Is MS lots of different conditions

Jarius S, König FB, Metz I, Ruprecht K, Paul F, Brück W, Wildemann B. Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis.
J Neuroinflammation. 2017; 14(1):171.

BACKGROUND:The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity.
OBJECTIVE:The aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis.
METHODS: Findings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively.
RESULTS: Oligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60-80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood-CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively).
CONCLUSIONS: Patients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood-CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS.

So I first have to explain what a pattern II and pattern III lesion.  Following analysis of brain biopsies some pathologists made a suggestion that their were four types of lesion Pattern I-IV. They can be summarised above

However it must be said that through standard analysis of post-mortem tissue it was found that lesions were just type I and II.

The type II is an immune centric demyelinated lesion with antibody in the lesions, the type III lesion is the lesion where the oligodendrocytes are destroyed  or damaged but there are few or no immune cells. These are not centred around blood vessels. Some would argue that these are the pre-active lesions that resolve or develop into full blown lesions

In this study they looked in matched CSF and found that 82% in people with type I lesions but only 27% in people with type II and III and people with type II & III had more blood proteins in their CSF. The implications are they there are more than one type of MS. This may be so does it mean that type II and type III are not MS or a different MS?

This is maybe what the pathologists would have us believe. Do they need different treatments?

Maybe it tells us that people with type I lesions have had MS for a bit longer and their disease was not as active as their blood brain barrier isn’t leaking as much because there is less blood proteins in the spinal fluid and no antibody in the lesions because they have stopped leaking. In animals it is very dynamic they leak for a few days and then stop. They have had time for their intrathecal antibody stores to develop, where as those with type II and type III have yet to develop.

Maybe the pathologists will come back in a few years and tell us where these cases clinically definite MS or a mis-diagnosis and how the different people responded to treatment, because if people really have different diseases we have to know this. However that type I and type II lesions are common at post-mortem, would argue that the distinction between type I and type II & III is more of staging thing.

As pathologists can’t seem to agree on anything, we will have to see what others think, but remember based on pathologists…for the longest time they told us MS was a white matter disease until they stopped using luxol fast blue and started staining for myelin with antibodies when it is a grey and white matter disease. You can see this with the naked eye is some brains, so sometimes whilst looking down a microscope to see the trees you can’t see the Wood:-)

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  • Hi Mouse Doctor,
    1. Aside from the brief mention of subtype IV being seen solely in PPMS, is there any other known correlation between subtypes 1-4 and clinical diagnosis with RRMS/PPMS/SPMS or PRMS? I.e. Would patients presenting with subtype 1 be primarily RR, etc..?
    2. This paper did not seem to specifically mention their patient population and what form of MS they were ultimately clinically diagnosed with. I believe that would have been useful to know at least to see if they saw any correlation between currently accepted MS subtypes and their lesion subtype findings.
    3. Do you think the OCB bands would be different in a patient newly diagnosed with RRMS and then, hypothetically after 20 years, then became progressive (i.e.SPMS)? If so, would this argue against their hypothesis?
    Thanks for posting this paper and discussion. I am relatively new to the field so sorry if any of these questions appear naïve. Thanks, David

    • I dont really know or remember properly.

      When first published they said that at a given time point of the disease, as reflected in autopsy cases-the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. Again their was disagreement between pathologists and in post-mortem there were plenty of type I and type II lesions a their are type III like lesions ands

      Maybe ProfG can ask Drs Luchinetti or Bruck to do a guest post. But at present I think you can't look at pathology to say this shows any specific type of MS and thats why your question 2 is not addressed
      3. The OCB will be different if sampled serially but also some of the bands could be common.

      "143 patients with definite MS and CSF analysis at time of diagnosis were followed over a period of 5 years. There were no differences in presence or number of CSF OCB between patients with significant worsening of disability and stable patients. There were no differences in presence or number of CSF OCB between patients with stable relapsing-remitting MS and patients developing secondary progression during follow-up. The presence or number of CSF OCB does not seem to influence early disease progression in MS." (

    • Thanks for your reply Mouse Doctor!
      IMHO some sort of discussion by the researchers studying these lesion subtypes and current MS classification would be useful if only to help non specialist doctors or MSers clarify how, if at all, these lesion subtypes relate to MS classification. On a very basic level, I thought RRMS lesions should have more inflammatory based agents than PPMS or SPMS patients. Surely then one could expect some sort of correlation? If this work has not been done, good to know that too.

  • And what would the OCBs really have to tell us about MS?

    Because I know several patients who are negative for OCBs and have a much more active course of the disease than those who are positive for OCBs.

    I would also like to know where type I to IV lesions fit into the MS classification (RRMS, SPMS, PPMS, PRMS).

  • sigh. the whole profession shits me. no offence, but your colleagues can't even agree on what constitutes a relapse (does it have to be accompanied by a new lesion? how do you know if it's a relapse or progression?) – let alone what the friggin disease is

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