Subtle Hippocampal Subfield Volumetric Alterations in Clinically Diagnosed MRI-Negative Temporal Lobe Epilepsy

Approximately 20-30% of temporal lobe epilepsy (TLE) cases present with no visible abnormalities on conventional magnetic resonance imaging (MRI). When interictal electroencephalography (EEG) recordings are also persistently normal, the diagnosis and lateralization become major clinical challenges. We aimed to investigate whether automated hippocampal subfield volumetry could detect subtle structural alterations in these "electro-clinically silent" MRI-negative cases and to correlate these findings with seizure semiology.

We analyzed 24 patients with clinically diagnosed MRI-negative/EEG-negative TLE and 26 age-matched healthy controls. Despite normal visual inspection on 1.5-T MRI, hippocampal subfield volumes were extracted using an automated segmentation pipeline (volBrain). Seizure semiology was systematically categorized to provide clinical-anatomical correlation.

TLE patients exhibited a significant and selective volume reduction in the right CA4-dentate gyrus (CA4-DG) subfield compared to healthy controls (p=0.003), even after adjusting for age, sex, and total intracranial volume (p=0.002). No statistically significant differences were observed in other hippocampal subfields (CA1, CA2/3, or subiculum), indicating a highly localized pattern of structural alteration.

These results imply that selective CA4-DG atrophy is a defining characteristic of the MRI-negative TLE phenotype, thereby corroborating the "dentate gate" failure hypothesis. Quantitative volumetry provides a crucial diagnostic tool in settings with limited resources, where advanced techniques like 3-T MRI or invasive monitoring are not accessible. This objective structural marker, when integrated with comprehensive semiological analysis, improves diagnostic accuracy and facilitates early clinical intervention in difficult non-lesional TLE cases.