Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

Abstract

Objective: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.

Methods: We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex.

Results: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging.

Significance: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

Keywords: cerebellum; limbic; magnetic resonance imaging; midbrain; sudden unexpected death in epilepsy.

Figure 1.

Regional gray matter volume loss in SUDEP compared with healthy controls, found in the bilateral cerebellum and vermis (A, B), PAG (B, C), the left medial and posterior thalamus (C), and the bilateral posterior cingulate (B). VBM contrast maps are overlaid onto a standard (MNI152) brain. The masks of segmented regions exhibiting reduced size in SUDEP

Figure 2.

Bar graphs showing group volume differences in the thalamus (A, B), exterior cerebellar gray matter (C, D), amygdala (E, F), parahippocampal gyrus (G, H), entorhinal cortex (I, J) and subcallosal cortex (K, L). ** = significant at p<0.05 (FDR) compared with low-risk and healthy controls. * = significant at p<0.05 (FDR) compared with healthy controls only.

Figure 3.

Regional volume increases in SUDEP compared with healthy controls, in the bilateral amygdala,entorhinal cortex, subcallosal cortex and parahippocampal gyrus (B, D and F). SPM contrast is overlaid in warm colours (red-yellow). Parcellation analyses (A, C, and E) show masks of segmented regions exhibiting increased size in SUDEP>HC (p<0.05, FDR) overlaid in solid colours.

Figure 4.

Correlations between brain volumes and disease duration across all epilepsy subjects (A, B) and time from MRI to SUDEP in SUDEP cases only (C, D, E, F). * = significant at p<0.05 (FDR corrected). Covariates were seizure frequency, age, sex and total intracranial volume (and disease duration for C-D).