Histopathology of Human Epilepsy

Histopathologic lesions associated with seizures are found in a variety of disease conditions. The histopathology of temporal lobe epilepsy (TLE) is the most extensively investigated. In TLE with hippocampal sclerosis, several lines of evidence implicate the hippocampus as the predominant focus of seizure origin and maintenance In sclerotic hippocampi, two major pathological processes are observed. (1) The reorganization of the neural circuitry of the dentate gyrus that favors the hyperexcitability of dentate granule cells. These changes include the loss of populations of subgranular hilar interneurons, hilar mossy cells and granule cells. Additionally there is sprouting of granule cell mossy fiber recurrent collaterals into the dentate inner molecular layer and the sprouting of neuropeptide Y, somatostatin and substance P containing axons throughout the molecular layer. (2) The second process consists of glial activation and proliferation throughout Ammon’s horn along with neuronal loss. These astrocytes show a number of changes -- increased expression of specific glutamate receptors, redistribution of the water transporter AQP4, increased expression of Na⁺ and Ca²⁺ ion channels with down regulation of the Kir4.1 channels. The enzymes glutamine synthetase and lactate dehydrogenase are reduced whereas a number of molecules associated with immune function are upregulated. The density of the microvasculature is increased. The “astrocytes” associated with these changes may be subcategorized into two populations -- the strongly GFAP positive astrocytes and weakly GFAP reactive cells, which resemble the GluR astrocytes also known as NG2 cells. The functions of these two subpopulations may favor the creation of a high extracellular glutamate and K+ containing environment in the sclerotic hippocampus, which in turn may trigger seizure spread through a fairly normal subiculum. These changes may even provide an excitable substrate through which the hyperexcitability of dentate granule cells may spread out of the hippocampus to generate seizures.