Beyond NEDA: protecting the end-organ or your brain

Barts-MS rose-tinted-odometer: zero-★’s 

It became clear to me at least 6 years ago that we need to go beyond NEDA (no evident disease activity) when treating MS and we have to focus on protecting the end-organ, i.e. normalising the brain volume loss that occurs in people with MS (pwMS). To do this you really need to diagnose and treat MS as effectively as possible early on. From a research perspective, this means a focus on smouldering MS and the mechanisms responsible for the smouldering disease or the ‘real MS’.

This study below is another study showing a link between brain atrophy and cognitive impairment and supports the therapeutic strategy above. The criticism that is alway levelled at the flipping-the-pyramid argument is that too many pwMS will end up on high-efficacy DMTs and then what? My response to this is that if the majority of pwMS end-up on high-efficacy DMTs eventually is a testament to fact that the majority of pwMS need high-efficacy DMTs and hence it is best to get them there as soon as possible (#TreatMSASAP). 

This #TreatMSASAP principle underpins our #AttackMS trial design of using natalizumab ASAP after presentation and is aping the management of stroke. 

Another argument about flipping the pyramid is safety, i.e. we are putting pwMS at risk of severe adverse events. Yes, we are, but we can derisk a lot of the anticipated adverse events, i.e. the known-knowns and the unknown-knowns (anticipated AEs based on the mode-of-action of DMTs). In any event it is not for the neurologist or HCP to make the call on risk; surely it is up to the person with the disease to make the call? 

The following is a recording of my presentation from ACTRIMS-ECTRIMS 2020 that discusses these issues. Please note the presentation is targeting HCPs, but most pwMS should understand it. 

Golan et al. The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis. Brain Cogn 2020 Sep 11;145:105614. doi: 10.1016/j.bandc.2020.105614. Online ahead of print.

Background: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated.

Objective: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS.

Methods: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual-spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software.

Results: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing-remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores.

Conclusion: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

CoI: multiple Twitter: @gavinGiovannoni  Medium: @gavin_24211

15 thoughts on “Beyond NEDA: protecting the end-organ or your brain”

  1. So 6 years later, what do we have besides “treat early with a high efficacy ant-inflmation DMT that is no neuroprotective and will not stop back BVL”?

    Has the advice now shifted to treat with campath/HSCT first line and manage cancer risk later on?

    As you can tell from my tone – I am carrying a very heavy bag of 6ys of frustration. I am sure I am not the only one.

  2. Prof G,

    I typed in ‘combination therapies’ in to the search facility on the blog and it generated “399” results. I looked back at some of the Research Days (remember them) and there were lots of presentations on neuroprotection and remyelination. We have been round this buoy so many times, but nothing changes. I would love to be taking a neuroprotective therapy + a remyelination therapy (some sort of poly pill), but things never move beyond the discussion stage.

    Doing trials of add on therapies will take years. Will they be successful or will we see the usual “wrong trial design……wrong dosage” etc. etc. Isn’t their another way? As a neuro can’t you get a patient started ASAP on a highly effective anti-inflammatory drug and then have a discussion about some additional therapies that might be helpful in limiting brain loss e.g. a statin, anti-histamine…. The patient could then decide if these were options they wanted to pursue. I’m sure it goes against medical rules (not enough evidence), but surely if it could limit more damage to the patients brain / spinal cord, this is a good thing.

    If doctors take an oath to do no harm, then surely they are obliged to do something rather than nothing to limit harm. Those of us with MS today have been let down by a system (drug trials) which take far too long and by physicians who stand by and watch their patients deteriorate while knowing that they have some therapies they could prescribe which might / could reduce the amount of deterioration. Many of us with MS are risk takers – we know our fate so are happy to be guinea pigs to slow the inevitable climb up the EDSS. We would be happy to sign a form accepting full responsibility for our decisions. We can’t wait another 20 years for the arrival of “combination therapies”.

    1. I suspect until patents expire and the cost of the bottom rung falls there is no incentive for pharma to do this

    2. Okay, Sid if you were my patient and you asked me for an add-on a neuroprotective cocktail I would recommend oxcarbazepine, lipoic acid, metformin and a ketogenic diet (low-carb high-fat or intermittent fasting). Would you take my advice based on the current evidence base?

      1. I have PCOS as well as MS, so I’m thinking I might try and get someone to prescribe me metformin off label and attack two birds with one stone.

      2. Prof G,

        Thanks for your response. I would certainly take your advice as (1) I trust you; (2) there is some early / small scale evidence that theses suggestions have a positive effect; (3) I have nothing to lose (I can’t wait another 5, 10 years). I’m religiously following Keto / intermittent fasting.

        Thanks for all your work / contributions.

      3. With you on this one Luis especially as the initial study was a good quality one!

        This was reported yesterday by Medical Xpress
        SEPTEMBER 23, 2020
        Metformin treatment linked to slowed cognitive decline
        by Garvan Institute of Medical Research

        As with Lipoic Acid, Metformin is deemed to be safe as well as effective and has been in use for some 60 years.
        So why does it seem to take at least this long to have readily available treatments repurposed?
        Regrettably lots of us with MS go in search of our own neuro protectives instead, especially in view of the fact everything you say in this post makes perfect sense to us ProfG.

  3. This study design might be useful to look at from a cognitive rehabilitation aspect. The difficulty with measuring cognitive rehabilitation is that ppl get better at the tasks they practice but it doesn’t necessarily translate to skills in the real world, and if it does, it’s hard to measure accurately measure whether it does. I wonder if this study design could be used to identify whether a cognitive rehab program protects people with MS from atrophy across time? Maybe a surrogate of whether cognitive rehab is beneficial. I’m not across all the cognitive rehab literature, so not sure if it has been measured that way before? Thoughts?

  4. ‘what do you think about the research in which it turned out metformin blunted te effects of exercise and the both do not add-up’

    Thanks for asking me Tim, but I’m not in a position to provide anything resembling a sound and reliable response as a lay person. Added to which, of course, Metformin is only available on the nhs for those with Type2. It was only after seeing the piece in Medical Xpress and knowing it’s being studied as a possible remyelination agent that I added it to my comments on neuro protectives
    Am definitely taking lipoic acid though!

    1. If you are doing keto or intermittent fasting you probably don’t need metformin. Metformin stimulates the same pathway as β-Hydroxybutyric acid the so-called ketone body that is responsible for its neuroprotective effects, which are downstream of the hydroxycarboxylic acid receptor 2 (HCA2).

      Please read my post on diet being a DMT.

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