Is the real MS standing up?


You want some non-COVID stuff reported…ProfG has been doing this on his MS-selfie site and we can only report what people are publishing, so maybe this week we can do the “Real MS” for a change

One school of thought thinks that MS starts in the central nervous system and then lesions form, this is the “inside-out” brigade, in this study they use scans from trials and then find where lesions arise and look what happens before. They suggest that something happens before the lesions form. So evidence for inside-out.

Elliott C, Momayyezsiahkal P, Arnold DL, Liu D, Ke J, Zhu L, Zhu B, George IC, Bradley DP, Fisher E, Cahir-McFarland E, Stys PK, Geurts JJG, Franchimont N, Gafson A, Belachew S. Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise. Brain Commun. 2021 Aug 10;3(3):fcab176. doi: 10.1093/braincomms/fcab176. 

Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399n = 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.

Personally I don’t care too much if it is “inside out” or “outside-in” as the inside is connected to the out and the out has a route to an inside. I think the scientists made this construct to try and explain why so many MS drugs do not work in progressive MS but I am not sure you need to create such a polarised view. By the time you try to approach treatment both processess are at work in an MS brain

In terms of MS DMT the relapse problem are on balance the “outside-in”. I think the clinical trial is the ultimate experiment and response to therapy tells us this is part of the problem.

If this were not the case, things like natalizumab would do nothing.

Likewise in terms of progression, it is pretty obvious to me that there is an problem inside that needs dealing with. Yes I know we keep on targeting the “outside-in” in progressive MS. That is not my fault so don’t shoot the messenger.

Now the question is. Is the “outside-in” important as it is not targeting the “real MS”. However targeting the “outside-in” early in disease course, i.e. with a few years of onset, it does seem impact disability accumulation. However, there are elements in MS that are not going to response well/quickly to these approaches.

We need something to deal with the inside-out biology.

Now this study may support the concept of some biology occuring some time before you see the lesions form, we know this happens. This is what the MRI study suggests. However, MRI is not a microscope and the problem of using MRI is that maybe the problem is in “Birmingham” but the Magnet tells you something is happening in “Western Europe”. It is not high powered enough, Pathologically we can see the pre-active lesions that may be precursors for subsequent lesions and they are not going to seen in conventonal MRI.

It may indeed be the case that oligodendrocytes go first and it is inside out. However. MRI is never going to be able to exclude the possibility that cells enter the brain from the outside and cause damage inside. This damage may be caused by an immune cell that is nowhere near the damage because it does the damage elsewhere and by an invisible mechanism. e.g. you see an effect, which is interpreted to be “Ouch”, in the brain where you are looking because you have had your toe chopped off.

So you need other stuff to back this up. One of the key features that created the “outside in” was the case report of someone dying shortly (about 17 hours) after an attack.

In these areas of damage there were areas of cell suicide of oligodendrocytes with condensation of the nuclear material (e.g. the two blobs in the crazy frog ghost on the far right hand cell below).

This was reported in Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458-68. A few years later we had brain biopsies reporting the same thing

Remember the murderer seldom hangs round the body to be caught by the police. The histologist is like the police they come to the scence after the carnage and they try to work out what happened

However, this week Prof Prineas(histologist) is back. The original artical came out in 2004 BB BB=before the Blog. What would be have made of this?

However this case has surfaced again (case 9. Figure 30-32) and you can even see the caspar the friendly ghost oligodendrocyte (far right above. It is turned on its side)

Prineas JW, Parratt JD. Multiple Sclerosis: Microglia, Monocytes, and Macrophage-Mediated Demyelination. J Neuropathol Exp Neurol pp. 1–22 doi: 10.1093/jnen/nlab083

The original case was in 14 year old girl who had disease for 9 months. She had had 4 attacks in that time certainly time for the preverbial toe to have been affected. There was so called remyelination in the sections looked (so there had been demyelination and repar) at and there was myelin loss (looks white compared to the Blue. Had this really happened in 17 hours).

First question, was this case multiple sclerosis or something else like neuromyelitis optica?

Hopefully one of the pathology gang will explain this….The conclusion is that the target is astrocytes and oligodendrocytes and not myelin…..Maybe we can get the “Autoimmunity to myelin basic protein is MS” brigade to defend their position. I would say response to therapy tells us that MS is not simply a problem of targeting “myelin basic protein”..this is a concept made up by lazy T cell immunologists who found it easy to purified myelin basic protein..

Anyway something to look forward to…………

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

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  • To clarify the MS-Selfie site is not about MS research. All the posts are about MS self-management and/or information to help you make decisions about your MS care. At the moment most of the posts are repurposed and updated from previous posts from the MS-Blog. The MS-Selfie Case studies are new and from pwMS who contact me for advice.

    • It is an autoimmune 100%, MD is making the point whether if it is secondary or not it doesn’t matter for the treatment for now, maybe decades later. Maybe there are two types MS :), one outside-in one inside-out. I would think if it is a same thing consistent happening inside of every pwMS’ brain, it would have been spotted quite easily.

      • If it’s 100percent. What part of the immune system is causing Brian atrophy? Progression independent of relapses? Symptoms before any MRI spots occur?

        • Do you believe that MRI can detect all the lesions, I don’t it missed grey matter lesions for thirty years and ignored spinal cord lesions for much of that time
          Brain Atrophy is a combination of differnt bits of the immune system

    • Thank you. I’ve just watched some, il watch the whole video later.

      How are the anti viral trials mentioned in the video going?

      • “How are the anti viral trials mentioned in the video going?”

        Not Well…Raltegravir was an attempt to treat MS with an HIV antiviral drug..Probably some thing really basic why it failed… an EBV expert could have explained in minutes..instead of doing a trial and spending $1-2 million in Merck money.

        “What is raltegravir used for?”
        Raltegravir is an antiviral medicine that prevents human immunodeficiency virus (HIV) from multiplying in your body. Raltegravir is used to treat HIV, the virus that can cause acquired immunodeficiency syndrome (AIDS). Raltegravir is not a cure for HIV or AIDS.

        “Conclusions: Raltegravir did not have any impact on MS disease activity.”

    • I was looking at the slide with men:women incidence after reading this post and I thought that the two mechanisms (inside out and outside in) are impacted by sex. In fact relapsing disease occurs more frequently in women. This may imply that the outside in mechanism is influenced by sex while inside out is not (inside out, smouldering). In turn this means that if we know which part of the immune system is not influenced by sex hormones then we can get information of the inside out mechanisms involved in the disease. So the question is which parts of the immune system are and are not influenced by sex hormones?

  • Surely, if it was inside out, and an effective therapy targeted that, the outside in stuff could become redundant.

    It’s just the same old same old. The inside out stuff, the EBV stuff etc. etc. falls into the gutter on the DMT anti-inflammatory highway. I have 2 decades of slow smouldering and very little evidence of treatable inflammation and I’ve given up on a treatment. Other than exercise and lifestyle.

  • Thank you for this non-covid post. What could help us visualize/look deeper into the inside-out? Obviously 1.5T MRI is a no go.

    • Yes I agree scanners have improved and now we have the clinical seven tesla, which a few places have but still that does not have the power to be microscopic

      • “It’s just the same old same old. The inside out stuff, the EBV stuff etc. etc. falls into the gutter on the DMT anti-inflammatory highway. I have 2 decades of slow smouldering and very little evidence of treatable inflammation and I’ve given up on a treatment. Other than exercise and lifestyle.”

        “scanners have improved and now we have the clinical seven tesla”

        We don’t need 7T scanners we need someone with vision to break new ground. Every treatment seemingly only works on inflammation.

          • “the smouldering lesions are inflammation just a different kind”

            Different vocabularies mean different things to people. To me pure smouldering ms is progressive ms with No lesions…hence no treatment for ppms…just as no dmt stops evolution of spms.

            Just saw shark tank contestant(Dragon’s Den u.k.) say his father was diagnosed ms and was quadraplegic within the year. This is smouldering ms…ms minus inflammation = ALS or PSP…you have no lesions at all…just total nerve destruction. So no
            iron rimmed expanding/smouldering ones either.

          • To me pure smouldering ms is progressive ms with No lesions = To me this doesn’t exist….All autopsy of PPMS has lesions somewhere…MRI may not be able to see them

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