Friday, 2 September 2016

ResearchSpeak: converting from CIS to Multiple sclerosis

Do you know if you have OCBs in your spinal fluid? #MSBlog #MSResearch #ResearchSpeak

"The Mouse Doctor wants me to highlight our international CIS study's findings. The results are important in that they confirm that the best predictor we have of having a second attack of MS is the presence of local synthesised oligoclonal IgG (immunoglobulin G) bands in the CNS (central nervous systems). This test is done on the spinal fluid and is one of the reasons why I prefer to make the the diagnosis of MS with the help of spinal fluid analysis. Although you can make the diagnosis of MS without a lumbar puncture, and spinal fluid analysis, you are less likely to be misdiagnosed as having MS when you have a MS mimic with spinal fluid analysis. In addition, the presence of OCBs add prognostic information, i.e. the presence of OCBs are a poor prognostic factor."

"I am also in the camp that accepts that OCBs are an important part of the MS pathology and are driving MS disease progression. These OCBs are highly selected antibodies and there is a large body of evidence emerging to support the hypothesis that OCBs are pathogenic and responsible for driving many aspects of the MS pathology, in particular the gray matter lesions in the cortex. This is why in the future we may need to clear the CNS of OCBs if want to prevent the delayed non-relapsing secondary progressive phase of the disease."

"Interestingly, in our study below we showed that low vD levels weakly predicted the second attack or conversion to 'clinically definite MS'. This however could simply be an association, rather than causation. More inflammation may lower peripheral vD levels and lower levels could simply be a marker of more active disease; we call this reverse causation."

"Does this have relevance for pwMS? Yes, if I had MS I would want to know if I had OCBs. The latter are part of the diagnostic criteria and provide prognostic information. You can never have enough information about your disease. I predict that we are a bout to enter a phase where we try different treatments to get rid of the OCBs, i.e. treatments to eliminate the plasma cells from the CNS of MSers. Watch this space!" 


Kuhle et al. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler. 2015 Jul;21(8):1013-24. doi: 10.1177/1352458514568827. 

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort.


METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS.


RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres.


CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
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8 comments:

  1. Two years ago, my Australian neurologist told me that my OGBs just helped the diagnosis, they did not worsen my prognosis.

    Don't 90% of pwMS have OCBs? Surely they aren't all deemed to have a poor prognosis, since we know that 90% of pwMS don't end up disabled.

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    Replies
    1. Yes, 95-98% of MSers are OCB+ve. The OCB-ve group do very well (do they have MS?). In addition, to OCBs we do neurofilament levels that are also prognostic.

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    2. I understood that OCBs may be negative early in disease, later becoming positive. Is the test often repeated in normal clinical circumstances?

      How sensitive is the standard test for OCBs? Is there any way that they are present at a lower level than detectable in some of those 'negative' patients?

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  2. Thank you for all you do. I check here each morning for help and hope, as most days that is all we have left. Please keep going and don't stop. Know you are needed and respected a little bit of light in a dark disease. I also hate color orange.

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  3. I am OCB negative and have MS. EDSS score is 3 with 2 relapses under my belt. Due to me being OCB- I believe I was misdiagnosed after my first relapse. 3/5 neurologists thought MS, and 2 thought a rare virus or some other cause. My neuro also told me that at the start of MS, only about half are OCB positive. However, as MS progresses that number goes to about 95%. I also read that a lot of people are probably OCB positive, but the testing isn't good enough to catch it. More accurate tests for testing OCB's sounds like the answer, but I don't know how far off that is. Any thoughts on this Gavin?

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    Replies
    1. Re; "More accurate tests for testing OCB's sounds like the answer, but I don't know how far off that is."

      The state-of-the-art test in called iso-electric focusing with immunofixation. Using this test ~98% of people with clinically definite MS have OCBs. You are correct that very early in the course of the disease you can be OCB-ve and when retested you become positive. The important point worth making is that if you are OCB-ve there is a higher chance of you having another disease apart form MS. This is why it is useful, but not essential, to have a lumbar puncture and spinal fluid analysis, done as part of the diagnostic work-up of MS.

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  4. Please can someone enlighten me with regards to measuring neurofilament levels? (It's new to me) How does this help with prognosis info? And does it have to be measured ongoing to compare levels over time? Many thanks.

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  5. The study showed that positive OCBs were associated with higher levels of EBNA-1 IgG titles that caught my attention more than the low vitamin D levels are associated with CDMS...

    The study showed that positive CBOs were associated with higher levels of EBNA-1 IgG titles that caught my attention more than the low vitamin D levels are associated with CDMS ...

    Could verification of EBNA-1 IgG titers levels enter one of the routine examination of MS?
    Could ir be inserted in the health policy of the brain?

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