How big is your grey matter iceberg?
As you are aware, MS is an iceberg, with most of the MS disease activity and resultant damage being hidden. The study below expands the concept of the MS iceberg to the cerebral cortex or grey matter. Most lesions (~80%) found at post-mortem in the grey matter are not detected using specialised MR imaging. Please note that post-mortem MRI imaging in more standardised than that which happens in clinical practice and I suspect even more lesions will be missed in real-life.
Is this study important? You bet. We know that these grey matter lesions are associated with cognitive impairment, loss of brain volume and in particular progressive grey matter atrophy and are associated with poor longterm outcome and reduced quality of life.
Do you want to know what your true MS disease burden is? Based on this data and other studies it looks as if MRI is not the best way of doing this. I suspect a better marker will be ‘deep phenotyping’, i.e. interrogating the function of your nervous system using stress tests to see how you perform. Knowing you have cognitive impairments, for example, slow cognitive reaction times, difficulty with concentration and attention, poor memory or other specific deficits may be more meaningful to you. Or not? I say ‘or not’ as not all pwMS want to know that have cognitive impairment; they argue if nothing can be done about it is best to ignore it. This is called the ‘ostrich syndrome’.
Knowing you have cognitive deficits will allow you to take specific actions to address the problem and to potentially make important real-life decisions about your future. It also allows your HCP to take action to address some medical issues that are linked to cognitive impairment, i.e. poor adherence to treatments, physical accidents and comorbid depression and anxiety to name a few. One could argue that pwMS who have cognitive impairment should be put on a high-risk register for more proactive management and care.
It is clear that the burden of MS is not only physical but cognitive as well. This is another reason to diagnose, treat and manage MS effectively and as early as possible to prevent end-organ damage and preserve your grey matter. Can I please remind you that no all DMTs are made equal when it comes to preserving brain volume or grey matter.
This post reminds me of an infographic I put together about 5 years ago called ‘Grey Matter, Matters’, which I used to support a campaign I started to redefine MS as a ‘preventable dementia’.
Do you agree with me?
Piet M Bouman et al. Histopathology-validated recommendations for cortical lesion imaging in multiple sclerosis. Brain. 2020 Aug 21;awaa233. doi: 10.1093/brain/awaa233.
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.