What is MS?

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The more I read,  think and assimilate information the more I realise that the real pathology behind MS is not the new acute lesion or relapse, but what is going on behind the scenes in the so-called slowly expanding chronic MS lesion or SEL. 

MS is a smouldering disease. 

In an analysis of the ocrelizumab-PPMS or ORATORIO trial, it is clear that SELs already existed in the brains of PPMSers when they started the trial and best predicted their clinical course during the trial. In contrast, brain atrophy or brain volume loss and new lesion activity did not predict disability progression. What is nice about this analysis is that it is in a PPMS population with a very low relapse rate, which excludes relapses as a confounder. 

I am not that concerned about brain volume loss not predicting outcome in this population, because it is out of sync with clinical outcomes; i.e. brain volume loss today is caused by pathology 2-3 years ago and hence needs to be correlated with clinical outcomes in the past. 

What is important in this study is that new MRI activity in the form of new T2 lesions did not predict disability worsening. In other words, focal inflammation is not associated with clinical outcome. In comparison, SELs or smouldering MS predicted clinical outcome. Based on basic medical philosophical principles around the definition of surrogate markers it is clear that new T2 lesions can’t be the disease we call MS, but SELs can. 

It is clear to me that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip, of the tip, of the iceberg and that most of MS pathology is hidden from view when using conventional MRI. This is why you still deteriorate despite being NEDA (with no evident new disease activity). The NEDA in this context is referring to the absence of focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind the worsening despite being NEDA is driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is realistically modifiable by our current DMTs. 

The really important question this analysis raises is that when you treat someone with a DMT and they become NEDA how do you know they don’t have ongoing smouldering MS and hence would benefit from being escalated to a more effective DMT or should be included in add-on combination therapy trial? This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. Only then will we be able to start answering important questions. For example, does changing treatment in people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab result in them doing better? The ORATORIO analysis below would suggest the treatment effect in this situation is small. This is why we are going to need a new generation of add-on treatments that target CNS pathology, for example, hot microglia, antivirals (EBV and HERVs), CNS-penetrant anti-B-cell and plasma cell agents, neuroprotectives, etc. 

I have made the point that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease.  I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT, in particular, alemtuzumab or HSCT, appear to be in very longterm remission and may even be cured of their MS (see the previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree and this is why we need a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence. 

The MRI-centric view of MS has lulled many of us into a false sense of security and has resulted in us classifying MS as a focal inflammatory autoimmune disease of the CNS. In reality, MS is a diffuse disease of the CNS and the focal inflammatory events are simply the immune response to what causes MS. This is why the field hypothesis of MS is so relevant and fundamentally challenges our worldview of MS. 

If we don’t change our worldview of MS and explore what is happening in the trenches alongside the one we currently have our heads buried in we will be letting down the next generation of MSers. 

Image from ‘when is a paradigm shift required‘.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. BRAIN 2019: 142; 2787–2799. 

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/ evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1- weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

CoI: multiple

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.

30 comments

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  • Prof G,

    So what is causing the “slowly expanding chronic MS lesion or SEL”?

    I find this all very depressing given that we are approaching the 35th ECTRIMS! So many MSologists given prizes for their outstanding contributions to MS research yet it turns out they were all wrong.

    The new understanding will hopefully be good news for the next generation of MSers, but you also have to feel for the previous generations because of the blinkered approach to MS research – focusing on relapses (low hanging fruit) rather than trying to understand the real underlying disease.

    All we need is one effective neuroprotective agent to add to an effective anti-inflammatory. Are we asking too much i.e. to have this by 2025?

    • Jak, the ‘field hypothesis’ is just that a hypothesis it is not fact. I giving you an alternative take on the pathogenesis of MS based on some observations. I may be wrong, but then again I may be right. What we need to do it design experiments to test the hypothesis, i.e. try and disprove it.

  • If only that ‘thing’ that the immune system is unhelpfully reacting to could be stopped in its tracks. Then hazardous immunosuppressive therapy would be rendered obsolete.

    I have slow PPMS and I don’t believe that my immune system is the problem.

    • This is what I refer to as the ‘black swan’; who knows in a decade from now we may be treating MS with antivirals. Even better we may be preventing the next generation of MSers getting MS 😉

    • Cladribine is an IRT that does penetrate the CNS and there are hints that it targets CNS resident B-cells. The latter needs to be confirmed. Overall cladribine is a high-efficacy DMT, but I suspect we are slightly below the optimal dose with the currently licensed dose. There are many posts on this blog explaining and debating this issue.

  • Gavin
    September 2, 2019 at 2:22 pm

    Yes, I personally think MS is due to a virus and MS manifests as a result of the immune response to the virus.
    ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
    Am I right in thinking Epstein Barr and shingles?
    So if MS is the consequence of an infection at some point are the DMDs recommended just kind of masking the problem a bit longer?

    Should we be on antivirals similar to what people with HIV/AIDS get?
    Or am I on the complete wrong page?
    thanks

    • There was a story a couple of years ago where a woman with both HIV and Ms saw an improvement in her Ms after taking her HIV antivirals

      I do not understand why a trial is not being done!

      I mentioned this to my neurologist but as usual he just looked vacant

      PROF G is there any further data on which antiviral and and strength etc which the lady with HIV was taking and and have there been any small trials done for ms?

      • Yes, we have written on the HIV being protective for getting MS and feel it is likely to be the antivirals. We did a monotherapy antiretroviral trial, which was a mistake. We should have done the trial with a combination. We are still trying to get a trial of HAART in MS funded. Science is a slow process.

        • So how can us patients jivvy this along?

          Who do we need to be speaking to/writing to/badgering to get this accelerated?
          Anyone famous we could pester?

          I am sick of waiting and I’ve only been diagnosed 10 months!

          CAN YOU DO A POST ON THIS please……..

    • Paediatric MS is no different to adult MS; they just have a more reactive immune system (more relapses and MRI activity), more reserve hence recovery from attacks, which takes them longer to reach disability milestones. Because of the greater inflammatory burden they can develop encephalopathic presentations, but this is also seen in adults but less often. Children also take a massive hit on the end-organ. Under the microscope childhood, MS looks like adult MS.

      • From your reasoning they dont have time to have SEL

        Also the prodromal fase that you talk many time does seem to make much sense in kids with ms

  • I think my MS was smouldering in the background long before diagnosis. First symptom, looking back, was getting Clonus in both legs around puberty and that was fifty years ago. Glandular Fever (EBV) was much later when I was in my twenties. Clonus is MS related and was there before EBV, so I’m not convinced that my MS was caused by that virus. Instead, I think that genetic and environmental factors seem to make children vulnerable to the earliest stages of MS.

    • This is not very scientific but I also wonder if ms started earlier. At around 10 yrs i would loose my balance when walking in the dark and in my twenties i had glands on my neck really inflamed (big lump on my neck) .

      • I also had dreadful swollen neck glands as a child. So bad I couldn’t move my head or even support its weight. I wasn’t diagnosed with glandular fever. I then had tonsillitis twice a year every year from age 24 to 36. Then diagnosed age 37. My optic neuritis was preceded by tonsillitis. Since my diagnosis and further reading I’ve wondered if all events are linked.

        • Now 47 having been officially diagnosed at 35 but having had symptoms since 21 I also used to to fall over a lot in my teens had glandular fever at 20 and then had a large gland and on my neck in my late 20s to early 30s

          I do think neurologists should ask more questions when you are diagnosed in order to pick up on these small trends

  • Interesting take, that MS is a reaction to a virus of one sort or another. We all have tales/stories of a problem that could be an early indicator of MS. At school I would not dream or contemplate standing to attention for an hour when in the CCF (combined cadet force at school) or bladder retention urgency when aged 18. Both now significant issues with my MS.

    Who had heard of MS I the early 70’s when I had these problems? I was diagnosed in 1995 aged 40 with double vision and I did not string everything together until 2014 or thereabouts. Its all a hypothesis but certainly food for thought

  • So if MS is caused by a virus in the brain why do all these immunosuppresants, eg natalizumab, not cause a more severe brain infection or worsen the SELs?
    Can MS not be that it starts with inflammation and T2 lesions and progresses to SELs? Ok maybe SELs correlate with clinics, but is this a strong argument that thats how disease starts?
    Is not PPMS early RIS that converts to PMS?

  • I had glandular fever when i was 12yrs old. I had my first MS attack at 15yrs old, then i went into full remission for 10yrs. Then it came back, I’m now starting Mavenclad in a month & I’m still rrms.

  • You made the point but you don’t buy it?

    (“I have made the point that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease. I don’t buy this because…”)

    • It depends on when you treat with an IRT. Very early before you allow the immune system to set-up shop in the CNS can prevent this from happening, i.e. possible cure. Too late with your treatment and the CNS cascade is activated you are too late to stop the rot, slow burn, smoulder, shredder, or whatever else you want to call it ;-(

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