From Nonlesional to Localizable: Multimodal Postprocessing in MRI-Negative Focal Epilepsy—A Case Series of Five Patients

Background: Magnetic resonance imaging (MRI)-negative drug-resistant focal epilepsy (DRE) remains one of the most consequential bottlenecks in surgical epileptology, where absence of a visible lesion translates into diagnostic ambiguity and therapeutic inertia. Conventional visual analysis underutilizes the latent information embedded within structural and metabolic imaging. Objective: To determine whether integrative postprocessing across structural and metabolic domains can convert nonlesional data sets into actionable localization. Methods: Five patients with DRE and nonlesional epilepsy-protocol MRI underwent standardized presurgical evaluation (semiology, prolonged video-electroencephalography, interictal fluorodeoxyglucose-positron emission tomography [PET]). Structural MRI was interrogated using voxel-based and surface-based morphometry, hippocampal volumetry, and morphometric analysis of gray–white junction integrity. Metabolic imaging was processed using PaSCoM (PET asymmetry after anatomical symmetrization coregistered to MRI) with voxel-wise interhemispheric comparison, complemented by PET–MRI coregistration. Localization was defined by cross-modal convergence rather than any single modality. Results: Postprocessing converted all five cases from nonlesional to localizable. Structural analyses exposed subtle cortical or mesial temporal abnormalities in a subset, while PaSCoM consistently revealed sharply lateralized hypometabolic clusters with greater spatial specificity than visual PET. In cases with diffuse or bilateral abnormalities, asymmetry mapping isolated a dominant focal signature concordant with electroclinical data. Cross-modal integration yielded coherent, high-confidence localization in all patients. Resection in selected cases demonstrated focal cortical dysplasia on histopathology, with favorable seizure outcomes in concordant localizations. Conclusion: Multimodal postprocessing transforms MRI-negative epilepsy from an indeterminate category into a tractable surgical entity. The complementary yield of morphometric and asymmetry-based analyses provides decisive localization where conventional imaging fails. Systematic incorporation of these techniques should be considered essential in presurgical workflows, redefining thresholds for surgical candidacy and enabling confident, precision-targeted intervention in this historically challenging cohort. Publication History Article published online: 15 July 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Private Limited A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India