Evidence for a genetic effect in altered cortical surface area but not in cortical thinning in siblings of patients with mesial temporal lobe epilepsy: Commentary on: "Abnormal temporal lobe morphology in asymptomatic relatives of patients with hippocampal sclerosis: A replication study".

Abstract

Although studies have shown cortical and subcortical changes in first-degree relatives of patients with familial forms of temporal lobe epilepsy, few studies have addressed extrahippocampal morphology changes in unaffected siblings of patients with sporadic mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Alhusaini et al1 described subtle reduced cortical volumes in the anteromedial temporal cortex of asymptomatic siblings of sporadic MTLE-HS patients, suggesting that such localized traits are possibly heritable. In this issue of Epilepsia, Yaakub et al2 replicated these findings in first-degree asymptomatic relatives of patients with MTLE-HS.2 A positive history of simple febrile convulsions before the age of 4 years was present in two relatives in this study.2 Both these relatives had values above the median of the relative group for the reduced surface area in the anteromedial temporal cortex, further strengthening the possibility that these subtle morphological changes are inherited.2 Limitations of this study include the small number of subjects studied and that they side-flipped the images to increase power to detect differences, thus treating both hemispheres as if they were equal, which is not the case, as shown recently by Kong et al.3 The study by Alhusaini et al1 showed that the alterations of cortical morphology found in anteromedial regions of unaffected siblings of subjects with left MTLE-HS (more in the left entorhinal cortex and parahippocampal gyrus) differed from those found in unaffected siblings of subjects with right MTLE-HS (more in the right entorhinal cortex and temporal pole). It is of relevance that both studies1, 2 used FreeSurfer (http://surfer.nmr.mgh.harvard.edu), which measures cortical volume as a product of two distinct aspects of the cortical architecture: cortical thickness and surface area.4 Cortical thickness and surface area measurements appear to represent different early neurodevelopmental events with distinct genetic influences, as shown by Panizzon et al5 in a magnetic resonance imaging study of twins. They found that, although cortical thickness and surface area are both highly heritable (>0.80), they are mostly unrelated genetically (genetic correlation = 0.08).5 These results suggest some independence of these two surface-based measures, and potentially, their asymmetry patterns. A recent study that mapped cortical brain asymmetry in 17 141 healthy individuals showed regions with different asymmetrical patterns in cortical thickness and surface area and a significant heritability of these asymmetry characteristics.3 Effect sizes of cortical thickness and surface area were independent, and the asymmetry was generally more prominent for surface area compared with that of cortical thickness.3 Most regions showed significant asymmetry in surface area, although with no clear directional pattern affecting neighboring regions, or along the anterior-posterior axis, as they observed for cortical thickness.3 Widespread cerebral cortical thinning has been identified in patients with MTLE as compared to healthy controls within several cortical regions, including the mesiotemporal, limbic, and central sensorimotor cortices.6 This pattern of cortical thinning appeared progressive in patients with medically refractory epilepsy,6 but also to a lesser degree in MTLE patients under seizure control.7 Less attention has been paid to cortical surface area in studies of MTLE patients. Interestingly, both Alhusaini et al1 and Yaakub et al2 found reduced cortical surface areas in anteromedial temporal regions of asymptomatic siblings of sporadic MTLE-HS patients, but no significant changes in cortical thickness. This lack of cortical thickness changes has been confirmed in 127 asymptomatic first-degree relatives of MTLE-HS patients from three independent cohorts, each with a healthy control group.8 These findings altogether indicate that the previously characterized progressive cortical thinning in patients with MTLE-HS is not heritable and is likely driven by disease-related factors, whereas changes in the cortical surface area may represent an inherited trait that preceded seizure onset. This hypothesis needs to be confirmed in further studies with multiple large cohorts, also taking into account the asymmetric nature of cerebral hemispheres. The author has no conflict of interest to disclose. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.