Article of interest: the gray matter iceberg

For how much longer can we ignore gray matter pathology? #MSBlog #MSResearch

"I am sure you have heard of the the figure of speech 'looking for a needle in a haystack'? The following post-mortem study shows that only 3-5% of gray matter lesions, on the surface of the brain, are detected using conventional MRI when compared to pathological analysis. In other words 19 out of 20 or more of gray matter lesions are invisible to the MRI scanner. May be we need a better magnet, or a new technique, to find the needle or gray matter lesions?"

"Gray matter is the fraction of the brain where a substantial number of our neurones live and are important for cognition. Therefore it is not surprising that cognitive impairment correlates so poorly with focal MRI lesions numbers, when most of the pathology is being missed. What we need is a better way of detecting and quantifying the gray matter lesion burden in life. One way of doing this is by measuring brain atrophy and regional brain atrophy. There is data emerging that when you look at regional atrophy it correlates much more closely with MS-related cognitive impairment and interestingly MS fatigue."

Example of a tissue sample and the matching area on postmortem MR images. WM lesions (WM), as well as type I lesions (I, mixed GM-WM), can be seen with relative ease on the different MR images. Intracortical lesions (IC) are difficult to detect and define, even in retrospect.A, Photomicrograph (MBP immunohistochemical stain) reveals lesions (arrowheads) in the WM and cortical GM. B, Short-echo T2-weighted SE image. Insert, a higher magnification of the intracortical lesion. C, Long-echo T2-weighted SE image. D, 3D FLAIR image.

"Why all the focus on gray matter, brain atrophy and cognition? I think this is where real burden of MS resides and is what drives early impairment and disability in MSers. Why are 50% of MSers unemployed within 10 years of diagnosis when they are not physically disabled? I suspect this is due to poor cognition and the resulting mental fatigue and depression that occurs downstream of this pathology. If we want to make a difference to MSers' lives we need to intervene early in the disease course to prevent gray matter pathology and its downstream effects. With high-efficacy drugs we now have tools at our disposable to reduce the rate of brain atrophy in MS. Unfortunately, low efficacy drugs have little impact on this aspect of MS pathology. The problem in the field is that at present we don't measure brain atrophy in routine clinical practice and don't use it to make clinical decisions. I recently visited the MS unit in Prague to see how they are using brain atrophy in clinical practice. It was simply amazing to see a system that can be used in real-life to aid clinical decision making. I was particularly amazed to see that some MSers have NEDA, but continue to lose brain volume at a very high rate, implying that our current tools for monitoring MS are missing a substantial burden of the disease. This is why we are exploring a collaboration with Prague to see if we can implement and validate their system in our centre. MSers under our care need to know what is happening to their brain volumes so that the information can be incorporated into decision-making regarding DMTs. May be you disagree?" 

Geurts et al. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol. 2005 Mar;26(3):572-7.

BACKGROUND AND PURPOSE: Cortical lesions constitute a substantial part of the total lesion load in MS. They have been related to neuropsychological deficits, epilepsy, and depression. However, the proportion of purely cortical lesions visible on MR images is unknown. The aim of this study was to determine the proportion of intracortical and mixed gray matter (GM)-white matter (WM) lesions that can be visualized with postmortem MR imaging.

METHODS: We studied 49 brain samples from nine cases of chronic MS. Tissue sections were matched to dual-echo T2-weighted spin-echo (T2SE) MR images. MS lesions were identified by means of myelin basic protein immunostaining, and lesions were classified as intracortical, mixed GM-WM, deep GM, or WM. Investigators blinded to the histopathologic results scored postmortem T2SE and 3D fluid-attenuated inversion recovery (FLAIR) images. 

RESULTS: Immunohistochemistry confirmed 70 WM, eight deep GM, 27 mixed GM-WM, and 63 purely cortical lesions. T2SE images depicted only 3% of the intracortical lesions, and 3D FLAIR imaging showed 5%. Mixed GM-WM lesions were most frequently detectable on T2SE and 3D FLAIR images (22% and 41%, respectively). T2SE imaging showed 13% of deep GM lesions versus 38% on 3D FLAIR. T2SE images depicted 63% of the WM lesions, whereas 3D FLAIR images depicted 71%. Even after side-by-side review of the MR imaging and histopathologic results, many of the intracortical lesions could not be identified retrospectively.

CONCLUSION: In contrast to WM lesions and mixed GM-WM lesions, intracortical lesions remain largely undetected with current MR imaging resolution.

Labels: , , ,