Data synthesis and analysis.

The meta-analysis for progressive hippocampal atrophy was conducted using the Metafor toolbox¹¹ implemented in R (version 3.2.2; R-project.org), after unbiased estimates of correlation coefficients were obtained to account for its moderate negative bias. We opted for random effects models to account for potential between-study heterogeneity, and fitted meta-regression models to assess (1) effects of epilepsy duration on the hippocampus ipsilateral to the seizure focus, (2) effects of epilepsy duration on the contralateral hippocampus, (3) effects of seizure estimates on the ipsilateral hippocampus, and (4) effects of seizure estimates on the contralateral hippocampus. We also assessed equivalent mixed-effect models with volumetric technique (automated vs manual) as a categorical moderator.

Inspection of funnel plots and Galbraith plots, together with regression tests relating effect size to sample size, addressed small sample and publication bias. The I² metric was implemented to quantify residual heterogeneity.

We excluded duplicate publications and performed 3 sensitivity analyses, which included only one type of study at a time from a given research group, i.e., the first study, the last study, or the one with the largest sample size.

For the narrative synthesis on whole brain progression, we summarized evidence from previous studies employing voxel-based morphometry, volumetry, cortical thickness mapping, and surface shape analyses. We counted reports of progressive structural changes in patients within the following regional categories, similar to a previous review on whole brain voxel-based morphometric studies¹²: (1) mesiotemporal, (2) extramesiotemporal, (3) extratemporal, (4) subcortical. Progression was considered as detected in the presence of (1) significant correlations between MRI markers and seizure estimates or epilepsy duration and (2) pertaining to either ipsilateral or contralateral regions of interest. For volumetric studies already included in the meta-analysis on hippocampal findings, the focus was limited to structures other than the hippocampus.