Clinical usefulness of cerebrospinal fluid evaluation.
Abstract: The importance of analysis of cerebrospinal fluid (CSF), especially oligoclonal IgG bands, in the diagnosis of multiple sclerosis (MS) and its predictive value in patients with clinically isolated syndromes has recently been evaluated and confirmed in several studies. Despite the focus on magnetic imaging techniques in modern MS diagnostic criteria, evaluation of CSF is of great usefulness both as a diagnostic and predictive tool.

KEY WORDS: MULTIPLE SCLEROSIS; CEREBROSPINAL FLUID; OLIGOCLONAL BAND; SPINAL TAP
Article Type: Report
Subject: Multiple sclerosis (Diagnosis)
Multiple sclerosis (Care and treatment)
Multiple sclerosis (Development and progression)
Immunoglobulin G (Health aspects)
Spine (Puncture)
Spine (Usage)
Author: Fredrikson, S.
Pub Date: 03/01/2010
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: March, 2010 Source Volume: 17 Source Issue: 1
Geographic: Geographic Scope: Sweden Geographic Code: 4EUSW Sweden
Accession Number: 232470977
Full Text: Introduction

Paraclinical tests with high sensitivity in the diagnosis of multiple sclerosis (MS) are magnetic resonance imaging (MRI) of the brain and examination of the cerebrospinal fluid (CSF). These tests complement each other and the clinical evaluation in modern diagnostic criteria. (1) MRI is the superior laboratory technique to visualize MS lesions and dissemination in space, but the MRI findings are usually non-specific abnormalities that may be caused by a variety of pathological processes, particularly in patients above 40 years of age. CSF is in connection with the extracellular space of the brain and could therefore be representative of the disease processes taking place within the central nervous system (CNS). Thus, CSF analysis has the advantage of giving evidence of an inflammatory response within the CNS. However, neither MRI nor CSF findings alone can give the diagnosis of MS. Both tests should be evaluated in their clinical context to become useful tools in the diagnostic process. The usefulness of both paraclinical tests is highest in patients with either clinically atypical presentation or those who are early in the course of the disease.

Over recent years, more and more focus has been put on MRI findings in the diagnosis of MS. Is CSF evaluation really necessary? Yes! This article will highlight some recent studies showing that CSF evaluation is still of great value and usefulness in the MS diagnostic process. Recommended standards of CSF analysis in MS was developed as a European consensus report in 1994. (2) The main conclusions of this report were later on reiterated by another consensus group including North American colleagues in 2005. (3) A Task Force report from the European Federation of Neurological Science (EFNS) recently described Class I evidence to support the use of isoelectric focusing for both predictive and diagnostic testing in the diagnosis of MS. (4)

This article will not explore the extensive literature on new research variables in CSF, such as cytokines, cell subtypes, autoantibodies etc. as these assays have yet to show sufficient diagnostic sensitivity and specificity to warrant their use in clinical practice. Attempts have been made to find a CSF disease activity marker that correlates to the clinical profile of the patient. Unfortunately, a reliable and widely accepted biomarker to incorporate into clinical practice has yet to be found.

Instead, focus of this article is on basic CSF examinations that can be of help in the diagnostic procedure of patients with suspected MS and also be of predictive value in patients with clinically isolated syndromes (CIS).

What Should be Included in a Routine CSF Analysis in CIS and Suspected MS?

Detection of oligoclonal IgG bands (OB) in CSF by isoelectric focusing (IEF) is the most sensitive (approximately 95% in Western patients) laboratory test for MS and the best method to show local intrathecal IgG-synthesis (Figure 1). The IEF technique is based on a separation of proteins depending on charges in a pH-gradient. The IEF technique can discriminate between similar proteins with minor differences in their amino acid residue content and therefore higher numbers of bands are demonstrable on IEF compared to what is seen on agarose electrophoresis. To show that the oligoclonal bands are IgG-specific, the IEF should be followed by immuno-fixation with IgG-specific antibodies.

[FIGURE 1 OMITTED]

It is important to emphasize that OBs should be demonstrable in unconcentrated CSF (5-10 microlitres) and not in the patients serum plasma run in parallel with the same amount of IgG applied. Identical band patterns in CSF and serum do not mean intrathecal synthesis.

The OB pattern in CSF remains constant in individual MS patients during the course of their disease--it is like a 'finger print'--but the banding pattern varies between different MS patients. OBs are not eradicated by corticosteroid treatment or disease-modifying therapies, e.g. interferon beta-1a, (5) rituximab (6) or natalizumab. (7) It has even been shown that OBs are detectable after heavy immunosuppression and autologous haematopoietic stem-cell transplantation in MS. (8) The oligoclonal banding pattern appears early during the course of MS and is therefore of great diagnostic help. In MS, no disease-specific antigen has yet been identified against which the majority of the OBs are directed. Whether the IgG synthesised intrathecally reflects an immune response which is antigen specific and of aetiological importance, or represents a general B-cell activation is still unknown.

OBs are not specific for MS, but can also be detected in about one third of patients with other inflammatory nervous system diseases like herpes encephalitis, AIDS or aseptic meningo-encephalitis. They can also be detected in the CSF in about 5-10% of patients with other neurological diseases, such as cerebrovascular diseases. However, this is usually not a cause of diagnostic confusion, since these disease entities have other different clinical features than MS, and can be ruled out by other laboratory tests. It has been described that the occurrence of OBs may be lower in non-Western patients. (9,10)

Predictive and Prognostic Value of CSF

Analysis of OBs in CSF has a predictive value in patients with an initial and CIS that may be the first manifestation of MS. For example, it was shown many years ago that detection of OBs in the CSF of patients with optic neuritis, isolated brain stem or spinal cord syndromes will increase the risk of subsequent progression to MS. (11-13)

More recently, it has been shown that presence of OBs doubles the risk for CIS patients for having a second attack, independently of MRI. (14) Other authors have found in a 6-years' follow-up study of CIS patients that presence of bands had a higher sensitivity for early prediction of conversion to MS and a better negative predicitive value than MRI findings. (15) In their study, the authors reported that OBs had a sensitivity of 91.4% and specificity of 94.1% for conversion of CIS to MS, while current MRI criteria had a sensitivity of 74.23% and a specificity of 88.2%.

It has recently been confirmed that presence of OBs can improve the diagnostic accuracy by increasing specificity and negative predictive value. (16) Interestingly, in this very recent study it was found that none of the patients who received other diagnosis than MS had OBs, but as many as 12 of these 28 patients fulfilled the MRI criteria of dissemination in space.

It has been suggested in some recent studies that the prognosis for neurological disability was significantly better for OB-negative MS patients, (17) while others have not found that their absence confers a more benign course of MS (18) or correlates with development of disability. (14)

In the recent modification of the McDonald criteria it is no longer a prerequisite to be 'CSF-positive' to establish a diagnosis of primary progressive MS (PPMS). How this will influence the diagnostic accuracy of PPMS is still unknown. It has been shown by some authors that CSF analysis was required in addition to MRI in about one third of the patients to establish a diagnosis of PPMS. (19)

The detection of IgM OBs has been suggested to have a prognostic value, but this was not confirmed by others. In contrast to IgG OBs, testing of IgM OBs has thus not been widely accepted and routinely used.

Other CSF Tests in MS Diagnosis

Several different formulae and quotients have been presented as quantitative methods for intrathecal IgG synthesis. These tests are generally less sensitive than detection of OBs on IEF. Around 75% of patients with clinically definite MS have abnormal findings in these quantitative assays. It is worth noting that when quantitative IgG analysis is equated to IEF there is a risk that many MS patients will be considered 'CSF negative' since quantitative IgG analysis will only pick up about 75% of the OB-positive patients. One simple and widely used quantitative method is the IgG index (CSF IgG/serum IgG: CSF albumin/serum albumin), which compensates for the influence of serum levels of IgG and albumin. Increased IgG index (>0.7) indicates IgG synthesis within the CNS/CSF compartment. There is no widely accepted correlation between clinical status of the patient and quantitative amount of intrathecal IgG synthesis.

The best and widely used method for detection of blood-CSF barrier damage is the CSF/serum albumin ratio, since albumin detected in CSF is derived from blood and not produced within the CNS/CSF compartment. The values of the albumin ratio are age dependent. Less than 20% of MS patients have a slightly elevated CSF/serum albumin ratio and severe barrier dysfunction is not expected to be found in MS patients.

It is preferred that the CSF cells are counted within 30-60 minutes after lumbar puncture. Mononuclear pleocytosis (>5 cells per microlitre) is found in approximately one third of the MS patients. Cell counts exceeding 50 cells per microlitre are very rare in MS and may suggest other diagnoses. The predominant cell type in MS CSF is lymphocytes and 80% of the lymphocytes are T cells. There is no relationship between higher cell counts and exacerbations or disability, but usually lower cell counts are found after a long duration of the disease. Corticosteroid treatment will reduce the cell count in CSF.

Summary

In conclusion, standardised analysis of CSF regarding presence of OBs is the most sensitive laboratory test for MS diagnosis, with a sensitivity of 95%. Oligoclonal bands are not specific for MS and their presence must be considered in their clinical context. 'OB- negative' MS is so rare with modern laboratory techniques that it should serve as a warning signal and may cast doubt on the diagnosis of MS. The combination of analysis of OBs in CSF, with the other tests, i.e. cell count, evaluation of barrier dysfunction and quantitative measurement of intrathecal IgG synthesis, will further increase the usefulness and specificity of CSF examination in MS diagnosis. Detection of OBs in CSF has excellent sensitivity, specificity and predictive value regarding conversion of CIS to MS.

Key Points

* Detection of oligoclonal IgG bands in CSF by isoelectric focusing is an important part of the diagnostic process in MS (Class I evidence).

* Detection of oligoclonal IgG bands in CSF is the test with the highest sensitivity to predict conversion from CIS to MS.

* In patients suspected of having MS, but without oligoclonal bands in CSF, alternative diagnoses should always be thoroughly investigated.

* The correlation between presence of oligoclonal IgG bands and disability progression is uncertain.

* The reported frequencies of oligoclonal IgG bands differ in different parts of the world.

Received: 24 February 2010

Accepted: 24 February 2010

References

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S Fredrikson

Department of Clinical Neuroscience, Karolinska University Hospital Hudding e, Stockholm, Sweden

Address for Correspondence:

Sten Fredrikson, Department of Clinical Neuroscience

Division of Neurology R54, Karolinska Institutet

Karolinska University Hospital Huddinge

S-141 86 Stockholm, Sweden

Tel: +46 736 841 179

Fax: +46 877 448 222

E-mail: sten.fredrikson@ki.se
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