Cerebrospinal Fluid IgM and Oligoclonal IgG Bands in Multiple Sclerosis: A Meta-Analysis of Prevalence and Prognosis

Round 1

Reviewer 1 Report

This is an interesting review pointing at additional prognostic information by the presence of ITMS. The paper is well written and structured, but it is difficult to understand the extensive information in the Supplementary table regarding time to EDSS steps, treatment responses and MRI. With so much information given it also deserves to be commented in the Discussion, otherwise it could be omitted. Also, in this table one might omit the journal column and site the reference in the Author column.

Additional minor comments is the use of attacks and relapses, one should aim at using one term consistently throughout the paper, when talking about RRMS the use of relapses are most appropriate in my view. In line 73 the abbreviation IgMLoc is used for the first time and should be explained. In line 198 Natalizumab is written with capital letter, this should be natalizumab.

Author Response

We thank the reviewer for his/her interest in our review. We have simplified Supplementary Table 1 by removing the author’s, journal’s and statistical analysis columns and merging the age column with that of sample size. We are aware that much information is given in the Table; however, we feel that a narrative description of main findings from all included studies would be beyond the scope of our manuscript that was focused on the prevalence of ITMS and its prognostic role.

Text and spell inconsistencies, as well as other minor comments, have been addressed (we agree with the reviewer that the term “relapse” is more appropriate).

Reviewer 2 Report

Thank you for this interesting paper.

Overall I think the methods are sound, and the paper is investigating a relevant question in MS: are there biomarkers that can predict disease phenotype?  CSF IgM oligoclonal bands is one possible biomarker, and this paper combines 30 papers in meta-analysis to examine IgM oligoclonal bands. 

Comments:

• The total number of CIS patients seems high relative to other types of MS.  Presumably this is related to the stage at which patients tend to have lumbar punctures i.e. early in the disease?
• Oligoclonal is spelled incorrectly in the abstract (line 15)
• Interestingly, many of the individual studies did not identify an association of IgG OCBs with hazard of second event, but the meta-analysis does indicate that there is a significant association.  The hazard ratio is smaller than for IgM OCBs, but I wonder if this translates into a clinically meaningful difference in prediction of second relapse?  

Author Response

We thank the reviewer for his/her interest in our results.

We agree with the reviewer that the relatively high percentage of CIS patients among the selected studies might be related to the stage at which patients tend to have lumbar puncture. Moreover, the cerebrospinal fluid examination (CSF) has been reintroduced with the latest McDonald criteria. Therefore, it is reasonable to believe that CSF evaluation, especially in patients at the first demyelinating event, will be used more and more.

Regarding the clinical meaning of the intrathecal IgM synthesis, since the reference class for the patients with ITMS comprises both IgG positive and negative patients, our results point to a higher relevance of ITMS compared to the IgG status. Moreover, the study findings would support that the risk of conversion to MS, previously ascribed to OCGBs, may be related to the presence of an ITMS. This point is commented in the discussion.

Finally, we have corrected the word “oligoclonal” in the abstract, as indicated.