Review article
Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness

https://doi.org/10.1016/j.jneuroim.2006.07.006Get rights and content

Abstract

Two or more oligoclonal IgG bands (OB) detected by separation of cerebrospinal fluid (CSF) proteins while not demonstrable in corresponding serum reflect a local B-cell response accompanying central nervous system (CNS) inflammation. Using optimized, standardized methodology, preferentially protein separation by isoelectric focusing followed by immunoblotting, more than 95% of patients with multiple sclerosis (MS) have CSF OB of IgG class not detectable in serum, thereby providing powerful evidence for the diagnosis of MS. Once present, CSF OB persists in the individual patient irrespective of MS course or therapy. Because of the high sensitivity of CSF OB in MS as well as its high specificity in the appropriate clinical setting, examination of CSF for OB of IgG class can be strongly recommended to obtain support for the diagnosis of MS and identify patients with clinically isolated syndrome (CIS) at increased risk of developing MS. The IgG index equal to CSF/serum IgG : CSF/serum albumin is elevated in about 70% of MS patients, but rarely in CSF OB-negative MS. Because of lower diagnostic sensitivity, IgG index cannot be recommended as replacement of CSF OB in the diagnosis of MS but, when elevated, as additional evidence for an augmented B-cell response within the CNS that is compatible with MS. Although the clinical picture as well as findings from magnetic resonance imaging of the brain and spinal cord are essential for an MS diagnosis, this should be re-evaluated in CSF OB-negative patients, keeping in mind the many disease entities imitating MS. Recommended diagnostic criteria for MS must include definitions of the role of lumbar puncture and of clearly specified, optimized and standardized routine CSF investigations including for the presence of CSF IgG OB. There is a need for concerted long-term follow-up studies of the subgroup of MS patients without CSF OB regarding e.g. prognostic and immunologic features. For inclusion in trials of disease-modulating drugs, it is recommended that patients with MS or CIS are selected regarding presence vs. absence of CSF OB. Development and evaluation of new technologies to define local vs. systemic B-cell responses in patients with MS or CIS vs. patients with other inflammatory neurological diseases should shed new light on the role of CSF OB, which remains enigmatic.

Introduction

Based on interest and dedication to improve the situation for neurological patients, in particular for those suffering from multiple sclerosis (MS), Donald Paty early in his career realized the necessity to establish specialized MS Clinics to provide state-of-the-art patient care. He was a driving force in the creation of the unique MS patient registry that soon covered all MS Clinics in Canada. As a result of this logistics, invaluable new information emerged regarding e.g. MS inheritance, diagnostic criteria for use of magnetic resonance imaging (MRI) in MS, and information about the prevalence in MS of cerebrospinal fluid (CSF) oligoclonal bands (OB). Here we review methodology and diagnostic usefulness of CSF OB in MS, an area where Donald Paty was actively involved over many years. We are aware that we will be unable to write this review in the humble way that was Donald Paty's signature.

Section snippets

Initial steps leading to current principles to detect CSF OB

Some 70 years ago, the origin of antibodies in the human CSF was suggested to be two-fold: “from the blood and from the cerebrospinal tissues” (Katzenelbogen, 1935; cited by Kabat et al., 1942). This view was strengthened by results from a series of collaborative studies that involved the immunologist Elvin Kabat and neurologists at the Neurological Institute of the College of Physicians and Surgeons at Columbia University in New York. Kabat and his colleagues adopted the first electrophoresis

Discovery of CSF OB by agar gel electrophoresis

While the electrophoresis era in clinical neurology originated in the United States, subsequent developments like introduction of more sensitive protein separation methods making possible the discovery of CSF OB, of isoelectric focusing (IEF) as an alternative for CSF protein separation, and of sensitive methods that allowed the identification of individual proteins after the initial separation of CSF and corresponding serum were mainly European contributions for which we have to thank

Agarose gel electrophoresis

In the early 1970s, agarose gel was introduced as supporting medium for electrophoresis. Agar and agarose gel electrophoresis give similar frequencies of positive findings for CSF OB in MS and OIND, but agarose is more easy to handle, the risks with the chemicals used for agar gel electrophoresis are eliminated, and multiple pairs of CSF + serum in addition to appropriate OB-positive and OB-negative controls can be run on the same agarose gel plate (Link, 1973). Agarose electrophoresis quickly

Isoelectric focusing

IEF allows the separation of proteins in biological fluids according to isoelectric point. IEF is usually performed with polyacrylamide gel or agarose gel as supporting medium, the latter being preferred because of non-toxicity and easiness in handling and storing. Compared to the many different variants of electrophoresis that have been developed over the years, including those that use silver or gold staining to increase sensitivity, IEF has a number of advantages. Sensitivity in detecting OB

Recommended procedure to detect IgG OB in unconcentrated CSF in MS

Development of a procedure allowing protein separation without the initial step of fluid concentration was early considered to be highly desirable but difficult to achieve. As previously reviewed by Kostulas (1985) and Correale and Molinas (2002), a first study appeared in the early 1970s showing that OB could be demonstrated by agar gel electrophoresis of unconcentrated CSF by using a sensitive silver staining procedure. Many techniques followed, including IEF that is mostly done on

Critics of current classification of results from analysis for CSF OB

A classification into “5 types” of patterns seen after separation of CSF proteins and corresponding serum has been proposed in two consensus reports (Andersson et al., 1994, Freedman et al., 2005). They are: type 1 = “normal” pattern reflected by the diffuse migration of polyclonal IgG present in both CSF and serum; type 2 = the classical pattern of CSF OB comprising of 2 or more bands present in CSF while absent in the patient's serum run in parallel on the same plate; type 3 = same as type 2 but,

Monoclonal IgG in CSF

The significance of IgG migrating as one sharp, monoclonal band in CSF while not detectable in corresponding serum is debated. It is a rare finding. If the IgG index is simultaneously elevated, then there is evidence for a local B-cell response, and this should be reported. Usually, however, the IgG index is normal. Then, the monoclonal CSF IgG band may reflect a technical problem, and the examination for CSF OB should be repeatedly performed on the same CSF and serum specimens, with particular

Other variables to demonstrate IgG production within the CNS in MS

There are a number of other CSF variables that are commonly measured to document Ig synthesis within the CNS. Mostly, the CSF IgG index equal to (CSF/serum IgG) : (CSF/serum albumin) is determined, being elevated in about 70% of patients with MS (Lefvert and Link (1985)). This means that the IgG index, like other formula constructed to document IgG synthesis within the CNS, has a significantly lower sensitivity compared to detection of CSF OB in MS. Furthermore, it is rare to find an elevated IgG

Significance of CSF OB

Besides observed in > 95% of patients with MS, CSF OB are also detected in other inflammatory conditions like paraneoplastic disorders, systemic lupus erythematosus affecting the CNS, neurosarcoidosis, Behcet's disease and various forms of cerebral angiitis. Many CNS infections, including aseptic meningitis, neuroborreliosis and neurosyphilis, are to a various extent associated with CSF OB. Some, but rarely all of the CSF OB observed in CNS infections may contain antibodies directed against the

Does B-cell response reflected by CSF OB differ among populations?

There are transcultural, partly latitude-related differences in MS prevalence. A low prevalence has been reported from some Asian countries including Japan where, on the other hand, an “oriental type” of MS has been identified, better described as optic–spinal form of MS (OSMS) because of certain clinical and MRI features considered unique for this MS type. Low frequencies of CSF OB have been reported from Japan both in conventional MS (CMS) and, in particular, in OSMS. However, as exemplified

MS without CSF OB – a more benign MS form?

Benign MS may be considered to be present in subjects with MS who are functional in all neurologic systems 15 years after disease onset. Other definitions may also be applied. One early study involving 105 consecutive MS patients examined for OB by agarose gel electrophoresis of paired CSF + serum standardized for IgG content revealed a more benign disease course in the 17 patients who had no CSF OB. Fourteen of these 17 patients (82%) had no or slight disability after a mean MS duration of

New diagnostic criteria for MS and CSF OB

New diagnostic criteria for MS, known as McDonald Criteria after Ian McDonald who chaired an International Panel on the Diagnosis of MS, were introduced in 2001 and followed by the 2005 Revisions to the McDonald Criteria (McDonald et al., 2001, Polman et al., 2005). The intent was that the Criteria could “be used by the practicing neurologist to better and more reliably diagnose MS, balancing earlier diagnosis with the need to avoid false-positive diagnosis”. Regarding diagnostic usefulness of

The natalizumab disaster and CSF OB

Thought-provoking incidents occurred in the context of a clinical trial of 589 MS patients receiving natalizumab (Tysabri, Biogen Idec and Elan) in addition to ongoing therapy with interferon beta-1a (IFN beta-1a; Avonex, Biogen Idec), while a similar number of MS patients received placebo in addition to IFN beta-1a (Chaudhuri, 2006). Two of the patients treated with the drug combination developed progressive multifocal leukoencephalopathy (PML), a frequently lethal CNS disease resulting from

Conclusions

Examining CSF for OB is an important tool to identify the abnormal local B-cell response that takes place in most MS cases. In the patient where MS is suspected, presence of CSF OB is strong support for the MS diagnosis. In the patient with CIS, presence of CSF OB is important in evaluating the prognosis for future MS development. In the patient with MS, this tool is useful as additional support for the diagnosis. Like the clinical picture and the MRI results, presence of CSF OB may be

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