Brain Hypertrophy in Patients With Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis and Its Clinical Correlates

Abstract

Background and objectives: Mesial temporal lobe epilepsy (mTLE) is generally associated with focal brain atrophy, but little knowledge exists on possible disease-related hypertrophy of brain structures. We hypothesized that repeated seizures or adaptive plasticity may lead to focal brain hypertrophy and aimed to investigate associated clinical correlates.

Methods: In this cohort study, we included patients with mTLE undergoing detailed epilepsy evaluations and matched healthy volunteers (HVs) from 2 tertiary centers (discovery and validation cohorts). We assessed areas of brain hypertrophy and their clinical correlates using whole-brain voxel-based or surface-based morphometry (VBM, SBM), subcortical volumetry, and shape analysis of T1-weighted MRI data by fitting linear models. We evaluated the functional implications of the findings on memory encoding using fMRI.

Results: We included 135 patients with mTLE with neuropathology-confirmed hippocampal sclerosis (77 left, 58 right; 82 women; mean age 37 ± 11 years) and 47 HVs (29 women, mean age 36 ± 11 years) in the discovery cohort. VBM detected increased gray matter volume of the contralateral amygdala in patients with both left (t = 8.7, p < 0.001) and right (t = 7.9, p < 0.001) mTLE. We confirmed the larger volume of the contralateral amygdala using volumetry (left mTLE 1.74 ± 0.16 mL vs HVs 1.64 ± 0.11, p < 0.001; right mTLE 1.79 ± 0.18 mL vs HVs 1.70 ± 0.11, p = 0.002) and shape analysis (left mTLE p ≤ 0.005; right mTLE p = 0.006). We validated the hypertrophy of the contralateral amygdala in the validation cohort (mTLE, n = 18, 1.91 ± 0.20 mL; HVs, n = 18, 1.75 ± 0.13; p = 0.009). In left mTLE, contralateral amygdala hypertrophy was associated with poorer verbal memory and, in right mTLE, with more frequent focal-to-bilateral tonic-clonic seizures. A larger volume of the contralateral amygdala correlated with increased functional activation of the right parietal memory encoding network in a subgroup (44/135 patients with mTLE, 26/47 HVs) receiving fMRI.

Discussion: Unilateral mTLE due to hippocampal sclerosis is associated with hypertrophy of the contralateral amygdala. This may represent plasticity to compensate for verbal memory deficits or may be the consequence of seizure spread to the contralateral hemisphere.

Figure 1. Morphological Analyses of Atrophy and Hypertrophy in mTLE

Panel A shows changes in gray matter volume assessed using voxel-based morphometry. The location of the coronal slices is displayed on a 3D brain model (bottom right). Panel B shows changes in cortical thickness. Panel C shows subregional morphological changes of the hippocampus and amygdala assessed using surface shape analysis. Atrophy is displayed using the yellow-red color scheme, and hypertrophy is shown in blue. All results were thresholded at p < 0.05 on a cluster level after correction for multiple testing.

Figure 2. Volumetry of the Amygdala

The figure shows amygdala volumes in left mTLE (blue), HVs (gray), and right mTLE (orange). Vertical lines represent standard deviations. HVs = healthy volunteers; mTLE = mesial temporal lobe epilepsy.

Figure 3. Association of Amygdala Hypertrophy With Altered Activation of Memory Networks

This figure displays the correlation between volume of the contralateral amygdala and fMRI memory encoding activation in the right superior parietal lobe obtained using a verbal encoding task. FMRI results are reported at a p < 0.05 on a cluster level corrected for multiple testing using family-wise error correction.