Widespread, depth-dependent microstructural damage in the cortex of children with drug resistant focal epilepsy: A quantitative T1 and T2 mapping study

Our current understanding of focal epilepsy is evolving as increasing evidence suggests that tissue abnormalities may extend beyond the focus. In adults, widespread structural changes remote from the epileptic focus have been demonstrated with MRI, predominantly using morphological markers. However, the underlying pathophysiology of these changes is unclear, and it is not known whether these result from ongoing disease processes or treatment-related side-effects, or whether they emerge earlier. Few studies have focused on children, who typically have shorter disease duration. Fewer still have utilised quantitative MRI, which may provide a more sensitive and interpretable measure of tissue microstructural changes. In this study, we aimed to determine if there were common spatial modes of changes in cortical architecture in children with drug-resistant focal epilepsy, and secondarily if changes were related to disease severity. To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 89 children - 43 with drug-resistant focal epilepsy [age-range=4-18 years] and 46 healthy controls [age-range=2-18 years]. We assessed depth-dependent qT1 and qT2 values across the cortex, as well as their gradient of change across cortical depths. As a post-hoc analysis, we determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically-defined abnormalities (MRI-positive) and healthy controls, and tested if this could classify patients without reported radiological abnormalities (MRI-negative). We detected depth-dependent qT1 and qT2 increases in widespread cortical areas, likely representing loss of structure such as altered cortical stratification, gliosis, myelin and iron alterations, oedema-associated increases in free-water, or a combination of these. Changes did not correlate with disease severity measures, suggesting they may appear during cerebral development and represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 62% at 100% specificity on held-out MRI-negative patients and controls. Our findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically-identified abnormalities, and possibly evident at a pre-symptomatic disease stage. ### Competing Interest Statement The authors have declared no competing interest.