Histopathology-validated recommendations for cortical lesion imaging in multiple sclerosis

Abstract

Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.

Keywords: cortical lesions; double inversion recovery; multiple sclerosis; phase-sensitive inversion recovery; post-mortem imaging.

Figure 1

Overview of methods. (A) Five coronally cut brain slices were obtained as part of the Amsterdam MS Center rapid autopsy protocol, which were scanned simultaneously in a custom-made brain-slice holder. (B) Acquired pulse-sequences were 2D-T₁-weighted and 2D-PD/T₂-weighted, 3D-FLAIR, 3D-DIR and 2D-PSIR (shown). (C and D) Tissue samples are obtained based on a standardized protocol aided by MRI guided tissue dissection. (E) MRI scans were prospectively scored for cortical lesions, blinded to histopathology. (F) Subsequently, histopathological validation was performed using myelin-staining followed by a retrospective, unblinded, scoring for cortical lesions and sensitivity and specificity measures were calculated.

Figure 2

Representative example of MRI sequences evaluated for a specific patient. (A) Photo of scanned brain slice. (B) T₁-weighted MRI. (C) PD/T₂-weighted MRI. (D) FLAIR image. (E) DIR image. (F) PSIR image.

Figure 3

Three examples of cortical lesions visible on DIR and PSIR, but not on other sequences. (A) MRI overview of a DIR scanned brain slice from which a tissue block (yellow box) was processed. (B) Histopathological section of the processed tissue block stained for myelin, in which a type IV lesion is indicated by the black arrowhead and bordered by the black line; the dotted line indicates the cortex. (C–G) Excerpts of, respectively, DIR, PSIR, FLAIR, T₁ and PD/T₂ scans. The type IV lesion is indicated by the red arrowhead on DIR (C) and PSIR (D). (H) MRI overview of a DIR scanned brain slice from which a tissue block (yellow box) was processed. (I) Histopathological section of the processed tissue block stained for myelin, in which a type III lesion is indicated by the black arrowhead and bordered by the black line; the dotted line indicates the cortex. (J–N) excerpts of, respectively, DIR, PSIR, FLAIR, T₁ and PD/T₂ scans. The type III lesion is indicated by the red arrowhead on DIR (J) and PSIR (K). (O) MRI overview of a DIR scanned brain slice from which a tissue block (yellow box) was processed. (P) Histopathological section of the tissue block stained for myelin, in which a type I lesion is visible. The lesion is indicated by the black arrowhead and bordered by the black line; the dotted line indicates the cortex. (Q–U) Excerpts of, respectively, DIR, PSIR, FLAIR, T₁ and PD/T₂ scans. The type I lesion is indicated by the red arrowhead on DIR (Q) and PSIR (R).