ProfG’s real MS


People work on what interests them and what they can get funding to do. But we have been challenged to switch focus to work on the “Real MS”…but what is it.? Would it be sensible to all work on the same thing, because what if the idea is wrong?

You can read this review to get ProfGs idea. (He wrote the original version and the rest conceptulaized and edited). However the question remains what we are going to do about it? The best way to get support for the idea is do something about it and make a real difference to MS and the clinical study is key.

I am not going to comment on this paper/ It is a review and as it is open access you can read it and then you can ask questions.

It is ProfGs baby and is not my crusade. He and his colleges have to convince our peers that they are right and then the funders have to do something about it.

But, is it like the film National Lampoons Animal House where Bluto (John Belushi) makes a rallying speech (after they had been kicked out of College) and charges-off into the night hoping the masses will charge with him and then…..yep………no-one follows (Click contains bad language). However eventually someone else (Otter) gets the people going so do we need more opinion leaders to pipe-up?

However, I don’t see a clear path, but it is OK to highlight the problems with the current worldview

The “real MS” concept seemed to me to come from the realisation that MS continued to worsen in people getting drugs and there was a question if it started on the inside of the brain or outside of the brain. This suggests that the fundemental approaches to dealing with MS should be overhauled. I have no problem with that, but I think the basis on which the original ideas came from was based on results using weakly effective treatments that may have been started too late and was based on a sterile argument because what is “inside” can easily be moved “outside” as it has now been shown that there are channels for this process. Some types of inflammation will always come in from the outside and other types of inflammation will always be started from within and do not need the outside. This happens even if it is outside-in or inside-out. My view is its best to cover all bases. However the drivers must be located on the inside of the brain otherwise we would be looking at arthritis, lupus etc. Should this be what we should be doing? One can make a plausible case that starts with EBV and ends with disease in some cases MS, others not, as about 5-10% of the population has clinical autoimmunity/ Your genetics could determine which one(s).

If a virus is central to the cause why has it not been found? We have been looking for this for years. We found the virus causing HIV, we found the monkey-virus causing demyelination, we found the virus causing COVID. This didn’t take a hundred years. Is it under our noses and we just can’t see it? or we have seen it and nobody believes it is important.

Whilst a case is made that some MS drugs are anti-viral and punch above their weight in dealing with atrophy, the fact is if they were that good at getting to the cause….surely they should be more effective than they are. The interferons have been tried in progressive disease and it was not that great.

However, I will say I can see many of these processes playing out in EAE where we know what the cause is which central damage creates an environment for continual worsening that is not dependent on relapses, or current immunotherapeutics. This occurs from onset and kicks in after one or more attacks, it occurs after relapses burn out and what do we do about it….we have given so many suggestions…but we can’t do the clinical studies.

ProfG says “‘real MS’ is likely to be driven by a primary smouldering process accompanied by a superimposed inflammatory activity that potentially represents the host immune response to underlying causes of the disease”.

So the question what is the primary smouldering cause…Is it the sick looking oligodendrocytes? Why are they sick looking? Immune attack and we are back where we started? Genetics? Not so sure as MS is increasing and twin studies an argument against but could be, Virus/Bacteria? What are they?

You could now do this experiment get the oligodendrocytes out of tissue, work out which are the sick ones (HSPB5 expressing?) and hunt inside these cells to look at their contents. Where is ProfLove when you need her?…Made to Retire:-(But what if it is the astrocytes making the oligodendrocytes sick?). Plenty of stuff to do.

However is it time to ditch the current medications….I think ProfG would be Bluto (and not the Popeye character) if he thinks that is going to happen any time soon.

Giovannoni G, Popescu V, Wuerfel J, Hellwig K, Iacobaeus E, Jensen MB, García-Domínguez JM, Sousa L, De Rossi N, Hupperts R, Fenu G, Bodini B, Kuusisto HM, Stankoff B, Lycke J, Airas L, Granziera C, Scalfari A. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022 Jan 25;15:17562864211066751.

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.

COI: Multiple

Disclaimer: These are the views of the author and no-one else

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  • I thought there is a new review, I was not impressed by this paper, pushing ideas too far with limited pieces of evidence. Maybe this is what we need for science at the beginning stage, sad we are still at this stage.

    no other diseases looking at oligodendrocytes?

  • ”the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS)” where is this dominant view stated, a reference? There are thousands of researchers doing research on microglia, astrocytes, oligodendrocytes etc…
    The ”realms” is just a strong wording to make a point and it is more politics than science. These things are known for years but yes reinventing the wheel makes you an opinion leader…

  • ‘Is it under our noses and we just can’t see it? or have we seen it and nobody believes it is important’…

    Could be.

    ‘bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose to brain direct’
    Rev neurologique 175, (2019) 644-649.

    With the papers leading up…….and more shortly to come.

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