Multidimensional Profiling of MRI‐Negative Temporal Lobe Epilepsy Uncovers Distinct Phenotypes

Objective Although hippocampal sclerosis (TLE-HS) represents the most frequent cause of temporal lobe epilepsy (TLE), up to 30% of patients show no lesion on visual MRI inspection (TLE-MRIneg). These cases pose diagnostic and therapeutic challenges and are underrepresented in surgical series. We investigated whether TLE-MRIneg constitutes a distinct clinical and neuroanatomical entity compared to TLE-HS and aimed to identify subtypes within the TLE-MRIneg group.Methods We analyzed MRI and clinical data from 209 patients with TLE and 102 healthy controls from the multicenter "3TLE project". Based on expert radiological review, 96 patients were classified as TLE-MRIneg and 76 as TLE-HS; the remaining 37 were excluded due to other focal lesions. We compared clinical characteristics and brain morphometry between TLE-MRIneg and TLE-HS and applied clustering techniques to detect TLE-MRIneg subtypes.Results Compared with TLE-HS, TLE-MRIneg was associated with later onset, shorter disease duration, and milder clinical presentation. TLE-HS patients exhibited widespread cortical and subcortical atrophy, while TLE-MRIneg showed only subtle cortical thinning. Cluster analysis revealed two subtypes of TLE-MRIneg: one characterized by ipsilateral amygdala enlargement (AE) and the other by diffuse cortical atrophy.Interpretation These findings demonstrate that TLE-MRIneg represents a distinct clinical-imaging entity from TLE-HS. The identification of morphologically defined subtypes, particularly AE, highlights the heterogeneity of TLE-MRIneg and its potential clinical relevance. This work supports the use of advanced imaging and data-driven methods to improve diagnosis and guide individualized management in non-lesional epilepsies.