THE PATHOGENIC AND PROGRESSIVE FEATURES OF CHRONIC HUMAN HIPPOCAMPAL EPILEPSY

To design useful experimental models of epilepsy, it is necessary to c learly understand the known clinical-pathologic features of the diseas e process. Studies of mesial temporal lobe epilepsy (MTLE) patients ha ve identified several distinctive clinical and pathophysiologic charac teristics and many of these can be analyzed in experimental models. Fo r example, patients with typical MTLE have medical histories that ofte n contain an initial precipitating injury (IPI), are likely to have hi ppocampal sclerosis in the surgical specimen, and have better seizure outcomes than patients with atypical idiopathic temporal seizures (i.e . cryptogenic). Hippocampi from children as young as age 1 year with I PI histories also demonstrate neuron damage similar to adults with hip pocampal sclerosis. Compared to LPI patients without seizures (i.e. tr auma, hypoxia, etc.), IPI cases with severe seizures showed younger ag es at the IPI, shorter latent periods, and longer durations of habitua l MTLE. Hippocampal damage is often bilateral, however, the epileptoge nic side shows hippocampal sclerosis and the opposite side usually sho ws only mild neuron losses. Moreover, MTLE patients show declines in h ippocampal neuron densities with very long histories of habitual seizu res (15 to 20 years), however, the additional neuron loss adds to the template of hippocampal sclerosis and occurs in limited subfields (gra nule cells, CA1 and prosubiculum). Hippocampal axon and synaptic reorg anization is another pathologic feature of MTLE, and involves granule cell messy fibers and axons immunoreactive for neuropeptide Y, somatos tatin, and glutamate decarboxylase (which synthesizes GABA). Finally, MTLE patients with hippocampal sclerosis show increased granule cell m RNA levels for brain derived neurotrophic factor, nerve growth factor, and neurotrophin-3 that correlate with messy fiber sprouting or with declines in Ammon's horn neuron densities. Taken together, our data su pport the following concepts: (1) The pathogenesis of MTLE is associat ed with IPI histories that probably injure the hippocampus at some tim e prior to habitual seizure onsets, (2) most of the damage seems to oc cur with the IPI, (3) there can be additional neuron loss associated w ith long seizure histories, (4) another pathologic feature of MTLE is axon reorganization of surviving fascia dentata and hippocampal neuron s, and (5) reorganized axon circuits probably contribute to seizure ge nesis or propagation.