Purpose: Extratemporal epilepsy often coincides with cognitive decline, which may be associated with hippocampal dysfunction. Severe hippocampal sclerosis can be detected with conventional neuroimaging in some patients with chronic extrahippocampal epilepsy (so-called dual pathology). However, subtle structural hippocampal changes may already develop at a much earlier phase, and in a larger number of patients. Our goal was to longitudinally characterize the development of bilateral hippocampal pathology in an experimental neocortical focal epilepsy model. Methods: Focal unilateral neocortical epilepsy was induced by microinjection of tetanus toxin in the primary motor cortex in adult male Sprague-Dawley rats. Another group of age-matched rats served as controls. In both groups, structural magnetic resonance imaging (MRI) was performed at 1, 3, 7, and 10 weeks of follow-up. Bilateral hippocampi were outlined and macroscopically analyzed using a state-of-the-art point-based morphometry model. Hippocampal microstructural changes at the end of follow-up, 10 weeks after epilepsy induction, were assessed with postmortem standard cresyl-violet, Fluoro-Jade, proteolipid protein 1, vimentin, glial fibrillary acidic protein, and ionized calcium binding adaptor molecule 1 stainings. Key Findings: All rats in the injected group developed seizures. The ipsilateral hippocampal volume was on average 8.76 (mean) +/- 3.32% (standard deviation) smaller in the epileptic animals as compared to controls (p = 0.01) during the 10 weeks of follow-up. The contralateral hippocampus showed a similar reduction of 8.49 (mean) +/- 3.27% (standard deviation) in total volume (p = 0.02). Clear hippocampal shape differences were found between the two groups. The most affected areas after epilepsy induction were the bilateral dorso-mediorostral, dorsolateral, and ventrolateral areas of the hippocampi. Normal developmental shape changes of the hippocampus, as detected in control rats, were largely absent in the ipsilateral hippocampus of epileptic rats. Quantitative histologic analysis revealed significant neuronal loss in the hippocampus, most pronounced in the hilar subregion, globally impaired myelination, reactive astrocytosis, and activated microglia. We found a weak but significant correlation between the number of neurons and hippocampal volume (r = 0.25, p = 0.0025). Significance: We found evidence of hippocampal pathology in both hemispheres following experimental focal neocortical epilepsy. The observed development of bilateral hippocampal pathology, with onset in the early stages of focal neocortical epilepsy, may be a significant factor in comorbidities, such as cognitive dysfunction, found in patients with extratemporal localization-related epilepsy.
