How is your end-organ functioning?

H

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?

Retinal thinning in 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.

Thalamic atrophy in MS

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.

CoI: multiple

Twitter: @gavinGiovannoni                                       Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

15 comments

  • Hi

    Could lifestyle choices be just as neuroprotective than potential drugs that aren’t yet available to people with MS especially smouldering MS. I understand that the clinical studies haven’t been carried out on certain lifestyle choices as it’s difficult to monitor such as diet, sleep, exercise, supplements etc.
    Also sometimes it’s the things you don’t do that are just, if not more important than the things you do, ie poor diet, lack of exercise, smoking, drink and drugs, not lowering stress.
    Maybe a bigger push and shift onto positive lifestyle choices by the individual if not already done, I think a lot of people with MS want to feel as though there is something they can do for themselves today, but don’t have to clinical confirmation of this.
    In your opinion could smouldering MS be slowed or possibly stopped with lifestyle choices such as –

    Diet- to support the brain, gut and mitrocondria/cellular health. Eat fresh and washed fruit and vegetables, plenty of leafy greens, high sulfer vegetables ie onion, cabbage broccoli, mushrooms, plenty of healthy fats such as all omega 3s, walnuts, avocados, oily fish, olive oil, flax seed oil, low saturated fats, plenty of fibre, eliminate dairy. The list goes on on diet.

    Exercise where you can if your able, get the heart pumping, and the release of feel good hormones

    Sleep, try and get quality undisturbed sleep, And the the recommended 8 hours

    Lower stress, though take if frequent breaks, meditation, read, find a way to escape from your stress for at least a while.

    Learning something new and testing your brain ie learning an instrument, crosswords and puzzles a new language

    Socialising

    Supplements such as vitamin D, get sunlight, turmeric, probiotics also the list goes on with this.

    It could be discussed for endless hours. I know the world of all the above is open ended and not everything suits people lifestyles and some aren’t proven to help with MS.

    However do you believe that lifestyle choices may help to slow the mechanisms of smouldering MS or is it only medical intervention that can slow or stop it?

    And just an addition to this do you think (if successful) remyeliation therapy’s will stop smouldering MS or has it already begun in the lesion area and cannot be stopped?

    Kind regards

    • I’ve followed your suggestions here despite the consensus it makes no difference. It certainly worked for me. Had DMTs been available to me I would have qualified for them. I have met pwMS on treatments that are the age I was at diagnosis. I don’t think it is emphasised enough that lifestyle is important. It appears rather than the rhetoric DMTs stop progression patients are realising they’re not the magic answer alone, by which time it’s too late to turn the clock back and failure to combine treatment and healthy lifestyle is costly. The NHS doesn’t have a money tree and monitoring patients that are otherwise well is all very well, but what happens when someone needs a scan as they’re having an exacerbation, but end up on a waiting list!

  • Talking of ” simply suppressing the immune response to what is causing MS”…. I presume that is what something like Ocrevous is for?

    Four months after mine I have noticed a return of the broken brain again. I take it because the Ocrevous is just supressing the immune system and probably in no way is actually adressing the MS is it?

    I wish things were further forward with this rubbish condition. Scientists knowing what it is for a start would be good.

  • The questions are how hard do you want to look if we have no treatments for these processes and also how do we deal with premature or early ageing?

    Only a couple of days ago you posed this question in response to a query concerning SPMS.

    You have also repeatedly confirmed that there is insufficient studies and data into effective add-on therapies.
    You and the rest of the Bart’s team are helpful via sharing what data there is on things such as Lipoic Acid and by advocating exercise, good quality diet and sleep. But this doesn’t alter the key fact that until smouldering MS is universally accepted studies concerning add-on therapies will not be widely pursued.
    In the meantime we are our own add-on therapists, keenly hoping that the yoga, gym class, supplements, Intermittent Fasting, Mindfulness etc, etc will slow up the smouldering disease damage, alongside DMTs.

    I know from previous posts your view of the ‘prefer not to know in the face of nothing being available to assist’ is head-in-the-sand/denial,. However, I am persuaded by the validity of not to predominantly focus on deficits, but rather to focus on what has been maintained. Deficits focus – yes, when repair is achievable with either a prospect of improvement or maintenance. But when the trajectory is downward why not adopt some aspects of positive psychology focussing on your own strengths and attributes, counting your blessings/gratitudes and from Mindfulness: living in the moment.

    I will remain hopeful that at some point your assertion is correct and that at some future point, not horrendously far off, scientifically endorsed and NHS approved add-on therapies are provided.

  • If real MS is smouldering MS, and not a inflammatory disease. Then are we saying taking DMTs is a waste of time based damming the immune? Is so how do you explain the high efficacy of HSCT and alemt8zumab?

    • They obviously address the cause of MS, whereas the other DMTs don’t, which is why if I had MS my poison would be alemtuzumab or HSCT.

      • “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.”

        Prof G,

        You’re not in my neuro’s good books. I will ask him / demand from him “more detailed functional and structural monitoring” of my brain and spinal cord, but he’ll say no. The reason – he will say he can currently treat focal inflammation / relapses, but not smouldering MS. Until treatments are available to effectively treat smouldering MS, all he will be doing (by undertaking such monitoring) is scaring the pants off me at every visit.

        How near are we to treatments to address smouldering MS? If effective treatments are approved to address smouldering MS, would we still need treatments to address focal inflammation / relapses? (or are they likely to fade away as smouldering MS is addressed).

      • Interested to hear how you would go about this Prof, if you did have MS. Climb the DMT ladder accepting that you will take hits along the way? Fabricate relapses? Go on holiday to Russia or mexico? I know that there are other options. Pay for treatment in the UK if you’re rich enough or try and participate in a trial but this requires EDSS 3. My point is that many of us would choose the same poison (based on your advice, which is good enough for me) but unfortunately do not have the choice to make

        • Local HSCT unit has actually gone towards without radiological activity while on high efficacy DMT we won’t want to do HSCT, the benefits are simply not clear enough otherwise – even if you were to pay yourself.

          Reading the studies I can see where they are coming from to some degree.

      • Thanks Prog G. That’s the reason I took Alemtuzumab after reading this blog as well as enthusiastic videos on Alemtuzumab by Aaron Boster.

      • They only potentially address it if administered early enough.

        If you have early onset PPMS like me, that’s no use.

  • I am in the lucky position to have neuro who is quite open to do monitoring (MRI and bloodwork for sure). But do I really need gadolinium with my MRI every time while on ocrelizumab? I don’t mind the MRI (it’s mildly annoying but does not panic me or anything) but I question the impact of frequent gadolinium injections…

    • I have been asking this of my MS team for atleast the last couple of years, after following this blog.
      I don’t think my MS nurses have any idea what I’m talking about & my consultant humours me for a bit & then dismisses this as unfeasible to do.
      This is easier said than done.

  • Brain atrophy is getting some traction as a number of studies are popping up measure it in addition to the typical NEDA criterions. If we deal with COVID quickly, I’m thinking this will be the year of MS, not strictly smoldering MS. A lot of cool ideas are coming out. Can’t wait for your EBV trial as well as the HHV6 trial by GeNeuro.

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