More evidence to support the smouldering MS hypothesis?

M

Barts-MS rose-tinted-odometer: ★★★★★ (neon tennis ball green #dfff4f)

Yet another study showing that there are abnormalities in the so-called normal-appearing white matter (NAWM) that precede the development of new MS lesions. 

This supports the hypothesis that there is something in the brain tissue that triggers the development of lesions and relapses. Could this be a virus, like an isolated seed or flower in a field of wheat? Why do I say this? Firstly, when pwMS were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was a fundamental observation and was telling us something important about MS. 

Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab the field (brain and spinal cord) becomes more abnormal and when you let these cells back in they detect the abnormal field and run amok trying to clear the field of the offending agent. This is what happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post natalizumab is simply IRIS in response to the virus that causes MS.

Other serial MRI studies have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. 

These studies all suggest that the primary pathology is smouldering MS and is due to something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The inflammation is secondary to what is causing the disease. The challenge for us all is to find out what the abnormality is that is causing these changes in the NAWM. I think the best chance we have of doing this is to study the brains of pwMS on natalizumab. To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for pwMS to donate their brains for medical research.

If you are interested in more musing about the field hypothesis please read a previous post of mine from 2012 on this subject.

Well done to Emma Raducanu, whose US Open victory was a joy to watch. But best of all is her Twitter bio which contains just four words “london|toronto|shenyang|bucharest”. Another example of the pros of diversity, similar to the author list of the paper below “Colm Elliott, Parya Momayyezsiahkal, Douglas L Arnold, Dawei Liu, Jun Ke, Li Zhu, Bing Zhu, Ilena C George, Daniel P Bradley, Elizabeth Fisher, Ellen Cahir-McFarland, Peter K Stys, Jeroen J G Geurts, Nathalie Franchimont, Arie Gafson, Shibeshih Belachew”.

Elliott et al. Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise

Brain Communications, Volume 3, Issue 3, 2021, fcab176. 

Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis.

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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.

34 comments

  • “To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation.”

    But if the virus is identified (likely to be EBV) what can be done about it? I thought you had previously identified B cells as the carriers of EBV, but can EBV just reside in tissue?

    What does this mean for the Sizomus trial?

    • This is an article of interest. But how many swallows does it take to make a summer?

      Serafini et al. Epstein-Barr Virus-Specific CD8 T Cells Selectively Infiltrate the Brain in Multiple Sclerosis and Interact Locally with Virus-Infected Cells: Clue for a Virus-Driven Immunopathological Mechanism. J Virol. 2019 Nov 26;93(24):e00980-19.

      Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). However, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS can stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique. Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus and influenza A virus) proteins, and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a positive, suggesting a cytotoxic phenotype, and stuck to EBV-infected cells. Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV contribute to inflammation causing CNS injury.IMPORTANCE EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage. To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

  • Or is the possibility of natalizumab rebound is, possibly EBV taking on residence in more B cells, outside the CNS. So once the ability is given for these immune cells to enter the CNS they are more auto reactive than before

    Or

    Is MS not auto immune at all and lesions are simply the aftermath of some reaction in the CNS. And MS is a neurodegenerative disease starting in early life

  • Surely this will also apply to Alemtuzumb?. Why isn’t there a rebound once immune cell population bounce back? Why doesn’t secondary MS occur in these patients? Also if what your saying is correct, then those on ocrelizumab will convert to secondary ms because your not addressing the smouldering MS? Lastly, this would imply not treating MS with DMT is best option to allow the immune to clear the virus? There too many inconsistencies.

    • Some Lemtrada patients do go on to SPMS – I suspect older patients who were treated later.

      Really need some well powered anti-viral trials. Also need trials using HAART – there are case studies showing MS patients (with HIV) treated with HAART saw their MS go quiet.

    • With IRTs (alemtuzumab, cladribine, AHSCT) what comes back is not what was there before. In comparison anti-trafficking therapies such as natalizumab allow rebound to occur.

    • Rebound happens when they cells are lines up waiting to go and they all pour in when the brakes come off, because with alemtuzumab the cells come back in dribbles there are not enough to cause the mega attack so you will call it a relapse and not rebound

      • I sympathise with regards to the situation it is discouraging seeing that. Being as the individuals that go threw the grant application have little interest from my understanding which is unfortunate, I believe that the therapeutic vaccine for EBV being developped by Moderna could be a pharmaceutical company to reach out to in order to have discussions with them.

        Another possibility is since you already succeeded a few times with crowdfunding ideas before perhaps another round of crowdfunding for this idea could be worth a try with better results.

  • IRIS is well known in HIV patients who have low CD 4( <20) and upon HAART mount an immune response to “smouldering” HIV, MTB crytococcocus inthe CNS or other tissues after CD 4 rebound. The treatment of these opportunistic infections prior to HAART lessens the risk of IRIS. My question is – is it possible to treat say latent EBV with anti virals before cessation of natalizumab to lessen the risk of IRIS thus implicating EBV contributing to smouldering MS. Or is it too difficult for anti virals to penetrate the CNS

      • “Also if what your saying is correct, then those on ocrelizumab will convert to secondary ms because your not addressing the smouldering MS?”

        Yes…of course…all these so called highly effective therapies conert to spms.
        Tysabri..Ocrevus..Fingolimod…all of them do.

        Lesson learned go for hsct and don’t look back.

        “Why isn’t there a rebound once immune cell population bounce back?”

        In hsct the chemo cuts inflammation and immune cell levels.
        Cell repopulation in the absence of inflammation..induces tolerance hopefully.

        Of course…pretty much 20% fail hsct right off the bat and will still
        show active disease. This what they say in Sweden where they perform it on
        newly diagnosed…same failure rate found in Mexico/Russia.

  • So what of those of us with slow, slow PPMS with an apparent predominance of spinal damage, no sign of optic neuritis and next to no apparent relapses? Our immune systems are not primed for unhelpful overreaction?

    • I suspect if we gave pwPPMS interferon-gamma they will have relapses. Interferon-gamma converts lepromatous leprosy into tuberculoid leprosy. I think the same thing will happen in MS.

      This is why I have proposed calling PPMS lepromatous MS, and RRMS tuberculoid MS.

  • Why does ocrevus stop inflammation in the brain if antibodies can’t really cross the blood brain barrier ? Also being as only 2 percent of b cells are in the blood stream.

    • It depends on how you define inflammation. Yes, it stops relapses and new MRI lesions from forming, but it doesn’t get rid of OCBs or normalise brain volume loss. In addition, many of the established slowly expanding lesions continue expanding. So does it really stop inflammation in the CNS?

      • My neuro recently advised that the appealing data for HSCT and Alemtuzumab cannot be relied upon on compared to more recent DMTs as it was based on techniques that were proved to be faulty or outdated. Is this correct?

        • Faulty or incorrect. Not sure the alemtuzumab trials and the most recent HSCT trials are using similar MRI technology to other trials. I would disagree with this assessment.

    • Not sure I agree. MD has even created an animal model of smouldering MS.

      Al-Izki et al. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler. 2011 Aug;17(8):939-48.

      Background: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination.

      Methods: The effect of FTY720 was assessed in relapsing-progressive EAE in mice.

      Results: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course.

      Conclusions: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.

  • If so, why ocrevus reduces PIRA?

    I think you really need to distinguish two different components in your theory of smouldering MS :
    1. Eventually, what comes before the inflammatory activity and trigger it.
    2. What comes after the inflammatory activity, remains even if there is no more RA, and basically drives PIRA.

    About the first component of smouldering MS, yes it might be EBV. It makes sense. But, it’s clear today that ‘time is brain’ and that the sooner you are put on a DMT (and especially a highly efficacy DMT) the better is your outcome. So even if our immune system reacts to EBV, what the data shows to my mind is that it’s for the better!

  • Very pertinent reflections, and very likely to be very near to the truth. Just one very large anomaly. ‘..the necessary techniques to look for viruses’…..

    The necessary techniques of increasing sensitivity and specificity have repeatedly been applied to early, appropriate autopsy tissues over the past 20 to 30 years. Occasional claims to be positive in the search have not been reproducible. The situation is not unlike the failure to establish clear evidence of ‘autoimmunity’ in MS Its just not there!

    Think again. There is a key missing link in the understanding if the pathogenesis of MS.

By Prof G

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