Smouldering MS – not all bad news


Barts-MS rose-tinted-odometer: ★★★★★ (today’s colour is Delta Red Iron Oxide #9b2f1c)

One of the smouldering MS dogmas that have entered the MS lexicon is that the iron-rimmed slowly expanding MS lesions (SELs) go on enlarging and destroying or shredding the brain tissue around it forever. Another dogma states these SELs don’t respond to current DMTs. The good news is that both of these statements are probably incorrect. 

In the recently published longitudinal MRI study below iron rims around lesions gradually diminished with time. However, having these iron rim lesions is not good news in that they are significantly more destructive than non-iron rimmed MS lesions. The question I have is what drives these lesions to form? Knowing the answer to this question will tell us what is causing MS.

The second study below demonstrates that ocrelizumab significantly reduces the expansion of slowly expanding/evolving lesions. This suggests that these lesions may be driven by intrathecal or CNS-derived immunoglobulins. This is why we are doing the high-dose ocrelizumab, SIZOMUS (ixazomib) and CHARIOT-MS (cladribine) studies to see if reducing intrathecal B and plasma cell activity has an impact on smouldering MS.

If the former studies are positive, who would want to go onto a lower-dose anti-CD20 therapy (standard-dose ocrelizumab, ofatumumab, rituximab, ublituximab)? Please note that although these lower dose anti-CD20 therapies are very effective at stopping relapses and focal MRI activity this is not MS. The real MS is smouldering MS and what we see with end-organ damage markers. This is why if I had MS I would choose a DMT that offered the best chance of normalising my brain volume loss and I would volunteer for the SIZOMUS trial. 

The good news is that these two studies below show that the so-called chronic active lesions or SELs evolve over many years after their initial formation and that they may be modifiable with DMTs. Let’s celebrate these facts. 

Iron-rimmed lesion of SEL expanding over 7 years; image from BRAIN.

Dal-Bianco et al. Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI. Brain. 2021 Apr 12;144(3):833-847.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation periods were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Ocrelizumab reduces the increase in the volume of SELs compared to placebo; image from BRAIN.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019 Sep 1;142(9):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.

Conflicts of Interest

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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 and are not meant to be interpreted as personal clinical advice. 

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.


  • Prof, given that Alemtuzumab and HSCT will be out of reach for most patients due to being second line, would you consider ocrelizumab plus sizomus as the next best treatment option?

    • No, because SIZOMUS is a safety study and it is not licensed for treating MS. Ocrelizumab is a very effective therapy; just not that effective on the smouldering processes we need to target to optimise MS outcomes. Even Pharma know this, which is why Roche, who manufacture and market ocrelizumab, are testing a CNS penetrant BTK inhibitor in MS.

  • Well you seem to be perpetuating the dogma ::)

    SELs continue to expand over years to decades and are responsible for the slow accumulation of damage over many years. SELs can be seen on MRI; they typically cause black holes on so-called T1-weighted MR images and have a dark rim of iron around them when viewed with special MR sequences (susceptibility imaging). The iron rim is a marker of these so-called ‘hot microglia’.

    Getting worse
    This newsletter explains why people with MS get worse despite having no evident inflammatory disease activity

    Gavin Giovannoni
    Jul 2



    In my MS clinic, I have to continually work on a narrative to explain to people with MS (pwMS) why they are getting worse despite having no evidence of inflammatory disease activity (NEIDA). The following is a narrative I use to explain what I now refer to as smouldering multiple sclerosis.

    Photo by Josh Riemer on Unsplash

    Disease worsening or disability progression in MS can be explained under 4 headings:
    1. SS (scissors and stripper)

    The acute focal inflammatory MS lesion acts like molecular scissors and strippers, cutting axons and stripping myelin off the axons or nerve fibre. These cut and naked axons are blocked from conducting signals and result in a neurological deficit. The neurological deficit from this block in the conduction of electrical signals will vary depending on the pathway affected, for example, if the lesion affects the optic nerves it will cause loss of vision. The way to prevent the SS from causing conduction block is to prevent new lesions from forming. To achieve this you need to be on an effective anti-inflammatory therapy and be rendered free from relapses and new MRI lesion formation, i.e. NEIDA.
    2. EF (energy failure)

    The demyelinated axons from the lesions may recover function by a process called axonal plasticity or remyelination. Axonal plasticity is the process by which the neuron inserts new ion channels into the demyelinated axonal segments, which restores conduction. Remyelination may also occur, but the new myelin is never as thick and as efficient as the old myelin and is susceptible to intermittent failure. These demyelinated and thinly remyelinated sections of axons are susceptible to temperature and fatigue. If the temperature rises these sections block and if the axons are used too much, for example with exercise, they run out of energy and also block. Sometimes the type of ion channel that is inserted into the axon’s fire spontaneously can cause intermittent symptoms, for example, pins and needles, pain, neuralgia and muscle spasms. As these ion channels are sodium channels it explains why these intermittent symptoms respond to drugs that block sodium channels, for example, carbamazepine, oxcarbazepine, phenytoin and lamotrigine.

    Another process that helps with recovery is that the surviving axons form sprouts to reconnect disconnected pathways and create new synapses, which are the connections between nerve fibres. All these processes increase the energy requirements of the axon, which makes it vulnerable to die-off later.

    At the same time the ‘MS lesion’ remains inflamed and some of the chemicals produced as part of the inflammation poison the mitochondria, which are energy factories of the axons. A further reduction in energy production puts further stress on the system. As a result of these processes, there is a delayed dying off of axons that takes place over months to years after the initial MS lesion has formed. This delayed dying off of axons explains why despite effective treatments stopping new MS lesions from forming some people with MS still notice a slow deterioration in their functioning.

    The following videos demonstrate normal conduction in a myelinated nerve and what happens in a demyelinated nerve that has undergone axonal plasticity mentioned above. In the first video, you can see how quickly and efficiently electrical impulses pass down the nerve. In the second video of a demyelinated nerve, the electrical signal crawls very slowly across the demyelinated segment; at one stage it looks like the signal is not going to make it or get blocked. The red shadow lines are an integrator of the energy it takes to restore the nerve back to its basal state so that it can transmit another electrical impulse. You can imagine this happening across the many MS lesions in the brain of a person with MS and explains why it takes so much energy for someone with MS to think and function normally. This also explains why pwMS suffer from both physical and cognitive fatigue.
    3. SB (slow burn)

    Some MS lesions never recover and become slowly expanding lesions or SELs. SELs have a rim of hot microglia (innate immune cells) at their edges and continue to swallow up the myelin and axons of the surrounding ‘normal-appearing’ tissue. These lesions don’t have much acute inflammation left in them, i.e. there are very few T and B cells in these lesions. SELs continue to expand over years to decades and are responsible for the slow accumulation of damage over many years. SELs can be seen on MRI; they typically cause black holes on so-called T1-weighted MR images and have a dark rim of iron around them when viewed with special MR sequences (susceptibility imaging). The iron rim is a marker of these so-called ‘hot microglia’.

    At present we have no idea what causes some MS lesions to regress and recover and for others to expand and become SELs. What we do know is that our standard anti-inflammatory DMTs have little or no effect on SELs once they have developed. It is important to realise that SELs are found throughout the course of MS and are even seen in people with a radiologically isolated syndrome (RIS) or asymptomatic MS. In other words, the so-called ‘progressive MS pathology’ is found very early in the MS disease course. We do know that the number and size of the SELs increase with disease duration, i.e. the more MS lesions that develop the more SELs will be formed. Another important observation that has recently emerged is that a single strategically located SEL can cause an extraordinary amount of damage; for example, a single SEL in the so-called pyramidal tract or motor pathway can cause progressive weakness down one side of the body. I have a few patients like this and it is very disheartening when their weakness fails to respond to standard anti-inflammatory therapies

    • Do I tell him to hang in there and wait for an evidence-based therapy to emerge or do I give advice about things that may make a difference? If I did give him advice would a scientific rationale be enough (preclinical data) to support my position or should my advice be based on data from preliminary trials in people with MS? Do you think it is irresponsible to give generic advice on managing smouldering MS? Finally, do any of you have advice on how you are self-managing your smouldering MS?

      Well you have the evidence now 🙂

      Anti cd-20 theraphy

    • Luis, you spend far too much time reading the blog. It is probably not good for your mental health.

      The other good news is that it looks like natalizumab also has a positive impact on SELs albeit like ocrelizumab a small effect.

      • Lollllllllllllllllllllllllllllll

        For you to prof Giovannoni

        I just like to check if your comments make sense

        Lots of people read your posts and they take them as gospel

        You rarely say “i dont know”

        And in this case you say on think in one week and another the week after

        Almost like a Chameleon

        • Yep, when the evidence changes I change my colours or spots; it is called science. I am not a believer; beliefs are immutable 😉

        • To be brutally honest the treatment effect of ocrelizumab on SELs is quite small. The real question is can we boost this treatment with higher-dose ocrelizumab.

          Wouldn’t you be interested to know the treatment effect of alemtuzumab and HSCT on SELs? I asked Doug Arnold in Montreal who has both sets of data sitting on his computer servers but needs a research grant to pay for someone to do the analyses. Let’s hope Sanofi-Genzyme read this comment.

          • Re: “What would you consider a higher dose?”

            1200 or 1800-mg 6-monthly, which is what we are testing in the high-dose studies. This is based on body weight.

        • I second you Luis, There are also more subtle chameleon moments you don’t pick up straight away. I appreciate Prof G share every single little thoughts of his when he feels like expressing his opinions. Just after a while, he lost his credibility to me ;). Anyway it would be great to see comparable data on Clad/Alem.

          • 😉

            There is research showing that MS patients and patients with other chronic diseases deal very poorly with uncertainty. It is an interesting observation that needs further explanation. It is also clear from the population’s response to the COVID-19 pandemic this is a systemic problem. Maybe we need to teach uncertainty theory to kids at school. It is interesting that even statisticians have a problem with uncertainty and predicting risk and interpreting risk when it pertains to themselves. C’est la vie!

          • Well it’s interesting for sure as we also learned pwMS generally accepts more risks than Neuros, but probably not neuros of your kind.

            How you lost credibility to me (which is not a big deal at all ;)), has nothing to do with uncertainty, but I could see some of your motivations behind the opinions. The opinions sometimes are contradicted to one and another, I think you need to construct the expression of opinions in a more systematic way.

            I don’t know about Luis but I agree with you that I should read your posts less for my own good.

          • As I have said before I am not a priest; I don’t have beliefs but opinions based on hypotheses. When new data emerges I read it think about it and change my position. This is science it is a uncertain and moving target. Science is also about cognitive dissonance, i.e. holding or putting forward two apposing hypotheses at the same time.

          • “There is research showing that MS patients and patients with other chronic diseases deal very poorly with uncertainty. It is an interesting observation that needs further explanation.”

            Oh for pity’s sake. And we wonder why there isn’t funding for meaningful research. But at least we know grant-writing is alive and well.

          • @Karen

            It only takes a few minutes of browsing the pubmed results for MS to realize that huge amounts of MS research is being done on useless garbage that has zero chance of ever making a difference in the lives of MS patients or serving any purpose whatsoever beyond pumping up some academic’s CV. Some examples of truly scintillating and novel research from the most recent results:

            “Interferons and Multiple Sclerosis: Lessons from 25 Years of Clinical and Real-World Experience with Intramuscular Interferon Beta-1a (Avonex).”

            ‘They’re getting a taste of our world’: A qualitative study of people with multiple sclerosis’ experiences of accessing health care during the COVID-19 pandemic in the Australian Capital Territory.”

            “Development of clinical guidelines for service provision of functional electrical stimulation to support walking: mixed method exploration of stakeholder views.”

            “A Smartphone-based Application for Self-Management in Multiple Sclerosis.”

            “Novel Drug Delivery System for Curcumin: Implementation to Improve Therapeutic Efficacy against Neurological Disorders.”

            Please God, someone implement some common-sense oversight of MS research grants.

    • What is 4th heading? “Disease worsening or disability progression in MS can be explained under 4 headings:”
      Personally,I have multiple sclerosis and have been (almost) neida since lemtrada four-ish years ago. I did have old stuff flare up last year and did a third round. ANYWAY, your succinct comments are a wonderful explanation of ms “progression” curious about the 4th “heading” and a link to videos…thank you in advance, much respect to you.

  • Could the lesion be caused by some sort of blood clotting and the iron rim is from the extra build up of red blood cells that have clotted in the area?

    Or an attempt of the body to repair in some way, but blocking the oligodendrocytes from carrying out the repair process, there for they don’t differentiate leading to more disability.

    Would iron chelators be of any use in some way.

    • Iron is pretty essential for bodily functioning… I don’t think you could take iron chelating agents safely unless you already had an iron overload in the blood. Not to mention you probably wouldn’t be able to direct a chelating agent to only chelate the iron around a smoldering lesion, it would suck iron out of the entire brain, which would be really bad.

  • Are all SELs ‘iron rimmed’ and equally destructive? I don’t think MRIs state ‘SEL iron rimmed lesion’, just SEL – because they are all iron rimmed?

    • No, they are not all iron-rimmed. What defines them is if they are enlarging. There may be something different between SELs that are and are not iron-rimmed.

    • Ofatumumab is lower-dose anti-CD20 than ocrelizumab to begin with, so doubling the dose might not be enough to achieve any additional effect.

  • Would this possibly explain why people on Ocrevus begin to feel symptoms increase both a month before next infusion?

      • The outcome in octupus is MRI but I suspect it is brain atrophy

        Note not that OCTOPuS (Optimising Cardiac surgery ouTcOmes in People with diabeteS) or the other OCTOPUS is an umbrella phase II framework for testing whether the addition of novel targeted agents to weekly paclitaxel (wPxl) improves efficacy in PROC

      • That’s great to hear professor Gavin. I am happy that lipoic acid will be further tested in a bigger trial ( Octopus ms trial ).

  • Thanks Prof G. Great article. But doesn’t that imply MS is curable? Meaning no more damage and not reversing damage done already. Stop smouldering MS was the only missing piece in the jigsaw.

    • Re: No not really. Ocrelizumab and natalizumab only slow down the expansion of the SELs relative to placebo they don’t necessarily stop their expansion. In addition, there are other processes driving smouldering MS outside of SELs, i.e. cortical lesions, premature ageing, etc.

      Curing MS needs IRTs given very early at a phase before smouldering MS is set up or there is too little of it to detect.

      What this study shows is that SELs may burn themselves out with a little help from DMTs, i.e switching off new and ongoing focal inflammation.

  • Thus Mean my brain is not like SELs Swiss cheese full of black holes being on Nalalizumub. Thank you

    • How long have neuros known about smoldering MS? I heard term once from my neuros 15 years ago when I asked why I was FUBAR and my MRI lesion was lit up with ring 6 mos after CIS. I thought it was a war metaphor and had no idea it was a medical term of art until much much later.

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