Dynamic structural and metabolic changes during the epileptogenesis in the pilocarpine model of temporal lobe epilepsy: A longitudinal MRI study.

Abstract

PURPOSE: We aimed to evaluate longitudinal structural and metabolic changes after induced status epilepticus (SE) in the pilocarpine model of TLE, over the three phases of epileptogenesis. METHODS: We analyzed 48 male eight-week-old Wistar rats assigned to sham-control and SE-induced groups. T2-weighted images and 1H-MR spectra were acquired using a 3&#xa0;T MRI clinical scanner (Philips Achieva) equipped with an animal coil. We measured hippocampal volumes (dorsal-HVol) and total N-acetylaspartate ratios to total creatine (tNAA/tCr) in four points in time (MRI-scan): baseline (before pilocarpine or sham treatments), 48&#xa0;h (acute phase), 15&#xa0;days (silent period), and 30&#xa0;days (beginning of the chronic phase) after experimental treatment. To test differences in dorsal-HVol and hippocampal tNAA/tCr we built generalized linear mixed effects models including groups (pilo-SE and control) and MRI-scan as main effects and a group*MRI-scan interaction. RESULTS: Pilo-SE and control animals showed similar baseline dorsal-HVol and hippocampal tNAA/tCr (both p&#xa0;>&#xa0;0.1). Pilo-SE showed reduced dorsal-HVol and tNAA/tCr at all MRI-scans (all p&#xa0;<&#xa0;0.001) when compared to controls. Intragroup analysis revealed that dorsal-HVol and tNAA/tCr significantly increased at 15- and 30-days (all p&#xa0;<&#xa0;0.001) when compared to 48&#xa0;h, although remaining lower than the baseline scan. There were no changes over time in sham-controls (all p&#xa0;>&#xa0;0.4). CONCLUSIONS: The novelty of our study was to analyze non-invasively structural and metabolic markers of hippocampal dysfunction across the three main phases of pilocarpine-induced epileptogenesis in comparison to the typical brain development over the same period. Acute dorsal hippocampal volume loss and hippocampal neuronal dysfunction are present as early as 48&#xa0;h post-pilocarpine-induced SE, dynamically changing over time. This acute damage is followed by a pattern of gradual recovery throughout the silent and chronic phases of epileptogenesis, though with an offset for the pilo-SE group. A better understanding of the course of noninvasive markers of epileptogenesis and HS may contribute to stablish surrogate endpoints in interventions to treat or prevent focal epilepsy.