The Scientific Process-If you can’t disprove it, it may be true!..But if you can, It’s not.

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The scientific process is you set test a hypothesis that there is no difference between your idea and the control. If there is no difference you try something else and if there is a difference you move on. For regular readers you will have heard of Karl Popper before. Most of my peers have forgotten him. He told us we should not do experiments to prove our idea, we should do them to try and disprove our idea. Because if we can disprove it, then the idea is wrong. If we did experiments that disproved ideas, we would be not getting as much science-tripe as we do.

So we hear some some scientists say “Will the real MS stand up” and we have heard some Scientist say…Is MS “Outside-In” (Starts on the outside and the immune sytem enters the brain) or is it Inside-Out” (Starts in the brain) or maybe. Scientists have picked this up and it is consuming them….How do you test for this? You will be funding this?

What do you do? First point of call is you read.

However you could ask is it ” “Inside-Outside-In”? Because when we look at their earliest time point there is virtually always active inflammation around. There are some pathologists X that say “Hey, we see oligodendrocyte damage but we can’t see lymphocytes so it must start on the inside”. Then some pathologists Y say to me, what Pathologist X was not looking at MS at all and so the ideas are also based on quick-sand. But as Pathologist X is an opinion leader…..Glug, Glug, Glug. Pathologist Y is now labelled a maverick and no one listens to them and their alternative views are ignored Glug, Glug Glug:-(

If the issue is a virus..surely it comes from the outside-in?

You say “Who cares?” “Do something about it rather that sit on your bums ponificating!” However, it becomes important when you want to try and treat MS. If you are told it’s futile, is it futile?

This idea above was made all because of the thought that advanced MS does not respond to DMT that block relapses and as this is “Outside-In” is not being blocked there must be a push from the inside.

Therefore, you give up on the outside in. Now, I would say do some reading and thinking and you will find that your base-idea is made on quick-sand and does not stand-up to scrutiny. Prof Popper would be poppin..Your treatment idea is going to struggle yes but it is it not all in vane. But, until the community get this, you will not get the best treatment approaches.

Slowly you hand sink under the quick-sand..Glug, Glug, Glug:-(

It is simply not true that DMT have no effect on progressive /advanced MS. There is data from HSCT for all to see and a HSCT tribe that will tell you this. Do a trial that lasts more than 2 years and it is there to see, do a trial based on hand function and not the crappy EDSS and it is there to see. Look at the Natalizumab ASCEND trial with an open mind and it is there for all to see. Yet speak to a Dinosaur and they say “it failed”…This is because they only remember the punch line, as it did not affect the E….D….bloody SS walking scale.

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdová EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, Steiner D; ASCEND investigators.Lancet Neurol. 2018;17:405-415.

We have all heard of Tyranosaurus Rex with the small brain but it seems that way within neurology Dinanosaurus ******* (Insert the name of your favour candidate)

Scanning Neurosaurus rex….the Dinosaur Neurologist with the tiny brain case. I am told they have a sense of humour so they may let me off with this on. Otherwise it is the Doghouse:-)

Yet the MS Dinosaurs are short-sighted and the scientists don’t really bother too much with people, they spend most of their time saving their furry friends, so have no real idea what the” real MS” is even if it stood in front of them.

OK, that’s a bit harsh but how many times do we see the idea that it is simply Th17 T cells controlled by T regulatory cells that is all important….virtually every review….me thinks:-) Maybe Immunosaurus rex

Don’t believe me, check out below for today’s offering

However, it is also clear that DMT are not the complete answer and until you realise this, MS will be one or three diseases. Hopefull, pharma will not disenguage whilst they wait for the old school dinosaurs to retire, as they don’t want to do six trials (or six papers to put the dinosaurs on:-), when they could do 2 (Two phase III).

Is Smouldering MS the real MS? This creates the suggestion that MS must be a two stage process, relapses and then progression so at least 2 maybe 3 diseases.

The “Chameleon from Sidcupp” critisized us for not working on smouldering MS, the “real MS” because that is there from the start.

I asked “How do we know that?”

“Do we ever see MS at the start?”

In animal models, it is clear that the smoldering lesions occur but this is secondary to the active inflammation causing the damage in the first place. But sure, MS can start in the brain in MS. However, as there are drainage pathways from the brain to the lymph gland then the outside-in idea collapses to some extent.

I have serious doubts that the immune response would ever be generated inside the CNS as we have evolved lymph glands for that to happen in lymph glands and with a drainage pathway from brain to lymph glands present, why do we have to make up hard stuff? The immune response is always “outside-in” even if it started inside. On balance there is no protective autoimmunity as we have done the experiment and DMT inhibit damage so on balance there is no effective protective immunity and Mr Popper says move on and get a better idea. We believe this occurs in MS because of MRI and FLAIR*, which puts central veins at the core of the lesion, but the smoldering lesion does not have to be within a blood vessel or be near lymphocytes (White blood cells). The imagers have problems seeing these, so out of sight out of mind/thought

However, if I fart after eating a few eggy-sandwiches, you may be able to smell it round the corner (Phew what’s that stink!) from where I am standing. Just because you can’t see the problem came from a human, it does not mean the smell did not come form a human, sure I’ll blame it on the dog, and given the smell you may think it was an alien-life form:-). So, OK I am making a point here, but if pathologist X cannot see the infiltration on the slide, it is not there. Come-on time to retire…Oh they Have:-)

This is nonsense, you may just have to look in a different place in a different way. The grey matter has a ribbon of demyelination and few cells to be seen, but we think the initial problem was caused by a rogue cell somewhere in the CNS, what’s the difference?.

So now I turn to pathologist Z and ask is the smoldering lesion are there at the start..They look at people with a (0-1) death from diagnosis and you see below (Far left there is no orange). Idea rather disproved..back to drawing board perhaps

So there is not much smoldering activity from the start, the idea seems to be disproved, and suggests the inflammatory lesion conditions the CNS enviroment to make smouldering lesions, yes it can start in the CNS, there are more pre-acive lessions than there are lesions so some may regress. This says start as early as possible to limit those smouldering lesions from starting, it is not one or the other that needs targeting it is both, but getting rid of what you can early is the best approach

The idea that advanced MS does not respond at all to DMT is likewise very debatable. In fact it is also simply not true.

A simple way to see it is that a match lights a fuse and then the fuse will burn for a long time after the match has gone out or has been blown out. Some of those fuses are 3-5 or more years long. If you have a lot of fuses burning at the same time you are more likely to notice it when the lit fuse enters the dynamite.

We know that MS is damaging because it liberates nerve proteins (neurofilaments) into the blood

Blood neurofilament light levels segregate treatment effects in multiple sclerosis. Delcoigne B, Manouchehrinia A, Barro C, Benkert P, Michalak Z, Kappos L, Leppert D, Tsai JA, Plavina T, Kieseier BC, Lycke J, Alfredsson L, Kockum I, Kuhle J, Olsson T, Piehl F. Neurology. 2020 Feb 11. pii: 10.1212/ WNL.0000000000009097.

Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.

Looking at the results

teri-is not stopping nerve damage, it is not good enough

So if you have a choice think about this diagram.

Having the immune response in the CNS is on balance damaging. The damage from the so called “real MS” is dwarfed because, if it were not then when you get rid of the damage the levels of nerve damage seen with neurofilaments would be high. They are not (See below). It does not say the that the “real MS?” is not there but its impact is relatively minor incomparison to the inflammation. Do what you can as early as you can.

Neurofilaments were measured in the cerebrospinal fluid levels

But that’s relapsing MS what about progressive/advanced MS you say.

That has been done also. We all know that when you expression an opinion, it seems that scientists are so frightened they soil their pants. It was done in 2018 and has still not surfaced….sounds like the dinosaur-referees are putting the boot in

Neurofilaments were measured in the blood. This less sensitive than the cerebrospinal fluid

So they you have it, natalizumab that inhits cells getting to the brain also stops nerve damage, whether you are ACTIVE (gadolinium positive) or so called IN-ACTIVE (gadolinium negative).

Hey and it also saves loss of Hand Function, but it was too late for the legs

There you go, treat Early and Effectively…..It’s not Rocket Science.Is it?

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MouseDoctor

14 comments

  • Congrats …Very nice post

    Anyway the hsct ” zealot ”

    Reports this study in advance ms with no b cell no plasma cell and very few t cell and still progression

    “no B cells, plasma cells or
    lymphoid follicle-like structures in our cases, although it is
    suggested that pretransplant plasma cells and, accordingly,
    possible pathogenetic antibodies persist in the CNS after
    extremely lymphoablative conditioning (Storek et al., 2004).
    Thus, the pathogenic role of plasma cells or antibodymediated
    damage remains uncertain.”

    Autologous haematopoietic stem cell transplantation
    fails to stop demyelination and neurodegeneration in
    multiple sclerosis

    https://www.ncbi.nlm.nih.gov/pubmed/17293360

    • HSCT does not target the CNS adequately, cyclophophosamide can get into the CNS but it target proliferating cells and therefore would not necessarily target plasma cells as they do not necessarily divide. As such in 50% of cases in a paper I read the oligoclonal bands persisted.

      If you look at a lymph node you see germinal centres…this is where plasma cells are made…this is not where plasma cells live which is in the bone marrow and within the lymph gland they migrate out of the germinal centre as soon as they are made, so looking for B cell follicles amy not be where you should be looking…there are none until you find one. It depends how you look

      • Md they looked into the lesions and found no plasma nor b cell and only few t cell
        ” The inflammatory infiltrate within the lesions showed only very few T cells and CD8+ cytotoxic T cells dominated the T cell population. B cells and plasma cells were completely absent from the lesions”

        Busulfan and cyclophosphamide are both cns penetrating

        If there is virtually no peripheral immune cells in the lesions who go them out?

        Ms lesions contain both of those type of cells

        “The phenotype of lymphocytes infiltrating active MS lesions in acute, relapsing and progressive MS suggests a dominant role of CD8+ T-cells and cells from the B-cell lineage. The CD8+ T-cells reveal the phenotype of tissue resident effector memory cells, which show focally and temporally restricted activation, associated with active tissue damage. B-lineage cells in active lesions are mainly CD19 and CD20 expressing B-lymphocytes. With lesion maturation these B-cells apparently differentiate into immunoglobulin secreting plasmablasts and plasma cells, which also express anti-inflammatory cytokines. These data suggest that new treatment strategies should focus on the elimination or de-activation of CD8+ T-cells and B-cells.

        H. Lassmann

        https://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/148

        Obrigado

        • H lassman gave a talk at charcot 5mins before Alex Pratt gave a talk that completely disagreed with Hans Lassman and nothing was said…it makes you wonder what the reality is.

          As I said just because you cant see it doesnt mean it is not important

  • Wish you had taught me chemistry, I would have paid more attention. Thank you for this post. From a physio perspective I can do little to alter the rate of progression other than ‘lifelstyle’ advice and rehab but, with the emphasis on ‘early’ intervention, I altered my approach to treatment from reactive to proactive, a while ago.
    Keep up the good work, it is greatly appreciated.

  • Thank you for this post. I enjoyed it & learned something. 🙂

    After reading about CD20s possibly acting as IRTs, I’d be interested to know if people’s NFL levels after stopping a CD20 have been tested. I know the B cells come back eventually, but does the nerve damage also resume at some point? Maybe it’s hard to say because mostly they probably go onto a different DMT.

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