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SUMMARYPurpose: In comparison to temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (TLE-HS), TLE patients without HS (TLE-NH) have a similar clinical course but may result in worse surgical outcome. We investigated whether the clinical features related to the lack of HS in TLE patients (TLE-NH) can be explained by water diffusion abnormalities throughout diffusion tensor imaging (DTI) by voxel-based analysis. Methods: Nineteen patients with TLE-HS (left/right TLE 12:7), 18 patients with TLE-NH (left/right TLE 10:8), and 20 controls were included in the study. By statistical parametric mapping (SPM2), the diffusion properties specific to disease characteristics (TLE-HS vs. TLE-NH) were analyzed. Results: In TLE-HS, we found the areas of increased mean diffusivity (MD) in their ipsilateral temporal and extratemporal areas including the hippocampus, parahippocampal, and frontoparietal regions. Left TLE-HS showed a characteristic MD increase in the ipsilateral posterior cingulum, isthmus of corpus callosum, and contralateral occipital and temporal regions, which was not observed in right TLE-HS group. In left TLE-NH, two regions of increased MD were observed in the ipsilateral posterior fornix (within fusiform gyrus) and posterior cingulum. Right TLE-NH did not show any increased MD. Discussion: In left TLE-NH, we could find the water diffusion change along the posterior cingulum, which was quite different from the extensive abnormality from TLE-HS. In addition, there was a lesion-side-specific distribution (left predominant) of pathology in mesial TLE. This provides a possibility that TLE-NH is a heterogenous or entity different from TLE-HS.