Tract‐specific atrophy in focal epilepsy: Disease, genetics, or seizures?

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 (TLE) 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 subjects 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 magnetic resonance imaging (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 subjects 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 multifactorial model of white matter atrophy in focal epilepsy is proposed. Ann Neurol 2017;81:240–250