The Match


No I am not talking about football.

There is a lot of talk about whether smouldering lesions are something different, where their origins may be something other than immune attack. Whilst I have no problem with this, based on histology by the pathologists they accumulate over time.

Smouldering lesions are lesions with microglial edge

There are more smouldering lesions evident in progression

Now you can see whatt one person calls a smouldering lesion, which can be seen on MRI with an iron rim and has been there for a while another calls the smoldering lesion a pre-active lesion which is not going to be seen by MRI. When you do histology these are probably the early drivers and has a sick looking oligodendrocyte and microglia and no lymphocytes .

However, there has been some debate in the last couple of days about whether relapses matter. They do and you don’t want them, because with a relapse comes lesions and with lesions comes damage and with damage comes more smouldering lesions. This is the match that lights the fire and once enough fires have been lit they are going to burn for a long long time…maybe for ever.

We see this in the beasties there is nothing smouldering to start with but they certainly appear. Yes this is not MS, but it shows you what matches do and as we know people shouldn’t play with matches.

It is also the case the more fires you have at the beginning of MS the more likely that disability will appear. I guess there is a major window of opportunity to put the fires out. How long is the window open…I am suspecting not that long for some nerve tracts. (Red bettom looks at disability in those starting late with high efficacy treatment), but is early and you can see it is not a flat line. However the more fires you put out the better things will be, you just need differnt fire extinguishers to put out the embers..

Relapses add to permanent disability in relapsing multiple sclerosis patients.Koch-Henriksen N, Sørensen PS, Magyari M.Mult Scler Relat Disord. 2021 May 17;53:103029. doi: 10.1016/j.msard.2021.103029

Objective: Whether relapses have direct effects on permanent disability in multiple sclerosis is still an unsettled issue. We aimed at investigating the cumulative effect of breakthrough relapses on the Expanded Disability Status Scale (EDSS) in relapsing-onset MS patients under disease modifying therapy (DMT).

Methods: From the Danish Multiple Sclerosis Registry we identified all patients in Denmark with relapsing-onset MS who had started DMT and followed them from the first day of treatment. We included patients aged 18-59 with Kurtzke’s EDSS score < 6.0 at entry, and we compared patients with and without relapses during follow-up. Endpoints were 1) annualized increase in EDSS; 2) time to 6-month sustained EDSS-worsening; 3) time to EDSS 6.0; and 4) time to increase in pyramidal- and cerebellar functional systems. Patients with and without relapses after entry were 1:1 matched by sex, EDSS, and age at entry. We analysed EDSS-worsening with adjusted Generalized Linear Models and time to the endpoints with adjusted Cox regression.

Results: We included 1,428 patients with breakthrough relapses and 1,428 without. The adjusted annualized increase in EDSS was 0.179 in patients with relapses (95% CI 0.164 – 9.194) and 0.086 in patients without relapses (95% CI 0.074 – 0.097), but in patients with EDSS ≥ 4.0 at entry there was no difference. The hazard ratio for irreversible worsening of EDSS was 1.83 (95% CI 1.58 – 2.12) and for irreversible increase to EDSS 6.0 or more 1.62 (95% CI 1.25 – 2.10). Irreversible increase in pyramidal and cerebellar functional system scores also happened significantly earlier in patients with breakthrough relapses.

Conclusions: Our results indicate that breakthrough relapses under DMT is associated with increasing permanent disability in patients with EDSS < 4.0 at treatment start which calls for effective prevention of relapses.

Today we may as well have a 2 for 1

Sotiropoulos MG, Lokhande H, Healy BC, Polgar-Turcsanyi M, Glanz BI, Bakshi R, Weiner HL, Chitnis T. Relapse recovery in multiple sclerosis: Effect of treatment and contribution to long-term disability. Mult Scler J Exp Transl Clin. 2021 May 28;7(2):20552173211015503. doi: 10.1177/20552173211015503.

Background: Although recovery from relapses in MS appears to contribute to disability, it has largely been ignored as a treatment endpoint and disability predictor.

Objective: To identify demographic and clinical predictors of relapse recovery in the first 3 years and examine its contribution to 10-year disability and MRI outcomes.

Methods: Relapse recovery was retrospectively assessed in 360 patients with MS using the return of the Expanded Disability Status Scale (EDSS), Functional System Scale and neurologic signs to baseline at least 6 months after onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and predict 10-year outcomes.

Results: Recovery from relapses in the first 3 years was better in patients who were younger, on disease-modifying treatment, with a longer disease duration and without bowel or bladder symptoms. For every incomplete recovery (meaning damage accumulated match struck and fire smouldering away) and , 10-year EDSS increased by 0.6 and 10-year timed 25-foot walk increased by 0.5 s. These outcomes were also higher with older age and higher baseline BMI. Ten-year MRI brain atrophy was associated only with older age, and MRI lesion volume was only associated with smoking.

Conclusions: Early initiation of disease-modifying treatment in MS was associated with improved relapse recovery, which in turn prevented long-term disability.

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

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  • Of course relapses and lesions matter. Your explanation of the process and mechanism highlights exactly why they do matter, hugely. It’s also why anti-CD20 therapies are far more effective than doing nothing / natural remedies.

    I guess the point is that once relapses and active lesions are dealt with, that’s not, “battle won, disease cured, anything else is the patient being a hypochondriac”.

    There is still this smouldering mess to clean up, where the immune system is still convinced the brain myelin is evil and we must be protected from it at all costs. And there is the equally awful situation where MSologists simply don’t believe that smouldering even exists, effectively neglecting their patients and condemning us to a long, slow, irreversible decline

    • I agree in the beasties we can get rid of the relapsing stuff forever and once the worsening starts it gets to the stage is does not stop.

  • Does HSCT and Alemtuzamab stop smouldering lesions?

    If they do how can they stop them if they can’t cross the BBB

    Or does cladrabine have a better effect on shouldering lesions? As it can cross the BBB.

    • “Does HSCT and Alemtuzamab stop smouldering lesions?
      If they do how can they stop them if they can’t cross the BBB”

      CYC cyclophophosphamide is the chemo used in hsct and is a
      small molecule that crosses BBB to kill b and t cells.
      Alemtuzumab is large molecule like all -mab drugs so no BBB crossing…and
      so only used in rr. Alemtuz stops smoldering before it begins.
      HSCT can stop progression pretty’s just a matter of for how long as
      people do relapse..Is the relapse from EBV or smoldering lesions…don’t know.

  • MD,

    Nice post.

    I see the first paper is from Danish researchers. A reminder to keep my fingers crossed for a speedy recovery for Christian Eriksen.

    “However the more fires you put out the better things will be, you just need differnt fire extinguishers to put out the embers.” Are there any drugs in the pipeline to put out the embers? Is the Sizomus trial looking at putting out the embers?

    I’m still unclear with the chicken and egg situation. I thought one theory was that there is something going on in the CNS before the external immune system gets involved ie the smouldering starts and the external immune system then gets involved rather than the external immune system being the cause of the smouldering.

    PS I’ve just spoken to Prof G and we both agree that you have behaved impeccably since the incident a few weeks ago. We are happy for you to have a couple of hours off this afternoon to watch the football. Enjoy your vegan burger and club soda.

    • Yes lets wish Christan a speedy recovery

      I think we already have a few but until we put them on top of the big guns and do it early we wont see maximum benefit, the BTK inhibitors target microglia.

      I think the chicken or egg is not that much difference because the chicken becomes egg pretty quickly as there are conduits between brain and outside and vice versa. The pre active lesions may be the egg but one could ask if the problem driving that is elsewhere. However once the issue starts the chick is there too

  • Hi MD,

    How would you identify these smouldering lesions in a living person? Looking at progress of EDSS retrospectively is too blunt an instrument.

  • Did anyone picked hot microglia cells from a lesion and put them on healthy brain tissue (Post mortem of course or EAE if possible)? If it was done what happened? The microglia started chewing the brain or shut down?

      • Maybe it is interesting to add also antibodies from MS and healthy control on top of hot and cold microglia to see what happens… new student project?

    • People are starting to look at EBV and immune system in bipolar disease..schizo…etc.
      But they found nothing here…

      “genetic, epidemiological, and biomarker studies suggest that the immune system is involved in the pathogenesis of bipolar disorder (BD). It has therefore been hypothesized that immune activation of microglia, the resident immune cells of the brain, is associated with the disease. Only a few studies have addressed the involvement of microglia in BD so far and a more detailed immune profiling of microglial activation is lacking. Here, we applied a multi-level approach to determine the activation state of microglia in BD post-mortem brain tissue. We did not find differences in microglial density, and mRNA expression of microglial markers in the medial frontal gyrus (MFG) of patients with BD. Furthermore, we performed in-depth characterization of human primary microglia isolated from fresh brain tissue of the MFG, superior temporal gyrus (STG), and thalamus (THA). Similarly, these ex vivo isolated microglia did not show elevated expression of inflammatory markers. Finally, challenging the isolated microglia with LPS did not result in an increased immune response in patients with BD compared to controls. In conclusion, our study shows that microglia in post-mortem brain tissue of patients with BD are not immune activated.

  • Nice post

    The money shot ( can i say this) is: 🙂

    Traditional escalating strategy may increase risk of disability accumulation

    All neuros sound read this print it and put it on the hall behind their chair office

    For every patient to see

  • How much more “hit it hard and early” evidence do we need before neuros actually begin to adopt this and abandon the escalation strategy?

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