A decade ago we had the issue of CCSVI, where by it suggested that blocked veins was the cause of MS. People with MS got their veins expanded and claimed success without the need for a neuro. ProfK went straight into the argument to say “hang on a minute”
Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010;68(2):173-83.
As a result he was taken off a few people’s Chrimbo card list and put on their SH1 list:-). Many years later and a few million dollars research money lighter, CCSVI has largely been forgotten.
Recently you asked about this paper “Carotentuto et al. Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability. Brain. 2021 Dec 17:awab454”. I thought great we can learn about the Glymphatics and the title of the post could be blocked drains as an issue for MS”. Will Canada and Italy who bought into the CCSVI idea big time get get clinical Dyno-Rod in to clear them drains, as the glympathics is a brain waste disposal system for the brain. So I got excited as it is time to talk about glymphatics and meningeal drainage pathways and maybe its influence in MS. So off I started to write the post but it is too long so I split it up.
The real MS
Will the real multiple sclerosis please stand up? Nat Rev Neurosci. 2012 Jun 20;13(7):507
ProfG and others have talked about the “RealMS” which in part comes from the observation that you get microglial associated lesions in the CNS when there is no apparent lymphocytes in the area and then lymphocytes come in to the brain with the characteristic MS lesion in response to that and so the disease starts on the inside of the brain and this is called “inside-out”. It is also in part a way to explain treatment failure. In the “inside-out” idea some people see this inflammation as “good inflammation” and has been called “protective immunity”. The other scenario is where lymphocytes are activated in the lymph glands and enter the brain to cause damage a bit like you see in animals and this is “outside-in” disease. The “inside out” disease has some traction and in part explains progressive worsening despite effective control of the immune response that inhibits relapsing MS.
Which is true?….This is important, but I believe the observations on which the arguments are made cannot give you the simple answers. So it is abit of a sterile argument.
It is evident that if you only monitor leg function you miss the benefit that can be seen when you monitor hand function. So it may not be true that currrent MS drugs cannot inhibit progressive MS. We will see if this pans out with ORATORIO HAND and CHARIOT MS, but although it showed itself evenutally in the ASCEND trial using natalizumab
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. 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. Lancet Neurol. 2018;17(5):405-415.
But it is viewed as a failure and the other supportive data from meeting abstracts has yet to see the light of day
However, in my mind there is more to be done to try and deal with the problems of MS. But, there seems to be a mantra that single treatment will do the whole job and this is were I think we are wrong. Pharma to a large part dictates treatment of MS and monotherapy is the current model….at least perhaps until their patents expire.
Inside-out, outside-in, both leave you with a situation needing effective control of lymphocytic and macrophage inflamation and the realisation that processes are set in motion that will take time to play out and that blocking the lymphocytic inflammation alone is not going to stop all issues arising.
The idea of “inside-out” in part from stems from the “17h lesion” where someone died after 17 hours into their attack and in the tissue they saw oligodendrocytes dying by cell suicide without a lymphocyte in sight.
Barnett MH, Prineas JW Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion..Ann Neurol. 2004 Apr;55(4):458-68. doi: 10.1002/ana.20016.
However, to whilst the pathologists cannot see a lymphocyte in a lesion, it does not mean it was not caused by a lymphocytic problem. In EAE we see lesions where we know lymphocytes are in the causative pathway but given time you can find microglial/astroglial lesions containing few or no T cells. The animals get progressive worsening due to inflammation associated with glial inflammation, which results for a damaged environment caused by a lymphocyte driven inflammation. So we have a fair idea what the “Real EAE” is…..but look at it 4-6 months later and the picture is different.
In EAE it can take one attack to set the progression in motion or in other individuals 3-4 relapses and for some probably more. Yes it it not MS but it shows you how such processes can occur.
Pryce G, O’Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J Neuroimmunol. 2005;165(1-2):41-52.
Likewise, a lesion in the spinal cord caused by lymphocytes could result in brain damage because of the down-stream effects from the spinal lesion, such as due to the die back of a nerve. Therefore the nerve would go first if you look in certain areas,
In the individual, with the 17h lesion there was a fair amount of myelination loss (have a look make your own mind up..it is loss of blue staining) , so thay had had MS for some time. This was their forth attack and they were only 13-14 years old…so not exactly your standard MS picture. You cannot exclude that the lesion was a result of lymphocyte activity causing release of damaging antibody somewhere else, damaging cytokines produced somewhere else, lack of tissue oxgyen because of events somewhere else….For lymphocytes to directly kill a target they have to see molecules called MHC class II or MHC class I and neither is usually expressed by oligodendrocytes and certainly not MHC class II so direct killing is not likely to happen in the best of times.
The 17h lesion has been revisited recently and as this paper is not behind a paywall you can have a look if interested
Multiple Sclerosis: Microglia, Monocytes, and Macrophage-Mediated Demyelination.Prineas JW, Parratt JDE.J Neuropathol Exp Neurol. 2021;80(10):975-996. (The 17h lesion is figure 30 and the same as figure 1 in the paper above). There they looked at 22 cases with 10 cases of duration of less than 9 weeks. They say “the capillaries in the cerebral cortex were plugged by large numbers of monocytes” suggesting that lack of oxygen in the tissue may be a problem, So if this is the case then it not “inside-out” as the problem is occurring from the outside? So is the problem of MS blocked veins?
Based on chance observations in radiologically isolated syndrome where people have scans and maybe a biopsy, regulatar MS lesions are found, perhaps years before an MS diagnosis was given and they are not always the oligodendrocyte distressed lesions. So the “real MS” may be appearing months or years before MS declares itself clinically and months/years before a pathologist get to look at the brain
Then to throw the next curve ball into the arena, some pathologists argue that the 17h case presented may not even be MS, maybe neuromyelitis optica, so you could be basing your ideas on “quick sand”. Neuromyelitis optica is a disease originally called Devics multiple sclerosis that is associated with the production of antibodies against a channel on astrocytes, These are damaged and can lead to oligodendrocyte damage.
However in MS, there is also astrocyte damage
Multiple Sclerosis: Destruction and Regeneration of Astrocytes in Acute Lesions.Prineas JW, Lee S.J Neuropathol Exp Neurol. 2019 ;78(2):140-156. doi: 10.1093/jnen/nly121.
Confused? You are not the only one
That is why you have to keep an open mind. Could it be an infection triggering an autoimmune reaction….maybe but maybe not. There are other explanations. Just because one is forceful in a view, does not mean to say it is right. Indeed where is the proof that MS is an autoimmune disease….Yes there is alot of dogma, but the hard evidence.
However, the clinical study is one of the best experiences to help inform and what we know is that neuromyelitis optica responds differently to some MS drugs, so there are fundementally different biologies somewhere.
Now whilst we are talking “inside-out” one can argue that the “protective autoimmunity” is on balance wishful thinking, because on balance we know that the inflammation is damaging. Why?
Because MS treatments inhibit disease and do not augment it. Of course there is good inflammation as this is part of the response. Get rid of the problem and repair the damage doing it. But on balance when you use an MS drug it blocks cells, entering the CNS and relapses don’t occur so that part of inflammation is on balance bad inflammation and it you do this early enough, recovery occurs as shown with early trated of alemtuzumab for example.
Now to the lymphocyte-less lesion is this the problem, it may well be and I have no issue with this. We have talked-about “pre-acute” lesions where you have distressed oligodendrocytes not nessecarily around blood vessels as the early lesion. But the motivating factors of the “outside-in” and inside out concept was to discuss where the lymphocytes come from and in part suggested MS was not EAE.
They are not the same but that is not the point. However, I would argue if MS is “inside-out” or “outside-in” the end result you see is the same by the time you present with MS. This is because when the argument was made it was perhaps considered that the brain was seperate from the lymph system and I can understand why you make such a concept. But once you know there is a connection from the brain to the lymph tissue and anything that starts in the brain is going to alert the immune system in the lymph glands. The reasons for the appearence of cells into the brain is blurred and hypothectical. In my opinion lymphocyte responses do not get generated in the brain, they get generated in lymph glands where the environment has evolved to generate an activated immune response. There is no reason to make something complicated out of something simple.
There is pathological gold dust that should be able to give answers, such as what is the picture in natalizumab treated PML-deaths or perhaps post-HSCT infection related deaths (but perhaps I should strike this idea as the HSCT process is apparently causing 10-15 years worth of nerve loss in the first year), but are they full of dying oligodendrocytes because the real MS is untreated, and just because some people contiune to progress does not mean the “outside-in” attack is not important as we have to realise no treatment is 100% infective. What is special about those ill-looking oligodendrocytes? Are they infected with EBV, or endogenous retro virus W or not. The technology is there to answer these questions if you have the capacity to look and importantly the gold-dust samples and doubly important the permission to look.
Is what triggers MS the same as what drive MS…some people argue no and some people argue yes…but do they argue together to get the right answer. This is important as it determines effective treatments. Anyway enough of that part II as the brain-brains tomorrow