Limited sex-specific structural alterations across common epilepsies: A worldwide ENIGMA study

Epilepsy is characterized by widespread cortical and subcortical structural alterations beyond the epileptic zone. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy are seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. We therefore tested whether epilepsy-related structural alterations differ between males and females, and whether the associations between structural measures and clinical characteristics vary by sex.

We analyzed clinician-assigned biological sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multicenter cohort of 1253 epilepsy patients and 1077 healthy controls. We studied cortical thickness and subcortical volume in temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE).

Both male and female patients with TLE showed widespread cortical and subcortical alterations in sex-stratified analyses, whereas GGE showed more extensive alterations in female patients and only subtle alterations in male patients. However, no significant sex-by-diagnosis interactions were identified in either the TLE (t = -2.153 to 1.705, all p_FDR >.05) or GGE (t = -1.797 to 2.774, all p_FDR >.05) cohort. Likewise, no significant interactions were found between sex and age at onset (t_TLE = -1.835 to 1.092, t_GGE = -2.394 to 1.392, all p_FDR >.05) or disease duration (t_TLE = -2.643 to 2.048, t_GGE = -1.234 to 2.017, all p_FDR >.05) in either patient group.

Overall, although sex differences in behavioral and clinical outcomes of epilepsy have been consistently reported in previous studies, our results indicate that sex-related clinical differences in epilepsy are not strongly captured by macroscale structural magnetic resonance imaging measures, and may instead arise from hormonal, neurochemical, or functional-network mechanisms.