Barts-MS rose-tinted-odometer: ★
My prediction or dream for 2021 is that smouldering MS will be accepted by the wider MS community as being the ‘real MS’ and that simply suppressing the immune response to what is causing MS, i.e. relapses and/or focal MRI activity, will be accepted as folly. What matters most to pwMS will be their end-organ, i.e. the size, reserve capacity and function of their brains and spinal cords.
In the same way as patients with a chronic heart or kidney disease ask their cardiologists or nephrologists what is my cardiac ejection fraction or creatinine clearance, markers of end-organ function of the heart and kidneys, respectively, I suspect pwMS will be asking what is the current state of their brains and spinal cords and how has the measures changed from last year. To answer our patients’ questions we are going to have much better functional and structural outcome measures or just maybe patients will be telling us how they are doing via their own self-monitoring initiatives.
The two studies below one looking at the thickness of retinal layers in the eye and the other the size of the thalamus, or deep grey matter structures, in the brain, show that loss of neurons or atrophy predicts future disability. The problem I have with anatomical studies is that by the time you measure and show loss of neurons or atrophy it is too late, i.e. the damage is done and is irreversible. There is data out there that shows loss of function precedes the loss of neurons and that some of the early loss of function may in fact be reversible. Therefore we are going to need to measure function as well as structure.
It is clear that our current clinical outcome measures are too insensitive to change, which is why we are going to need more sensitive and frequent monitoring of function to get on top of smouldering MS. The question is ‘so what if you detect subclinical worsening of function in MS what are you going to do about it?’. In the future, we will be adding-on new therapies to existing anti-inflammatory DMTs that will allow us to go beyond NEIDA (no evident inflammatory disease activity) to tackle smouldering MS. I am acutely aware that we are not there yet when it comes to combination therapies, but that is clearly the direction of travel the MS community is heading. Let’s hope the regulators agree and support the emerging development framework for combination therapies and allow us to start as many trials as soon as possible.
So if you are an MSologist and are reading this post don’t be too surprised if your patients start demanding more detailed functional and structural monitoring of their brains and spinal cords. Wouldn’t you if you had MS?
Maria Cellerino et al. Relationship Between Retinal Layers Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis. J Neuroophthalmol. 2020 Dec 29.
Background: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS.
Methods: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively.
Results: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-μm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS.
Conclusions: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.
Burggraaff et al. Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study. Neuroimage Clin. 2020 Dec 25;29:102549.
Background and rationale: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining.
Methods: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor.
Results: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings.
Conclusion: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.