Tract-specific atrophy in focal epilepsy: disease, genetics or seizures?

Abstract

OBJECTIVE: To investigate whether genetics, underlying pathology or repeated seizures contribute to atrophy in specific white matter tracts. METHODS: Medically-refractory unilateral temporal lobe epilepsy with hippocampal sclerosis (HS-TLE, n=26) was studied as an archetype of focal epilepsy, using fixel-based analysis of diffusion-weighted imaging. A genetic effect was assessed in first-degree relatives of HS-TLE who did not have epilepsy themselves (HS-1°Rel; n=26). The role of disease process was uncovered by comparing HS-TLE to unilateral TLE with normal clinical MRI (MRI-neg TLE; n=26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS-TLE and MRI-neg TLE, in comparison to healthy controls (n=76). RESULTS: HS-1°Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS-TLE had lateralized atrophy of most temporal lobe tracts, and hippocampal volumes in HS-TLE correlated with parahippocampal cingulum and anterior commissure atrophy, indicating an effect of the underlying pathology. Ipsilateral atrophy of the tapetum, uncinate and inferior fronto-occipital fasciculus was found in both HS-TLE and MRI-neg TLE, suggesting a common lateralized effect of focal seizures. Both epilepsy groups had bilateral atrophy of the dorsal cingulum and corpus callosum fibers, which we interpret as a consequence of bilateral insults (potentially generalized seizures and/or medications). INTERPRETATION: Underlying pathology, repeated focal seizures and global insults each contribute to atrophy in specific tracts. Genetic factors make less of a contribution in this cohort. A multi-factorial model of white matter atrophy in focal epilepsy is proposed.