Tuesday, 1 July 2014

Is OCB negative MS a different disease?

Do you know your OCB result? If your are OCB-ve you are likely to do better. #MSBlog #MSResearch

"The study below shows that MSers without OCBs (oligoclonal immunoglobulin bands) in the spinal fluid have less brain atrophy (end-organ damage) than MSers with OCBs. This data supports the findings of our meta-analysis that showed that OCB-ve MS has a better prognosis than OCB+ve MS. Am I surprised? No I am not. I have always maintained that when we find the cause of MS and change our definition of the disease, that OCB-ve MS will turn-out to be a different disease. A lot of people don't agree with me on this. The answer lies in the philosophy of how define a disease. In medicine, but not psychiatry, we typically define a disease as a clinico-pathological correlate; i.e. a certain clinical presentation (dissemination in time and space in white matter tracts, with or without evidence of conduction slowing on evoked potentials) in the presence of characteristic pathology (MRI lesions, CSF OCBs or biopsy) defines MS."

"The problem in MS is that we can't do biopsies in everyone to make a diagnosis of MS so we rely on MRI and spinal fluid studies. Spinal fluid is a liquid biopsy and is the closet we can get to the pathological process in MS. The presence of OCBs in the spinal fluid that are produced within the central nervous system tells us that there is a specific B-cell response occurring within the brain and spinal cord. These B cells must be responding to something. Why do I say this? The list of conditions associated with spinal fluid OCBs is relatively small. OCBs are typically found CNS infections and rare paraneoplastic syndromes and other putative autoimmune diseases; diseases in which we have a pretty good idea of the antigens driving the disease. This is why we need to find out what the OCBs in MS are responding to; this is likely to be key to finding the cause of MS."

"The diseases referred to above that are associated with OCBs are usually easy to differentiate from MS, which is why spinal OCBs in the correct clinical setting is very characteristic of MS. What is interesting is that MSers who fulfill the diagnostic criteria for having MS differ in their clinical course based on whether or not they have OCBs. What this is telling me is that the pathology underlying OCB-ve MS is different to that that what is present in OCB+ve MS and the study below corroborates this finding. It would be interesting to know if OCB-ve and OCB+ve MS also differ in their response rates to DMTs. I would predict that OCB-ve MS is less likely to respond to anti-B cells therapies such as rituximab or ocrelizumab. Please note this is a hypothesis."

"These findings argue for a renaissance in spinal fluid sampling. Since MRI has entered clinical practice the number of lumbar punctures done to diagnose MS has plummeted. I think these data suggest we should relook at this practice. Why? We only have one opportunity to get the diagnosis of MS correct and that is early in the course of the disease in the so called diagnostic phase. A lumbar puncture helps exclude MS mimics and provides prognostic information that may affect decision making around DMTs. It may also allow us to include this information in our registers so that we can explore the course of OCB-ve and OCB+ve MS in more detail and assess whether or not they respond differently to DMTs."

"This post is very technical; if you don't understand it I am prepared to do a short google hangout to explain it further. Please let me know if it does not make sense."

"In conclusion and to stop me rambling on about a topic close to my heart, I can't stress how important the issue of OCBs is to the field of MS."



Ferreiraa et al.  Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy. Journal of Neuroimmunology, online 26 June 2014.

Background: To investigate whether MSers with and without CSF oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. 

Methods: 28 OCB-negative and 35 OCB-positive MSers were included. 

Results: Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. 

Conclusions: OCB-negative MSers, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS may represent a clinically relevant MS subgroup.

16 comments:

  1. Thanks for this. Weren't you going to use spinal taps in one of the progressive ms trials? Might the difference (ocb negative or positive) relate to a different virus?

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    1. Or maybe the titer for the virus is lower in OCB-negative ppl. so they don't develop the bands?

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    2. Re: "spinal taps in one of the progressive ms trials."

      Yes, we are using them in the PROXIMUS trial that is literally about to start. We had delays in getting the trial off the ground around setting up the assay to pass strict rule of performance. We have now cleared that hurdle and are ready to role.

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    3. Re: "Or maybe the titer for the virus is lower in OCB-negative ppl."

      Maybe. The virus theory of MS is exactly that a theory with a hypothesis that needs to be disproved or proved.

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  2. Prof G, where does that leave us in the OCB -ve basket? Is there anything we can do give that the DMT's are likely to be less effective?

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    1. Re: "where does that leave us in the OCB -ve basket?"

      For one you have a better prognosis; i.e. less relapses, less disease progression and less brain atrophy. The point about responding to treatments is a hypothesis. If the OCBs are pathogenic and in some way responsible for progressive MS then drugs that target them may not work in OCB-ve MS.

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  3. I think OCB-ve is just a case of recurrent ADEM. It is estimated that about 30% of ADEM cases are reclassified as MS because it cannot be distingushed from MS when ADEM becomes recurrent. This is my situation.

    OCB's are rare in ADEM and it seems to be a T cell mediated disease. Incidentally, I have been relapse free since starting Copaxone last year after being dxed with MS due to ongoing relapses after an intense attack in 09.

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    1. > OCB's are rare in ADEM and it seems to be a T cell mediated disease
      Are you sure? Most studies I have seen say that OCBs are typical finding in adem, but they are of different kind than in MS (type 4 in ADEM, type 2/3 in MS). Some researches consider type 4 as marker of systemic Ig production so possible they could be considered OCB- (?), and 2/3 as CNS-limited Ig production. Although I have seen different opinions on type 4, so it would be very interesting to know what Prof G thinks.

      p.s. looks like Blogspots/google spam filter does not allow me to post a links but you can find the proof of OCBs in ADEM by searching "Oligoclonal IgG band patterns in inflammatory demyelinating human and mouse diseases" for example in pubmed or google, and there are others

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    2. You need to remember we are referring to locally synthesized OCBs. This occurs in isolation and in the so called greater than pattern. The mirror pattern indicates bands from the peripheral blood that diffuse into the CSF. The mirror pattern is more likely to be found in ADEM. Anon Tuesday, July 01, 2014 12:39:00 pm is correct in saying that the majority of ADEMers are negative for locally synthesized OCBs. If you do find the latter then these cases are more likely to develop MS in the future.

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  4. It would be very interesting to see how research results would vary if you separated out the OCB-ves from the data.

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  5. It might be that OCB's are not present in all msers when they have the lumbar puncture. Maybe early in the disease they are absent but apear later in the disease.

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  7. Prof G,
    Are type 4 (mirror pattern) OCBs considered OCB- or OCB+ in relation to this article and the prognosis?
    I have seen conflicting opinions on interpretations of this result:
    - systemic + CNS production, hence possible "+"? (but what is the difference with the type3 then?);
    - only systemic production and passive Ig migration from circulation into CNS, hence possible "-"?;
    - common laboratory error: http://www.clinchem.org/content/53/8/1557.full
    Thanks.

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    1. Re: "Are type 4 (mirror pattern) OCBs considered OCB- or OCB+ in relation to this article and the prognosis?"

      Negative. In the greater than pattern some of the bands are unique to the CNS only and occurs in MS.

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  8. What evidence it there that OCBs are generated by a disease causing antigen? Maybe OCBs are simply generated when the immune system is exposed to intracellular components when cells are damaged during the disease process. Are they simply a marker of cell death?

    Are OCBs similar between different patients? If they are different does this not imply different antigens? Is there not a chemical engineer somewhere who could work backwards and look at the binding site of the antibody to give us some idea of what shape antigen we are looking for?

    I think OCBs are very interesting and would quite enjoy more topics on this subject.

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