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.

New Prospects for Ultra-High-Field Magnetic Resonance Imaging in Multiple Sclerosis

“…Cortical MS lesions are notoriously difficult to visualize, likely due to their small dimension, lower baseline myelination of the cortex, low-inflammatory phenotype, and partial volume effects with CSF. 80 At 3 T, a recent postmortem study showed that fewer than a quarter of histopathologically confirmed cortical lesions could be depicted in T2w fluid-attenuated inversion recovery (T2-FLAIR), DIR, or PSIR sequences, 62 and these rates are likely much lower in the clinical setting. Observations from postmortem studies suggest that UHF imaging enhances sensitivity for cortical lesion detection up to approximately 30% to 40%, depending on the lesion type 14 , 81 (Table 1 ).…”

Imaging cortical multiple sclerosis lesions with ultra-high field MRI

“…Phase sensitive inversion recovery (PSIR) imaging uses phase-sensitive reconstruction along with a T1weighted sequence to increase the range of signal intensities, which seems to improve detection of cortical lesions at 3T compared to DIR imaging (Sethi et al 2013;Sethi et al 2012). However, superiority of PSIR over DIR was not confirmed in recent post-mortem work using immunohistochemical stains (Bouman et al 2020). Very recently, a susceptibility-weighted image contrast that utilizes signal inversion (IR-SWIET) has been proposed as another promising avenue for cortical lesion visualization at 3T (Beck et al 2020).…”

“…Despite these efforts, prospective sensitivity remains poor at 3T (18-23% for DIR in post-mortem studies including histological validation (Seewann et al 2012;Bouman et al 2020)). Using multiple sequences for lesion segmentation increases lesion detection rates (Nelson et al 2008;Maranzano et al 2016), but further improvements for the in vivo depiction of cortical lesions are still warranted in order to accelerate correct diagnosis and management of the MS spectrum.…”

“…In one of the first studies comparing multiple sequences at 7T, de Graaf et al (2012) found no difference in cortical lesion detection between 7T FLAIR and 7T DIR, although the DIR sequence has been shown to be superior at 3T (Bouman et al 2020;Nelson et al 2007). However, in an expanded cohort, FLAIR detected 89% more (primarily type I) cortical lesions than DIR at 7T (Kilsdonk et al 2013).…”

“…WHAT T1w (Bluestein, Pitt, Sammet, et al 2012b;Saranathan et al 2015), is a promising tool for improving detection of especially type I lesions (Bluestein, Pitt, Sammet, et al 2012b). More recently, PSIR, popular for visualization of cortical lesions at 3T (Bouman et al 2020), has been adapted to 7T by including a null point image (NPI) into the MP2RAGE sequence (Mougin et al 2016), yielding another promising avenue for future improvements. However, more head-to-head comparisons with existing sequences at 7T are needed in order to assess the advantages of these new sequences.…”