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

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 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 h (acute phase), 15 days (silent period), and 30 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 > 0.1). Pilo-SE showed reduced dorsal-HVol and tNAA/tCr at all MRI-scans (all p < 0.001) when compared to controls. Intragroup analysis revealed that dorsal-HVol and tNAA/tCr significantly increased at 15- and 30-days (all p < 0.001) when compared to 48 h, although remaining lower than the baseline scan. There were no changes over time in sham-controls (all p > 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 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.