusions: The behavioral manifestation of generalized seizures may be a useful predictor of cell loss, which occurs slowly over one week. The timing of cell loss is consistent with the possibility of apoptotic or autophagic pathways for cell death. Cell loss occurs without initial effects on neuropil volume. This uncoupling is consistent with clinical reports that volume loss occurs months, but not weeks after seizures. Just what maintains volume is unclear, but includes proliferation of glial cells. The progression of cell loss over time suggests that this model provides a window of time in which to test behavioral and pharmaceutical interventions aimed at sparing damaged cells.