The New MS Subtype. Is ProfG Wrong to Suggest MS is a Single Entity? Is MS just more like EAE?

Yesterday it seemed to me that we had someone who was making a comment and was rubbing their hands with glee (gloating) to suggest that BartsMS was wrong. 

I am sure we are wrong many times and anyone reading the blog regularly will note that we are humble enough to accept our mistakes. 

Likewise, the tone of a different comment, seemed to me, to be a complaint that “you” were bringing “News to us”, rather than “we bringing news to you”.
This makes an important point

The blog is not our day job . We cannot always search the internet for the next news story. Therefore we can’t be proactive about everything. 

Sometimes we are reactive, sometimes we are absent (I am currently taking some vacation time and writing this at 2.30 in the morning). Maybe we can comment after the story that has broken. 

Likewise, sometimes we don’t have the time to search for the items (the media get access to things before they go in the public domain), which you may find of interest. Likewise, we may find the story to be of such little importance that we don’t comment or don’t have the time to comment. 

Therefore simply put, we need your help to be part of our team. 

One vital part of this is that you are our ears and eyes and if you find something that interests you or don’t understand, it is likley to interest someone else or likely that someone will not understand either. 

You can simply come to the blog and write a comment.  

We will not comment on personal circumstance as this is not a consultation vehicle, so keep it general if you are asking health related questions.  Likewise we are here to discuss science.

We have been suggesting that MS is one disease not two or three diseases, but you write to say that we must be wrong because someone has found that there is a subtype. Are we wrong?

Firstly and whilst I do not want to discuss this further on the how you feel about the “them and us” attitude. 

Frankly it rather saddens me if people think that we need to be adversorial. However, I can see some people will believe this, just as I sometimes (currently as I write think) think that there is a “them” (dumb-assed neurologists) and “us” (enlightened scientists. Sorry can’t say more as the air would be blue:-). 
It know it could be a lone voice, a troll and likewise I know that many of you will defend us (Thank you). 

Anyway back to the post.

ProfG has been making the point that MS is one disease. Is this wrong?

In this new report there is a suggestion that a subtype has been found.

Bruce D Trapp, Megan Vignos, Jessica Dudman, Ansi Chang, Elizabeth Fisher, Susan M Staugaitis, Harsha Battapady, Sverre Mork, Daniel Ontaneda, Stephen E Jones, Robert J Fox, Jacqueline Chen, Kunio Nakamura, Richard A RudickCortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol 2018.

Background: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination.
Methods:Brains and spinal cords were removed at autopsy from patients, who had died with multiple sclerosis, at the Cleveland Clinic in Cleveland, OH, USA. Visual examination of centimetre-thick slices of cerebral hemispheres was done to identify brains without areas of cerebral white-matter discoloration that were indicative of demyelinated lesions (referred to as myelocortical multiple sclerosis) and brains that had cerebral white-matter discolorations or demyelinated lesions (referred to as typical multiple sclerosis). These individuals with myelocortical multiple sclerosis were matched by age, sex, MRI protocol, multiple sclerosis disease subtype, disease duration, and Expanded Disability Status Scale, with individuals with typical multiple sclerosis. Demyelinated lesion area in tissue sections of cerebral white matter, spinal cord, and cerebral cortex from individuals classed as having myelocortical and typical multiple sclerosis were compared using myelin protein immunocytochemistry. Neuronal densities in cortical layers III, V, and VI from five cortical regions not directly connected to spinal cord (cingulate gyrus and inferior frontal cortex, superior temporal cortex, and superior insular cortex and inferior insular cortex) were also compared between the two groups and with aged-matched post-mortem brains from individuals without evidence of neurological disease.
Findings: Brains and spinal cords were collected from 100 deceased patients between May, 1998, and November, 2012, and this retrospective study was done between Sept 6, 2011, and Feb 2, 2018. 12 individuals were identified as having myelocortical multiple sclerosis and were compared with 12 individuals identified as having typical multiple sclerosis. Demyelinated lesions were detected in spinal cord and cerebral cortex, but not in cerebral white matter, of people with myelocortical multiple sclerosis. Cortical demyelinated lesion area was similar between myelocortical and typical multiple sclerosis (median 4·45% [IQR 2·54–10·81] in myelocortical vs 9·74% [1·35–19·50] in typical multiple sclerosis; p=0·5512). Spinal cord demyelinated area was significantly greater in typical than in myelocortical multiple sclerosis (median 3·81% [IQR 1·72–7·42] in myelocortical vs 13·81% [6·51–29·01] in typical multiple sclerosis; p=0·0083). Despite the lack of cerebral white-matter demyelination in myelocortical multiple sclerosis, mean cortical neuronal densities were significantly decreased compared with control brains (349·8 neurons per mm 2 [SD 51·9] in myelocortical multiple sclerosis vs419·0 [43·6] in controls in layer III [p=0·0104]; 355·6 [46·5] vs 454·2 [48·3] in layer V [p=0·0006]; 366·6 [50·9] vs 458·3 [48·4] in layer VI [p=0·0049]). By contrast, mean cortical neuronal densities were decreased in typical multiple sclerosis brains compared with those from controls in layer V (392·5 [59·0] vs 454·2 [48·3]; p=0·0182) but not layers III and VI.
Interpretation: We propose that myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and can be an independent pathological event in myelocortical multiple sclerosis. Compared with control brains, cortical neuronal loss was greater in myelocortical multiple sclerosis cortex than in typical multiple sclerosis cortex. The molecular mechanisms of primary neuronal degeneration and axonal pathology in myelocortical multiple sclerosis should be investigated in future studies.

In this study they find that they can detect lesions in the brain that are associated with nerve loss, which they call myelocortical multiple sclerosis.

This is distinct from primary demyelination which is where there is the relative sparing of axons, but loss of the oligodendrocyte. This new lesion type is found in about 10% of cases. However, they have demyelinating lesions typical of MS in the spinal cord and deeper layers of the brain, although the level of demyelination in the spinal cord was less than in “normal” MS.

The authors suggest that “myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter.”

There is an inference that the two forms of MS may respond to treatment differently.

As a person who deals with animals models. The first thing we should say is….What does this say about MS pathologists? 

They often spend their lives slagging off animal studies, but how on Earth can we be expected to model MS, if the MS pathologists don’t tell us (don’t know) what to model. 

First MS was a demyelinating disease, now it’s a neurogenerative disease (after they rediscover in the 1990s that there is nerve loss in MS). All they had to do was read and remember the work done over a hundred years before.

Next, it was a white matter disease, now its a grey (& white) matter condition. This was found once the pathologists changed their staining technique, so they could see myelin in the grey matter. The MRIers still struggle with this (i.e. seeing lesions in grey matter with conventional MRI).

Now there are 10% of people with this neurodegenerative brain lesions and it’s an MS subtype. 

It has taken hundreds of years to find them.

This is a pretty shocking state of affairs, if these observations are found to be reproducible. It is likewise shocking that pathologists can often not agree with each other on what is going on.

OK now I have got this off my chest.

Well first thing first. This is simples. Should we be surprised that you can find lesions that are neurodegenerative without real evidence of demyelination? 

Not really, you have to look no further than EAE. 

What is suprising to me is that one can think that the idea that you can have neurodegeneration without apparent demyelination is new. 

Mouse EAE is a neurodegenerative disease without much  evidence or no evidence of primary demyelination (axon present with no myelin). It  has the same root of trigger as marmoset or guinea pig EAE, which can have lots of primary demyelination, but has different genetics and biology that means that the nerves go rather than the oligodendrocytes.

Is this a different disease? 

Not really. It is a variant of the same disease.

Therefore, they did the study to show something that even the MRIers said was going on.Indeed, there already been a number of pathology studies showing that neurodegenerative brain lesions that occur, not correlate with demyelination

Carassiti D, Altmann DR, Petrova N, Pakkenberg B, Scaravilli F, Schmierer K.Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex. Neuropathol Appl Neurobiol. 2018 Jun;44(4):377-390.

Next thing to think about is neuroanatomy and MS.

This is because even if demyelination was the cause of the nerve loss. Would it have to occur in the same area being examined? I think the answer is no.

Some nerves have to grow to stretch over a long distance. The spinal cord is about 45cm long so that would be 
450mm and 450,000 micrometre, so about 90,000 five  micrometer pathological tissue section. So you fail to find demyelination in section X when the damage occurred maybe 50,000 sections away. They only looked a centimeter (2000 sections) away Likewise the survival of nerves depends on imput from the nerves that innovate them.So the damage does not even need to be in the nerve (e.g. you have your leg cut off and you will loose nerves that control you leg in the brain).  

In these individuals there was demyelination in the spinal cord for example and this could and probably would affect the inputs into the nerves in the brain

Will it need a different treatment. Well maybe? 

There is little point using remyelination therapy, if the nerves are gone. It does not take a rocket scienctist to realise that you can’t raise the dead. 

The sad thing would be however, if neuros who would plan pointless trials to do this.

Therefore, we really do need better imaging tools to detect remylination verses nerve loss. 

Again we know that brain atrophy MRI measures does not directly measure nerve loss, as such in the spinal cord we have shown that you can loose significant numbers of nerves without apparent tissue shrinkage.

Maybe DrK will have something to say on this. 

Is this an MS subtype? Maybe, 

Many years ago we used to call neuromyelitis optica, Devics MS. Now it is considered to be a different entity, with different treatment requirements. 

Should we surprisied if we cannot find different pathologies within MS? 

Not really. We have found different subsets with the NMO spectrum disorders, with some giving response to aquaporin 4 and others to myelin oligodendrocyte glycoprotein for example.  MS will be no different.

However, this is not the same as what ProfG has been talking about.  

He is suggesting that MS is one disease and that primary and secondary MS are not distinct diseases. 

Obviously we know that secondary progressive MS follows relapsing remitting MS but this is part of spectrum that encompassess PPMS.  

This is important because, if it is one disease it can have the same treatment. 

Whilst you may argue that ProfG is simply being a mouth piece for pharma, now that ocrelizumab is available in the US for RRMS and PPMS (why not SPMS), if it is two or three diseases it means that subtype X may not have access to treatments of subtype Y. 

This happens now in the UK where pwMS with relapsing MS get access to a treatment, those with progressive MS don’t or treatment is stopped.

It also means that they will treat progress MS differently. 

So the trial could be of a stand alone compound-W. This would not have to be on top of a DMT known to control the active parts of MS.  

We know that inflammation is present from the begiing to the end of MS, so why not treat it?

Likewise, we know that neurodegeneration is present from the beginning to the end of MS. So why not treat it too?

Some of the neurodegeneration is caused by the inflammation and some of it will be probably be a consequence and need additional treatment to slow or stop the nerve loss.

If we do not get this latter point, we are not learning from biology and from our mistakes in the past. The future for MS treatments must surely be combinational therapies to target different pathologies. Your MS Socieities want treatments for you. Are monotherapy trials for Progessive MS the future?

Whilst speaking of heterogeneity in MS, we know it exists. Here’ another new example.

Behrens JR, Wanner J, Kuchling J, Ostendorf L, Harms L, Ruprecht K, Niendorf T, Jarius S, Wildemann B, Gieß RM, Scheel M, Bellmann-Strobl J, Wuerfel J, Paul F, Sinnecker T.. 7 Tesla MRI of Balo’s concentric sclerosis versus multiple sclerosis lesions. Ann Clin Transl Neurol. 2018 Jun 29;5(8):900-912.

Baló’s concentric sclerosis (BCS) is a rare condition characterized by concentrically layered white matter lesions. While its pathogenesis is unknown, hypoxia-induced tissue injury and chemotactic stimuli have been proposed as potential causes of BCS lesion formation. BCS has been suggested to be a variant of multiple sclerosis (MS). Here, we aimed to elucidate similarities and differences between BCS and MS by describing lesion morphology and localization in high-resolution 7 Tesla (7 T) magnetic resonance imaging (MRI) scans.
METHODS: Ten patients with Baló-type lesions underwent 7 T MRI, and 10 relapsing remitting MS patients served as controls. The 7 T MR imaging protocol included 3D T1-weighted (T1w) magnetization-prepared rapid gradient echo, 2D high spatial resolution T2*-weighted (T2*w) fast low-angle shot and susceptibility-weighted imaging.
RESULTS: Intralesional veins were visible in the center of all but one Baló-type lesion. Four Baló-type lesions displayed inhomogeneous intralesional T2*w signal intensities, which are suggestive of microhemorrhages or small ectatic venules. Eight of 10 BCS patients presented with 97 additional lesions, 36 of which (37%) had a central vein. Lesions involving the cortical gray matter and the U-fibers were not detected in BCS patients.
CONCLUSION:Our findings support the hypothesis that BCS and MS share common pathogenetic mechanisms but patients present with different lesion phenotypes.

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  • Great post Md

    I dont consider myself to have "them or us " posture

    When i find studies that are in favor off the "black swan" i will post it

    on the bloag, likewise when i find sudies against , i will post them to

    Because trying to understand ms is such an enormous task we need the

    time an efford of everybody (even those that dont agreed) but with a

    construtive attitude

    I really wish the "Black swan" is corect

    Nobody can accuse Team G , not taking a stand and provide an explanation

    to ms understanding

    Bottom line: I think everybody should think with their own head


  • I made the original comment could barts be wrong or why aren't you commenting on news plastered across the Media. It was more for food for thought or to play devils advocate. I too wish your 100% right at least the there's light at the end of the tunnel for all MS suffers. Will never glee or put down barts team. But like the previous reader want you to have all the info as you pointed out your fulltime job is research.

    • Thanks for the clarification and apologies if I seem grumpy. One of the problems of writing comments is you cannot guage the context they were made in. Anyway the point was made to say that we value your comments and finding this stuff.

  • MS may be one disease, but I do not feel that it presents in the same way in everyone, and I think treatment requires an individualised approach. I am not considering immunosuppressants for my progressive MS, as I do not believe that they would benefit me sufficiently to warrant the potentially severe side effects.

  • Very interesting post MD, thanks. Possibly a stupid simplistic question MD but doesn't this study tell researchers much information?

    Maybe the virus, like EBV, primarily attacks neurons and changes the myelin-neuron interface which then turns on hot microglia, A1 astrocytes and then calls in the B-cell army in RRMS and to a much lesser extent in SPMS and PPMS?

    Wouldn't that explain why a myelin antibody has never been found? Wouldn't this also explain that MS is one disease and not 3 or 4 diseases? Wouldn't this just be the most true form of MS with RRMS just being neurons attacked that have myelin shedded and progressive MS just being death of neurons?

  • Thanks for this “expose” of differences in theories and research directions. Without the differences and a desire to resolve them in a civil manner, there can be no anticipation of progress.

    I have commented (in relation to an entirely separate field of science) that those who stop questioning themselves (and others) forego their place as true investigators. In the long history of science, all the “great leaps forward” have occurred when one has the curiosity and commitment to question (possibly at risk of career, or even life) what is thought to be known (or the “settled science” oxymoron).

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