RATIONALE AND OBJECTIVES: To evaluate the diagnostic relevance of ipsilateral atrophy of the collateral white matter in the parahippocampal gyrus (ACWMp) and temporal lobe gray/white matter demarcation loss (GWDL) on magnetic resonance imaging in patients with histologically confirmed hippocampal sclerosis. In the second part of this investigation, histologic specimens were analyzed to find an explanation for GWDL. METHODS: Retrospective visual assessment of hippocampal signal intensity and size and of ACWMp and GWDL was performed using 4- to 5-mm coronal T2-weighted spin-echo magnetic resonance images of 80 patients with histologically proven hippocampal sclerosis and of 30 age-matched controls without epilepsy. Frequency of occurrence and likelihood ratios of ACWMp and GWDL were calculated and their contribution to the diagnosis of hippocampal sclerosis was assessed, particularly in patients with no or restricted hippocampal abnormalities (either high signal or smaller size) on magnetic resonance imaging. The second part of the study involved the morphologic histologic assessment of neocortical temporal lobe specimens of all patients. Myelin density was evaluated in specimens of a subgroup of six patients with hippocampal sclerosis and GWDL on MRI and six patients with hippocampal sclerosis without GWDL. RESULTS: ACWMp was found in 68% and GWDL in 65% of patients with hippocampal sclerosis on magnetic resonance imaging. Both features had an infinite positive likelihood ratio. Sixty-two patients (77.5%) had concomitant hippocampal signal increase and smaller size. Eighteen patients (22.5%) had no or restricted hippocampal abnormalities on magnetic resonance imaging. When using ACWMp and GWDL as additional diagnostic parameters, 13 of these 18 patients were more unambiguously diagnosed as having hippocampal sclerosis. No significant morphologic differences were found between GWDL-positive and GWDL-negative specimens. A significantly lower average myelin stain was found in the white matter of the GWDL-positive group compared to the GWDL-negative group. CONCLUSIONS: ACWMp and GWDL can improve the visual diagnosis of hippocampal sclerosis, particularly in patients with no or restricted hippocampal abnormalities. These results suggest that loss of myelin may be the underlying cause of GWDL in association with hippocampal sclerosis.