Proteins of the Cerebrospinal Fluid: Analysis & Interpretation in the Diagnosis and Treatment of Neu

Proteins of the Cerebrospinal Fluid: Analysis and Interpretation in the Diagnosis and Treatment of Neurological In this new edition, which has new references, the author emphasizes qualitative electrophoresis methods in CSF analysis and describes their clinical relevance, particularly for diagnosis of multiple.
Table of contents

Pattern type 1 is considered negative ie, no specific CSF bands , whereas pattern type 2 definitively shows specific bands present only in the CSF but not the serum sample. Pattern types 3 and 4 require more careful interpretation. In particular, type 4 can be misinterpreted if the amount of IgG in the serum sample is too high, which can blur the serum bands. Pattern type 5 indicates the presence of a monoclonal gammopathy, but IEF resolves what would be a single band using other electrophoretic techniques into multiple bands differing by 1 U of charge.

This peculiarity is probably due to posttranslational modifications such as glycosylation. The method for this technique of IEF and immunoblotting has been standardized and is commercially available. Using this technique requires a certain level of technical expertise and the interpretation similarly necessitates some experience. This is best left to laboratories and clinical biochemists with experience in CSF diagnostics. If a single specific band is seen in the CSF, or only faint bands are seen, but bands resolve with staining for light chains, then this would imply there are, in fact, oligoclonal bands that fail to resolve on IgG staining.

Light chain staining would also be positive in rare cases where oligoclonal bands are caused by the presence of IgA or IgM, which will not appear on gels stained only for IgG.

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Some laboratories have proceeded with this analysis in patients in whom MS is strongly suspected on the basis of their clinical or MRI findings but were negative on IgG oligoclonal band testing. Any staining for light chains in the CSF is most likely caused by local synthesis since serum-free light chains are readily removed by the kidney.


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The evidence for studies from approximately patients Table 2 is presented from individual publications using IEF with immunofixation on more than patients for sensitivity and for specificity using prospective studies with follow-up exceeding 2 years. Specificities vary depending on how sure one is that there is no other reason for intrathecal inflammation. Rarely will quantitative IgG analysis findings be elevated in the absence of oligoclonal bands using IEF with immunoblotting in a true case of MS, whereas the converse is commonly true.

Zeman et al 27 of the Queen Square group found 34 cases that were oligoclonal band negative when the diagnosis of MS was considered likely by the clinician. After further study only 3 patients with clinically definite MS were found to be oligoclonal band negative. That means that more times than not a negative test result is more likely to point to another disease than be falsely negative.

There are some special considerations in CSF—serum sample pairs where the CSF but not the serum sample demonstrates a single band. In a group of such patients who underwent subsequent follow-up lumbar punctures, nearly one third converted to an oligoclonal band pattern as early as 6 months later.

Importance of Follow-Up Cerebrospinal Fluid Analysis in Cryptococcal Meningoencephalitis

Of the nonconverters, many were diagnosed as having alternative disorders. Therefore, although negative by definition, a single CSF band may be a good reason for repeating CSF analysis, unless other criteria clearly point to MS. This study 29 also verifies why oligoclonal bands have the highest specificity for MS and a single band is not diagnostic. Few other large studies exist.

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It is unlikely that each IgG oligoclonal band seen represents the product of a single B-cell clone and that if gels could be further resolved eg, 2-dimensional gels , oligoclonal bands would probably separate out into several different clones. To date, there has been no definite association of these oligoclonal bands with any consistent antigen in patients with MS. It is clear 9 , 12 , 37 , 38 that intrathecal antibody synthesis against many different antigens contributes to the IgG oligoclonal bands in CSF, either detected by antigen-driven immunoblots 12 or by quantitative detection with the antibody index.

Some particular observations, such as the high frequency despite low intensity of intrathecal antibodies against neurotropic viruses in MS 9 , 37 need further discussion.

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It is also clear that many of these antibodies are low affinity. Elevated immunoglobulin levels and oligoclonal banding indicate localized B-cell expansion in the brain. Analysis of the immunoglobulin heavy chain repertoire in CSF-derived B cells has demonstrated both clonal expansion and the process of somatic hypermutation.

As new techniques in molecular biology are applied to the study of CSF B cells in MS, it is likely that the phenomena of elevated immunoglobulin levels and oligoclonal bands may provide new opportunities for understanding the pathogenesis of this disease.

Proteins of the Cerebrospinal Fluid Analysis & Interpretation in the Diagnosis and Treatment of

After reviewing all the information available on the quality, sensitivity, and specificity of CSF analysis for a diagnosis of MS, this committee drew up a series of conclusions and recommendations. This committee, including some of the foremost experts in CSF analysis, took as its principal mandate to decide on the most acceptable approach today toward the use of CSF as part of the workup in a patient suspected of having MS.

The committee has agreed to 12 recommendations regarding the analysis of CSF so that neurologists know what to expect and laboratory medicine specialists should seek to maintain a minimal acceptable standard Table 3. The single most informative analysis is a qualitative assessment of CSF for IgG, best performed using IEF together with some form of immunodetection blotting or fixation.

That this technique should become the gold standard has met with recent approval from the Food and Drug Administration. This qualitative analysis should be performed using unconcentrated CSF and must be compared directly with a serum sample run simultaneously in the same assay in an adjacent track. Recognized positive and negative controls should be run with each set of samples and the entire gel rejected if oligoclonal bands in the positive controls are poorly developed or the negative controls are overdeveloped.

Cerebrospinal fluid reports of qualitative analysis should be made in terms of 1 of the 5 recognized staining patterns of oligoclonal banding. Neurologists need to consider the results of all other tests performed as part of the CSF panel eg, cell count; protein, glucose, and lactate levels; and others.

In certain cases, an evaluation using light chains for immunodetection can help to resolve equivocal oligoclonal IgG patterns. Consideration should be given to repeating the lumbar puncture and CSF analysis if clinical suspicion is high but results of CSF are equivocal, negative, or show only a single band. Quantitative IgG analysis is an informative complementary test but is not considered a substitute for qualitative IgG assessment, which has the highest sensitivity and specificity.

Laboratories performing routine CSF analysis should be those that ensure their own internal quality control and participate in external quality assessment controls to assure maintenance of a high standard of reliability and performance, as has been recommended in some international consensus papers. Given that patients need to undergo a lumbar puncture to obtain CSF, they deserve to have it analyzed in a manner that will yield the most informative results. It is hoped that neurologists will, therefore, demand that CSF be analyzed at least in the way that was outlined earlier herein and that laboratories performing CSF testing are aware of the standards expected.

The only way to accomplish this would be for neurologists to find out which laboratory will be analyzing the CSF and inquire about the assays that are used. Given that the Food and Drug Administration has acknowledged the first criterion, it should become easier to find laboratories fulfilling the outlined criteria. Study concept and design: Analysis and interpretation of data: Drafting of the manuscript: Freedman, Thompson, Giovannoni, Grimsley, and Tourtellotte. Critical revision of the manuscript for important intellectual content: Administrative, technical, and material support: Freedman, Thompson, and Giovannoni.


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The development of the manuscript was made possible through an educational grant from the Consortium of Multiple Sclerosis Clinics, Teaneck, NJ. Recommended diagnostic criteria for multiple sclerosis: Handbook of Clinical Neurology. North-Holland Publishing Co; Cerebrospinal fluid in the diagnosis of multiple sclerosis: Cerebrospinal Fluid Analysis in Multiple Sclerosis. Springer Publishing Co Inc; Comparison of seven formulae and isoelectrofocusing for determination of intrathecally produced IgG in neurological diseases.

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Postgenomics is remodeling our figuring out of ailment and wellbeing and fitness, our surroundings, and the types of race, type, and gender. Additional resources for Proteins of the Cerebrospinal Fluid: If the PT is E. The occurrence of polymers in CSF is always a pathological sign []. The ratio of monomeric to dimeric IgA is also tipped in favor of the monomer when measured in the CSF []. Since there are varieties of alphamacroglobulin molecule [41], it would be expected that there would be more of the smaller variety in CSF.