Abstracts

Rationale: Hippocampal sclerosis (HS) is the most common pathology finding for drug-resistant temporal lobe epilepsy (TLE) and is characterized by neuronal loss and gliotic Cornu Ammonis. Nearly 20% of the surgical specimens obtained from drug-resistant TLE surgery patients contain “normal” populations of neurons yet still benefit from their surgical resection, possibly pointing to a neuropathological explanation for the epileptogenic focus present in the resected tissue that is not able to be detected through standard diagnostic practices. Currently, it is not clear if no-HS represents a subtype of HS, precedes the characteristically observed pyramidal neuron loss, or if no-HS is a distinct disease entity from HS. If no-HS represents a distinct disease entity, some degree of difference should be observed in clinical and/or pathological investigations, particularly in regions overlooked during routine clinical examination (e.g. the dentate gyrus; DG). We will characterize the morphological and genomic features of the hippocampal DG in TLE patients and investigate the underlying epileptogenic mechanisms.

Methods: In this study, 21 TLE surgical resection cases were examined, including 14 HS and 7 no-HS cases, to investigate morphometry of the DG. Information on histopathological diagnosis and post-operative outcome were included in a clinicopathological correlation database. The digital image analysis software QuPath was used to perform cell detection analysis on the DG. Measures including Delaunay mean and cell density were analyzed. Eighteen TLE, including 10 HS and 8 no-HS, surgical resection cases were selected for gene expression profiling using the NanoString Neuroinflammatory and Glial Profiling panels.

Results: HS patients show a significant increase in granule cell (GC) spacing and decrease in GC density within the DG compared to no-HS patients. Regardless of the histological diagnosis, patients that achieved seizure freedom post-operatively demonstrated an increase in granule cell spacing and decrease in granule cell density in comparison to those that did not achieve seizure freedom post-operatively. We have observed disease-dependent differentially expressed genes, including C1R, C1S, SERPING1, C4A/B, and differentially expressed cellular pathways within the DG, including cell migration, apoptosis, and neurogenesis.

Conclusions: HS and no-HS diagnosis groups have distinct DG morphometry and gene expression profile, possibly indicating distinct disease entities.

Funding: Epilepsy Research Program of the Ontario Brain Institute (QZ); Lawson’s Internal Research Fund Studentship (CT); Ontario Graduate Scholarship (CT)