Which side of the fence are you on?

Barts-MS rose-tinted-odometer: zero-★s (still seeing red)

Apologies some more definitions: 

Side of the fence: used to refer to either of the opposing positions or interests involved in a particular situation.

Status quo: the current situation; the way things are now. The MS community, i.e. patients and HCPs are content with the status quo and aren’t looking for a change. 

NEDA: no evident MS disease activity

The question you need to ask yourself is which side of the fence are you on? MS is a focal inflammatory disease of the central nervous system vs. MS is a smouldering disease process and focal inflammatory events are in response to what is causing the disease. If you favour the former you will be happy with being NEDA-2, i.e. having no relapses or new focal inflammatory lesions. If you are in the latter camp you will want to focus on end-organ damage and preserving your brain and spinal cord volume for old age. 

The wider MS community seems to prefer the current dogma and status quo; i.e. that MS is a focal inflammatory disease and that everything we see can be explained by relapses and focal MRI activity. I think this is wrong and have argued this from not only a scientific point of view but also from a philosophical one. 

Deciding which side of the fence you are on may make an enormous difference to your outcome. It is clear that not all DMTs are made equal when it comes to preserving brain volume and hence brain reserve. 

Did you know that pwMS lose brain volume at a 2-7x faster rate than age-matched controls from the general population? Accelerated brain volume loss predicts and is strongly associated with cognitive impairment and long term disability. The following picture shows you just how much brain someone with MS can lose over an 18 month period. 

If we moved our treatment target to go beyond NEDA to focus on protecting the end-organ so that pwMS may have a brain that is in good enough condition to withstand the ageing process in later life I suspect the treatment landscape would change dramatically. To achieve this we need to diagnose MS and treat it early and effectively and in many cases, we need to flip the pyramid and use high efficacy therapies at the beginning, in particular agent such as alemtuzumab and AHSCT, which have been shown to protect the end-organ better than other DMTs. 

Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

26 thoughts on “Which side of the fence are you on?”

  1. I have so many questions:
    I’ve had MS 20 years, it’s still RRMS, I’m now on Ocrelizumab. It wasn’t really made clear to me earlier in the disease (did they even know?) that so much damage was being done when I was on copaxone and it stopped working… Right now, I don’t even know if it’s worth flipping pyramids – I’m 45 – is there even much brain left to rescue? As far as I know, no-one has even been measuring brain volume with me – just “are there lesions?”.
    I’m no longer in the UK and now have a neurologist who “doesn’t like Professor Giovannoni” (personality style clashes I guess). I can suggest alemtuzumab or cladribine but I imagine it’ll go down like a bag of bricks. Ocrevus is the wonder drug, it “heals” MS – no more relapses, no more disease activity on low-power MRI scanners – it’s fixed…
    I’m acutely aware that any damage from MS can’t heal. I haven’t bothered to tell him I’m taking metformin and alpha-lipoeic acid and on the look out for clemastine to try to stimulate remyelination – along with having taken up cycling. Is it even worth bringing up the idea of flipping the pyramid when I should just be grateful that I have access to meds and they “kinda” work? It feels like I’m being especially demanding and my requests would fall on deaf and unsympathetic ears…
    Meanwhile, in subtle but noticeable ways, things continue to deteriorate. I can no longer play music as my right hand cramps up – a huge part of my life and identity (and quality of life) wiped away. I struggle to concentrate and learn – but I can still do basic work, I should be grateful… I’m feeling less than optimistic – which of course isn’t helped by MS affecting my mental health.
    So what can you advise to the veterans among us looking to stack the odds in our favours for a change?

  2. Does the 2-7x increased rate typically occur in treated patients or untreated patients? What is the standard loss % for someone on an anti-CD20?

    1. I believe that OPERA trials for Ocrevus shown that annual BVL rate was around 0.32-0.36%. For HSCT/Lemtrada it was around 0.2%. I can be a little wrong, but the rates were around that

      1. yes but there are caveats and I have seen anti-CD20 at less than 0.2%

      2. Could you please elaborate on that? What caveats do you mean?

        It has been stated on this blog numerous times that the most effective DMTs in terms of brain atrophy are HSCT/Alemtuzumab, and that Ocrelizumab is not that effective in that matter. Should someone consider taking Ocrelizumab if brain atrophy is the main effectiveness criteria ?

      3. RE: “Unfortunately, not when analysed blind in phase 3 trials.”

        I am a little bit confused, was this a reply to “I have seen anti-CD20 at less than 0.2%” or ” the most effective DMTs in terms of brain atrophy are HSCT/Alemtuzumab, and that Ocrelizumab is not that effective in that matter.”?

        Was this answer about the fact that Anti-CD20 therapies are not as effective in suppressing the accelerated brain atrophy as observed in Phase 3 clinical trial, or that HSCT / Alemtuzumab did not do as well in a deeper analysis (blind analysis) of the results from the phase 3 clinical trials?


  3. I think you are right and the second rationale is more persuasive .
    My case history which you have cited on this blog is I feel indicative of that.
    However too late for me now ..too old and NEDA !

  4. If you are concerned about end-organ damage, what treatment approach do you use for patients that have had stable MRIs for years and a “mild” disease course? None of my neuros have ever looked at brain volume loss, and I have been diagnosed for 12+ years. I started on interferon but was unmedicated for several years during pregnancies/nursing. After my last pregnancy, I chose ocrevus but am now wondering if that choice makes sense in a Covid world. I wish there was data on using Ocrevus as part of an induction/maintenance regime.

    1. There is data on Ocrevus and brain atrophy, it is around 0.32-0.36% annually.

      You can try comparing your own MRIs, check the first few ones and compare them to the latest, if you can clearly see a massive brain matter reduction, then clearly brain atrophy was present.


    2. Nor do we look at BVL. The measurement is too wobbly for individuals over a short period of time. It either has to be obvious, that is above a threshold or used at a group level.

      The trajectory is important over several years, but then it is generally too late. Atrophy is after the event. Brain volume loss this year is primed by damage caused one to two years ago. When looking at BVL it is important to rebaseline at 12 months and ignore what is happening in year 1 on a treatment.

  5. Definitely a no star post as even if brain volume loss bothers me, I don’t believe I can do anything about it save for going abroad and/or private. Maybe I made a mistake on diagnosis and should have taken alemtuzumab but the thought of my thyroid going wonky as well when I’d suffered post natal depression/anxiety only a couple of years earlier put me off. Now been through DMF and now on ocrelizumab and keeping as fit and healthy as I can.

    How often are routine NHS MRIs sent for report on volume? It’s only been mentioned once as not concerning and I don’t know whether it was actually not concerning or whether it was still above average but within normal for being on a DMT.

    1. Re: “How often are routine NHS MRIs sent for report on volume?”

      They are generally not. We tried to set this up a few years ago and it failed. Prof K is leading a push to get this set up again for our unit.

    1. Yes, but on a treatment that didn’t work; i.e. it is a study subject from the negative anti-CD4 trial in the 90’s.

  6. Is it possible that the reduced brain atrophy rate “acquired” via HSCT/Alemtuzumab is permanent? Are there any suspicions on that, is there any medical data? If someone already had HSCT and still has relapses/new lesions, is it justified to use Alemtuzumab in concern of brain atrophy, or the best DMT would be something more successful in terms of reducing relapses/new T2/T1 lesions (ocrelizumab)?

    1. Re: “Is it possible that the reduced brain atrophy rate “acquired” via HSCT/Alemtuzumab is permanent?”

      Once rebaselined the BVL rate is ‘normalised’ and in the range, you see in healthy adults from the general population. BVL is normal after 35 years of age. Don’t forget life is a neurodegenerative disease and we all lose brain as part of the ageing process. PwMS lose it much faster.

      1. Thanks you for responding,

        Yes, I am fully aware of age ralated BVL, I have read atricles/studies on that – I am not concerned about the mean BVL in healthy individuals as it is much slower than in people with MS. 20 year old person with MS can have brain atrophy rate similar/greater to healthy 70-80 year old individual, that is scary…

        Is there any biological/medical basis on that constant maintenance of “normalised” brain atrophy in pwMS who undergone treatment with Alemtuzumab or HSCT?

        If the inflammatory proccess still occurs, pwMS are relapsing and having more MRI disease activity, new/enlarging T2/T1 lesions, what is the basis for concluding that brain atrophy has “slowed” and will not return to unhealthy levels that were seen before treatment? I am aware that smouldering MS and relapses are 2 different things, however, the theory is that inflammatory lesions are a response to chronic ongoing inflammation within the brain, so their appearance in some way indicates that MS smouldering is still ongoing.

        I am really confused right now, If somebody could explain that to me, I would be really grateful,

      2. There are different views one is a peripheral inflammation is cause and another view its a consequence. But brain atrophy is a flawed measure because the brain can shrink because the water swelling is removed by water and there can be no shrinkage when massive amounts of nerve loss has occurred because the space is filled with astrocytes. So before you can use it you have to let the anti -inflammatory effect to remove swelling show itself….this takes 6 months.

      3. Thank You for replying, I really appreciate Your time.

        So, as of today, there is no reason to claim that the effect of slowing brain atrophy after HSCT or Alemtuzumab is permanent?

        Of course, I understand that you need to define a new baseline – preferably at least 1-2 years after applying a specific treatment, and not take into account the first 1-2 years.

        It is very possible that I did not understand the context of the answer, but Prof G in his answer mentioned that after establishing a new baseline, further brain atrophy should be within the values ​​observed in healthy individuals. I fully understand some flaws in the measurements of brain atrophy, however, are there any medical / biological basis for which the level of brain atrophy should remain at these healthy levels rather than revert to “unhealthy” values, bearing in mind the continued prevalence of new demyelinating plaques and relapses ?


      4. “No reason to claim that the effect of slowing brain atrophy after HSCT or Alemtuzumab is permanent?” For a number of people this will be true, but hopeful for some people that is it.

        For alemtuzumab and atrophpy rate in year 1 = 0.4 then year 2 = 0.2, year 3 = 0.2 etc etc.

        In our spinal cord atrophy study the difference beteen control and MS was less than 20% but nerve loss was 80%

  7. Its obviously not relapses alone but its more of a which came first the chicken or the egg. Are the relapses a reaction to smouldering MS or does it happen in conjunction? Maybe its something related to why MS is CNS only. Would really love a post on why MS attacks the CNS. It doesn’t fit with neither the autoimmunity or EBV hypos.

    1. Why can’t the PhD’s discover the cause of MS, if you go back 20 years, you can read the same theories as today, still no serendipity!

      Thus, I believe pollution and toxic chemical accumulation is the smoking gun, most of the time the solution is the obvious one, if you will. The Immune system attacks the chemicals on the nerves fibers, then bam MS begins, Also, prolonged stressors weaken the body, is a vital part of the MS equation. Then you start the mild MS phantom pain, numbness and fatigue fun.

      Why does the age of onset of MS differ? My theory: depends on high toxicity levels/accumulation of fat soluble toxins and/or dose dependent of the toxic accumulation in body.

      Why eating organically, drinking the cleanest water, and improving the stressors of life typically improves MS vs declining. A No brainer to eat the cleanest or organic food vs chemically treated apple for example.

      What has increased since the 1880’s? Answer: man made toxic chemicals, most of the planet is contaminated/affected. Hello immune system, you are under attack.

  8. 80% nerve loss sounds scary…after how many years was this MD? Can people still function with such a high degree

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